Name Reactions

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Name Reactions Fourth Expanded Edition

Jie Jack Li

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications Fourth Expanded Edition

123

Jie Jack Li, Ph.D. Discovery Chemistry Bristol-Myers Squibb Company 5 Research Parkway Wallingford, CT 06492 USA [email protected]

ISBN 978-3-642-01052-1 e-ISBN 978-3-642-01053-8 DOI 10.1007/978-3-642-01053-8 Springer Dordrecht Heidelberg London New York Library of Congress Control Number: 2009931220 c Springer-Verlag Berlin Heidelberg 2009  This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Cover design: K¨unkelLopka GmbH Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To Vivien

Foreword I don't have my name on anything that I don't really do. –Heidi Klum Can the organic chemists associated with so-called “Named Reactions” make the same claim as supermodel Heidi Klum? Many scholars of chemistry do not hesitate to point out that the names associated with “name reactions” are often not the actual inventors. For instance, the Arndt–Eistert reaction has nothing to do with either Arndt or Eistert, Pummerer did not discover the “Pummerer” rearrangement, and even the famous Birch reduction owes its initial discovery to someone named Charles Wooster (first reported in a DuPont patent). The list goes on and on… But does that mean we should ignore, boycott, or outlaw “named reactions”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original discoverers, contribute greatly to its general use, and/or are the first to popularize the transformation. Regardless of the controversial history underlying certain named reactions, it is the students of organic chemistry who benefit the most from the cataloging of reactions by name. Indeed, it is with education in mind that Dr. Jack Li has masterfully brought the chemical community the latest edition of Name Reactions. It is clear why this beautiful treatise has rapidly become a bestseller within the chemical community. The quintessence of hundreds of named reactions is encapsulated in a concise format that is ideal for students and seasoned chemists alike. Detailed mechanistic and occasionally even historical details are given for hundreds of reactions along with key references. This “musthave” book will undoubtedly find a place on the bookshelves of all serious practitioners and students of the art and science of synthesis. Phil S. Baran May 2009 La Jolla, California

Preface The first three editions of this book have been warmly embraced by the organic chemistry community. Many readers have indicated that while they like the detailed mechanisms, they prefer to have more real case applications in synthesis. For this edition, we have revolutionized the format, which finally liberated more space to accomodate many more synthetic examples. As a consequence, the subtitle of the book has been changed to A Collection of Detailed Mechanisms and Synthetic Applications. When putting together the 4th edition, I also strived to capture the latest references, up to 2009 whenever possible. Coincidentally, my daughter Vivien, a sophomore at the University of Michigan, will take soon Organic Chemistry. I hope she finds this book useful in preparing for her exams. I am very much indebted to the readers who have kindly written to me with suggestions, which helped transform this book into a useful reference book for senior undergrate and graduate students around the world—the second edition was translated to both Chinese and Russian. I am grateful to my good friend Derek A. Pflum at Ash Stevens Inc. who kindly proofead the entire manuscript and provided many invaluable suggestions. Prof. Derrick L. J. Clive at University of Alberta also proofread the first half of the manuscript and offered helpful comments. I also wish to thank Prof. Phil S. Baran at Scripps Research Institute and his students, Tanja Gulder, Yoshi Ishihara, Chad A. Lewis, Jonathan Lockner, Jun Cindy Shi, and Ian B. Seiple for proofreading the final draft of the manuscript. Their knowledge and time have tremendously enhanced the quality of this book. Any remaining errors are, of course, solely my own responsibility. As always, I welcome your critique!

Jie Jack Li May 2009 Killingworth, Connecticut

Table of Contents Foreword............................................................................................................... VII Preface .................................................................................................................. IX Abbreviations ....................................................................................................... XIX Alder ene reaction ..................................................................................................... 1 Aldol condensation.................................................................................................... 3 Algar–Flynn–Oyamada reaction ............................................................................... 6 Allan–Robinson reaction........................................................................................... 8 Arndt–Eistert homologation.................................................................................... 10 Baeyer–Villiger oxidation ....................................................................................... 12 Baker–Venkataraman rearrangement...................................................................... 14 Bamford–Stevens reaction ...................................................................................... 16 Barbier coupling reaction ........................................................................................ 18 Bartoli indole synthesis ........................................................................................... 20 Barton radical decarboxylation ............................................................................... 22 Barton–McCombie deoxygenation ......................................................................... 24 Barton nitrite photolysis .......................................................................................... 26 Batcho–Leimgruber indole synthesis...................................................................... 28 Baylis–Hillman reaction.......................................................................................... 30 Beckmann rearrangement........................................................................................ 33 Abnormal Beckmann rearrangement ............................................................ 34 Benzilic acid rearrangement.................................................................................... 36 Benzoin condensation.............................................................................................. 38 Bergman cyclization................................................................................................ 40 Biginelli pyrimidone synthesis................................................................................ 42 Birch reduction ........................................................................................................ 44 Bischler–Möhlau indole synthesis .......................................................................... 46 Bischler–Napieralski reaction ................................................................................. 48 Blaise reaction ........................................................................................................ 50 Blum–Ittah aziridine synthesis ............................................................................... 52 Boekelheide reaction ............................................................................................... 54 Boger pyridine synthesis ......................................................................................... 56 Borch reductive amination ...................................................................................... 58 Borsche–Drechsel cyclization................................................................................. 60 Boulton–Katritzky rearrangement........................................................................... 62 Bouveault aldehyde synthesis ................................................................................. 64 Bouveault–Blanc reduction..................................................................................... 65 Bradsher reaction..................................................................................................... 66 Brook rearrangement............................................................................................... 68 Brown hydroboration .............................................................................................. 70 Bucherer carbazole synthesis .................................................................................. 72

XII Bucherer reaction..................................................................................................... 74 Bucherer–Bergs reaction ......................................................................................... 76 Büchner ring expansion........................................................................................... 78 Buchwald–Hartwig amination ................................................................................ 80 Burgess dehydrating reagent................................................................................... 84 Burke boronates....................................................................................................... 87 Cadiot–Chodkiewicz coupling................................................................................ 90 Camps quinoline synthesis...................................................................................... 92 Cannizzaro reaction................................................................................................. 94 Carroll rearrangement ............................................................................................. 96 Castro–Stephens coupling....................................................................................... 98 Chan alkyne reduction........................................................................................... 100 Chan–Lam C–X coupling reaction ....................................................................... 102 Chapman rearrangement ....................................................................................... 105 Chichibabin pyridine synthesis ............................................................................. 107 Chugaev reaction................................................................................................... 110 Ciamician–Dennsted rearrangement..................................................................... 112 Claisen condensation............................................................................................. 113 Claisen isoxazole synthesis................................................................................... 115 Claisen rearrangement........................................................................................... 117 para-Claisen rearrangement ....................................................................... 119 Abnormal Claisen rearrangement ................................................................ 121 Eschenmoser–Claisen amide acetal rearrangement .................................... 123 Ireland–Claisen (silyl ketene acetal) rearrangement ................................... 125 Johnson–Claisen (orthoester) rearrangement .............................................. 127 Clemmensen reduction.......................................................................................... 129 Combes quinoline synthesis.................................................................................. 131 Conrad–Limpach reaction..................................................................................... 133 Cope elimination reaction ..................................................................................... 135 Cope rearrangement .............................................................................................. 137 Anionic oxy-Cope rearrangement................................................................. 138 Oxy-Cope rearrangement.............................................................................. 140 Siloxy-Cope rearrangement .......................................................................... 141 Corey–Bakshi–Shibata (CBS) reagent ................................................................. 143 Corey−Chaykovsky reaction................................................................................. 146 Corey–Fuchs reaction............................................................................................ 148 Corey–Kim oxidation............................................................................................ 150 Corey–Nicolaou macrolactonization .................................................................... 152 Corey–Seebach reaction........................................................................................ 154 Corey–Winter olefin synthesis.............................................................................. 156 Criegee glycol cleavage ........................................................................................ 159 Criegee mechanism of ozonolysis ........................................................................ 161 Curtius rearrangement........................................................................................... 162 Dakin oxidation ..................................................................................................... 165 Dakin–West reaction............................................................................................. 167 Darzens condensation............................................................................................ 169

XIII Delépine amine synthesis...................................................................................... 171 de Mayo reaction................................................................................................... 173 Demjanov rearrangement...................................................................................... 175 Tiffeneau–Demjanov rearrangement ............................................................ 177 Dess–Martin periodinane oxidation ...................................................................... 179 Dieckmann condensation ...................................................................................... 182 Diels–Alder reaction.............................................................................................. 184 Inverse electronic demand Diels–Alder reaction ......................................... 186 Hetero-Diels–Alder reaction ........................................................................ 187 Dienone–phenol rearrangement ............................................................................ 190 Di-π-methane rearrangement ................................................................................ 192 Doebner quinoline synthesis ................................................................................. 194 Doebner–von Miller reaction ................................................................................ 196 Dötz reaction.......................................................................................................... 198 Dowd–Beckwith ring expansion........................................................................... 200 Dudley reagent....................................................................................................... 202 Erlenmeyer−Plöchl azlactone synthesis................................................................ 204 Eschenmoser’s salt ................................................................................................ 206 Eschenmoser–Tanabe fragmentation .................................................................... 208 Eschweiler–Clarke reductive alkylation of amines .............................................. 210 Evans aldol reaction .............................................................................................. 212 Favorskii rearrangement........................................................................................ 214 Quasi-Favorskii rearrangement..................................................................... 217 Feist–Bénary furan synthesis ................................................................................ 218 Ferrier carbocyclization......................................................................................... 220 Ferrier glycal allylic rearrangement...................................................................... 222 Fiesselmann thiophene synthesis .......................................................................... 225 Fischer indole synthesis ........................................................................................ 227 Fischer oxazole synthesis ...................................................................................... 229 Fleming–Kumada oxidation ................................................................................. 231 Tamao−Kumada oxidation............................................................................ 233 Friedel–Crafts reaction.......................................................................................... 234 Friedel–Crafts acylation reaction.................................................................. 234 Friedel–Crafts alkylation reaction................................................................. 236 Friedländer quinoline synthesis ............................................................................ 238 Fries rearrangement............................................................................................... 240 Fukuyama amine synthesis ................................................................................... 243 Fukuyama reduction .............................................................................................. 245 Gabriel synthesis ................................................................................................... 246 Ing–Manske procedure.................................................................................. 249 Gabriel–Colman rearrangement............................................................................ 250 Gassman indole synthesis...................................................................................... 251 Gattermann–Koch reaction ................................................................................... 253 Gewald aminothiophene synthesis........................................................................ 254 Glaser coupling...................................................................................................... 257 Eglinton coupling .......................................................................................... 259

XIV Gomberg–Bachmann reaction............................................................................... 262 Gould–Jacobs reaction .......................................................................................... 263 Grignard reaction................................................................................................... 266 Grob fragmentation ............................................................................................... 268 Guareschi–Thorpe condensation........................................................................... 270 Hajos–Wiechert reaction....................................................................................... 271 Haller–Bauer reaction ........................................................................................... 273 Hantzsch dihydropyridine synthesis ..................................................................... 274 Hantzsch pyrrole synthesis.................................................................................... 276 Heck reaction......................................................................................................... 277 Heteroaryl Heck reaction .............................................................................. 280 Hegedus indole synthesis ...................................................................................... 281 Hell–Volhard–Zelinsky reaction........................................................................... 282 Henry nitroaldol reaction ...................................................................................... 284 Hinsberg synthesis of thiophene derivatives ........................................................ 286 Hiyama cross-coupling reaction ........................................................................... 288 Hofmann rearrangement ....................................................................................... 290 Hofmann–Löffler–Freytag reaction...................................................................... 292 Horner–Wadsworth–Emmons reaction ................................................................ 294 Houben–Hoesch synthesis .................................................................................... 296 Hunsdiecker–Borodin reaction ............................................................................. 298 Jacobsen–Katsuki epoxidation.............................................................................. 300 Japp–Klingemann hydrazone synthesis................................................................ 302 Jones oxidation ...................................................................................................... 304 Collins–Sarett oxidation................................................................................ 305 PCC oxidation ............................................................................................... 306 PDC oxidation ............................................................................................... 307 Julia–Kocienski olefination................................................................................... 309 Julia–Lythgoe olefination ..................................................................................... 311 Kahne glycosidation.............................................................................................. 313 Knoevenagel condensation ................................................................................... 315 Knorr pyrazole synthesis....................................................................................... 317 Koch–Haaf carbonylation ..................................................................................... 319 Koenig–Knorr glycosidation................................................................................. 320 Kostanecki reaction ............................................................................................... 322 Kröhnke pyridine synthesis................................................................................... 323 Kumada cross-coupling reaction........................................................................... 325 Lawesson’s reagent ............................................................................................... 328 Leuckart–Wallach reaction ................................................................................... 330 Lossen rearrangement ........................................................................................... 332 McFadyen–Stevens reduction............................................................................... 334 McMurry coupling ................................................................................................ 335 Mannich reaction................................................................................................... 337 Martin’s sulfurane dehydrating reagent................................................................ 339 Masamune–Roush conditions ............................................................................... 341 Meerwein’s salt ..................................................................................................... 343

XV Meerwein–Ponndorf–Verley reduction ................................................................ 345 Meisenheimer complex ......................................................................................... 347 [1,2]-Meisenheimer rearrangement ...................................................................... 349 [2,3]-Meisenheimer rearrangement....................................................................... 350 Meyers oxazoline method ..................................................................................... 351 Meyer–Schuster rearrangement ............................................................................ 353 Michael addition.................................................................................................... 355 Michaelis–Arbuzov phosphonate synthesis.......................................................... 357 Midland reduction ................................................................................................. 359 Minisci reaction ..................................................................................................... 361 Mislow–Evans rearrangement............................................................................... 363 Mitsunobu reaction................................................................................................ 365 Miyaura borylation ................................................................................................ 368 Moffatt oxidation................................................................................................... 370 Morgan–Walls reaction ........................................................................................ 371 Mori–Ban indole synthesis.................................................................................... 373 Mukaiyama aldol reaction..................................................................................... 375 Mukaiyama Michael addition ............................................................................... 377 Mukaiyama reagent ............................................................................................... 379 Myers−Saito cyclization........................................................................................ 382 Nazarov cyclization............................................................................................... 383 Neber rearrangement ............................................................................................. 385 Nef reaction ........................................................................................................... 387 Negishi cross-coupling reaction............................................................................ 389 Nenitzescu indole synthesis .................................................................................. 391 Newman−Kwart reaction ...................................................................................... 393 Nicholas reaction ................................................................................................... 395 Nicolaou dehydrogenation .................................................................................... 397 Noyori asymmetric hydrogenation........................................................................ 399 Nozaki–Hiyama–Kishi reaction ............................................................................ 401 Nysted reagent ....................................................................................................... 403 Oppenauer oxidation ............................................................................................. 404 Overman rearrangement........................................................................................ 406 Paal thiophene synthesis........................................................................................ 408 Paal–Knorr furan synthesis ................................................................................... 409 Paal–Knorr pyrrole synthesis ................................................................................ 411 Parham cyclization ................................................................................................ 413 Passerini reaction................................................................................................... 415 Paternò–Büchi reaction ......................................................................................... 417 Pauson–Khand reaction......................................................................................... 419 Payne rearrangement ............................................................................................. 421 Pechmann coumarin synthesis .............................................................................. 423 Perkin reaction....................................................................................................... 424 Petasis reaction ...................................................................................................... 426 Petasis reagent ....................................................................................................... 428 Peterson olefination............................................................................................... 430

XVI Pictet–Gams isoquinoline synthesis...................................................................... 432 Pictet–Spengler tetrahydroisoquinoline synthesis ................................................ 434 Pinacol rearrangement........................................................................................... 436 Pinner reaction....................................................................................................... 438 Polonovski reaction ............................................................................................... 440 Polonovski–Potier rearrangement......................................................................... 442 Pomeranz–Fritsch reaction.................................................................................... 444 Schlittler–Müller modification ..................................................................... 446 Prévost trans-dihydroxylation .............................................................................. 447 Prins reaction......................................................................................................... 448 Pschorr cyclization ................................................................................................ 450 Pummerer rearrangement...................................................................................... 452 Ramberg–Bäcklund reaction................................................................................. 454 Reformatsky reaction ............................................................................................ 456 Regitz diazo synthesis ........................................................................................... 458 Reimer–Tiemann reaction..................................................................................... 460 Reissert reaction.................................................................................................... 461 Reissert indole synthesis ....................................................................................... 463 Ring-closing metathesis (RCM)........................................................................... 465 Ritter reaction ........................................................................................................ 468 Robinson annulation.............................................................................................. 470 Robinson–Gabriel synthesis.................................................................................. 472 Robinson–Schöpf reaction .................................................................................... 474 Rosenmund reduction............................................................................................ 476 Rubottom oxidation............................................................................................... 478 Rupe rearrangement .............................................................................................. 480 Saegusa oxidation.................................................................................................. 482 Sakurai allylation reaction .................................................................................... 484 Sandmeyer reaction ............................................................................................... 486 Schiemann reaction ............................................................................................... 488 Schmidt rearrangement ......................................................................................... 490 Schmidt’s trichloroacetimidate glycosidation reaction ........................................ 492 Shapiro reaction..................................................................................................... 494 Sharpless asymmetric amino hydroxylation......................................................... 496 Sharpless asymmetric dihydroxylation................................................................. 499 Sharpless asymmetric epoxidation ....................................................................... 502 Sharpless olefin synthesis ..................................................................................... 505 Simmons–Smith reaction ..................................................................................... 507 Skraup quinoline synthesis.................................................................................... 509 Smiles rearrangement............................................................................................ 511 Truce−Smile rearrangement ......................................................................... 513 Sommelet reaction................................................................................................. 515 Sommelet–Hauser rearrangement......................................................................... 517 Sonogashira reaction ............................................................................................. 519 Staudinger ketene cycloaddition ........................................................................... 521 Staudinger reduction ............................................................................................. 523

XVII Stetter reaction....................................................................................................... 525 Still–Gennari phosphonate reaction...................................................................... 527 Stille coupling........................................................................................................ 529 Stille–Kelly reaction.............................................................................................. 531 Stobbe condensation.............................................................................................. 532 Strecker amino acid synthesis ............................................................................... 534 Suzuki–Miyaura coupling ..................................................................................... 536 Swern oxidation..................................................................................................... 538 Takai reaction ........................................................................................................ 540 Tebbe olefination................................................................................................... 542 TEMPO oxidation ................................................................................................. 544 Thorpe−Ziegler reaction........................................................................................ 546 Tsuji–Trost allylation ............................................................................................ 548 Ugi reaction ........................................................................................................... 551 Ullmann coupling .................................................................................................. 554 van Leusen oxazole synthesis ............................................................................... 556 Vilsmeier–Haack reaction ..................................................................................... 558 Vinylcyclopropane−cyclopentene rearrangement ................................................ 560 von Braun reaction ................................................................................................ 562 Wacker oxidation .................................................................................................. 564 Wagner–Meerwein rearrangement........................................................................ 566 Weiss–Cook reaction............................................................................................. 568 Wharton reaction ................................................................................................... 570 White reagent......................................................................................................... 572 Willgerodt–Kindler reaction ................................................................................. 576 Wittig reaction ....................................................................................................... 578 Schlosser modification of the Wittig reaction ............................................. 580 [1,2]-Wittig rearrangement ................................................................................... 582 [2,3]-Wittig rearrangement ................................................................................... 584 Wohl–Ziegler reaction........................................................................................... 586 Wolff rearrangement ............................................................................................. 588 Wolff–Kishner reduction....................................................................................... 590 Woodward cis-dihydroxylation............................................................................. 592 Yamaguchi esterification....................................................................................... 594 Zincke reaction ...................................................................................................... 596 Subject Index ......................................................................................................... 599

Abbreviations and Acronyms

3CC 4CC 9-BBN A Ac ADDP AIBN Alpine-borane® AOM Ar B: [bimim]Cl•2AlCl3 BINAP Bn Boc BT Bz Cbz CuTC DABCO dba DBU DCC DDQ de DEAD (DHQ)2-PHAL (DHQD)2-PHAL DIAD DIBAL DIPEA DMA DMAP DME DMF DMFDMA DMS DMSO DMSY DMT DPPA dppb

polymer support three-component condensation four-component condensation 9-borabicyclo[3.3.1]nonane adenosine acetyl 1,1'-(azodicarbonyl)dipiperidine 2,2ƍ-azobisisobutyronitrile B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane p-Anisyloxymethyl = p-MeOC6H4OCH2aryl generic base 1-butyl-3-methylimidazolium chloroaluminuminate 2,2ƍ-bis(diphenylphosphino)-1,1ƍ-binaphthyl benzyl tert-butyloxycarbonyl benzothiazole benzoyl benzyloxycarbonyl copper thiophene-2-carboxylate 1,4-diazabicyclo[2.2.2]octane dibenzylideneacetone 1,8-diazabicyclo[5.4.0]undec-7-ene 1,3-dicyclohexylcarbodiimide 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diastereoselctive excess diethyl azodicarboxylate 1,4-bis(9-O-dihydroquinine)-phthalazine 1,4-bis(9-O-dihydroquinidine)-phthalazine diisopropyl azodidicarboxylate diisobutylaluminum hydride diisopropylethylamine N,N-dimethylacetamide 4-N,N-dimethylaminopyridine 1,2-dimethoxyethane N,N-dimethylformamide N,N-dimethylformamide dimethyl acetal dimethylsulfide dimethylsulfoxide dimethylsulfoxonium methylide dimethoxytrityl diphenylphosphoryl azide 1,4-bis(diphenylphosphino)butane

XX dppe dppf dppp dr DTBAD DTBMP E1 E1cB E2 EAN EDDA ee Ei Eq Et EtOAc HMDS HMPA HMTTA IBX Imd KHMDS LAH LDA LHMDS LTMP M m-CPBA MCRs Mes MPS Ms MWI MVK NBS NCS NIS NMP Nos N-PSP N-PSS Nu PCC PDC Piv

1,2-bis(diphenylphosphino)ethane 1,1ƍ-bis(diphenylphosphino)ferrocene 1,3-bis(diphenylphosphino)propane diastereoselctive ratio di-tert-butylazodicarbonate 2,6-di-tert-butyl-4-methylpyridine unimolecular elimination 2-step, base-induced β-elimination via carbanion bimolecular elimination ethylammonium nitrate ethylenediamine diacetate enantiomeric excess two groups leave at about the same time and bond to each other as they are doing so. equivalent ethyl ethyl acetate hexamethyldisilazane hexamethylphosphoramide 1,1,4,7,10,10-hexamethyltriethylenetetramine o-iodoxybenzoic acid imidazole potassium hexamethyldisilazide lithium aluminum hydride lithium diisopropylamide lithium hexamethyldisilazide lithium 2,2,6,6-tetramethylpiperidide metal m-chloroperoxybenzoic acid multicomponent reactions mesityl morpholine-polysulfide methanesulfonyl microwave irradiation methyl vinyl ketone N-bromosuccinimide N-chlorosuccinimide N-iodosuccinimide 1-methyl-2-pyrrolidinone nosylate (4-nitrobenzenesulfonyl) N-phenylselenophthalimide N-phenylselenosuccinimide nucleophile pyridinium chlorochromate pyridinium dichromate pivaloyl

XXI PMB PPA PPTS PT PyPh2P Pyr Red-Al Red-Al (SMEAH) Salen SET SIBX SM SMEAH SN1 SN2 SNAr TBABB TBAF TBAO TBDMS TBDPS TBS t-Bu TDS TEA TEOC Tf TFA TFAA TFP THF TIPS TMEDA TMG TMP TMS TMSCl TMSCN TMSI TMSOTf Tol Tol-BINAP TosMIC Ts TsO

para-methoxybenzyl polyphosphoric acid pyridinium p-toluenesulfonate phenyltetrazolyl diphenyl 2-pyridylphosphine pyridine sodium bis(methoxy-ethoxy)aluminum hydride sodium bis(methoxy-ethoxy)aluminum hydride N,N´-disalicylidene-ethylenediamine single electron transfer Stabilized IBX starting material sodium bis(methoxy-ethoxy)aluminum hydride unimolecular nucleophilic substitution bimolecular nucleophilic substitution nucleophilic substitution on an aromatic ring tetra-n-butylammonium bibenzoate tetra-n-butylammonium fluoride 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane tert-butyldimethylsilyl tert-butyldiphenylsilyl tert-butyldimethylsilyl tert-butyl thexyldimethylsilyl triethylamine trimethysilylethoxycarbonyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid trifluoroacetic anhydride tri-2-furylphosphine tetrahydrofuran triisopropylsilyl N,N,Nƍ,Nƍ-tetramethylethylenediamine 1,1,3,3-tetramethylguanidine tetramethylpiperidine trimethylsilyl trimethylsilyl chloride trimethylsilyl cyanide trimethylsilyl iodide trimethylsilyl triflate toluene or tolyl 2,2ƍ-bis(di-p-tolylphosphino)-1,1ƍ-binaphthyl (p-tolylsulfonyl)methyl isocyanide tosyl tosylate

XXII UHP Δ

urea-hydrogen peroxide solvent heated under reflux

1

Alder ene reaction The Alder ene reaction, also known as the hydro-allyl addition, is addition of an enophile to an alkene (ene) via allylic transposition. The four-electron system including an alkene ʌ-bond and an allylic C–H ı-bond can participate in a pericyclic reaction in which the double bond shifts and new C–H and C–C ı-bonds are formed. ‡

H ene

X Y

Δ, or

enophile

Lewis acid

X Y

H

HOMO

‡ H

H

LUMO

X Y

X=Y: C=C, CŁC, C=O, C=N, N=N, N=O, S=O, etc. Example 15 ‡

O O

O

O

xylene

6-membered

O reflux, 31%

transition state

H

O

ene

enophile ‡

O O

O O

Alder ene O

reaction

H

O

Example 27 O H2N N O H

(Kishner reduction)

H

O

O

KOH, Pt/Clay, 35%

O

O H

O

0 oC, CH2Cl2, 89% (Alder ene reaction)

OH

Example 3, Intramolecular Alder-ene reaction8 O N

O

H

toluene, reflux

O N

5 h, 95% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_1, © Springer-Verlag Berlin Heidelberg 2009

O

H

2

Example 4, Cobalt-catalyzed Alder-ene reaction9 Et

[Co(dppp)Br2], Zn, ZnI2, CH2Cl2

Et

OTMS

Ph

o

25 C, 8 h, 95% (GC yield)

OTMS

Ph

Example 5, Nitrile-Alder-ene reaction10 NC CH3 sealed ampule

CH3

CN

NC

CN

CH3 NC

o

120−130 C, 5 h H3 C 70%

CN CH3

CH3 H CH3

H H3 C

H CN

CN CH3

CN

11

Example 6

OAc CpRu(CH3CN)3•PF6

C6H13

C6H13

OAc

acetone, rt, 81% SiEt3

SiEt3

References Alder, K.; Pascher, F.; Schmitz, A. Ber. 1943, 76, 27−53. Kurt Alder (Germany, 1902−1958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 1876−1954) for the development of the diene synthesis. 2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 3. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). 4. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.; Wiley−VCH: New York, 2000, 543−568. (Review). 5. Sulikowski, G. A.; Sulikowski, M. M. e-EROS Encyclopedia of Reagents for Organic Synthesis (2001), John Wiley & Sons, Ltd., Chichester, UK. 6. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-Catalyzed Alder-ene Reaction. In Modern Rhodium-Catalyzed Organic Reactions 2005, 151−172. (Review). 7. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70, 2862−2865. 8. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70, 4332−4337. 9. Hilt, G.; Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500−8502. 10. Ashirov, R. V.; Shamov, G. A.; Lodochnikova, O. A.; Litvynov, I. A.; Appolonova, S. A.; Plemenkov, V. V. J. Org. Chem. 2008, 73, 5985−5988. 11. Cho, E. J.; Lee, D. Org. Lett. 2008, 10, 257−259. 12. Curran, T. T. Alder ene reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). 1.

3

Aldol condensation The Aldol condensation is the coupling of an enolate ion with a carbonyl compound to form a ȕ-hydroxycarbonyl, and sometimes, followed by dehydration to give a conjugated enone. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.

O R

R2 OH O

1. Base R1

R

O

2. R2

3

R2

Δ R

1

R

R

R3

O

3

R1 R

O

O R

R

1

deprotonation

R

condensation

R1 R2

R3

H

O

B:

R2 O

O

R3

acidic R1

workup

R2 OH O R3

R

R1 R

Example 13 LDA, THF, then MgBr2, −110 oC, then

O OTMS

BnO

CHO

O

OH BnO

O OTMS

O 85% yield

Example 28 LDA, THF, −78 to −40 oC, then aldehyde, 1 h, 43%, 3:2 dr O

CO2H OTBS

HO

7 6

H O

CO2H O OTBS 22% of of 6S,7R-diastereomer and 10% recovered SM

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_2, © Springer-Verlag Berlin Heidelberg 2009

4

Example 3, Enantioselective Mukaiyama-aldol reaction10

O

O

N

Ph

Ph

N

N cat.

O

OTMS

CO2CHPh2

Ph

O

OSii-Pr3

OSii-Pr3

OH

Ph CO2CHPh2 83% yield, 98% ee

Sc(OTf)3, 4 Å MS, CH2Cl2, −40 oC

Example 4, Intermolecular aldol reaction using organocatalyst12 H O NH O

O

N H

N

O

OH

O

H Cl

DMSO, 10 equiv H2O, rt 72 h, 57%, 46% ee, 95% de

Cl

Example 5, Transannular aldol reaction13 OH O

OMe O OMe O MeO MeO

OMe 1. LiN(SiMe2Ph)2, THF −105 oC, 74%, 10:1, dr

OH CH3 CH3

MeO MeO

2. MgI2, Et2O, 57% OMe O

O OMe

OH

O

O OMe

References 1.

2. 3.

Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436−442. Charles Adolphe Wurtz (1817−1884) was born in Strasbourg, France. After his doctoral training, he spent a year under Liebig in 1843. In 1874, Wurtz became the Chair of Organic Chemistry at the Sorbonne, where he educated many illustrous chemists such as Crafts, Fittig, Friedel, and van’t Hoff. The Wurtz reaction, where two alkyl halides are treacted with sodium to form a new carbon−carbon bond, is no longer considered synthetically useful, although the Aldol reaction that Wurtz discovered in 1872 has become a staple in organic synthesis. Alexander P. Borodin is also credited with the discovery of the Aldol reaction together with Wurtz. In 1872 he announced to the Russian Chemical Society the discovery of a new byproduct in aldehyde reactions with properties like that of an alcohol, and he noted similarities with compounds already discussed in publications by Wurtz from the same year. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1−438. (Review). Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031−1034.

5

4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14.

Mukaiyama, T. Org. React. 1982, 28, 203−331. (Review). Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1−103. (Review on Tin(II) enolates). Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325−335. (Review). Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432−440. (Review). (a) Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J. A.; Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.; Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D. J. Am. Chem. Soc. 2000, 122, 8890–8897. (b) Yang, Z.; He, Y.; Vourloumis, D.; Vallberg, H.; Nicolaou, K. C. Angew. Chem., Int. Ed. 1997, 36, 166−168. (c) Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973. Mahrwald, R. (ed.) Modern Aldol Reactions, Wiley−VCH: Weinheim, Germany, 2004. (Book). Desimoni, G.; Faita, G.; Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2006, 5228−5230. Guillena, G.; Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249−2293. (Review on enantioselective direct aldol reaction using organocatalysis.) Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org. Chem. 2008, 1759−1766. O’Brien, E. M.; Morgan, B. J.; Kozlowski, M. C. Angew. Chem., Int. Ed. 2008, 47, 6877−6880. Trost, B. M.; Maulide, N.; Rudd, M. T. J. Am. Chem. Soc. 2009, 131, 420−421.

6

Algar−Flynn−Oyamada Reaction Conversion of 2ƍ-hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by an oxidative cyclization.

R1

OH

R1

Ar

O

R1

Ar

O

Ar

H2O2, NaOH

OH

OH R2

R2

O

R2

O

O

OH

OH

O

HO O

O

O OH

O

OH

O

β-attack

α

H2O2 O

β O

O

O

OH O flavonol

OH O

A side reaction:

O

O

α-attack

β

α

then dehydration

O

aurone

O

O

Example 15 OH

O

1. PhCHO, NaOH, EtOH, rt

OH

2. H2O2, 15 to 50 oC, 54%

O

Ph

O

Example 25 CHO 1. O

OH

O

, aq. NaOH, EtOH OMe

OMe O

2. aq. NaOH, 30% H2O2 47% for two steps

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_3, © Springer-Verlag Berlin Heidelberg 2009

O OH O

7

Example 3, The side reaction dominated to give the aurone derivative:9 MeO

OH

Ph OMe

MeO aq. NaOH H2O2, 80%

OMe O

O

OMe Ph H OH O OMe

Example 412 CHO BnO

OH

BnO

OH

OMe

NaOH EtOH, 54%

O

O

OMe

OMe H2O2, NaOH EtOH, dioxane 76%

BnO

O OH O

References Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, B42, 1−8. Oyamada, T. J. Chem. Soc. Jpn 1934, 55, 1256−1261. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182−186. Wheeler, T. S. Record Chem. Progr. 1957, 18, 133−161. (Review) Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425−426. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H., Eds.; Academic Press: New York, 1975, 1, pp 127−213. (Review). 7. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry, T. J., Eds; Chapman and Hall: New York, 1982; pp 189−259. (Review). 8. Wollenweber, E. In The Flavonoids: Advances in Research Since 1986; Harborne, J. B., Ed.; Chapman and Hall: New York, 1994, pp 259−335. (Review). 9. Bennett, M.; Burke, A. J.; O’Sullivan, W. I. Tetrahedron 1996, 52, 7163−7178. 10. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae); Springer-Verlag: New York, 2000. (Review). 11. Limberakis, C. Algar−Flynn−Oyamada Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 496−503. (Review). 12. Li, Z.; Ngojeh, G.; DeWitt, P.; Zheng, Z.; Chen, M.; Lainhart, B.; Li, V.; Felpo, P. Tetrahedron Lett. 2008, 49, 7243−7245. 1. 2. 3. 4. 5. 6.

8

Allan–Robinson reaction Synthesis of flavones or isoflavones by the treatment of of o-hydroxyaryl ketones with aromatic aldehydes. Cf. Kostanecki reaction on page 322. O OH R R

1

OH R1 enolization

R

R O

H

R O

OH R1

O O

R1

O

R1

O

R1CO2Na, Δ

O

OH

O

O R1

O

O OCOR1 R

acylation

− O2CR1

O

1

R CO2

OH R1

H O

O: R1

enolization O

R

O

R1 OH

O

R

H

O

R

O2CR1

OH

R

H

O

O2CR1

Example 16 OMe

O

O

OH

HO

O OMe

MeO

OMe

OMe O

OMe

OMe PhCO2Na, 170−180 oC

O

HO

8 h, 45%

OMe OMe O

Example 29 OH

O

O

O

O

CO2H

S O

R1

O

S

N

pyr., 40 oC, 72 h, 85% Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_4, © Springer-Verlag Berlin Heidelberg 2009

O

N Me

9

Example 310 O OH

O

OMe O

O

O

O

OMe

Et3N, reflux, 12 h, 87% O

O

References Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192–2195. Robert Robinson (United Kingdom, 1886−1975) won the Nobel Prize in Chemistry in 1947 for his studies on alkaloids. However, Robinson himself considered his greatest contribution to science was that he founded the qualitative theory of electronic mechanisms in organic chemistry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the arrow pushing approach to organic reaction mechanism. Robinson was also an accomplished pianist. James Allan, his student, also coauthored another important paper with Robinson on the relative directive powers of groups for aromatic substitution. 2. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715–724. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405–1409. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037– 1038. 5. Patwardhan, S. A.; Gupta, A. S. J. Chem. Res., (S) 1984, 395. 6. Horie, T.; Tsukayama, M.; Kawamura, Y.; Seno, M. J. Org. Chem. 1987, 52, 4702– 4709. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987, 35, 4465–4472. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989, 37, 1216–1220. 9. Poyarkov, A. A.; Frasinyuk, M. S.; Kibirev, V. K.; Poyarkova, S. A. Russ. J. Bioorg. Chem. 2006, 32, 277–279. 10. Peng, C.-C.; Rushmore, T.; Crouch, G. J.; Jones, J. P. Bioorg. Med. Chem. Lett. 2008, 16, 4064–4074. 1.

10

Arndt–Eistert homologation One-carbon homologation of carboxylic acids using diazomethane.

O R

O

SOCl2 OH

O

1. CH2N2 R

Cl 2. Ag+, H2O, hv

R

OH

O O R

O R

Cl

Cl N

H2C N N

O

− CH3N2

N

R

H H N

Cl

O

N

H

hv

OH

O

C

C C O R

R

H

− N2↑

N

H

H :

R

N

R

H

O

N

N

R

R

OH

OH

:OH2

α-ketocarbene intermediate ketene intermediate Example 17 O BnO BnO

CO2H 1. ClCO Et, Et N, THF, −10 oC, 15 min 2 3 HN

2. CH2N2, Et2O, 0 oC to rt, 18 h, 78%

Boc

PhCO2Ag, Et3N, MeOH/THF, dark

BnO

−25 oC to rt, 3 h, 61%

BnO

N2

BnO HN

BnO

CO2Me HN

Boc

Example 2, An interesting variation9

Ph

CO2H OH

1. Fmoc-Cl, pyridine, 0 oC 2. isobutylchloroformate, Et3N

O

o

then CH2N2, 0 C, 39%

Ph

N2

Ph OFmoc

CONH2 H N

NH2 PhCO2Ag, dioxane 15 min., 50 oC, 72%

Ph O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_5, © Springer-Verlag Berlin Heidelberg 2009

Ph CONH2

Boc

11

Example 310 H H MeO2C

N Cbz

H

1. LiOH, MeOH/H2O, reflux 2. ClCO2Et, Et3N, THF, 0 oC

H

MeO2C

OTBDPS 3. CH2N2, Et2O 4. PhCO2Ag, Et3N, MeOH, rt 69% for 4 steps

H

H N Cbz

OTBDPS

References Arndt, F.; Eistert, B. Ber. 1935, 68, 200−208. Fritz Arndt (1885−1969) was born in Hamburg, Germany. He discovered the Arndt−Eistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt’s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (1902−1978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke up the conglomerate after WWII. 2. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. 1995, 34, 471−472. 3. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. In Enantioselective Synthesis of β-Amino Acids Juaristi, E. ed.; Wiley-VCH: New York, N. Y. 1997, pp 105−126. (Review). 4. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789−3791. 5. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651−657. 6. Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden, C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W. L.; Schmatz, D. M.; Wyvratt, M. J.; Fisher, M. H.; Meinke, P. T. Bioorg. Med. Chem. Lett. 2003, 13, 147−150. 7. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.P. Tetrahedron: Asymmetry 2005, 16, 857−864. 8. Podlech, J. In Enantioselective Synthesis of β-Amino Acids (2nd Edn.) John Wiley & Sons: Hoboken, NJ, 2005, pp 93−106. (Review). 9. Spengler, J.; Ruiz-Rodriguez, J.; Burger, K.; Albericio, F. Tetrahedron Lett. 2006, 47, 4557−4560. 10. Toyooka, N.; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Bioorg. Med. Chem. Lett. 2007, 17, 5872−5875. 11. Fuchter, M. J. Arndt–Eistert Homologation. In Name Reactions for HomologationsPart I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 336−349. (Review). 1.

12

Baeyer–Villiger oxidation General scheme: O O R

H

1

R

2

O

R3

O

O

O

R1

or H2O2

R2

O

R3

HO

The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order: tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H. For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar Example 1: H O

AcO

O HOAc

O Cl

:

O

H

O

Cl O H O

O

alkyl O

Cl

HO

O O

migration O

Example 24 O

UHP, Zr-salen (5 mol%)

O

Zr-salen: O

CH2Cl2, rt 68%, 87% ee

Ph

UHP, O Zr-salen (5 mol%)

N Y N Zr O Y O Ph Ph

Ph

O O O

O PhCl, rt normal product 26%, 82% ee

abnormal product 12%, > 99% ee

UHP = Urea-hydrogen peroxide complex Example 35 OH

OH

O

OH

O

O

m-CPBA O NH O

CH2Cl2, rt quant.

NH O

NH 100%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_6, © Springer-Verlag Berlin Heidelberg 2009

O

O 0%

13

Example 46 O

AcO O

O

m-CPBA, NaHCO3 O

O

CH2Cl2, 0 °C, 4 h 60%

O

O H

H

Example 58 O OAc

m-CPBA, CF3SO3H

O

O OAc

CH2Cl2, 45 min., 90%

References v. Baeyer, A.; Villiger, V. Ber. 1899, 32, 3625−3633. Adolf von Baeyer (1835−1917) was one of the most illustrious organic chemists in history. He contributed to many areas of the field. The Baeyer−Drewson indigo synthesis made possible the commercialization of synthetic indigo. Another Baeyer’s claim of fame is his synthesis of barbituric acid, named after his then girlfriend, Barbara. Baeyer’s real joy was in his laboratory and he deplored any outside work that took him away from his bench. When a visitor expressed envy that fortune had blessed so much of Baeyer’s work with success, Baeyer retorted dryly: “Herr Kollege, I experiment more than you.” As a scientist, Baeyer was free of vanity. Unlike other scholastic masters of his time (Liebig for instance), he was always ready to acknowledge ungrudgingly the merits of others. Baeyer’s famous greenish-black hat was a part of his perpetual wardrobe and he had a ritual of tipping his hat when he admired novel compounds. Adolf von Baeyer received the Nobel Prize in Chemistry in 1905 at age seventy. His apprentice, Emil Fischer, won it in 1902 when he was fifty, three years before his teacher. Victor Villiger (1868−1934), born in Switzerland, went to Munich and worked with Adolf von Baeyer for eleven years. 2. Krow, G. R. Org. React. 1993, 43, 251−798. (Review). 3. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737−750. (Review). 4. Wantanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481−4485. 5. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194−3197. 6. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A. Chem. Eur. J. 2005, 11, 7175−7190. 7. Curran, T. T. Baeye−Villiger oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 160−182. (Review). 8. Demir, A. S.; Aybey, A. Tetrahedron 2008, 64, 11256−11261. 9. Baj, S.; Chrobok, A. Synth. Commun. 2008, 38, 2385−2391. 10. Malkov, A. V.; Friscourt, F.; Bell, M.; Swarbrick, M. E.; Kocovsky, P. J. Org. Chem. 2008, 73, 3996−4003. 1.

14

Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts α-acyloxyketones to βdiketones. O OH Ph

O

O

O

O

base Ph

Ph

O Ph

O

:B

O

O

Ph O

O

H

O

acyl

O O

O

O

OH

O

O

O

H3 O Ph

transfer

Ph

workup

Example 1, Carbamoyl Baker−Venkataraman rearrangement5 O

NEt2 O

NaH, THF

OH NEt2

reflux, 2 h, 84% O

O

O

Example 2, Carbamoyl Baker−Venkataraman rearrangement6 O

NEt2 O

then 6 equiv TFA, reflux, 1 h, 93%

MeO

O

2.5 eq. NaH, PhMe, reflux, 2 h

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_7, © Springer-Verlag Berlin Heidelberg 2009

MeO OH

O

15

Example 3, Ester Baker−Venkataraman rearrangement9 O O O

O

O

OH

O

O

LiH, THF CH3

reflux, 12 h, 50%

CH3

CH3 O

O

Example 4, Ester Baker−Venkataraman rearrangement10 O

OH

O 2 equiv DBU

Cl

OH

O

O Cl

Cl

Cl

pyridine, 80 oC 90%

OH Cl

References Baker, W. J. Chem. Soc. 1933, 1381−1389. Wilson Baker (1900−2002) was born in Runcorn, England. He studied chemistry at Manchester under Arthur Lapworth and at Oxford under Robinson. In 1943, Baker was the first one who confirmed that penicillin contained sulfur, of which Robinson commented: “This is a feather in your cap, Baker.” Baker began his independent academic career at University of Bristol. He retired in 1965 as the Head of the School of Chemistry. Baker was a well-known chemist centenarian, spending 47 years in retirement! 2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767−1771. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the Director of the National Chemical Laboratory at Poona. 3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212−3214. 4. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561−1565. 5. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4995−4998. 6. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999−5002. 7. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515−4517. 8. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575– 4585. 9. Krohn, K.; Vidal, A.; Vitz, J.; Westermann, B.; Abbas, M.; Green, I. Tetrahedron: Asymmetry 2006, 17, 3051–3057. 10. Abdel Ghani, S. B.; Weaver, L.; Zidan, Z. H.; Ali, H. M.; Keevil, C. W.; Brown, R. C. D. Bioorg. Med. Chem. Lett. 2008, 18, 518–522. 1.

16

Bamford–Stevens reaction The Bamford−Stevens reaction and the Shapiro reaction share a similar mechanistic pathway. The former uses a base such as Na, NaOMe, LiH, NaH, NaNH2, heat, etc., whereas the latter employs bases such as alkyllithiums and Grignard reagents. As a result, the Bamford−Stevens reaction furnishes more-substituted olefins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products. R1 R2

N

H N

R1

NaOMe

R2

Ts

R3

MeO

R1

R1

H N

N

R2 H

Ts

R3

R1 N

N

R2 H

Ts

:

R2 H

H R3

R3

N R3

N

In protic solvent (S–H): 1

R1

S H R R2 N H 3 N R

2

R H

R

H R

R3

− N2 N R1

R1

R1 R2 H

H N

R

2

3

3

R

SH

H

H R2

3

S

In aprotic solvent: R1

R1 R2 H

N R3

R1 2

N

1,2-hydride

R

shift

3

− N2 N

R3

N

R1 R

R1

2

H

:

R H

R2 H

R

R3

3

H R2

Example 1, Tandem Bamford–Stevens/thermal aliphatic Claisen rearrangement sequence2 Ph N Ph

Rh2(OAc)4 ClCH2CH2Cl

N O

Ph

130 oC 87% (> 20:1)

Ph

O H Ph

The starting material N-aziridinyl imine is also known as Eschenmoser hydrazone.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_8, © Springer-Verlag Berlin Heidelberg 2009

17

Example 2, Thermal Bamford–Stevens6 N Me3Si

N

Tol., 145 oC

Ph

Me3Si

sealed tube, 65%

Ph

Ph

E : Z = 90 : 10

Example 37 N NHTs

t-BuOK, t-BuOH

O

reflux, 83%

Ot-Bu O

Example 48

R2

Rh2(OAc)4 tetrahydrothiophene

Na

O H

R1

N

N

Ts

BnEt3N+Cl−, MeCN, 40 oC, 3 h, 59−97%

O

R1

R2

References Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735−4740. Thomas Stevens (1900−2000), another chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Stevens also contributed to another name reaction, the McFadyen−Stevens reaction (page 334). 2. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319. 3. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 4. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55−59. (Review on the Shapiro reaction). 5. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 6. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184−1185. 7. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001, 1779−1780. 8. Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430−1433. 9. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426−12427. 10. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377−380. 11. Baldwin, J. E.; Bogdan, A. R.; Leber, P. A.; Powers, D. C. Org. Lett. 2005, 7, 5195−5197. 12. Paul Humphries, P. Bamford−Stevens reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 642−652. (Review). 1.

18

Barbier coupling reaction In essence, the Barbier coupling reaction is a Grignard reaction carried out in situ although its discovery preceded that of the Grignard reaction by a year. Cf. Grignard reaction (Page 266). O R1

OH

R3X, M

R M

R1

R2

R

R2

According to conventional wisdom,3 the organometallic intermediate (M = Mg, Li, Sm, Zn, La, etc.) is generated in situ, which is intermediately trapped by the carbonyl compound. However, recent experimental and theoretical studies seem to suggest that the Barbier coupling reaction goes through a single electron transfer pathway. Generation of the Grignard reagent, R3 X

SET-1

R X

SET-2

MX

M

R

R

M

Ionic mechanism, R2 δ δ O R1 R MgX δ δ

R1 R2 R

H3 O

OMgX

R1 R2 R

OH

Single electron transfer mechanism, R2 R1

R2 R1

O R MgX

R1 R 2

O MgX

R

R

H3O

R1 R2

OMgX

R

Example 16 OH

O O

Br

Sm, THF, rt 20 min., 70%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_9, © Springer-Verlag Berlin Heidelberg 2009

O

OH

R M

19

Example 29 O Me

Zn, THF, aq. NH4Cl Br

Ph NHCO2Et

o

0 C, 82%, 95% de

OH Me

Ph

NHCO2Et

Example 310 Mg 20 mol% CuCN H3C

n-C4H9Br

Cl THF, rt, 1.5 h, 86%

n-C4H9 H3 C

n-C4H9

H3 C

10 : 90

Example 411 I

H MeO

O

n-BuLi, THF O OBn −78 oC, 96% MeO

H

O

OH OBn

References Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110–111. Phillippe Barbier (1848−1922) was born in Luzy, Nièvre, France. He studied terpenoids using zinc and magnesium. Barbier suggested the use of magnesium to his student, Victor Grignard, who later discovered the Grignard reagent and won the Nobel Prize in 1912. 2. Grignard, V. C. R. Hebd. Seanes Acad. Sci. 1900, 130, 1322–1324. 3. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619– 7622. (Theoretical study). 4. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397–436. (Review). 5. Russo, D. A. Chem. Ind. 1996, 64, 405–409. (Review). 6. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187–189. 7. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798–1799. 8. Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725– 11732. 9. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119–120. 10. Erdik, E.; Kocoglu, M. Tetrahedron Lett. 2007, 48, 4211–4214. 11. Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462–6465. 1.

20

Bartoli indole synthesis 7-Substituted indoles from the reaction of ortho-substituted nitroarenes and vinyl Grignard reagents.

1. NO2

MgBr

2. H2O

N H

R

R

BrMg

R

N O

BrMg

O

O N OMgBr

R

OMgBr

N

O

R

nitroso intermediate O [3,3]-sigmatropic O

N MgBr

R

rearrangement R

BrMg

H N MgBr

H

H

H3O OMgBr N

OH2

workup R

R

N H

R

Example 13 1.

MgBr (3 eq) −40 oC, THF

NO 2

N H

2. aq. NH4Cl, 67%

Example 26 Me

Me MgCl NO2

Br

THF, −40 oC 67%

Br

N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_10, © Springer-Verlag Berlin Heidelberg 2009

N H

21

Example 310 4 equiv MeO

MeO

MgCl MeO

NO2 Br Br

THF, 66%

4 equiv

MeO

N H

MeO Br Br MeO

MgCl MeO

NO2 Br

THF, 38%

N H

MeO Br

Example 411 2 equiv MgCl Br

NO2 Br

THF, −40 oC 52%

Br Br

N H

References Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978, 692−696. Giuseppe Bartoli is a professor at the Università di Bologna, Italy. 2. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Chem. Commun. 1988, 807−805. 3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129−2132. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657−663. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757−2761. 6. Dobbs, A. J. Org. Chem. 2001, 66, 638−641. 7. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179−13184. 8. Li, J.; Cook, J. M. Bartoli indole synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 100−103. (Review). 9. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163−178. (Review). 10. Huleatt, P. B.; Choo, S. S.; Chua, S.; Chai, C. L. L. Tetrahedron Lett. 2008, 49, 5309−5311. 11. Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201−204. 1.

22

Barton radical decarboxylation Radical decarboxylation via the corresponding thiocarbonyl derivatives of the carboxylic acids. S

O

HO

R

Cl

O

N

R

O

n-Bu3SnH

N

R

AIBN, Δ

S

H

Barton ester Δ NC

N N

CN

N2↑

homolytic cleavage

2

CN

AIBN = 2,2ƍ-azobisisobutyronitrile n-Bu3Sn

CN

H

H

n-Bu3Sn

CN

O R

O

O

N

N R

S Bu3Sn

SnBu3

CO2↑

H SnBu3

R

O

S

Bu3Sn

R H

Example 13 OAc OAc 1. (COCl)2 NaO H

H

S

2. N

CO2H

O S

O N

OAc OAc 1. m-CPBA, −78 oC

Δ 98%

2. 100 oC, 78%

H S

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_11, © Springer-Verlag Berlin Heidelberg 2009

H

23

Example 26 S

Ph HO2C

2

N

OTBDPS

Ph

O

Bu3P, THF, PhH

Me3SiH, AIBN

N O

OTBDPS PhH, 80 oC, 75%

O

Ph

OTBDPS

S

Example 39 S

CO2H

MeO2C

HO

O

DCC, CH2Cl2

N

rt, 2 h

MeO2C

Ph N

O 5 equiv O

O

N S

hv 15 oC, 30 min, 82%

N 1. m-CPBA, CH2Cl2, 0 oC

S MeO2C O O

N Ph

MeO2C

O

o

2. toluene, 110 C, 1 h, 90%

O

NPh

References Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939−941. Derek Barton (United Kingdom, 1918−1998) studied under Ian Heilbron at Imperial College in his youth. He taught in England, France and the US. Barton won the Nobel Prize in Chemistry in 1969 for development of the concept of conformation. He passed away in his office at the University of Texas A&M in 1998. 2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675−684. (Review). 3. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30, 7111−7114. 4. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 5. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189−6198. 6. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 9255−9262. 7. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford, UK, 2003. (Book). 8. Carry, J.-C.; Evers, M.; Barriere, J.-C.; Bashiardes, G.; Bensoussan, C.; Gueguen, J.C.; Dereu, N.; Filoche, B.; Sable, S.; Vuilhorgne, M.; Mignani, S. Synlett 2004, 316−320. 9. Brault, L.; Denance, M.; Banaszak, E.; El Maadidi, S.; Battaglia, E.; Bagrel, D.; Samadi, M. Eur. J. Org. Chem. 2007, 42, 243−247. 10. Guthrie, D. B.; Curran, D. P. Org. Lett. 2009, 11, 249−251. 1.

24

Barton–McCombie deoxygenation Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives. R1 R2

O

R1

n-Bu3SnH, AIBN

S

H

Δ

NC

N N

CN

O C S↑

n-Bu3SnSMe

R2

PhH, reflux

S

N2↑

homolytic cleavage

2

CN

AIBN = 2,2ƍ-azobisisobutyronitrile CN

n-Bu3Sn H

n-Bu3Sn R1 R2

R1

S O

R2

S

n-Bu3Sn

S O

SnBu3

n-Bu3Sn

H

β-scission

n-Bu3Sn

S

O

R1

hydrogen atom

R2

abstraction

O

S

R2

n-Bu3Sn

n-Bu3SnSMe

O C S↑

S

H2 Si Si H2 (1.5 equiv)

S O

H

S

H

Example 12

PhO

R1

S

R1

H

n-Bu3Sn

CN

10 mol% AIBN nonane, 80 °C 2 h, 85%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_12, © Springer-Verlag Berlin Heidelberg 2009

H

R

2

25

Example 26 O O

O

O

O

AIBN, Δ, 74%

O

O

O

O

O

(CH2)4Bu2SnH

O

OPh S

Example 310 O

O

OH

O

OBn O

O

1. NaH, CS2, MeI, 80% 2. Bu3SnH, AIBN, 70%

O

OBn O

O

Example 411 S Ts

MeO2C

N

N Boc

OH H

O

S Ts

NaH, CS2

Ts

MeI, THF rt MeO2C

N

O H

Toluene, reflux MeO C 2 72% 2 steps N Boc

O

N

Bu3SnH, AIBN N Boc

H

O

References Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585. Stuart McCombie, a Barton student, now works at Schering−Plough. 2. Gimisis, T.; Ballestri, M.; Ferreri, C.; Chatgilialoglu, C.; Boukherroub, R.; Manuel, G. Tetrahedron Lett. 1995, 36, 3897–3900. 3. Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 673–685. 4. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949–6950. 5. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925–1930. 6. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41, 3377–3380. 7. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763–766. 8. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192–1198. 9. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492–1493. 10. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830– 1840. 11. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791–1793. 12. Mancuso, J. Barton–McCombie deoxygenation. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 614−632. (Review). 1.

26

Barton nitrite photolysis Photolysis of a nitrite ester to a γ-oximino alcohol.

NO O

O

HO

OAc

OAc

OAc NOCl

O

OAc

OAc

O N Cl

NO O

O

HO

O

hν

− HCl

homolytic cleavage − ON•

O

O

OAc

OAc O N

O

O

O

O

O

O

HO OH H N

hν

O

HO

1,5-hydrogen

H

abstraction O

O

Nitric oxide radical is a stable and therefore, long-lived radical OAc

OAc O

O H OH N

O

HO H OH N

tautomerization

O

O

nitroso intermediate Example 12 O N H

O

hυ Pyrex, 250-W Hg lamp

H

PhH, reflux, 2 h, 67%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_13, © Springer-Verlag Berlin Heidelberg 2009

OH NOH

27

Example 26

O

O N H

O

H H

hν H

PhH, 6 oC 46%

H N OH

Example 37 HO O H OAc

HO HO N 1. NOCl, CH2Cl2, −20 oC, 100% 2. Irradiation at 350 nM 5 h, PhH, 0 oC, 50%

O H OAc

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960, 82, 2640−2641. In 1960, Derek Barton took a “vacation” in Cambridge, Massachusetts; he worked in a small research institute called the Research Institute for Medicine and Chemistry. In order to make the adrenocortical hormone aldosterol, Barton invented the Barton nitrite photolysis by simply writing down on a piece of paper what he thought would be an ideal process. His skilled collaborator, Dr. John Beaton, was able to reduce it to practice. They were able to make 40 to 50 g of aldosterol at a time when the total world supply was only about 10 mg. Barton considered it his most satisfying piece of work. (b) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641−2641. (c) Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083−4089. (d) Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., (C) 1968, 1031−1040. Nickon, A; Iwadare, T.; McGuire, F. J.; Mahajan, J. R; Narang, S. A.; Umezawa, B. J. Am. Chem. Soc. 1970 92, 1688–1696. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin Trans. 1 1979, 1159−1165. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3−10. (Review). Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). Sicinski, R. R.; Perlman, K. L.; Prahl, J.; Smith, C.; DeLuca, H. F. J. Med. Chem. 1996, 22, 4497–4506. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen, M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295−5305. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn.; 2004, 102/1−102/16. (Review). Hagan, T. J. Barton nitrite photolysis. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 633−647. (Review).

28

Batcho–Leimgruber indole synthesis Condensation of o-nitrotoluene derivatives with formamide acetals, followed by reduction of the trans-β-dimethylamino-2-nitrostyrene to furnish indole derivatives.

R1 R2

R

OR3 N C OR3 H

R1 N R2

NO2 DMF, 130 oC, 86%

R

1. Pd/C, H2

R

2. 5% HCl 82%

NO2

N H

Example 14 NMe2

DMFDMA DMF, Δ

NO2

Pd/C, H2 N H

NO2

DMFDMA = N,N-dimethylformamide dimethyl acetal, Me2NCH(OMe)2 MeO

MeO

N

N

OMe

MeO

OMe H CH2

CH2

N O O

N O

MeO

MeO

NMe2

N

H

O

NO2

:

NMe2

MeOH NO2

[H] NH2 H

NMe2 N H

NH

NMe2

reduction

− NHMe2

NMe2

N H

Example 24 CO2H

1. MeI, NaHCO3

CO2Me

CO2Me NMe2

NO2

2. Me2NCH(OMe)2 DMF, Δ 80%, 2 steps

Pd/C, H2 PhH, 82%

NO2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_14, © Springer-Verlag Berlin Heidelberg 2009

N H

29

Example 35 Me2NCH(OMe)2 pyrrolidine

OBn

NO2

OBn

OBn NMe2

DMF, 110 oC 3 h, 95%

NO2

NO2

15 : 1

OBn

OBn NMe2

Ra-Ni, NH2NH2

THF, MeOH 96%

NO2

N H

Example 410 NO2

NO2

NMe2

Me2NCH(OMe)2, CuI, DMF

MeO2C

NO2

microwave, 180 oC, 10 min. 76%

MeO2C

NO2

NH2

Pd/C, H2 MeOH, 3 d 89%

MeO2C

N H

References Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemistry: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at HoffmannҟLa Roche in Nutley, NJ, USA. 2. Leimgruber, W.; Batcho, A. D. USP 3732245 1973. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London, 1970. (Review). 4. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3350–3352. 5. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214–225. 6. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195–221. (Review). 7. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106–5110. 8. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2004, 2, 160–167. 9. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 104–109. (Review). 10. Braun, H. A.; Zall, A.; Brockhaus, M.; Schütz, M.; Meusinger, R.; Schmidt, B. Tetrahedron Lett. 2007, 48, 7990–7993. 11. Leze, M.-P.; Palusczak, A.; Hartmann, R. W.; Le Borgne, M. Bioorg. Med. Chem. Lett. 2008, 18, 4713–4715. 1.

30

Baylis–Hillman reaction Also known as Morita–Baylis–Hillman reaction. It is a carbon−carbon bondforming transformation of an electron-poor alkene with a carbon electrophile. Electron-poor alkenes include acrylic esters, acrylonitriles, vinyl ketones, vinyl sulfones, and acroleins. On the other hand, carbon electrophiles may be aldehydes, α-alkoxycarbonyl ketones, aldimines, and Michael acceptors. General scheme:

X R1

R2

R1

catalytic

EWG

XH EWG

R2

tertiary amine

X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2, CH2=CHCO2Me Alternative catalytic tertiary amines: N N

N

N

Example 1:

N O

O Ph

OH

N

O

Ph

H

O

O

O H O

Ph

aldol

conjugate

Ph

H

addition

N:

N N

N

N

N

OH

O OH

Ph

O

Ph N N

E2 (bimolecular elimination) mechanism is also operative here: J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_15, © Springer-Verlag Berlin Heidelberg 2009

N N

O

31

OH

O

Ph

OH

E2

H

O N

2

Ph

N

N

N:

N N

Example 2, Intramolecular Baylis–Hillman reaction6

PMB CO2Me O N OBn

PMB

N

N O

DME, 0 oC, 7 d 90% (dr = 9:1)

O

PMB

CO2Me

N

OBn

CO2Me OBn OH

O

OH major

minor

Example 37

OEt O

O

O

DABCO

dioxane:water (1:1) 24 h, 72%, de 80%

CHO

O O

O

OEt HO

Example 48

O

O O

O

O2 N

O

H , TiCl4, TBAI

O O

O

O

O

HO

O

CH2Cl2, −78 to −30 oC 85%, dr > 99:1

OCH(CH3)2

OCH(CH3)2 H

NO2

Example 5

9

O H Cl

N

O

OH

N OMe

MeOH, rt, 8 h, 79%

O OMe

Cl

32

Example 610

N

N

O

O N H

Ts R

OH OH (10 mol%)

cyclopentyl methyl ether/toluene, −15 oC 87−100%, 88−95% ee

NHTs R

R = p-Cl-C6H5 R = p-OMe-C6H5 R = p-NO2-C6H5 R = 2-furyl R = 2-naphthyl

References 1.

Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B. Baylis and Melville E. D. Hillman were chemists at Celanese Corp. USA. 2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001−8062. (Review). 3. Ciganek, E. Org. React. 1997, 51, 201−350. (Review). 4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402−2403. 5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404−2405. 6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230−6231. 7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773−4775. 8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399−11406. 9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338−2341. 10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680−3681. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147−150. A novel mechanism involving a hemiacetal intermediate is proposed. 12. Limberakis, C. Morita–Baylis–Hillman reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 350−380. (Review).

33

Beckmann rearrangement Acid-mediated isomerization of oximes to amides. In protic acid: N

N R1

OH

O

H3O

R1

R2

H3O

N

R2

R

1

OH2

:

R1

OH

R2

R2

N H

R1 N

R1 N

R2

R2 :OH2

the substituent trans to the leaving group migrates N R2

R1 −H

H

O H

N R2

R1

tautomerization

HN R2

OH

R1 O

With PCl5: N R1

Cl

R1

R2

− HCl

O

H

N R1

OPCl4 R2

R2

N H

:

R1

PCl5

PCl4

: N

O

OH

R1 N

R1 N

R2

R2 :OH2

R2

Again, the substituent trans to the leaving group migrates N R

2

R1 O H

−H

H

N R2

R1

tautomerization

OH

R2

Example 1, Microwave (MW) reaction3 N

OH BiCl3

HN

O

MW, 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_16, © Springer-Verlag Berlin Heidelberg 2009

N H

R1 O

34

Example 24 NOH

H N

FeCl3

O

Solvent free 81%

Example 36 N

OH

H N

PPA

HO O

O

N

PPA

NH

21%

72%

PPA = polyphosphoric acid Example 48 N

OH

O p-TsCl/Et3N

OEt syn

HN

OEt

THF, 10% K2CO3 80%

Abnormal Beckmann rearrangement is when the migrating substituent fragment (e.g., R1) departs from the intermediate, leaving a nitrile as a stable product.

N R

1

OH R

H

2

R2

N R1

R2

N

R1

Example 19 H3C NOH AcO

H H H

HC(OMe)3 F3CCOOH

OH2 H3 C N AcO

H

o

THF, 60 C 40 min., 79%

H H

35

H

H

H

CN

CN AcO

AcO

H

H H

H H H

References Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (1853−1923) was born in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addition to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions to determine the molecular weights. 2. Gawley, R. E. Org. React. 1988, 35, 1−420. (Review). 3. Thakur, A. J.; Boruah, A.; Prajapati, D.; Sandhu, J. S. Synth. Commun. 2000, 30, 2105−2011. 4. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31, 2047−2050. 5. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12, 387−390. 6. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067−2069. 7. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005, 44, 2370−2373. 8. Collison, C. G.; Chen, J.; Walvoord, R. Synthesis 2006, 2319−2322. 9. Wang, C.; Rath, N. P.; Covey, D. F. Tetrahedron 2007, 63, 7977−7984. 10. Kumar, R. R.; Vanitha, K. A.; Balasubramanian, M. Beckmann rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 274−292. (Review). 1.

36

Benzilic acid rearrangement Rearrangement of benzil to benzylic acid via aryl migration. O Ar

Ar Ar

Ar O benzil

OH OH benzylic acid

Ar

O Ar

O

KOH

Ar

Ar

O OH O

migration

Ar Ar

OH O

O

O

OH

O Ar Ar

O

workup

O

Ar Ar

H OH OH benzilate anion

OH OH

Final deprotonation of the carboxylic acid drives the reaction forward. Example 13 H3C H3 C

O O

KOH, MeOH/H2O

H H

H 3C

130−140 oC, 3 h, 32%

H

H3C CO2H OH H H

H

O

O

Example 26 KOH, dioxane O

30 min., rt, 74%

HO

COOH

O

Example 3, Retro-benzilic acid rearrangement7 Boc O N Boc

Boc O Boc N

OMe

H O

Boc O Boc N

OH

O

OTBS K2CO3, MeOH

N H

OMe

rt, 2 h, 98% N H

H O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_17, © Springer-Verlag Berlin Heidelberg 2009

N H

H O

37

References 1.

2. 3. 4. 5. 6. 7. 8.

Liebig, J. Justus Liebigs Ann. Chem. 1838, 27. Justus von Liebig (1803−1873) pursued his Ph.D. In organic chemistry in Paris under the tutelage of Joseph Louis GayLussac (1778−1850). He was appointed the Chair of Chemistry at Giessen University, which incited a furious jealousy amongst several of the professors already working there because he was so young. Fortunately, time would prove the choice was a wise one for the department. Liebig would soon transform Giessen from a sleepy university to the Mecca of organic chemistry in Europe. Liebig is now considered the father of organic chemistry. Many classic name reactions were published in the journal that still bears his name, Justus Liebigs Annalen der Chemie.2 Zinin, N. Justus Liebigs Ann. Chem. 1839, 31, 329. Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037−1049. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn, K. B. J. Org. Chem. 1991, 56, 6709−6712. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001, 4357−4365. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 15, 2556−2562. Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082−5084. Kumar, R. R.; Balasubramanian, M. Benzilic Acid Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 395−405. (Review).

38

Benzoin condensation Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction. OH Ar

H

cat. CN

Ar

O

CN Ar

H

Ar

Ar NC Ar

CN H

proton

H O

OH

Ar

proton

NC Ar

transfer

CN

Ar

O

H

transfer

O

O

Ar O

Ar

OH

OH

H OH

Ar

CN

Ar

O

O

Example 12 O EtO

Cl

O

O

H

NaCN, EtOH

H

81%

MeO

EtO OH

MeO

Cl

Example 27 N

CHO

HO

O

Br S

CH3 O

CH3 CH3 OH

Et3N, t-BuOH, 60 oC, 24 h, 40%

Example 37 H3C

O O

N HO

CH3 Br

O

O O

OH

S Et3N, DMF, 60 oC, 96 h, 69%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_18, © Springer-Verlag Berlin Heidelberg 2009

O2 (air)

39

Example 49

Ar 5% O

O SiEt3

Me Me

O Ar

H OMe

Ar O O P O H

O

OMe

O

Ar

20% n-BuLi THF Ar = 2-FPh

OSiEt3 87% yield; 91% ee

Example 510 N N Ph N

BF4

10 mol% CHO

O

OTMS Ph Ph 10 mol% KHMDS toluene, rt, 16 h

OH 66% yield, 95% ee

References Lapworth, A. J. J. Chem. Soc. 1903, 83, 995−1005. Arthur Lapworth (1872−1941) was born in Scotland. He was one of the great figures in the development of the modern view of the mechanism of organic reactions. Lapworth investigated the benzoin condensation at the Chemical Department, The Goldsmiths’ Institute, New Cross, UK. 2. Buck, J. S.; Ide, W. S. J. Am. Chem. Soc. 1932, 54, 3302−3309. 3. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269−304. (Review). 4. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407−496. (Review). 5. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124−5131. 6. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432−8433. 7. Enders, D.; Niemeier, O. Synlett 2004, 2111−2114. 8. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326−1328. (Review). 9. Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 3070−3071. 10. Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367−1371. 11. Cee, V. J. Benzoin condensation. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp381−392. (Review). 1.

40

Bergman cyclization 1,4-Benzenediyl diradical formation from enediyne via electrocyclization.

Δ or

electrocyclization

H

H

reversible

enediyne

2

hydrogen donor

hv

1,4-benzenediyl diradical

Example 16

S

S

Ph

S

S

Ph

S

S

o Ph DMSO, 180 C, 24 h, 60%

S

S

Ph

Example 27 H3C N N

H3C N

hv THF, 45%

N

Example 3, Wolff rearrangement followed by the Bergman cyclization8 O

OH

N2

CO2R OH

CO2R

O

hv or Δ, ROH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_19, © Springer-Verlag Berlin Heidelberg 2009

7:4

41

Example 410 O

O TMS

TMS

142 oC, t1/2 = 14.4 h

References Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660−661. Robert G. Bergman (1942−) is a professor at the University of California, Berkeley. His discovery of the Bergman cyclization was completed far in advance of the discovery of ene-diyne’s anti-cancer properties. 2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25−31. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212−7214. 4. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205−280. (Review). 5. Basak, A.; Mandal, S.; Bag, S. S. Chem. Rev. 2003, 103, 4077−4094. (Review). 6. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. 2005, 44, 592−595. 7. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46, 1373−1375. 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Kar, M.; Basak, A. Chem. Rev. 2007, 107, 2861−2890. (Review). 10. Lavy, S.; Pérez-Luna, A.; Kündig, E. P. Synlett 2008, 2621−2624. 11. Pandithavidana, D. R.; Poloukhtine, A.; Popik, V. V. J. Am. Chem. Soc. 2009, 131, 351−356. 1.

42

Biginelli pyrimidone synthesis One-pot condensation of an aromatic aldehyde, urea, and β-dicarbonyl compound in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs). O O Ar

O

O H 2N

Ar

Δ

CHO O

O

HN

HCl, EtOH

NH2

NH O

H H

O

O

O

O

H

O

H

O

O

H

O

Ar Ar

conjugate

O

O

OH

OH

OH2

addition :

Ar

O

Ar

O

H

O

O

H

addition

O H

O

O

aldol

Ar

O H

H

H

O

enolization

H2N

NH2 O

OH

O O O

O

O H

HO

H H2N

Ar NH2

O

O H

O

O

O H

H2 O HN

O

:

HN

H

N H

HN

Ar

Ar

NH

NH O

O

O

− H2O

Ar HN

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_20, © Springer-Verlag Berlin Heidelberg 2009

NH O

Ar

43

Example 14 F O S F

CHO

H2N

O

HCl NH2

O NH

EtOH, Δ 81%

N H

S

Example 25 OMe OMe O

O

O

MeO

H2 N O

CeCl3 •7H2O NH2

H

MeOOC

EtOH, Δ, 2.5 h 95%

NH N H

O

Example 3, Microwave-induced Biginelli condensation (MWI = microwave irradiation)9 OMe OMe O

O

O

EtO

H2 N O

H

Bi(NO3)3, MWI NH2

EtOH, Δ, 5 h 80%

EtOOC

NH N H

O

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

Biginelli, P. Ber. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita pubbl. In Roma, Italy. Kappe, C. O. Tetrahedron 1993, 49, 6937−6963. (Review). Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888. (Review). Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043−1052. (Review). Ghorab, M. M.; Abdel-Gawad, S. M.; El-Gaby, M. S. A. Farmaco 2000, 55, 249−255. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587−590. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1−116. (Review). Limberakis, C. Biginelli Pyrimidone Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 509−520. (Review). Banik, B. K.; Reddy, A. T.; Datta, A.; Mukhopadhyay, C. Tetrahedron Lett. 2007, 48, 7392−7394.

44

Birch reduction The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadienes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol. Benzene ring bearing an electron-donating substituent: O

O Na, liq. NH3 ROH

O single electron

O

O

H

transfer (SET)

H OR

H

radical anion O

O

H

H

e

O H

H H

H

H OR

Benzene ring with an electron-withdrawing substituent: CO2H

CO2H Na, liq. NH3

CO2

CO2H

CO2 e

e H

radical anion CO2

CO2

CO2H

H

H

H NH2

H H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_21, © Springer-Verlag Berlin Heidelberg 2009

45

Example 14 OMe

OMe 1. Na, NH3, THF, −78 C o

N

O

N

O

2. MeI, 98%, 30:1 dr

O

O

OMe

OMe

Example 27

Na, NH3, THF N

N

−78 oC, quant.

Example 38 Ph

Na, NH3 THF, EtOH

H

Ph

−33 oC, 1 h 16.3%

Ph

Ph

H H H

H

H H

H H

Ph

Ph

H

H

Ph H

Ph

H H

H H H

Ph H

References 1.

2. 3. 4. 5. 6. 7. 8.

Birch, A. J. J. Chem. Soc. 1944, 430−436. Arthur Birch (1915−1995), an Australian, developed the “Birch reduction” at Oxford University during WWII in Robert Robinson’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1−334. (Review). Birch, A. J. Pure Appl. Chem. 1996, 68, 553−556. (Review). Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett. 2001, 42, 5841−5844. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611−642. (Review). Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443−1451. (Review). Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054−2059. Gealis, J. P.; Müller-Bunz, H.; Ortin, Y.; Condell, M.; Casey, M.; McGlinchey, M. J. Chem. Eur. J. 2008, 14, 1552−1560.

46

Bischler–Möhlau indole synthesis The Bischler–Möhlau indole synthesis, also known as the Bischler indole synthesis, refers to the synthesis of 3-arylindoles from the cyclization of Ȧarylamino-ketones and excess anilines.

Δ Br O

H2N O

H2N

N H

N H

H :

:

SN2 O

Br

N H

HO H

H

O

N H

H dehydration N H

N H

Example 15 O O

NaHCO3, EtOH

Br reflux, 4 h

NH2

230−250 oC

O N H

O

silicone oil, 10−15 min 35−80%

O

N H

Example 29 N OTBS

N

O

F

OMe

OMe DME, H2SO4

H 2N

N

NH2 reflux, 53%

F H2 N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_22, © Springer-Verlag Berlin Heidelberg 2009

N

N H

47

Example 310 MeO

OMe LiBr, NaHCO3 Br O

OMe

H2N

OMe

EtOH, reflux 6 h, 74%

N H

Example 4, Microwave-assisted, solvent-free Bischler indole synthesis11 Cl

neat NaHCO3 Br O

H2N

Cl

rt, 3 h

O

N H

Cl Br

H3N

cat. DMF, microwave, 540 W 60 s, 52%

N H

References Möhlau, R. Ber. 1881, 14, 171–175. Bischler, A.; Fireman, P. Ber. 1893, 26, 1346–1349. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, pp 164. (Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971, 2606–2609. 5. Houlihan, W. J., Ed.; The Chemistry of Heterocyclic Compounds, Indoles (Part 1), Wiley & Sons: New York, 1972. (Book). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoï, N. P. J. Chem. Soc., Perkin 1 1972, 2573–2576. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852–1858. 8. Coïc, J. P.; Saint-Ruf, G.; Brown, K. J. Heterocycl. Chem. 1978, 15, 1367–1371. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763–8764. 10. Pchalek, K.; Jones, A. W.; Wekking, M. M. T.; Black, D. S. C. Tetrahedron 2005, 61, 77–82. 11. Sridharan, V.; Perumal, S.; Avendaño, C.; Menéndez, J. C. Synlett 2006, 91–95. 1. 2. 3.

48

Bischler–Napieralski reaction Dihydroisoquinolines from β-phenethylamides in refluxing phosphorus oxychloride.

POCl3 HN

O

N

R

O Cl P Cl O Cl

HN

− Cl

R

HN

NH

POCl2

R

R

R

N H H

O

OPOCl2

O

N H

HCl

NH

O R O P Cl Cl

R OPOCl2

Cl

O P

HCl

Cl

R

Example 12

H O N H

N H

1. POCl3 2. NaBH4

H

CO2Me

CO2Me

CO2Me N H 60%

H

N H

N H H

23%

Example 24 Bn N

MeO

MeO POCl3, P2O5 CO2Me

N 96%

Bn

O

Example 36 H

H H

O O

H N MeO2C

POCl3 80 oC, 81%

H

O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_23, © Springer-Verlag Berlin Heidelberg 2009

HN O

N H H

49

Example 47 O

O HN

O

O

POCl3

N

O

toluene, 95% MeO

OMe

MeO

OMe OMe

OMe

Example 59

N H

O H

AcO

H

N

POCl3, PhH, reflux, 3 h H

OAc

then LiAlH4, THF, 1.5 h 64%

N H

N H

H

HO

OH

References Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903–1908. Augustus Bischler (1865−1957) was born in Southern Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler–Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski. 2. Aubé, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009–9018. 3. Sotomayor, N.; Domínguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062–4072. 4. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609–6612. 5. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yamazaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143–9151. 6. Banwell, M. G.; Harvey, J. E.; Hockless, D. C. R., Wu, A. W. J. Org. Chem. 2000, 65, 4241–4250. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297–8303. 8. Wolfe, J. P. Bischler–Napieralski Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 376−385. (Review). 9. Ho, T.-L.; Lin, Q.-x. Tetrahedron 2008, 64, 10401–10405. 10. Csomós, P.; Fodor, L.; Bernáth, G.; Csámpai, A.; Sohár, P. Tetrahedron 2009, 65, 1475–1480. 1.

50

Blaise reaction β-Ketoesters from nitriles, α-haloesters and Zn. Cf. Reformatsky reaction.

R1

Br

CO2R

OR BrZn

R1

R1

H2 O H

N

Zn(0)

CO2R2

R

2. H3O+

R 2

O

CO2R2 1. Zn, THF, reflux

Br

R CN

2

nucleophilic

N

addition

O

ZnBr

workup

CO2R2

R R1

R1

The Zn enolate itself is a C-enolate (in the crystal form), but for the reaction to occur, it equilibrates back into an O-enolate H

N

H

H2O H

CO2R2

R H2O:

R

O H2N O H CO2R2 R R1

1

CO2R2

R R1

Example 1, Preparation of the statin side chain5

Cl

OTMS CN

1. cat. Zn, THF, reflux Br

OH

CO2t-Bu

O

Cl

+

CO2t-Bu

2. H3O , 85%

Example 26 F

CN Br

Cl

N

F Cl

THF, reflux, 2.5 h

Cl

HN

Br Zn

Zn, MeSO3H

CO2Et

O

O

HCl, 72%

F

OEt

OEt N

Cl

Cl

O

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_24, © Springer-Verlag Berlin Heidelberg 2009

Cl

51

Example 37 O Me OH NC

OMe

O

Br OBn

OH

MeO2C

OBn

3 equiv Zn, 1 mol% MeSO3H THF, reflux, 78%

Example 4, The first chemoselective tandem acylation of the Blaise reaction intermediate9 Zn* BrCH2CO2Et

Br HN

Ph CN THF, reflux, 1 h

NH2 O n-BuLi, Ac2O

Zn O

Ph

OEt

rt, 3 h, 82% Ph

OEt

O

CH3

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478–480. (b) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 978–980. Blaise was at Institut Chimique de Nancy, France. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091–2096. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36, 303–311. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324–6334. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-w.; Chang, J. H.; Lee, K. W.; Nam, D. H.; Kim, N.-S. Synthesis 2004, 2629–2632. Choi, B. S.; Chang, J. H.; Choi, H.-w.; Kim, Y. K.; Lee, K. K.; Lee, K. W.; Lee, J. H.; Heo, T.; Nam, D. H.; Shin, H. Org. Proc. Res. Dev. 2005, 9, 311–313. Pospíšil, J.; Markó, I. E. J. Am. Chem. Soc. 2007, 129, 3516–3517. Rao, H. S. P.; Rafi, S.; Padmavathy, K. Tetrahedron 2008, 64, 8037–8043. (Review). Chun, Y. S.; Lee, S.-g.; Ko, Y. O.; Shin, H. Chem. Commun. 2008, 5098–5100.

52

Blum–Ittah aziridine synthesis Ring opening of oxiranes using azide followed by PPh3-reduction of the intermediate azido-alcohol to give the corresponding aziridines. N3

O R1

NaN3

R1

R2

H N

PPh3

R2

R1

OH

N3

O R1

R2

R1

SN2 R2

R2 OH

N3

Regardless of the regioselectivity of the SN2 reaction of the azide, the ultimate stereochemical outcome for the aziridine is the same. R1

R1

R1

HO

HO

HO N N N

:PPh3

R2

R2

N N N PPh3

N

N2 X

proton transfer

N N N PR3

PR3 N

N PR3 N

R2

R1

PR3 N HO

R2

R1

R3P NH :O R2

O

R1

R2 R1

OH

NH

H N

R2 PPh3

R1

R2

Example 13 O

1. NaN3, NH4Cl, MeOH, reflux, 4 h OTr

HN

2. Ph3P, CH3CN, reflux, 30 min. 60−75%

Example 25 NaN3, NH4Cl, MeOH

O OTBS

reflux, 4 h, 50%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_25, © Springer-Verlag Berlin Heidelberg 2009

OTr

53

OH

N3

OTBS

OTBS N3

OH

Ph3P, CH3CN

NH OTBS

reflux, 99%

Example 37

Cbz

H N

O 1. NaN3, NH4Cl, MeOH, 3 h, 64 oC

Cbz

H N

H N

2. PPh3, MeCN, 1 h, reflux 66%

Example 48 OH NaN 3, NH 4Cl

O

N3

microwave, 15 min. 93%

PPh3

H N

CH3CN, reflux 2 h, 95%

References 1. 2. 3. 4. 5. 6. 7. 8.

Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271– 4273. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211–1214. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639–3642. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649–659. Oh, K.; Parsons, P. J.; Cheshire, D. Synlett 2004, 2771–2775. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004, 6, 1561–1564. Torrado, A. Tetrahedron Lett. 2006, 47, 7097–7100. Pulipaka, A. B.; Bergmeier, S. C. J. Org. Chem. 2008, 73, 1462–1467.

54

Boekelheide reaction Treatment of 2-methylpyridine N-oxide with trifluoroacetic anhydride, or acetic, anhydride gives rise to 2-hydroxymethylpyridine.

TFAA N O

OH

N

TFAA, trifluoroacetic anhydride

O2CCF3

N O

acyl

N O

transfer F3C

O O

H

CF3

N O

O

O CF3

CF3

O

hydrolysis O

N

CF3

OH

N

O

Example 14

Ac2O, CH2Cl2 N

N O

reflux, 1 h, 90%

N

N OAc

Example 26 Ot-Bu

Ot-Bu 1. TFAA, CH2Cl2

N O

2. Na2CO3, 3 h 89%

N OH

Example 38 OTBDPS

OTBDPS 1. Ac2O, 100 oC, 18 h N N O O

2. K2CO3, MeOH−H2O, rt, 2 h 63%

N HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_26, © Springer-Verlag Berlin Heidelberg 2009

N OH

55

Example 49 NO2

N O

NO2 Ac2O, HOAc, 90 oC, 3 h then HCl, 79%

N

OH

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286−1291. Virgil Boekelheide (1919−2003) was a professor at the University of Oregon. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423−1424. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides, Academic Press: NY, 1971. (Review). Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org. Chem. 1989, 54, 1766−1769. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011−1049. (Review). Fontenas, C.; Bejan, E.; Haddou, H. A.; Balavoine, G. G. A. Synth. Commun. 1995, 25, 629−633. Galatsis, P. Boekelheide Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 340−349. (Review). Havas, F.; Danel, M.; Galaup, C.; Tisnès, P.; Picard, C. Tetrahedron Lett. 2007, 48, 999−1002. Dai, L.; Fan, D.; Wang, X.; Chen, Y. Synth. Commun. 2008, 38, 576−582.

56

Boger pyridine synthesis Pyridine synthesis via hetero-Diels−Alder reaction of 1,2,4-triazines and dienophiles (e.g., enamine) followed by extrusion of N2.

N N

N

N H N

O

H O

N

N N

H2O

OH

hetero-Diels-Alder N reaction

N

: HN

enamine N

:B

N retro-Diels-Alder N

H

reaction, − N2

N

N

N

N

Example 13 EtO2C

N

EtO2C

N

CO2Et N

N

CHCl3, 60 oC

EtO2C

26 h, 92%

EtO2C

N

CO2Et

O

Example 2, Intramolecular Boger pyridine synthesis8 Ph N Ph

N

N N

N

Ph

Ph

N

Ph

triisopropylbenzene N 232 oC, 36 h CH3

N CH3

70%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_27, © Springer-Verlag Berlin Heidelberg 2009

Ph

N 27%

Ph

57

Example 310 H 3C O H N H N

N N

H

H3C

HO 1. pyrrolidine, xylene, Δ 10 h, sealed tube 2. silica, 5 h, 67%

N

H H

H

N

HO

Example 411 N

N

N

N N

S

N S

p-cumene, 30 h, 150 oC 67%

N S

N S

References Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179−2182. Dale Boger obtained his Ph.D. under Elias J. Corey at Harvard University in 1980. He started his independent career at the University of Kansas, moving onto Purdue University, and currently he is a professor at The Scripps Research Institute. 2. Boger, D. L. Tetrahedron 1983, 39, 2869−2939. (Review). 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142−150. 4. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451−512. (Review). 5. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 5259−5288. (Review). 6. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099−6138. (Review). 7. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379−471. (Review). 8. Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. J. Org. Chem. 2006, 69, 7171−7182. 9. Galatsis, P. Boger Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 323−339. (Review). 10. Catozzi, N.; Bromley, W. J.; Wasnaire, P.; Gibson, M.; Taylor, R. J. K. Synlett 2007, 2217−2221. 11. Lawecka, J.; Bujnicki, B.; Drabowicz, J.; Rykowski, A. Tetrahedron Lett. 2008, 49, 719−722. 1.

58

Borch reductive amination Reduction (often using NaCNBH3) of the imine, formed by an amine and a carbonyl, to afford the corresponding amine—basically, reductive amination. O R1

R3

R2

H N

R1

H R4

R3

O R1

OH

R2 R3

H N

R1 R2 N: R3 R4

R4

H N

H R1 R3

N

R2 R4

R2

R1

R4

R3

H N

R2 R4

Example 14

O

1. TiCl4, Et3N, CH2Cl2, rt, 18 h CH3 NH2

HN

2. NaCNBH3, MeOH, rt, 15 min. 94%

CH3

Example 25

NH2

O

5 N HCl, NaCNBH3

N

MeOH, rt, 72 h, 75%

O

Example 38 O

0.3 equiv InCl3 H

N H •HCl

2 equiv Et3SiH MeOH, rt, 48 h, 66%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_28, © Springer-Verlag Berlin Heidelberg 2009

N

59

Example 49 OBn

OBn

O

O 1. NaIO4, 8:2 acetone−H2O, rt

O

O N

N O OH

2. BnNH2, MeOH, HOAc NaCNBH3, 3 Å MS, −78 oC to rt 64%

O N Bn

OH

References Borch, R. F., Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996–3997. Richard F. Borch, born in Cleveland, Ohio, was a professor at the University of Minnesota. 2. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897–2904. 3. Borch, R. F.; Ho, B. C. J. Org. Chem. 1977, 42, 1225–1227. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547–5550. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638–4640. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171–174. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Léonce, S.; Pierré, A.; Atassi, G. Heterocycles 2000, 53, 2353–2356. 8. Lee, O.-Y.; Law, K.-L.; Ho, C.-Y.; Yang, D. J. Org. Chem. 2008, 73, 8829–8837. 9. Sullivan, B.; Hudlicky, T. Tetrahedron Lett. 2008, 49, 5211–5213. 10. Koszelewski, D.; Lavandera, I.; Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W. Angew. Chem., Int. Ed. 2008, 47, 9337–9340. 1.

60

Borsche–Drechsel cyclization Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fischer indole synthesis.

HCl N

N H

N H

H

[3,3]-sigmatropic N H

N N H

H

H

rearrangement

NH

NH

NH

H

H

NH

N H

NH2

NH2

N H

H

Example 16 CH3 H3CO

HCl, NaNO2, NaOAc

HO NH2

O

H2O, MeOH, 54%

CH3

CH3 HOAc, HCl, reflux H3CO

O N H

H3CO

10 min., 44%

N H

N

O

Example 210 O N

O CO2Et

KOAc, H2O

retro-Claisen condensation

− 4 C to rt

followed by Japp-Klingemann hydrazone synthesis

o

N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_29, © Springer-Verlag Berlin Heidelberg 2009

61

O N

CO2H

H3O , 100 oC N

NH 68% 2 steps

N O

EtO2C

CO2Et N H

CO2H

Example 310 CO2Et

CO2H conc. HCl, EtOH N H

N

reflux, 85% CO2Et

CO2Et N H

References Drechsel, E. J. Prakt. Chem. 1858, 38, 69. Borsche, W.; Feise, M. Ann. 1908, 359, 49–80. Walther Borsche was a professor at Chemischen Institut, Universität Göttingen, Germany when this paper was published. Borsche was completely devoid of the arrogance shown by many of his contemporaries. Both Borsche and his colleague at Frankfurt, Julius von Braun, suffered under the Nazi regime for their independent minds. 3. Bruck, P. J. Org. Chem. 1970, 35, 2222–2227. 4. Gazengel, J.-M.; Lancelot, J.-C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27, 1947–1951. 5. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795–796. 6. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163–7171. 7. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11–14. 8. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370–372. 9. Takahashi, K.; Kasai, M.; Ohta, M.; Shoji, Y.; Kunishiro, K.; Kanda, M.; Kurahashi, K.; Shirahase, H. J. Med. Chem. 2008, 51, 4823–4833. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835–2838. 1. 2.

62

Boulton–Katritzky rearrangement Rearrangement of one five-membered heterocycle into another under thermolysis.

A B N D

X

Y Z H

H

B D

A

X Y

N Z

Example 14

N: H

N

150 oC N O

H

H

N

N O

Ph

O

N

N

N

N H

Ph

Ph

Example 2, Hydrazinolysis7 Ph

O N F3C

O

NH2NH2, DMF

Ph

rt, 1 h

N

F3C

F3C

O

HO NH

Ph

N N H 5%

N

N Ph

N

O N

N NH2

N

F3C

N N H 92%

Example 43 CF3 H3 C NH N O

N

O

O t-BuOK, DMF reflux, 2 h, 75%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_30, © Springer-Verlag Berlin Heidelberg 2009

N H

CH3 N

CF3 N H

O

63

References Boulton, A. J.; Katritzky, A. R.; Majid Hamid, A. J. Chem. Soc. (C) 1967, 2005–2007. Alan Katritzky, a professor at the University of Florida, is best known for his series Advances of Heterocyclic Chemistry, now in its 93rd volume. 2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocycl. Chem. 1981, 29, 141–169. (Review). 3. Vivona, N.; Buscemi, S.; Frenna, V.; Gusmano, C. Adv. Heterocyl. Chem. 1993, 56, 49–154. (Review). 4. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453– 459. 5. Rauhut, G. J. Org. Chem. 2001, 66, 5444–5448. 6. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002, 257–261. 7. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288–3291. 8. Pace, A.; Pibiri, I.; Piccionello, A. P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2007, 64, 7656–7666. 9. Piccionello, A. P.; Pace, A.; Buscemi, S.; Vivona, N.; Pani, M. Tetrahedron 2008, 64, 4004–4010. 10. Pace, A.; Pierro, P.; Buscemi, S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74, 351–358. 1.

64

Bouveault aldehyde synthesis Formylation of an alkyl or aryl halide to the homologous aldehyde by transformation to the corresponding organometallic reagent then addition of DMF (M = Li, Mg, Na, and K).

1. M 2. DMF R X

R CHO 3. H

O R X

M

Me2N

O M

H

H

Me2N

R CHO

R

R M

Comins modification:4 O Li N

N

LiO

N

N

H H

N O n-BuLi

N

ortho-lithiation

1. RX, X = Br, I O Li

H

2. H3O

R

Example3 Br

Li, DMF, THF, 10 oC

CHO

ultrasound 5 min., 85%

References 1.

2. 3. 4. 5. 6.

Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306−1322, 1322−1327. Louis Bouveault (1864−1909) was born in Nevers, France. He devoted his short yet very productive life to teaching and to working in science. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697−3700. Pétrier, C.; Gemal, A. L.; Luche, J.-L. Tetrahedron Lett. 1982, 23, 3361−3364. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078−1083. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793−1796. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466−471.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_31, © Springer-Verlag Berlin Heidelberg 2009

65

Bouveault–Blanc reduction Reduction of esters to the corresponding alcohols using sodium in an alcoholic solvent. O R

O R

Na, EtOH R

OEt

single-electron OEt

O

transfer (SET)

R

OH

OH

H OEt R

OEt

OEt

e

ketyl (radical anion) OEt

OH e

R

O

OEt R

H OEt

O R

OH

H OEt

H

O R

OEt

R

H

OH

e R

H

e

H

H

R

OH

H OEt

Example2 O OEt

Na, Al2O3 t-BuOH, Tol.

OH

reflux, 6 h, 66%

References 1. 2. 3. 4. 5. 6.

Bouveault, L.; Blanc, G. Compt. Rend. Hebd. Seances Acad. Sci. 1903, 136, 1676−1678. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666−672. Rühlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J. Organomet. Chem. 1971, 27, 327−332. Seo, B.-I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993, 23, 15−22. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959−10964. Schopohl, M. C.; Bergander, K.; Kataeva, O.; Föehlich, R.; Waldvogel, S. R. Synthesis 2003, 2689−2694.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_32, © Springer-Verlag Berlin Heidelberg 2009

66

Bradsher reaction The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ortho-acyl diarylmethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels–Alder reaction of a pyridium with a vinyl ether or vinyl sulfide.

HBr R CH3CO2H

R

O

anthracene

H

R

R O

H

RO H

O

H

H

−H

H

R

OH

R

R

OH2

Example 1, Intramolecular Bradsher reaction2

O

HBr, CH3CO2H Br

Br

150 oC, 7 h, 21%

Example 2, Intramolecular Bradsher reaction5 CH3

H3C AcOH Cl

Cl S

S

PPA

O

Cl

Cl

Cl S

Cl S

S

S O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_33, © Springer-Verlag Berlin Heidelberg 2009

CH3

67

Example 3, Intermolecular Bradsher cycloaddition (DNP = dinitrophenyl)8 EtO2CO CHO

OCO2Et H N

OEt CaCO3, MeOH

EtO O

OEt

N DNP 66%

rt, 2 d

DNP

19%

NHDNP

Cl

Example 4, Intermolecular Bradsher cycloaddition10

Cl

DNP N

DNP N H

SPh

CaCO3, MeOH

PhS

NHAc

Cl NHAc

DNPHN

SPh

H3 O 80%

OH N Ac

References (a) Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486–488. Charles K. Bradsher was born in Petersburg, VA in 1912. After his Ph.D. under Louis F. Fieser at Harvard and postdoctoral training with R. C. Fuson, he became a professor at Duke University. (b) Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451–452. (c) Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786–789. (d) Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79–81. 2. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091– 2094. 3. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669–2670. 4. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 5. Ahmed, M.; Ashby, J.; Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1970, 1094– 1095. 6. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744–1747. 7. Bradsher, C. K. Chem. Rev. 1987, 87, 1277–1297. (Review). 8. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904–6911. 9. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837–840. 10. Soll, C. E.; Franck, R. W. Heterocycles 2006, 70, 531–540. 1.

68

Brook rearrangement Rearrangement of α-silyl oxyanions to α-silyloxy carbanions via a reversible process involving a pentacoordinate silicon intermediate is known as the [1,2]Brook rearrangement, or [1,2]-silyl migration. [1,2]-Brook rearrangement

OH R1 R2

RLi

O R1 R2

SiR3

SiR3 Li

R O

O

O R1 SiR3 R2

H

R1 SiR3 R2

R1 R2

SiR3

pentacoordinate silicon intermediate

O Ph Ph

SiPh3

O

workup Ph Ph

H OH

SiPh3 H

[1,3]-Brook rearrangement OLi SiR3

R1

O

O SiR3

SiR3 Li

R1

R1

R2

R2

R2

[1,4]-Brook rearrangement OLi

SiR3

R1

R2

O SiR3 R1

R2

R3Si

O

Li

R1

R2

Example 16 O

o CN 1. 4 eq. NaHMDS, −30 to 15 C

t-BuMe2Si Ph

CN t-BuMe2SiO

2. PhCH2Br, −10 oC, 75%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_34, © Springer-Verlag Berlin Heidelberg 2009

Ph Ph

69

Example 2, [1,2]-Brook rearrangement followed by a retro-[1,5]-Brook rearrangement8 O t-BuLi, Et2O Br

Me3Si

Ph

Li

Ph

−78 oC

O

Ph

−78 oC to rt, 30 min. then NH4Cl, H2O, 44%

Ph

Ph SiMe3

Example 3, [1,5]-Brook rearrangement9

S S TMS

S S

KHMDS, THF Bu − 78 oC, 1 h, 93%

OH

H

Bu OTMS

Example 4, Retro-[1,4]-Brook rearrangement10 TESO Me

OTMS SnBu3

n-BuLi, THF − 78 C, 30 min. 91% o

TESO

OH

Me TMS 11% [1,2]-Brook

OH

OTMS

Me TES 89% [1,4]Brook

References Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886−1889. Adrian G. Brook (1924−) was born in Toronto, Canada. He was a professor in Lash Miller Chemical Laboratories, University of Toronto, Canada. 2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77−84. (Review). 3. Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147−195. (Review). 4. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257−262. 5. Moser, W. H. Tetrahedron 2001, 57, 2065−2084. (Review). 6. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973−2975. 7. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367−4369. 8. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195−3203. 9. Smith, A. B., III; Xian, M.; Kim, W.-S.; Kim, D.-S. J. Am. Chem. Soc. 2006, 128, 12368–12369. 10. Mori, Y.; Futamura, Y.; Horisaki, K. Angew. Chem., Int. Ed. 2008, 47, 1091–1093. 11. Greszler, S. N.; Johnson, J. S. Org. Lett. 2009, 11, 827–830. 1.

70

Brown hydroboration Addition of boranes to olefins followed by alkalinic oxidation of the organoborane adducts to afford alcohols. 1. R'2BH R 2. H2O2, NaOH

H R

R' B R'

R' B R'

H R

H

synR

addition

OH

R

R' B

H R'

R

R' R' OH B O

O OH

alkyl migration

R

O

OH R

B R'

O OH

R'

OH

O

R

OR' B OR'

B(OH)3

2

Example 1

1. BH3•SMe2, LiAlH4, Et2O

H H

2. NaOOH

H

H

OH H

H

HO

H

H H

H

35%

H

H 40%

Example 27 OMe

MeO

OMe

NO2

BH3•SMe2, NaOOH

OMe

Me

THF, 85%, dr 8:1~11:1 OBn

MeO

NO2 OMe

Me HO

HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_35, © Springer-Verlag Berlin Heidelberg 2009

HO

OBn

71

Example 38 OH

1. Pyridine•BH3, I2, CH2Cl2, 2 h Ph

2. H2O2, NaOH, MeOH, 92%

Ph OH

Ph

15:1

Example 4, Asymmetric hydroboration10 O Ph

N H

CH3 O

Ph

0.5 mol% Rh(nbd)2•BF4 1.1% cat., 2 equiv PinBH

N H

O

Ph P N CH3 O

cat. =

THF, 40 oC, 2 h CH3 O Ph

B(OCMe2)2

N H

CH3

O H2O2, aq. NaOH

Ph

80%

OH

N H

CH3 99% ee

Example 511 t-Bu

OH

t-Bu Si NH

H

BH3•SM2, THF; Ph

Ph

H

NaOH, H2O 2 85%

(t-Bu)2Si

NH2 Ph

H Ph

OH

References Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552−1558. Herbert C. Brown (USA, 1912−2004) began his academic career at Wayne State University and moved on to Purdue University where he shared the Nobel Prize in Chemistry in 1981 with Georg Wittig (Germany, 1897−1987) for their development of organic boron and phosphorous compounds. 2. Nussim, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120−1131. 3. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents, Academic Press: New York, 1972. (Book). 4. Brewster, J. H.; Negishi, E. Science 1980, 207, 44−46. (Review). 5. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1, 95−121. (Review). 6. Hayashi, T. Comprehensive Asymmetric Catalysis I−III 1995, 1, 351−364. (Review). 7. Carter K. D.; Panek J. S. Org. Lett. 2004, 6, 55−57. 8. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766−5767. 9. Clay, J. M. Brown hydroboration reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 183−188. (Review). 10. Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734−3735. 11. Anderson, L. L.; Woerpel, K. A. Org. Lett. 2009, 11, 425−428. 1.

72

Bucherer carbazole synthesis Carbazole formation from naphthols and aryl hydrazines promoted by sodium bisulfite. Another variant of the Fischer indole synthesis.

NaHSO3

OH

NH

NHNH2

H H

H H

H H

H

H

O

O

OH

OH

H :NH2NHPh

H H

H OH NHNHPh

NHNHPh

H

NH NH

:B H OSO2H

OSO2H

[3,3]-sigmatropic rearrangement

OSO2H

OSO2H

OSO2H

H

NH2 NH

NH2 H NH

NH

then H

Example 12 NaHSO3, NaOH Δ, 130 oC

OH NHNH2

CO2H

several days, 46%

N H

Example 23 OH

1. aq. NaHSO3, Δ H2NHN

2. H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_36, © Springer-Verlag Berlin Heidelberg 2009

N H

73

Example 37

OH

Br

Br Na2S2O5 HCl, Δ

H2NHN

N H

Example 34

NH HO

HN

OH

1. NaHSO3, Δ H2NHN

2. H 0.5% yield!

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. Hans Th. Bucherer (1869−1949) was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369−417. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1−48. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. (Review). Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982. (Book). Hill, J. A.; Eaddy, J. F. J. Labelled Compd. Radiopharm. 1994, 34, 697−706. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry 1996, 7, 109−116. Moore, A. J. Bucherer carbazole synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 110−115. (Review).

74

Bucherer reaction Transformation of β-naphthols to β-naphthylamines using ammonium sulfite. OH

NH2

(NH4)2SO3•NH3 H2O, 150 oC

H H H O

H H

H O

O

H

OSO2NH4

OSO2NH4

OH NH2

O tautomerization

H

:NH3 OSO2NH4

H

OSO2NH4

H NH2

NH2

:

OH2 NH2

H OSO2NH4

OSO2NH4

Example 1, Although the classic Bucherer reaction requires high temperatures, it may be carried out at room temperature with the aid of microwave (150 watts):7 OH

NH2

NH3, (NH4)2SO3, H2O, rt microwave 30 min. 93%

Example 2, Retro-Bucherer reaction7 OMe

O N N NH2

10 mol% NaOH reflux, 24 h 46%

OMe

O

5 mol% Na2S2O5 H2O, reflux, 4 h;

N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_37, © Springer-Verlag Berlin Heidelberg 2009

OH

75

Example 38

OH OH

(NH4)2SO3 NH3, H2O o

200 C, 5 d, 91%

NH2 OH

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49−91. Drake, N. L. Org. React. 1942, 1, 105−128. (Review). Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p 166. (Review). Seeboth, H. Angew. Chem., Int. Ed. 1967, 6, 307−317. Gruszecka, E.; Shine, H. J. J. Labelled Compd. Radiopharm. 1983, 20, 1257–1264. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539−540. Deady, L. W.; Devine, S. M. Tetrahedron 2006, 62, 2313−2320. Körber, K.; Tang, W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43, 7163–7165. Budzikiewicz, H. Mini-Reviews Org. Chem. 2006, 3, 93–97. (Review).

76

Bucherer–Bergs reaction Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2CO3] or from cyanohydrins and ammonium carbonate. It belongs to the category of multiple component reactions (MCRs).

R1 O R

2

H N

R1

KCN (NH4)2CO3

R2 O

O NH

(NH4)2CO3 = 2 NH 3 + CO2 + H2O

O

:

OH R1 O

NH2 R1

H N

R2

N

NC

O

R OH O

R

O

1

H N

R1

C N

R2 O

HN

N R2

R2 O

:

R2

R2

:

:

H N

R1

R1

:

OH H2N R2 R1

R2

H3 N

O C O

NH2

R1

NH2

O NH

isocyanate intermediate Example 15 CH3O

CH3O

CH3O KCN, (NH4)2CO3

N

CH3O

CH3O

48 h, 60 oC, 83%

N

N

CH3O

H

H

O

O

HN

O

NH HN

NH

O

O

Example 26 O

O

HN

H O O

H

KCN, (NH4)2CO3 CO2Et H

EtOH/H2O, 70 oC, 50%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_38, © Springer-Verlag Berlin Heidelberg 2009

NH O O O

H

H CO2Et H

77

Example 37 O O HN CH3

KCN, (NH4)2CO3

NH CH3

O

EtOH/H2O (1:1) 60 oC, 4 h, 83% B(OH)2

B(OH)2

Example 49

EtO2C

H F O

O

1. 1 M NaOH, EtOH, rt, 30 min.

HO2C F

2. KCN, (NH4)2CO3, 60 oC, 5 days 77%

H

O

H N

O N H

O

References 1.

Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Germany. 2. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291–316. (Mechanism). 3. Ware, E. Chem. Rev. 1950, 46, 403–470. (Review). 4. Wieland, H. In Houben−Weyl’s Methoden der organischen Chemie, Vol. XI/2, 1958, p 371. (Review). 5. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992, 27, 61–66. 6. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511–514. 7. Zaidlewicz, M.; Cytarska, J.; Dzielendziak, A.; Ziegler-Borowska, M. ARKIVOC 2004, iii, 11−21. 8. Li, J. J. Bucherer–Bergs Reaction. In Name Reactions in Heterocyclic Chemistry, Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 266−274. (Review). 9. Sakagami, K.; Yasuhara, A.; Chaki, S.; Yoshikawa, R.; Kawakita, Y.; Saito, A.; Taguchi, T.; Nakazato, A. Bioorg. Med. Chem. 2008, 16, 4359–4366. 10. Wuts, P. G. M.; Ashford, S. W.; Conway, B.; Havens, J. L.; Taylor, B.; Hritzko, B.; Xiang, Y.; Zakarias, P. S. Org. Proc. Res. Dev. 2009, 13, 331–335.

78

Büchner ring expansion Reaction of a phenyl ring with diazoacetic esters to give cyclohepta-2,4,6trienecarboxylic acid esters. Intramolecular Büchner reaction is more useful in synthesis. Cf. Pfau−Platter azulene synthesis. CO2CH3

N2

CO2CH3 [Rh]

[Rh]

N2 ↑

CO2CH3

N2

[Rh]

CO2CH3

rhodium carbenoid CO2CH 3

[2 + 2]

CO2CH3

cycloaddition

[Rh]

reductive elimination

[Rh]

electrocyclic

CO2CH3

CO2CH3 ring opening

Example 1, Intramolecular Büchner reaction7 O N2

Rh2(OAc)4 CH2Cl2

H O

Example 2, Intramolecular Büchner reaction8 I

Br

I cat. Rh2(OCOt-Bu)4, DMAP O

Ac2O, CH2Cl2, 73%

OAc

N2

Example 3, An intramolecular Büchner reaction within the Grubbs’ catalyst!9

N

N Ru

Cl

Ph PCy3

N

1 atm CO

Cl CH2Cl2, 90%

N

Cl Ph OC Ru CO Cl PCy3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_39, © Springer-Verlag Berlin Heidelberg 2009

79

Example 410 CPh3 Ar

0.5 mol%

N2

[Rh]

CO2Et [Rh]

O 4 Rh Ar

CH2Cl2, −78 oC, 49−66%

EtO2C

Ar

O Rh

CO2Et

Ar

CO2Et

Ar CO2Et

References Büchner, E. Ber. 1896, 29, 106–109. von E. Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352–356. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431–469. (Review). Anciaux, A. J.; Demoncean, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J. Org. Chem. 1981, 46, 873–876. 5. Duddeck, H.; Ferguson, G.; Kaitner, B.; Kennedy, M.; McKervey, M. A.; Maguire, A. R. J. Chem. Soc., Perkin Trans. 1 1990, 1055–1063. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933–935. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484–485. 8. Crombie, A. L; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69, 8652–8667. 9. Galan, B. R.; Gembicky, M.; Dominiak, P. M.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2005, 127, 15702–15703. 10. Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 22–23. 11. Gomes, A. T. P. C.; Leão, R. A. C.; Alonso, C. M. A.; Neves, M. G. P. M. S.; Faustino, M. A. F.; Tomé, A. C.; Silva, A.M. S.; Pinheiro, S.; de Souza, M. C. B. V.; Ferreira, V. F.; Cavaleiro, J. A. S. Helv. Chim. Acta 2008, 91, 2270–2283. 1. 2. 3. 4.

80

Buchwald–Hartwig amination The Buchwald–Hartwig amination is an exceedingly general method for generating an aromatic amine from an aryl halide or an aryl sulfonates. The key feature of this methodology is the use of catalytic palladium modulated by various electronrich ligands. Strong bases, such as sodium tert-butoxide, are essential for catalyst turnover.

X R2 + HN R3

R1

R2 N

cat. LnPd(0) R1

NaOt-Bu

R3

X = I, Br, Cl, OSO2R

Mechanism: Br

N

Pd(OAc)2, dppf NaOt-Bu, Tol., Δ

N H

Br

Pd(II)

Pd(0)

Br

ligand exchange − HBr

oxidative addition

Pd(II)

N

N H

reductive

N

elimination − Pd(0)

The catalytic cycle is shown on the next page. Example 13

R1

I R2 + HN R3

0.5 mol% Pd2(dba)3 2 mol% P(o-tol)3 NaOt-Bu, dioxane 65–100 °C, 2–24 h 18–79% yield

R2 N R1

R1 = EWG or EDG amine = 2° cyclic or acyclic amine = 1° aliphatic: low yield, unless R1 ortho

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_40, © Springer-Verlag Berlin Heidelberg 2009

R3

81

Catalytic cycle: Ln+1Pd(0) k-1 k1 2

R Ar N R3

Ar H

LnPd(0)

k4

Ln-1Pd(0)

k2

NR2(R3)

H LnPd

ArX

LnPd

Ar

X LnPd

Ar

NR2 R3'

Ar

k3 R2 HN + NaOt-Bu R3

H NaX + HOt-Bu

Pd(BINAP)2 catalyzed –d[ArX] dt

=

k1k2 k–1[L]

[ArX][Pd]

Example 24

R1

X R2 + HN R3

5 mol% (DPPF)PdCl2 15 mol% DPPF

R2 N R1

R3

NaOt-Bu, THF 100 °C (sealed), 3 h 80–96% yield (11 examples)

Fe

PPh2 PPh2

X = Br or I R1 = EWG or EDG amine = 2° acyclic (one example) amine = 1° aliphatic or aromatic

DPPF

Example 3, Room temperature Buchwald–Hartwig amination9

R1

Br R2 + HN R3

1–2 mol% Pd(dba)2 (t-Bu)3P (P/Pd = 0.8/1) NaOt-Bu, tol. 22 °C, 1–6 h 81–99% yield

R1 = EDG or EWG amine = 2° cyclic or acyclic: aromatic, aliphatic, or azoles amine = 1° anilines: no aliphatic

R2 N R1

R3

82

Example 410 Me

Me

0.25 mol% Pd2(dba)3 0.75 mol% rac-BINAP

Br n-HexNH2

NaOt-Bu (1.4 equiv) tol., 80 °C, 18–23 h 94%

MeO

H N

n-Hex

MeO

Example 511 0.5 mol% Pd2(dba)2 1 mol% ligand O

HN

Cl

O

O

N

O

1.4 eq. NaOt-Bu, Tol. 100 oC, 24 h, 92% i-Bu i-Bu

ligand =

P N

N N

i-Bu

N

Example 612 NH2

CO2Me I

MeO2C

Pd(OAc)2, Cs2CO3

H N

DPE-Phos, Tol., 95 oC 95%

OCF3

PPh2

OCF3

PPh2 O

DPE-Phos =

Example 7, Amination of volatile amines14 5 equiv R1NHR2 5 mol% Pd(OAc)2 10 mol% dppp 2 equiv NaOt-Bu

O O

N X

N

Br 80

X = N, CH2

oC,

O O

N X

14 h, sealed tube 55−98%

N

R1 N

O

Ot-Bu

R2

Example 815 O

Ot-Bu 1 mol% Pd(OAc)2 2 mol% XPhos

MeO

NH2

Cl

N

Cl

1.4 equiv NaOt-Bu toluene, rt, 4 d, 67%

MeO

N H

N

Cl

83

XPhos = P

References 1.

2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

14. 15. 16.

(a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969−5970. John Hartwig earned his Ph.D. at the University of California-Berkeley in 1990 under the guidance of Robert Bergman and Richard Anderson. He moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald independently discovered this chemistry. (b) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413−5418. (c) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005−8008. (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901−7902. Stephen Buchwald received his Ph.D. in 1982 under Jeremy Knowles at Harvard University. He is currently a professor at MIT. (b) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333−10334. Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133−1135. Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217−7218. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805−818. (Review). Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852−860. (Review). Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615−2624. (Review). Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125−146. (Review). Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575−5580. Wolfe, J. P.; Buchwald, S. L. Org. Syn. 2002, 78, 23−30. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135−9142. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737−5750. Janey, J. M. Buchwald–Hartwig amination, In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 564−609. (Review). Li, J. J.; Wang, Z.; Mitchell, L. H. J. Org. Chem. 2007, 72, 3606−3607. Lorimer, A. V.; O’Connor, P. D.; Brimble, M. A. Synthesis 2008, 2764−2770. Nodwell, M.; Pereira, A.; Riffell, J. L.; Zimmerman, C.; Patrick, B. O.; Roberge, M.; Andersen, R. J. J. Org. Chem. 2009, 74, 995−1006.

84

Burgess reagent O CH3O2C N S NEt3 O

The Burgess reagent [(methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt], a neutral, white crystalline solid, is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination takes place—the two groups leave at about the same time and bond to each other concurrently) mechanism prevails. Preparation2 O N S Cl O

O

MeOH, PhH

O N S Cl H O

CH3O2C

rt, 88−92%

NEt3, PhH rt, 84−86%

H3C OH

O N S Cl :NEt3 O H

CH3O2C

O CH3O2C N S NEt3 O

:NEt3

Mechanism5 O MeO2C N S NEt3 O HO H Ph

D Ph H

O CO2Me S N O D Ph H H Ph

slow SN2

O CO2Me S N HNEt3 O D H Ph Ph H O

O

fast Ei HNEt3

H Ph

Ph H

O CO2Me O S N O D HNEt3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_41, © Springer-Verlag Berlin Heidelberg 2009

85

Example 1, On primary alcohols, the hydroxyl group does not eliminate but rather undergoes substitution3 OH OMe Burgess reagent O H

NH THF, 21 oC, 9 h, 71% H OMe O H

N

H

Example 26 N Si

OH

1.5 eq. Burgess, THF

N Si

reflux, 1 h, 97%

O

O

Example 37 NC

NC HO

H

O

H

O

Burgess reagent

o OBn toluene, 50 C, 60%

OBn

Example 48 OBn

OBn O

OH

BnO

CO2Me N O S O O

O 2.5 equiv Burgess reagent

OH OBn

THF/CH2Cl2 (4:1) reflux, 6 h, 86%

BnO

OBn α/β = (8:1)

Example 510 O NHBoc

N

2.5 equiv Burgess reagent THF, reflux, 30 min., 86%

O

HN O2S

O

N

NHBoc

86

References 1

2

3 4 5 6 7 8 9

10

(a) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744–4745. (b) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224–5226. (c) Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135– 6141. (d) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973, 38, 26– 31. (a) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A.; Williams, W. M. Org. Synth. Coll. Edn. 1987, 6, 788–791. (b) Duncan, J. A.; Hendricks, R. T.; Kwong, K. S. J. Am. Chem. Soc. 1990, 112, 8433–8442. Wipf, P.; Xu, W. J. Org. Chem. 1996, 61, 6556–6562. Lamberth, C. J. Prakt. Chem. 2000, 342, 518–522. (Review). Khapli, S.; Dey, S.; Mal, D. J. Indian Inst. Sci. 2001, 81, 461–476. (Review). Miller, C. P.; Kaufman, D. H. Synlett 2000, 8, 1169–1171. Keller, L.; Dumas, F.; D’Angelo, J. Eur. J. Org. Chem. 2003, 2488–2497. Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X. Chem. Eur. J. 2004, 10, 5581–5606. Holsworth, D. D. The Burgess Dehydrating Reagent. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007; pp 189−206. (Review). Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H. S.; Krishnananthan, S.; Kennedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.; Balasubramanian, B.; Chen, B.-C. Org. Lett. 2008, 10, 2897−2900.

87

Burke boronates MeN MeN Br

S

B O O

MeN

MeN O O

Br

B O O

B O O

O O

O O

B O O

HO

O O

Stable boronic acid surrogates

B-protected haloboronic acids

Burke boronates can serve as B-protected haloboronic acids for a wide variety of applications in iterative cross-coupling.1–6 The corresponding boronic acids can be liberated using mild aqueous bases such as NaOH or NaHCO3.1–4 Burke boronates are also compatible with many synthetic reagents, enabling the synthesis of complex boronic acids from simple B-containing starting materials.3,6 They can also serve as stable building blocks for cross-coupling, i.e., under aqueous basic conditions, the corresponding boronic acid is released and coupled in situ.2,3,7 Moreover, Burke boronates are highly crystalline, monomeric, free-flowing solids that are indefinitely stable to benchtop storage under air and compatible with silica gel chromatography.1–3,6 Preparation:1,2,4,6 Me N Br

S

HO2C B(OH)2

MeN

CO2H

S

Br

PhH:DMSO 10:1 Dean-Stark 99%

B O O

O O

Burke boronate

Me N TMS

BBr3 CH2Cl2

NaO2C BBr2

CO2Na

CH3CN 86% 30 mmol scale

MeN B O O O O Burke boronate

Burke boronates can be conveniently prepared from the corresponding boronic acids via complexation with N-methyliminodiacetic acid (MIDA)1,4 or from dibromoboranes via complexation with MIDA2−Na+22,6 Alternatively, many of these building blocks are now commercially available.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_42, © Springer-Verlag Berlin Heidelberg 2009

88

Example 12 A wide range of selective couplings can be performed at the halide terminus of a B-protected haloboronic acid.

B O O

Ph

B(OH)2

Ph

MeN O O

Suzuki coupling

TMS

Pd(OAc)2

Pd(PPh3)4, CuI

SPhos, KF PhMe, 23°C 92 %

piperidine THF 23 °C, 73%

B O O

O O

Stille coupling

SnBu3

Pd2dba3, Fur3P DMF, 45 °C, 91%

MeO

O

Me O Me B Me O Me

O

B O O B O O Me O Me Me Miyaura coupling

2 PhMe 45 °C, 71%

MeO

MeN B O O

O O

O Heck reaction

MeN

Bu3Sn

O

Pd(OAc)2, PPh3 Et3N, DMF, 45 °C 90%

O O

Sonogashira coupling

PdCl2(CH3CN)2 O SPhos, KOAc Me

B O O

Br

B O O TMS

MeN

MeN

MeN

MeN

ZnCl

Pd(OAc)2, SPhos THF, 0 °C 66%

B O O

Bu3Sn

O O

Negishi coupling

Example 22 Small molecule natural products can be prepared via iterative cross-coupling with B-protected haloboronic acids. MeN

Me

Br

Me

Me

B O O

O O

Me

MeN

Me

Me

B O O

B(OH)2

Pd(OAc)2, SPhos K3PO4,Toluene 23 °C, 78%

Me

Me

1. aq. NaOH, THF, 23 °C 2. Br

Me

H O

Pd(OAc)2 SPhos

K3PO4, THF, 23 °C 66% over two steps

Me

Me

Me

Me

H O

Me

all-trans-retinal

O O

89

Example 33 Burke boronates are stable to a wide range of synthetic reagents, including acids, non-aqueous bases, oxidants, reductants, electrophiles, and soft nucleophiles. This reagent compatibility enables multistep synthesis of complex boranes from simple boron-containing starting materials. Swern and then

Bn Me N

MeN B O O

CrO3, H2SO4 Acetone

O O

HO

O

23 °C, 30 min 90%

O

MeN

n-BuOTf Et3N, DCM −78→0 °C, 2 h;

O O

Bn

H2O2, MeOH pH 6.0 buffer, 79%

B O O

Me O

O O

N O

O

OH MeN

MeN B O O

MeN

O TBSCl, Imid, THF O 23 °C, 9 h, 98%

HF•Py, THF 23 °C, 20 min 83%

TBSO

MeN B O O

O O

B O O

O

B O O

OEt

O O

EtO

NaH, DMF 23 °C, 30 min, 71%

O

HO

PMBOC(NH)CCl3 TfOH, THF 0→23 °C , 5 h, 64% DDQ, DCM 23 °C, 1.5 h, 79%

PMBO

O O

O (EtO)2P

MeN

morpholine NaBH(OAc)3 DCE, 23 °C, 8 h, 76%

B O O

O

O O

N

Example 42 Burke boronates can be hydrolyzed in situ under aqueous basic coupling conditions, as evidenced by this synthesis of the complex polyene skeleton of amphotericin B. Me TESO NMe O O

O B O

5

Me

OAc Me

Me

Me Pd(OAc)2, XPhos 1 N aq. NaOH THF, 45 °C, 48%

Cl

TESO

OAc Me

Me

Me

References 1. 2. 3. 4. 5. 6. 7.

Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716–6717. Lee, S. J., Gray, K. C., Paek, J. S., Burke, M. D. J. Am. Chem. Soc. 2008, 130, 466– 468. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–14085. Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth. 2009, in press. Gillis, E. P.; Burke, M. D. Aldrichimica Acta 2009, in press. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2009, 65, 3130–3138. Knapp, D. M.; Gillis, E. P., Burke, M. D. J. Am. Chem. Soc. 2009, 131, ASAP.

90

Cadiot–Chodkiewicz coupling Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro−Stephens reaction. R1

X

R1

X

R2

Cu

R1

R2

Cu

R2

X Cu

oxidative addition

R1

R2

Cu(III) intermediate reductive CuX

R1

R2

elimination

Example 13 cat. CuCl, NH2OH•HCl Br OH

EtNH2, MeOH 30−40 oC, 70−80%

OH

Example 27 cat. CuCl, NH 2OH•HCl TBS

Br

OH

TBS

OH

30% n-BuNH2, H2O, 92%

Example 39 MeO

OMe

MeO

OMe n = 1 to 7

H

H

CuBr, NH2OH•HCl

Br

Br

piperidine, MeOH rt, 3.5 h, 80% MeO

MeO

OMe

n

n = 1, 8% n = 2, 11% n = 3, 32% n = 4, 8% n = 5, 13% n = 6, 3% n = 7, 8%

OMe

Example 4, Cadiot–Chodkiewicz active template synthesis of rotaxanes and switchable molecular shuttles with weak intercomponent interactions10

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_43, © Springer-Verlag Berlin Heidelberg 2009

91

H O

1. 1 equiv n-BuLi THF, −78 oC 2. 1 equiv CuI, 0 oC 3. 1 equiv 3 1 equiv 2

1

N O

N O

O O

O

N O

O

N O

O

Br

trapping molecule 3 = O

O

2

References 1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055−1057. Both Paul Cadiot (1923−) and Wladyslav Chodkiewicz (1921−) are French chemists. 2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker: New York, 1969, 597−647. (Review). 3. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.; Halazy, S. J. Med. Chem. 1995, 38, 3207−3216. 4. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997, 21, 739−750. 5. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54, 11741−11748. 6. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687−3689. 7. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841−6844. 8. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim. Acta 2004, 87, 698−718. 9. Bandyopadhyay, A.; Varghese, B.; Sankararaman, S. J. Org. Chem. 2006, 71, 4544– 4548−4548. 10. Berna, J.; Goldup, S. M.; Lee, A.-L.; Leigh, D. A.; Symes, M. D.; Teobaldi, G.; Zerbetto, F. Angew. Chem., Int. Ed. 2008, 47, 4392−4396.

92

Camps quinoline synthesis Base-catalyzed intramolecular condensation of a 2-acetamido acetophenone (1) to a 2-(and possibly 3)-substituted-quinolin-4-ol (2), a 4-(and possibly 3)-substitutedquinolin-2-ol (3), or a mixture. O

R

NaOR NH R2

O

R1

OH

R1 ROH

1

R2 R2

N 2

1

OH

N 3

Pathway A: O

O

OR

R1 H

R1

R2

NH R2

O

O

R1 N H

1

N H OH

O

H R2

H2O

2

Pathway B:

O

R1 HO

R1

R1 O 2

R

O

R2

R2

NH N H

H 1

N H

O

O

OR

Example 11 O

OH NaOH, H2O

NH O

104 °C

N

OH

69%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_44, © Springer-Verlag Berlin Heidelberg 2009

N 20%

H H2 O

3

93

Example 26 O

OH N

HN O Me

N

NaOH Me

H2O, 90%

Me

N Me

References 1.

2. 3. 4. 5. 6. 7.

(a) Camps, R. Chem. Ber. 1899, 32, 3228−3234. Rudolf Camps worked under Professor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. (b) Camps, R. Arch. Pharm. 1899, 237, 659−691. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, Elderfield, R. C., ed.; Wiley and Sons, New York, 1957, 576. (Review). Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345−1353. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110−115. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641−2647. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Heterocycl. Chem. 2000, 37, 241−244. Pflum, D. A. Camps Quinolinol Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 386−389. (Review).

94

Cannizzaro reaction Redox reaction between aromatic aldehydes, formaldehyde or other aliphatic aldehydes without α-hydrogen. Base is used to afford the corresponding alcohols and carboxylic acids. O

O

OH

2 R

H

R

O H

R

OH

OH

HO O R

R

OH

O O

H

R

H

OH

Pathway A: O R

hydride

H H O R

O

O

transfer

R

O

H

R

O

R

OH

R

O

OH

Final deprotonation of the carboxylic acid drives the reaction forward. Pathway B: O R

H O R

R

transfer

O

acidic

O

hydride

H

O

R

O

workup

R

OH

O

Example 14 CHO

OH

CO2H

KOH powder 100 oC, 5 min solvent-free

38%

41%

Example 26 H CHO

N

O

H N

OH

Na THF, 0 oC, 5 h, 76%

81%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_45, © Springer-Verlag Berlin Heidelberg 2009

76%

R

OH

95

Example 38 O2N

CHO

1 equiv TMG

O2 N

OH

O2N

CO2H

H2O, rt, 10 h 43%

42%

TMG = 1,1,3,3-tetramethylguanidine Example 4, Desymmetrization by intramolecular Cannizzaro reaction9 CHO

CH2OH

O

O 1 M BaCl2

O 2

H2O, reflux quant.

O 2

O

O

CHO

CO2H

References Cannizzaro, S. Ann. 1853, 88, 129−130. Stanislao Cannizzaro (1826−1910) was born in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Sicilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Cannizzaro to the Italian Senate and he later became its vice president. 2. Geissman, T. A. Org. React. 1944, 1, 94−113. (Review). 3. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381−8383. 4. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. 5. Reddy, B. V. S.; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32, 219−223. 6. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. 7. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005, 7, 1331−1333. 8. Basavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron Lett. 2006, 47, 5771−5774. 9. Ruiz-Sanchez, A. J.; Vida, Y.; Suau, R.; Perez-Inestrosa, E. Tetrahedron 2008, 64, 11661−11665. 10. Yamabe, S.; Yamazaki, S. Org. Biomol. Chem. 2009, 7, 951−961. 1.

96

Carroll rearrangement Thermal rearrangement of β-ketoesters followed by decarboxylation to yield γunsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 117). O

O

O Δ

O

O

O

O Δ

O

H

O

O

H

O

[3,3]-sigmatropic

O

O rearrangement O

H

O keto–enol

– CO2

α

tautomerization

β

δ γ

Example 1, Asymmetric Carroll rearrangement4,5

N

N

2.4 equiv LiTMP

O

toluene –100 °C to rt de > 96%

O

OMe

OMe Li Li N O

OMe

N

N

O CO2H

Example 2, Hetero-Carroll rearrangement6 O H3C

O N

O

O

H3C O

CH3

O N

O

OH

H3 C

NH

CH3

110 °C toluene 82%

O

O

CH3

CH3

CH3

CH3

Example 37 H3 C H3C

H O

TESO

H

O

O S

H3C H H3 C

NaH, xylenes, 140 °C, 82% OPh

TESO

H3C Me H

H

O

H SO2Ph ONa

TESO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_46, © Springer-Verlag Berlin Heidelberg 2009

H

SO2Ph

97

Example 4, Similar to Example 37

O

O

TESO

O

2 eq. NaH, xylene

O

O

reflux, 96%

H TESO

O

H

CO2H Carroll

CO2

O

O

rearrangement TESO

TESO

H

H

Example 58 O O

HO2C

O LDA, THF −78

MeO OMe

oC

Me

Me O

CCl4

O

reflux, 86%

to rt MeO

OMe

MeO

OMe

References (a) Carroll, M. F. J. Chem. Soc. 1940, 704−706. Michael F. Carroll worked at A. Boake, Roberts and Co. Ltd., in London, UK. (b) Carroll, M. F. J. Chem. Soc. 1941, 507−511. 2. Ziegler, F. E. Chem. Rev. 1988, 88, 1423−1452. (Review). 3. Echavarren, A. M.; Mendosa, J.; Prados, P.; Zapata, A. Tetrahedron Lett. 1991, 32, 6421–6424. 4. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. 1995, 34, 2278−2280. 5. Enders, D.; Knopp, M. Tetrahedron 1996, 52, 5805–5818. 6. Coates, R. M.; Said, I. M. J. Am. Chem. Soc. 1977, 99, 2355−2357. 7. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009−5012. 8. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107−109. 9. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69, 4626−4647. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−87. (Review). 1.

98

Castro–Stephens coupling Aryl–acetylene synthesis, Cf. Cadiot–Chodkiewicz coupling and Sonogashira coupling. The Castro–Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. R1

Cu

pyridine, Δ

R2

+ X

or: DMF, base, Δ

2 1: copper acetylide 2: sp halide

R1 = alkyl or aryl

R1

R2

3: disubstituted alkyne

R2 = aryl, vinyl, X = I, Br

+ ligands (solvent)

C C Cu

R1

L

L Cu L

C

C

R1

R2

L

R1 C C

Cu

C

L

I

CuII

R2

I

L

L Cu

C

R1

R1 C C

I

R2

R2

An alternative mechanism similar to that of the Cadiot–Chodkiewicz coupling: oxidative Ar

X

Cu

R

addition

X Ar Cu

reductive R

CuX

Ar

R

elimination

Cu(III) intermediate Example 1, A variant, also known as the Rosenmund–von Braun synthesis of aryl nitriles2 O

CuCN 1-methyl-2-pyrrolininone

N

170 oC, 3 h, 55%

Br

N

NC O N

N

Example 24 CuSO4, NH2OH•HCl aq. NH3, EtOH

H

Cu ca. 95%

OH O N

I

pyridine, Δ 75%

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_47, © Springer-Verlag Berlin Heidelberg 2009

99

Example 35 O OMe I

N MeO

O O

OMe

pyridine, Δ

O

N

87%

Cu N

MeO

N

Example 48 O

O cat. CuI, Ph3P, K2CO 3

O

O o

DMF, 120 C, 37%

I

Example 5, In situ Castro–Stephens reaction10 MeO2C

MeO2C O

I OH CO2Me

Cu2O, pyridine 100 oC, 43%

MeO2C O O

References (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens worked in the Department of Nematology and Chemistry at University of California, Riverside. (b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313–3315. 2. Clark, R. L.; Pessolano, A. A.; Witzel, B.; Lanza, T.; Shen, T. Y.; Van Arman, C. G.; Risley, E. A. J. Med. Chem. 1978, 21, 1158–1162. 3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Owsley, D.; Castro, C. Org. Synth. 1988, 52, 128–131. 5. Kundu, N. G.; Chaudhuri, L. N. J. Chem. Soc., Perkin Trans 1 1991, 1677–1682. 6. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299–302. 7. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407–5413. 8. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487–3490. 9. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489–1494. 10. Bakunova, A.; Bakunov, S.; Wenzler, T.; Barszcz, T.; Werbovetz, K.; Brun, R.; Hall, J.; Tidwell, R. J. Med. Chem. 2007, 50, 5807–5823. 11. Gray, D. L. Castro–Stephens coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 212−235. (Review). 1.

100

Chan alkyne reduction Stereoselective reduction of acetylenic alcohols to E-allylic alcohols using sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH, also known as Red-Al) or LiAlH4. OH

OH

NaAlH2(OCH2CH2OCH3)2 in PhH

R1

Et2O, heat

R

R

OH

H

AlH2R2

H2↑

R1

R

R1

R Al

R

O

OH

R

workup

Al H

O

R

R1

R

R

R

R1

R1

Example 13 OH

OH

LiAlH4 77%

Example 24 OH

1.5 eq. Red-Al, −72 oC, 25 min.

Ph

OH

then 5 eq. I2, −72 to −10 oC, THF, 2 h 78%

CO2Me

I

Ph

CO2Me

Example 36

OTBDPS

1. Red-Al, THF/PhMe −78 oC to rt, 4 h

OTBDPS OH

2. NCS, −78 to rt 65% oC

OH

Cl

Example 47 OMe MeO O Me BnO

OMe OMe

MeO Red-Al, Et2O

O

0 oC, 80%

OH

O Me BnO

O Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_48, © Springer-Verlag Berlin Heidelberg 2009

OMe O OH

O

Me

101

References 1.

2. 3. 4. 5. 6. 7.

Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497−3505. Ka-Kong Chan was a chemist at Hoffmann−La Roche, Inc. in Nutley, NJ, USA. Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820−821. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143−1144. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785−1787. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. Xu, S.; Arimoto, H.; Uemura, D. Angew. Chem., Int. Ed. 2007, 46, 5746−5749. Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron 2008, 64, 5162−5167.

102

Chan–Lam C–X coupling reaction Arylation of a wide range of NH/OH/SH substrates by oxidative cross-coupling with boronic acids in the presence of catalytic cupric acetate and either triethylamine or pyridine at room temperature in air. The reaction works for amides, amines, anilines, azides, hydantoins, hydrazines, imides, imines, nitroso, pyrazinones, pyridones, purines, pyrimidines, sulfonamides, sulfinates, sulfoximines, ureas, alcohols, phenols, and thiols. It is also the mildest method for N/Ovinylation. The boronic acids can be replaced with siloxanes or stannanes. The mild condition of this reaction is an advantage over Buchwald–Hartwig’s Pdcatalyzed cross-coupling. The Chan–Lam C–X bond cross-coupling reaction is complementary to Suzuki–Miyaura’s C–C bond cross-coupling reaction. cat. Cu(AcO)2

H XR

Ar M

Ar

XR

air M = B(OH)2, B(OR)2, B(OR)3−, BF3−, SnMe3, Si(OMe)3. X = N, O, S, Se, Te.

N

N B(OH)2

cat. Cu(AcO)2

HN

R

N

air, > 90%

R

Example 11a,d H3C

B(OH)2

NH

N

CH3

Cu(OAc)2, pyridine rt, 48 h, air 74%

Mechanism:1c,d,17 L Cu(OAc)2, pyridine NH

coordination and deprotonation

L H3C

B(OH)2

transmetallation

L

CuIII

CuII

N

L OAc pyridinium acetate

Ph

CuII

L

N

AcOB(OH)2 CH3

+ [CuII] – [CuI]

Ph

L reductive

N CH3

elimination

Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_49, © Springer-Verlag Berlin Heidelberg 2009

N

CH3

103

Example 24 O

OH

B(OH)2 1.1 eq Cu(OAc)2, TEA rt, 24 h, air 52%

Example 35 OH

O B(OH)2 OMe Cu(OAc)2 TEA, air

O t-BuO2C

OMe

N H

O t-BuO2C

54%

CO2Me

N H

CO2Me

Example 413 O

BnO

O O

BnO

(HO)2B

N

N O

O

N

Cu(OAc)2/Et3N/Py

NH O

93% (α-ester assistance, acetal lower yield, e.g., dimethyl acetal, 23%)

1eq/3 eq/ 3 eq 4 Å MS, air

Example 514 CO2Me

CO2Me

N H

B(OH)2 NaHMDS, Cu(AcO)2 DMAP, air, 95 oC 93%

N

Example 615 B(OH)2

NH4OH

0.1 eq Cu2O MeOH, air, rt

NH2

92%

References 1.

(a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2949. Dominic Chan is a chemist at DuPont Crop Protection, Wilmington, DE, USA. He did his PhD research with Prof. Barry Trost at the University of Wisconson, Madison. Patrick Lam is a research director at Bristol–Myers Squibb, Princeton, NJ, USA. He was formerly with DuPont Pharmaceuticals Company. He did his PhD research with Prof. Louis Friedrich at the Univeristy of Rochester and Postdoc research with Prof. Mi-

104

2.

3.

4. 5. 6.

7.

8.

9. 10. 11.

12. 13. 14. 15. 16. 17.

chael Jung and the late Prof. Donald Cram at UCLA. (c) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937–2940. Prof. Evans’ group found out about the discovery of this reaction on a National Organic Symposium poster and became interested in the O-arylation because of his long interest in vancomycin total synthesis. (d) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676. (e) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691–1694. Reviews: (a) Chan, D. M. T.; Lam, P. Y. S., Book chapter in Boronic Acids Hall, ed. 2005, Wiley–VCH, 205–240. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. Catalytic copper: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077–2079. (c) Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397– 4400. (d) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233–1236. (e) Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004, 1095–1097. Vinyl boronic acids: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927–4931. Intramolecular: Decicco, C. P.; Song, Y.; Evans, D.A. Org. Lett. 2001, 3, 1029–1032. Solid phase: (a) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623–1626. (b) Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem. 2002, 4, 179–182. Boronates/borates: (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863–3865. (b) Yu, X. Q.; Yamamoto, Y.; Miyuara, N. Chem. Asian J. 2008, 3, 1517–1522. Siloxanes: (a) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601. (b) Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G. Tetrahedron Lett. 2001, 42, 2427–2429. Stannanes: Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2002, 43, 3091–3094. Thiols: (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019–2022. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. . Org. Lett. 2002, 4, 4309–4312. Sulfinates: (a) Beaulieu, C.; Guay. D.; Wang, C.; Evans, D. A. Tetrahedron Lett. 2004, 45, 3233–3236. (b) Huang, H.; Batey, R. A. Tetrahedron. 2007, 63, 7667–7672. (c) Kar, A.; Sayyed, L. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse, M. K. Org. Lett. 2007, 9, 3405–3408. Sulfoximines: Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667–2669. β-Lactam: Wang, W.; Devsathale, P.; et al. Bio. Med. Chem. Lett. 2008, 18, 1939– 1944. Cyclopropyl boronic acid: Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653–1655. Ammonia: Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Ang. Chem., Int. Ed. 2009, 48, 1114– 1116. Alcohol: Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 1381–1384. Mechanism: (a) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196– 9197. (b) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 5044– 5045

105

Chapman rearrangement Thermal aryl rearrangement of O-aryliminoethers to amides. Ar1

O

Δ

N

Ar Ar

Ar1 Ar

OPh

S NAr

N:

N Ph

Ar1

O

Ar1 N

Ar O

O

Ar

N Ph

Ar1

oxazete intermediate Example 12

Cl Cl MeO

MeO2C

Cl N

NaO

MeO2C

NaOEt, EtOH/Et2O Ph

MeO

0 oC to rt, 48 h

O N

MeO

o

210−215 C, 70 min

MeO2C

Cl MeO

N

28% for 2 steps O

N H

Ph

Example 24 Ph Ph Ph

O N

HO2C

Ph 300 oC Ph

O N

30 min., 87%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_50, © Springer-Verlag Berlin Heidelberg 2009

Ph

Ph

Cl

106

Example 3, Double Chapman rearrangement10 C12H25

C12H25

C12H25

C12H25

N

N

110−140 oC N

O

Me2N MeO2C

O

N

70−74%

Me2N

O MeO2C

NMe2 CO2Me

NMe2

O CO2Me

Example 4, Chapman-like thermal rearrangement11 O

OR Δ N S O O

NR S O O

References Chapman, A. W. J. Chem. Soc. 1925, 127, 1992−1998. Arthur William Chapman was born in 1898 in London, England. He was a Lecturer in Organic Chemistry and later became Registrar of the University of Sheffield from 1944 to 1963. 2. Dauben, W. G.; Hodgson, R. L. J. Am. Chem. Soc. 1950, 72, 3479−3480. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 1−51. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245−2253. 5. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903−5909. 6. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315−320. 7. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305−3308. 8. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem. Commun. 1992, 132−134. 9. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199−2210. 10. Marsh, A.; Nolen, E. G.; Gardinier, K. M.; Lehn, J. M. Tetrahedron Lett. 1994, 35, 397−400. 11. Almeida, R.; Gomez-Zavaglia, A.; Kaczor, A.; Cristiano, M. L. S.; Eusebio, M. E. S.; Maria, T. M. R.; Fausto, R. Tetrahedron 2008, 64, 3296−3305. 1.

107

Chichibabin pyridine synthesis Condensation of aldehydes with ammonia to afford pyridines.

R 3 R

H

H

H3N:

R

R

N

H3N:

O

R

NH3

CHO

NH2

R

OH

R

H

NH2

enamine H

:NH3 R

H O

R

NH

R

H

H

H

H

H

R

− H2 O

O OH H

condensation R

O

R

HN

H3 N H R

Michael R

addition

O

H OH

O

H R

R

N

R H

R

R

N H

H OH R R

R

R H

H

R

N

H

R

R

autoxidation

N

[O]

R

O NH4OAc, HOAc reflux, 1 h, 68% N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_51, © Springer-Verlag Berlin Heidelberg 2009

R N

Example 14

CHO

R N H

:

R

O

R :

H

R

Aldol

O

imine

R

108

Example 28 HO Me

1. AcOH, rt, 1 d, 49% N Troc

CH2

N

CHO

2. Zn, HCl, MeOH, 65 oC, 72%

HO Me

N Troc

CH2

10

HO Me

N Troc

CH2

N 10

Cl

Example 39 CH3CO2NH4, MeOH

O O2N

OHC

O

O2N

CF3

N

O

reflux, 4 h, 45%

O

NO2

Ar

Ar

CF3

Example 4, An abnormal Chichibabin reaction10 Br

1 equiv BnNH3Cl 0.5 equiv Yb(OTf)3

O H

N Bn TfO

H2O/dioxane, rt, 65%

dehydration

[O] benzaldehyde

Ar

Ar

Ar

Ar

6π N Bn

Ar

N Bn

Ar

References 1.

Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin (1871−1945) was born in Kuzemino, Russia. He was Markovnikov’s favorite student. Markovnikov’s successor, Zelinsky (of Hell–Volhard–Zelinsky reaction fame) did not

109

want to cooperate with the pupil and gave Chichibabin a negative judgment on his Ph.D. work, earning Chichibabin the nickname “the self-educated man.” 2. Sprung, M. M. Chem. Rev. 1940, 40, 297−338. (Review). 3. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182−4183. 4. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200−202. 5. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825−826. 6. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous Mesoporous Materials 1998, 21, 447−451. 7. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 308−309. (Review). 8. Snider, B. B.; Neubert, B. J. Org. Lett. 2005, 7, 2715−2718. 9. Wang, X.-L.; Li, Y.-F.; Gong, C.-L.; Ma, T.; Yang, F.-C. J. Fluorine Chem. 2008, 129, 56−63. 10. Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 205−208. 11. Liaw, D.-J.; Wang, K.-L.; Kang, E.-T.; Pujari, S. Pu.; Chen, M.-H.; Huang, Y.-C.; Tao, B.-C.; Lee, K.-R.; Lai, J.-Y. J. Polymer Sci., A: Polymer Chem. 2009, 47, 991−1002.

110

Chugaev elimination Thermal elimination of xanthates to olefins.

OH

R

1. CS2, NaOH

O

R

Δ

S

CH3SH

OCS

R

2. CH3I

S

xanthate R O

R

Δ

S

H

O S

S

S

O S

R

H

O C S↑

CH3SH↑

S

Example 14 OH 1. NaH, CS2; MeI, 90% OH

OH

2. HMPA, 230 oC, 90%

Example 25 O

O

H

H

H

O

H

O CS2, MeI, NaH

H

S

H O H

reflux (216 oC) 48 h, 74%

S O O

dodecane

H

THF, rt, 2 h, 51%

HO

O

H

O

O O

O O

Example 3, Chugaev syn-elimination is followed by an intramolecular ene reaction6 S OH O O

CS2, MeI, NaH

O

N Cbz

THF, 92%

S

O O

N Cbz

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_52, © Springer-Verlag Berlin Heidelberg 2009

111

NCbz NaHCO3, Ph2O oC,

280 25 min Chugaev

O

72% H

O O

Alder ene

N Cbz

O

References 1.

2. 3. 4. 5. 6. 7. 8.

9.

Chugaev, L. Ber. 1899, 32, 3332. Lev A. Chugaev (1873−1922) was born in Moscow, Russia. He was a Professor of Chemistry at Petrograd, a position once held by Dimitri Mendeleyev and Paul Walden. In addition to terpenoids, Chugaev also investigated nickel and platinum chemistry. He completely devoted his life to science. The light in Chugaev’s study would invariably burn until 4 or 5 a.m. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467−472. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615−617. Fu, X.; Cook, J. M. Tetrahedron Lett. 1990, 31, 3409−3412. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org. Chem. 1999, 64, 9178−9188. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181−3183. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523−4526. Fuchter, M. J. Chugaev elimination. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 334−342. (Review). Ahmed, S.; Baker, L. A.; Grainger, R. S.; Innocenti, P.; Quevedo, C. E. J. Org. Chem. 2008, 73, 8116−8119.

112

Ciamician–Dennsted rearrangement Cyclopropanation of a pyrrole with dichlorocarbene generated from CHCl3 and NaOH. Subsequent rearrangement takes place to give 3-chloropyridine. Cl

CHCl3 N H

Cl3C H

NaOH

N

CCl2 Cl

H2O OH

− Cl

:CCl2

carbene Cl Cl CCl2

Cl

N H

N H

N

HO 4

Example 1

2 eq. PhHgCCl3 N H

Cl

PhH, Δ, 54% N

Example 25 Cla Clb N H

NaO2CCl3

H N

26%

Cla

N N

N

HN

NH

Clb

N

Cla Clb

Clb Cla

References 1.

2. 3. 4. 5. 6.

Ciamician, G. L.; Dennsted, M. Ber. 1881, 14, 1153. Giacomo Luigi Ciamician (1857−1922) was born in Trieste, Italy. Ciamician is considered the father of modern organic photochemistry. Wynberg, H. Chem. Rev. 1960, 60, 169−184. (Review). Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1−36. (Review). Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775−3779. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J. Chem. Soc., Chem. Comm. 1998, 9−10. Pflum, D. A. Ciamician–Dennsted Rearrangement. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 350−354. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_53, © Springer-Verlag Berlin Heidelberg 2009

113

Claisen condensation Base-catalyzed condensation of esters to afford β-keto esters. O O R

R2

OR1

O OR3

R

base

OR1 R

O R

O

2

O deprotonation

OR1

R

B:

condensation

OR1 OR3

R2

H

O

R2 O

O

O

3

R O

OR

1

R

O

2

OR1 R

R

Example 14 O

O

t-BuOK, solvent-free

O

Ph

Ph

O

Ph

O

90 oC, 20 min., 84%

Ph

Ph

Example 26

Cbz

H N

3.5 eq. LDA, THF −45 to −50 oC

O

CO2Me

O Ph

t-Bu

Cbz then H+, 97%

O

H N

O

Ph

Example 3, Retro-Claisen condensation9 O

5 equiv H2O 5 mol% In(OTf)3

O

O

O OH

neat, 80 oC, 24 h 85%

H2O: O

In

O

H

HO

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_54, © Springer-Verlag Berlin Heidelberg 2009

In

O

O t-Bu

114

Example 4, Solvent-free Claisen condensation10 KOt-Bu, 100 oC, 30 min.

O OBn

solvent-free, 51%

O

O

= 13C OBn

References 1

2 3 4 5 6 7 8 9 10

Claisen, R. L.; Lowman, O. Ber. 1887, 20, 651. Rainer Ludwig Claisen (1851−1930), born in Cologne, Germany, probably had the best pedigree in the history of organic chemistry. He apprenticed under Kekulé, Wöhler, von Baeyer, and Fischer before embarking on his own independent research. Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266−302. (Review). Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1−203. (Review). Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983−7985. Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581−596. (Review). Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447−449. Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73−78. Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838−845. Kawata, A.; Takata, K.; Kuninobu, Y.; Takai, K. Angew. Chem., Int. Ed. 2007, 46, 7793−7795. Iida, K.; Ohtaka, K.; Komatsu, T.; Makino, T.; Kajiwara, M. J. Labelled Compd. Radiopharm. 2008, 51, 167−169.

115

Claisen isoxazole synthesis Cyclization of β-keto esters with hydroxylamine to provide 3-hydroxy-isoxazoles (3-isoxazolols). O

O

R1

O

− H2O

R2

O

O

O

R1

O

R2

NH2OH R

R

R1

O

O OR

R1

N H

R2

R2

OH N

O

O

OH R1

OH

N H

R2

:NH2OH

R2

O

R1 O

HO

− H2 O

NH

R2

R2

O

R1

O

NH

OH

R1

O

N

3-isoxazolol A side reaction: O

O

R1

O

R

NH2OH

H HON: OH O R1

R2

H O:

N O

N O

O

R1

O

R

− H2O

R

R2

:NH2OH

N

O

O H OR

R1

O

R1 R2

R2

R2

5-isoxazolone Example 1, A thio-analog6 O

SH

O OEt

MeO

N

1. aqueous NH3, 67% 2. H2S, HCl, EtOH, 53%

O NH2

MeO

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_55, © Springer-Verlag Berlin Heidelberg 2009

N O

116

R I2, K2CO3, 59%

OH S

MeO

N

N O

Example 27 O

O O

74−100% For R = Ph: (PhCO)2O, DMF

O O

O

OBoc HN Boc

O

53−91%

O o Cl , pyr., 0 C

R

HO R O

Meldrum’s acid O

OH

O OBoc N Boc

R

HCl 76−99%

R

O

N

R = Me, Et, i-Pr, cyclopropyl, cyclohexyl, Ph, Bn, neopentyl

Example 38 O

O OMe

NH2OH•HCl, NaOH MeOH, −50 oC, 2 h then 85 oC, 1 h, 65%

OH O

N

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

(a) Claisen, L; Lowman, O. E. Ber. 1888, 21, 784. (b) Claisen, L.; Zedel, W. Ber. 1891, 24, 140. (c) Hantzsch, A. Ber. 1891, 24, 495−506. Barnes, R. A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York, 1957; Vol. 5, p 474ff. (Review). Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Amsterdam, 1957; Vol. 4a, p. 345ff. (Review). McNab, H. Chem. Soc. Rev. 1978, 7, 345−358. (Review). Chen, B.-C. Heterocycles 1991, 32, 529−597. (Review). Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A. B.; Krogsgaard-Larsen, K.; Falch, E. J. Med. Chem. 1995, 38, 3287−3296. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65, 1003−1007. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Nielsen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051−1059. Brooks, D. A. Claisen Isoxazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 220−224. (Review).

117

Claisen rearrangements The Claisen, para-Claisen rearrangements, Belluš–Claisen rearrangement; Corey– Claisen, Eschenmoser–Claisen rearrangement, Ireland–Claisen, Kazmaier– Claisen, Saucy–Claisen; orthoester Johnson–Claisen, along with the Carroll rearrangement, belong to the category of [3,3]-sigmatropic rearrangements. The Claisen rearrangement is a concerted process and the arrow pushing here is merely illustrative.

1

R

2

O 1

rearrangement

3

1

3

π2S

σ2S

4

π2S

π2S

chair-like

3 2

1

O

2

2

2

σ2S 3

R O

O

2

4

π2S

2 R 1 3

Δ, [3,3]-sigmatropic

3

1

O

6

6

6 4

4

4 5

5

5

boat-like

Example 17 OBn OBn

BnO BnO

BnO BnO

O O

BnO

O

O

n-decane/toluene 5:1 BnO

O

O 180 oC, 70%

O

O

O

O

Example 28

Et2AlCl, hexanes

O

O

−78 oC, 81%

O

OH

Example 39 O Et

SiMe3 Ph

1 mol% Ir(PCy3)3+ PPh3, Δ, 50% yield syn:anti 95:85, 91% ee

1

O

OHC Et

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_56, © Springer-Verlag Berlin Heidelberg 2009

SiMe3 Ph

118

Example 4, Asymmetric Claisen rearrangement10 O MeO

CH3

CH3 O

cat, 7.5 mol% CF3CH2OH CH2Cl2, rt, 12 h

O

2+ O

OMe

OBn

2 SbF6 − N Cu t-Bu H2 O OH2 N

O

BnO

O

cat. =

t-Bu

98%, > 90% de, 99% ee

Example 5, Asymmetric Claisen rearrangement11 O

20 mol%, hexane, 8 days, 35 °C

MeO

CH3

H3C

CF3 –

NH2

O Ph

N

N H

N H

O

CH3 CH3

MeO O

B N

Ph

4

73%, 96% ee

CF3

References Claisen, L. Ber. 1912, 45, 3157−3166. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 827−873. (Review). 4. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 937−945. (Review). 5. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 6. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 7. Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631−1638. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005, 46, 2457−2460. 9. Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232–4233. 10. Körner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982. 11. Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228–9229. 12. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−43. (Review). 1. 2. 3.

119

para-Claisen rearrangement Further rearrangement of the normal ortho-Claisen rearrangement product gives the para-Claisen rearrangement product. OH R

O R

R

Δ

R

Mechanism 1: OH O O R

ortho-

R

R

R

R

R

Cope rearrangement

Claisen dienone

Mechanism 2: OH

O R

O R

R

R

R H 2C

R

CH2

Dewar intermediate

Mechanism 3: OH

O O

O R

R

R

R

[3,3]-sigmatropic

R

R

rearrangement H

R

R

120

Example 16 OH

OH HO 160−170 oC

O HO

HO

OH

CHO

CHO

HO

CHO

CHO 25.5%

58%

4.6%

Example 27 CO2Me Me

Me HO

O

PhNEt2 reflux

Me

Me

Me HO

Me

O 80%

O HO

O 12%

O

Example 38 TBSO

O

220 oC

TBSO

O

O O

O

xylene, 70% OH

Example 410 MOMO

OMOM PhNMe2, reflux MOMO O

O

OMOM

200 oC, 64% OH

O

References Alexander, E. R.; Kluiber, R. W. J. Am. Chem. Soc. 1951, 73, 4304–4306. Rhoads, S. J.; Raulins, R.; Reynolds, R. D. J. Am. Chem. Soc. 1953, 75, 2531–2532. Dyer, A.; Jefferson, A.; Scheinmann, F. J. Org. Chem. 1968, 33, 1259–1261. Murray, R. D. H.; Lawrie, K. W. M. Tetrahedron 1979, 35, 697–699. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Chem. Commun. 1986, 1264– 1266. 6. Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591–2594. 7. Cairns, N.; Harwood, L. M.; Astles, D. P. J. Chem. Soc., Perkin Trans. 1 1994, 3101– 3107. 8. Pettus, T. R. R.; Inoue, M.; Chen, X.-T.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160–6168. 9. Al-Maharik, N.; Botting, N. P. Tetrahedron 2003, 59, 4177–4181. 10. Khupse, R. S.; Erhardt, P. W. J. Nat. Prod. 2007, 70, 1507–1509. 1. 2. 3. 4. 5.

121

Abnormal Claisen rearrangement Further rearrangement of the normal Claisen rearrangement product with the β-carbon becoming attached to the ring. α

β

O

OH

Δ

β

δ

α

α

β

O

[3,3]-sigmatropic rearrangement

δ

Hα O

ene

δ

H O

δ

tautomerization

H

β

[1,5]-H-atom

δ

reaction

δ

β

O

"normal Claisen"

β

α

α

OH

α β

shift

δ

Example 13 OH

O

OH

PhNEt2, 230 oC 5.5 h, 63% Me normal, 58%

Me

O

OH

10 equiv HSi(NMe2)2 PhNEt2, 230 oC

Me abnormal, 42%

OH

8.0 h, 70% Me normal, > 99%

Me

Me abnormal, < 1%

Example 2, Enantioselective aromatic Claisen rearrangement4 Ph

Ph

S N B N S O2 O2 Br

O OH

Et3N, −23 C, 2 d 92%, 95% ee o

OH OH

122

Example 35 CHO MeO

CHO PhNEt2

O

180 oC 40%

MeO

MeO

O

OMe

MeO

OMe

kodsurenin M

Example 46 O

O Tol., 180 oC

O O

O

= 13C

O

24 h, 65%

Example 57 O

AlM3, CH2Cl2

OH

50%

50% OH

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B. S., ed.; Wiley-Interscience: New York, 1971, pp 177−236. (Review). Kilényi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591−2594. Fukuyama, T.; Li, T.; Peng, G. Tetrahedron Lett. 1994, 35, 2145−2148. Ito, H.; Sato, A.; Taguchi, T. Tetrahedron Lett. 1997, 38, 4815−4818. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561−4564. Wipf, P.; Rodriguez, S. Ad. Synth. Catal. 2002, 344, 434−440. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002, 41B, 868−870. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−87. (Review).

123

Eschenmoser–Claisen amide acetal rearrangement [3,3]-Sigmatropic rearrangement of N,O-ketene acetals to yield γ,δ-unsaturated amides. Since Eschenmoser was inspired by Meerwein’s observations on the interchange of amide, the Eschenmoser–Claisen rearrangement is sometimes known as the Meerwein–Eschenmoser–Claisen rearrangement.

OH

MeO OMe R1

R

CONMe2

Δ

NMe2

OMe

MeO OMe :

H

H Me2N: OMe H O

NMe2 O: R1

R

OMe

NMe2

NMe2

OMe

R1

R

R

O

CONMe2

[3,3]-sigmatropic R1

R

rearrangement

OMe

R1

R

R1

NMe2 O

NMe2 H

R1

R

Example 14 CF3 O

CH3C(OMe)2NMe2

F3C

O OH

Ph

Ph

O

NMe2

PhH, 100 oC, 2 h, 75%

Example 25

OMe LiNEt2, THF N O

CH3 CH3

–78 °C to rt 5 h, 78 %

O Li

CH3

CH3

N O H H CH3 H3C

*ArHN O

CH3

(dr 97:3)

124

Example 36 H HO

H

OTBS OTBS TBS H

O

OTBS OTBS

MeO OMe NMe2

TBS H O

xylene, 150 °C 18 h, 91% OPMB

OPMB

O

NMe2

Example 48 O 5 eq. CH3C(OMe)2NMe2

NMe2

xylene, reflux, 48 h, 50% HO

CO2Me

CO2Me

References Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Ann. 1961, 641, 1−39. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425−2429. Albert Eschenmoser (Switzerland, 1925−) is known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds dual appointments at both ETH Zürich and the Scripps Research Institute in La Jolla, CA. 3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 827−873. (Review). 4. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81−87. 5. Metz, P.; Hungerhoff, B. J. Org. Chem.1997, 62, 4442–4448. 6. Kwon, O. Y.; Su, D. S.; Meng, D. F.; Deng, W.; D’Amico, D. C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1877–1880. 7. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43−50. (Review). 8. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279−281. 9. Castro, A. M. M. Chem. Rev. 2004, 104, 2939−3002. (Review). 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 60−68. (Review). 1. 2.

125

Ireland–Claisen (silyl ketene acetal) rearrangement Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield γ,δ-unsaturated carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions. O CO2H

LDA, then O Me3SiCl

O

OSiMe3 O

LDA, then O

OSiMe3

Δ, [3,3]-sigmatropic

CO2H

H

O

rearrangement

Me3SiCl

Example 12

S

S

S LDA, TBSCl

O O

O

THF, reflux 77%

O

H

O

S

S

S O HH

O

OTBS O

O CO2TBS

Example 23 O

O

TIPSOTf, Et3N PhH, rt, 62%

N Bn

N Bn

CO2TIPS

Example 3, Enantioselective ester enolate-Claisen Rearrangement6 F3C

CH3

110 mol%

O O

F 3C

Ph

Ph

S N B N S O2 O2 Br

CF3

H3C CF3

pentaisopropylguanidine, –94 to 4 °C 86%, dr > 98:2, > 98% ee

H3C CO2H

126

Example 4, A modified Ireland–Claisen rearrangement8 O

F BBr3, Et3N, PhMe chiral ligand

O

F

O

F

F

HO

F

−78 to rt, 63%, > 99% ee F

Example 59 OPMP KHMDS, TMSCl, THF O

O

−78 to 25 C, 1 h, 81% o

PMPO CO2H O

O

References Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897−5898. Also J. Am. Chem. Soc. 1976, 98, 2868−2877. Robert E. Ireland obtained his Ph.D. from William S. Johnson before becoming a professor at the University of Virginia and later at the California Institute of Technology. He is now retired. 2. Begley, M. J.; Cameron, A. G.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1986, 1933–1938. 3. Angle, S. R.; Breitenbucher, J. G. Tetrahedron Lett. 1993, 34, 3985−3988. 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17−29. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. 1996, 35, 936−945. (Review). 6. Corey, E.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229−1230. 7. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 2905−2928. (Review). 8. Churcher, I.; Williams, S.; Kerrad, S.; Harrison, T.; Castro, J. L.; Shearman, M. S.; Lewis, H. D.; Clarke, E. E.; Wrigley, J. D. J.; Beher, D.; Tang, Y. S.; Liu, W. J. Med. Chem. 2003, 46, 2275−2278. 9. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 3465−3468. 10. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 45−51. (Review). 1.

127

Johnson–Claisen orthoester rearrangement Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid gives a mixed orthoester. Mechanistically, the orthoester loses alcohol to generate the ketene acetal, which undergoes [3,3]sigmatropic rearrangement to give a γ,δ-unsaturated ester.

R1

R

R1

R

H+

R1

R

H+

CH(OR2)3

OH

CO2R2

CH(OR2)3

OH

H R2O: OR2 H O

OR2

R1

R

R1

R

:B H

O

OR2

CO2R2

[3,3]-sigmatropic O rearrangement R1

R

CH3C(OEt)3 EtCO2H (cat.)

OEt

R

R1

Example 12 CO2Et

OH CH3

xylene, Δ, 3 h 72%

O

H H3 C

Example 23 TBSO

TBSO H HO

170 °C, 30 min 77%

THPO THPO

Example 3

CH3C(OEt)3 MeCO2H (cat.)

• THPO

OPh

THPO

4

OH Cl Cl OTBS

CH3C(OCH3)3, TsOH 170 oC, 55%

CO2Et H

Cl Cl

O OMe

OTBS

OPh

128

Example 49 OMe OMe N

CH3C(OCH3)3 cat. CH3CH2CO2H

N O

reflux, 77%

OMe OH

Example 510 OTBS TBS OH O (EtO)3CCH3 O O

H

O

H

OTBS

EtO2C

O O

pivalic acid xylene, 140 °C 54%, E:Z > 95:5

TBSO E

O O

H

O

H

O O

References 1.

Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li, T.-t.; Faulkner, D. J.; Peterson, M. R. J. Am. Chem. Soc. 1970, 92, 741–743. William S. Johnson (1913−1995) was born in New Rochelle, New York. He earned his Ph.D. in only two years at Harvard under Louis Fieser. He was a professor at the University of Wisconsin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department. 2. Paquette, L.; Ham, W. H. J. Am. Chem. Soc. 1987, 109, 3025–3036. 3. Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A. R.; Li, T. T. J. Org. Chem. 1993, 58, 4280–4286. 4. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2085–2087. 5. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713– 718. 6. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem. 2003, 122, 237–242. 7. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063–3073. 8. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089–1092. 9. Zartman, A. E.; Duong, L. T.; Fernandez-Metzler, C.; Hartman, G. D.; Leu, C.-T.; Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan, M. E.; Meissner, R. S. Bioorg. Med. Chem. Lett. 2005, 15, 1647–1650. 10. Hicks, J. D.; Roush, W. R. Org. Lett. 2008, 10, 681–684. 11. Williams, D. R.; Nag, P. P. Claisen and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 68−72. (Review).

129

Clemmensen reduction Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc in hydrochloric acid. Zn(Hg)

O R1

R

H H

HCl

R1

R

The zinc-carbenoid mechanism:3 O Ph

Zn(Hg), HCl CH3

SET

ZnCl

O Ph

CH3

radical anion

Ph

Zn

Ph

CH3

H

H

Zn

OZnCl

Ph

CH3

H

CH3

zinc-carbenoid The radical anion mechanism: H O Ph

Zn(Hg), HCl CH3

ZnCl

O

SET

Ph

OZnCl

e;H Ph

CH3

H

H

Ph

CH3 Cl

radical anion H Ph

Cl

H

e

SN2 CH3

Ph

e;H CH3

H H Ph

CH3

Example 15

Zn(Hg), HCl OH O OH

O

MeOH, reflux, 1 h

OH 18%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_57, © Springer-Verlag Berlin Heidelberg 2009

OH 67%

OZnCl H

CH3

130

Example 26 O

H

H Zn(Hg), HCl

H O

N

Et2O, −5 oC, 57% Ph

H O

N Ph

Example 38 H3C H3 C

O H3 C H3C

H H

HO

O H

diosgenin

Zn dust 37% HCl, EtOH reflux, 15 min. 50%

H3C

H H

CH3

H OH

H

OH

HO

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

Clemmensen, E. Ber. 1913, 46, 1837−1843. Erik C. Clemmensen (1876−1941) was born in Odense, Denmark. He received the M.S. degree from the Royal Polytechnic Institute in Copenhagen. In 1900, Clemmensen immigrated to the United States, and worked at Parke, Davis and Company in Detroit as a research chemist for 14 years, where he discovered the reduction of carbonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corporation in Newark, New Jersey. Martin, E. L. Org. React. 1942, 1, 155−209. (Review). Vedejs, E. Org. React. 1975, 22, 401−422. (Review). Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46, 6047−6052. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron 1991, 47, 9215−9224. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996, 1113−1124. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995, 51, 12923−12928. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69, 789−794. Dey, S. P.; Dey, D. K.; Dhara, M. G.; Mallik, A. K. J. Indian Chem. Soc. 2008, 85, 717−720.

131

Combes quinoline synthesis Acid-catalyzed condensation of anilines and β-diketones to assemble quinolines. Cf. Conrad–Limpach reaction. R2 O

O

H

R1

NH2

Δ

R2

R1

N

O

O NH2

:

R

R2

O

N 1 OH2 H R

R2

O R2

H

R1

N H

R2

transfer

N 1 OH H2 R

O H

proton :

R1

O

2

O N H

R1

N

imine

R

H

O

R2

H

H

: N H

R

1

H

H

O

: N H

N H

R1

N H

R2

R2

R

1

R2 H

N H

R1

R1

N

R1

An electrocyclization mechanism is also possible: R2

H

R2

H

O

O : N H

1

enamine

H O 2 H R

H R2 O

H

R2

R1

6π-electrocyclization N H

R1

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_58, © Springer-Verlag Berlin Heidelberg 2009

132

R2

HO

proton

R2

OH2 R2

H2O

transfer

R1

N H

H

N

N

R1

R1

Example 16 NH2

N PPA, 110 °C

MeO

O

O

MeO

N H

N H

35%

Example 27 O CO2Et NH2

N H

O Ph

cat. p-TsOH, 220 °C neat, 38%

CO2Et

Ph N

N H

References 1.

2. 3. 4. 5. 6. 7. 8.

Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes (1858−1896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the Friedel−Crafts reaction fame. He became the president of the French Chemical Society in 1893 at the age of 35. His sudden death shortly after his 38th birthday was a great loss to organic chemistry. Roberts, E. and Turner, E. J. Chem Soc. 1927, 1832−1857. (Review). Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons: New York, 1952, vol. 4, 36–38. (Review). Popp, F. D. and McEwen, W. E. Chem. Rev. 1958, 58, 321–401. (Review). Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons, New York, 1977, Quinolines Vol. 32, pp 119–125. (Review). Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993, 48, 817−820. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Res. (S) 1998, 92−93. Curran, T. T. Combes Quinoline Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 390−397. (Review).

133

Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with β-ketoesters leads to quinolin-4-ones. Cf. Combes quinoline synthesis. O O

Ph2O

O

NH2

260 oC

OEt

O

CO2Et

proton

H2O

:

NH2

N H

:

transfer

N H

EtO2C

OH

H O H OEt

OEt CO2Et

HO

6π electron

tautomerize electrocyclization

N

N

N

Schiff base H

O

OH

O

− HOEt

proton N

transfer

N H

H OEt

N

Example 13 NH2

O

OEt

60%

Ph2O, reflux

N

N

HN CO2Et N

CHCl3, HCl (cat.)

O

OH

60% N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_59, © Springer-Verlag Berlin Heidelberg 2009

134

Example 27 O + N

EtO2C

PPA,

CO2Et

120 °C 25%

3

NH2

N

N CO2Et

O

3

O paraffin, 280 °C 75%

N

CO2Et

N H

3

Example 38 NH2 HO 2 MeO2C

CO2Me

HCl, MeOH

O2N

MeO2C N H

64%

O

NO2

O Dowtherm A 250 °C, 55%

O2N N H

H N

NHPhNO2 CO2Me

NO2

CO2Me

References Conrad, M.; Limpach, L. Ber. 1887, 20, 944. Max Conrad (1848−1920), born in Munich, Germany, was a professor of the University of Würzburg, where he collaborated with Leonhard Limpach (1852−1933) on the synthesis of quinoline derivatives. 2. Manske, R. F. Chem Rev. 1942, 30, 113–114. (Review). 3. Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347–365 4. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68. (Review). 5. Elderfield, R. C. In Chemistry of Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New York, 1952, vol. 4, 31–36. (Review). 6. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York, 1977, Quinolines, Vol 32, 137–151. (Review). 7. Deady, L. W.; Werden, D. M. Synth. Commun. 1987, 17, 319−328. 8. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077−5080. 9. Curran, T. T. Conrad–Limpach Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 398−406. (Review). 10. Chan, B. K.; Ciufolini, M. A. J. Org. Chem. 2008, 72, 8489−8495. 1.

135

Cope elimination reaction Thermal elimination of N-oxides to olefins and N-hydroxyl amines.

O N

H R

R 1 R2

R3

Δ

R

R3

Ei

R1

R2

OH N

Example 1, Solid-phase Cope elimination5 O O m-CPBA, CHCl3

N

rt, 67% OH

O O H

HO N

O O N

O OH OH

Example 26 OBn

OBn m-CPBA

BnO

OTBDPS

OTBDPS BnO

N(CH3)2

OBn

BnO

CH2Cl2, 0 oC 83%

BnO

N(CH3)2 O

145 oC

BnO OTBDPS

63%

BnO

Example 38

N O

rt, 100% CN

N

m-CPBA, CH2Cl2

O O NC

H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_60, © Springer-Verlag Berlin Heidelberg 2009

CN

N OH

O

136

Example 4, Retro-Cope elimination9 O

O Me

Ph N NC

OTBDPS

Me

m-CPBA, K2CO3

Ph

−78 oC, 3 h, then rt NC

H

O Me

Ph HO

N

Me

OTBDPS

MeOH, Δ, 5 d 67%, 2 steps

Ph

O

retro-Cope elimination

Me

N Me

Me

OTBDPS

N Me O H

elimination

Ph

O

5:2

N

Me

O

Me OTBDPS

Cope

O OTBDPS

References Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929−3934. Arthur Clay Cope (1909−1966) was born in Dunreith, Indiana. He was a professor at MIT when he discovered the Cope elimination reaction and the Cope rearrangement. The Arthur Cope Award is a prestigious award in organic chemistry from the American Chemical Society. 2. Cope, A. C.; Trumbull, E. R. Org. React. 1960, 11, 317−493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431−457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126−130. (Review). 5. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419−3422. 6. Vasella, A.; Remen, L. Helv. Chim. Acta. 2002, 85, 1118−1127. 7. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17−19. 8. O’Neil, I. A.; Ramos, V. E.; Ellis, G. L.; Cleator, E.; Chorlton, A. P.; Tapolczay, D. J.; Kalindjian, S. B. Tetrahedron Lett. 2004, 45, 3659−3661. 9. Henry, N.; O’Meil, I. A. Tetrahedron Lett. 2007, 48, 1691−1694. 10. Fuchter, M. J. Cope elimination reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 342−353. (Review). 11. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874−875. 1.

137

Cope rearrangement The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the category of [3,3]-sigmatropic rearrangements. Since it is a concerted process, the arrow pushing here is only illustrative. This reaction is an equilibrium process. Cf. Claisen rearrangement.

Δ, [3,3]-sigmatropic

R

R

R

rearrangement

Example 14 H

H Br

CO2CH3

160 °C

OTMS

toluene Cope

CO2CH3

Br

NaCl wet DMSO reflux Krapcho

OTMS

Br

71%

Example 26 CO2Me

100 oC, 12 h

CO2Me O

O TMS

84%

TMS

Example 39 CO2Me

CO2Me

dioxane, Et3N, 60 oC

O

O CO2Me

22 h, 1 bar, 92%

CO2Me

Example 410 H H

OH

H3CO

140 °C H OH

OH

H H3CO

H

benzene OH

OH

94% OH

Example 511

MOMO

OMOM OTBDPS O O

O

OMOM

1,2-dichlorobenzene reflux, 95%

TBDPSO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_61, © Springer-Verlag Berlin Heidelberg 2009

O

O

OMOM

138

Example 612 OCH3 H3CO

OCH3

H3CO O

1. HCl, MeOH

N

2. 1,2-dichlorobenzene reflux, 80%

OCH3

H3CO O

H3CO

N O

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441−444. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103−124. (Review). Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1−252. (Review). Wender, P. A.; Schaus, J. M. White, A. W. J. Am. Chem. Soc. 1980, 102, 6159–6161. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 785−826. (Review). Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658−4667. Davies, H. M. L. Tetrahedron 1993, 49, 5203−5223. (Review). Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815−824. (Review). Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org. Chem. 1999, 64, 3806–3812. Lo, P. C.-K.; Snapper, M. L. Org. Lett. 2001, 3, 2819–2821. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559–4563. Malachowski, W. P.; Paul, T.; Phounsavath, S. J. Org. Chem. 2007, 72, 6792–6796. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Anionic oxy-Cope rearrangement OH R

O

KH

R

THF

OH R

OK R

KH THF

OK R

Δ, [3,3]-sigmatropic rearrangement

H2O

OH R

tautomerize

KH, THF, rt then H2O, 88%

O R

Example 11 OH

OK R

O

139

Example 24

OH CH3

OHC H3 C

H3C

OH KH, THF 70%

O

H

H

Example 35 H3C

CH3 OMOM OH OPMB BnO X

KHMDS 18-crown-6, THF temperature; OTBS

H3 C

CH3 OMOM

OTBS

H O

then NH4Cl, H2O X

OPMB

H BnO

OPMB OPMB

0 °C; 71%

X = OCH2CH2TMS X = SPh

−78 °C; 85%

Example 48 O OH

NaH, THF, reflux 22 h, 88%

Example 59 MeO MeO

OMe HO MeO OMe

MeO KOt-Bu 18-crown-6 THF, −10°C 74%

MeO

O OMe MeO OMe

References 1. 2. 3. 4. 5. 6.

Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37, 3967–3975. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319– 4322. Paquette, L. A. Tetrahedron 1997, 53, 13971−14020. (Review). Corey, E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741–744. Paquette, L. A.; Reddy, Y. R.; Haeffner, F.; Houk, K. N. J. Am. Chem. Soc. 2000, 122, 740–741. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519–2527.

140

Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633–3636. 8. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631–3634. 9. Jones, S. B.; He, L.; Castle, S. L. Org. Lett. 2006, 8, 3757–3760. 10. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review). 7.

Oxy-Cope rearrangement While the anionic oxy-Cope rearrangements work at low temperature, the oxyCope rearrangements require high temperature but provide a thermodynamic sink. OH Δ, [3,3]-sigmatropic R rearrangement

OH R

O

OH tautomerize R

R

Example 12 OPMB H Me Me

H

TMS

H

O

Me O

1. 230−240 °C DMF, 19 h

OPMB H O Me

2. CsF, DMF 210 °C, 65%

Me

Me

HO

H H

OMe

Me

Example 23 EtO2C CO2Et

ene

o-dichlorobenzene 90%

OH

EtO2C H

reflux

O

OH

H

Example 34 PhMe2SiO

O

t-Bu

1. 170 oC

PhMe2Si O

O

PhMe2SiO OHC

2. p-TsOH•H2O 65−75%

O

Example 46 OH

xylene, Ace® tube 225 oC, 24 h, 49%

O

O

t-Bu

O

141

References 1. 2. 3. 4. 5. 6. 7.

Paquette, L. A. Angew. Chem., Int. Ed. 1990, 29, 609−626. (Review). Paquette, L. A.; Backhaus, D.; Braun, R. J. Am. Chem. Soc. 1996, 118, 11990–11991. Srinivasan, R.; Rajagopalan, K. Tetrahedron Lett. 1998, 39, 4133–4136. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850−2858. Schneider, C. Synlett 2001, 1079−1091. (Review on siloxy-Cope rearrangement). DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley, M. Org. Biomol. Chem. 2003, 1, 4423−4434. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

Siloxy-Cope rearrangement OSiR3 R'

OSiR3

Δ, [3,3]-sigmatropic

R'

rearrangement

Example 11 CH3 OTMS H

sealed tube high vacuum

OTBS OTMS

H

310 °C, 1 h > 79%

H3C

H OTBS OTMS

OTMS

Example 22 TDSO

O

TDSO

Bn

O

Bn

180 °C N O

O

toluene, 3 h 63%

N > 97:3 dr

O

O

TDS = thexyldimethylsilyl Example 33 AOM

O OTBDPS

Et3SiO O

OSiEt3

chlorobenzene reflux, 3 h, 99%

TBDPSO

O

AOM = p-Anisyloxymethyl = p-MeOC6H4OCH2-

O OAOM

142

Example 44 OTBDPS

TESO

TESO

H3C

H3C

4

115 °C

4

O O H3C

TBDPSO

OH

O

O toluene, reflux 95%

O

O H3C

OH

References 1. 2. 3. 4. 5.

Askin, D.; Angst, C.; Danishefsky, D. J. J. Org. Chem. 1987, 52, 622–635. Schneider, C. Eur. J. Org. Chem. 1998, 1661–1663. Clive, D. L. J.; Sun, S.; Gagliardini, V.; Sano, M. K. Tetrahedron Lett. 2000, 41, 6259–6263. Bio, M. M.; Leighton, J. L. J. Org. Chem. 2003, 68, 1693–1700. Mullins, R. J.; McCracken, K. W. Cope and Related Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 88−135. (Review).

143

Corey–Bakshi–Shibata (CBS) reagent H Ph Ph O N B Me

The CBS (Corey–Bakshi–Shibata) reagent is a chiral catalyst derived from proline. Also known as Corey’s oxazaborolidine, it is used in enantioselective borane reduction of ketones, asymmetric Diels–Alder reactions and [3 + 2] cycloadditions. Preparation1,3 O

H

H MeOH

OH NH

O O

NH

H3O

1. PhMgCl 2. BH3•THF 50% 3 steps

O

O H Ph Ph NH

OH

MeB(OH)2, toluene reflux, 3 h, 86%

H Ph Ph O N B Me

The mechanism and catalytic cycle:1,3 H Ph Ph O

cat.

O N B Me

OH

BH3, THF, rt, 97% ee

H Ph Ph

H Ph Ph

H2BO

H

BH3•THF

O N B R

O N B H3 B R

CH3

:

H Ph Ph

BH3 H CH3

CH3

O N B R CH3 O H B H Ph H H

H2B

HCl, MeOH

HO

O:

Ph R O CH3 N B Ph B O H2 H Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_62, © Springer-Verlag Berlin Heidelberg 2009

Ph R O N B Ph H B O 2 H

CH3 Ph

144

Example 16 0.1 eq. (S)-CBS 1.0 eq. i-Pr(Et)NPh•BH3

O SO2C6H4CH3-p

OH SO2C6H4CH3-p

THF, rt, syringe pump 1.5 h, 98%, 97% ee

O

O

H Ph Ph

(S)-Me-CBS =

O N B CH3

Example 29 BH3•SMe2 cat. (R)-Me-CBS

O

O

O

O

HO

O

CH2Cl2, 30 oC 84%, > 99% ee

O

O

Example 311 H Ph Ph N H CO2CH2CF3

O B o-Tol

O

Tf2N

Ac

OCH2CF3

H2PO4

10 mol%, neat 23 oC, 30 h, 97%

> 97% ee

H N

H3 N

O

CO2Et

oseltamivir (Tamiflu®)

Example 4, Asymmetric [3 + 2]-cycloaddition10 OH

H Ph Ph N

O

H

MeO O O

O B o-Tol

MeO Tf2N

CH3CN−CH2Cl2 65%

H O H O 92% ee 99% ee recryst.

References 1.

2.

(a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551–5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925–7926. (c) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861–2863. Reviews: (a) Corey, E. J. Pure Appl. Chem. 1990, 62, 1209–1216. (b) Wallbaum, S.; Martens, J. Tetrahedron: Asymm. 1992, 3, 1475–1504. (c) Singh, V. K. Synthesis

145

1992, 605–617. (d) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784. (e) Taraba, M.; Palecek, J. Chem. Listy 1997, 91, 9–22. (f) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986–2012. g) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650–1667. (h) Itsuno, S. Org. React. 1998, 52, 395–576. (i) Cho, B. T. Aldrichimica Acta 2002, 35, 3–16. (j) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev. 2004, 73, 581–608. (k) Cho, B .T. Tetrahedron 2006, 62, 7621–7643. 3. (a) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsteen, K.; Carroll, J. D.; Corley, E. G.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880–2888. (b) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley, E. G.; Desmond, R. Org. Synth. 1997, 74, 50–71. 4. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. 5. Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550–4551. 6. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043–2047. 7. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086– 8089. 8. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495–1499. 9. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652–4658. 10. Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959. 11. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310–6311. 12. Patti, A.; Pedotti, S. Tetrahedron: Asymmetry 2008, 19, 1891–1897.

146

Corey−Chaykovsky reaction The Corey−Chaykovsky reaction entails the reaction of a sulfur ylide, either dimethylsulfoxonium methylide 1 (Corey’s ylide) or dimethylsulfonium methylide 2, with electrophile 3 such as carbonyl, olefin, imine, or thiocarbonyl, to offer 4 as the corresponding epoxide, cyclopropane, aziridine, or thiirane. CH2 S O H3C CH3

CH2 S H3C CH3

1

2

X

X 1 or 2

R1

R

R1

R 4

3 2

X = O, CH2, NR , S, CHCOR3, CHCO2R3, CHCONR2, CHCN

Preparation1 H3C

O S CH3 I CH3

NaH H3C

DMSO

CH2 S O CH3

1

Mechanism

O O S

R1

R O S H3C CH2 CH3

H3C H3C

R

R

R1 O

O

R1

H3C

O S

CH3

Example 111 O

O +−

Me3S(O) I NaH, DMSO

N

N

O

O

60 oC, 3.5 h 79%

F Cl

F Cl

Example 29 OAc OAc Me2S O

CO2Et

O OEt

PhH, rt, 8 h, 62%

OEt

CO2Et 10

Example 3

O

O

Me3SCl 50% aq. NaOH Bu4NHSO4

N

N H

H

CH2Cl2, 84% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_63, © Springer-Verlag Berlin Heidelberg 2009

O

147

Example 414 H

2.5 equiv t-Bu3Ga

Me2S Br

CHO

SiEt3

O

PhCl, rt, 3 h, 66% Z:E = 94:6

SiEt3

Example 515

O Ph OH

4 equiv (CH3)3SOI n-BuLi, THF 60 oC, 4 h

Ph

Ph

O S O

O

O 50%

Ph O OH 20%

References 1

2 3 4 5 6 7 8 9 10 11 12 13 14 15

(a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867−868. (b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 3782. (c) Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 169−171. (d) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1639−1640. (e) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353−1364. Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2139−2141. (Review). Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 2159−2165. (Review). Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides; Academic Press: New York, 1975. (Review). Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review). Gololobov, Y. G.; Nesmeyanov, A. N. Tetrahedron 1987, 43, 2609−2651. (Review). Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Pergamon: Oxford, 1991, Vol. 1, pp 820−825. (Review). Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341−2372. (Review). Rosenberger, M.; Jackson, W.; Saucy, G. Helv. Chim. Acta 1980, 63, 1665−1674. Tewari, R. S.; Awatsthi, A. K.; Awasthi, A. Synthesis 1983, 330−331. Vacher, B.; Bonnaud, B. Funes, P.; Jubault, N.; Koek, W.; Assie, M.-B.; Cosi, C.; Kleven, M. J. Med. Chem. 1999, 42, 1648−1660. Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003, 44, 3629−3630. Li, J. J. Corey−Chaykovsky Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 1−14. (Review). Nishimura, Y.; Shiraishi, T.; Yamaguchi, M. Tetrahedron Lett. 2008, 49, 3492−3495. Chittimalla, S. K.; Chang, T.-C.; Liu, T.-C.; Hsieh, H.-P.; Liao, C.-C. Tetrahedron 2008, 64, 2586−2595.

148

Corey−Fuchs reaction One-carbon homologation of an aldehyde to dibromoolefin, which is then treated with n-BuLi to produce a terminal alkyne.

R CHO

Br3C

CBr4, PPh3

R

Br

Zn

H

Br

Br

n-BuLi

SN2

:PPh3

R

CBr3

H

Br PPh3

Br Br PPh3

SN2

Br

SN2 Br

CBr3

PPh3 Br

O Br

R

Br2

H

R

Br

H

Br

O PPh3

PPh3 Br

Wittig reaction (see page 578 for the mechanism) Br2

R

Br

H

Br

R

ZnBr2

Zn

acidic

Br

R

R

H

workup

Bu Bu

Example 13 Br

OMe O O OHC OTBS

OMe O

CBr4, Ph3P, CH2Cl2

O Br

rt, 35 min., 90%

OTBS

OMe O 3.0 eq. n-BuLi/hexanes, THF

O

−78 oC, 1 h; rt, 1 h, 99%

OTBS OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_64, © Springer-Verlag Berlin Heidelberg 2009

149

Example 27 Br

O Fe

H

Br

PPh3, quant.

H

n-BuLi

CBr4, Zn Fe

H 75%

Fe

Example 38

CHO OTBS

1. CBr4, Ph3P, Zn, CH2Cl2 2. n-BuLi, then NH4Cl, 90%

OTBS

Example 410

CHO CHO

4 equiv CBr4 8 equiv PPh3 8 equiv Zn

Br

Br H H

CH2Cl2, 0 oC to rt 3 h, 94% Br

Br

H n-BuLi, n-hexane −78 oC to rt, 1 h, 96% H

References Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769−3772. Phil Fuchs is a professor at Purdue University. 2 For the synthesis of 1-bromalkynes see Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529−3530. 3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607−1630. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563−6566. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M. Tetrahedron: Asymmetry 1999, 10, 3417−3430. 6 Okamura, W. H.; Zhu, G.-D.; Hill, D. K.; Thomas, R. J.; Ringe, K.; Borchardt, D. B.; Norman, A. W.; Mueller, L. J. J. Org. Chem. 2002, 67, 1637−1650. 7 Tsuboya, N.; Hamasaki, R.; Ito, M.; Mitsuishi, M.; Miyashita, T. Yamamoto, Y. J. Mater. Chem. 2003, 13, 511–513 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245−3248. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527−4531. 10 Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2007, 2477– 2489. 11 Han, X. Corey−Fuchs reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 393−403. (Review). 1

150

Corey–Kim oxidation Oxidation of alcohol to the corresponding aldehyde or ketone using NCS/DMS, followed by treatment with a base. Cf. Swern oxidation. OH R1

NCS, DMS

R2

O 1

then NEt3

R

R2

NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide. O

O

O

N Cl O

NH

H

N S

S Cl

N

:S

O

Cl

:O O

O

R1

R2

O

Cl S O R1

H :NEt3

S

Et3N·HCl

O

O

H R2

R1

R2

(CH3)2S↑ H

Example 1, Fluorous Corey−Kim reaction5 NO2

S

C6F13 OH

NO2 CHO

NCS, toluene, −25 oC, 2 h then Et3N, 86%

Example 2, Odorless Corey−Kim reaction7 S

N O OH D

0.5 eq. NCS, CH2Cl2, −40 oC, 2 h then Et3N, −40 oC to rt, 8 h

S

N O 45%

O

86%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_65, © Springer-Verlag Berlin Heidelberg 2009

D

R

1

R2

151

Example 39 OH H

H

CHO H H

NCS, Me2S Et3N, CH2Cl2 −78 oC to rt, 90%

N H H H

N H H H

Example 410 N

N

O H N

O NCS, DMS

O

O O O O

H N

N BzO O

OH

O

Et3N, CH2Cl2 > 300 Kg scale

O

O O O O

N BzO O

O

O

References Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586−7587. Choung U. Kim now works at Gilead Sciences Inc., a company specialized in antiviral drugs in Foster City, California, where he co-discovered oseltamivir (Tamiflu). 2 Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178−183. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099−2102. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604−8609. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865−3870. 6 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron 2003, 59, 8393−8398. 7 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142−146. 8 Iula, D. M. Corey−Kim Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J. (eds), John Wiley & Sons: Hoboken, NJ, 2007, pp 207−217. (Review). 9 Yin, W.; Ma, J.; Rivas, F. M.; Cook, M. Org. Lett. 2007, 9, 295−298. 10 Cink, R. D.; Chambournier, G.; Surjono, H.; Xiao, Z.; Richter, S.; Naris, M.; Bhatia, A. V. Org. Pro. Res. Dev. 2007, 11, 270−274. 1

152

Corey–Nicolaou macrolactonization Macrolactonization of ω-hydroxyl-acid using 2,2ƍ-dipyridyl disulfide. known as the Corey–Nicolaou double activation method. O

Also

N S

OH

S

O

N

n

OH

O

n

Ph3P

N H

N S

S

S

N N H

Ph3P:

PPh3 O

S

O

H

n

OH N H

N

S

O

S

PPh3

O

PPh3 N H

O PPh3

O n

O

S O

OH

n

OH O N H

S n

O

O

O

N H

n

S

2-pyridinethione Example 13 Ph Ph Ph

Ph

O

O O

H

HO2C

OH (2-pyr-S)2, PPh3 CHCl3, Δ, 75%

O

O H

N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_66, © Springer-Verlag Berlin Heidelberg 2009

O

H O n

153

Example 26 O OH

OMOM

O

O

O

(2-pyr-S)2, PPh3 OH

HO

AgClO4, Δ, 33%

O

O O

Example 39 C5H11 O O

O O

O

BnO HO

(PyS)2, PPh3

O

toluene, reflux 7 d, 69%

OH HO2C

C5H11

C5H11 O

O O

O O

BnO O O

O

O

O

O

HO

OH 58%

O

O

BnO

O

O O

11%

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614–5616. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117– 1121. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475–2478. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169–1172. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780–8785. Lu, S.-F.; O’yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62, 8400–8405. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299–5303. Zhu, X.-M.; He, L.-L.; Yang, G.-L.; Lei, M.; Chen, S.-S.; Yang, J.-S. Synlett 2006, 3510–3512.

154

Corey–Seebach reaction Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an example of umpolung. SH

CH2(OMe)2

S

1. BuLi

SH

Et2O•BF3

S

2. Cl-(CH2)4-I 80%

S

HgCl2, 50 oC

S

50%

Cl

S

S

S

H H

S

Cl

I

Cl

Bu

OHC

S Cl

S

2

Example 1

CHO

n-BuLi, THF

S S

0 oC, 30 min., 99%

Ph

S HO

S

PhI(O2CCCl3)2

HO

O

Ph

CH3CN, H2O, rt, 5 min., 95%

Ph

Ph

Ph

Example 24 O

Ph

CHO

OH

S S

O

n-BuLi, THF, −78 to 0 oC

S

Ph

Example 3, Ethyl is infinitely different from methyl6 S O

Me

OMe S

O

OMe

S

Li

Et

S S

S OH

Me

O S

S

CO2H

n-BuLi, THF rt, overnight 80−90%

S Me

HO2C

Et

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_67, © Springer-Verlag Berlin Heidelberg 2009

S

Et S

S

S

155

S

S

O

Et O

Et

S

S

S

HO2C

S

HO2C

O

O

Et S

S

S S

S

Et

HO2C

Et

SET

S

Et

HO2C

Et

S

S

Example 48 HO S

OBn OBn S O

n-BuLi, THF

S OBn NHTfa

−10 oC, 78%

S

HO BnO

NHTfa OBn

OBn

54%

BnO

S

BnO BnO

S NHTfa 23%

Tfa = Trifluoroacetyl HO

HO BnO

S

BnO BnO

S NHTfa

BnO Ra-Ni, EtOH reflux, 71%

BnO BnO

NHTfa

References 1.

2. 3. 4. 5. 6. 7. 8.

(a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075–1077. Dieter Seebach is a professor at ETH in Zürich, Switzerland. (b) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097–4099. (c) Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300–305. (d) Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. (e) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307–310. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518–526. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454–3460. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193–1199. Valiulin, R. A.; Kottani, R.; Kutateladze, A. G. J. Org. Chem. 2006, 71, 5047–5049. Chen, Y.-L.; Leguijt, R.; Redlich, H. J. Carbohydrate Chem. 2007, 26, 279–303. Chen, Y.-L.; Redlich, H.; Bergander, K.; Froehlich, R. Org. Biomol. Chem. 2007, 5, 3330–3339.

156

Corey–Winter olefin synthesis Transformation of diols to the corresponding olefins by sequential treatment with 1,1ƍ-thiocarbonyldiimidazole (TCDI) and trimethylphosphite. Also known as Corey–Winter reductive elimination, or Corey–Winter reductive olefination.

R

S

OH

R N

R

1

OH

N

P(OMe)3

S R1

N

N

O O

R

H

R1

H

TCDI = Thiocarbonyldiimidazole S N

R

: R1

OH

R

OH

R

O

O

R1

OH

R

O

S

R

O

Imd

R1

O

S H Imd

OH

:P(OMe)3

P(OMe)3 S

O

1

R

O

1

S R

N S H

N

N

N R

N

N

N

O

R1

1,3-dioxolane-2-thione (cyclic thiocarbonate) R R1

:P(OMe)3 O

S P(OMe)3

O

R

O

R1

O

P(OMe)3

S P(OMe)3

R

H

O

R1

H

O

P(OMe)3

O C O↑

P(OMe)3

A mechanism involving a carbene intermediate can also be drawn and is supported by pyrolysis studies: R

O

:P(OMe)3

S R1

R

O

R

1

O

O

R1

O

S P(OMe)3

O

S P(OMe)3

R

:P(OMe)3

R

O P(OMe)3

R

1

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_68, © Springer-Verlag Berlin Heidelberg 2009

157

R

H

R1

H

O :P(OMe)3

P(OMe)3

O C O↑

O

Example 12 S OH O O

O

O O

Cl

Cl

O O

O O O

O

CH2Cl2, DMAP 0 oC, 1 h, 93%

OH

Ph H3C N P N CH3

O

S

O

40 °C, 88%

O

Example 24 O

O HO HO

N

N

OMe Imd2CS, toluene reflux, 79%

OMOM CF3

O S

OMe

OMOM CF3

O

O P(OMe)3

N

92%

OMe

F3C OMOM

Single olefin isomer Example 38 OMe TBSO

H OAc

HO

OMe

CH2Cl2, rt, 96%

HO

TBSO

CSCl2, DMAP

H OAc

O S O

H

H

OMe TBSO

H OAc

P(OEt)3, reflux 76%

H

158

Example 49 CH3

H3CO

O O CH3

O S O

H3 C

P(OMe)3

O

N O

CH3

120 °C, 66%

OCH3 CH3 O

N

O

CH3 O

O

Example 510 S

OAc OH AcO

Cl

OAc OAr(F)5

Ph P CH3 N N

OAc

O

pyridine, DMAP 23 °C, 5 h, 78%

OH

H3C

O

AcO

S

THF, 40 °C 4 h, 65%

AcO

Example 611 OH CbzHN Ph

S

Ph

Ph O

TCDI, THF CbzHN

NHCbz

NHCbz

70 oC

OH

O Ph

Ph P(OEt)3, 160

oC

77%, 2 steps

CbzHN

NHCbz

Ph

References Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677−2678. Roland A. E. Winter works at Ciba Specialty Chemicals Corporation, USA. 2. Corey, E. J.; Carey, F. A.; Winter, R. A. E. J. Am. Chem. Soc. 1965, 87, 934−935. 3. Block, E. Org. React. 1984, 30, 457−566. (Review). 4. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998, 54, 5485−5506. 5. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359−377. 6. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66, 4180−4186. 7. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593−9603. 8. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401−2403. 9. Brüggermann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284−15285. 10. Freiría, M.; Whitehead, A. J.; Motherwell, W. B. Synthesis 2005, 3079−3084. 11. Mergott, D. J. Corey−Winter olefin synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 354−362. (Review). 12. Xu, L.; Desai, M. C.; Liu, H. Tetrahedron Lett. 2009, 50, 552−554. 1.

159

Criegee glycol cleavage Vicinal diol is oxidized to the two corresponding carbonyl compounds using Pb(OAc)4, (lead tetraacetate, LTA). HO OH R1 R3 R2 R4

O

Pb(OAc)4 R1

O R2

R

AcO Pb(OAc)3 HO OH R1 R3 R2 R4

HOAc

Pb(OAc)2

R4

2 HOAc

OAc (AcO)2Pb O OH R1 R3 R2 R4

HOAc

OAc AcO Pb O O R1 R3 2 R R4

3

O

O R1

R2

R3

Pb(OAc)2

R4

An acyclic mechanism is possible as well. It is much slower than the cyclic mechanism, but is operative when the cyclic intermediate can not form:3 H

H

Pb(OAc)3 O

O:

O

O

O Pb(OAc)2

HOAc

O OH

H

O

AcO

O PbII(OAc)2

HOAc

O

Example 17 CO2Et OH Ph

N O

OH

CO2Et

Pb(OAc)4, K2CO3 PhH, 0 oC, 80%

N H

O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_69, © Springer-Verlag Berlin Heidelberg 2009

160

Example 29

H HO PhO2S

Pb(OAc)4, CH2Cl2, K2CO3 −15 oC to rt, 1 h, then

OH

H

Ph3P=CHCO2Me, CH3CN, 80%

H

H

PhO2S

CO2Me

E:Z = 10:1

Example 310

HO

O O

HO

Ar Ar

Pb(OAc)4, PhH rt, 1.5 h, quant.

OHC

H

O

H

Ar

Example 411 OMe

OH

OH Me

HO Me

Me

Me

Me Me OH

OMe

Pb(OAc)4, EtOAc 0 oC, 5 min., 99%

OH

O

HO

H Me

Me

Me

Me

References Criegee, R. Ber. 1931, 64, 260–266. Rudolf Criegee (1902−1975) was born in Düsseldorf, Germany. He earned his Ph.D. at age 23 under K. Dimroth at Würzburg. Criegee became a professor at Technical Institute at Karlsruhe in 1937, a chair in 1947. He was known for his modesty, mater-of-factness, and his breadth of interests. 2 Mihailovici, M. L.; Cekovik, Z. Synthesis 1970, 209–224. (Review). 3 March, J. Advanced Organic Chemistry, 5th ed., Wiley & Sons: Hoboken, NJ, 2003. (Review). 4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181–1190. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941–944. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993–2012. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M. R. Synthesis 2003, 1844–1850. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042– 6043. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783–799. 10 Prasad, K. R.; Anbarasan, P. Tetrahedron 2006, 63, 1089–1092. 11 Perez, L. J.; Micalizio, G. C. Synthesis 2008, 627–648. 1

161

Criegee mechanism of ozonolysis O O

O3

O

O

O

1,3-dipolar

:

O

O

O

O

cycloaddition

primary ozonide (1,2,3-trioxolane) O

O O

1,3-dipolar

O O

cycloaddition

O

zwitterionic peroxide secondary ozonide (1,2,4-trioxolane) (Criegee zwitterion) also known as “carbonyl oxide” Example 17 H

O3, EtOAc, −78 oC, then

HO

Ac2O, Et3N, DMAP, −78 oC to rt, 75%

HO

O OAc

O O H

Example 28 O O

O3, CH2Cl2 O OMe

H

−70 oC

MeOH

CO2Me

quant.

CO2Me

O

References 1. 2. 3. 4. 5. 6. 7. 8.

(a) Criegee, R.; Wenner, G. Ann. 1949, 564, 9−15. (b) Criegee, R. Rec. Chem. Prog. 1957, 18, 111−120. (c) Criegee, R. Angew. Chem. 1975, 87, 765−771. Bunnelle, W. H. Chem. Rev. 1991, 91, 335−362. (Review). Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79−83. (Review). Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675−3680. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757−2762. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377−3379. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150−1153. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025−2049.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_70, © Springer-Verlag Berlin Heidelberg 2009

162

Curtius rearrangement Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-tonitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, often in situ, provides carbamates, ureas, and other N-acyl derivatives. Alternatively, hydrolysis of the isocyanates leads to primary amines. O O R

O

Heat N3

Nu–H

R N H

C

Curtius R N Rearrangement

H2 O –CO2

Nu

R NH2

The thermal rearrangement: O R

R

Cl

O R

O

NaN3

Δ

N2↑

N3

O N3 Cl

R

O

Cl

R

N3

Δ

N3

O

R

R

O

R NH2

H

O

:OH2

R

N N N

H N

:B

isocyanate intermediate The photochemical rearrangement: O R

hν N N N

O

N2↑

R

N:

Nitrene O R

N:

R N C O

CO2↑

R NH3

O

H R N C O

N2↑

H2O

R N C O

R NH2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_71, © Springer-Verlag Berlin Heidelberg 2009

CO2↑

N N N

CO2↑

163

Example 1, The Shioiri–Ninomiya–Yamada modification2 O

H

HO

21

NO2

DPPA, Et3N PhH, Δ then MeOH, Δ O 89%

O

NO2

H 21

NH

O

OMe

DPPA = diphenylphosphoryl azide Example 23 O

O

O

CO2Me

HO2C

DPPA, Et3N, t-BuOH 80 oC, 16 h, 64%

O

CO2Me

BocHN O

O

Example 34 CO2H O O

EtO(CO)Cl, then NaN3 EtOH, PhH, reflux, 55%

NHCO2Et O O

Example 4, The Weinstock variant of the Curtius rearrangement6 O N

O

COOH H

Cl OEt i-PrNEt2, acetone, 0 °C

NH N H Me

OEt

HN N

then NaN3, rt, 12 h 75%

H NH N H Me

Example 57 O Ph

Ph

Cl 1. n-Bu3SnN3 PhBr, 0 °C to RT 30 min., 97% 2. t-BuOH/o-xylene Δ, 6 h, 77%

NHBoc

164

Example 6, The Lebel modification8 OMPM O

CO2H

HO

O

BnO BnO

OBn OBn

OMe OBn

OBn (2 equiv)

2 equiv DPPA 0.1 equiv Ag2CO3 2 equivK2CO3

OMPM O

PhH, Δ, 16 h, 81% BnO

H N

O

O BnO OBn OBn

O

OMe OBn

OBn

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

Curtius, T. Ber. 1890, 23, 3033−3041. Theodor Curtius (1857−1928) was born in Duisburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music. Ng, F. W.; Lin, H.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9812–9824. van Well, R. M.; Overkleeft, H. S.; van Boom, J. H.; Coop, A.; Wang, J. B.; Wang, H.; van der Marel, G. A.; Overhand, M. Eur. J. Org. Chem. 2003, 1704–1710. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455–7457. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42, 259–264. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995–3998. Tada, T.; Ishida, Y.; Saigo, K. Synlett 2007, 235–238. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J. Org. Chem. 2007, 1064– 1068. Rojas, C. M. Curtius Rearrangements. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 136−163. (Review).

165

Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen peroxide conditions. Cf. A variant of Baeyer–Villiger oxidation. H2O2, NaOH HO

CHO

HO

45−50 oC

O

O

O HO

H O

O

aryl

H

HO

HO H

HCO2

OH

migration

OH HO

hydrolysis

O

HO

O

H H

O

H HO

O OH

workup HO

O

OH

Example 16 OBn

OBn

OBn O

CHO 2.5 eq. 30% H2O2 CO2H

4% (PhSe)2 CH2Cl2, 18 h

CHO

CO2H

OH NH3, MeOH 1 h, 78% CO2H

NHCO2t-Bu

NHCO2t-Bu

NHCO2t-Bu

Example 27 CHO

urea-hydrogen peroxide (UHP) solvent-free, 55 oC, 3 h, 83%

HO

OH HO

Example 3, Improved solvent-free Dakin oxidation protocol9 MeO BnO

CHO

1.5 equiv m-CPBA, neat, 5 min.

MeO

then10% aq. NaOH 85%

BnO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_72, © Springer-Verlag Berlin Heidelberg 2009

OH

166

Example 410 O

OMe H2O2, HCl MeO CHO

N H

MeOH, THF 50%

MeO O

N H

References: Dakin, H. D. Am. Chem. J. 1909, 42, 477−498. Henry D. Dakin (1880−1952) was born in London, England. During WWI, he invented his hypochlorite solution (Dakin’s solution), which became a popular antiseptic for the treatment of wounds. After the Great War, he emmigrated to New York, where he investigated the B vitamins. 2. Hocking, M. B.; Bhandari, K.; Shell, B.; Smyth, T. A. J. Org. Chem. 1982, 47, 4208−4215. 3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740−4741. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett. 1993, 34, 7401−7404. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado, L. A. Synth. Commun. 1995, 25, 2121−2133. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553−1555. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189−191. 8. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg. Med. Chem. Lett. 2001, 11, 51−54. 9. Teixeira da Silva, E.; Camara, C. A.; Antunes, O. A. C.; Barreiro, E. J.; Fraga, C. A. M. Synth. Commun. 2008, 38, 784−788. 10. Alamgir, M.; Mitchell, P. S. R.; Bowyer, P. K.; Kumar, N.; Black, D. St. C. Tetrahedron 2008, 64, 7136−7142. 1.

167

Dakin−West reaction The direct conversion of an α-amino acid into the corresponding α-acetylaminoalkyl methyl ketone, via oxazoline (azalactone) intermediates. The reaction proceeds in the presence of acetic anhydride and a base, such as pyridine, with the evolution of CO2. O R

CO2H

Ac2O

R

NH2

R

O

CO2H

R

NH2

H O

OH

:

HN

O O

CO2↑ NHAc

R O H O O

H

O

OH O

N

AcO

H

AcO H O R

OH

H OH

R

O

N

O

O

O O OH

N

O

N

O

R

H

oxazolone (azalactone) intermediate H O

O

R HN

O H

O

− CO2

O

O

R

tautomerization N

R

OH

NHAc

Example 16 Me

Ac2O, AcOH, Et3N

CO2H NH2

O

Me

DMAP, 50 oC, 14 h, > 90%

Me NHAc

Example 27 HO O N H

O

Ac2O, pyr.

O OBn

O

90 oC, 2 h, 58%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_73, © Springer-Verlag Berlin Heidelberg 2009

O N H

Me O OBn

168

Example 3, Green Dakin–West reaction using the heteropoly acid catalyst, acetonitrile is a reactant9 O CHO

CH3CN, H3PW12O40

Ph

CH3COCl rt, 60 min., 75%

NHAc O

CN

Ph NC

Example 4, Acetonitrile is a reactant10 O CHO R1

R2

CH3CN 10 mol% Ln(OTf)3 CH3COCl, reflux 78−87%

R1

R2

NHAc O

References: Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Dakin and Rudolf West, a clinician, reported on the reaction of α-amino acids with acetic anhydride to give α-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and α-phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an opportunity to be immortalized by a name reaction. 2. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91–109. (Review). 3. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555. 4. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Commun. 1998, 641–642. 5. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4, 283−293. (Review). 6. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581–588. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623–2632. 8. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105– 2108. 9. Rafiee, E.; Tork, F.; Joshaghani, M. Bioorg. Med. Chem. Lett. 2006, 16, 1221–1226. 10. Tiwari, A. K.; Kumbhare, R. M.; Agawane, S. B.; Ali, A. Z.; Kumar, K. V. Bioorg. Med. Chem. Lett. 2008, 18, 4130–4132. 1.

169

Darzens condensation α,β-Epoxy esters (glycidic esters) from base-catalyzed condensation of α-haloesters with carbonyl compounds.

X R

O CO2Et

R

1

O

OEt R

R1 R2

2

R CO2Et

O X

OEt H

R

R

X

OEt

1

OEt

R

O

R1 R2

R2

O

X

intramolecular

R CO2Et

SN2

O R1 R2

R CO2Et

O

Example 14 O

O Cl

t-BuOK, t-BuOH

CO2Et

CO2Et

10 °C, 85–95%

Example 26

H3C

O

LDA, THF, –78 °C then

O Br

H3C t-BuMe2Si

PhCHO, –90 °C

t-BuMe2Si

O

H Ph

H

66%, 90% de

Example 39 O N

Ar

N Co

O

O X

NPh2 X = Cl, Br, I

O

Ar

H

MeO

CONPh2 ee up to 50%

O

2 mol%

O OMe

Solid MOH, M = Na, K, Rb CH2Cl2, 4−24 h, rt

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_74, © Springer-Verlag Berlin Heidelberg 2009

Ar

CONPh2 ee up to 43%

170

Example 4, the phenyl ring substituting for the carbonyl to acidify the protons10 O MeO Br Br

PO(OMe)2 O

PO(OMe)2

DBU, CH3CN 6 h, 48%

OMe Br

References 1

2 3 4 5

6 7 8

9 10

Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214–1217. George Auguste Darzens (1867−1954), born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor. Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review). Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. IV, 1963, 459. Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, pp 409–439. (Review). Enders, D.; Hett, R. Synlett 1998, 961−962. Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410−2419. Myers, B. J. Darzens Glycidic Ester Condensation. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 15−21. (Review). Achard, T. J. R.; Belokon, Y. N.; Ilyin, M.; Moskalenko, M.; North, M.; Pizzato, F. Tetrahedron Lett. 2007, 48, 2965−2969. Demir, A. S.; Emrullahoglu, M.; Pirkin, E.; Akca, N. J. Org. Chem. 2008, 73, 8992−8997.

171

Delépine amine synthesis The reaction between alkyl halides and hexamethylenetetramine, followed by cleavage of the resulting salt with ethanolic HCl to yield primary amines. Cf. Gabriel synthesis, where the product is also an amine and Sommelet reaction, where the product is an aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and α-halo-ketones. N Ar

X

N N

N N

X

N N

Ar

Ar

3 HCl

+ 6 H2O

N

NH3 X

hexamethylenetetramine [ArCH2C6H12N4]+X−

+

ArCH2NH2•HX

+

6 CH2O

+

3 NH4Cl

H2O:

N :

N N

N

N:

SN2

Ar

X

H N N N

N

N N

N

Ar

N

N N

X

O H Ar

H N

O CH2

N N

N

N

Ar

Ar

Ar

NH3 X

Example 13 1. (CH2)6N4, NaHCO3 15 h, EtOH, H2O

O Br

OH 2. HCl, EtOH, reflux, 15 h, 85%

O H2N

Example 27 hexamethylenetetramine Br

N

N Br

CH2Cl2, refux, 5 h, then −30 oC

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_75, © Springer-Verlag Berlin Heidelberg 2009

OH

172

Br

conc. HCl, EtOH

N

N

N4C6H12+Br−

reflux, 1 d 78%, 2 steps

Br

N

N

NH2

Example 38 NH2

Br O

O

O

O O

O

O

1. hexamethylenetetramine CHCl3, reflux, 6 h 2. 2 N HCl, EtOH, 100 oC, 15 min.

O

O

O

O O

O

O

OO

OO

O

O O

O

Example 49 N N N

Br O CHCl3, rt, 18 h

48% HBr CH3OH, rt, 5 d

O

hexamethylenetetramine NO2

N

Br

NO2

89% 2 steps

NH3 Br O NO2

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 352−355; (b) Delépine, M. Bull. Soc. Chim. Paris 1897, 17, 292−295. Stephe Marcel Delépine (1871−1965) was born in St. Martin le Gaillard, France. He was a professor at the Collège de France after working for M. Bertholet at that institute. Delépine’s long and fruitful career in science encompassed organic chemistry, inorganic chemistry, and pharmacy. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585−3586. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375−384. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979, 512−516. Blažzeviü, N.; Kolnah, D.; Belin, B.; Šunjiü, V.; Kafjež, F. Synthesis 1979, 161−176. (Review). Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org. Chem. 1990, 55, 1796−1801. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101−1109. Xie, L.; Yu, D.; Wild, C.; Allaway, G.; Turpin, J.; Smith, P. C.; Lee, K.-H. J. Med. Chem. 2004, 47, 756−760. Loughlin, W. A.; Henderson, L. C.; Elson, K. E.; Murphy, M. E. Synthesis 2006, 1975−1980.

173

de Mayo reaction [2 + 2]-Photochemical cyclization of enones with olefins is followed by a retroaldol reaction to give 1,5-diketones. O

O

O CO2Me

hν

OH

CO2Me

OH

O

CO2Me

Head-to-tail alignment gives the major product: O

O

δ

δ δ OH

δ

hν, [2 + 2] CO2Me

cycloaddition

CO2Me

OH

O H

O

O

retro-aldol cyclobutane cleavage O

CO2Me

O

H

O

CO2Me

CO2Me

Head-to-head alignment gives the minor regioisomer: O

O

hν, [2 + 2]

CO2Me

CO2Me

cycloaddition OH

OH

O H

O CO2Me

retro-aldol

cyclobutane cleavage O

O

H

CO2Me

CO2Me O

O

Example 13 O

O Ph

1. hν, cyclohexane, 83%

O

2. H2 (3 atm), Pd/C (10%) HOAc, rt, 18 h, 83% O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_76, © Springer-Verlag Berlin Heidelberg 2009

174

Example 26 O

O

O

H

H

HO H

H O

hν, MeOH

> 90% OH

Example 39 O

O

O H

OH

H

O

hv, Pyrex filter

O

CH3CN, rt, 1.5 h, 72%

N

H

N

N

O

O

O

Example 410 R R O R=H R = Me R = t-Bu

O

hv

O

Et2O

H H

O

R

O

H H

O H

70% 58% 72%

100 50 0

O O

O H

: : :

0 50 100

References (a) de Mayo, P.; Takeshita, H.; Sattar, A. B. M. A. Proc. Chem. Soc., London 1962, 119. Paul de Mayo received his doctorate from Sir Derek Barton at Birkbeck College, University of London. He later became a professor at the University of Western Ontario in London, Ontario, Canada, where he discovered the de Mayo reaction. (b) Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794−806. 2. de Mayo, P. Acc. Chem. Res. 1971, 4, 41−48. (Review). 3. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583−2584. 4. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181−1201. (Review). 5. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845−2848. 6. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905−2910. 7. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297−588. (Review). 8. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939−3942. 9. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603−1606. 10. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582−4595. 1.

175

Demjanov rearrangement Carbocation rearrangement of primary amines via diazotization to give alcohols through C−C bond migration.

HNO2

OH OH

NH2

H 2 HO

N

N

O

H O

O

H2O

O

N

O

N

O

− H2 O

N

O

O

N

O

N

O

− HNO2

:

N H

NH2

N O

− H2O

H N N OH2

N N

:

N N OH

H O :

− N2

−H

H

OH

N N

:

H O

− N2

H

or

−H

N N

OH

Example 13 NH2

N Ph

NaNO2, HOAc 100

oC,

Ph OH

N

2h

N Ph

30%

16%

Example 26 H

NH2

NaNO2, AcOH/H2O

H

100−110 oC, 2 h, 61%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_77, © Springer-Verlag Berlin Heidelberg 2009

OH

176

Example 37 O NaNO2, 0−4 oC 0.25 M H2SO4/H2O NH2

O

O

OH

HO

Example 48 O H2 N

H

5 equiv NaNO2 5 equiv AcOH

HO

O O

H H

MeO

O

H2O/THF (1:1) 0 oC, 2 h, 61%

MeO

H

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26−42. Nikolai J. Demjanov (1861−1938) was a Russian chemist. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−184. Kotani, R. J. Org. Chem. 1965, 30, 350−354. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840−1844. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289−2291. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649−1664. Kürti, L.; Czakó, B.; Corey, E. J. Org. Lett. 2008, 10, 5247−5250. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review).

177

Tiffeneau–Demjanov rearrangement Carbocation rearrangement of β-aminoalcohols via diazotization to afford carbonyl compounds through C−C bond migration.

OH

O

NaNO2

NH2

H

Step 1, Generation of N2O3 H HO

H

N

O

O

N

− H2 O

O

H2 O

N

O

N

−H

O

O

N

O

Step 2, Transformation of amine to diazonium salt O OH

N

O

N

OH

O HONO

:

N N O H

NH2

OH

N

N N OH2

:

N N OH

OH

− H2O

OH

H

N

Step 3, Ring-expansion via rearrangement

N

N

O H

O

:

OH

− N2

−H

Example 15 NaNO2, H2O HO H2 N

AcOH, 0 oC, then rt−60 oC

O O

76% yield

90 : 6

178

Example 26 AcOH•H2N

CONEt2 OH

H O

NaNO2, AcOH O

O NEt2 N2

H2O, 0−5 oC 60%

N Me

CONEt2 O

O

N Me

Example 37 NaNO2, AcOH/H2O, 0 oC, 1 h OH then reflux 1 h, 98% O

NH2

Example 49 O HO

NH2 SiMe3

O

NaNO2 SiMe3

AcOH 72% SiMe3

28%

References Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54−56. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157−188. (Review). Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975−1979. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941−1947. Miyashita, M.; Yoshikoshi, A. J. Am. Chem Soc. 1974, 96, 1917–1925. Steinberg, N. G.; Rasmusson, G. H.; Reynolds, G. F.; Hirshfield, J. H.; Arison, B. H. J. Org. Chem. 1984, 49, 4731–4733. 7. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342−5352. 8. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649–1664. 9. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648−650. 10. Curran, T. T. Demjanov and Tiffeneau–Demjanov Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 293−304. (Review). 1. 2. 3. 4. 5. 6.

179

Dess−Martin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triacetoxyperiodinane. The Dess–Martin periodinane, 1,1,1-triacetoxy-1,1-dihydro-1,2benziodoxol-3(1H)-one, is one of the most useful oxidant for the conversion of primary and secondary alcohols to their corresponding aldehyde or ketone products, respectively. AcO OAc I OAc O OH R1

O O

R2

R1

R2

Preparation,1,2 The oxone preparation is much safer and easier than KBrO3. The IBX intermediate that comes out of it has proven to be far less explosive12 I

KBrO3, H2SO4, 93%

HO

O I

CO2H

O

or 1.3 equiv Oxone H2O, 70 oC, 3 h 79-81%

IBX

AcO OAc I OAc O

Ac2O, 0.5% TsOH 80 oC, 2 h, 91%

O

O

However, The Dess–Martin periodinane is hydrolyzed by moisture to oiodoxybenzoic acid (IBX), which is a more powerful oxidating agent3

AcO OAc I OAc O

HO

H2O

O

CH2Cl2 IBX

O

O I

O

Mechanism1 AcO OAc I OAc O

H :O

R2

R1 O

SN2

AcO OAc I O H O 2 R1 R

OAc

O

OAc I O

O R1

R2 O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_78, © Springer-Verlag Berlin Heidelberg 2009

AcOH

180

Example 16 AcO OAc I OAc O O

OH

O

O

O O

O O

CH2Cl2, 2 h, 67%

O

O

O

Example 2, An atypical Dess–Martin periodinane reactivity7 AcO OAc I OAc O

O

CHO O

N3

NaN3, CH2Cl2 0 oC, 3 h, 86%

N

N

Example 310 O S S

O t-BuO2C

N H NHBoc

OH

N H Dess−Martin periodinane

H N

N H

CH2Cl2, rt, 1 h, 70%

O

CO2t-Bu

O S S

O t-BuO2C

N H NHBoc

N H

O

N H

H N O

CO2t-Bu

Example 411 PMBO

BnO O

BnO BnO

O AllO

OH

OTDS NHAc

Dess−Martin periodinane CH2Cl2, rt, 2 h, 90%

PMBO

BnO BnO BnO

O

O O

O AllO

O OTDS NHAc

TDS = Thexyldimethylsilyl

181

References (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155−4156. James Cullen (J. C.) Martin (1928−1999) had a distinguished career spanning 36 years both at the University of Illinois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bartlett at Harvard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that lead to his landmark investigations into hypervalent compounds of the main group elements. Over a 20-year period the Martin laboratories successfully prepared unprecedented chemical structures from sulfur, phosphorus, silicon and bromine while the ultimate “Holy Grail” of stable pentacoordinate carbon remained elusive. Although most of these studies were driven by J. C.’s fascination with unusual bonding schemes, they were not without practical value. Two hypervalent compounds, Martin’s sulfurane (for dehydration, page 365) and the Dess−Martin periodinane have found widespread application in synthetic organic chemistry. J. C. Martin and his student Daniel Dess developed this methodology at the University of Illinois at Urbana. (Martin’s biography was kindly supplied by Prof. Scott E. Denmark). (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−7287. 2. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 3. Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549−7552. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588−590. (Review). 5. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622−625. 6. Bach, T.; Kirsch, S. Synlett 2001, 1974−1976. 7. Bose, D. S.; Reddy, A. V. N. Tetrahedron 2003, 44, 3543−3545. 8. Tohma, H.; Kita, Y. Adv. Synth. Cat. 2004, 346, 111−124. (Review). 9. Holsworth, D. D. Dess−Martin oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ; 2007, pp 218−236. (Review). 10. More, S. S.; Vince, R. J. Med. Chem. 2008, 51, 4581−4588. 11. Crich, D.; Li, M.; Jayalath, P. Carbohydrate Res. 2009, 344, 140−144. 12. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537−4538. 1.

182

Dieckmann condensation The Dieckmann condensation is the intramolecular version of the Claisen condensation.

CO2Et OEt O

H

O

NaOEt

CO2Et CO2Et

CO2Et

O enolate

OEt OEt

formation

5-exo-trig

O OEt

O

CO2Et

CO2Et

ring closure

O OEt

Example 16

MeO2C

H

OBn

H

NaHMDS, THF OTBS

N

−78 C, 58%

O

OTBS

N

o

MeO2C

OBn

MeO2C

Example 28 EtO2C O

MeO2C 1. t-BuOK, Tol., reflux, 5 min.

N

2. 18 N H2SO4, THF, 4 h 61% for two steps

O

N

O

Example 39 O Ar1 O

OH OCH2CF3

3 equiv KOt-Bu, DMF

Ar2

0 oC, 30−90 min., 75−88%

Ar1

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_79, © Springer-Verlag Berlin Heidelberg 2009

Ar2

O O

183

Example 410

H N O CO2Me

1. K2CO3, DMSO, 24 h 2. 60 oC, 48 h

N CO2Me

O

N NH

3. 5 oC, 2 M HCl, 1 h 63%

CO2Me

OMe O

H N

O

H N

N

N O

CO2Me

O

HO

CO2Me

References Dieckmann, W. Ber. 1894, 27, 102. Walter Dieckman (1869−1925), born in Hamburg, Germany, studied with E. Bamberger at Munich. After serving as an assistant to von Baeyer in his private laboratory, he became a professor at Munich. At age 56, he died while working in his chemical laboratory at the Barvarian Academy of Science. 2. Davis, B. R.; Garratt, P. J. Comp. Org. Synth. 1991, 2, 795−863. (Review). 3. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507−6508. 4. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32, 563−566. 5. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403−1405. 6. Rabiczko, J.; UrbaĔczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433−1441. 7. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109-114. 8. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617−1617. 9. Bernier, D.; Brueckner, R. Synthesis 2007, 2249−2272. 10. Koriatopoulou, K.; Karousis, N.; Varvounis, G. Tetrahedron 2008, 64, 10009−10013. 11. Takao, K.-i.; Kojima, Y.; Miyashita, T.; Yashiro, K.; Yamada, T.; Tadano, K.-i. Heterocycles 2009, 77, 167−172. 1.

184

Diels–Alder reaction The Diels–Alder reaction, inverse electronic demand Diels–Alder reaction, as well as the hetero-Diels–Alder reaction, belong to the category of [4+2]-cycloaddition reactions, which are concerted processes. The arrow pushing here is merely illustrative. ‡ EDG

EDG EWG

HOMO

‡

EDG EWG

EWG

Δ

LUMO

diene dienophile adduct EDG = electron-donating group; EWG = electron-withdrawing group Example 16 OMe OMe CO2Et Me3SiO

Me3SiO

hydroquinone CO2Et H

180 oC, 1.5 h, 62%

AcO

OAc

Alder’s endo rule

The Danishefsky diene

OMe

OMe CO2Et

EtO2C OSiMe3

AcO

Me3SiO

AcO

4:1 α-OMe : β-OMe

Example 2, Intramolecular Diels–Alder reaction7

O F

F O

Br4-BIPOL, AlMe3 CH2Cl2, rt, 8 h, 65%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_80, © Springer-Verlag Berlin Heidelberg 2009

O O

H

‡

185

Example 3, Asymmetric Diels–Alder reaction5,8 H Ph Ph N Br3Al

B

O O

CH3

O O CO2CH2CF3

4 mol%, CH2Cl2 −78 oC, 12 h, 99%

OCH2CF3

94% ee 90:10 endo:exo

Example 4, Retro-Diels–Alder reaction4,9 O H MeO2C H

O MeAlCl2, maleic anhydride MeO2C CH2Cl2, μ-wave, 110 oC 1 min., 74−84%

Example 5, Intramolecular Diels–Alder reaction11

O

O

OH

O

Me2AlCl, CH2Cl2 Me

−78 to −30 oC, 71%

Me O

HO

References 1.

2. 3. 4.

5.

Diels, O.; Alder, K. Ann. 1928, 460, 98−122. Otto Diels (Germany, 1876−1954) and his student, Kurt Alder (Germany, 1902−1958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their territory in applying the Diels–Alder reaction in total synthesis: “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.” Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315−399. (Review). Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401−449. (Review). (a) Rickborn, B. The retro-Diels−Alder reaction. Part I. C−C dienophiles in Org. React. John Wiley & Sons, 1998, 52. (b) Rickborn, B. The retro-Diels−Alder reaction. Part II. Dienophiles with one or more heteroatom in Org. React. John Wiley & Sons, 1998, 53. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667. (Review).

186

Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478−8482. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem. 2005, 126, 709−714. 8. Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 1498−1499. 9. Iqbal, M.; Duffy, P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo, A.; Verdaguer, X.; Riera, A. Org. Biomol. Chem. 2008, 6, 4649−4661. 10. Ibrahim-Ouali, M. Steroids 2009, 74, 133−162. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412. 6. 7.

Inverse electronic demand Diels–Alder reaction ‡

‡

EWG

LUMO

EWG

Δ

EDG

EWG EDG

EDG

HOMO Diene dienophile

adduct

Example 12 Me EtO O

B

O

O

B

O

Cat. = N

3 mol% Cat., BaO, rt, 5 h O

O

OEt

O Cr Cl O

CO2Et

OHC

EtO2C

110 oC, 48 h 76% 2 steps

OH

O OEt H 98% dr, 95% ee

Example 23

N O

O

H

R1 Cl

O R2

R3

Mes N N Cl 5 mol%

1.5 equiv NEt3, EtOAc, rt, 6 h

O O R2

R1 R3

70−90% yield 95−99% ee

187

Example 3, Catalytic asymmetric inverse-electron-demand Diels–Alder reaction4

Ph

O2 N S

N

OEt 5 equiv 10 mol% Ni(ClO4)2•6H2O 10 mol% DBFOX-Ph

SO2Ar OEt

Ph

CH2Cl2, rt, 73% yield

Ph

Ph

O DBFOX-Ph =

O

N Ph

97:3 endo/exo 88% ee

O N Ph

Example 45 O

MeO

OMe

O

EWG O EWG = CONEt2, CO2Et, COR, SO2Ph, CN, Aryl

1. MeO OMe solvent, 135 oC

EWG O EWG = CONEt2, CO2Et, COR, SO2Ph, CN, Aryl

O

MeO

OMe OMe

2. Et2O•BF3, CH2Cl2, rt

MeO

O

EWG

O EWG

NR2

PhH, Δ

O OMe

References 1. 2. 3. 4. 5.

Boger, D. L.; Patel, M. Prog. Heterocycl. Chem. 1989, 1, 30–64. (Review). Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628–1629. He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. Esquivias, J.; Gomez Arrayas, R.; Carretero, J. C. J. Am. Chem. Soc. 2007, 129, 1480– 1481. Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett. 2008, 10, 233–236.

Hetero-Diels–Alder reaction Heterodiene addition to dienophile or heterodienophile addition to diene. Typical hetero-Diels–Alder reactions are aza-Diels–Alder reaction and oxo-Diels–Alder reaction.

188

X

X

X

X

Y

Y

Y X

Y X

e.g.: SO2Ph N

EtO2C

‡

EtO2C OEt

N

SO2Ph

EtO2C

OEt H

Ph Ph

SO2Ph N OEt

Ph

Example 1, Heterodienophile addition to diene1 MeO

MeO

toluene

CO2Et

CO2Et O

110 oC, 60%

O

Example 2, Similar to the Boger pyridine synthesis (see page 59)2 MeO2C CO2Me OMe MeO OMe MeO

N N

N MeO MeO

CHCl3, reflux

N N

CO2Me CO2Me

5 days, 65% MeO2C

CO2Me

N

N N

Example 3, Using the Rawal diene4 NMe2

CHCl3, −40 oC

O Me

CO2Me

71% OTBS Rawal diene

O Me MeO2C

O

Example 4, Also similar to the Boger pyridine synthesis6 N N

N

Δ or MW

N

n

SCH3

N

O n

O

SCH3

n = 1, 75% n = 2, 65% n = 3, 54% n = 4, 30%

189

Example 57 Me O O EtO

O

Me

N OEt

Me3C H O 2

Me O Cu

OTf O

N

OTf

CMe3

OH2 2 mol%

3 Å MS, THF, 0 oC, 87%

EtO

O

OEt

24:1 endo/exo Me 97% ee

References 1. 2. 3. 4. 5. 6. 7.

Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390–4392. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451−512. (Review). Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418−11425. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321−3323. Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093−2102. (Review). LipiĔska, T. M. Tetrahedron 2006, 62, 5736−5747. Evans, D. A.; Kvaerno, L.; Dunn, T. B.; Beauchemin, A.; Raymer, B.; Mulder, J. A.; Olhava, E. J.; Juhl, M.; Kagechika, K.; Favor, D. A. J. Am. Chem. Soc. 2008, 130, 16295−16309.

190

Dienone–phenol rearrangement Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4disubstituted phenols. OH

O H

R R R

H

H

R

OH

O

:

O

OH

1,2-alkyl H

− H H

shift

R

R R

R R

R

R R

Example 14 O

O O

O

50% aq. H2SO4 reflux, 80% OH

O

Example 25 OH

O HO

conc. H2SO4

HO

Et2O, 95%

Example 39 OH O conc. HCl, CH3CN

O

1.5 h, rt, 73%

O NBoc

NH

O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_81, © Springer-Verlag Berlin Heidelberg 2009

191

Example 410

O

Ac2O H2SO4 0 oC to rt 62%

OAc

(1:1)

OAc AcO

O

References Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55−68. (Review). 2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105−1111. 3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824−1829. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron 1992, 48, 8179−8188. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59, 1831−1834. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619−624. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135−140. 8. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60, 4901−4907. 9. Bru, C.; Guillou, C. Tetrahedron 2006, 62, 9043−9048. 10. Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Tetrahedron Lett. 2007, 48, 6590−6593. 1.

192

Di-π-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement.

R R1

hν

R2

R2

1,4-diene

R3

vinylcyclopropane R R1

R R1 R2

R1

R4

R4 R3

R R1

R

hν

R4 R3

diradical

Example 1, Aza-π-methane rearrangement2 hν, acetophenone Ph

benzene, 86%

N OAc Ph

Ph

N

Ph

Example 24 CN hν, acetone

CN CN

90% CN

Example 38 X hv, 300 nM CH3COCH3 S O2

X

23−64%

S O2

X = CH3, CH2Ph, COCMe3, CO2CH2Ph SiMe3, SnBu3, SePh, (CH2)3CH3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_82, © Springer-Verlag Berlin Heidelberg 2009

R

R4

R4 R3

R4 R3

diradical

R2

R2

R2

OAc

R1 R3

193

Example 4, Oxa-π-methane rearrangement8 Me

O

Me

Me

H

hv, acetone Pyrex, 76%

O Me H

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183–184. Known for the Traxler–Zimmerman trasition state for the asymmetric synthesis, Howard E. Zimmerman is a professor at the University of Wisconsin at Madison. (b) Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065–3112. (Review). (c) Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365–2367. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc., Perkin Trans. I 1991, 223–228. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341–2342. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365–8367. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org. Chem. 2002, 526–533. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155–1158. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44, 751–754. Dura, R. D.; Paquette, L. A. J. Org. Chem. 2006, 71, 2456–2459. Singh, V.; Chandra, G.; Mobin, S. M. Synlett 2008, 2267–2270.

194

Doebner quinoline synthesis Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid. CO2H O NH2

N

CO2H

OHC

H

O H

CO2H

− H2 O

OH2 :

NH2 H

:

N H

B:

H

O

CO2H

O

N H

HO CO2H H

H2O CO2H H

H N H

N

N H

H

CO2H

CO2H − H2O

air oxidation −2H

N H

N

Example 12 CO2H

H

MeO

O

NO2

O NH2

EtOH

MeO

Δ, 95%

CO2H

N

Example 26 CO2H H O O NH2

CO2H

EtOH, reflux 3 h, 20%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_83, © Springer-Verlag Berlin Heidelberg 2009

N

NO2

195

Example 3, Combinatorial Doebner reaction7 R2

R3

H N O

R2

O N H

NH2 R1 O

OHC

N PhH

R1 R3

reflux, 8 h O

N H

H N O

References 1.

2. 3.

4. 5. 6. 7. 8.

Doebner, O. G. Ann. 1887, 242, 265. Oscar Gustav Doebner (1850−1907) was born in Meininggen, Germany. After studying under Liebig, he actively took part in the Franco-Prussian War. He apprenticed with Otto and Hofmann for a few years after the war, then began his independent researches at the University at Halle. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520−1523. Elderfield, R. C. Heterocyclic Compounds; Elderfield, R. C., Ed.; John Wiley & Sons, Inc.: New York, 1952, Vol. 4, Quinoline, Isoquinoline and Their Benzo Derivatives, pp. 25−29. (Review). Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125−131. (Review). Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396−401. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119−7138. Gopalsamy, A.; Pallai, P. V. Tetrahedron Lett. 1997, 38, 907−910. Pflum, D. A. Doebner quinoline synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 407−410. (Review).

196

Doebner–von Miller reaction Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 509). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. The following mechanism is favored by Denmark’s mechnistic study using 13C-labelled α,β-unsaturated ketones.9 O HCl or N H

ZnCl2

NH2

O

O reversible NH

conjugate addition

NH2

O irreversible

condensation

fragmentation

N

NH2

N

NH

conjugate addition

N

cyclization N H

rearomatization

NH2

Example 15 CO2Me

NH2

O MeO2C

TsOH, CH2Cl2 CO2Me

reflux, 24 h

N

CO2Me

Example 26 F

F

H

F

6 N HCl, Tol.

F

O NHAc

100 °C, 2 h, 70%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_84, © Springer-Verlag Berlin Heidelberg 2009

N

Me

197

Example 3, A novel variant10 B(OH)2 NH2 2 equiv

R2 R3

O R1

3% [RhCl(cod)]2 KOH, rt, 24 h then 10% Pd/C air, reflux, 4 h 42−96%

R3 R2 N

R1

References Doebner, O.; von Miller, W. Ber. 1883, 16, 2464. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599−5600. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39, 5133−5134. 5. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1999, 9, 2607−2712. 6. Sprecher, A.-v.; Gerspacher, M.; Beck, A.; Kimmel, S.; Wiestner, H.; Anderson, G. P.; Niederhauser, U.; Subramanian, N.; Bray, M. A. Bioorg. Med. Chem. Lett. 1998, 8, 965−970. 7. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731−3734. 8. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 488−494. (Review). 9. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones. 10. Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10, 4117−4120. 1. 2. 3. 4.

198

Dötz reaction Cr(CO)3-coordinated hydroquinone from vinylic alkoxy pentacarbonyl chromium carbene (Fischer carbene) complex and alkynes. OH

OR

Δ

(OC)5Cr

RL R1

RL

R1

RS OR Cr(CO)3

RS

R2

RL

OR

OR

−CO

(OC)5Cr R1

R2

R1

R2

R

alkyne insertion

alkyne

(OC)4Cr R2

(OC)4Cr

coordination

R1

R2 O C

CO insertion RL

RS

Cr CO OC CO OH

O R2

RL

R1

RS

RL

Cr CO OC OC CO

ring closure

R2

OR

OR

electrocyclic

R3

R1

R1

2

RS OR

R2

RL

R1

RS OR Cr(CO)3

tautomerization

RS OR Cr(CO)3

Example 15 NO2 Se

O

OMe 1. THF, reflux

(OC)5Cr

Se NO2

2. CAN, 22% O

Example 38 MOMO

OMe

H

MOMO

OMe

MOMO

OH

ClCH2CH2Cl

Cr(CO)5 O

O

70 oC, 1 h, 76%

O

MOMO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_85, © Springer-Verlag Berlin Heidelberg 2009

O

199

Example 38 BnO Cr(CO)5

MOMO

MeO

OMOM OH

OMe

BnO

THF, 50 oC, 61% MeO OMe

Example 39

MeO

1. 1.5 equiv t-BuLi, THF, −78 oC 2. 1.02 equiv Cr(CO)6, THF −78 oC to rt

O

MeO

F OMe

3. 1.02 equiv Et3O•FB4, rt 29%

OEt 5 equiv Ph THF, 80 oC

H

MeO

O

MeO MeO

F

MeO

OEt

MeO

F OMe

O Cr(CO)n

Ph O

Cr(CO)5 O

CAN−HNO3 84%, 2 steps

MeO

O Ph

MeO MeO

O

References 1. 2. 3. 4. 5. 6.

7. 8. 9.

Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644−645. Karl H. Dötz (1943−) was a professor at the University of Munich in Germany. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press, Greenwich, CT; 1989; Vol. 1. (Review). Wulff, W. D. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12. (Review). Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439−494. (Review). Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428−1430. Solá, M.; Duran, M.; Torrent, M. The Dötz reaction: A chromium Fischer carbenemediated benzannulation reaction. In Computational Modeling of Homogeneous Catalysis Maseras, F.; Lledós, eds.; Kluwer Academic: Boston; 2002, 269−287. (Review). Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511−5514. White, J. D.; Smits, H. Org. Lett. 2005, 7, 235−238. Boyd, E.; Jones, R. V. H.; Quayle, P.; Waring, A. J. Tetrahedron Lett. 2005, 47, 7983−7986.

200

Dowd−Beckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones. O

O

Br

Bu3SnH, AIBN

CO2CH3

PhH, reflux

CO2CH3

Δ NC

N N

CN

N2↑

homolytic cleavage

2

CN

2,2ƍ-azobisisobutyronitrile (AIBN) n-Bu3Sn

CN

H

n-Bu3Sn

SnBu3

O

Br

H

O

O Bu3SnBr

CN

CO2CH3

CO2CH3

CO2CH3

O

O H SnBu3

Bu3Sn CO2CH3

CHO2CH3

Example 14

O

H

H

H 1.2 eq. Bu3SnH cat. AIBN

H CO2Et

O O

H CO2Et 86%

Tol., reflux, 23 h

I

H CO2Et H

13%

Example 29 O O O

AIBN, Bu3SnD

CO2Me I

PhH, 80 oC

O

CO2Me H

D

CO2Me

D

77%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_86, © Springer-Verlag Berlin Heidelberg 2009

8%

CO2Me D 15%

201

References 1. 2.

3. 4. 5. 6. 7. 8. 9.

Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493−3494. Paul Dowd (1936−1996) was a professor at the University of Pittsburgh. (a) Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987, 666−667. Athelstan L. J. Beckwith is a professor at University of Adelaide, Adelaide, Australia. (b) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565−2575. (c) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77−90. (d) Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129−6132. (e) Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847−4860. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091−2115. (Review). Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525−526. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080−3082. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317−4353. (Review). Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171−3177. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691−8694. Ardura, D.; Sordo, T. L. J. Org. Chem. 2005, 70, 9417−9423.

202

Dudley reagent CH3

O

N CH3 OTf

O

N

H3CO

Dudley benzyl reagent

Dudley PMB reagent

The Dudley reagents are employed for the protection of alcohols as benzyl1 or PMB2 ethers, respectively, under mild conditions. Carboxylic acids are readily protected as well.3 Activation of the appropriate Dudley reagent in the presence of an alcohol furnishes the desired arylmethyl ether. The benzyl reagent is activated upon warming to approximately 80–85 °C, whereas activation of the PMB reagent occurs at room temperature upon treatment with methyl triflate (CH3OTf) or protic acid.4 Aromatic solvents, most commonly trifluorotoluene, often provide the best results. Magnesium oxide (MgO) is typically included in the reaction mixture as an acid scavenger.5 For benzylation of carboxylic acids, triethylamine (Et3N) is used in place of MgO.3 Preparation:1–3

CH3OTf, toluene O

N

O

0 °C to rt, 1 h, 99%

N CH3 OTf

Dudley benzyl reagent

CH3 CH3 KOH, 18-crown-6

OH H3CO

Cl

N

toluene, reflux (–H2O) 90–93%

O H3CO

N

Dudley PMB reagent

The Dudley reagents are conveniently prepared from readily available starting materials and are indefinitely stable to storage and handling under standard laboratory conditions. Alternatively, both reagents are commercially available. Example 16 OH OAc

Dudley benzyl reagent, MgO PhCF3, 85 °C, 24 h, 96%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_87, © Springer-Verlag Berlin Heidelberg 2009

OBn OAc

203

Benzylation of a monoacetylated diol is shown in Example 1.6 The Dudley benzyl reagent was uniquely effective for protection of the free alcohol without loss and/or migration of the labile acetyl group. Example 22 Dudley PMB reagent CH3OTf, MgO

OH Si(CH3)3

Ph

PhCF3, rt, 1 h, 80%

OPMB Si(CH3)3

Ph

PMB-protection of a β-hydroxysilane can be accomplished without competition from the Peterson elimination (Example 2),2 which would occur under the basic or acidic conditions required for many other alkylation reactions. Example 34 O

O O

Dudley PMB reagent, CSA OH

O

O

CH2Cl2, rt, 72 h, 85%

O

OPMB O

O

The Dudley PMB reagent can also be activated under mildly acidic conditions using catalytic camphorsulfonic acid (CSA) in lieu of CH3OTf (Example 3).4 Example 4, In situ-formation of the Dudley benzyl reagent is achieved by treating a mixture of an alcohol and 2-benzyloxypyridine with CH3OTf 7 OH

O O

N H

OCH3 O

CH3OTf, MgO, toluene O

N

0 to 85 °C, 24 h, 84%

OBn

O O

N H

OCH3 O

References 1. 2. 3. 4. 5. 6. 7.

Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923–3927. Nwoye, E. O.; Dudley, G. B. Chem. Commun. 2007, 1436–1437. Tummatorn, J.; Albiniak, P. A.; Dudley, G. B. J. Org. Chem. 2007, 72, 8962–8964. Stewart, C. A.; Peng, X.; Paquette, L. A. Synthesis 2008, 433–437. Poon, K. W. C.; Albiniak, P. A.; Dudley, G. B. Org. Synth. 2007, 84, 295–305. Schmidt, J. P.; Beltrân-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid, M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041–4044. Lopez, S. S.; Dudley, G. B. Beilstein J. Org. Chem. 2008, 4, No. 44.

204

Erlenmeyer−Plöchl azlactone synthesis Formation of 5-oxazolones (or “azlactones”) by intramolecular condensation of acylglycines in the presence of acetic anhydride. Ac2O

HN

N

CO2H

R1

R1

O

O

O

AcO O HN R1

N

O

O O O

H

O R1

H

N

O O

O O

R1

O

2 AcOH

O

mixed anhydride

Example 12 O HN CO2H

Ph

NaOAc, Ac2O

H

O

O N

110 oC, 69−73%

O

Ph

O

O

O

O

Example 28

O

O

OH

H

THF, reflux, 15 h

O

H

O

O

BuNH2

O O

Pb(OAc)4, Ac2O

O

CO2H

Ph

OH

O

HN

N

O

O O

HN

NH-Bu O

67% Ph

5.5:1 Z/E

Ph

Example 39 O

O HN Ph

CO2H

OBn

H

O

NaOAc, Ac2O 95%

F

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_88, © Springer-Verlag Berlin Heidelberg 2009

BnO O F

N Ph

205

References (a) Plöchl, J. Ber. 1884, 17, 1616−1624. (b) Erlenmeyer, E., Jr. Ann. 1893, 275, 1−3. Emil Erlenmeyer, Jr. (1864−1921) was born in Heidelberg, Germany to Emil Erlenmeyer (1825−1909), a famous chemistry professor at the University of Heidelberg. He investigated the Erlenmeyer−Plöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. The Erlenmeyer flasks “ ” are ubiquitous in organic chemistry laboratories. 2. Buck, J. S.; Ide, W.S. Org. Synth. Coll. II, 1943, 55. 3. Carter, H. E. Org. React. 1946, 3, 198−239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150−173. (Review). 5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Heterocyclic Chem; Katritzky, A. R.; Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp 175−206. (Review). 6. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995−2034. (Review). 7. Mukerjee, A. K. Heterocycles 1987, 26, 1077−1097. (Review). 8. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419−6422. 9. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 27−32. 10. Brooks, D. A. Erlenmeyer−Plöchl Azlactone Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 229−233. (Review). 1.

206

Eschenmoser’s salt

H3C

CH2 I N CH3

Eschenmoser’s salt, dimethylmethylideneammonium iodide, is a strong dimethylaminomethylating agent, used to prepare derivatives of the type RCH2N(CH3)2. Enolates, enolsilylethers, and even more acidic ketones undergo efficient dimethylaminomethylation—employed in the Mannich reaction. Mechanism O R2

R1

Li

THF

CH2 I N H3C CH3

OLi

LDA

R2

R1

O O

R2

R1

R1

CH2 N H3C CH3

R2

CH3 N CH3

Example 13 Once prepared, the resulting tertiary amines can be further methylated and then subjected to base-induced elimination to afford methylenated ketones.

H3C H

O O O

TBSO

H

1. 15 equiv NaN(SiMe3)2, THF −78 oC, 45 min. then 15 equiv of Me2(CH2)N+I− 0 oC, 15 min.

OTBS

H

H

O

H

CO2Me

CH3

H3C H

O

H

2. 20 equiv MeI, MeOH, 0.5 h 3. 10 equiv DBU, PhH, rt, 1 h 51% 3 steps

OTBS

O O

H

H

O

H

CO2Me

TBSO CH 3

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_89, © Springer-Verlag Berlin Heidelberg 2009

207

Example 24

N H

N H

H N

O O S O N O

N

Et3N, DMF, rt 12 h, 64%

O O S O N O Et3NH

H N

H N

:

H N

CH2 I N H 3C CH3

O O S O N O Et3NH

N CH 3 CH3

O O S O N O

Et3NH

H N N

N H

N N CH3 CH 3

Example 35 O

O

H3C O N H

CH2 I N CH3

DMF, 90 oC, 62%

O O O

O N H

O

References 1. 2.

3. 4. 5. 6.

Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem., Int. Ed. 1971, 10, 330–331. Kleinman, E. F. Dimethylmethyleneammonium Iodide and Chloride. In Encyclopedia of Reagents for Organic Synthesis (Ed: Paquette, L. A.) 2004, John Wiley & Sons, New York. (Review). Nicolaou, K. C.; Reddy, K. R.; Skokotas, G.; Sato, F.; Xiao, X. Y.; Hwang, C. K. J. Am. Chem. Soc. 1993, 115, 3558–3575. Saczewski, J.; Gdaniec, M. Tetrahedron Lett. 2007, 48, 7624–7627. Hong, A.-W.; Cheng, T.-H.; Raghukumar, V.; Sha, C.-K. J. Org. Chem. 2008, 73, 7580–7585. Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 449–452.

208

Eschenmoser−Tanabe fragmentation Fragmentation of α,β-epoxyketones via the intermediacy of α,β-epoxy sulfonylhydrazones. O 1. H2O2, −OH 2. H2NNHSO2Ar, H+ 3. −OH

O

O OH O

OH O

N

H

O O

O

H2NNHSO2Ar

O

N SO2Ar H

O

O O

OH

SO2Ar N

N

N SHO2Ar

N SO2Ar

Example 14

O

Tol-SO2NHNH2 CHCl3-AcOH (1:1) O

rt, 5 h, 73%

AcO

AcO

O

Example 27 Me

Me 1. TsNHNH2, rt O

O

Me

2. 55 oC, 2 h, 50%

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_90, © Springer-Verlag Berlin Heidelberg 2009

Me

N2↑

209

Example 39

H

O

O

H

O

OMe OAc NNs

O

1. NsNHNH2, AcOH, THF; evaporation, 60 oC, NaBH4, AcOH, THF, 0 oC

OMe TESO

2. TESOTf, 2,6-lutidine CH2Cl2, rt 60%, 2 steps

OAc NNs

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708−713. Albert Eschenmoser (Switzerland, 1925−) is best known for his work on, among many others, the monumental total synthesis of Vitamin B12 with R. B. Woodward in 1973. He now holds appointments at ETH Zürich and Scripps Research Institute, La Jolla. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943−3946. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta 1972, 55, 1276−1319. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313−317. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315−5318. Chinn, L. J.; Lenz, G. R.; Choudary, J. B.; Nutting, E. F.; Papaioannou, S. E.; Metcalf, L. E.; Yang, P. C.; Federici, C.; Gauthier, M. Eur. J. Med. Chem. 1985, 20, 235−240. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900−1908. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366−1375. Kita, Y.; Toma, T.; Kan, T.; Fukuyama, T. Org. Lett. 2008, 10, 3251−3253.

210

Eschweiler–Clarke reductive alkylation of amines Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart–Wallach reaction.

R NH2

R N

HCO2H

CH2O

formic acid is the hydride source as a reducing agent H

O

OH H

H R N

:

H

OH2 R N

H

R NH2

H

H

O

H

H H

H

:

O C O↑

O

R NH

H O

H R N

O

O C O↑

OH2

R N

:

R N

R N H

− H

R N

H O

Example 17

O

NH CH3

H3 C

O DCOD, DCO2D, DMSO microwave (120 W) 1−3 min.

H3 C

CD3 N CH3

d3-tamoxifen

Example 29 H N

1.2 equiv 37% CH2O in H2O 5 equiv 85% HCO2H in H2O

CH3 N

steam bath, 84% OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_91, © Springer-Verlag Berlin Heidelberg 2009

OH

211

Example 310 N

N

CHO

N varenicline (Chantix)

N

O N N N

OH N

:

NH

H

N O

N N

References 1

2 3 4 5 6 7 8

9 10

(a) Eschweiler, W. Chem. Ber. 1905, 38, 880–892. Wilhelm Eschweiler (1860−1936) was born in Euskirchen, Germany. (b) Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571–4587. Hans T. Clarke (1887−1927) was born in Harrow, England. Moore, M. L. Org. React. 1949, 5, 301–330. (Review). Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829–832. Bobowski, G. J. Org. Chem. 1985, 50, 929–931. Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755–7758. Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S. Synlett 2000, 104–106. Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487– 9488. Brewer, A. R. E. Eschweiler–Clarke reductive alkylation of amine. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 86−111. (Review). Weis, R.; Faist, J.; di Vora, U.; Schweiger, K.; Brandner, B.; Kungl, A. J.; Seebacher, W. Eur. J. Med. Chem. 2008, 43, 872–879. Waterman, K. C.; Arikpo, W. B.; Fergione, M. B.; Graul, T. W.; Johnson, B. A.; Macdonald, B. C.; Roy, M. C.; Timpano, R. J. J. Pharm. Sci. 2008, 97, 1499–1507.

212

Evans aldol reaction Asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone, the Evans chiral auxiliary. O

O

O

Lewis acid

+

R*

H

Me

R*

base

R'

OH R' Me

Evans syn chiral auxiliary O

O R* = O

O

N

N

Ph

Bn

O

Me

O

O

O O

N

O

N

N i-Pr

t-Bu

Ph

Example 12 OH

O

O N

1. Bu2BOTf, R3N

O

Ph

O

O N

O

2. PhCHO, − 78 oC 79%, 80:20 de

Bu Bu B O O

Bu2B OTf O

O N

O

PhCHO

Z-(O)-boron enolate O

N

H Bu

N

O

H

O

formation

B

O

H

Bu

O

H

Ph

R3N:

Bu O

Bu B

OH

O

O

aldol Ph

N

O

workup

O

O

Ph

N

O

condensation

Example 25 O

O

MeO

N OMe CO2Me

TiCl4, DIPEA CH2Cl2, −78 oC, 1.5 h

O

O N

N MeO2C

N

O

then rt, overnight, 52% OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_92, © Springer-Verlag Berlin Heidelberg 2009

O

213

Example 39 S O

O

1 eq. Bu2BOTf 1.1 eq. Et3N

O

O

N OBn Bn

S

PhMe, 0.15 M − 50 to − 30 oC 2 h, 72%

OTES

O

OH OTES

N OBn Bn

Example 4, Crimmins procedure10 O

O TBDPSO

CHO

N

OH O

TiCl4 (−)-sparteine TBDPSO

O

N

96%, 96% de Bn

O O

Bn

References (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127−2129. David Evans is a professor at Harvard University. (b) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876−2878. 2. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990, 55, 173−181. 3. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3−12. (Review). 4. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591−3607. 5. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411−7422. 6. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463−8469. 7. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13, 675−680. 8. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett. 2003, 5, 329−331. 9. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004, 69, 2569−2572. 10. Ghosh, S.; Kumar, S. U.; Shashidhar, J. J. Org. Chem. 2008, 73, 1582−1585. 11. Zhang, J. Evans aldol reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 532−553. (Review). 1.

214

Favorskii rearrangement Transformation of enolizable α-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively. O R1 X

R2

R4

R1 R2

Nuc-H

R3 H

H

O X = Cl, Br, I Nuc

Nuc = OH, OR, NRR'

R3 R4

base

The intramolecular Favorskii Rearrangement: O

O R1 X

R2 H

( )n

Nuc-H

Nuc R1

base

( )n

O

O Cl

n = 0−5

R2 H

OR

OR

enolizable α-haloketone O

O

O H

Cl

Cl

OR

Cl

HOR OR

cyclopropanone intermediate O

OR

O

OR H OR

O

OR

HOR OR

Example 12 O

O

Br2, CH3CO2H 50 oC, 1 h, 97%

Br

KOH, DMSO Br

100 oC, 1 h 47%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_93, © Springer-Verlag Berlin Heidelberg 2009

H

CO2H

215

Example 2, Homo-Favorskii rearrangement3 TsO

O

O

O

O

1.96 eq. NaOH

H dioxane/H2O 90 oC, 3 h, 86%

51 : 40 : 9

Example 36 O

O CO2Me

Br

Br2

O Br

CO2Me

NaOMe, MeOH

MeO

37% 2 steps

MeO

Et2O

O

Example 4, Photo-Favorskii Rearrangement7 O

O

300 nm light

hν

5% aq. CH3CN propylene oxide 4 h, 81%

homolysis

Cl

Cl

O

Cl

H H

electron transfer

H H

H H Cl

1,2-aryl

OH H 2O O

migration

O

Example 58 O

O Br

Br

KCN, α-cyclodextrin MeCN, H2O 10−15 oC, 12 h 80%

NC

O

NC Br Br

NC Br

216

NC

HO

O

H NC

H

H NC

HO

O H NC

H

9

O H

Ratio : 1

Example 610 O

O NaOMe

Cl THPO

MeOH 0 oC, 15 min. 96%

OMe THPO

References (a) Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533−563. Aleksei E. Favorskii (1860−1945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became a professor since 1900. (b) Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658. 2. Wagner, R. B.; Moore, J. A. J. Am. Chem. Soc. 1950, 72, 3655−3658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem. Soc. 1971, 93, 3208−3216. 4. Chenier, P. J. J. Chem. Ed. 1978, 55, 286−291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum Press: New York, 1982, 2, pp 527−585. (Review). 6. White, J. D.; Dillon, M. P.; Butlin, R. J. J. Am. Chem. Soc. 1992, 114, 9673−9674. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53, 16789−16794. 8. Kitayama, T.; Okamoto, T. J. Org. Chem. 1999, 64, 2667−2672. 9. Mamedov, V. A.; Tsuboi, S.; Mustakimova, L. V.; Hamamoto, H.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A. Chem. Heterocyclic Compd. 2001, 36, 911. (Review). 10. Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2006, 62, 1743−1748. 11. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 238−252. (Review). 1.

217

Quasi-Favorskii rearrangement If there are no enolizable hydrogens present, the classical Favorskii rearrangement is not possible. Instead, a semi-benzylic mechanism can lead to a rearrangement referred to as quasi-Favorskii. O R1 X

R2

R5

R3 R4

Nuc

R4 R3

R5

O

X = Cl, Br, I Nuc

R 2 R1

Nuc = OH, OR, NRR' R3,4,5 = H

Example 1, Arthur C. Cope’s initial discovery1 O

OEt

OEt

O

Hg(OAc)2 EtOH, reflux 4 h, 71%

Br

CO2Et

Br

non-enolizable ketone Example 25 NHLi Br O

O N H

Et2O, hexane 25 oC, 67%

Example 36 Li Br O

THF, −78 to −30 oC, 90%

O

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

Cope, A. C.; Graham, E. S. J. Am. Chem. Soc. 1951, 73, 4702−4706. Smissman, E. E.; Diebold, J. L. J. Org. Chem. 1965, 30, 4005−4007. Sasaki, T.; Eguchi, S.; Toru, T. J. Am. Chem. Soc. 1969, 91, 3390−3391. Baudry, D.; Begue, J. P.; Charpentier-Morize, M. Tetrahedron Lett. 1970, 2147−2150. Stevens, C. L.; Pillai, P. M.; Taylor, K. G. J. Org. Chem. 1974, 39, 3158−3161. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563−2565. Harmata, M.; Wacharasindhu, S. J. Org. Chem. 2005, 70, 725−728. Filipski, K.J.; Pfefferkorn, J. A. Favorskii rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 438−452. (Review). Harmata, M.; Wacharasindhu, S. Synthesis 2007, 2365−2369.

218

Feist–Bénary furan synthesis α-Haloketones react with β-ketoesters in the presence of base to fashion furans.

O

O Cl

Et3N:

OEt

54−57%

CO2Et

OH

Et3N H CO2Et O

H

O

Et3N, 0 °C, 52 h

O

CO2Et rate-determining

Cl O

CO2Et H

Cl

step

O

:NEt3

O

HO

CO2Et

CO2Et

H2O

Et3N H

H O

O

O

Et3N:

:

O

CO2Et

CO2Et

Example 12,3 H3CO2C

O O

OEt

57%

OCH3

O

Cl

O

KOH, MeOH

O

H3CO

O

Example 24 O H

O Cl

O

pyridine, rt to 50 °C, 4 h OEt

O

then rt, overnight, 86%

CO2Et

Example 3, Ionic liquid-promoted interrupted Feist–Benary reaction10 O R1

Br

O

R1OC HO

O [bmim]OH

R2

R3

OEt O

rt

R1 = CH3, Et, Ph, n-Pr, etc. R2 = CH3, OCH3, PEt [bmim]OH = R3 = H, n-Bu, CO2Et

CO2Et [pmim]Br

R3 O interrupted Feist−Benary products

R1

N

OH N C H 4 9

70−75 oC

R1OC R1

CO2Et O

R3

Feist−Benary products

[pmim]Br =

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_94, © Springer-Verlag Berlin Heidelberg 2009

N

Br N C H 4 9

219

References (a) Feist, F. Ber. 1902, 35, 1537−1544. (b) Bénary, E. Ber. 1911, 44, 489−492. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756−1757. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317−2321. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147−4160. Dean, F. M. Recent Advances in Furan Chemistry. Part I. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Ed.; Academic Press: New York, 1982; Vol. 30, 167−238. (Review). 6. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923−1929. 7. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.; Bird, C. V. Eds.; Pergamon: New York, 1996; Vol. 2, 351−393. (Review). 8. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review). 9. Shea, K. M. Feist–Bénary Furan Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 160−167. (Review). 10. Ranu, B. C.; Adak, L.; Banerjee, S. Tetrahedron Lett. 2008, 49, 4613−4617. 1. 2. 3. 4. 5.

220

Ferrier carbocyclization This process (also known as the “Ferrier II Reaction”) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry.1,2 General examples:3 HgCl BzO BzO

O

HgCl2, Me2CO, H2O

BzO BzO

reflux, 4.5 h, 83% TsO OMe

O TsO OMe

1 HgCl

HgCl

O OMe 2 HO Ts

O

BzO BzO

3

O O Ts O

OBz BzO BzO BzO

O

BzO

BzO BzO OMe O OH

OMe

O BzO BzO

TsO OH

4

OBz O

BzO BzO

OBz

O

BzO BzO

BzO BzO

O

BzO BzO

O OBz

BzO

83%6 OH

OH 93%4

OBz 80%6

More complex products: O

BzO AcO

BzO AcO

AcO OMe

O

O AcO

O

OMe

OMe

O

OC6H4OMe(p) O

O

O

BzO

BzO AcO

OH OAc

OAc

83%7

O AcO

OH

75%7

OH O 8 OC6H4OMe(p) 86% (2:1)

Complex bioactive compounds made following the application of the reaction: OH OH O O

O O Paniculide A9

HO H

OH H NH

O OH O

OH

HO HO HO

Pancratistatin10

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_95, © Springer-Verlag Berlin Heidelberg 2009

NH

HO Calystegine B211

221

Modified hex-5-enopyranosides and reactions OAc O

BnO BnO

HO a,b

BnO BnO

BnO OMe BnO BnO

H c BnO BnO

O BnO OMe

OAc

BnO OH 85%14

HO

79%13 d

O Bn OMe

O BnO BnO 98%13

BnO OMe

a, Hg(OCOCF3)2, Me2CO, H2O, 0 oC; b, NaBH(OAc)3, AcOH, MeCN, rt; c, iBu3Al, PhMe, 40 °C; d, Ti(Oi-Pr)Cl3, CH2Cl2, –78 °C, 15 min. (Note: The aglycon is retained in the Al- and Ti-induced reactions). References 1. 2. 3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779−2831. (Review). Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277−291 (Review). Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455−1458. The discovery (1977) was made in the Pharmacology Department, University of Edinburgh, while R. J. Ferrier was on leave from Victoria University of Wellington, New Zealand where he was Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413−2416. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118−2121. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231−239. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett. 1991, 17−20. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711−714. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55, 3855−3870. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195−196. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443−10458. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem., Int. Ed. 1997, 36, 493−496. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471−3472. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883−9884. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885−9887. Yadav, J. S.; Reddy, B. V. S.; Narasimha Chary, D.; Madavi, C.; Kunwar, A. C. Tetrahedron Lett. 2009, 50, 81−84.

222

Ferrier glycal allylic rearrangement In the presence of Lewis acid catalysts O-substituted glycal derivatives can react with O-, S-, C- and, less frequently, N-, P- and halide nucleophiles to give 2,3unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Ferrier Rearrangement”. However, the reaction was first noted by Emil Fischer when he heated tri-O-acetyl-D-glucal in water.3 When carbon nucleophiles are involved, the term “Carbon Ferrier Reaction” has been used,4 although the only contribution the Ferrier group made in this area was to find that tri-O-acetyl-D-glucal dimerizes under acid catalysis to give a C-glycosidic product.5 The general reaction is illustrated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and Cnucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most common. Allyloxycarbenium ions are involved as intermediates, high yields of products are obtained, and glycosidic compounds with quasi-axial bonds (as illustrated) predominate (commonly in the Į,ȕ-ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1 i) HOCH2CCH6 ii) HSPh7 AcO AcO AcO

+ Lewis acid

O

AcO

O OAc

4

R = i) OCH2CCH6 ii) SPh7 iii) 4

OAc O R

AcO

iii)

General examples4 OAc OAc

SnBr4, C6H14, EtOAc

O

AcO AcO

AcO

O

H

rt, 5 min, 94%

More complex products made directly from the corresponding glycols: O

OH

O OH

OMe O

OH AcO

O O

In benzene, BF3•OEt2, 5 oC, 10 min, (67%, α-anomer).8

AcO

O O

OAc O

O

NHC(O)CCl3

Ph

EtO O O

In PhCOCH2CO2Et, BF3.OEt2, rt, 15 min, (81% α-anomer).9

By spontaneous sigmatropic rearrangement of the glycal 3-trichloroacetimidate made with NaH, Cl3CCN, (78% α-anomer).10

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_96, © Springer-Verlag Berlin Heidelberg 2009

223

Products formed without acid catalysts HO

OO

OMe AcO

O

OO

O O

O

O O

O Promoter: DEAD, Ph3P (80%, α-anomer)11

O O

DDQ (88%, mainly α)12

N-iodonium dicollidine perchlorate (65%, mainly α)13

C-3 leaving group of glycal: acetoxy hydroxy

pent-4-enoyloxy

Modified glycals and their reactions: OBn O OBn +

OH

Me

O O Ph

N N H

O OAc

I O

OBn O BnO BF3•OEt2, CH2Cl2, 0 oC (70%, mainly α)14

N Cl

O O

N

+

BnO

N

N

Ph O

N H

N

AgNO3, Na2CO3, reflux MeNO2, 6 h (58%, α,β 1:1).15

References 1.

Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl derivatives, In Org. React. 2003, 62, 569−736. (Review). It was almost 50 years after Fischer’s seminal finding that water took part in the reaction3 that Ann Ryan, working in George Overend’s Department in Birkbeck College, University of London, found, by chance, that p-nitrophenol likewise participates.16 Robin Ferrier, her immediate supervisor, who suggested her experiment, then found that simple alcohols at high temperatures also take part,17 and with other students, notably Nagendra Prasad and George Sankey, he explored the reaction extensively. They did not apply it to make the very important C-glycosides. 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 153−175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196−210. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans. 1 1990, 1995−2009. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581−586. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999−1007. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org. Chem. 1990, 55, 1979−1981. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Ann. 1991, 509−512. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68−69. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36, 4311−4314.

224

11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35, 3661−3664. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc., Chem. Commun. 1993, 704−705. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 3851−3858. 14. Booma, C.; Balasubramanian, K. K. Tetrahedron Lett. 1993, 34, 6757−6760. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996−4001. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667−3670. 17. Ferrier, R. J. J. Chem. Soc. 1964, 5443−5449. 18. De, K.; Legros, J.; Crousse, Be.; Bonnet-Delpon, D. Tetrahedron 2008, 64, 10497−10500.

225

Fiesselmann thiophene synthesis Condensation reaction of thioglycolic acid derivatives with Į,ȕ-acetylenic esters, which upon treatment with base result in the formation of 3-hydroxy-2thiophenecarboxylic acid derivatives.

CO2Me O MeO2C

HS

CO2Me

NaOMe

OH

S

OMe MeO2C

O MeO2C

O

OCH3 O S

S

OMe H S

H3CO

OMe

MeO2C

O

OMe S S

S MeO2C

O S

OMe

O

O MeO2C

O

OMe CO2Me

MeO2C

O

H S

OMe

OMe

OMe OMe

O H MeO

O

O

S S

NaOMe OMe

CO2Me

MeO2C

H S

MeO2C S

H

MeO2C S

CO2Me

H

HOMe

S

OMe

CO2Me

CO2Me

CO2Me O

S

OH

MeO2C

MeO2C

CO2Me

OMe

OMe

MeO

O

S

S S

MeO2C

CO2Me

CO2Me O

O

Example 15 O

12 equiv HSCH2CO2H

CO2R3 R3OH, HCl (g), −10 oC, 1 h

S

CO2R3 NaOR , R OH 3 3

CO2R3

S CO2R3

rt, 24 h, 46−98%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_97, © Springer-Verlag Berlin Heidelberg 2009

OH

226

Example 26

N

CH3

CH3

N

CH3

O HSCH2CO2H O O

N

CH3

OCH3

MeOH

S O

CH3

NaOMe

O

HCl, MeOH

CH3

S

O

O

CO2CH3

Example 37 O N

HS

Cl

N OEt

NaH, DMSO, 89%

CN

S CO2Et NH2

Example 49 HSCH2CO2Me CN

NaOMe, 68%

S

CO2Me NH2

References Fiesselmann, H.; Schipprak, P. Ber. 1954, 87, 835−841; Fiesselmann, H.; Schipprak, P.; Zeitler, L. Ber. 1954, 87, 841−848; Fiesselmann, H.; Pfeiffer, G. Ber. 1954, 87, 848; Fiesselmann, H.; Thoma, F. Ber. 1956, 89, 1907−1912; Fiesselmann, H.; Schipprak, P. Ber. 1956, 89, 1897−1902. 2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88−125. (Review). 3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem., Int. Ed. 1990, 29, 1064−1068. 4. Mullican, M. D.; Sorenson, R. J.; Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Conroy, M. C. J. Med. Chem. 1991, 34, 2186−2194. 5. Donoso, R.; Jordan de Urries, P.; Lissavetzky, J. Synthesis 1992, 526−528. 6. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7, 3101−3106. 7. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J. Med. Chem. 1999, 42, 5464−5474. 8. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett. 2000, 41, 4973−4975. 9. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; Wild, H.; Paulsen, H.; Caringal, Y.; Gunn, D.; Renick, J.; Osterhout, M. Bioorg. Med. Chem. Lett. 2001, 11, 9−12. 10. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 11. Mullins, R. J.; Williams, D. R. Fiesselmann Thiophene Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 184−192. (Review). 1.

227

Fischer indole synthesis Cyclization of arylhydrazones to indoles. R1

R1 N H

R2

NH3

N H

O

phenylhydrazine

H

H

N

R1

H R2

R2 N

N H

H

protonation

R2 N H

NH3

phenylhydrazone

R1

N H

R1 R2

H

double imine R1

R1 H R

N NH2 H H

N H2

NH2

N H

R2

NH2

tautomerization

rearrangement

NH2

R1 H

R2

R2

[3,3]-sigmatropic

ene-hydrazine

R1

R1

N H

NH3

2

R2

NH3

N H

Example 13 N O

HN

Ph

1. neat, 160 oC, 24 h

N O

N

N H

N H

NH2

N 2. NH2NH2, 120 oC, 12 h 71%

N H

Example 213 O

NH

NH2

CN CO2Et

AcOH, Δ, 5 h N H

57%

Example 4 (Severe racemization)9 H

O

H N

H

CO2Me or

CO2Me O

Ph

N H

1. PhNHNH2 2. AcOH

Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_98, © Springer-Verlag Berlin Heidelberg 2009

CN CO2Et

228

CO2Me

Ph

H

H

N

H

CO2Me H

N H

Ph

22%

N

H

N

N H

CO2Me

Ph

H N H

16%

6%

H

H

H CO2Me H 5%

Ph

CO2Me

CO2Me

N

N H

N

N H

H 4%

Ph

N

N H

H

Ph

4%

References (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241−2245. H. Emil Fischer (1852−1919) is arguably the greatest organic chemist ever. He was born in Euskirchen, near Bonn, Germany. When he was a boy, his father, Lorenz, said about him: “The boy is too stupid to go in to business; so in God’s name, let him study.” Fischer studied at Bonn and then Strassburg under Adolf von Baeyer. Fischer won the Nobel Prize in Chemistry in 1902 (three years ahead of his master, von Baeyer) for his synthetic studies in the area of sugar and purine groups. (b) Fischer, E.; Hess, O. Ber. 1884, 17, 559. 2. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons: New York, NY, 1982. (Book). 3. Martin, M. J.; Trudell, M. L.; Arauzo, H. D.; Allen, M. S.; LaLoggia, A. J.; Deng, L.; Schultz, C. A.; Tan, Y.; Bi, Y.; Narayanan, K.; Dorn, L. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1992, 35, 4105−4117. 4. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607−632. (Review). 5. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57, 1041−1048. 6. Ergün, Y.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2002, 39, 315−317. 7. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537−2539. 8. Li, J.; Cook, J. M. Fischer Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 116−127. (Review). 9. Borregán, M.; Bradshaw, B.; Valls, N.; Bonjoch, J. Tetrahedron: Asymmetry 2008, 19, 2130−2134. 10. Donald, J. R.; Taylor, R. J. K. Synlett 2009, 59−62. 1.

229

Fischer oxazole synthesis Oxazoles from the condensation of equimolar amounts of aldehyde cyanohydrins and aromatic aldehydes in dry ether in the presence of dry hydrochloric acid.

OH R1

ether R2CHO

CN

R2

O

HCl

H OH

H

R1

R1

NH

R1

Cl

R2

R2 SN2

HCl

R1

HCl

N

isomerization

H

N

Cl

R2 elimination

R1

O

HCl

Cl

Cl

R1

Example 14 OH

TsOH, Tol.

NH2

H3C

CHO

O

reflux

POCl3, 80−85 oC

O CH3

HN

O 15 min., 40%

CH3

N O

Example 28 Cl

OH

NH

dry HCl gas CN SOCl2, ether HO

R2 N

R2 O

H O

H2 O

Cl

H

N

R1

R2

HO

Cl

O

H O

:

O OH

N

H2O

R1

N

HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_99, © Springer-Verlag Berlin Heidelberg 2009

Cl

N

230

N

N

O

CHO dry HCl gas, 16.5%

N

OH

halfordinal

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Fischer, E. Ber. 1896, 29, 205. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292−1294. Wiley, R. H. Chem. Rev. 1945, 37, 401−442. (Review). Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028-1030. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons: New York, 1957, 5, 309−312. (Review). Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85−89. Brossi, A.; Wenis, E. J. Heterocycl. Chem. 1965, 2, 310−312. Onaka, T. Tetrahedron Lett. 1971, 4393−4394. Brooks, D. A. Fisher Oxazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 234−236. (Review).

231

Fleming−Kumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols using peracids. 1. HX 2. ArCO3H, base

SiMe2Ph R

R

1

OH R1

R

3. hydrolysis

retention of configuration H

ipso Si

substitution

H

R1

R

X

H :O

Si

Si X

R1

R

R1

R

Ar O

O

O

Ar

the β-carbocation is stabilized by the silicon group H O

HX

O

Si

O

:

Ar ArCO2

O

Si

R1

R

O O

O Si

Ar

O

R

O

R1

R

R1

O

O H O

:

− ArCO2 O Si R

O O

O

O Ar O Si O O O R R1

Ar

O R1

Ar

O Si O O R

R1

O O

HO O

O Ar O Si O O OH R

hydrolysis

R1

O Ar O Si O O R

HO

Ar

OH

O R

R1

R

R1

R1

Example 14

C8H18

O

O

OH O

m-CPBA, KHF2, DMF

C8H18

O

O

NBoc

NBoc 0 to 25 oC, 55−70%

(EtO)2PhSi

OH O

OTBS

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_100, © Springer-Verlag Berlin Heidelberg 2009

HO OTBS

232

Example 25 TsO H O N TBSO i-Pr

O

O TsO H O N

H2O2, KHCO3

H Si O i-Pr

Ph THF, H2O 55 oC, 90%

TBSO OH

O

O

H

Ph OH

Example 38 H3C H3C

Si

CH3

O CH3 H3 C

BnO

H CH3

HO

H3C

H2O2, KF, KHCO3

HO CH3

H 3C DMF, 93%

BnO

H CH3

H3C

H3C

Example 49 MeO2C

CO2Me

SiMe2(OMe)

KF, KHCO3 THF/MeOH 30% H2O2, 77%

MeO2C

OH

CO2Me

References (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29−31. (b) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229−4232. (c) Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). 2. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112−1124. 3. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613−616. 4. Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A. J. P.; Williams, D. J. J. Org. Chem. 1999, 64, 6005−6018. 5. Denmark, S.; Cottell, J. J. Org. Chem. 2001, 66, 4276−4284. 6. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337−3339. 7. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572−2582. 8. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2003, 125, 1567−1574. 9. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron 2004, 60, 4205−4221. 10. Mullins, R. J.; Jolley, S. L.; and Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review). 1.

233

Tamao−Kumada oxidation Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the Fleming−Kumada oxidation. F F Si R R

KF, H2O2

F F R Si F R

F F Si R R

:

F

H

O

O

2 ROH

KHCO3, DMF

F R Si O F HO H

H

F F R Si O F R HO H

F R

F F O Si O R F R

F F O Si R R F

2 ROH

Example 13 O

O NaCO3, CH3CO3H Me2FSi

CO2Me

HO

CO2Me

3 h, 64% O

O

Example 24 Et O

Et

R

OH

H 2O2, KF, KHCO3

Si OSiMe3

THF−MeOH 51−85%

SiEt2F

R OH

OH

OH

R OH

References 1. 2. 3. 4.

5. 6.

Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120−2122. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57−576. (Review). Kim, S.; Emeric, G.; Fuchs, P. L. J. Org. Chem. 1992, 57, 7362−7364. Mullins, R. J.; Jolley, S. L.; Knapp, A. R. Tamao–Kumada–Fleming Oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 237−247. (Review). Beignet, J.; Jervis, P. J.; Cox, L. R. J. Org. Chem. 2008, 73, 5462−5475. Cardona, F.; Parmeggiani, C.; Faggi, E.; Bonaccini, C.; Gratteri, P.; Sim, L.; Gloster, T. M.; Roberts, S.; Davies, G. J.; Rose, D. R.; Goti, A. Chem. Eur. J. 2009, 15, 1627– 1636.

234

Friedel–Crafts reaction Friedel–Crafts acylation reaction Introduction of an acyl group onto an aromatic substrate by treating the substrate with an acyl halide or anhydride in the presence of a Lewis acid. O R

O

Cl

HCl

R AlCl3

O O R

R

Cl:

O

O:

complexation

AlCl3

R

Cl

AlCl3

AlCl4 R

acylium ion Cl Cl Al Cl Cl O H

electrophilic substitution

O

aromatization

AlCl3

R

HCl R

Example 1, Intermolecular Friedel–Crafts acylation6 F F

O

O

F

Cl N

CHO

AlCl3, CH2Cl2 88%

N

F

CHO

Example 2, Intramolecular Friedel–Crafts acylation7 OMe

OMe OMe

O

OH

OMe

(COCl)2, DMF then AlCl3, 84% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_101, © Springer-Verlag Berlin Heidelberg 2009

235

Example 3, Intramolecular Friedel–Crafts acylation8 CO2CH3 CO2CH3 PPSE, CH3NO2

CO2H

HN

reflux, 10 min., 44%

N H

O

PPSE = Trimethylsilyl polyphosphate Example 4, Intramolecular Friedel–Crafts acylation9 O

CONMe2 POCl3, K2CO3 CH3CN, 60 oC 74%

N H

CO2H MeO N H

NH

O PPA, 80 oC

MeO

35%

NH

O O 20 mol% BF3OEt2 O

O

O

MeNO2, 100 oC 15 min., 98% N Ns

N Ns

References 1.

Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392−1395. Charles Friedel (1832−1899) was born in Strasbourg, France. He earned his Ph.D. In 1869 under Wurtz at Sorbonne and became a professor and later chair (1884) of organic chemistry at Sorbonne. Friedel was one of the founders of the French Chemical Society and served as its president for four terms. James Mason Crafts (1839−1917) was born in Boston, Massachusetts. He studied under Bunsen and Wurtz in his youth and became a professor at Cornell and MIT. From 1874 to 1891, Crafts collaborated with Friedel at École de Mines in Paris, where they discovered the Friedel–Crafts reaction. He returned to MIT in 1892 and later served as its president. The discovery of the Friedel– Crafts reaction was the fruit of serendipity and keen observation. In 1877, both Friedel and Crafts were working in Charles A. Wurtz’s laboratory. In order to prepare amyl iodide, they treated amyl chloride with aluminum and iodide using benzene as the solvent. Instead of amyl iodide, they ended up with amylbenzene! Unlike others before them who may have simply discarded the reaction, they thoroughly investigated

236

the Lewis acid-catalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions. 2. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533−542. (Review). 3. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241−330. (Review). 4. Metivier, P. Friedel-Crafts Acylation. In Friedel-Crafts Reaction Sheldon, R. A.; Bekkum, H., eds.; Wiley-VCH: New York. 2001, pp 161−172. (Review). 5. Basappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004, 43B, 1954−1957. 6. Olah, G. A.; Reddy, V. P.; Prakash, G. K. S. Chem. Rev. 2006, 106, 1077−1104. (Review). 7. Simmons, E.M.; Sarpong, R. Org. Lett. 2006, 8, 2883−2886. 8. Bourderioux, A.; Routier, S.; Beneteau, V.; Merour, J.-Y. Tetrahedron 2007, 63, 9465−9475. 9. Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920−2923. 10. de Noronha, R. G.; Fernandes, A. C.; Romao, C. C. Tetrahedron Lett. 2009, 50, 1407−1410.

Friedel–Crafts alkylation reaction Introduction of an alkyl group onto an aromatic substrate by treating the substrate with an alkylating agent such as alkyl halide, alkene, alkyne and alcohol in the presence of a Lewis acid.

R

AlCl3

R

Cl

Cl:

AlCl3

AlCl4

Cl Cl Al Cl Cl H

R

R aromatization R

HCl

alkyl cation Example 11 O

O O

O

SnCl4, CH2Cl2

O

0 oC, 1 h, 84% O

O

O

Br

Example 24 Me O O R

R2 N R1

R3

N

OH R3 = aryl, alkyl

Me3C

Me O

O

N

Cu TfO OTf

OH

R3 H CMe3

10 mol% 32−96% yield, 83−98% ee

R

R2 N R1

237

Me O O N Me

R3

Me O

Me3C

OH

N Cu TfO OTf

R3

N

CMe3

10 mol%

R3 = aryl, alkyl

H

N Me

O

80−95% yield, 68−97% ee

OH

Example 35 O

B(OH)2 O

Me

O

Me N

Bu N 20 mol%

Me N Me H•HCl Me

DME, rt, 36 h 1 equiv HF

O

O Me

51% yield, 92% ee

References 1. 2.

3. 4. 5. 6. 7.

Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahedron Lett. 1999, 40, 4437−4438. Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation. In Friedel−Crafts Reaction Sheldon, R. A.; Bekkum, H., eds.; Wiley-VCH: New York. 2001, pp 550−556. (Review). Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550−556. (Review). Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garcia, J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154−4155. Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438−15439. Poulsen, T. B.; Jorgensen, K. A. Chem. Rev. 2008, 108, 2903−2915. (Review). Silvanus, A. C.; Heffernan, S. J.; Liptrot, D. J.; Kociok-Kohn, G.; Andrews, B. I.; Carbery, D. R. Org. Lett. 2009, 11, 1175−1178.

238

Friedländer quinoline synthesis The Friedländer quinoline synthesis combines an α-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene α adjacent to the carbonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.

CHO

O R

NH2

1

R O

R1 H

OH R1

OH

R H COR1 NH2

Aldol condensation

H HO

R1

N

O

O R

R

OH

R

NH2

R R

R R

N H

1

:

NH2O

OH R1

R1

N

HO

Example 15 CHO NH2

NaOMe, EtOH

NBn

reflux, 3 h, 90%

O

NBn N

Example 27

H O

N

O AcOH, 100 °C

N

N

O

O 88% NHBoc OBn

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_102, © Springer-Verlag Berlin Heidelberg 2009

OBn

239

Example 38 CHO N

NH2

Me

Me O

Me

N

Conditions NaOH, rt pyrrolidine, 5% H2SO4, rt TBAO, 5% H2SO4, rt TBAO, 5% H2SO4, slow addition, 65 °C

N

Me

N

N

Conversion > 99% 97% > 99% > 99%

Ratio 37:63 86:14 87:13 94:6

Me TBAO = 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane

Me

H N

Me Me

Example 4

10

Mes N

OH NH2

O R2

1 mol% R1

N Mes

Cl Ru Cl PCy3Ph

KOH, 1,4-dioxane 80 oC, 1 h

R2 N

R1

References Friedländer, P. Ber. 1882, 15, 2572−2575. Paul Friedländer (1857−1923), born in Königsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in music and was an accomplished pianist. 2. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed.; Wiley & Sons,: New York, 1952, 4, Quinoline, Isoquinoline and Their Benzo Derivatives, 45–47. (Review). 3. Jones, G. In Heterocyclic Compounds, Quinolines, vol. 32, 1977; Wiley & Sons: New York, pp 181–191. (Review). 4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37−201. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka, H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522−2529. 6. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400−405. 7. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601−605. 8. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; and Volante, R. P. J. Org. Chem. 2003, 68, 467−477. 9. Pflum, D. A. Friedländer Quinoline Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 411−415. (Review). 10. Vander Mierde, H.; Van Der Voot, P.; De Vos, D.; Verpoort, F. Eur. J. Org. Chem. 2008, 1625−1631. 1.

240

Fries rearrangement Lewis acid-catalyzed rearrangement of phenol esters and lactams to 2- or 4ketophenols. Also known as the Fries−Finck rearrangement. OH

O O

OH R

AlCl3

O R

and/or O

R

AlCl3 Cl3Al

O: O

complexation

R

O

O

O R

C−O bond fragmentation

AlCl3 O R

aluminum phenolate, acylium ion O

AlCl3 O

H

O

H

OH

O

O R

R R

O

O

AlCl3

R

OH

OH

H R

O

O

R

Example 15 Br OH

O

OH

ZrCl4, PhCl

OMe O O

Br 160 oC, 3 h, 63%

Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_103, © Springer-Verlag Berlin Heidelberg 2009

Br

241

Example 26 O O

OH

O

10% Bi(OTf)3, PhMe 110 oC, 15 h, 64% OAc

OAc

Example 3, Photo-Fries rearrangement7 O NH2 O

Ph

HN

Ph

Low-pressure Hg lamp 254 nM, MeCN, 36 h, 65%

Example 4, ortho-Fries rearrangement8 MeO

OMe

O

MeO 2.1 equiv LTMP

OCONEt2

OMe

O

CONEt2

−78 oC to rt, 97%

O

Example 5, Thia-Fries rearrangement9 O H

O S CF3 O O Cl

LDA, THF, −78 oC then H3O+, 80%

CF3 S O

OH Cl

References 1.

2. 3. 4. 5. 6.

Fries, K.; Finck, G. Ber. 1908, 41, 4271−4284. Karl Theophil Fries (1875−1962) was born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theodor Zincke. Although G. Finck co-discovered the rearrangement of phenolic esters, somehow his name has been forgotten by history. In all fairness, the Fries rearrangement should really be the Fries−Finck rearrangement. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369−435. (Review). Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem. 2000, 65, 4712−4714. Guisnet, M.; Perot, G. The Fries rearrangement. In Fine Chemicals through Heterogeneous Catalysis 2001, 211−216. (Review). Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982−8983. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794−2796.

242

7. 8. 9.

Ferrini, Serena; Ponticelli, Fabio; Taddei, Maurizio. Org. Lett. 2007, 9, 69−72. Macklin, T. K.; Panteleev, J.; Snieckus, V. Angew. Chem., Int. Ed. 2008, 47, 2097−2101. Dyke, A. M.; Gill, D. M.; Harvey, J. N.; Hester, A. J.; Lloyd-Jones, G.C.; Munoz, M. P.; Shepperson, I. R. Angew. Chem., Int. Ed. 2008, 47, 5067−5070.

243

Fukuyama amine synthesis Transformation of a primary amine to a secondary amine using 2,4-dinitrobenzenesulfonyl chloride and an alcohol. Also known as the Fukuyama−Mitsunobu procedure. SO2Cl NO2

1. R1NH2, pyr. 2. R2OH, PPh3, DEAD

S R1

3. HSCH2CO2H

H N

CO2H NO2 SO2

R2

NO2

NO2

H

R1NH2

S

1

NO2

SO2NHR NO2

H

CO2H

:

:

Cl SO2

SO2NR1R2 NO2

R2OH, PPh3 DEAD

NO2

NO2

NO2

See page 365 for mechanism of the Mitsunobu reaction.

SNAr

HO2C

NR1R2 S SO2 NO2

S R1

H N

CO2H NO2 SO2

R2

H NO2

NO2

Meisenheimer complex Example 16 Ns NH2

HO Br n

DEAD, PPh3 67–74% for n = 1–3

NsHN Br

Cs2CO3

NsN

n-Bu4NI 62–66% n

n

Example 27 O

Et

O

Et

NsHN

OH NsNH2 DEAD, PPh3 MsO

N Boc

MsO

N Boc

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_104, © Springer-Verlag Berlin Heidelberg 2009

OTBDPS CO2Me

244

OH Et

NsN K2CO3 DMF

MsO

N Boc

OTBDPS CO2Me

Example 38 H2N OH

SO2 NO2

K2CO3, PhSH

PyPh2P, DTBAD HN SO2 CH2Cl2, 84%

NO2

CH3CN, 80%

NH2

PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate References (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373−6374. Tohru Fukuyama moved to the University of Tokyo from Rice University in 1995. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38, 5831−5834. 2. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667−2670. 3. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130−133. 4. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309−3313. 5. Olsen, C. A.; JØrgensen, M. R.; Witt, M.; Mellor, I. R.; Usherwood, P. N. R.; Jaroszewski, J. W.; Franzyk, H. Eur. J. Org. Chem. 2003, 3288-3299. 6. Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 6267−6276. 7. Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. Pure Appl. Chem. 2003, 75, 29−38. 8. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org. Biomol. Chem. 2005, 3, 1049−1057. 9. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron 2005, 61, 6046−6055. 10. Janey, J. M. Fukuyama amine synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 424−437. (Review). 1.

245

Fukuyama reduction Aldehyde synthesis through reduction of thiol esters with Et3SiH in the presence of Pd/C catalyst. Et3SiH, Pd/C

O R

O

THF, rt

SEt

R

H

Path A: O R

Pd(0) SEt

oxidative addition

O R

O

Et3SiH Pd

Et3Si SEt

R

O

reductive

SEt Pd

H

elimination

R

Pd(0) H

Path B: Et3SiH

O R

Pd(0)

Et3SiPdH

OSiEt3

Et3SiPdH R

SEt

OSiEt3

SEt Pd H

R

Pd(0)

SEt

O Et3Si

SEt

Example 11 CO2Me

CO2Me O

O Et3SiH, 10% Pd/C O

O

COSEt

O

O

CHO

acetone, rt, 92%

Example 23 HO2C

EtSH, DCC, DMAP EtS CO2Me O NHBoc CH3CN, rt, 1 h, > 70%

Et3SiH, 10% Pd/C acetone, rt, 30 min., >74%

H O

CO2Me NHBoc

CO2Me NHBoc

Example 38 COSEt MeO

CHO

0.5 mol% Pd/C 2 equiv Et3SiH rt, 2 h, 92%

MeO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_105, © Springer-Verlag Berlin Heidelberg 2009

R

H

246

References 1. 2. 3. 4. 5. 6. 7. 8.

Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050–7051. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451–8452. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667–1673. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121– 1123. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569– 4573. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048–4049. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219–3223. (Possible mechanisms were proposed in this paper). Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477–480.

247

Gabriel synthesis Synthesis of primary amines using potassium phthalimide and alkyl halides.

O

CO2H

1. R⎯X N

K

H2N R

2. Nu or R'OH

CO2H

O

O N

OH

O

R X SN2

K

O

N R

N R

O

O

OH

hydrolysis

O

OH O

H O H N

CO2 H N R

CO2 H2 N R

R

CO2

O OH

O OH

Example 12 Br

O

O

O O

NPhth

KNPhth, DMF

Br

O 90 oC, 40 min. 90%

O NPhth

O

NH2 H2NNH2, CH3OH

O

O

reflux, 1 h, 80%

O

O O

NH2

Example 26 DIAD, PPh3 phthalimide

R1 R2

OH R3

THF, rt, 4 h 76−98%

R1

R1

NH2H2 or CH3NH2 R2 CH3OH NPhth

R2 R3

76−88%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_106, © Springer-Verlag Berlin Heidelberg 2009

NH2 R3

248

Example 38 O

O Br

NK

CO 2Et

CO2Et

N

DMF, 90 oC, 3 h, 77% O

O

O O

O

O

O O

6 M HCl, reflux N

14 h, 93%

OH =

13

C

HCl•H2N

O

Example 49 OH

NPht

phthalimide, PPh3 OH

DEAD, THF 54%

NH2

1. NH2NH2•H2O, THF, reflux, 8 h 2. Pd/C, H2, THF, 95%, 2 steps NPht

NH2

References Gabriel, S. Ber. 1887, 20, 2224−2226. Siegmund Gabriel (1851−1924), born in Berlin, Germany, studied under Hofmann at Berlin and Bunsen in Heidelberg. He taught at Berlin, where he discovered the Gabriel synthesis of amines. Gabriel, a good friend of Emil Fischer, often substituted for Fischer in his lectures. 2. Sheehan, J. C.; Bolhofer, V. A. J. Am. Chem. Soc. 1950, 72, 2786−2788. 3. Han, Y.; Hu, H. Synthesis 1990, 122−124. 4. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 5. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357−2361. 6. Sen, S. E.; Roach, S. L. Synthesis, 1995, 756−758. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063−8068. 8. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002, 45, 569−570. 9. Tanyeli, C.; Özçubukçu, S. Tetrahedron Asymmetry 2003, 14, 1167−1170. 10. Ahmad, N. M. Gabriel synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 438−450. (Review). 11. Al-Mousawi, S. M.; El-Apasery, M. A.; Al-Kanderi, N. H. ARKIVOC 2008, (16), 268−278. 1.

249

Ing–Manske procedure A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide: O

O 1. RX N

K

NH NH

H 2N R

2. NH2NH2

O

O N

O

R X

O SN2

K

:NH2NH2

O

O

O

O :

NH R

O

O NH NH

NHNH2

NHNH2 N R

N R

O

O

NH NH

H2 N R

O NH R

O

Example 16 O

O Br

N

P(OEt)3 Δ

O

PO(OEt)2 N

H2NNH2, EtOH rt, 18 h, 97%

PO(OEt)2 H2N

O

References 1.

2. 3. 4. 5. 6. 7. 8.

Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348–2351. H. R. Ing was a professor of pharmacological chemistry at Oxford. R. H. F. Manske, Ing’s collaborator at Oxford, was of German origin but trained in Canada before studying at Oxford. Manske left England to return to Canada, eventually to become Director of Research in the Union Rubber Company, Guelph, Ontario, Canada. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228–237. Khan, M. N. J. Org. Chem. 1995, 60, 4536–4541. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615–622. Khan, M. N. J. Org. Chem. 1996, 61, 8063–8063. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167–1170. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34, 4439–4445. Ali, M. M.; Woods, M.; Caravan, P.; Opina, A. C. L.; Spiller, M.; Fettinger, J. C.; Sherry, A. D. Chem. Eur. J. 2008, 14, 7250–7258.

250

Gabriel–Colman rearrangement Reaction of the enolate of a maleimidyl acetate to provide isoquinoline 1,4-diol. O

O

OH

R N G G = CO, SO2

O

ROH

G

N

O

O OMe O N

R

O

O

O

Me O O O

OMe H N

O

OH

O

N

NH

OH

O

O

O R

R

R

O

R

O

NH

O

NH

N R

O

R

Ar

O OMe

OMe

O

NaOR

Ar

6

Example 1

O

OH

O Oi-Pr

N S O O

O

4 equiv i-PrONa i-PrOH, reflux 5 min., 85%

Oi-Pr S O

NH O

Example 29 O

OH

N CO2Et O

CO2Et

NaOMe, MeOH

NH

reflux, 24 h 91% O

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

(a) Gabriel, S.; Colman, J. Ber. 1900, 33, 980−995. (b) Gabriel, S.; Colman, J. Ber. 1900, 33, 2630−2634. (c) Gabriel, S.; Colman, J. Ber. 1902, 35, 1358−1368. Allen, C. F. H. Chem. Rev. 1950, 47, 275−305. (Review). Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons., New York, N.Y., 1952, 378. (Review). Hill, J. H. M. J. Org. Chem. 1965, 30, 620−622. (Mechanism). Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14, 1171−1175. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281−1288. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980−989. Pflum, D. A. Gabriel−Colman Rearrangement. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 416−422. (Review). Kapatsina, E.; Lordon, M.; Baro, A.; Laschat, S. Synthesis 2008, 2551−2560.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_107, © Springer-Verlag Berlin Heidelberg 2009

251

Gassman indole synthesis The Gassman indole synthesis involves a one-pot process in which a hypohalite, a ȕ-carbonyl sulfide derivative, and a base are added sequentially to an aniline or a substituted aniline to provide 3-thioalkoxyindoles. The sulfur can be easily removed by hydrogenolysis or Raney nickel.

S t-BuOCl

R

S NH Cl

NH2

Et3N

R

O

N H

Et3N :

R

S : NH Cl

O

SN 2

O

H N H

R S

sulfonium ion O

Et3N: R

N H

H

[2,3]-sigmatropic rearrangement (Sommelet−Hauser)

S

Et3N:

S : N H

S

H

O R NH

S

H S

R OH

NEt3

R

R N H

N H

Example 11 S

1. t-BuOCl NH2

CH3

2. S O

N H

Me

3. Et3N, 69%

SCH3 1. t-BuOCl NH2

O

2.

SCH3

LiAlH4, Et2O N

0 oC, 48% overall

3. Et3N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_108, © Springer-Verlag Berlin Heidelberg 2009

N H

252

Example 22 MeS MeS

t-BuOCl, PhNH2 O

O

Et3N, 93%

O

NH2 O

O

O

Ra-Ni EtOH

p-TsOH, PhH, reflux O

NH2 O O

71% 2 steps

O

N H O

References 1.

2. 3. 4. 5. 6. 7.

(a) Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc. 1974, 96, 5495−5508. Paul G. Gassman (1935−1993) was a professor at the University of Minnesota (1974−1993). (b) Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508−5512. (c) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512−5517. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621−5623. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Nakagawa, K. Chem. Pharm. Bull. 1990, 38, 2459−2462. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197−8198. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438−1449. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696−8697. Li, J.; Cook, J. M. Gassman Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 128−131. (Review).

253

Gattermann–Koch reaction Formylation of arenes using carbon monoxide and hydrogen chloride in the presence of aluminum chloride under high pressure. CHO

AlCl3 HCl

CO

Cu2Cl2

:

O Cl

AlCl3

Cl3Al

Cl

:C O

AlCl3 AlCl3

H

O

O

:O:

AlCl3

C O

:

: :

:C O

:C O:

Cl

HCl

:C O

:

Cl AlCl3

AlCl4

H

H

H

H

acylium ion Cl CHO

H

CHO

CHO

AlCl3

HCl AlCl4

AlCl4

Example, A more practical variant4 OH

H2O 0 to 100 oC

OH

OH Zn(CN)2, AlCl3

CHO

NH2 HCl (g), 0 oC

HO

HO

Cl

95%

HO

orcinol

References 1.

2. 3. 4. 5.

6.

Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622−1624. Ludwig Gattermann (1860−1920) was born in Freiburg, Germany. His textbook, “Die Praxis de organischen Chemie” (1894) was one of his major contributions to organic chemistry. Crounse, N. N. Org. React. 1949, 5, 290−300. (Review). Truce, W. E. Org. React. 1957, 9, 37−72. (Review). Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry 1990, 1, 187−198. (a) Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106−2111. (b) Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159−160. (c) Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem. Soc. 1997, 119, 5100−5105. (d) Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T. J. J. Org. Chem. 1998, 63, 4408−4412. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr, O.; Haas, R. J. Prakt. Chem. 2000, 342, 297−310.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_109, © Springer-Verlag Berlin Heidelberg 2009

254

Gewald aminothiophene synthesis Base-promoted aminothiophene formation from ketone, α-active methylene nitrile and elemental sulfur.

R

O

CO2R2 S8

R1

CO2R2

R

Base R1

CN

NH2

S

R1 O

O

OR2

O

R

OR

2

BH

H B:

Knoevenagel

CN

R1

:B

OR2

O OR2

O BH

R

HO NC

O

R

OR2

R1

R

CN

CN

R1

S S S S

H :B

H BH R

S S

S

N 1

R H

S S S 6

S S

CO2R2

R

NH

R

:

R1

S S

R2O2C

OR2

O

OR2

H

condensation

CN

R1

R O

HO NC

S7

S S S S S

R1

NH2

S

Ylidene-sulfur adduct Example 14 H3 C

N

CH3

CO2Et CO2Et

S8

NH2

S CN

morpholine

N

82%

N

Example 27 O O

O

CO2Et CN

Me

S8, EtOH, morpholine 60 oC, 5 h, 74%

t-BuO2C

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_110, © Springer-Verlag Berlin Heidelberg 2009

CO2Et S

NH2

B

255

Example 39 O

HN(TMS)3, HOAc toluene, 65 oC, 90%

Me

NC

CN Knoevenagel condensation

O2N

NC

CN Me

NH2

NC

1.2 atom equiv S8 1 equiv NaHCO3

S

THF, H2O, 80−85% O2N

O2N

Example 410

O

NC

NH2 S

O

O

O

O

3 equiv morpholine 1 equiv S8, 55 oC, 24 h

O

85% conversion 64% yield

O

O O

Example 511

O O

N

O

N

S N

O

O O

O

Addition of sulfur

N

N N

S S Sx

N ylidene

ylidene-sulfur adduct

Dimerization

NC

O NH2

20−45 oC, 24 h 72%

Condensation MPS = morpholinepolysulfide

O

3 equiv morpholine 2 equiv S8, MeOH

Cyclization

NH2 CO2CH3 CN CN

O

O

Re-cyclization NH2 S

dimer

N

256

References (a) Gewald, K. Z. Chem. 1962, 2, 305−306. (b) Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94−100. (c) Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. (d) Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 271−275. 2. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. 1967, 6, 294−306. (Review). 3. Gewald, K. Chimia 1980, 34, 101−110. (Review). 4. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953-1955. 5. Sabnis, R. W. Sulfur Reports 1994, 16, 1−17. (Review). 6. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333−345. (Review). 7. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999, 42, 5437. 8. Tinsley, J. M. Gewald Aminothiophene Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 193−198. (Review). 9. Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.; Mei, J.; Tedrow, J. S.; Dalla Riva Toma, J. Tetrahedron 2006, 62, 11311−11319. 10. Tormyshev, V. M.; Trukhin, D. V.; Rogozhnikova, O. Yu.; Mikhalina, T. V.; Troitskaya, T. I.; Flinn, A. Synlett 2006, 2559−2564. 11. Puterová, Z.; Andicsová, A.; Végh, D. Tetrahedron 2008, 64, 11262−11269. 1.

257

Glaser coupling Oxidative homo-coupling of terminal alkynes using copper catalyst in the presence of oxygen. CuCl R C CH

R C C C C R

NH4OH, EtOH

+2 L

+2

L

L

Cu R

X

L

X

X

Cu

Cu

R

Cu

L

L

Cu

Cu

R L

L

:

R or

+2

Cu+

L

L = Amine X = Cl, OAc

L Cu

R

Cu+2

R

R

R

Cu L

L

2 Cu

Alternatively, the radical mechanism is also operative: H

CuCl

Base

O2 Cu(II)

dimerization

Example 11 2

O2 Cu NH4OH, EtOH 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_111, © Springer-Verlag Berlin Heidelberg 2009

Cu(I)

Cu(I)

258

Example 2, Homo-coupling2 Cu, NH4Cl O2, 90%

HO

HO

OH

Example 37

R R

S S

CuCl

S

R

R

S

S

S

S

TMEDA

S

O2, CH2Cl2, 0°C 47%

R = n-Hexyl

S S R

S R

S S

S

S

R

S R

References 1. 2. 3. 4. 5. 6. 7. 8.

Glaser, C. Ber. 1869, 2, 422–424. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583– 1590. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556–4557. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632– 2657. (Review). Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J. S. J. Org. Chem. 2002, 67, 2111–2117. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501–5504. Andersson, A. S.; Kilsa, K.; Hassenkam, T.; Gisselbrecht, J.-P.; Boudon, C.; Gross, M.; Nielsen, M. B.; Diederich, F. Chem. Eur. J. 2006, 12, 8451–8459. Gribble, G. W. Glaser Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 236−257. (Review).

259

Eglinton coupling Oxidative homo-coupling of terminal alkynes mediated by stoichiometric (or often excess) Cu(OAc)2. A variant of the Glaser coupling reaction. Cu(OAc)2 R

H

R

pyridine/MeOH

AcO Cu

R

OAc

pyridine R

H

R

R

N H

R

dimerization

R

Cu

OAc

R

R

Example 12

Cu(OAc)2 pyr., 25 °C 20%

Example 2, Cross-coupling3 SPh SPh Cu(OAc)2 pyridine/MeOH (1:1) rt, 72% Ph

CO2Me

CO2Me Ph

Example 3, Homo-coupling4 Cl NC

N

NC Cu(OAc)2, pyridine

N N

MeOH, 1.5 h, 68% Cl Cl

CN

260

Example 45 TMS

R Cu(OAc)2 K2CO3 pyr., MeOH 61–70%

R TIPS

TIPS 1. TBAF

R = H, t-Bu

2. CuCl, Cu(OAc)2 pyr. R

R

51–64% TIPS

R R

R

Example 511 CN O Fe

2 equiv Cu(OAc)2•H2O 1 : 1 Pyr : MeOH 70 oC, 12 h, 41%

CN O Fe

Fe O CN

Example 612

Cu(OAc)2 Pyr./MeOH/Et2O 62%

261

References (a) Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737−738. Geoffrey Eglinton (1927−) was born in Cardiff, Wales. (b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614−3625. (c) Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225−328. (Review). 2. McQuilkin, R. M.; Garratt, P. J.; Sondheimer, F. J. Am. Chem. Soc. 1970, 92, 6682– 6683. 3. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558−5560. 4. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123−125. 5. Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.; Wan, W. B. Tetrahedron Lett. 1997, 38, 7483–7486. 6. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632-8633. 7. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem., Int. Ed. 2001, 40, 3402−3405. 8. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632−2657. (Review). 9. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4, 2533−2536. 10. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem. Soc. 2003, 125, 10057−10065. 11. Shanmugam, P.; Vaithiyananthan, V.; Viswambharan, B.; Madhavan, S. Tetrahedron Lett. 2007, 48, 9190−9194. 12. Miljanic, O. S.; Dichtel, W. R.; Khan, S. I.; Mortezaei, S.; Heath, J. R.; Stoddart, J. F. J. Am. Chem. Soc. 2007, 129, 8236−8246. 1.

262

Gomberg–Bachmann reaction Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound. O

N2

OH O

N N

Ph

OH

OH

Ph

Ph N N

:

N N

N2 ↑

N N O

N N O

N N Ph Ph N N O

Ph N N

H

O

OH

O O

4

Example 1

N2 BF4

O

O

KOAc, 18-C-6 rt, 55%

O

O O

O

Example 25 NH2 N

N MeO

ONO N

PhH, TFAA, reflux 2 d, 33%

N

N

N MeO

N

N

References 1.

2. 3. 4.

Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339−2343. Moses Gomberg (1866−1947) was born in Elizabetgrad, Russia. He discovered the triphenylmethyl stable radical at the University of Michigan in Ann Arbor, Michigan. In this article, Gomberg declared that he had reserved the field of radical chemistry for himself! Werner Bachmann (1901−1951), Gomberg’s Ph.D. student, was born in Detroit, Michigan. After his postdoctoral trainings in Europe Bachmann returned to the University of Michigan as the Moses Gomberg Professor of Chemistry. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594−1603. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859−861. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412−4417.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_112, © Springer-Verlag Berlin Heidelberg 2009

263

Gould–Jacobs reaction The Gould–Jacobs reaction is a sequence of the following reactions: a. Substitution of an aniline with either alkoxy methylenemalonic ester or acyl malonic ester providing the anilinomethylenemalonic ester; b. Cyclization of to the 4-hydroxy-3-carboalkoxyquinoline (4-hydroxyquinolines exist predominantly in 4-oxoform); c. Saponification to form acid; d. Decarboxylation to give the 4-hydroxyquinoline. Extension could lead to unsubstituted parent heterocycles with fused pyridine ring of Skraup type.

RO2C NH2

R'

CO2R OR''

− R''OH

CO2R

N H

Δ

R' O

OH

OH CO2R N

RO2C

heat

CO2H

HO− N

R'

Δ N H

R'

R'

R = alkyl; R' = alkyl, aryl, or H; R'' = alkyl or H O EtO2C

EtO2C OEt substitution

OEt

OEt

H

N H2

CO2Et

OEt

N H

O

OH

O CO2Et

cyclization

O

EtO

− EtOH

:

NH2

O

CO2Et

CO2Et

tautomerization

N H

N

N

Example 13

O

EtO2C N H

CO2Et

O Ph2O, reflux 75%, 10:1

CO2Et

O N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_113, © Springer-Verlag Berlin Heidelberg 2009

O O

CO2Et N H

264

Example 28 H

EtO

H N

H

H2N

PhOPh

CO2Et

EtO2C

N R

EtO2C

EtOH, reflux

N R

CO2Et

O

250 oC

Cl POCl3

N R

EtO2C

70

N H

N R

EtO2C

oC

N

Example 3, Microwave-assisted Gould–Jacobs reaction9 NH2

R

N N R1

EtO2C

CO2Et Ph−O−Ph

H

o

N

OEt

130−140 C

CO2Et

HN

R

N N R1

N

R

N

N R1

N

CO2Et

Ph−O−Ph 250 oC

Microwave, neat

CO2Et O

N

10−12 min., 64−75%

Example 410 Ar

Ar

EtO2C

N

N Ph

NH2

H

CO2Et

EtOH

OEt

reflux

N

EtO2C N Ph

CO2Et

N H

H

POCl3 reflux Ar Ph-O-Ph heat

O

Ar CO2Et

N N Ph

N H

POCl3 reflux

Cl CO2Et

N N Ph

N

References 1.

Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890−2895. R. Gordon Gould was born in Chicago in 1909. He earned his Ph.D. at Harvard University in 1933. After serving as an instructor at Harvard and Iowa, Gould worked at Rockefel-

265

ler Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs. 2. Reitsema, R. H. Chem. Rev. 1948, 53, 43−68. (Review). 3. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110−1114. 4. Elguero J., Marzin C., Katritzky A. R., Linda P., The Tautomerism of Heterocycles, Academic Press, New York, 1976, pp 87−102. (Review). 5. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med. Chem. 1995, 38, 950−957. 6. Milata, V.; Claramunt, R. M.; Elguero, J.; Zálupský, P. Targets in Heterocyclic Systems 2000, 4, 167–203. (Review). 7. Curran, T. T. Gould–Jacobs Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423−436. (Review). 8. Ferlin, M. G.; Chiarelotto, G.; Dall’Acqua, S.; Maciocco, E.; Mascia, M. P.; Pisu, M. G.; Biggio, G. Bioorg. Med. Chem. 2005, 13, 3531−3541. 9. Desai, N. D. J. Heterocycl. Chem. 2006, 43, 1343−1348. 10. Kendre, D. B.; Toche, R. B.; Jachak, M. N. J. Heterocycl. Chem. 2008, 45, 1281−1286.

266

Grignard reaction Addition of organomagnesium compounds (Grignard reagents), generated from organohalides and magnesium metal, to electrophiles. O Mg(0)

R1

R MgX

R X

R 1 R2

R2

R

OH

Formation of the Grignard reagent: Mg Mg

Mg Mg R X

R

X

Mg Mg single electron

R MgX R

transfer

MgX

Grignard reaction, ionic mechanism: R2 δ δ O R1 R MgX δ δ

R2 R1

‡

R 1 R2

O R MgX

R

OMgX

Radical mechanism, R2 R1

R O R MgX

R2 R1

R1 R2 O MgX

R

R1 R 2

H

R

OMgX

OH

Example 14 EtMgBr NOH

NH

reflux, tol./ether, 76% H

This reaction is known as the Hoch–Campbell aziridine synthesis, which entails treatment of ketoximes with excess Grignard reagents and subsequent hydrolysis of the organometallic complex to produce aziridines.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_114, © Springer-Verlag Berlin Heidelberg 2009

267

Example 25 O O

O O O

O

Br

O O

Mg Ph

65%

OMe O MeO

N

O

MeO

Ph

N MeO

OMe

OMe

MeO

MeO

OMe

Example 510 OH O

THF

O

MgBr

CHO

O O

0 oC to rt, 91%

Garner's aldehyde

Example 611 OH

HO

O

3 equiv BrMg

O

O THF, 55

oC,

OH

1 h, 85%

HO

HO 52%

28%

5%

References Grignard, V. C. R. Acad. Sci. 1900, 130, 1322−1324. Victor Grignard (France, 1871−1935) won the Nobel Prize in Chemistry in 1912 for his discovery of the Grignard reagent. 2. Ashby, E. C.; Laemmle, J. T.; Neumann, H. M. Acc. Chem. Res. 1974, 7, 272−280. (Review). 3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521−546. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235−242. 5. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446−5452. 6. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 7. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000, Chapter 1, pp 1−26. (Review). 8. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081−2091. (Review). 9. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733−763. (Review). 10. Babu, B. N.; Chauhan, K. R. Tetrahedron Lett. 2008, 50, 66−67. 11. Mlinaric-Majerski, K.; Kragol, G.; Ramljak, T. S. Synlett 2008, 405−409. 12. Chen, D.; Yang, C.; Xie, Y.; Ding, J. Heterocycles 2009, 77, 273−277. 1.

268

Grob fragmentation The C−C bond cleavage primarily via a concerted process involving a five atom system. General scheme:

: D

L

L

D

D = O−, NR2; L = OH2+, OTs, I, Br, Cl Example 12

NaH 15-crown-5

MsO

OMOM

OMOM

OMOM MsO

0 oC to rt, 95% O

O

OH

Example 2, Aza-Grob fragmentation3

N

OH

15 eq. NaBH4, THF

O

SH

N H

70 oC, 31 h, 53%

S

Example 37 OTs NaH, DMSO, 40 oC, 1 h; OH MeO

O

then tosylate, 40 oC, 1 h 52%

MeO

Example 48 H H

OMs 1.1 equiv KHMDS

H

OH H

H

HO

THF, 0 oC, 15 min. 93%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_115, © Springer-Verlag Berlin Heidelberg 2009

H

269

References (a) Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594−603. (b) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. 1967, 6, 1−15. Cyril A. Grob (1917−2003) was born in London (UK) to Swiss parents, studied chemistry at ETH Zürich and completed his PhD in 1943 under the guidance of Leopold Ruzicka (A Nobel laureate) on artificial steroidal antigens. He then moved to Basel to work with Taddeus Reichstein (another Nobel laureate) first at the pharmaceutical institute and from 1947 at the organic chemistry institute of the university, where he moved up the academic career ladder to become the director of the institute and holder of the chair there as Reichstein’s successor in 1960. An investigation of the reductive elimination of bromine from 1,4-dibromides in the presence of zinc led in 1955 to the recognition of heterolytic fragmentation as a general reaction principle. The heterolytic fragmentation has now entered textbooks under his name. Experimental evidence for vinyl cations as discrete reactive intermediates was also first provided by Grob. Cyril Grob never acted impulsively, but always calmly and deliberately. He never sought attention in public, but fulfilled his social duties efficiently, reliably, and without a fuss. He died in his home in Basel (Switzerland) on December 15, 2003 at the age of 86. (Schiess, P. Angew. Chem., Int. Ed. 2004, 43, 4392.) 2. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215−5218. 3. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208−4029. 4. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511−4516. 5. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542−6543. 6. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett. 2003, 5, 905−908. 7. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495−499. 8. Maimone, T. J.; Voica, A.-F.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3054−3056. 9. Yuan, D.-Y.; Tu, Y.-Q.; Fan, C.-A. J. Org. Chem. 2008, 73, 7797−7799. 10. Barbe, G.; St-Onge, M.; Charette, A. B. Org. Lett. 2008, 10, 5497−5499. 1.

270

Guareschi–Thorpe condensation 2-Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia. R

R CN

R

CN

H3N: R1O

R1 O

O

R1O

O

O

R

H3N:

CN 1

H2 N

CN

NH3

O

R OH

N H

O

H3 N H H

O

CN R

O H

H2 N

O

R

H2N

R

O

CN H O NH2

H3N:

R

R OH

CN

OH

R CN

:NH3 R H3N H

O

O :NH2

O

R H R

N O H H

CN

O

O

CN

H2 O R

N H

O

Example6

O

CN

NH3

CO2Et

75%

NC O

CN N H

O

Guareschi imide

References 1.

2. 3. 4. 5. 6. 7. 8.

(a) Guareschi, I. Mem. R. Accad. Sci. Torino 1896, II, 7, 11, 25. (b) Baron, H.; Renfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726−1961. Jocelyn F. Thorpe spent two years in Germany where he worked in the laboratory of a dyestuff manufacturer before taking a post as a lecturer at Manchester. Thorpe later became FRS (Fellow of the Royal Society) and professor of organic chemistry at Imperial College. Vogel, A. I. J. Chem. Soc. 1934, 1758−1765. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384−389. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960−966. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946−2950. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem. 1982, 47, 1445−1451. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. Galatsis, P. Guareschi−Thorpe Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 307−308. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_116, © Springer-Verlag Berlin Heidelberg 2009

271

Hajos–Wiechert reaction Asymmetric Robinson annulation catalyzed by (S)-(−)-proline. O cat. O

HO2C H CH3CN

O

O

O

N H O

H HO2C H

O Michael addition

O

O

enamine formation

O

O

N H

O O

O

N H

O

H2O:

:

catalytic asymmetric

N

hydrolysis

O

N

H H CO2 N CO2

enamine aldol

CO2

OH

of iminium salt

CO2

O

O

O

O

:

E1cB

HO N

O H

OH

OH

O

OH

O

B:

CO2

Example 11a O

O 3 mol% (S)-proline

O

CH3CN, 100%, 93.4% ee

O

O

Example 23 O

O

O

O

1 equiv L−phenylalanine D-CSA, DMF, rt, 24 h, then increase temperature 10 oC every 24 h for 5 days. 79%, 91% ee

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_117, © Springer-Verlag Berlin Heidelberg 2009

272

Example 38 O

O L-phenylalanine, PPTS

O

O

DMSO, 50 oC, 24 h sonication, 94%, 73% ee

O OBn

OBn

Example 49 O

O

O

O

1 equiv L-phenylalanine 0.5 equiv 1 N HClO4 DMSO, 90 oC 86%, 48% ee

O

References (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615−1621. Hajos and Parrish were chemists at Hoffmann−La Roche. (b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10, 496−497. 2. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108−3135. 3. Hagiwara, H.; Uda, H. J. Org.Chem. 1998, 53, 2308–2311. 4. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357−389. 5. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395−2396. 6. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573−576. 7. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16−17. 8. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron 2005, 61, 5057−5065. 9. Nagamine, T.; Inomata, K.; Endo, Y.; Paquette, L. A. J. Org. Chem. 2007, 72, 123– 131. 10. Kennedy, J. W. J.; Vietrich, S.; Weinmann, H.; Brittain, D. E. A. J. Org. Chem. 2009, 73, 5151−5154. 11. Christen, D. P. Hajos–Wiechert Reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 554−582. (Review). 12. Zhu, H.; Clemente, F. R.; Houk, K. N.; Meyer, M. P. J. Am. Chem. Soc. 2009, 131, 1632−1633. 1.

273

Haller–Bauer reaction Base-induced cleavage of non-enolizable ketones leading to carboxylic amide derivative and a neutral fragment in which the carbonyl group is replaced by a hydrogen. O

O R R1

R2

R

NaNH2

R5 4 3R

R R1

PhH, reflux

H NH2 R2

R5 R4 R3

non-enolizable ketone O R R1

R2

R

R5 4 3R

R R1

O

O NH2 R5 R4 R2 R3

R R1

NH3

R

R2

R5 4 3R

H

R5 R R3

4

NH2

Example 1

4

CO2H t-BuOK, t-BuOH 43% O

Example 29 OMe O

O

O 1. KOH, dioxane OMe O

2. CH2N2 77% 2 steps

OMe

OMe

OMe

Example 3, Racemization10 O H

LiNHC6H11

NHC6H11 H

O H

PhH, 80 oC 46%

H

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824−829. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399−1408. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044−5053. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167−201. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279−280. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399−1422. (Review). Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287−1288. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983−1986. Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006, 2556−2562. Braun, I.; Rudroff, F.; Mihovilovic, M. D.; Bach, T. Synthesis 2007, 24, 3896−3906.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_118, © Springer-Verlag Berlin Heidelberg 2009

274

Hantzsch dihydropyridine synthesis 1,4-Dihydropyridine from the condensation of aldehyde, β-ketoester and ammonia. Hantzsch 1,4-dihydropyridines are popular reducing reagents in organocatalysis. R CO2Et

O R

H

NH3

EtO2C

R1

O

CO2Et

R1

R1

N H

O H3N:

H

enolate

CO2Et

:NH3 CO2Et

R

R1

O

condensation O

R1

CO2Et :NH3

enamine

R1

formation

CO2Et

R

CO2Et O

R1

O

R1 CO2Et

− H2 O

HO R1 H2N : H2N H EtO2C

R H

H3N:

EtO2C

R1

CO2Et

R1

O

H2N

CO2Et

tautomerization O R1

H2N H

R

CO2Et

1 R1 O N R H

R1

R NH2

1

EtO2C

H

HO R1

R

R EtO2C

CO2Et N H

R1

R1

Example 12

O

CO2Et H

NO2

:NH3 H

H3N:

R EtO2C

Michael addition

:

H2 N

CO2Et

aldol

CO2Et

OH

H

O

H

H3N:

OH R

H

formation

R1

O

R

NH3

NO2 CO2Et

EtO2C O N H

nifedipine

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_119, © Springer-Verlag Berlin Heidelberg 2009

CO2Et N H

R1

275

Example 29 O O SiO2 O

HO3S O

O R'

H

CO2R2

RH R1O2C

CO2R2

NH4OAc (SiO2-SO3H), solvent-free 60 oC, 83−95%

N H

Example 3, Hantzsch 1,4-dihydropyridine as a hydrogen donor10 EtO2C

CO2Et N H

N

R O O P O OH

N H

R

84−99% ee

References Hantzsch, A. Ann. 1882, 215, 1−83. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578−585. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753−757. 4. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5187. 5. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J. Heterocycl. Chem. 1995, 32, 831−833. 6. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077−1080. 7. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67, 3499−3501. 8. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 304−307. (Review). 9. Gupta, R.; Gupta, R.; Paul, S.; Loupy, A. Synthesis 2007, 2835−2838. 10. Metallinos, C.; Barrett, F. B.; Xu, S. Synlett 2008, 720−724. 1. 2. 3.

276

Hantzsch pyrrole synthesis Reaction of α-chloromethyl ketones with β-ketoesters and ammonia to assemble pyrroles. O

CO2Et

Cl

CO2Et :NH 3

N H

O

CO2Et

enamine

− H2 O

H

H3N:

HO H2N:

formation

O

CO2Et

NH3

H2 N

H2N

H3 N H

OH

O Cl

CO2Et

− H2 O

CO2Et H

Cl

H2N

:

HN

:NH

CO2Et Cl

CO2Et

CO2Et

CO2Et

CO2Et H

:

H3N:

HN

N H

N H

Example 14 F3C

DME, 87−140 oC

O H2N

Br

CO2Me

2.5 h, 60%

F3C

N H

CO2Me

Example 27 CO2Et O Cl

O

CO2Et

NH3, EtOH 48 h, 48%

N H

References 1. 2. 3. 4. 5. 6. 7.

Hantzsch, A. Ber. 1890, 23, 1474−1483. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171−5186. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332, 143−147. Kameswaran, V.; Jiang, B. Synthesis 1997, 530−532. Trautwein, A. W.; Süȕmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381−2384. Ferreira, V. F.; De Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411−454. (Review). Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I. Chem. Heterocycl. Compounds 2004, 40, 1218−1219.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_120, © Springer-Verlag Berlin Heidelberg 2009

277

Heck reaction The palladium-catalyzed alkenylation or arylation of olefins.

H

R2

Pd(0) (catalytic)

R1

R2

R3

R4

base

R3

R4

R1 X

R1 = aryl, alkenyl, alkyl (with no β-hydrogen) X = Cl, Br, I, OTf, OTs, N2+

The catalytic cycle: Pd(0) or Pd(II) precatalysts

base•HX R1

LnPd(0) base

A

E

X LnPd(II) H R1

R2

R3

R4

X LnPd(II) R1

D

H R1 R3

H

R2

R3

R4

B Pd(II)LnX R2 R4

R1 C

R3 H

A: Oxidative addition B: Migratory insertion (syn) C: C−C bond rotation

Pd(II)LnX R2 R4

D: syn-β-elimination E: Reductive elimination

Example 1, Asymmetric intermolecular Heck reaction6

CO2Et N CO2Me

X

OTf

Pd[(R)-BINAP]2 3 mol% proton sponge PhH, 60 oC 95%, > 99% ee

EtO2C * N CO2Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_121, © Springer-Verlag Berlin Heidelberg 2009

278

Example 2, Intramolecular Heck7 N

OTBS

N

0.3 eq. Pd(OAc)2

I N

N

Bu4NCl, DMF, K2CO3 70 oC, 3 h, 74%

H

H

H

OTBS

O

O

Example 38 O Cl

O O

O

1.5% Pd2(dba)3, 6% P(t-Bu)3 1.1. eq. Cs2CO3, dioxane MeO 120 oC, 24 h, 82%

MeO

Example 4, Intramolecular Heck9 N

Cl

N

N H

10 mol% Pd(OAc)2

N

Bu4NCl, K2CO3 DMF, 100 oC, 67%

N

N H

Example 5, Intramolecular Heck13 Me NTs O MeN

H H N

N Bn TfO

N H H

Me Me

N Me

Me Me

MeN

Pd(OAc)2 (R)-Tol-BINAP MeCN, 80 oC (62%, 90% ee)

OTf Bn N

Me TsN

NMe

H H N

N H H N Bn

O TsN Me

NTs Me

O

Example 6, Reductive Heck reaction17

Me Br

Me H

Me H 5 mol% Pd(P(o-tol)3(OAc)2

NH

NaOCHO, TBAB, Et3N DMF, 80 oC, 65%

Me

Me

O

O N H

O

NMe

Bn N

279

References 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518−5526. Richard Heck discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular book,4 Heck had difficulties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida. Heck, R. F. Acc. Chem. Res. 1979, 12, 146−151. (Review). Heck, R. F. Org. React. 1982, 27, 345−390. (Review). Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985. (Book). Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 103−113. (Book). Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505−2508. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685−2686. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10−11. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009−3066. (Review). Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321. (Review). Link, J. T. Org. React. 2002, 60, 157−534. (Review). Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 9008−9009. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945−2963. (Review). Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd edn.) 2004, 1, 271−305. (Review). Oestreich, M. Eur. J. Org. Chem. 2005, 783−792. (Review). Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404−406. Fuchter, M. J. Heck Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 2−32. (Review). The Mizoroki-Heck Reaction; Oestreich, M., Ed.; Wiley & Sons: Hoboken, NJ, 2009.

280

Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl recipient. Pd(Ph3P)4, Ph3P, CuI

N

S

I

N

Cs2CO3, DMF, 140 oC

S

N Pd(0)

Pd(II)I

I

S

S

H

insertion

oxidative addition

Cs2CO 3

N Pd(II) I

B:

S N

Pd(0)

CsI

CsCHO3

Example 12

Br

N

N N

N Bu

O

N

Pd(OAc)2, NaHCO3 n-Bu4NCl, DMA 150 oC, 24 h, 83%

N Bu

O

Example 23 O N

N

N N

Cl

Pd(Ph3P)4, KOAc DMA, reflux, 65%

O

N N

References 1. 2. 3.

4. 5. 6.

Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.; Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951−1958. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915−6918. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257−272. Proudfoot, J. R.; Patel, U. R.; Kapadia, S. R.; Hargrave, K. D. J. Med. Chem. 1995, 38, 1406−1410. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467−473. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2nd ed.; 2007, Elsevier: Oxford, UK. (Review).

281

Hegedus indole synthesis Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to indoles. Cf. Wacker oxidation. PdCl2(CH3CN)2, THF then, Et3N, 84%

NH2

MeO2C

CH3 N H

MeO2C

PdCl2(CH3CN)2 palladation

NH2

MeO2C

Pd

NH2

MeO2C

Et3N

Cl Cl

precipitate Cl Cl Et3N Pd H :

N H2

MeO2C

NH2

MeO2C

Et3N Cl Pd Cl

– HCl N H

MeO2C

– "PdH"

H "PdH"

PdLn N H

MeO2C

Example 1

β-elimination

CH3

CH3 N H

MeO2C

1a

10 mol% (CH3CN)2PdCl2 100 mol% benzoquinone NH2

CH3 N H

10 eq. Et3N, THF, reflux, 84%

Example 21d Br

10 mol % (CH3CN)2PdCl2 100 mol% benzoquinone NHTs

Br

10 eq. LiCl, THF, reflux, 77%

N Ts

References 1.

2. 3. 4. 5.

(a) Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674−2676. Lou Hegedus is a professor at Colorado State University. (b) Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800−5807. (c) Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215−2221. (d) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657−2662. (e) Hegedus, L. S. Angew. Chem., Int. Ed. 1988, 27, 1113−1126. (Review). Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70−74. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587−1590. Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186−187. A ruthenium variant. Johnston, J. N. Hegedus Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 135−139. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_122, © Springer-Verlag Berlin Heidelberg 2009

282

Hell–Volhard–Zelinsky reaction α-Halogenation of carboxylic acids using X2/PBr3. O R

O

PBr3 OH

R

O

H2O

R

Br

Br2

Br

OH Br

α-bromoacid O Br

O

P Br Br R

R

O

O O

H

O R

Br

Br

O

Br P

R O P Br

Br

Br

H enolization

Br P

R

Br H

Br

O

B:

H O

Br R

H

hydrolysis R

Br

Br Br Br

:OH2

Br

O O Br OH

R

OH Br

Example 15 CO2H

Cl2, cat. PCl3

Cl

CO2H

97 oC, 6 h, 77%

Example 26 Br

PBr3 CO2H

Br2, 57%

Br CO2H

CO2H

H

References 1.

(a) Hell, C. Ber. 1881, 14, 891−893. Carl M. von Hell (1849−1926) was born in Stuttgart, Germany. He studied under Fehling and Erlenmeyer. After serving in the war of 1870, he became very ill. Hell became a professor at Stuttgart in 1883 where he discovered the Hell–Volhard–Zelinsky reaction. (b) Volhard, J. Ann. 1887, 242, 141−163. Jacob Volhard (1849−1909) was born in Darmstadt, Germany. He apprenticed under Liebig, Will, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing α-bromo-acid during his research in thiophenes. (c) Zelinsky, N. D. Ber. 1887, 20, 2026. Nikolai D. Zelinsky (1861−1953) was born in

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_123, © Springer-Verlag Berlin Heidelberg 2009

283

Tyaspol, Russia. He studied at Göttingen under Victor Meyer, receiving his Ph.D. In 1889. Zelinsky returned to Russia and became a professor at the University of Moscow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin. 2. Watson, H. B. Chem. Rev. 1930, 7, 173−201. (Review). 3. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237−246. (Review). 4. Harwood, H. J. Chem. Rev. 1962, 62, 99−154. (Review). 5. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). 6. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427−5431. 7. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097−2102. 8. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9621−9622. 9. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059−8062. 10. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4, 4487−4490.

284

Henry nitroaldol reaction The nitroaldol condensation reaction involving aldehydes and nitronates, derived from deprotonation of nitroalkanes by bases.

O R1

H

R1 R2

NO2

R2

R3

H

R4

NO2

B

R1

HB

R2

R1 R3 HO NO2 R2 R4 2-nitroalcohols

Base

R1

O N O

NO2 R2

nitroalkanes

HB

R1

B

R2

nitronates

nitronic acids or aci-nitroalkanes

O R3

H NO2 R3

NO2 R3

HB

R1

R1 OH

R2

B

O

R2

O N OH

2-nitroalcohols

Example 14

CHO HO Amberlyst A-21 (basic) rt, 62%

NO2

NO2

Example 2, Retro-Henry reaction5 OH NO2

CuSO4, SiO2

O NO2

PhH, reflux 67%

Example 3, Aza-Henry reaction8 O P Ph N Ph Ph

5 mol% TMG, 100 oC Ph

NO2

0.1 mBar, 26 h 95%, anti:syn = 98:2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_124, © Springer-Verlag Berlin Heidelberg 2009

HN

O P Ph Ph

Ph

Ph NO2

285

Example 4, Intramolecular Henry reaction10 HO O N

O NO2

DBU, MeCN 62%

O2N

H N O

References Henry, L. Compt. Rend. 1895, 120, 1265–1268. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233–1234. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, 2, 321−340. (Review). 4. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749–1750. 5. Saikia, A. K.; Hazarika, M. J.; Barua, N. C.; Bezbarua, M. S.; Sharma, R. P.; Ghosh, A. C. Synthesis 1996, 981–985. 6. Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (Review). 7. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151–153. (Review on aza-Henry reaction). 8. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 9. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int. Ed. 2005, 44, 3881–3884. 10. Kamimura, A.; Nagata, Y.; Kadowaki, A.; Uchidaa, K.; Uno, H. Tetrahedron 2007, 63, 11856–11861. 11. Wang, A. X. Henry Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 404−419. (Review). 1. 2. 3.

286

Hinsberg synthesis of thiophene derivatives Condensation of diethyl thiodiglycolate and α-diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarbonyls upon hydrolysis of the crude ester product with aqueous acid. O

O

1.

O

Ph

O

Ph

EtO

CO2Et S

S

S

Ph CO2Et

O

S

Ph

Ph HO2C

CO2Et

H

Ph

Ph

reflux

CO2Et

S

O Ph

H+, H2O

Ph CO2Et

Ph

EtO

CO2Et Ph O 2C

O

O Ph O

O

OH

Ph

O

Ph

O

S

HO

OEt

NaOEt, EtOH 2. H3O+

O

O

O

S

EtO

HO2C

CO2H

S

2

Example 1

CH3

O O

H3C

CH3 Ar H3 C

O NaOMe

O

HO

90%

O

O S

Ar CH3 OH

SOCl2, pyr.

O S

Ar

Ar

95% H3C

CH3

S O

O

81% NaOMe

Ar Ph

HO

O

O

O S

Ph

Ph CH3

O

Ar Ph

SOCl2, pyr.

O S

Ar

Ar

89% Ph

OH

Example 24 O

O (CHO)3, NaOMe S

S MeOH, 42% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_125, © Springer-Verlag Berlin Heidelberg 2009

O

Ph

287

Example 35 O

1.

O S

Ph

O

Ph Ph

O

KOH S

2. SOCl2, pyr. 9% yield, 2 steps

O

Ph

O

Example 46 H3 C

CH3

NaOH, MeOH NC

O

S

CN

94%

O

H3C

CH3 NH2

NC

S O

Example 5, Polymer-support Hinsberg thiophene synthesis9

O S

O

O

O

R2

R2

KOt-Bu

R1

R1 = CO2i-Pr CONEt2 PPh3+

O O 10% TFA

S

O

R1 R2

R2

CH2Cl2

S

HO

R1 R2

R2

References 1. 2. 3. 4. 5. 6. 7. 8.

9.

Hinsberg, O. Ber. 1910, 43, 901−906. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187−1188. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; WileyInterscience: New York, 1985, pp 34−41. (Review). Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177−1182. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem., Int. Ed. 1990, 29, 675−677. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223−2226. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gisselbrecht, J. P. Angew. Chem., Int. Ed. 1996, 35, 1520−1525. Mullins, R. J.; Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 199−206. (Review). Traversone, A.; Brill, W. K.-D. Tetrahedron Lett. 2007, 48, 3535−3538.

288

Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organosilicons with organic halides, triflates, etc. In the presence of an activating agent such as fluoride or hydroxide (transmetallation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 325.

R1 SiY

Pd catalyst

R2 X

activator

R 1 R2

R1 = alkenyl, aryl, alkynyl, alkyl R2 = aryl, alkyl, alkenyl Y = (OR)3, Me3, Me2OH, Me(3-n)F(n+3) X = Cl, Br, I, OTf activator = TBAF, base

Pd(0)

Ar1 Ar2

Ar1 X reductive elimination

Ar1 Pd(II)

oxidative addition

Ar2

Ar1 Pd(II)

X

trans"metal"lation

R3SiF

X

R R Ar2 Si R F

Bu4N

Example 11a I MeO2C S

Si(Et)F2

S

(η3-C

3H5PdCl)2 DMF, KF, 100 oC 82%

S MeO2C

S

Example 22 Br C5H11

Si(OMe)3

N Bu4NF, Pd(OAc)2, Ph3P DMF, reflux, 72%

C5H11

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_126, © Springer-Verlag Berlin Heidelberg 2009

N

289

Example 37 I Me

Si

Me

[allylPdCl]2 (7.5 mol%)

O

O

HO O

TBAF, THF, 25 °C, 60 h 61%

CH3 OPMB

Me PMBO

Example 49 CO2Me

CO2Me

MOMO

MOMO Me

H3C Me3Si

I

O

[allylPdCl]2 TBAF (12 mol%)

O Me

Me

Me O Me

O H

THF, 60 °C, 20 h 20% Me

Me O

O Ph

H

O

O Ph

References (a) Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303−306. (b) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471−1478. (c) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35, 6507−6510. 2. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309−1310. 3. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, pp 421–53. (Review). 4. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372−375. 5. Hiyama, T. J. Organomet. Chem. 2002, 653, 58−61. 6. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697−700. 7. Denmark, S. E.; Yang, S.-M. J. Am. Chem. Soc. 2004, 126, 12432−12440. 8. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Organometallics 2005, 24, 3957−3965. 9. Anzo, T.; Suzuki, A.; Sawamura, K.; Motozaki, T.; Hatta, M.; Takao, K.-i.; Tadano, K.-i. Tetrahedron Lett. 2007, 48, 8442−8448. 10. Yet L. Hiyama Cross-Coupling Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 33−416. (Review). 1.

290

Hofmann rearrangement Upon treatment of primary amides with hypohalites, primary amines with one less carbon are obtained via the intermediacy of isocyanate. Also know as the Hofmann degradation reaction. O

Br2

H2O

R

NH2

NaOH

O

O R

CO2↑

R NH2

R N C O

NH H

O R

R

Br Br

N H

NH

Br

O R

N

Br

OH

OH H N

R N C O R

O

H

CO2↑

R NH2

O

OH

OH

isocyanate intermediate Example 1, NBS variant2 O

H N

NBS, DBU, MeOH NH2

reflux, 25 min., 70%

O2N

O O

O2N

Example 2, Iodosobenzene diacetate5 OCOCF3

O

I

OH

CH3CN/H2O, 4.5 h, 100%

O :

OCOCF3

NH2

N H OH

Ph I

O O

CF3

H N

C

O

H N O

:

O

OH

Example 3, Bromine and alkoxide6 H N

O NH H AcO

H

O

O

Br2, NaOMe MeOH, rt → reflux HO 75%

H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_127, © Springer-Verlag Berlin Heidelberg 2009

H H

H

291

Example 4, Sodium hypochlorite7 OH O

HO HO

OH O

NaOCl CONH2

aq. NaOH 50 °C, 81%

HO HO

NH2

Example 5, The original conditions, bromine and hydroxide9 Ph

Ph

N N

N N

N

Br2, aq. KOH CONH2

N Me

Ph

Ph

N N

N 0 °C to reflux 80%

N

N

NH2

N Me

Example 6, Lead tetraacetate10 O

Pb(OAc)4

O

CONH2 NO2

NHBoc t-BuOH, Et3N reflux, 75%

NO2

References Hofmann, A. W. Ber. 1881, 14, 2725–2736. Jew, S.-s.; Kang, M.-h. Arch. Pharmacol Res. 1994, 17, 490–491. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495–7496. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391–8394. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449–1452. Jiang, X.; Wang, J.; Hu, J.; Ge, Z.; Hu, Y.; Hu, H.; Covey, D. F. Steroids 2001, 66, 655–662. 7. Stick, R. V.; Stubbs, K. A. J. Carbohydr. Chem. 2005, 24, 529–547. 8. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893−2903. (Review). 9. El-Mariah, F.; Hosney, M.; Deeb, A. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181, 2505–2517. 10. Jia, Y.-M.; Liang, X.-M.; Chang, L.; Wang, D.-Q. Synthesis 2007, 744–748. 11. Gribble, G. W. Hofmann rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 164−199. (Review). 1. 2. 3. 4. 5. 6.

292

Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated N-haloamines.

R

R

Cl N

1

Cl N

1

1. H+, Δ R

H

N R2

Δ

Cl H N 2 R

R1

R2

R1

2. −OH

2

H Cl

homolytic cleavage

R

chloroammonium salt

R1

N H R2

H

1

S N2

OH R

1

Cl

NH2 R

NH2 R2

Cl

2

R1

: NH R2

R1

N

R1

N H R2

R1

OH

N R2

Example 12 N

NH O

1. NaOCl, 95%

O H H

H

2. TFA, hv, 87% 3. NaOH, MeOH, 76%

H

H

H

HO

HO

Example 24 O

N

Ph Br

84% H2SO 4 65 oC, 30 min.

N

N

N N

25%

Example 35 NCS, ether, Et3N then hv, (Hg0 lamp) NH

N

H R2

Cl H N 2 R

atom transfer R

H R2

nitrogen radical cation

R1

1,5-hydrogen

N

1

0 oC, 3.5 h in N2 100%

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_128, © Springer-Verlag Berlin Heidelberg 2009

N

Ph

293

Example 47

PhI(OAc)2 or Pb(OAc)4 HN AcO

P(O)(OEt)2

I2, hv, 99%

P(O)(OEt)2

N AcO

H

H

Example 512 O Me Me

O

CF3 N Br Me Me

O

1.0 equiv CBr4, hv 0.05 M PhCF3

Me

100 W flood lamp rt, 7 min.

CF3 N H Br Me Me

O

1.25 equiv Ag2CO3 CH2Cl2, rt, 1 h then AcOH, 15 min. > 69% overall

Me

O

Me Me

O

O Me Me

References (a) Hofmann, A. W. Ber. 1883, 16, 558−560. (b) Löffler, K.; Freytag, C. Ber. 1909, 42, 3727. 2. Wolff, M. E.; Kerwin, J. F.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.; Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117−4118. 3. Wolff, M. E. Chem. Rev. 1963, 63, 55−64. (Review). 4. Dupeyre, R.-M.; Rassat, A. Tetrahedron Lett. 1973, 2699−2701. 5. Kimura, M.; Ban, Y. Synthesis 1976, 201−202. 6. Stella, L. Angew. Chem., Int. Ed. 1983, 22, 337−422. (Review). 7. Betancor, C.; Concepcion, J. I.; Hernandez, R.; Salazar, J. A.; Suarez, E. J. Org. Chem. 1983, 48, 4430−4432. 8. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095−7129. (Review). 9. Togo, H.; Katohgi, M. Synlett 2001, 565−581. (Review). 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455−476. (Review). 11. Li, J. J. Hofmann–Löffler–Freytag Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 89−97. (Review). 12. Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17247−17249. 1.

294

Horner–Wadsworth–Emmons reaction Olefin formation from aldehydes and phosphonates. Workup is more advantageous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water. Typically gives the trans- rather than the cisolefins. O EtO P EtO

O EtO P EtO

O

R

O EtO P EtO ONa

O

OEt

O EtO P EtO O

R

CO2Et

NaH, then OEt

O

RCHO

O EtO P EtO

OEt H

O H

O

R

OEt

H

The stereochemical outcome: erythro (kinetic) or threo (thermodynamic) O OEt O P OEt H H CO2Et R

O OEt P OEt H CO2Et

O H R

R

CO2Et

erythro, kinetic adduct O OEt P OEt CO2Et H

O H R

O OEt O P OEt CO2Et H H R

CO2Et R

threo, thermodynamic adduct Example 13 O EtO P EtO

O CHO

O

O

CO2Et

OEt

NaH, THF, 95% OMe

OMe 4

Example 2

CHO

O EtO P EtO

O

KOH, THF, 95%

BnO

CO2Et

OEt BnO

Example 37 O

H

OMe N

EtO

OMOM O OTBDPS

EtO P O

O

H

OMOM

O

NaH, THF 92%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_129, © Springer-Verlag Berlin Heidelberg 2009

OTBDPS O

OMe N

295

Example 4, Intramolecular Horner–Wadsworth–Emmons9 TBSO

O O OTBS

O OMe 3

N O

O N MeO

O

O

O N

O OTIPS

3 2

O

Toluene −20 oC 67% Z/E = 5:1

Br

MeO

O

K2CO3 18-crown-6

O

O

N

2 O

P OEt OEt

O MeO

MeO

O

OTIPS

Br

MeO

References (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499– 2505. (b) Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733– 1738. (c) Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680–685. 2. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863−927. (Review). 3. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509–9525. 4. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602– 2621. 5. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115–4118. 6. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333–1337. 7. Ahmed, A.; Hoegenauer. E. K.; Enev, V. S.; Hanbauer, M.; Kaehlig, H.; Öhler, E.; Mulzer, J. J. Org. Chem. 2003, 68, 3026–3042. 8. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281–4283. 9. Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J. 2006, 12, 1185–1204. 10. Rong, F. Horner–Wadsworth–Emmons reaction in. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review). 1.

296

Houben−Hoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles. OH

OH

OH RCN

H2O OH

HCl, AlCl3

OH

OH R

NH•HCl

R

O

H

:OH

O electrophilic

AlCl3 complexation R

N:

OH R

substitution

OH

H R

N AlCl3

NH

OH

OH

OH OH

H2O: R

hydrolysis

NH•HCl

OH NH2 H R O H

OH R

O

Example 1, Intramolecular Houben−Hoesch reaction3 O

OMe

O

OMe

1. ZnCl2, HCl(g), Et2O CN

2. H2O, reflux, 89%

OMe

O

OMe

6

Example 2

OPiv OH

F PivO

OMe

MeO CO2Me

CN MeO

OH

F OMe

SbCl5, 2-chloropropane N H

CH2Cl2, rt, 2 h, 95%

O

OH CO2Me

Example 38

NH2•HCl 14C

u

NC Cl BCl3•CH2Cl2, ZnCl2

NH2 14

14

Cu Cl

then aq. HCl O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_130, © Springer-Verlag Berlin Heidelberg 2009

Cu =

14

C-labelled

297

Example 49 Cl

OMe Cl NC HCl (g), THF, overnight OMe then 2% aq. HCl reflux, 3 h, 43% MeO

N H

MeO O

N H

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Hoesch, K. Ber. 1915, 48, 1122−1133. Kurt Hoesch (1882−1932) was born in Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family business. (b) Houben, J. Ber. 1926, 59, 2878−2891. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691−692. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994, 35, 6347−6350. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037−3043. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751−753. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294−5303. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36, 135−140. Wager, C. A. B.; Miller, S. A. J. Labelled Compd. Radiopharm. 2006, 49, 615−622. Black, D. St. C.; Kumar, N.; Wahyuningsih, T. D. ARKIVOC 2008, (6), 42−51.

298

Hunsdiecker−Borodin reaction Conversion of silver carboxylate to halide by treatment with halogen. O R

X2 O

X X

O

AgX

O

O R

CO2↑

R X

Ag

AgX

Ag

R

homolytic X

O

cleavage

O O CO2↑

X R

O

R

R

O

X

O R X

R

O

Example 15 HgO, Br2, Δ Cl

CO2H

Cl

Br

CCl4, dark, 35−46%

Example 26 Br

CO2H NBS, n-Bu4N+CF3CO2− ClCH2CH2Cl, 96% MeO

MeO

Example 38 Cl CO2H

N N F

HO

Br

2 BF4 "Select fluor"

KBr, CH3CN, 82%

HO

Example 4, One-pot microwave-Hunsdiecker−Borodin followed by Suzuki10

CO2H BnO OMe

Br NBS, LiOAc CH3CN−H2O 9:1 MW 1 min.

BnO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_131, © Springer-Verlag Berlin Heidelberg 2009

OMe

299

PhB(OH)2, K2CO3 Pd(PPh3)4 CH3CN/H2O 2:1 microwave, 5 min. 64% 2 steps

BnO OMe

References (a) Borodin, A. Ann. 1861, 119, 121−123. Aleksandr Porfireviþ Borodin (1833−1887) was born in St Petersburg, the illegitimate son of a prince. He prepared methyl bromide from silver acetate in 1861, but another eighty years elapsed before Heinz and Cläre Hunsdiecker converted Borodin’s synthesis into a general method, the Hunsdiecker or Hunsdiecker−Borodin reaction. Borodin was also an accomplished composer and is now best known for his musical masterpiece, opera Prince Egor. He kept a piano outside his laboratory. (b) Hunsdiecker, H.; Hunsdiecker, C. Ber. 1942, 75, 291−297. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She developed the bromination of silver carboxylate alongside her husband, Heinz. 2. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326−421. (Review). 3. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979−4982. 4. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Pergamon, 1991, Vol. 7, pp 723−734. (Review). 5. Lampman, G. M.; Aumiller, J. C. Org. Synth. 1988, Coll. Vol. 6, 179. 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699−702. 7. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861−7864. 8. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561−8563. 9. Li, J. J. Hunsdiecker reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds., John Wiley & Sons: Hoboken, NJ, 2007, pp 623−629. (Review). 10. Bazin, M.-A.; El Kihel, L.; Lancelot, J.-C.; Rault, S. Tetrahedron Lett. 2007, 48, 4347−4351. 1.

300

Jacobsen–Katsuki epoxidation Mn(III)salen-catalyzed asymmetric epoxidation of (Z)-olefins. R

R

N

N Mn R R

3

R

R4

1

R1

O

O Cl

5

O

R3

R2

R2

R5

6 R4 * * R

R6 terminal oxidant, solvent

1.

Concerted oxygen transfer (cis-epoxide): R R

2.

O Mn(V)

R1

R1

R

R1

R

O Mn(V)

O Mn(V)

R1 O

Oxygen transfer via radical intermediate (trans-epoxide): R R

R1

O Mn(V)

R

R1

R1

R

O Mn(V)

O Mn(V)

R1 O

Oxygen transfer via manganaoxetane intermediate (cis-epoxide):

3. R

R1

R1

O Mn(V)

[2 + 2] O Mn(V) cycloaddition

R

R1

O Mn(V)

R

Example 12 cat, 4-phenylpyridine-N-oxide CO2Et

CO2Et NaOCl, CH2Cl2, 4 oC, 12 h 56%, 95−97% ee

H

O

H N

N Mn cat. =

t-Bu

O

O

t-Bu

Cl t-Bu

t-Bu

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_132, © Springer-Verlag Berlin Heidelberg 2009

R

R1 O

301

Example 25 OMe

OMe cat., NaOCl

O N

O

58% yield, 89% ee

N

O Ph

Ph

Example 26 N cat. NaOCl

N

N O

88% 88% ee

OH

O

Ph H N

OH

NHt-Bu Crixivan

References (a) Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801–2903. (b) Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345–7348. (c) Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055–1058. (d) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320–4323. (e) Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457–5460. 2. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296–2298. 3. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, New York, 1993, Ch. 4.2. (Review). 4. Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkinson, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995, vol 12, Chapter 11.1. (Review). 5. Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223–9228. 6. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3–15. (Review). 7. Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Eds.; Springer: New York; 1999, Chapter 18.2. (Review). 8. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, 287. (Review). 9. Katsuki, T. Synlett 2003, 281–297. (Review). 10. Palucki, M. Jacobsen–Katsuki epoxidation. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 29−43. (Review). 11. Engelhardt, U.; Linker, T. Chem. Commun. 2005, 1152–1154. 12. Fernandez de la Pradilla, R.; Castellanos, A.; Osante, I.; Colomer, I.; Sanchez, M. I. J. Org. Chem. 2009, 74, 170–181. 1.

302

Japp–Klingemann hydrazone synthesis Hydrazones from β-ketoesters and diazonium salts with the acid or base.

ArN2

KOH

CO2R

Cl

Diazonium salt

O

O

Ar

β-keto-ester

hydrazone

N

CO2R

OH

N N Ar

OH H CO2R

H N

coupling

deprotonation

Ar N N CO2R

HO

CO2R O

O

O

Ar N N CO2R

H

O OH

N

Ar

N

O OH

Ar

CO2R

H N

N

CO2R

Example 14 CO2Et Me

CO2Et

N

NaNO2

S O O NH2

Me

conc. HCl, H2O 0 oC

O

N

S O O

Cl N

CO2Et

Me

NMe2 CO2Et

Me

NaOAc (pH 3−4) 0 to 50 oC 72%

N

NMe2

N

S O O

N

N H

CO2Et

Example 26 0.5 N KOH, THF, rt, 1 h NH

HO2C

H N

then

OBn

O

N2+Cl OBn

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_133, © Springer-Verlag Berlin Heidelberg 2009

NH

N O

62% yield

303

Example 310 NR1R2 O

O

KOAc, H2O OEt N N

−4 oC to rt 60−85%

NR1R2 CO2H H+, 100 oC HN

N

NR1R2

70−85% OEt

HO2C O

CO2Et N H

References (a) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 2942−2944. (b) Japp, F. R.; Klingemann, F. Ber. 1887, 21, 2934−2936. (c) Japp, F. R.; Klingemann, F. Ber. 1887, 20, 3398−3401. (d) Japp, F. R.; Klingemann, F. Ann. 1888, 247, 190−225. (e) Japp, F. R.; Klingemann, F. J. Chem. Soc. 1888, 53, 519−544. 2. Phillips, R. R. Org. React. 1959; 10, 143−178. (Review). 3. Loubinoux, B.; Sinnes, J.-L.; O’Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60, 953−959. 4. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665−673. 5. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385−1386. 6. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791−1799. 7. He, W.; Zhang, B.-L.; Li, Z.-J.; Zhang, S.-Y. Synth. Commun. 2005, 35, 1359−1368. 8. Li, J. Japp–Klingemann hydrazone synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 630−634. (Review). 9. Chen, Y.; Shibata, M.; Rajeswaran, M.; Srikrishnan, T.; Dugar, S.; Pandey, R. K. Tetrahedron Lett. 2007, 48, 2353−2356. 10. Pete, B. Tetrahedron Lett. 2008, 49, 2835−2838. 1.

304

Jones oxidation The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Corey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations follow a similar pathway as the Jones oxidation (chromium trioxide and sulfuric acid in acetone). All these oxidants have a chromium (VI), normally black or yellow, which is reduced to Cr(IV), often green.

Jones

N H

2

N

Cr2O7

CrO3Cl

CrO3

CrO3/H2SO4

PCC

Collins/Sarett

2

N H PDC

Jones oxidation By the Jones oxidation, the primary alcohols are oxidized to the corresponding aldehyde or carboxylic acids, whereas the secondary alcohols are oxidized to the corresponding ketones. R1

O

CrO3

OH

H2SO4, acetone

R2

R1

R2

CrO3 + H2O ĺ H2CrO4

Cr(VI) black

O H O: R1

O Cr

O O

O H

R1

R2

OH2 Cr OH

O R1

H R2

O

R2

Cr

Cr(III) OH

green

:B

The intramolecular mechanism is also operative: O O R1

OH Cr O

H R2

OH Cr O OH

O R1

R2

Example 16 OH O O

O O

O O

H

O 1. Jones reagent acetone, 20 min. 2. HCO2H, rt, 1 h 96% 2 steps

CO2t-Bu

O O

O O

O O

CO2H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_134, © Springer-Verlag Berlin Heidelberg 2009

H

(−)-CP-263114

305

Example 27 O

O

CO2Me

CO2Me CrO3, H2SO4 acetone/H2O

HO H

O H

rt, 74% H

H

Example 3

19

CrO3, H2SO4 acetone, 0 oC 1−2 h, 86%

O O

HO

References Bowden, K.; Heilbron, I. M., Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946, 39−45. Ewart R. H. (Tim) Jones worked with Ian M. Heilbron at Imperial College. Jones later succeeded Robert Robinson to become the prestigious Chair of Organic Chemistry at Manchester. The recipe for the Jones reagent: 25 g CrO3, 25 mL conc. H2SO4, and 70 mL H2O. 2. Ratcliffe, R. W. Org. Synth. 1973, 53, 1852. 3. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995−998. 4. Luzzio, F. A. Org. React. 1998, 53, 1−222. (Review). 5. Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323−5326. (Catalytic CrO3 oxidation). 6. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825−7826. 7. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett. 2001, 3, 251−254. 8. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2003, 44, 1275−1278. 9. Hunter, A. C.; Priest, S.-M. Steroids 2006, 71, 30−33. 10. Dong, J.; Chen, W.; Wang, S.; Zhang, J. J. Chromatogr., B 2007, 858, 239−246. 1.

Collins–Sarett oxidation Different from the Jones oxidation, the Collins–Sarett oxidation converts primary alcohols to the corresponding aldehydes. Example 15 O Ph

O

O OH O O

8 eq CrO3•2Pyr CH2Cl2, 15 min., 86%

Ph

O

CHO O O

306

Example 27 OMe

OMe Me

7 equiv CrO3•Py2

Me

CHO

CH2Cl2, 30 min., 75% OH MeO2C

MeO2C

Me

Me

Example 39 R1

R2

N PhO2S

R1 R3

CrO3, Pyr.

R4

50−60 oC, 48 h 50−65%

N PhO2S

R2

R3 R4

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422– 429. Collins, J. C; Hess, W. W.; Frank, F. J. Tetrahedron Lett. 1968, 3363–3366. J. C. Collins was a chemist at Sterling-Winthrop in Resselaer, New York. Collins, J. C; Hess, W. W. Org. Synth. 1972, Coll. Vol. V, 310. Hill, R. K.; Fracheboud, M. G.; Sawada, S.; Carlson, R. M.; Yan, S.-J. Tetrahedron Lett. 1978, 945–948. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14, 429–433. Li, M.; Johnson, M. E. Synth. Commun. 1995, 25, 533–537. Harris, P. W. R.; Woodgate, P. D. Tetrahedron 2000, 56, 4001–4015. Nguyen-Trung, N. Q.; Botta, O.; Terenzi, S.; Strazewski, P. J. Org. Chem. 2003, 68, 2038–2041. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313–2320.

PCC oxidation Example 1, One-pot PCC–Wittig reactions2

t-Bu

Si

PCC, Celite, CH2Cl2, rt, 3 h OH

then Ph3P=CHCO2CH3 80%

t-Bu

O Si 95 : 5 E : Z

O

307

Example 23

EtO2C

OH N

1.5 eq PCC, CH2Cl2

EtO2C

rt, 3 h, 75%

O N

Example 34 O OAc O

PCC, pyr.

Ph OAc OAc

CH2Cl2, reflux 8 h, 64%

OAc O Ph OAc OAc

Example 45 HO

O

O

O PCC, CH2Cl2 75%, 93:7 er

Cl

Cl

References 1. 2. 3. 4. 5.

Corey, E. J.; Suggs, W. Tetrahedron Lett. 1975, 16, 2647–2650. Bressette, A. R.; Glover, L. C., IV Synlett 2004, 738–740. Breining, S. R.; Bhatti, B. S.; Hawkins, G. D.; Miao, L.; Mazurov, A.; Phillips, T. Y.; Miller, C. H. WO2005037832 (2005). Srikanth, G. S. C.; Krishna, U. M.; Trivedi, G. K.; Cannon, J. F. Tetrahedron 2006, 62, 11165–11171. Kim, S.-G. Tetrahedron Lett. 2008, 49, 6148–6151.

PDC oxidation Example 12

PDC, CH2Cl2

S O S

OH

S

24 h, 68%

O S

CHO

308

Example 2, Cleavage of primary carbon–boron bond3 B(OH)2

PDC, DMF CO2H

rt, 24 h 75%

Example 34 OTBDMS OH OH

OTBDMS

PDC, DMF rt, 24 h, 56% O

O

References 1 2 3 4 5

Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399–402. Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230–208. Brown, H. C.; Kulkarni, S. V.; Khanna, V. V.; Patil, V. D.; Racherla, U. S. J. Org. Chem. 1992, 57, 6173–6177. Chênevert, R. Courchene, G.; Caron, D. Tetrahedron: Asymmmetry 2003, 2567–2571. Jordão, A. K Synlett 2006, 3364–3365. (Review).

309

Julia–Kocienski olefination Modified one-pot Julia olefination to give predominantly (E)-olefins from heteroarylsulfones and aldehydes. A sulfone reduction step is not required. N N R1 1. KHMDS SO2 N N 2. R2CHO Ph

N N OH N N Ph

R2

R1

SO2

O

N(TMS)2 R2

H N N R1 SO2 N N Ph

R2 S O

K R2 N N O N R1 N S O Ph 2

N N R1 SO2 N N Ph

N N R1 SO2 N N Ph N N O N N Ph R1

R2

O

H

O

N N OH N N Ph

R2

R1

SO2

Alternatives to tetrazole: N N N N Ph

S

PT

PYR

BT

F 3C

N N N N t-Bu

N

N

F 3C

TBT

BTFP

The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl): O R1

H R1

R2 SO2PT

H

SO2PT R2 OK

Example 1, (BT = benzothiazole)2 SO 2BT

OHC

OTIPS

NaHMDS, DMF

OTIPS

−78 oC to rt, 90%

Example 2

E:Z (78:22)

3

OTBS OPiv O

O

N O

S O O

S

OMe

KHMDS, THF, −78 oC, 85%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_135, © Springer-Verlag Berlin Heidelberg 2009

310

OPiv

OTBS

O O

OMe

Example 37

N

CHO

O S O

KHMDS, toluene

OTIPS OTIPS

25 oC, 64%

TIPSO

88 : 12

Example 48 OMe

MeO F3C

F3C

OMe O S O

1) P4−t-Bu, THF, −78 oC CHO

2) MeO

OMe MeO

74%, yield E/Z = 98/2

References (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175−1178. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336−357. (c) Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856−878. (d) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morely, A. Synlett 1998, 26−28. 2. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327−10328. 3. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955−968. 4. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924−4925. 5. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365−366. 6. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772−10773. 7. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149–5153. 8. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573–577. 9. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review). 1.

311

Julia–Lythgoe olefination (E)-Olefins from sulfones and aldehydes. R

S

1. n-BuLi 2. R1CHO

Ar

O O

3. Ac2O

R

S

R

SO2Ar

α-deprotonation

Na(Hg)

R

R

SO2Ar R1

coupling

1

O

H

O O

SO2Ar R1 O

acetylation O

Ar

O O

R

R1

R

CH3OH

OAc

n-Bu H

SO2Ar R1

R

R

O O

SO2Ar R1

O

Na(Hg) single electron transfer (SET)

OAc O

SO2Ar

R1

R

OAc

4 possible diastereomers Na(Hg)

R1

R

OAc

single electron transfer (SET)

R1

R

OAc

Example 12 SO2Ph

1. n-BuLi, THF, −78 oC

3. Ac2O

2.

4. Na(Hg) 43%

E:Z (99:1)

OHC

Example 23 O OTBS

SO2Ph

O

N TEOC

Li

N TEOC

H CHO

OTBS

H

1. THF, −78 oC 2. Ac2O 3. 5% Na(Hg), 77%

Example 37

Ph S

n-BuLi, THF, 0 oC to rt 61−75% OHC

CH3

Ph S

Ph m-CPBA, CH2Cl2 CH3

HO

0 oC, 80−98%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_136, © Springer-Verlag Berlin Heidelberg 2009

SO2 OH

CH3

312

Ph

CH3

SO2

Ac2O, DMPA, CH2Cl2 0 oC to rt, 60−95%

Na/Hg THF, MeOH −20 oC, 53%

OAc

H3C

Example 48 O S

Ph

Ph Ph

Ph Ph

S O

Ph OBz

1. LDA, THF, −78 oC CHO

2. BzCl, −78 oC to rt 3. Me2N(CH2)3OH

SmI2, THF HMPA, −78 oC Ph

Ph

67%, E/Z = > 95:1

References (a) Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833–4836. (b) Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1978, 834–837. 2. Kocienski, P. J.; Lythgoe, B.; Waterhause, I. J. Chem. Soc., Perkin Trans. 1 1980, 1045–1050. 3. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003– 2005. 4. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. 5. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453–456. 6. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664–1668. 7. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 6, 1064–1068. 8. Pospíšil, J.; Pospíšil, T, Markó, I. E. Org. Lett. 2005, 7, 2373–2376. 9. Gollner, A.; Mulzer, J. Org. Lett. 2008, 10, 4701−4704. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 447−473. (Review). 1.

313

Kahne glycosidation Diastereoselective glycosidation of a sulfoxide at the anomeric center as the glycosyl acceptor. The sulfoxide activation is achieved using Tf2O. OPiv

PivO

O PivO

O Ph O HO

O S Ph

PivO

O N3

SPh

CH3 OPiv

PivO t-Bu

N

t-Bu

Tf2O, CH2Cl2, −78 to −30 oC

O O S O S O O

F F PivO

OPiv O

PivO

Ph

S

PivO PivO

F

PivO

N3

F

PivO

F

SPh

OPiv O:

TfO PivO

OPiv

PivO

OPiv

O

O HO N3

SN1

OTf S Ph

PivO

PivO

O

Ph

O

O

F

O S Ph

OTf PivO

PivO

O

Ph O O

O

O PivO

PivO

SPh

Ph O O

O

O N3

SPh

oxonium ion Example 11d OMOM OMOM

O O BzO

OMOM OMOM OMe OH

O OBn OBn

S(O)Ph Tf2O, DTBMP, CH2Cl2 OBn −70 to −50 oC, 38%

BzO

OMe O O OBn OBn

Example 24

O

O Ph

O

O SPh

OTBS OPMB

O MeO

OTIPS OTBS

OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_137, © Springer-Verlag Berlin Heidelberg 2009

OBn

314

Ph Tf2O, DTBMP, CH2Cl2 −78 to 0 oC, 67%

O O

PMBO

MeO O O OTBS

O OTIPS OTBS

Example 3, Reverse Kahne-type glycosylation6 O

S

Et

Nu O

O O O O MeO

OMe OCbz

O Tf2O, CH2Cl2

O O

−78 oC, NuH MeO

OMe OCbz

NuH = ROH, ArOH, ArNH2, CH2=CHCH2TMS

References 1.

2. 3. 4. 5. 6. 7. 8.

(a) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881−6882. (b) Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116, 6953−6954. (c) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239−9248. (d) Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961−5969. Daniel Kahne now teaches at Harvard University. Boeckman, R. K., Jr.; Liu, Y. J. Org. Chem. 1996, 61, 7984−7985. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435−436. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 801−805. Nicolaou, K. C.; Rodríguez, R. M.; Mitchell, H. J.; Suzuki, H.; Fylaktakidou, K. C.; Baudoin, O.; van Delft, F. L. Chem. Eur. J. 2000, 6, 3095−3115. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2, 1149−1152. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem. Soc. 2001, 123, 5826−5828. Crich, D.; Lim, L. B. L. Org. React. 2004, 64, 115−251. (Review).

315

Knoevenagel condensation Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.

N H

CH2(CO2R1)2

R CHO

CO2R1

R

H CH(CO 2R1)2 :

(CO2R1)2CH

H :

NH R

NH

:

R

H

N

CO2R1 CO2R1

O

O

R

O R1

hydrolysis

R O HO

OH R

workup

Example 1

O

O

N

O

HO O

R1

OH

H

NH2

H

OH

O

R H

OH R : N

formation

O

CH(CO2R1)2

NH2

iminium ion

O R1

O

R1

R

O O

O

H decarboxylation

O H

•

R

CO2↑

O

R

H

OH

3

O S H N

N

O O

O

N H

S

piperidine, AcOH toluene, reflux Dean−Stark trap 95%

N

O

N

O

N H

O

Example 2, EDDA = Ethylenediamine diacetate5 O

O O

N H Boc

CO2H

R

deprotonation

NH

H

OH

CO2R1

O

NCbz

Meldrum's acid

CHO

EDDA, PhH, 60 oC 12 h, 84%

NCbz

N H Boc

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_138, © Springer-Verlag Berlin Heidelberg 2009

O

O O

O

CO2H

316

Example 3, Using ionic liquid ethylammonium nitrate (EAN) as solvent8 CHO

CN

CN

ethylammonium nitrate

CO2Et

rt, 10 h, 87%

CO 2Et

Example 49 SO2Me

O N

N

N

MeO2S H O

SO2Me N piperidine 2-propanol, reflux 89%

H O N MeO2S

N

References Knoevenagel, E. Ber. 1898, 31, 2596−2619. Emil Knoevenagel (1865−1921) was born in Hannover, Germany. He studied at Göttingen under Victor Meyer and Gattermann, receiving a Ph.D. In 1889. He became a full professor at Heidelberg in 1900. When WWI broke out in 1914, Knoevenagel was one of the first to enlist and rose to the rank of staff officer. After the war, he returned to his academic work until his sudden death during an appendectomy. 2. Jones, G. Org. React. 1967, 15, 204−599. (Review). 3. Cantello, B. C. C.; Cawthornre, M. A.; Cottam, G. P.; Duff, P. T.; Haigh, D.; Hindley, R. M.; Lister, C. A.; Smith, S. A. Thurlby, P. L. J. Med. Chem. 1994, 37, 3977−3985. 4. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129−4132. 5. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045−2047. 6. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001−2004. 7. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67, 4615−4618. 8. Hu, Y.; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Commun. 2005, 35, 739−744. 9. Conlon, D. A.; Drahus-Paone, A.; Ho, G.-J.; Pipik, B.; Helmy, R.; McNamara, J. M.; Shi, Y.-J.; Williams, J. M.; MacDonald, D. Org. Process Res. Dev. 2006, 10, 36−45. 10. Rong, F. Julia–Lythgoe olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−501. (Review). 1.

317

Knorr pyrazole synthesis Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal–Knorr pyrrole synthesis (page 411). R3

R O

NH NH3

O R1

N

R2

R N

R1

R2

R N N

R2

R1

R3

R3

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc. R3

R NH NH2

O

O R1

N

OR2

R1

R

R OH NH NH R OH

NH2NH2

O O R

R N

OH

N

R3

R N

O

R1

R

R3

R N NH

R

N NH

OH

R

Alternatively, R NH2NH2

N NH2 O

O R

R

R

R O

R

N NH

N NH R

OH

R

HCl, H2O

Me N

Example 12 OMe O MeO

MeNHNH2 Me

68%

N Me

Example 2

8

O

O EtO2CCF3, NaH, THF

CF3

Me −5 to 0 C, 30 min., rt, 5 h, 95% o

Me

O

Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_139, © Springer-Verlag Berlin Heidelberg 2009

318

Me O H2N S O

H N NH2•HCl EtOH, reflux, 46%

N N

CF3

O S H2 N

O

Celebrex

References 1

2 3 4 5 6 7 8

(a) Knorr, L. Ber 1883, 16, 2597. Ludwig Knorr (1859−1921) was born near Munich, Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. (b) Knorr, L. Ber 1884, 17, 546, 2032. (c) Knorr, L. Ber. 1885, 18, 311. (d) Knorr, L. Ann. 1887, 238, 137. Burness, D. M. J. Org. Chem. 1956, 21, 97−101. Jacobs, T. L. in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York, 1957, 5, 45. (Review). Houben−Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C. W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). Stanovnik, E.; Svete, J. In Science of Synthesis, 2002, 12, 15; Neier, R., Ed.; Thieme. (Review). Sakya, S. M. Knorr Pyrazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, pp 292−300. (Review). Ahlstroem, M. M.; Ridderstroem, M.; Zamora, I.; Luthman, K. J. Med. Chem. 2007, 50, 4444−4452.

319

Koch–Haaf carbonylation Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO. R

OH

R

CO, H2O

CO2H

H

H O:

R

protonation

H O H

R

R

CH2

H

:C O:

R

alkyl

O

R

migration

The tertiary carbocation is thermodynamically favored R

O

O

O

R

OH2

H

R

OH

:OH2

acylium ion Example 13 OH

CO2H HCO2H, H2SO4 rt, 66%

Example 2

5

OH

HCO2H, H2SO4

CO2H

CCl4, 5 oC, 95%

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Koch, H.; Haaf, W. Ann. 1958, 618, 251–266. Hiraoka, K.; Kebarle, P. J. Am. Chem. Soc. 1977, 99, 366–370. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365–2366. Takeuchi, K.; Akiyama, F.; Miyazaki, T.; Kitagawa, I.; Okamoto, K. Tetrahedron 1987, 43, 701–709. Takahashi, Y.; Yoneda, N. Synth. Commun. 1989, 19, 1945–1954. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem. Soc. 1995, 117, 3615–3616. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed. 2000, 39, 2547–2548. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070–2071. Davis, M. C.; Liu, S. Synth. Commun. 2006, 36, 3509–3514.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_140, © Springer-Verlag Berlin Heidelberg 2009

320

Koenig–Knorr glycosidation Formation of the β-glycoside from α-halocarbohydrate under the influence of silver salt. AcO AcO AcO

AcO

O H H

O

ROH

H

O Br Ac

AcO AcO

Ag2CO3

AcO AcO AcO

AcO AcO Ag

H2 O

O

H

O Br Ac

CO2↑

AgBr

AcO

O: H H

OR

O H Ac

H H

O

H H

O:

oxonium ion AcO AcO

:

AcO

O H H

O

H O R

AcO β-anomer is

AcO AcO

favored

O

O H H

OR

O H Ac

β-anomer Example 17 MeO2C

O

PivO

NO2

Br

HO

N N

OPiv

CF3

OPiv

NO2 Ag2O, 10 eq. HMTTA

MeO2C

CH3CN, rt, 6 h, 41%

O

PivO

O

N N

OPiv

CF3

OPiv

Example 28 OMe

AcO AcO AcO

O H H

H

O Br Ac

OH

OMe Cd2CO3, Tol. reflux, 6 h, 84%

AcO AcO AcO

O H H

O

O Ac

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_141, © Springer-Verlag Berlin Heidelberg 2009

321

Example 39

H

PivO O PivO PivO

H H

H

H

O Br Piv

H HO

H cholesterol

H H AgOTf, TMU, CH2Cl2 4 Å MS, −20 C to rt 16 h, 58% o

PivO O PivO PivO

H H

H

H

O

O Piv

References Koenig, W.; Knorr, E. Ber. 1901, 34, 957−981. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 243−83. (Review). Schmidt, R. R. Angew. Chem. 1986, 98, 213−236. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092−2112. 5. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000, 65, 8758−8762. 6. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc., Perkin Trans. 1 2002, 242−256. 7. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004, 69, 1097−1103. 8. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902−912. 9. Presser, A.; Kunert, O.; Pötschger, I. Monat. Chem. 2006, 137, 365−374. 10. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 5506−5513. 11. Schoettner, E.; Simon, K.; Friedel, M.; Jones, P. G.; Lindel, T. Tetrahedron Lett. 2008, 49, 5580−5582. 1. 2. 3. 4.

322

Kostanecki reaction Also known as Kostanecki−Robinson reaction. Transformation 1→2 represents an Allan−Robinson reaction (see page 8), whereas 1→3 is a Kostanecki (acylation) reaction: O OH

R

O O

R

O

O

R

O R

1

O

O 2

R

R

:

O

O

O H O

O

O

H O

O O

O

6-exo-trig

enolization

O

O

H O R

R

transfer

R

O

O

acyl

O

R

3

O

O

R H

ring closure

O

− H 2O

R :B

OH

O

O R

OH

O

Example 12 O

O

O

OH H

O

OEt

OEt O

HCO2Na, rt, 15 h, 76%

O

O

O

3

Example 2

O

O NaOAc, Ac2O, reflux HO

O

O

62 %

O

O

O

O

O

References 1. 2. 3. 4. 5.

von Kostanecki, S.; Rozycki, A. Ber. 1901, 34, 102−109. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599−604. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303−1313. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Y. A. Chemistry of Heterocyclic Compounds 2003, 39, 96−100. Limberakis, C. Kostanecki−Robinson Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 521−535. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_142, © Springer-Verlag Berlin Heidelberg 2009

323

Kröhnke pyridine synthesis Pyridines from α-pyridinium methyl ketone salts and α,β-unsaturated ketones. O O

R2

Br

N

R

NH4OAc, HOAc

H O

H

R2

N

R Br Michael

N

R R1

R1

H O

R2

Br

N

O

addition

O

H Br AcO

R

Br

O

enolization

N

R

R1

R1

H

R2

R

R

R R1

O

:NH3

R2

R2

R1

HO H2N :

R1 H

O

O

O

N

O

R2

The ketone is more reactive than the enone R1

R

R1

O R1

HN R2

R2

OAc

H

N H

R OH

R2

H

N

R

AcO

Example 11b Ph

NH4OAc AcOH

Ph N

90% Ph

O

O

Ph

Ph

N

Ph

Example 24 N N

N

N N N N O

O

NH4OAc AcOH

N

81%

N N

N

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_143, © Springer-Verlag Berlin Heidelberg 2009

N

324

Example 36 N O

NH4OAc, AcOH 115 oC, overnight

O X

N X

X = H, 65% X = F, 83% X = Br, 82% X = OMe, 40%

References (a) Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690−697. (b) Kröhnke, F.; Zecher, W. Angew. Chem. 1962, 74, 811−817. (c) Kröhnke, F. Synthesis 1976, 1−24. (Review). 2. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584−3585, 3585−3586. 3. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850−853. 4. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774−2781. 5. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589−592. 6. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045−3048. 7. Cave, G. W. V.; Raston, C. L. J. Chem. Soc., Perkin Trans. 1 2001, 3258−3264. 8. Malkov, A. V.; Bell, M.; Vassieu, M.; Bugatti, V.; Kocovsky, P. J. Mol. Cat. A: Chem. 2003, 196, 179−186. 9. Galatsis, P. Kröhnke Pyridine Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311−313. (Review). 10. Yan, C.-G.; Wang, Q.-F.; Cai, X.-M.; Sun, J. Central Eur. J. Chem. 2008, 6, 188−198. 1.

325

Kumada cross-coupling reaction The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) was originally reported as the nickel-catalyzed crosscoupling of Grignard reagents with aryl- or alkenyl halides. It has subsequently been developed to encompass the coupling of organolithium or organomagnesium compounds with aryl-, alkenyl or alkyl halides, catalyzed by nickel or palladium. The Kumada cross-coupling reaction, as well as the Negishi, Stille, Hiyama, and Suzuki cross-coupling reactions, belong to the same category of Pd-catalyzed cross-coupling reactions of organic halides, triflates and other electrophiles with organometallic reagents. These reactions follow a general mechanistic catalytic cycle as shown below. There are slight variations for the Hiyama and Suzuki reactions, for which an additional activation step is required for the transmetallation to occur. Pd(0)

R1 MgX

R X

oxidative R X

MgX2

L2Pd(0)

L

R

addition L Pd R1 R

R R1

L Pd X L

reductive

MgX2

R1 MgX

transmetallation isomerization

R R1

elimination

L2Pd(0)

The catalytic cycle: LnPd(II)

R1M

transmetallation

R1 LnPd(II)

R1

reductive

R1 R1

LnPd(0)

elimination

R X L2Pd(0) R R1 oxidative addition

R

L Pd X L

reductive elimination transmetallation and isomerization L

L Pd R1 R MX

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_144, © Springer-Verlag Berlin Heidelberg 2009

R1M

326

Example 12 Pd(dppf)Cl2, Et2O Br

O

S

O

MgBr

–30 oC to rt, 5 h, 98%

S

Example 23 Me

H Me

MgBr

Ni/Ligand

Br Me

MeO Ph2P

Me Me

(2−5 mol%) 69%

Fe

Ligand 95% ee

Example 35 Br

N

MgBr N

N

Br

S

PdCl2•(dppb) THF, rt, 87%

N

Br

MgBr

PdCl2•(dppb) THF, reflux, 98%

N N S

Example 48 S

S OTBS

N

3 equiv

MgBr

OTBS

N

23 mol% PdCl2(dppf) Et2O, rt, 12 h, 75% I

Example 59 O EtO P EtO O

Me

C5H11 TESO

MeO

MeO

2.5 equiv MeMgCl

MeO

10 mol% Ni(acac)2 THF, 0 oC, 10 min. 90%

C5H11 TESO

MeO

327

References 1.

Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958−1969. 2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919−1929. 3. Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153−8156. 4. Kalinin, V. N. Synthesis 1992, 413−432. (Review). 5. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737−3746. 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889−9890. 8. Rivkin, A.; Njardarson, J. T.; Biswas, K.; Chou, T.-C.; Danishefsky, S. J. J. Org. Chem. 2002, 67, 7737−7740. 9. William, A. D.; Kobayashi, Y. J. Org. Chem. 2002, 67, 8771−8782. 10. Fuchter, M. J. Kumada cross-coupling reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 47−69. (Review).

328

Lawesson’s reagent 2,4-Bis(4-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide transforms the carbonyl groups of aldehydes, ketones, amides, lactams, esters and lactones into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis. S P S S P S

O O R

1

R

O

S

2

R

Lawesson's reagent

1

R2

R1,R2 = H, R, OR, NHR

S P S S P S

O

O

N H

O S

N H

Lawesson's reagent

S

O

S P S S P S

2 O

S

O

S P S O

O

:

O

NH

S S P O

O

P

O

H N N H

O

S

P S

Example 14 H

H

O

O H O

Lawesson's reagent (Me2N)2C=S

O

xylene, 160

oC,

47%

O S

O H S OMe

OMe

Example 25

S

O MeO2C

N

H

Lawesson's

MeO2C

N

reagent, quant.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_145, © Springer-Verlag Berlin Heidelberg 2009

H

NH

329

Example 3, Thiophene from dione8 O

O

R

R N SO2Ph

Lawesson's reagent toluene, reflux 88−99%

N SO2Ph

R

R

S N SO2Ph

N SO2Ph

R= R= R= R= R=

H Me OMe Cl Br

Example 410

O O

MeO O

Lawesson's reagent Me

N

O

Me

O

Me

toluene, reflux, 100%

O O

MeO S

Me N

References Scheibye, S.; Shabana, R.; Lawesson, S. O.; Rømming, C. Tetrahedron 1982, 38, 993– 1001. 2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885–5886. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Nugiel, D. A.; Abe, Y.; Bal Reddy, K.; DeFrees, S. A.; Reddy, D. R.; Awartani, R. A.; Conley, S. R.; Rutjes, F. P. J. T.; Theodorakis, E. A. J. Am. Chem. Soc. 1995, 117, 10227–10238. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003– 2005. 6. Luheshi, A.-B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123–127. 7. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555–1558. 8. Diana, P.; Carbone, A.; Barraja, P.; Montalbano, A.; Martorana, A.; Dattolo, G.; Gia, O.; Dalla Via, L.; Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 2342–2346. 9. Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278. (Review). 10. Taniguchi, T.; Ishibashi, H. Tetrahedron 2008, 64, 8773–8779. 11. de Moreira, D. R. M. Synlett 2008, 463–464. (Review). 1.

330

Leuckart–Wallach reaction Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes the Eschweiler–Clarke reductive alkylation of amines on page 210. R3 HN R4

R1 O R2

R1

R3 N R4

R2

CO2↑

H HO

HO H R1 N R3 R2 R 4

O H

R2

R1

R1

:

R4 H R3

HCO2H

N R2 R4

H2 O

− H2O R3

R1 R2

R3 N R4

:N

gem-aminoalcohol; iminium ion intermediate R1 HCO2H

R3 N R4 − CO 2 H O

R2 H

R1 R2 H

R3 N R4 H

R1

H

R3 N R4

R2

O

reduction Example 14 H N CHO

O

HCO2H 60 oC, 57%

O N

Example 26 HCO2H, H2O 190 oC, autoclave

O OHC

N

N 16 h, 75%

Example 37 N O S

H

H2N

HN

HCO2H, reflux

N

N N

7 h, 45%

S

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_146, © Springer-Verlag Berlin Heidelberg 2009

331

Example 48 H2NCHO O

NHCOCH3

HCO2H 150oC

OHCHN

NHCOCH3

An unexpected intramolecular transamidation via a Wagner–Meerwein shift after the Leuckart–Wallach reaction H2NCHO, HCO2H O

NHCOCH3

150 oC

CH3COHN

NHCHO

References Leuckart, R. Ber. 1885, 18, 2341−2344. Carl L. R. A. Leuckart (1854−1889) was born in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he became an assistant professor at Göttingen. Unfortunately, chemistry lost a brilliant contributor by his sudden death at age 35 as a result of a fall in his parent’s house. 2. Wallach, O. Ann. 1892, 272, 99. Otto Wallach (1847−1931), born in Königsberg, Prussia, studied under Wöhler and Hofmann. He was the director of the Chemical Institute at Göttingen from 1889 to 1915. His book “Terpene und Kampfer” served as the foundation for future work in terpene chemistry. Wallach was awarded the Nobel Prize in Chemistry in 1910 for his work on alicyclic compounds. 3. Moore, M. L. Org. React. 1949, 5, 301−330. (Review). 4. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073−3075. 5. Lukasiewicz, A. Tetrahedron 1963, 19, 1789−1799. (Mechanism). 6. Bach, R. D. J. Org. Chem. 1968, 33, 1647−1649. 7. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033−1039. 8. Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; Ruiz, P. M.; San Antonio, R. M.; Alcazar, M. P. M. Tetrahedron: Asymmetry 1999, 10, 1499−1505. 9. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67, 8685−8687. 10. Brewer, A. R. E. Leuckart–Wallach reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 451−455. (Review). 11. Muzalevskiy, V. M.; Nenajdenko, V. G.; Shastin, A. V.; Balenkova, E. S.; Haufe, G. J. Fluorine Chem. 2008, 129, 1052−1055. 1.

332

Lossen rearrangement The Lossen rearrangement involves the generation of an isocyanate via thermal or base-mediated rearrangement of an activated hydroxamate which can be generated from the corresponding hydroxamic acid. Activation of the hydroxamic acid can be achieved through O-acylation, O-arylation, chlorination, or O-sulfonylation. Such hydroxamic acids can also be activated using polyphosphoric acid, carbodiimide, Mitsunobu conditions, or silyation. The product of the Lossen rearrangement, an isocyanate can be subsequently converted to an urea or an amine resulting in the net loss of one carbon atom relative to the starting hydroxamic acid. O R1

N H

R2

O

OH

H2O

R1 N C O

CO2↑

R1 NH2

O

O R1

N H

R2

O

HO H

O R1

O

N

R1 N C O

R2CO2

R2

O O

:OH2

OH

isocyanate intermediate

R1

H N

O O

decarboxylation

H

CO2↑

R1 NH2

:B

Example 16

O O

N

O N MsO

O O

NH

BnOH, CH3CN, 85 oC, 78%

Example 27 O Cl Br

EtO2C

H N

O

CO2Et

Et3N, H2O

N

C

O NH2

EtOH, H2O

Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_147, © Springer-Verlag Berlin Heidelberg 2009

50%

Br

333

Example 38 O H3C

N O S O O O

ArNH2:

NHCONHAr

NH2

PhH, rt, 6 h, 54%

CONHAr ArNH2

O

O

N N OSO2Ph O

N Ar H2

OSO2Ph

N C O

Lossen

H N

H N

Ar

O

Ar

O

Example 49 N

N AcO

DBU, THF, H2O

H N

N reflux, 1 h O

O MeO

OMe

O

C

N

N N

O MeO

H2 N OMe

N O MeO

OMe

References Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (1838−1906) was born in Kreuznach, Germany. After his Ph.D. studies at Göttingen in 1862, he embarked on his independent academic career, and his interests centered on hydroxyamines. 2. Bauer, L.; Exner, O. Angew. Chem., Int. Ed. 1974, 13, 376. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735−756. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485−495. 5. Zalipsky, S. Chem. Commun. 1998, 69−70. 6. Stafford, J. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E. M.; Feldman, P. L. J. Org Chem. 1998, 63, 10040–10044. 7. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291−5293. 8. Abbady, M. S.; Kandeel, M. M.; Youssef, M. S. K. Phosphorous, Sulfur and Silicon 2000, 163, 55–64. 9. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.; Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299−301. 10. Choi, C.; Pfefferkorn, J. A. Lossen rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 200−209. (Review). 1.

334

McFadyen–Stevens reduction Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes. O R

O R

N H

H N

N H

H N

O SO2Ar

R

N

O

Base SO2Ar

N

R

H

cleavage

O

O

homolytic H

N2 ↑

R

H

R

H

B:

Example 18 O O2N

NH HN SO2

O K2CO3, MeOH

O2N

H

reflux, 1 h, 75%

Example 210 O N N H

O NHNHTs

Na2CO3, glass powder ethylene glycol microwave (450 W) 90%

O N N H

O H

References McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584−587. Thomas S. Stevens (1900−2000) was born in Renfrew, Scotland. After earning his Ph.D. under W. H. Perkin at Oxford University, he became a reader at the University of Sheffield. J. S. McFadyen (1908−?) was born in Toronto, Canada. After studying under Stevens at the University of Glasgow, he worked for ICI for 15 years before returning to Canada where he worked for the Canadian Industries, Ltd., Montreal. 2. Newman, M. S.; Caflisch, E. G., Jr. J. Am. Chem. Soc. 1958, 80, 862−864. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664−3666. 4. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 7, 2927−2931. 5. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem. 1975, 12, 1225−1231. 6. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13, 841−844. 7. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793−796. 8. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645−4648. 9. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9−16. 10. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569−2573. 1.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_148, © Springer-Verlag Berlin Heidelberg 2009

335

McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. A single-electron process. R1

1. TiCl3, LiAlH4

R1

R1

2. H2O

R2

R2

O R2

TiO

Ti(III)Cl3 R1

Ti(0)

LiAlH4 Ti Ti O O

single electron O

:Ti(0)

R2

R1

transfer

homocoupling R1

R2 R2

radical anion intermediate Ti Ti O O R1

Ti Ti O O R1

R1

R2 R 2

R1 R 2 R2

R1

R1

R2

R2

Ti Ti O O

oxide-coated titanium surface Example 1, Cross-McMurry coupling7 OH

MeO2S

OH

MeO2S Zn, TiCl4, reflux O O

4.5 h, 75%, > 99% Z

Example 2, Homo-McMurry coupling8

S

CHO

Zn, TiCl4, THF,110 oC microwave (10 W), 10 min. 87%

S S

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_149, © Springer-Verlag Berlin Heidelberg 2009

336

Example 3, Cross-McMurry coupling9 OMe

OMe N O N

Zn, TiCl4

O N

N

THF, 78%

N

O

N

O

O

O

Example 4, Cross-McMurry coupling10

BnO

CHO

OHC

O

OH

MeO

O

MeO

Zn−TiCl4, THF −5 to 0 oC then reflux, 2.5 h, 77%

O O

BnO

OH

References (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708−4712. (b) McMurry, J. E. Chem. Rev. 1989, 89, 1513−1524. (Review). 2. Hirao, T. Synlett 1999, 175−181. 3. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett. 2002, 43, 3645−3648. 4. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843−1850. 5. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035−3038. 6. Ephritikhine, M.; Villiers, C. In Modern Carbonyl Olefination Takeda, T., Ed.; WileyVCH: Weinheim, Germany, 2004, 223−285. (Review). 7. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513−1516. 8. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491−5494. 9. Zeng, D. X.; Chen, Y. Synlett 2006, 490−492. 10. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem. 2007, 72, 10283−10286. 11. Debroy, P.; Lindeman, S. V.; Rathore, R. J. Org. Chem. 2009, 74, 2080−2087. 1.

337

Mannich reaction Three-component aminomethylation from amine, aldehyde and a compound with an acidic methylene moiety.

R

H

R H

H

1

R

R2

H

O

OH R

H

H

N R

H

R2

N R

R1

OH2 R

R

:

H H N: R R

O

O

O

R NH

N R

N R

H

When R = Me, the +Me2N=CH2 salt is known as Eschenmoser’s salt (page 206) O O R

R

H

O R2

1

R2

enolization

R

H

1

R

N R

R2

N R

R1

The Mannich reaction can also operate under basic conditions: O

O R1

R1

enolate

R2

R

formation

H B:

O

R2

R

N R

R2

N R

R1

Mannich Base Example 1, Asymmetric Mannich reaction2 O NH2 OHC

O

35 mol% L-proline NO2

O

HN

DMSO, rt, 50%, 94% ee

O

NO2

Example 2, Asymmetric Mannich-type reaction9

N

o-Ts

o-Ts

O N OH

O

NH

O

In(Oi-Pr)3, ligand 5 Å MS, THF, rt, 80%

N O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_150, © Springer-Verlag Berlin Heidelberg 2009

OH

338

Example 3, Asymmetric Mannich reaction10 H

R3

R1 R2

O

ArO2S

O

HO

O

O

N NH

N

R4

O

H 10 mol %

HN

R1

Na2CO3, NaCl, −15 ºC 72−98%, 99:1 er

R3 R4

R2

O

Example 411 N EtO2C

PMP

PMP

O

NH

O

L-proline, DMSO EtO2C syn

rt, 81%

H

Ph Ph Ph Ph N O

O L-proline, DMSO rt, 81%

NH

O

O O

O

References Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647–667. Carl U. F. Mannich (1877−1947) was born in Breslau, Germany. After receiving a Ph.D. at Basel in 1903, he served on the faculties of Göttingen, Frankfurt and Berlin. Mannich synthesized many esters of p-aminobenzoic acid as local anesthetics. 2. List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. 3. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023–10030. 4. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (Review). 5. Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862. (Review). 7. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580−591. (Review). 8. Córdova, A. Acc. Chem. Res. 2004, 37, 102−112. (Review). 9. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44, 4365–4368. 10. Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998–10008. 11. Hahn, B. T.; Fröhlich, R.; Harms, K.; Glorius, F. Angew. Chem., Int. Ed. 2008, 47, 9985−9988. 12. Galatsis, P. Mannich reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 653−670. (Review). 1.

339

Martin’s sulfurane dehydrating reagent Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols. Cf. Burgess dehydrating reagent. OH

Ph2S[OC(CF3)2Ph]2

HOC(CF3)2Ph

Ph2S O

H Ot-Bu

Ph2S

O−C(CF3)2Ph

OC(CF3)2Ph HOC(CF3)2Ph

Ph2S

O

: OC(CF3)2Ph

The alcohol is acidic H OC(CF3)2Ph :

H O−C(CF3)2Ph Ph2S O

Ph2S O

Ph2S

OC(CF3)2Ph

protonation OC(CF3)2Ph

OC(CF3)2Ph β-elimination

O H

Ph2S O

HOC(CF 3)2Ph

E1cB

Example 15 OMe

OBn O

BzO

OH

O

O

O OMe

O O

Martin's sulfurane

OPMB Et N, CHCl , 50 oC 3 3 85%

OBn OMe

OBn O

BzO

O

O

O OMe

O O

OPMB

OBn

Example 26 OBn

BnO OH OBn OBn

O O

Martin's sulfurane PhH, reflux O 88%

OBn OBn O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_151, © Springer-Verlag Berlin Heidelberg 2009

340

Example 37 CO2Me

HO CO2Me 1.5 eq. Martin's sulfurane TBSO

O O MeO

OMe

CH2Cl2, rt, 24 h, 84%

TBSO

O O MeO

OMe

Example 49 i-PrO

OMOM

i-PrO

O

H3CO

H3CO OCH3

Martin's sulfurane

O

N O O

TESO

O OCH3

HN

Cl

OMOM

O

OTIPS OH

PhH, rt 83%

HN O

N Cl

O

OTIPS

O

TESO

O

References (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339–2341; (b0 Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2341–2342; (c) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–4329. (d) Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22–26. 2. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347–3353. 3. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807–7814. 4. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317–4320. 5. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J. Angew. Chem., Int. Ed. 1999, 38, 3340–3345. 6. Kok, S. H. L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001, 66, 7184–7190. 7. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C. Synlett 2002, 358–360. 8. Myers, A. G.; Glatthar, R.; Hammond, M.; Harrington, P. M.; Kuo, E. Y.; Liang, J.; Schaus, S. E.; Wu, Y.; Xiang, J.-N. J. Am. Chem. Soc. 2002, 124, 5380–5401. 9. Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew. Chem., Int. Ed. 2002, 41, 1062–1067. 10. Shea, K. M. Martin’s sulfurane dehydrating reagent. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 248−264. (Review). 11. Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291−1294. 1.

341

Masamune–Roush conditions for the Horner–Emmons reaction Applicable to base-sensitive aldehydes and phosphonates for the Horner– Wadsworth–Emmons reaction. α-Keto or α-alkoxycarbonyl phosphonate required. O (EtO)2P

CHO

AcO

O OEt

N N DBU LiCl, CH3CN, 70%

CO2Et

AcO

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene O (EtO)2P

O OEt

O (EtO)2P

deprotonation

H

LiCl

O

OEt chelation

: N N O (EtO)2P

Li

O OEt

O P OEt OEt

EtO2C

H AcO

AcO

O

EtO2C AcO

O P(OEt)2 O

O

CO2Et

AcO

Example 15 O N H

O P

O

RCHO (OEt)2

N H

LiBr, Et3N

O

TFA R

75−95%

H2 N

R

Example 26 O

O 7

H MOMO

O OMe

O

MeO

LiCl, Hunig base

O 7

OO

MeCN, rt, 14 h, 58% (EtO)2(O)P

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_152, © Springer-Verlag Berlin Heidelberg 2009

MOMO

OMe OO MeO

342

Example 37 Ph Ph CHO

BocN

O

O

Ph

O

N

(EtO)2(O)P

Ph N

O

BocN O

LiBr, DBU, CH3CN, rt, 67%

O

O O

Example 48 N

(EtO)2

O P

O CO2Et

Ph

N H

N

CO2Et

Ph

THF, 92%

Example 510 O (MeO)2P

O

Ph N H

MeO CO2Me

CHO

DBU, LiCl, THF, rt 90%

OMe O

Ph N H

MeO

CO2Me 98 : 2

O

Ph N H

CO2Me

References 1.

Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186. 2. Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2636. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035–1039, and 6389–6391. 4. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703–1708. 5. Johnson, C. R.; Zhang, B. Tetrahedron Lett. 1995, 36, 9253–9256. 6. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058–2059. 7. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123–125. 8. Simoni, D.; Rossi, M.; Rondannin, R.; Mazzali, A.; Baruchello, R.; Malagutti, C.; Roberti, M.; Invidiata, F. P. Org. Lett. 2000, 2, 3765–3768. 9. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Redshaw, S.; Watson, W. Synlett 2004, 679–683. 10. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436. 11. Zanato, C.; Pignataro, L.; Hao, Z.; Gennari, C. Synthesis 2008, 2158–2162.

343

Meerwein’s salt Meerwein’s salts, also known as the Meerwein reagent, refer to trimethyloxonium tetrafluoroborate (Me3O+BF4−) and triethyloxonium tetrafluoroborate (Et3O+BF4−). Named after the inventor Hans Meerwein,1 these trialkyloxonium salts are powerful alkylating agents. F F

F

B

F

F F

O

F

B

F

O

Preparation:2 3 Me3O+BF4− + 4 Et2O

4 BF3•OEt2 + 6 Me2O

+

O

+ 3 Cl

B

O

O

Me

Cl

3 Et3O+BF4−

4 BF3•OEt2 + 2 Et2O

+

O

+ 3 Cl

3

B

O

O

Et

Cl

3

Example 1, The Meerwein reagent is an excellent O-alkylating agent:5 Et O Et3O•BF4, NaHPO4

N H

CH3CN, rt, 6 h

Cl

O

O

H3 O N

81%

Cl

O

Et

Cl

Transforming an amide into its corresponding ethyl or methyl esters Example 2, Metal-methylation4 OH 1. PhLi, Et2O, 0 oC Co(CO)6

OMe

t-Bu, t-BuOMe o

Ph

2. Me3O•BF4

45 C, 79% Dötz reaction

OMe

Example 3, N-Alkylation, the product is an ionic liquid8 Me3O•BF4 N

N

t-Bu

Co(OC)5

Et2O, 94%

BF4

H3C N

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_153, © Springer-Verlag Berlin Heidelberg 2009

CH3

344

Example 4, N-Methylation9 SPh N

N SO2NMe2 I

SPh 1. Me3O•BF4, slow addition CH2Cl2, rt 2. BuMeNH, CH3CN, Δ, quant.

Me

N

N I

References (a) Meerwein, H.; Hinz, G.; Hofmann, P.; Kroning, E.; Pfeil, E. J. Prakt. Chem. 1937, 147, 257–285. (b) Meerwein, H.; Bettenberg, E.; Pfeil, E.; Willfang, G. J. Prakt. Chem. 1939, 154, 83–156. 2. (a) Meerwein, H. Org. Synth.; Coll. Vol. V, 1973, 1080. Triethyloxonium tetrafluoroborate. (b) Curphey, T. J. Org. Synth.; Coll. Vol. VI, 1988, 1019. Trimethyloxonium tetrafluoroborate. 3. Chen, F. M. F.; Benoiton, N. L. Can. J. Chem. 1977, 55, 1433–1534. 4. Dötz, K. H.; Möhlemeier, J.; Schubert, U.; Orama, O. J. Organomet. Chem. 1983, 247, 187–201. 5. Downie, I. M.; Heaney, H.; Kemp, G.; King, D.; Wosley, M. Tetrahedron 1992, 48, 4005–4016. 6. Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923–937. 7. Pichlmair, S. Synlett 2004, 195−196. (Review). 8. Egashira, M.; Yamamoto, Y.; Fukutake, T.; Yoshimoto, N.; Morita, M. J. Fluorine Chem. 2006, 127, 1261–1264. 9. Delest, B.; Nshimyumukiza, P.; Fasbender, O.; Tinant, B.; Marchand-Brynaert, J.; Darro, F.; Robiette, R. J. Org. Chem. 2008, 73, 6816–6823. 10. Perst, H.; Seapy, D. G. Triethyloxonium Tetrafluoroborate In Encyclopedia of Reagents for Organic Synthesis John Wiley & Sons, New York, 2008, (Review). 1.

345

Meerwein–Ponndorf–Verley reduction Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol. Reverse of the Oppernauer oxidation. Al(Oi-Pr)3

O R1

R2

OH R1

HOi-Pr

Al(Oi-Pr)3 :

coordination

O R

1

R1

R

i-PrO Oi-Pr Al O O

‡

Oi-Pr O Al Oi-Pr O

R2 H

2

O

R2

R1

R2

‡

H

cyclic transition state hydride

O

O

transfer

R1

Al(Oi-Pr)2

OH

H R

R2

1

R2

Example 12 O H O

H MeO2C

OH H

H

Al(Oi-Pr)3

OH

HOi-Pr, 90%

O

H

H

Example 24 (R)-BINOL (0.1 eq) AlMe3 (0.1 eq)

O

OH

R

* R

43−99% yield 30−80% ee

i-PrOH (4 eq) toluene

Example 37

MeO

Me Me

Me Me

Me Me O O

MeO 4 equiv Me3Al, i-PrOH

OH

MeO

OH O

O

0 oC to rt, 24 h OTBDPS

OTBDPS 84%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_154, © Springer-Verlag Berlin Heidelberg 2009

OTBDPS 15%

346

Example 49 MeO

MeO

O

O

O

O

O

OH

O

73%

OH

OMe

OMe

3 equiv AlMe3 9 equiv HOCH(Ph)2 CH 2Cl2

MeO

O

OH

O

12%

OMe

OH

References 1.

2. 3. 4. 5. 6. 7. 8.

9.

Meerwein, H.; Schmidt, R. Ann. 1925, 444, 221−238. Hans L. Meerwein, born in Hamburg Germany in 1879, received his Ph.D. at Bonn in 1903. In his long and productive academic career, Meerwein made many notable contributions in organic chemistry. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1−57. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007−1017. (Review). Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. 2002, 41, 1020−1022. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004, 69, 1492−1496. Cha, J. S. Org. Proc. Res. Dev. 2006, 10, 1032−1053. Manaviazar, S.; Frigerio, M.; Bhatia, G. S.; Hummersone, M. G.; Aliev, A. E.; Hale, K. J. Org. Lett. 2006, 8, 4477−4480. Clay, J. M. Meerwein–Ponndorf–Verley reduction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 123−128. (Review). Dilger, A. K.; Gopalsamuthiram, V.; Burke, S. D. J. Am. Chem. Soc. 2007, 129, 16273−16277.

347

Meisenheimer complex Also known as the Meisenheimer−Jackson salt, the stable intermediate for certain SNAr reactions. R HN

:

R NH2 F

NO2

NO2

SNAr, slow,

NO2

R

R NH F

F

fast

rate-determining step

NO2 F

NO2 NO2 Meisenheimer complex

NO2

Sanger’s reagent, ipso attack

NH

NO2

ipso substitution

Example 17 O NO2 CO2Et Ph

N

O CO2Et

t-BuOK, DMF/THF −70 oC, argon

CN

H NC

Ph nitronate

Example 29 OH O2N

CH2Cl2

NO2 2

N C N

argon, rt, 3 h

NO2

H N O N i-Pr i-Pr N N O2N NO2

O N O2N

N H NO2 15.8%

O

N

15.5%

NO2

O

The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and iododinitrobenzene—the fluoro-Meisenheimer complex is the most stabilized because F is the most electron-withdrawing. The reaction rate does not depend upon the capacity of the leaving group.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_155, © Springer-Verlag Berlin Heidelberg 2009

348

Example 310 R' R NH F

F NO2

NO2

R HN R'

R

R' NH

NO2

NO2 F

NO2

NO2

H

R' R N

H

R F

N

R' NO2

NO2 F NO2

NO2

References Meisenheimer, J. Ann. 1902, 323, 205–214. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181–188. (Review). Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147–152. (Review). Terrier, F. Chem. Rev. 1982, 82, 77–152. (Review). Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614–7620. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 4572–4573. 7. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099– 1101. 8. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548–2555. 9. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408–3411. 10. Um, I.-H.; Min, S.-W.; Dust, J. M. J. Org. Chem. 2007, 72, 8797–8803. 11. Han, T. Y.-J.; Pagoria, P. F.; Gash, A. E.; Maiti, A.; Orme, C. A.; Mitchell, A. R.; Fried, L. E. New J. Chem. 2009, 33, 50–56. 1. 2. 3. 4. 5. 6.

349

[1,2]-Meisenheimer rearrangement [1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to substituted hydroxylamines. R R1 N R2 O

Δ

R2

R1 N

R O

R2

R1 N

O

R

Example 17 O

35% H2O2, CHCl3/MeOH, rt, 15 h N

O

then PtO2, rt, 4.5 h

O O

N

O

THF, reflux, 1 h

O

64%, 2 steps

O

N O

References 1. 2. 3. 4. 5. 6. 7. 8.

Meisenheimer, J. Ber. 1919, 52, 1667–1677. Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26, 4319–4327. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). Kurihara, T.; Sakamoto, Y.; Tsukamoto, K.; Ohishi, H.; Harusawa, S.; Yoneda, R. J. Chem. Soc., Perkin Trans. 1, 1993, 81–87. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Minami, K.; Harusawa, S.; Kurihara, T. Tetrahedron Lett. 1994, 35, 3749–3752. Kurihara, T.; Sakamoto, Y.; Takai, M.; Ohishi, H.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1995, 43, 1089–1095. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563–14576. Yoneda, R.; Araki, L.; Harusawa, S.; Kurihara, T. Chem. Pharm. Bull. 1998, 46, 853– 856.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_156, © Springer-Verlag Berlin Heidelberg 2009

350

[2,3]-Meisenheimer rearrangement [2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines: 3

3

2 1

2

O N R R 1'

Δ

1

R

2'

O N

2' 1'

R

Example 17

PhSO2

O N

Ph

Et2O, rt, 48 h 48%, 61% de

N

N

*

O

Example 28 Bn HO O N O

Bn N O

O

m-CPBA OH

OH

Al2O3 (alumina) MeOH

CH2Cl2, 100%

Bn O O N O

Bn CDCl3, rt OH 67%, 65% de

O N O *

O OH

References Meisenheimer, J. Ber. 1919, 52, 1667–1677. Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303–306. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266. (Review). Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1994, 42, 475–480. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279– 8283. 6. Enders, D.; Kempen, H. Synlett 1994, 969–971. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322–324. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tetrahedron: Asymmetry 2000, 11, 4227–4238. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc. 2005, 127, 7615–7621. 10. Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874–875. 1. 2. 3. 4.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_157, © Springer-Verlag Berlin Heidelberg 2009

351

Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon–carbon bonds.

O

Ph OMe

N

N(i-Pr)2

H

O

2. R-X

Ph

H3C

O N Li

H3 C

O

Ph H3 C

O

H

OMe

N

OMe

N

R

Ph

Ph H

Ph

O

1. LDA

R X

N Li

N

H O

O

R O

Me

Me

Me

Example 12 O N

Ph

TMSO

1. LDA 2. TMSO

O

Br H

3. LDA OMe 4. Me2SO4

O

Ph

H3O

N OMe

O

66% yield 70% ee

Example 25 OMe Ph O

O N

1.

O

O

OMe

O

Li

2.

Ph

N O 99% yield

I

Example 39

O

N

3 equiv n-BuLi 3 equiv (−)-sparteine Et2O, −78 oC, 4 h

O

N

O Li

N

MeOH n-Bu

n-Bu 79%

er (S:R) = 86:14

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_158, © Springer-Verlag Berlin Heidelberg 2009

352

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

(a) Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268–270. While Albert I. Meyers was an assistant professor at Wayne State University, neighboring pharmaceutical firm Parke–Davis (Drs. George Moersch and Harry Crooks) donated several kilograms of (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (Meyers referred to it as the Parke–Davis diol), from which his chemistry with chiral oxazolines began. He taught at Colorado State University since 1972. Meyers passed away in 2007. (b) Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508–6510. (c) Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 15, 1333–1336. (d) Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266–6267. (e) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186–1187. (f) Meyers, A. I.; Mihelich, E. D. Angew. Chem., Int. Ed. 1976, 15, 270–271. (Review). (g) Meyers, A. I. Acc. Chem. Res. 1978, 11, 375– 381. (Review). Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792–2796. Meyers, A. I., Lutomski, K. A. In Asymmetric Synthesis, Morrison, J. D. Ed.; Vol III, Part B, Chapter 3, Academic Press, 1983. (Review). Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607–2609. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). Wolfe, J. P. Meyers Oxazoline Method. In Name Reactions in Heterocycl. Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 237–248. (Review). Hogan, A.-M. L.; Tricotet, T.; Meek, A.; Khokhar, S. S.; O’Shea, D. F. J. Org. Chem. 2008, 73, 6041–6044.

353

Meyer–Schuster rearrangement The isomerization of secondary and tertiary α-acetylenic alcohols to α,βunsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is terminal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement. OH

R R

R

H , H2O R

R1

R R

OH

R R

H

R R R1

R1

R

R •

R1

OH2

R1

R

O

R1

R

H •

:OH2

R

tautomerization R1

O

R

R1

OH

Example 16 O

OH N

Br

H

98% H2SO4

H Br

N

50%

O

O

Example 27 O P O O O O O P P O O P OTMS TMSO OTMS

OH PhS

ClCH2CH2Cl, 83 oC, 30 min.

O PhS 54% PhS 6%

Example 38 O

O O

O

O

O O

O

O

10% H2SO4 THF, rt, 1.5 h HO

OEt

70%

CO2Et

HO 21% CO2Et

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_159, © Springer-Verlag Berlin Heidelberg 2009

354

Example 49 PMBN

PMBN

CO2Et OMe

EtO2C

OH

OMe

CO2Et

BF3·Et2O TFA, 89%

OMe OMe

EtO2C

O

References Meyer, K. H.; Schuster, K. Ber. 1922, 55, 819–823. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429–438. (Review). Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977, 42, 3403–3408. 4. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666–674. 5. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829– 835. 6. Brown, G. R.; Hollinshead, D. M.; Stokes, E. S.; Clarke, D. S.; Eakin, M. A.; Foubister, A. J.; Glossop, S. C.; Griffiths, D.; Johnson, M. C.; McTaggart, F.; Mirrlees, D. J.; Smith, G. J.; Wood, R. J. Med. Chem. 1999, 42, 1306–1311. 7. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem. 1995, 60, 4798–4802. 8. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139–7158. 9. Williams, C. M.; Heim, R.; Bernhardt, P. V. Tetrahedron 2005, 61, 3771–3779. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review). 1. 2. 3.

355

Michael addition Also known as conjugate addition, Michael addition is the 1,4-addition of a nucleophile to an α,β-unsaturated system. R1

O

Nuc R2

Nuc:

R2

Y

R1

R3

R1

Nuc:

O

R2

R3

Nuc R2

conjugate Y

O

addition

R1

O Nuc R2

workup

Y H

R3 enolate

R3

Y

H

R1

O

R3

H

Example 1, Asymmetric Michael addition2 O

O

O

O

N

PhMgBr, CuBr•DMS

Si(Me)2Ph

Ph

N

ether, THF, −55 C 92%, 92% de

Si(Me)2Ph

o

O

CPh3

O

CPh3

Example 2, Thia-Michael addition3 O

O H2S, NaOMe

O

HS

O

MeOH, 75%

N

N

Example 3, Phospha-Michael addition7 O MeO

(EtO)2P(O)H R

Me2N

R OEt

NH

cat.

O MeO

NMe2

P O

OEt

R = H, 71% R = Me, 51%

Example 4, Asymmetric aza-Michael addition9 Ph MeO2C

NH2 MeO2C

MeO2C Cl

NaI, Na2CO3, Bu4NBr CH3CN, 82%

N

N Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_160, © Springer-Verlag Berlin Heidelberg 2009

2:1

Ph

Y

356

Example 5, Intramolecular Michael addition10 O Me Boc N CO2Me

O

O

LiHMDS, DMF −60 oC, 20 min. 95%

H O Me H

H CO2Me N H Boc

References Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (1853−1942) was born in Buffalo, New York. He studied under Robert Bunsen, August Hofmann, Adolphe Wurtz, and Dimitri Mendeleev, but never bothered to take a degree. Back to the United States, Michael became a Professor of Chemistry at Tufts University, where he married one of his most brilliant students, Helen Abbott, one of the few female organic chemists in this period. Since he failed miserably as an administrator, Michael and his wife set up their own private laboratory at Newton Center, Massachusetts, where the Michael addition was discovered. 2. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705−749. 3. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459−505. 4. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135−631. (Review). 5. Hoz, S. Acc. Chem. Res. 1993, 26, 69−73. (Review). 6. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. 1993, 32, 1010−1022. (Review). 7. Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lampronti, I.; Rondanin, R.; Roberti, M.; Pollini, G. P. Tetrahedron Lett. 1998, 39, 7615−7618. 8. Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29−49. (Review on the phospha-Michael addition). 9. Chen, L.-J.; Hou, D.-R. Tetrahedron: Asymmetry 2008, 19, 715−720. 10. Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711−1714. 11. Thaler, T.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 645−648. 1.

357

Michaelis−Arbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites. General scheme: O R2 P OR1 OR1

Δ (R1O)3P

R2 X

R1 X

R1 = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I For instance: O O (CH3O)3P

Br

Br

Δ O

O

CH3

SN2

(CH3O)3P:

Br CH3 O CH3O P CH3O

O CH3O P CH3O

S N2

O O

CH3

O CH3Br↑

O

Example 12

Br

(EtO)3P, Tol.

P(OEt)2 O

145 oC, 4 h, 70%

Br

Example 26 140 oC

O BnO P BnO

O BnO P BnO

(BnO)3P

Cl

8 h, 92%

O OBn P OBn

Example 37

F

O

F

F

Br

(EtO)3P, NiCl2

F

O

100 oC, 72 h, 10%

F

F

O P OEt OEt

Example 49 O Br

Me N Bn

Ph

(MeO)3P 105−110 oC 92−98%

O (MeO)2P

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_161, © Springer-Verlag Berlin Heidelberg 2009

Me N Bn

Ph

358

Example 510 BnO

BnO O BnO BnO

O Bn

TMSO−P(OEt)2 SCN 50 oC, 1 h, 82%

O BnO BnO

O Bn

S

P(OEt)2 O

References (a) Michaelis, A.; Kaehne, R. Ber. 1898, 31, 1048−1055. (b) Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. 2. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559−560. 3. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. 1973, 12, 91−119. (Review). 4. WaschbĦsch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727−743. 5. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393−5395. 6. Erker, T.; Handler, N. Synthesis 2004, 668−670. 7. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125, 1317−1324. 8. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J. Fluorine Chem. 2004, 125, 1407−1410. 9. Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.; Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.; Garcia-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427−2436. 10. Piekutowska, M.; Pakulski, Z. Carbohydrate Res. 2008, 343, 785−792. 1.

359

Midland reduction Asymmetric reduction of ketones using Alpine-borane®. Alpine-borane® = B-isopinocampheyl-9-borabicyclo[3.3.1]nonane. O

OH

Alpine-borane R

R1

1

neat

R

R

H B

THF

B

reflux

(1R)-(+)-α-pinene 9-BBN (R)-Alpine-borane 9-BBN = 9-borabicyclo[3.3.1]nonane

O

H

B O R1

B

R1 R

R

hydride

O

transfer

B

H2O2, NaOH

R1

workup

OH R1 R

R

Example 16 OH

O

(R)-Alpine-borane, THF

BnO H

BnO

−10 oC to rt, 95%, 88% ee

H

Example 27 OH

O (R)-Alpine-borane

OPMB

OPMB TBSO

22 oC, 6 kbar, 82% 80% de

TBSO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_162, © Springer-Verlag Berlin Heidelberg 2009

360

Example 38 OH

O (R)-Alpine-borane (neat)

TBSO

rt, 74%, 93% ee

TBSO

References 1.

2. 3. 4. 5. 6. 7. 8. 9.

Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979, 101, 2352−2355. M. Mark Midland was a professor at the University of California, Riverside. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867−869. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606−1608. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531−1533. Singh, V. K. Synthesis 1992, 605−617. (Review). Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2724. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891−898. Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163−5165. Clay, J. M. Midland reduction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2007, pp 40−45. (Review).

361

Minisci reaction Radical-based carbon–carbon bond formation with electron-deficient heteroaromatics. The reaction entails an intermolecular addition of a nucleophilic radical to protonated heteroaromatic nucleus. 2 AgNO3 (NH4)2S2O8

R CO2H N

R CO2H

N

H2SO4

2 AgNO3, (NH4)2S2O8, H2SO4

N H

R

CO2

R

H2SO4

silver-catalyzed oxidative decarboxylation

N H

R

Example 14 S2O8

•CH2OH

CH3OH

CN BF4 N OCH3

H+

SO4

• SO4

CN

(NH4)2S2O8 MeOH, H2O reflux, 1 h, 40%

OH

N

Example 25 1.6 equiv m-CPBA N

acetone, rt, 1.5 h 75%

(CH3)3O•BF4 N O

CH2Cl2, rt 90 min.

Meerwein’s reagent (NH4)2S2O8 MeOH, H2O N OCH3

BF4

reflux, 1 h 40%, 2 steps

OH

N

1.6 equiv m-CPBA N

acetone, rt, 1.5 h 78%

N O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_163, © Springer-Verlag Berlin Heidelberg 2009

362

(CH3)3O•BF4

BF4

CH2Cl2, rt 90 min., 85%

N OCH3

OH

(NH4)2S2O8 MeOH, H2O reflux, 1 h, 41% N

Example 3, Intramolecular Minisci reaction6 EtO2C

CO2Et

N

N O

OH O

O

AgNO3, (NH4)2S2O8 CH2Cl2, H2O, AcOH, TFA rt, 1 h, 46%

NH

N H

Example 47 H BzN

Me

(NH4)2S2O8, AgNO3

N N

TFA, H2O, 75 °C 53%

Cl

Me

Me

CO2H H BzN

BzN H

N N Cl

90 : 10

N N Cl

Example 510 N CO2H

N N

HO2C

CO2H 1 equiv

10 equiv

N

10 equiv FeSO4•7H2O H2O2, H2O, H2SO4 CH2Cl2, 0 oC, 15 min. 24%

N

N

N

N

References Minisci, F, Bernardi. R, Bertini, F, Galli, R, Perchinummo, M. Tetrahedron 1971, 27, 3575–3579. 2. Minisci, F. Synthesis 1973, 1–24. (Review). 3. Minisci, F. Acc. Chem. Res. 1983, 16, 27–32. (Review). 4. Katz, R. B.; Mistry, J.; Mitchell, M. B. Synth. Commun. 1989, 19, 317–325. 5. Biyouki, M. A. A.; Smith, R. A. J.; Bedford, J. J.; Leader, J. P. Synth. Commun. 1998, 28, 3817–3825. 6. Doll, M. K. H. J. Org. Chem. 1999, 64, 1372–1374. 7. Cowden, C. J. Org. Lett. 2003, 5, 4497–4499. 8. Kast, O.; Bracher, F. Synth. Commun. 2003, 33, 3843–3850. 9. Benaglia, M.; Puglisi, A.; Holczknecht, O.; Quici, S.; Pozzi, G. Tetrahedron 2005, 61, 12058–12064. 10. Palde, P. B.; McNaughton, B. R.; Ross, N. T.; Gareiss, P. C.; Mace, C. R.; Spitale, R. C.; Miller, B. L. Synthesis 2007, 2287–2290. 11. Brebion, F.; Nàjera, F.; Delouvrié, B.; Lacôte, E.; Fensterbank, L.; Malacria, M. J. Heterocycl. Chem. 2008, 45, 527–532. 1.

363

Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.

O S

R

Δ

Ar

Ar

S

O

HO

P(OCH3)3

R

R

2

R

O S

3 2 1

S N2

[2,3]-sigmatropic

2 1

Ar

Ar

S

S

O

1

3

R

rearrangement

:P(OCH3)3 O

Ar

2

1

HO

H

P(OCH3)3

R

R

Example 12 O

O NaIO4 dioxane/H2O 50%

TBSO OMe

PhS

Example 2

TBSO CHO

7

OMe MeO

OMe

O O

MeO

OTBS

(EtO)3P, EtOH

O O

OTBS

reflux, 16 h, 98% OH

O S Ph

Example 3, Seleno-Mislow-Evans8 TBDPSO

TBDPSO PMBO

OTBS

H

HO H O

PMBO

OTBS

OH

1. PhSeCN, Bu3P, THF H 2. H2O2, pyr., THF, −30 oC 62%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_164, © Springer-Verlag Berlin Heidelberg 2009

O

H

364

References (a) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100–2104. (b) Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957. (c) Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672–3674. (d) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147–155. (Review). 2. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936–3937. 3. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077–9078. 4. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682–6683. 5. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23–27. 6. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334–8341. 7. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341–1343. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485– 3499. 9. Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792–2793. 10. Pelc, M. J.; Zakarian, A. Tetrahedron Lett. 2006, 47, 7519–7523. 11. Brebion, F.; Najera, F.; Delouvrie, B.; Lacote, E.; Fensterbank, L.; Malacria, M. Synthesis 2007, 2273–2278. 1.

365

Mitsunobu reaction SN2 inversion of an alcohol by a nucleophile using disubstituted azodicarboxylates (originally, diethyl diazodicarboxylate, or DEAD) and trisubstituted phosphines (originally, triphenylphosphine).

OH R1 o

R2

N N EtO2C

HNuc

0

1 or 2 alcohol

CO2Et H

Nuc R1

PPh3

O PPh3

R2

EtO2C

H

CO2Et N N

CO2Et

adduct

Ph3P

CO2Et

EtO2C

N N

formation

:PPh3

H N N

H Nuc EtO2C

CO2Et

N N

Ph3P

EtO2C

:OH R1

R2

Diethyl azodicarboxylate (DEAD) alcohol

EtO2C

activation

H

SN2

O PPh3

H N N CO2Et

R1

R2

Nuc R

reaction

1

R2

O PPh3

Nuc

Example 12 CH2OAc O

CH2OAc O

PhCO2H DIAD, PPh3, THF OH

OAc OAc

−50 oC to rt, 2 h, 80%

O2CPh

OAc OAc OAc

OAc

2:1 β:α

Example 23

OH

DEAD, PPh3, Tol.

O O

O2N

CO2H

−30 to 0 oC, 1 h, 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_165, © Springer-Verlag Berlin Heidelberg 2009

4-O2NPhCOO

O O

366

Example 3, Ether formation6 BnO BnO2C

OH

O

OBn

OH O

BnO

OBn O

OBn

CO2Bn

OBn N

PBu3, ADDP, THF, 0 oC to rt, overnight 100%

O

N O

OMe

OMe

ADDP = 1,1'-(azodicarbonyl)dipiperidine Example 47 O TMS

OH

PPh3, DIAD, PhCH3

HN

O TMS Ph

N

reflux, 60% Ph

Example 58 CH3

H

H n-BuLi

HO

N

H 3C H

O

O

Ph2PO

then Ph2PCl

CH3

CH3

N

H3 C H

O

O

H O

OH 80%

O2N

O2N

CH3

CH3

N

H3C H

CH3

Example 6, Intramolecular Mitsunobu reaction9 OH NsHN

NHNs R MeO OMe

N Boc

DEAD, PPh3 CO2Et

R

PhH, 92 % R=CH(OMe)2

MeO OMe

N Boc

CO2Et

367

References (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380−2382. (b) Mitsunobu, O. Synthesis 1981, 1−28. (Review). 2. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813−5816. 3. KocieĔski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin Trans. 1, 1987, 2183−2187. 4. Hughes, D. L. Org. React. 1992, 42, 335−656. (Review). 5. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127−164. (Review). 6. Vaccaro, W. D.; Sher, R.; Davis, H. R., Jr. Bioorg. Med. Chem. Lett. 1998, 8, 35–40. 7. Cevallos, A.; Rios, R.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron: Asymmetry 2000, 11, 4407–4416. 8. Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem. Soc. 2003, 125, 10538– 10539. 9. Sumi, S.; Matsumoto, K.; Tokuyama, H.; Fukuyama, T. Tetrahedron 2003, 59, 8571– 8587. 10. Christen, D. P. Mitsunobu reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 671−748. (Review). 1.

368

Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagents to produce arylboronates. Also known as Hosomi−Miyaura borylation.

O

O Ar

X

O

Pd(0)

B B

Ar B base

O

O

O

X = I, Br, Cl, OTf. Ar

oxidative Ar

X

L2Pd(0)

addition

L Pd X L

base O

O

base

B B O

B B

O

O

L O I B O

transmetallation

O

O

L Pd B O Ar O

Ar O

reductive elimination

L Pd I L

O L2Pd(0)

Ar B O

Example 17 OAc O

O

O

O B B

Ph O

O

B O O

Ph CuCl, LiCl, KOAc, DMF, 92%

Example 28 O

O B B O OTf N Cbz

O

3% (Ph3P)2PdCl2, 6% Ph3P 1.5 eq. K2CO3, dioxane, 90 oC 85%

N B O Cbz O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_166, © Springer-Verlag Berlin Heidelberg 2009

369

Example 39 O

O CbzHN

B B

CO2Bn O

O

I

O Pd(dppf)Cl2, KOAc DMSO, 80 oC, 24 h 85%

BnO

O B

CO2Bn

BnO

CbzHN CbzHN

CbzHN

CO2Bn

CO2Bn

I

BnO OBn

BnO Pd(dppf)Cl2, K2CO3 DMSO, 80 oC, 24 h 85%

BnO2C

NHCbz

Example 4, One-pot synthesis of biindolyl10 1. 1 mol% Pd2(dba)3, 4 mol% XPhos 3 equiv HB(pin), 3 equiv Et3N dioxane, 100 oC

MeO MeO Br

N H

2. 1 mol% Pd2(dba)3, 3 equiv K3PO4•H2O dioxane/H2O (10 : 1), 100 oC Br MeO MeO

MeO MeO MeO

N H

MeO

N H

N H

References Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508−7510. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). Suzuki, A. J. Organomet. Chem. 1995, 576, 147−168. (Review). Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477−3480. Giroux, A. Tetrahedron Lett. 2003, 44, 233−235. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885−7887. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org. Lett. 2004, 6, 481−484. 8. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324−7330. 9. Skaff, O.; Jolliffe, K. A.; Hutton, C. A. J. Org. Chem. 2005, 70, 7353−7363. 10. Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. J. Org. Chem. 2008, 73, 9177−9180. 11. Jo, T. S.; Kim, S. H.; Shin, J.; Bae, C. J. Am. Chem. Soc. 2009, 131, 1656−1657. 1. 2. 3. 4. 5. 6. 7.

370

Moffatt oxidation Oxidation of alcohols using DCC and DMSO, aka “Pfitzner−Moffatt oxidation”. OH R

1

R

O

DCC 2

DMSO, HX

R

1

R2

DCC, 1,3-dicyclohexylcarbodiimide H H

H

N C N

HN C N O S

N C N O

H :O

S

R1

N H

H H H

S

O

O N H

R1

R2

O

S

X

O R1

R2

R

H R2

1

R2

(CH3)2S

1,3-dicyclohexylurea Example 12 OH DCC, DMSO, C5H5NH+CF3CO2 OH

O

PhH, rt, 70%

O

Example 28 A

A

OH

O

O

CHO

DCC, DMSO, Cl2CHCO2H O

O

rt, 90 min., 90%

O

O

A = adenosine References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027−3028. Schobert, R. Synthesis 1987, 741−742. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167–3170. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin Trans. 1, 1992, 3019−3022. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25, 437−443. Adak, A. K. Synlett 2004, 1651−1652. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med. Chem. 2005, 48, 3649−3653. van der Linden, J. J. M.; Hilberink, P. W.; Kronenburg, C. M. P.; Kemperman, G. J. Org. Proc. Res. Dev. 2008, 12, 911–920.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_167, © Springer-Verlag Berlin Heidelberg 2009

371

Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene. R

R O

NH

POCl3

N

R1

R

POCl2 O NH R

:

O P Cl Cl O R

Cl

1

NH R1

1

R

R

OPOCl2 NH

N

HOPOCl2

:

R H

R1

R1

Example 16 O2 N

NO2 HN

O2 N

NO2 N

nitrobenzene, POCl3 O SnCl4, 98%

CN CN

Pictet–Hubert reaction The Morgan-Walls reaction is a variant of the Pictet-Hubert reaction where the phenanthridine cyclization was accomplished by dehydrative ring closure of acylo-aminobiphenyls on heating with zinc chloride at 250−300 °C. R

R O R

NH

1

N

ZnCl2 250−300 oC

R1

Example 24 ZnCl2, 250−300 oC H

N

80% O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_168, © Springer-Verlag Berlin Heidelberg 2009

N

372

References 1.

2. 3. 4. 5. 6. 7.

(a) Pictet, A.; Hubert, A. Ber. 1896, 29, 1182−1189. (b) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1931, 2447−2456. (c) Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225−2231. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423−4426. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664−3667. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774−779. Peytou, V.; Condom, R.; Patino, N.; Guedj, R.; Aubertin, A.-M.; Gelus, N.; Bailly, C.; Terreux, R.; Cabrol-Bass, D. J. Med. Chem. 1999, 42, 4042−4043. Holsworth, D. D. Pictet–Hubert Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465−468. (Review).

373

Mori−Ban indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole. CO2Me

CO2Me

Br

Pd(OAc)2, Ph3P

N Ac

NaHCO3, DMF, 130 oC

N Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P: AcO Pd OAc

AcO

Ph3P Pd OAc

:PPh3 O Pd(0)

AcO

O O PPh3

O PPh3

O O

Mori−Ban indole synthesis: Br PdLn

CO2Me Br N Ac

Pd(0) oxidative addition

MeO2C

CO2Me insertion

N Ac

CO2Me addition

H PdBrLn N Ac

CO2Me β-hydride PdBrLn elimination H

of PdH

CO2Me

CO2Me

N Ac

N Ac

Regeneration of Pd(0): H PdBrLn

NaHCO 3

PdBrLn

N Ac

N Ac

β-hydride elimination

H

Pd(0)

NaBr

CO2↑

H2 O

Example 11a I

Pd(OAc)2

N H

Et3N, MeCN sealed tube 110 °C, 87%

Me N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_169, © Springer-Verlag Berlin Heidelberg 2009

374

Example 24 N

Cl

N

N

10 mol% Pd(OAc)2

N

Bu4NBr, K2CO3, DMF, 100 oC 67%

N

N

Example 37 SO2NHMe Br N Br

COCF3 Cbz N

Pd(OAc)2, Bu4NCl

Cbz N SO2NHMe

Et3N, DMF heat, DME, 76% Br

N H

References 1.

2.

3. 4. 5. 6. 7. 8.

Mori−Ban indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977, 18, 1037−1040; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711−1715. Reduction of Pd(OAc)2 to Pd(0), (a) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14, 5605−5614; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818−1826; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009−3013; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375−8384. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289−4293. Li, J. J. J. Org. Chem. 1999, 64, 8425−8427. Gelpke, A. E. S.; Veerman, J. J. N.; Goedheijt, M. S.; Kamer, P. C. J.; van Leuwen, P. W. N. M.; Hiemstra, H. Tetrahedron 1999, 55, 6657−6670. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721−6724. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57, 1041−1048. Ma, J.; Yin, W.; Zhou, H.; Liao, X.; Cook, J. M. J. Org. Chem. 2009, 74, 264−273.

375

Mukaiyama aldol reaction Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether. R2 R CHO

O

OSiMe3

LA

R

X SiMe3

1

R2 R

1

OH

O

O R2

R

R2

R

R1

R1

SiMe3

O

O

R

acid

Me3SiO

X

H R2 R

R

OH

Lewis

1

Example 1, Intramolecular Mukaiyama aldol reaction3 CH(OMe)2

CH(OMe)2 1. LDA, THF, −78 oC, 10 min.

O EtO2C EtO2C

2. 1.8 equiv TMSCl, −78 oC, 4 h 92%

OTMS EtO2C EtO2C O

O

OMe H

H OMe

TiCl4, CH2Cl2 −78 oC to rt, 15 h

EtO2C

EtO2C

CO2Et

CO2Et 40%

12%

Example 2, Mukaiyama aldol reaction7 O

O O OHC

OTBDMS

N Boc

OH BF3•OEt2, DTBMP CH2Cl2, −78 to −50 oC, 73%

N O Bn

N Bn

Example 3, Vinylogous Mukaiyama aldol reaction8 CHO O

OH

1. PhCO2H, rt

O

CN

O O

2. TFA, 60%

OSiMe3

O

NC

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_170, © Springer-Verlag Berlin Heidelberg 2009

O N Boc

376

Example 4, Asymmetric Mukaiyama aldol reaction10 O OTMS

cat.

Ts

Bu3Sn

B H

O

OMe

CHO

Bu3Sn

Bu3Sn 38%

N

50%

OTMS

O HO

OMe

Example 5, Mukaiyama aldol reaction12 O Me Br

OTBS CHO

OTIPS Me

10 mol% Bi(OTf)3 CH2Cl2, −40 oC 76% out of 56% conversion

Me

OTBS O

Br

O Me

OH

References (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. 2. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125−9128. 3. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc., Perkin Trans. 1 2002, 1344−1350. 4. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161−164. 5. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions. In Modern Aldol Reactions Mahrwald, R., Ed.; 2004, 25−68. (Review). 6. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 7. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7, 2795−2797. 8. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett. 2005, 46, 6141−6144. 9. Jiang, X.; Liu, B.; Lebreton, S.; De Brabander, J. K. J. Am. Chem. Soc. 2007, 129, 6386−6387. 10. Webb, M. R.; Addie, M. S.; Crawforth, C. M.; Dale, J. W.; Franci, X.; Pizzonero, M.; Donald, C.; Taylor, R. J. K. Tetrahedron 2008, 64, 4778−4791. 11. Frings, M.; Atodiresei, I.; Runsink, J.; Raabe, G.; Bolm, C. Chem. Eur. J. 2009, 15, 1566−1569. 12. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412. 1.

377

Mukaiyama Michael addition Lewis acid-catalyzed Michael addition of silyl enol ether to an α,β-unsaturated system. O R2

O R1

R

Lewis OSiMe3

R1

R2

acid

O

R

Example 12 OSiMe3

O

OMe

1. 0.1 mol% TBABB, THF, 3 h

O

O

O

2. 1 N HCl, THF, 0 oC, 0.5 h 87%

TBABB = tetra-n-butylammonium bibenzoate Example 25 O O

OSiMe3

1. neat DBU, rt, 24 h

OMe

O

2. 1 N HCl, THF, 68% O

Example 38 OMe OMe

OMe 10 mol% Sc(OTf)3 CH2Cl2, −78 oC to rt

OMe

OMe TBSO O OMe O

10% HF/CH3CN quench 85%, 20 : 1 (syn/anti)

O MeO

O H OMe

Example 49 O

OTBS CO2Me

R1 R2

R3

CH2Cl2, 0−25 oC 78−81%

N2

O

OTBS R1 R2 R3

0.5 mol% Zn(OTf)2

4 N HCl

O CO2Me

THF

R1 R2 R3

O

N2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_171, © Springer-Verlag Berlin Heidelberg 2009

CO2Me N2

O

378

References (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011−1014. (b) Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503−7509. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590−5614. (Review). 2. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047−6049. 3. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046−10057. 4. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075−3083. 5. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507−508. 6. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637−1639. 7. Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8, 1921−1924. 8. Jewett, J. C.; Rawal, V. H. Angew. Chem., Int. Ed. 2007, 46, 6502−6504. 9. Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008, 10, 1605−1608. 10. Takahashi, A.; Yanai, H.; Taguchi, T. Chem. Commun. 2008, 2385−2387. 1.

379

Mukaiyama reagent Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation. General scheme:

X R1CO2H

N Y R3

O

R2OH

R1

O

R2

O

N R3

base

X = F, Cl, Br Example 11c N HO CO2H

O

Br BF4 O

O

Bu3N, CH2Cl2

O

O O Br

N

BF4

−H

− Br O Br

O

O

O

N

N BF4

:

O H

SNAr

:

O

O

HO Bn

NBu3 O O O Bn

OBn

O

N

O

BF4

HO

:

O

O

N

N BF4

H

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.1d Example 2, Polymer-supported Mukaiyama reagent5 TfO

OH O

N N

Cl

O

Cl

Tf2O, CH2Cl2, 16 h, rt 1.25 mmol/g

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_172, © Springer-Verlag Berlin Heidelberg 2009

380

O NHBoc NHBoc CO2H N H

O NH2

NH

polymer-supported Mukaiyama reagent Et3N, CH2Cl2, rt 16 h, 88%

O O

N H

O

Example 39 O

NHFmoc t-BuS

S N

HO S

O

S

N CO2TMSE

NHBoc

O

S

NH

N

Mukaiyama reagent t-BuS DIPEA, CH2Cl2, 91%

N S

S

O NHBoc CO2TMSE

Example 4, Fluorous Mukaiyama reagent10

RCO2H

R1NH2 or R2OH

1. Fluorous Mukaiyama reagent 1 equiv DMAP, 3 equiv Et3N dry DMF, rt, 1h

RCONHR1 or RCO2R2

2. H2O, rt, 5 min., 87−100%

N

Fluorous Mukaiyama reagent

Cl

TfO C10F21

References 1.

2. 3. 4. 5.

(a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045–1048. (b) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635–636. (c) Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707–708. (d) For amide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984, 1465– 1466. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402–8403. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540–1542. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170–8182. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582.

381

6. 7. 8. 9. 10.

Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 34, 3129–3134. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817–2819. Vandromme, L.; Monchaud, D.; Teulade-Fichou, M.-P. Synlett 2006, 3423–3426. Ren, Q.; Dai, L.; Zhang, H.; Tan, W.; Xu, Z.; Ye, T. Synlett 2008, 2379–2383. Matsugi, M.; Suganuma, M.; Yoshida, S.; Hasebe, S.; Kunda, Y.; Hagihara, K.; Oka, S. Tetrahedron Lett. 2008, 49, 6573–6574.

382

Myers−Saito cyclization Cf. Bergman cyclization and Schmittel cyclization. Δ or hv

•

hydrogen atom donor

H H

reversible •

allenyl enyne Example 13

diradical

PhH, reflux

Ph Ph

96 h, 40% Ph Ph

H

Example 2, Aza-Myers−Saito reaction8 N Ph

OMe

MeOH 0 oC, 14 h Ph

N

CDCl3

N

CHO

10 oC, 12 h Ph

References (a) Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212– 7214. (b) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386. 2. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975–4978. 3. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38, 6177–6180. 4. Bruckner, R; Suffert, J. Synlett 1999, 657−679. (Review). 5. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453–1461. 6. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124, 1823–1828. 7. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871–4874. 8. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059–2062. 9. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324–5325. 10. Karpov, G.; Kuzmin, A.; Popik, V. V. J. Am. Chem. Soc. 2008, 130, 11771–11777. 1.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_173, © Springer-Verlag Berlin Heidelberg 2009

383

Nazarov cyclization Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone. O

O H

H O

H

HO O

protonation H

O

OH tautomerization

Example 12 O

H O ZrCl4, (CH2Cl)2

N CO2Me

SiMe3 60 oC, 36 h, 76%

N H CO2Me

Example 26 O Ph

HClO4 (10−2 M) Ac2O (1 M) EtOAc, 9 h, 75%

O

OAc

H

Ph

O

Example 39 Ph

Me

Me 5 mol% Cu(ClO4)2

MeO2C O

Ph

MeO2C O OTIPS

OTIPS

DCE, 45 oC, 8 h, 80% OTIPS

OTIPS

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_174, © Springer-Verlag Berlin Heidelberg 2009

384

Example 410 OAc

N Ts

MeO

O

O

OAc 10 mol% Sc(OTf)3 LiClO4, 80 oC

MeO

ClCH2CH2Cl (0.3 M) 65%

O

N Ts

O

Example 511 Me

O

Me

O

O

O Me

Cl Me

Cl

O 1. hν (350 nm), CH3CN, rt

O Me

OTBS

Br

Cl Me

O

2. i-Pr2NH, MeOH, 50 oC 60%, 2 steps

Cl

O O Me

Me O Me O Me

9

O

OTBS

H H Br

References Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (1900−1957), a Soviet Union Scientist, discovered this reaction in 1942. It was said that almost as many young synthetic chemists have been lost in the pursuit of an asymmetric Nazarov cyclization as of the Bayliss−Hillman reaction. 2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 168−194; 195−208. 3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1−158. (Review). 4. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113−2116. 5. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221−10228. 6. Mateos, A. F.; de la Nava, E. M. M.; González, R. R. Tetrahedron 2001, 57, 1049−1057. 7. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328−14329. 8. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171−1174. 9. Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6379−6383. 10. Bitar, A. Y.; Frontier, A. J. Org. Lett. 2009, 11, 49−52. 11. Gao, S.; Wang, Q.; Chen, C. J. Am. Chem. Soc. 2009, 131, 1410−1412. 1.

385

Neber rearrangement α-Aminoketone from tosyl ketoxime and base. The net conversion of a ketone into an α-aminoketone via the oxime. N R1

OTs R

NH2

1. KOEt 2. H2O

H EtO

α-aminoketone

OTs N

deprotonation R2

H N R1

OTs cyclization R2

R1

TsO

TsOH

O

ketoxime N

R2

R1

2

R1

:OH2

hydrolysis R1

R2

H N O H R2

NH2 R

R2

1

O

azirine intermediate Example 13 O

N Me

1. NH2OH•HCl 2. TsCl, Pyr. 93%

N

OTs Me

EtO OEt 1. KOEt 2. HCl 82%

N

NH2

N

Example 2, A variant using iminochloride5 Ph

Ph OEt NH•HCl

HOCl

OEt

100%

NCl

1. KOt-Bu 2. HCl 71%

Ph

NH2 OH O

Example 38 Ts N

TsON N MeO

N O

N SEM

Br OMe

1. KOH, H2O, EtOH, 0 oC, 3 h 2. 6 N HCl, 60 oC, 10 h 3. K2CO3, THF, H2O, 10 min. 96%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_175, © Springer-Verlag Berlin Heidelberg 2009

386

Ts N

O N

H2 N MeO

Br

N O

OMe

HN

Example 49 R

R1 O

1. H2NOH 2. MsCl, Et3N; DBU, Bu3P 70–91%

R

R

R1 N

heat 41–89%

R1 N H

References Neber, P. W.; v. Friedolsheim, A. Ann. 1926, 449, 109–134. O’Brien, C. Chem. Rev. 1964, 64, 81–89. (Review). LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329–330. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491–8492. 5. Oldfield, M. F.; Botting, N. P. J. Labelled Cpd. Radiopharm. 1998, 16, 29–36. 6. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363-– 5366. 7. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640– 7641. 8. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. 9. Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–1059. 10. Richter, J. M. Neber rearrangement. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 464−473. (Review). 1. 2. 3. 4.

387

Nef reaction Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound. NO2 R1

O R1

N H

R1

N

R1

2. H2SO4

O

H2O R2

N

R1

O

H

R1

HO

H

HO

N

R2 R1

:OH2

O

H

O

N R1

R2 OH

O R2

HNO

R1

R2

1/2 N2O

Example 14 O

O

1. NaOH, EtOH, 0 oC, 30 min. NO2

O

2. 3 M HCl, 0 to 20 oC, 12 h, 68%

Example 27 HO

NO2

HO

1. 2 M NaOH, MeOH 2. ice-cooled KMnO4 45%

H

O

H

Example 39 t-Bu

S OTBS

O

t-Bu

S

O 2.2 equiv PMe3, THF, rt, 30 min.

NO2

OTBS

O

− H2O

nitronic acid

R1 R2 O H

R2 OH

OH

R2

nitronate

H

N

1/2 H2O

1/2 N2O

R2

HO

O

HO O

O

1. NaOH

R2

O

H2O, rt, 5 min.

OTBS

94%, 2 steps NH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_176, © Springer-Verlag Berlin Heidelberg 2009

O O

O

1/2 H2O

388

Example 410 R

*

CO2H NO2

HOAc, HCl reflux, 2 h

R

*

CO2H CO2H

References Nef, J. U. Ann. 1894, 280, 263−342. John Ulrich Nef (1862−1915) was born in Switzerland and emigrated to the US at the age of four with his parents. He went to Munich, Germany to study with Adolf von Baeyer, earning a Ph.D. In 1886. Back to the States, he served as a professor at Purdue University, Clark University, and the University of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles. 2. Pinnick, H. W. Org. React. 1990, 38, 655−792. (Review). 3. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335–1336. 4. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015–2021. 5. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000, 2681–2688. 6. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233–5235. 7. Chung, W. K.; Chiu, P. Synlett 2005, 55–58. 8. Wolfe, J. P. Nef reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds; John Wiley & Sons: Hoboken, NJ, 2007, pp 645−652. (Review). 9. Burés, J.; Vilarrasa, J. Tetrahedron Lett. 2008, 49, 441–444. 10. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C. D. Tetrahedron: Asymmetry 2008, 19, 945–955. 1.

389

Negishi cross-coupling reaction The Negishi cross-coupling reaction is the nickel- or palladium-catalyzed coupling of organozinc compounds with various halides or triflates (aryl, alkenyl, alkynyl, and acyl). R1 X

+ R2Zn Y

NiLn or PdLn solvent

R1 R 2

R1 = aryl, alkenyl, alkynyl, acyl R2 = aryl, heteroaryl, alkenyl, allyl, Bn, homoallyl, homopropargyl X = Cl, Br, I, OTf Y = Cl, Br, I Ln = PPh3, dba, dppe

Pd(0) or Pd(II) complexes (precatalysts) R

1

R

2

Pd(0)Ln

R1 X oxidative addition

reductive elimination

R2

R1

R1 Pd(II) 3

LnPd(II) 1

Ln

X transmetallation/ trans/cis isomerization

ZnX2

R2ZnX R1

X X

Zn R2 2

Pd(II) Ln

Example 13 CH2CO2Et

I N

N

BrZnCH2CO2Et, Pd(Ph3P)4

HO O O O O

Ph

HO O O O O

HMPA/(CH2OCH3)2 (1:1) 3.5 h, 40%

Ph

Ph Ph

Example 24 O

O

activated I

BnO

Zn/Cu couple NHTr

ZnI

BnO NHTr

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_177, © Springer-Verlag Berlin Heidelberg 2009

390

Boc

NHBoc

N I

N

Boc O

CO2t-Bu

NHBoc

N

CO2t-Bu

N

BnO PdCl2(Ph3P)2, DMA 40 oC, 79%

NHTr

Example 38 1. Zn, DMA, TMSCl, BrCH2CH2Br, 65 °C Boc N

Boc N

I

Ar

2. ArX (X = Br, OTf), PdCl2(dppf) (3 mol%) CuI (6 mol%), DMA, 80 °C 41–97%

Example 49 1. t-BuLi, ZnCl2, Et2O, –78 °C 2. Me Me Me

Me

I

PivO

Me

I

OTBS

PivO

Me

Me

Me OTBS

Pd(PPh3)4, THF, 0 °C 85%

References (a) Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596−597. (b) Negishi, E.-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821−1823. (c) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340−348. (Review). 2. Erdik, E. Tetrahedron 1992, 48, 9577−9648. (Review). 3. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Heterocycl. Chem. 1993, 30, 1245−1252. 4. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. 1993, 32, 1326−1327. 5. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley–VCH: Weinheim, Germany, 1998, pp 1–47. (Review). 6. Arvanitis, A. G.; Arnold, C. R.; Fitzgerald, L. W.; Frietze, W. E.; Olson, R. E.; Gilligan, P. J.; Robertson, D. W. Bioorg. Med. Chem. Lett. 2003, 13, 289−291. 7. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817−4830. 8. Corley, E. G.; Conrad, K.; Murry, J. A.; Savarin, C.; Holko, J.; Boice, G. J. Org. Chem. 2004, 69, 5120−5123. 9. Inoue, M.; Yokota, W.; Katoh, T. Synthesis 2007, 622−637. 10. Yet, L. Negishi cross-coupling reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 70−99. (Review). 1.

391

Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and β-aminocrotonate. CO2R3

H O R1

HN R2

O

O

H

CO2R3

addition

R1

N

O

R2

H

CO2R3

H

CO2R3

HO

N OH R2

R1

CO2R3 H

HO

conjugate

O HN R2

HO

N R2

R1

:

R1

CO2R3

HO

Δ

N R2

R1

H

Example 15 O

O O

HN

Bn O 1. acetone, rt, 48 h 2. 20% TFA, CH2Cl2 86%

N H

NH2

HO N Bn

Example 26 H O

CO2CH3

CO2CH3

HO CH3NO2, rt

HN

N

95%

O

Example 37

O R2

R1

R4-NH2

R4

rt

R2

O

O

NH R1

HOAc, rt

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_178, © Springer-Verlag Berlin Heidelberg 2009

392

R1 HO

HCHO, HNMe2

Me HO

Me N R1

R2 N R4

R2

ethanol, 50 oC

N R4

Example 410 O OEt

HO OEt

O NH

N

O ZnCl2, CH2Cl2

NH O

O

N

reflux, 80% OEt

OEt

HO O

References Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37−43. Allen, G. R., Jr. Org. React. 1973, 20, 337−454. (Review). Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai, M. J. Chem. Soc., Perkin Trans. 1 1995, 2677−2681. 4. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.; Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177−184. 5. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253−6257. 6. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415−2418. 7. Böhme, T. M.; Augelli-Szafran, C. E.; Hallak, H.; Pugsley, T.; Serpa, K.; Schwarz, R. D. J. Med. Chem. 2002, 45, 3094−3102. 8. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetrahedron 2005, 61, 9129−9139. 9. Li, J.; Cook, J. M. Nenitzescu indole synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 145−153. (Review). 10. Velezheva, V. S.; Sokolov, A. I.; Kornienko, A. G.; Lyssenko, K. A.; Nelyubina, Y. V.; Godovikov, I. A.; Peregudov, A. S.; Mironov, A. F. Tetrahedron Lett. 2008, 49, 7106−7109. 1. 2. 3.

393

Newman−Kwart rearrangement Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 513). S

S

O

SH

OH Cl

NMe2

O

NMe2

S

Δ

hydrolysis

NMe2

O

NMe2 O

S

S

O Me2N

NMe2

S

The Newman−Kwart rearrangement is a member of a series of related rearrangements, such as the Schönberg rearrangement and the Chapman rearrangement (page 105), in which aryl groups migrate intramolecularly between nonadjacent atoms. The Schönberg rearrangement is the most similar and involves the 1,3migration of an aryl group from oxygen to sulfur in a diarylthioncarbonate. The Chapman rearrangement involves an analogous migration but to nitrogen. Schönberg rearrangement S O

Chapman rearrangement NAr

O OAr

S

Δ

O

OAr

Ar

O Ar Δ

N

Ar

Example 15

Ph2O, 208 oC

NaH, DMF, 78%

O

S S OH

O N

Cl

NMe2

50 h, 55%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_179, © Springer-Verlag Berlin Heidelberg 2009

S

NMe2

394

Example 26 S Cl

OH OH

S NMe2

O OH

NaH, DMF 85 oC, 1 h, 45%

NMe2

O

275 oC 0.8 mmHg

S

NMe2

OH 55%

Example 37 O

O

1. Br2, CH2Cl2, 5 to 20 oC, 90 min. 2.

CH2Cl2, 20 C, 16 h, 37.4%

S

OH Cl

dimethylaniline Br

o

Me2N

NMe2

O

218 oC, 7 h, 65.7%

S

O

O 1. KOH, MeOH, reflux, 2 h Br

Me2N

S

2. MeI, K2CO3, 90%

Br S

O

References (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410–413. (b) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980–3984. (c) Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604–3606. 2. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetrahedron 1997, 53, 6073–6084. 3. Lin, S.; Moon, B.; Porter, K. T.; Rossman, C. A.; Zennie, T.; Wemple, J. Org. Prep. Proc. Int. 2000, 32, 547–555. 4. Ponaras, A. A.; Zain, Ö. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.; Wiley & Sons: New York, 1995, 2174–2176. (Review). 5. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahedron Lett. 2001, 42, 373–376. 6. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.; Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813–2819. 7. Bowden, S. A.; Burke, J. N.; Gray, F.; McKown, S.; Moseley, J. D.; Moss, W. O.; Murray, P. M.; Welham, M. J.; Young, M. J. Org. Proc. Res. Dev. 2004, 8, 33–44. 8. Nicholson, G.; Silversides, J. D.; Archibald, S. J. Tetrahedron Lett. 2006, 47, 6541– 6544. 9. Gilday, J. P.; Lenden, P.; Moseley, J. D.; Cox, B. G. J. Org. Chem. 2008, 73, 3130– 3134. 10. Lloyd-Jones, G. C.; Moseley, J. D.; Renny, J. S. Synthesis 2008, 661–689. 11. Tilstam, U.; Defrance, T.; Giard, T.; Johnson, M. D. Org. Proc. Res. Dev. 2009, 13, 321–323. 1.

395

Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives the propargylated product. OR2 R3 R4

R1

CO (CO)4Co Co(CO)3

− CO

1. Co2(CO)8

R1 2. H or Lewis acid

2. [O]

CO (CO)3Co Co(CO)3

− CO

2

OR R3 R4

R1

R1

(CO)3Co Co(CO)3 R

1

R4 R

(CO)3Co Co(CO)3 R1

OR2 R 4 R3

+H

OR2 R4 R3

(CO)3Co Co(CO)3

SN1

H O 2 3 R

Nu R3 R4

1. NuH

+

(CO)3Co Co(CO)3

NuH

R1

R1

Nu R4 R3

R4 R3

propargyl cation intermediate (stabilized by the hexacarbonyldicobalt complex). (CO)3Co Co(CO)2

[O]

O C O↑

R1

demetallation

Nu R3 R4

R1

Nu R4 R3

Example 1, A chromium variant of the Nicholas reaction3 OH

1. HBF4·Et2O, CH2Cl2, −60 oC 2. 5 eq. X, CH2Cl2, −60 oC, 86% Cl X = HN

Cr(CO)3

N O CO2n-Bu

Cl Cl

N

2HCl

N N

O

N O

CO2n-Bu

CO2H

Zyrtec

Cr(CO)3

Example 2, A Nicholas-Pauson–Khand sequence4 H

H O H Me3Si

OEt

(CO)3 Co Co(CO)3 NMO

1. Co2(CO)8 2. Et2AlCl, 82%

O

H

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_180, © Springer-Verlag Berlin Heidelberg 2009

H

H

70%

O H

H

396

Example 3, Intramolecular Nicholas reaction using chromium7 Cr(CO)3 OAc

BF3•OEt2, CH2Cl2 0 oC, 3.5 h, 49%

Cr(CO)3

Example 49 H

O

H

Me

R OH

OH

HO

H

H

O H Me H

(OC)3Co (OC)3Co

OH H

R

OTIPS H O O

O

1. Co2(CO)8, 100% 2. BF3•OEt2, 75% OH

Me H

H

Me

OTIPS H O O

O H Me

Me

OH

OH

References Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21–C24. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214. (Review). Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837–4840. Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353–4363. 5. Teobald, B. J. Tetrahedron 2002, 58, 4133−4170. (Review). 6. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625–628. 7. Ding, Y.; Green, J. R. Synlett 2005, 271–274. 8. Pinacho Crisóstomo, F. R.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett. 2005, 46, 2829–2832. 9. Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205–1208. 10. Shea, K. M. Nicholas reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 284−298. (Review). 1. 2. 3. 4.

397

Nicolaou IBX dehydrogenation α,β-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of o-iodoxybenzoic acid (IBX), alternative to the Saegusa oxidation (page 482). O I

HO O O

R

2

R1

R3

R2

O

O R1

IBX = o-iodoxybenzoic acid

R3

A SET mechanism has also been proposed. Additionally, silyl enol ethers are also viable substrates. R2

O R1

HO

tautomerization

R1

R3

O HO I O

R2 R3

O

O

OH O I O HO R1

R2

O R2 H

R1 R

R3

3

Example 11a IBX fluorobenzene DMSO

H H O

65 °C, 24 h 80%

H

H H O

H

H

H

Example 23 H

O H

O

IBX TBSO MeO2C

O H CO2Me

DMSO, Tol. 80 °C, 3 h, 52%

TBSO MeO2C

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_181, © Springer-Verlag Berlin Heidelberg 2009

O H CO2Me

398

Example 37 H

MeO

N Me

H

IBX

O

N H

H

H MeO

Tol., DMSO 70 °C

H

O

N

N Me

H

H O

O

Example 4, o-Methyl-IBX (Me-IBX)9 Me

OH O I O

MeO R1

S

O

R2

R1

CH3CN, reflux 40−90%

O S

R2

Example 5, Stabilized IBX (SIBX)10 O

OH SIBX, THF MeO

OMe

MeO

O OH MeO

OMe

rt, 98% O

O

1:1

OH

OMe O

References (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596– 7597. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993–996. (c) Nicolaou, K. C.; Gray, D. L.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int. Ed. 2002, 41, 996–1000. 2. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737–1740. 3. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755–767. 4. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839–9846. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int. Ed. 2004, 43, 1559–1562. 6. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309–4312. 7. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339–3342. 8. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342–5344. 9. Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron Lett. 2008, 49, 80–84. 10. Pouységu, L.; Marguerit, M.; Gagnepain, J.; Lyvinec, G.; Eatherton, A. J.; Quideau, S. Org. Lett. 2008, 10, 5211–5214. 1.

399

Noyori asymmetric hydrogenation Asymmetric reduction of carbonyls and alkenes via hydrogenation, catalyzed by a ruthenium(II) BINAP complex. OH

O R

R1

H2, (R)- or (S)-BINAP

R

R2

R3

Metal [Ru(II) or Rh(I)]

R 2 * R3

R3

R4

*

R1

R 4 * R5

PPh2 RuCl2L2 PPh2

(R)-BINAP-Ru =

[RuCl2(binap)(solv)2]

H2 − HCl

[RuHCl(binap)(solv)2]

The catalytic cycle: OR1 O

H+

(binap)ClHRu

solv

O R

O R

O OR1 OR1 O

[RuHCl(binap)(solv)2]

(binap)ClRu O H

H+, solv

H R solv

H2

OH

[RuCl(binap)(solv)2]+ R

O OR1

Example 11b Ru[(S)-BINAP](CF3CO2)2 OH

30 atm H2, rt, 96% ee

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_182, © Springer-Verlag Berlin Heidelberg 2009

OH

400

Example 21c Ru[(R)-BINAP]Cl2

O

OH

100 atm H2, rt, 92% ee

Br

Br

9

Example 3

5 bar H2 3.2 mol% Ru(II)-(+)-(R)-BINAP

O O H

O H

O

8

OMe

MeOH, 70 oC, 24 h, 90%

O

100 atm H2 Ru[(S)-BINAP]Cl2

O O

OH O

H

H

8

OMe

Example 410 O C5H11

OMe

EtOH, rt, 75% 98% ee

OH C5H11

O OMe

References (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117−7119. Ryoji Noyori (Japan, 1938−) and William S. Knowles (USA, 1917−) shared half of the Nobel Prize in Chemistry in 2001 for their work on chirally catalyzed hydrogenation reactions. K. Barry Sharpless (USA, 1941−) shared the other half for his work on chirally catalyzed oxidation reactions. (b) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; J. Am. Chem. Soc. 1987, 109, 1596−1598. (c) Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629−631. (d) Noyori, R.; Ohkuma, T.; Kitamura, H.; Takaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856−5858. (e) Noyori, R.; Ohkuma, T. Angew. Chem., Int. Ed. 2001, 40, 40−73. (Review). (f) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008−2022. (Review, Nobel Prize Address). 2. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, Chapter 2. (Review). 3. Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; McNamara, J. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7379−7382. 4. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015−2018. 5. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693−8698. 6. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733−736. 7. Ishibashi, Y.; Bessho, Y.; Yoshimura, M.; Tsukamoto, M.; Kitamura, M. Angew. Chem., Int. Ed. 2005, 44, 7287−7290. 8. Lall, M. S. Noyori asymmetric hydrogenation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 46−66. (Review). 9. Bouillon, M. E.; Meyer, H. H. Tetrahedron 2007, 63, 2712−2723. 10. Case-Green, S. C.; Davies, S. G.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Tetrahedron: Asymmetry 2008, 19, 2620−2631. 1.

401

Nozaki–Hiyama–Kishi reaction Cr−Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes. O Cr(II)Cl2

R1 X

R

R1 Cr(III)ClX

aprotic solvent

2

OH

R3 R

organochromium(III) reagent

1

R2

R3

allylic or homoallylic alcohols

1

R = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenyl R2 = R3 = aryl, alkyl, alkenyl, H X = Cl, Br, I, OTf Solvent = DMF, DMSO, THF

The catalytic cycle:2 OCr(III)X2 R

1

R2

Ni(II)Cl2

R3

2Cr(II)Cl2 2Cr(III)Cl3

O R2

R3

Ni(0)

R1 Cr(III)Cl2

R1 X

transmetallation

R1 Ni(II)

oxidative addition

X

Cr(III)Cl3

Example 13 OTHP I

AcO

OTBDPS

CHO OTHP

10 eq CrCl2, cat. NiCl2 AcO DMSO, 25 oC, 12 h, 80%

OTBDPS OH

Example 25 O OTf

OHC

O O

4 eq CrCl2 0.008 eq NiCl2 DMF, rt, 15 h 35%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_183, © Springer-Verlag Berlin Heidelberg 2009

OH

O O O

402

Example 3, Intramolecular Nozaki–Hiyama–Kishi reaction8 I

OH 5 equiv CrCl2, NiCl2 CHO OTBDMS

OTBDMS

THF, 84%

Example 4, Intramolecular Nozaki–Hiyama–Kishi reaction9 I 1. HCl, THF, 0.003 M dark O O

2. CrCl2, NiCl2, DMSO 0.0025 M, 50 oC 37%, 2 steps

HO

References (a) Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179−3181. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281−5284. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the reaction and is a professor at Okayama University. (c) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644−5646. Yoshito Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. (d) Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048−6050. (e) Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999−6002. 2. Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349−12357. (The catalytic cycle). 3. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565−566. 4. Fürstner, A. Chem. Rev. 1999, 99, 991−1046. (Review). 5. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250−2256. 6. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032−1035. 7. Takai, K. Org. React. 2004, 64, 253−612. (Review). 8. Karpov, G. V.; Popik, V. V. J. Am. Chem. Soc. 2007, 129, 3792−3793. 9. Valente, C.; Organ, M. G. Chem. Eur. J. 2008, 14, 8239−8245. 10. Yet, L. Nozaki–Hiyama–Kishi reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 299−318. (Review). 1.

403

Nysted reagent The Nysted reagent, cyclo-dibromodi-ȝ-methylene(ȝ-tetrahydrofuran)trizinc, is used for the olefination of ketones and aldehydes.

Br

O Zn

Zn

Br

Zn

Example 1, The Wittig reagent opened the lactone:6 OMOM

OMOM TBDPSO

TBDPSO excess Zn(CH2ZnBr)2•THF

O O

CH2 O

TiCl4, THF reflux, 64%

O

O O

O

Example 2

8

OTBS O OH

Example 3

1.5 equiv Zn(CH2ZnBr)2•THF 1.5 equiv TiCl4 THF, reflux

OTBS

OTBS

CH2

OH

OH 42%

CH2

14%

9

O BnO TBDPSO

H OH

2 equiv Zn(CH2ZnBr)2•THF 2 equiv TiCl4 THF, 0 oC to rt 1 h, 74%

CH2 BnO H OH TBDPSO

References 1. 2. 3. 4.

5. 6. 7. 8. 9.

Nysted, L. N. US Patent 3,865,848 (1975). Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.; Peters, E.-M.; Peters, K.; von Schnering, H. G. Tetrahedron 1995, 51, 1623í1630. Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313í315. Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.; Suemune, H. J. Org. Chem. 2000, 65, 5806í5816. Tarraga, A.; Molina, P.; Lopez, J. L.; Velasco, M. D. Tetrahedron Lett. 2001, 42, 8989í8992. Aïssa, C.; Riveiros, R.; Ragot, J.; Fürstner, A. J. Am. Chem. Soc. 2003, 125, 15512í15520. Clark, J. S.; Marlin, F.; Nay, B.; Wilson, C. Org. Lett. 2003, 5, 89í92. Paquette, L. A. Hartung, R. E., Hofferberth, J. E., Vilotijevic, I., Yang, J. J. Org. Chem. 2004, 69, 2454í2460. Hanessian, S.; Mainetti, E.; Lecomte, F. Org. Lett. 2006, 8, 4047í4049.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_184, © Springer-Verlag Berlin Heidelberg 2009

404

Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols. Reverse of the Meerwein– Ponndorf–Verley reduction. Al(Oi-Pr)3

OH R1

O

O

R2

Oi-Pr Al(Oi-Pr)2

R1

OH

OH R2

O

O

Al(Oi-Pr)2

: OH R1

R1

R2

coordination

R2 i-PrO

Oi-Pr R1 O H R2

Al

O

Oi-Pr

Oi-Pr Al

hydride

O

H

R1

O

transfer

O

R1

OH R2

R2

cyclic transition state Example 1, Mg-Oppenauer oxidation3 OH

O

1. EtMgBr, i-Pr2O 2. PhCHO, 60%

Example 26 OH

OH

O

(i-PrO)2AlO2CCF3 p-O2N-Ph-CHO PhH, rt, 24 h, 70%

OH

Example 3, Mg-Oppenauer oxidation8 RMgCl•LiCl

−20 oC R'CHO R

PhCHO

R

0 oC to rt

R'

O

OMgCl R'

H

H

R

R Ph

Mg

O H R'

PhCH2OMgCl

O

Cl

Ph

Mg

O H R'

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_185, © Springer-Verlag Berlin Heidelberg 2009

O

Cl

405

Example 410

H

OH

R

1

R

Al

O H3 C

CF3

2 equiv

EtOAlEt2

R

O

CH2Cl2, rt, 1 h

R1

H

H3C

H

O

O CF3

R

R1

H2 C

OH CF3

References Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137−144. Rupert V. Oppenauer (1910−), born in Burgstall, Italy, studied at ETH in Zurich under Ruzicka and Reichstei, both Nobel laureates. After a string of academic appointments around Europe and a stint at Hoffman−La Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina. 2. Djerassi, C. Org. React. 1951, 6, 207−235. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769−772. 4. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669−2672. 5. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601−1602. 6. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819−822. 7. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004, 45, 3313−3315. 8. Kloetzing, R. J.; Krasovskiy, A.; Knochel, P. Chem. Eur. J. 2006, 13, 215−227. 9. Fuchter, M. J. Oppenauer oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 265−373. (Review). 10. Mello, R.; Martinez-Ferrer, J.; Asensio, G.; Gonzalez-Nunez, M. E. J. Org. Chem. 2008, 72, 9376−9378. 11. Borzatta, V.; Capparella, E.; Chiappino, R.; Impala, D.; Poluzzi, E.; Vaccari, A. Cat. Today 2009, 140, 112−116. 1.

406

Overman rearrangement Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate. Δ

cat. NaH HN

R1

R

CCl3

CCl3

OH

O

HN

O

or Hg(II) or Pd(II)

Cl3CCN

R

R

R1

R

1

trichloroacetimidate N O

H

O

H

H2↑

R1

R

O

R

rearrangement

R1

R1

HN

O

HN

R

R

O H

O

O

H

O O

O

Cl3CCN, DBU

O

O O

CH2Cl2, −78 oC

HN O

HO

Cl3C O K2CO3, p-xylene

H

O

reflux, 90%, 2 steps

Cl3C

HN

O

O O

O

Example 26 TBDMSO

TBDMSO Cl3C

O NH

O

O

K2CO3, p-xylene O

R1

R

Example 15 O

O

CCl3

Δ, [3,3]-sigmatropic

O

N

1

H

CCl3

CCl3

R

R

H

R1

R

HN

CCl3

CCl3

O reflux, 77%

NH

Cl3C O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_186, © Springer-Verlag Berlin Heidelberg 2009

O R1

407

Example 37 OBn

OBn O

O

OH

O

O

CF3CN, n-BuLi; toluene, 120 °C 30%

HN

CF3

O

O

O

O

O

Example 49 O

O

O

OH DBU, CCl3CN

N

(CH2)3OTBDPS Me

Bn

F

toluene, reflux 51%

O

NHC(O)CCl3

N

(CH2)3OTBDPS Me

F

Bn

References (a) Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597−599. (b) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901−2910. (c) Overman, L. E. Acc. Chem. Res. 1980, 13, 218– 224. (Review). 2. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863−866. 3. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151−154. 4. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927−2930. 5. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 6. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401−405. 7. Hakansson, A. E.; Palmelund, A.; Holm, H.; Madsen, R. Chem. Eur. J. 2006, 12, 3243−3253. 8. Bøjstrup, M.; Fanejord, M.; Lundt, I. Org. Biomol. Chem. 2007, 5, 3164−3171. 9. Lamy, C.; Hifmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007, 48, 6177−6180. 10. Wu, Y.-J. Overman rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 210−225. (Review). 1.

408

Paal thiophene synthesis Thiophene synthesis from addition of a sulfur atom to 1,4-diketones and subsequent dehydration. H3 C

P2S5, tetralin

O O H3C

CH3

S CH3

reflux

The reaction now is frequently carried out using the Lawesson’s reagent. For the mechanism of carbonyl to thiocarbonyl transformation, see Lawesson’s reagent on page 328. S O CH3

H3C

P2S5

tautomerization

X = O or S X

O

H3C

SH

S XH

CH3

H3C

CH3

H3C

X

H3 C

− H2X

S CH3

CH3 H

2

Example 1

O N

Ph

Lawesson's reagent

Ph

S

N

110 ºC, 10 min, 82%

O

Example 23 O O

Ph O

Ph O

Ph Ph

Lawesson's reagent chlorobenzene, reflux, 36 h 69%

Ph

Ph

S Ph

S Ph

References 1. 2. 3. 4. 5. 6. 7.

8.

(a) Paal, C. Ber. 1885, 18, 2251−2254. (b) Paal, C. Ber. 1885, 18, 367−371. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.O. Chem. Lett. 1983, 809−810. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4308−4310. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409−423. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66, 7283−7286. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925−7929. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 207−217. (Review). Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_187, © Springer-Verlag Berlin Heidelberg 2009

409

Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-diketones to form furans. R2

O

R3

R R1

H

R1

R2

O

R2 H

R HO

:

O

:

R3

R R1

or P2O5

O

O

R3

R1

cat. H

R

R2

R

R1

O

R3

R1

R2

R2 H3O

O

R

3

R

O

R3

H

Example 13 F

Cl

O

Cl O

TsOH O

F

toluene, reflux

N

N

Example 26

O

MeO

OMe

n-Bu

OMe O

p-TsOH O

MeO

toluene

n-Bu

98% MeO

OMe

Example 39 O N H

phosphoric acid CH3

O

130−140 oC, 4−6 h

O N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_188, © Springer-Verlag Berlin Heidelberg 2009

CH 3

410

Example 410 SMe O R

O CH C R SMe

SnCl2, H 72−89%

R

O

R

Br2, CHCl3 88−92%

SMe

Br R

O

R

30% HBr−HOAc, CHCl3, 58−64%

References (a) Paal, C. Ber. 1884, 17, 2756−2767. (b) Knorr, L. Ber. 1885, 17, 2863−2870. (c) Paal, C. Ber. 1885, 18, 367−371. 2. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New York, 1996; Vol. 2, 351−393. (Review). 3. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694. 4. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 83−84. (Review). 5. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308−309. (Review). 6. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838−3848. 7. König, B. Product Class 9: Furans. In Science of Synthesis: Houben−Weyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183−278. (Review). 8. Shea, K. M. Paal–Knorr Furan Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168−181. (Review). 9. Kaniskan, N.; Elmali, D.; Civcir, P. U. ARKIVOC 2008, xii, 17−29. 10. Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.; Pan, Y. J. Org. Chem. 2008, 73, 3377−3383. 1.

411

Paal–Knorr pyrrole synthesis Reaction between 1,4-diketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 317). O

R2 NH2

R1

R

R

O

H2N R2 :

O

O R

HN R2

O

H

H N R2

HO R

R1

N R2

R

H R

R1

OH

HO

slow

H :

HO R

R1 OH

:

R1

R

R1

N R2

N R1 R2

H R N R2

R1

N R2

R1

Example 14 EtO

OEt

OEt F

O

OEt

H2 N

O CONHPh

F

N

1 eq. pivalic acid THF, reflux, 43%

CONHPh

Ca2+ HO

CO2

HO

F

N H N O

Lipitor

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_189, © Springer-Verlag Berlin Heidelberg 2009

2

412

Example 25 N

Cl

O

NH4OAc HOAc 110 °C 90%

O

F

N H

F

Cl

N

Example 39

NH4OAc, CSA

MeO

O

O O

MeOH, 50 oC 93%

MeO

O

NH

Example 410 RNH2, AcOH, MeOH, 40 oC; or RNH2, AcOH, NaOAc, toluene, 60 oC; or

O N H

H O

NH4OAc, 28% NH4OH, EtOH, 40 oC 30−96%

R N N H

References (a) Paal, C. Ber. 1885, 18, 367−371. (b) Paal, C. Ber. 1885, 18, 2251−2254. (c) Knorr, L. Ber. 1885, 18, 299−311. 2. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Review). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977, pp 51−57, 74−79. (Review). 4. (a) Brower, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279-2282. (b) Baumann, K. L.; Butler, D. E.; Deering, C. F.; Mennen, K. E.; Millar, A.; Nanninga, T. N.; Palmer, C. W.; Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283−2284. 5. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689−2694. 6. Braun, R. U.; Zeitler, K.; Müller, T. J. J. Org. Lett. 2001, 3, 3297−3300. 7. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75−78. 8. Gribble, G. W. Knorr and Paal−Knorr Pyrrole Syntheses. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds, Wiley & Sons: Hoboken, NJ, 2005, 77−88. (Review). 9. Salamone, S. G.; Dudley, G. B. Org. Lett. 2005, 7, 4443−4445. 10. Fu, L.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 7352−7354. 1.

413

Parham cyclization The Parham cyclization is the generation by halogen–lithium exchange of aryllithiums and heteroaryllithiums, and their subsequent intramolecular cyclization onto an electrophilic site. X

Li

RLi

E

E

E.g. CH3O

I CH3O

2.2 eq. t-BuLi N

CH3O

o NEt2 THF, −78 C→rt

O

I

halogen-metal N

CH3O

exchange O

Et2N Li

CH3O

cyclization

N

CH3O

O

Et2N O

O

CH3O

CH3O N

CH3O

CH3O

The fate of the second equivalent of t-BuLi: I

H I

Example 12 O Br O

MeO O

MeO

NMe2 O

O t-BuLi

MeO O

THF, –95 °C 92%

OMe

MeO

OMe

Example 24 OPMB O

OPMB O

O O

Br

O

O

n-BuLi

O

Et2O, –78 °C 64%

I

NEt2

O O H

O O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_190, © Springer-Verlag Berlin Heidelberg 2009

OH

N

414

Example 35 O

I

2 eq. n-BuLi

N O

MeO

THF, −78 oC 2.5 h, 83%

MeO N

MeO

O

OMe

Example 49 O

Br

O

t-BuLi, THF, −100 oC

O O N PMB

N OMe PMB

Ar, 30 min., 55%

References (a) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394−2399. William E. Parham was a professor at Duke University. (b) Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184−1186. (c) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300−305. (Review). 2. Paleo, M. R.; Lamas, C.; Castedo, L.; Domínguez, D. J. Org. Chem. 1992, 57, 2029– 2033. 3. Gray, M.; Tinkl, M.; Snieckus, V. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Exeter, 1995; Vol. 11; p 66. (Review). 4. Gauthier, D. R., Jr.; Bender, S. L. Tetrahedron Lett. 1996, 37, 13–16. 5. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997, 62, 2080−2092. 6. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59−67. (Review). 7. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275−300. (Review). 8. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69, 3875−3885. 9. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol. Chem. 2005, 3, 2305−2309. 10. Gribble, G. W. Parham cyclization. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 749−764. (Review). 1.

415

Passerini reaction Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford α-acyloxycarboxamides. Cf. Ugi reaction. 2 3 O H R R N R1 O R4 O

O 4

R1 N C

R2

R CO2H

R3

isocyanide H

O R4

O R2

R4 CO2H

R3

R

R

R3

R2 R3

R4 O N R1

1

R2 R3

4

transfer

H O O

R2

O C N

H O O

acyl

O

R1

O N

2 3 O H R R N O R4 O

R1 H

Example 13 Ts

MeO

OMe

CN

OMe

MeO

TFA, PhH

OMe

rt, 2 h, 93%

O

MeO

OMe

MeO

Ts OMe OMe

OMe

Example 25

HOAc, THF CHO

HN

rt, 93%

O

AcO

CN

Et

Example 36 Me Me FmocNH

H N

CHO CN

CbzNH

Me CO2Bn

BocNH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_191, © Springer-Verlag Berlin Heidelberg 2009

CO2H

416

Me Me CH2Cl2, 0 °C → rt

FmocNH O

3–5 days, 80%

O

CbzNH

O

Me N H

CO2Bn

NHBoc

Example 47 H2 N

N

OBn(Cl2)

NO2

NH

BocHN

CHO

O

O CN

N H

N OH Alloc

CO2Me

Ph

H2 N

N

OBn(Cl2)

NO2

NH

2 days, 59%

Ph

O

CH2Cl2, 0 °C → rt BocHN O

O

N H

H N O

CO2Me

NAlloc

References 1.

Passerini, M. Gazz. Chim. Ital. 1921, 51, 126−129. (b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181−188. Mario Passerini (b, 1891) was born in Scandicci, Italy. He

obtained his Ph.D. In chemistry and pharmacy at the University of Florence, where he was a professor for most of his career. Ferosie, I. Aldrichimica Acta 1971, 4, 21. (Review). Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1 1979, 652−661. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, p.1083. (Review). 5. Bock, H.; Ugi, I. J. Prakt. Chem. 1997, 339, 385−389. 6. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986. 7. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304. 8. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631−1634. 9. Banfi, L.; Riva, R. Org. React. 2005, 65, 1−140. (Review). 10. Klein, J. C.; Williams, D. R. Passerini reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 765−785. (Review). 2. 3.

417

Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubstituted oxetane ring systems O

O

hv R

1

R

R

R1

oxetane O

hv

O

R1

R

R1

R

n, π* triplet O

O R

R

R1

triplet diradical

O R

R1

R1

singlet diradical

Example 12 O

O O Ph

Me Me

H

Ph

hν, C6H6, 99%

O

O

O

O *ROOC

O Ph

H

Example 24

Ph

i-Pr

hν, C6H6

i-Pr

O

O Ph

Ph

SMe

73%

Ph

SMe

(E/Z = 6/1)

Example 36 O O

hv, MeCN 82% H

H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_192, © Springer-Verlag Berlin Heidelberg 2009

418

Example 48 Ph Ph

OH

O

hv O solvent

HO O

100% O

References (a) Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341−361. Emaubuele Paternó (1847−1935) was born in Palermo, Sicily, Italy. (b) Büchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76, 4327−4331. George H. Büchi (1921−1998) was born in Baden, Switzerland. He was a professor at MIT when he elucidated the structure of oxetanes, the products from the light-catalyzed addition of carbonyl compounds to olefins, which had been observed by E. Paternó in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland. 2. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217−3220. 3. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984, 425. (Review). 4. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964−965. 5. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151−192. (Review). 6. de la Torre, M. C.; Garcia, I.; Sierra, M. A. J. Org. Chem. 2003, 68, 6611−6618. 7. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70−75. (Review). 8. D’Auria, M.; Emanuele, L.; Racioppi, R. Tetrahedron Lett. 2004, 45, 3877−3880. 9. Liu, C. M. Paternó–Büchi Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 44−49. (Review). 10. Cho, D. W.; Lee, H.-Y.; Oh, S. W.; Choi, J. H.; Park, H. J.; Mariano, P. S.; Yoon, U. C. J. Org. Chem. 2008, 73, 4539−4547. 1.

419

Pauson−Khand reaction Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide mediated by octacarbonyl dicobalt to form cyclopentenones.

O Co2(CO)8

O

H Co(CO)3 Co(CO)3

O

H

CO (CO)4Co

toluene, 60−80 oC 4−6 d, 60%

Co(CO)3 Co(CO)3

− CO

Co(CO)3

H

O

− CO

Co(CO)3 Co(CO)3

OC H

hexacarbonyldicobalt complex H Co(CO)3 Co(CO)2 O

− CO

H

(CO)3Co

+ CO insertion toward CH

O

(CO)3Co H

exo complex (CO)3Co

H O

reductive

H

sterically-favored isomer

(CO)3Co (CO)3Co

H

O

− Co2(CO)6

O

O O

Example 13 O O

O

Co2(CO)8

O

benzene, 65 oC 16 h, 23%

O

Example 2, A catalytic version6

Ts N

5 mol% Co2(CO)8 20 mol% P(OPh)3

O

reductive elimination

elimination

(CO)3Co

+ CO insertion

Ts N

3 atm CO, DME 120 oC, 48 h, 94%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_193, © Springer-Verlag Berlin Heidelberg 2009

O

420

Example 3, Intramolecular Pauson−Khand reaction9 O N Cbz

Co2(CO)8, DMSO

Cbz N H

o

N H

THF, 65 C, 94%

N H

Example 4, Intramolecular Pauson−Khand reaction10 Co2(CO)8 5 equiv Me3NO•2H2O N

S

O O NO2

THF/H2O (3:1), 0 oC to rt 7 h, 71%

H O

N

S O O NH2

References (a) Pauson, P. L.; Khand, I. U.; Knox, G. R.; Watts, W. E. J. Chem. Soc., Chem. Commun. 1971, 36. Ihsan U. Khand and Peter L. Pauson were at the University of Strathclyde, Glasgow in Scotland. (b) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 975−977. (c) Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (S), 1977, 9. (d) Pauson, P. L. Tetrahedron 1985, 41, 5855−5860. (Review). 2. Schore, N. E. Chem. Rev. 1988, 88, 1081−1119. (Review). 3. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organomet. Chem. 1988, 356, 213−219. 4. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost, B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 5. Schore, N. E. Org. React. 1991, 40, 1−90. (Review). 6. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159−3160. 7. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263−3283. (Review). 8. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433−436. 9. Miller, K. A.; Martin, S. F. Org. Lett. 2007, 9, 1113−1116. 10. Kaneda, K.; Honda, T. Tetrahedron 2008, 64, 11589−11593. 11. Gao, P.; Xu, P.-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592−2593. 1.

421

Payne rearrangement The isomerization of 2,3-epoxy alcohol under the influence of a base to 1,2epoxy-3-ol is referred to as the Payne rearrangement. Also known as epoxide migration. R

R

OH

R

R

OH

O O

OH

aq. NaOH

O

O

O

SN2

O

H

O

R

OH

H R

workup

O

Example 12 O HO HO

O

NaOMe, MeOH

TrO

OH

TrO

reflux, 1 h, 84%

OTr

OTr

HO

Example 23 OBz

OH K2CO3, MeOH

OTs CO2Me

BzO

rt, 2 h, 98%

O

CO2Me

Example 3, Aza-Payne rearrangement8 HO

H

O

NaOH, t-BuOH/H2O N H Ts

rt, 4 h, 98%

TsHN

H

H

Example 4, Aza-Payne rearrangement9 OCH3 H Me

0.28 M NaOH, t-BuOH/H2O/THF (4:5:1), rt, 30%, or

H N OH Boc

OCH3

NaH, THF/HMPA (10:1), rt, 80%

Me Boc

H

OCH3 O

NH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_194, © Springer-Verlag Berlin Heidelberg 2009

OCH3

O

422

References Payne, G. B. J. Org. Chem. 1962, 27, 3819−3822. George B. Payne was a chemist at Shell Development Co. in Emeryville, CA. 2. Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1970, 10, 295−302. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436−1439, and 3663−3665. 4. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145−154. (Review). 5. Hanson, R. M. Org. React. 2002, 60, 1−156. (Review). 6. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073−4076. 7. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7, 3267−3270. 8. Feng, X.; Qiu, G.; Liang, S.; Su, J.; Teng, H.; Wu, L.; Hu, X. Russ. J. Org. Chem. 2006, 42, 514−500. 9. Feng, X.; Qiu, G.; Liang, S.; Teng, H.; Wu, L.; Hu, X. Tetrahedron: Asymmetry 2006, 17, 1394−1401. 10. Kumar, R. R.; Perumal, S. Payne rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 474−488. (Review). 1.

423

Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with β-ketoester to produce coumarin. O

OH

O

O

O

AlCl3

R

OEt R

EtO

O

O

O O

H

O

H

O

O

O

H

R

H

O

R OH2

R OH

O

H

R

Michael

Example 1

O

R

R

addition

AlCl3 O

O

:

O AlCl 3 O

H EtO O:

OH O

R

6

O

O OEt

HO

OH

[bimim]Cl•2AlCl3 130 oC, 35 min., 90%

HO

O

O

O

O

Example 28 O

O

OH

O

O

OH

OEt OH

BiCl3, 75 oC, 2 h, 66%

References von Pechmann, H.; Duisberg, C. Ber. 1883, 16, 2119. Hans von Pechmann (1850−1902) was born in Nürnberg, Germany. After his doctorate, he worked with Frankland and von Baeyer. Pechmann taught at Munich and Tübingen. He committed suicide by taking cyanide. 2. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151–2997. 3. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem. 1992, 57, 399–403. 4. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38–39. 5. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285–9287. 6. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152–154. 7. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997–4003. 8. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231–1233. 9. Manhas, M. S.; Ganguly, S. N.; Mukherjee, S.; Jain, A. K.; Bose, A. K. Tetrahedron Lett. 2006, 47, 2423–2425. 10. Rodriguez-Dominguez, J. C.; Kirsch, G. Synthesis 2006, 1895–1897. 1.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_195, © Springer-Verlag Berlin Heidelberg 2009

424

Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

Ar CHO

OAc O

AcONa

Ac2O

Ar

O

O

OH

O

Ar

H2 O

OH

cinnamic acid O O

enolate

O

aldol

O

OAc

H

O

O

O H

formation

Ar

O

condensation

O

Ar

O

O

O

intramolecular

O

O

Ar

acyl transfer

O

O

O

O

O

Ar

O

O

O H

O O

acyl transfer

O

Ar

O

O

O

AcOH

E2

O

elimination

Ar

O OH

H OH O

O HO O Ar

Ar

O

O

HOAc Ar

O

OH

Example 17 MeO H MeO CHO

Ac2O, Et3N, 90 oC

MeO

CO2H MeO

CO2H

5 h, 66%

MeO MeO

Example 29 Ac2O, Δ

ClF2C O Ph

AcONa, 46%

ClF2C Ph

CO2H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_196, © Springer-Verlag Berlin Heidelberg 2009

425

References Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (1838−1907), born in London, England, studied under A. W. von Hofmann at the Royal College of Chemistry. In an attempt to synthesize quinine in his home laboratory in 1856, Perkin synthesized mauve, the purple dye. He then started a factory to manufacture mauve and later other dyes including alizarin. Perkin was the first person to show that organic chemistry was not just mere intellectual curiosity but could be profitable, which catapulted the discipline into a higher level. In addition, Perkin was also an exceptionally talented pianist. 2. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71−79. 3. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723−3724. 4. Koepp, E.; Vögtle, F. Synthesis 1987, 177−179. 5. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969−971. 6. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131, 1097−1104. 7. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J. Org. Chem. 2001, 66, 8135−8138. 8. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315−3321. 9. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119−7126. 10. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47, 2249−2251. 11. Lacova, M.; Stankovicova, H.; Bohac, A.; Kotzianova, B. Tetrahedron 2008, 64, 9646−9653. 1.

426

Petasis reaction Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction. O R2

R1 B(OH)2

R3

N H

R2

R2 R2

N

R3

OH

N

R3 R2

H R2 NH R3

OH

R1

OH

O

R3

N

H

O R1 B OH HO

:OH R1 B(OH)2

N

R3

OH

R1

Example 12 OH B OH

Ph

Ph

EtOH, rt

C5H11

O

Ph

OH

N H

N C5H11

Ph

84%, 99% de

OH

Example 24 Me HO

(HO)2B CHO

HO

MeNHBn, EtOH, rt

N Bn

HO

24 h, 72%, 99% de HO

OMe

OMe

Example 39 H N

Ph

N

N

R3 OHC−CO2H, PhB(OH)2

R2 N

R1

BnS

R3

R2

N

50−94% BnS

CO2H

N

R1

Example 4, Asymmetric Petasis reaction10

R1

B(OEt)2

R1 = aryl, alkyl

R3

H N

R2

O R2

R2 = Bn, allyl R3 = alkyl

H

N

R3

15 mol% (S)-VAPOL CO2Et

R1

3 A MS, −15 oC, Tol.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_197, © Springer-Verlag Berlin Heidelberg 2009

CO2Et

70−92% yield 89:11 to 98:2 er

427

References (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. (c) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463–16470. (d) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798–11799. 2. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969–5970. 3. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471–1499. (Review). 4. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149–3153. 5. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahedron Lett. 2005, 46, 3053–3056. 6. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009– 1011. 7. Danieli, E.; Trabocchi, A.; Menchi, G.; Guarna, A. Eur. J. Org. Chem. 2007, 1659– 1668. 8. Konev, A. S.; Stas, S.; Novikov, M. S.; Khlebnikov, A. F.; Abbaspour Tehrani, K. Tetrahedron 2007, 64, 117–123. 9. Font, D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2007, 64, 5226–5235. 10. Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922–6923. 11. Abbaspour Tehrani, K.; Stas, S.; Lucas, B.; De Kimpe, N. Tetrahedron 2009, 65, 1957–1966. 1.

428

Petasis reagent The Petasis reagent (Cp2TiMe2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes as does the Tebbe’s reagent. The originally proposed mechanism5 was very different from that of Tebbe olefination. However, later experimental data seem to suggest that both Petasis and Tebbe olefination share the same mechanism, i.e., the carbene mechanism involving a fourmembered titanium oxide ring intermediate.9 Petasis reagent is easier to make than the Tebbe reagent.

Cp

Cl Ti

Cp

H H C H

CH3

MeLi or

heat

Ti

Cl MeMgCl

Ti

CH3

H

R1 Ti

O

H R1

R2

− CH4

H C H H

Cp

H2 C

R1

O

R2

Ti CH2

R1

− Cp2Ti=O

Ti

O

Cp

R2

R2

Example 12 O O MeO2C

O

N

Ph

CH3 CHO

Cp2TiMe2

O

THF, 65 °C 8 h, 52%

MeO2C

Ph

N

CH3

Example 23 Ti Cp Cp O

O

O

PhMe, 50 °C, 67%

Example 35 CF3

CF3 O

O O

CF3 O

N 250 kg (474 mol)

F

0.75 eq

O

Ph

CF3

2.4 eq MeLi

O

6 mol% Cp2TiCl2 PhMe, 80 °C, 6.5 h 91%

N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_198, © Springer-Verlag Berlin Heidelberg 2009

O

F 227 kg

429

Example 48 R3 R2

R1 N

OMe

1.8 equiv Cp2TiMe2

O Tol., THF, microwave, 65 oC 3−10 min., ~ 50−60%

R3 R2

R1

OMe

N

References Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392−6394. Colson, P. J.; Hegedus, L. S. J. Org. Chem. 1993, 58, 5918−5924. Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943–946. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Synth. 2002, 79, 19. 5. Payack, J. F.; Huffman, M. A.; Cai, D. W.; Hughes, D. L.; Collins, P. C.; Johnson, B. K.; Cottrell, I. F.; Tuma, L. D. Org. Pro. Res. Dev. 2004, 8, 256−259. 6. Cook, M. J.; Fleming, E. I. Tetrahedron Lett. 2005, 46, 297−300. 7. Morency, L.; Barriault, L. J. Org. Chem. 2005, 70, 8841−8853. 8. Adriaenssens, L. V.; Hartley, R. C. J. Org. Chem. 2007, 72, 10287−10290. 9. Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B. Tetrahedron Lett. 2008, 49, 6762−6764. 10. Zhang, J. Tebbe reagent. In Name Reactions for Homologations-Part I, Li, J. J. Ed., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review). 1. 2. 3. 4.

430

Peterson olefination Alkenes from α-silyl carbanions and carbonyl compounds. Also known as the sila-Wittig reaction. H

O R1

R2

HO R2 R1

SiR3

M R

3

SiR3 H R3

R1

acid or base

R

H

2

R3

Basic conditions: O R1

O

R2 H

R

R2

SiR3

M

R

O SiR3 R1 H R2 R3

SiR3 H R3

1

syn-

R1

H

elimination

R2

R3

3

β-silylalkoxide intermediate Acidic conditions: HO R1 R2

SiR3 H R3

rotation

R3 H SiR3

HO R1 R2

H2O R1 R2

H

R3 H SiR3

E2 anti-

R1

elimination R 2

R3 H

:OH2

β-hydroxysilane Example 16 OH HO

H2SO4, THF

HO

23 oC, 24 h 95%

HO

OBn OBn

SiMe2Ph OH OBn OBn

KHMDS, 18-C-6, THF

HO HO

−78 oC, 1 h 99%, > 20:1 dr

Example 27 PhO2S

F

1. n-BuLi, Et2O, −78 oC

F TBS

2. benzophenone, 63%

Ph

PhO2S Ph

Example 38 1. KHMDS, THF, −78 oC (t-BuO)Ph2Si

CN 2. N

CHO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_199, © Springer-Verlag Berlin Heidelberg 2009

OBn OBn

CN N 88% yield 92:8 Z:E

431

Example 410 O

O

OMOM

OMOM

o

1. LiCH2TMS, THF 0 C, 15 min. 2. KHMDS, 0 oC to rt, 1.5 h OMe

3. HCl, MeOH/Et2O, 5 min. 74%

OMe

References Peterson, D. J. J. Org. Chem. 1968, 33, 780−784. Ager, D. J. Org. React. 1990, 38, 1−223. (Review). Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764−770. (Review). 4. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195−200. (Review). 5. Ager, D. J. Science of Synthesis 2002, 4, 789−809. (Review). 6. Heo, J.-N.; Holson, E. B.; Roush, W. R. Org. Lett. 2003, 5, 1697−1700. 7. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81−84. 8. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917−3920. 9. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim, Germany, 2004, 18−103. (Review). 10. Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 13366. 11. Ahmad, N. M. Peterson olefination. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 521−538. (Review). 1. 2. 3.

432

Pictet–Gams isoquinoline synthesis The isoquinoline framework is derived from the corresponding acyl derivatives of β-hydroxy-β-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentoxide, or phosphorus oxychloride, under reflux and in an inert solvent such as decalin, isoquinoline frameworks are formed. OH 4

4

H N

1

R

3

O

3

P2O5, decalin 1

reflux

N

R

P2O5 actually exists as P4O10, an adamantane-like structure. OH HN :

O

OH

OH

O O P O P O O

HN

R

O R

H

O O O: P O P O O

P O

:NH H R OPO2

O

OPO2 H N

N

N

R

R

R

Example 14

HO O

N POCl3, P4O10, decalin

NH

180 oC, 6 h, 14% OH

H N

H N O

OH

N N

O

Example 27 OH

H

N

P2O5

O Cl

o-dichlorobenzene 80%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_200, © Springer-Verlag Berlin Heidelberg 2009

N Cl

433

Reference 1.

2. 3. 4. 5. 6. 7. 8.

(a) Pictet, A.; Kay, F. W. Ber. 1909, 42, 1973−1979. (b) Pictet, A.; Gams, A. Ber. 1909, 42, 2943−2952. Amé Pictet (1857−1937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977, 18, 4107−4110. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. K.; Hadi, A. H. A.; Sharif, A. M. J. Chem. Soc., Perkin Trans. 1 1979, 539−543. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697−9700. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343−348. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573−8580. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4, 1075−1081. Holsworth, D. D. Pictet–Gams Isoquinoline Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 457−465. (Review).

434

Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of β-arylethylamines and carbonyl compounds followed by cyclization. R1O

R1O

O R2

NH2

R1O

HCl NH

R1O

H

R2

NH2 H

:

R1O

R1O

H O

R1O

R

R1O

2

N:

OH2

N

R1O

2

R

R

R1O R1O

OH

R1O NH H

+H

R1O

− H2 O H

N R2

R1O R1O

H

H

2

R1O NH

R1O

H

R2

R

NH

R1O

2

R

2

Example 14 HO

O O HO

AcO NH2

MeO

S O

dry EtOH N

O AcO

Me O

NH

MeO

silica gel S O

Me

80%

N O

O

O

Example 27 N MeO

NHMe

(CH2O)n

i-PrO

MeO i-PrO

aq. HCl, EtOH i-PrO

75%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_201, © Springer-Verlag Berlin Heidelberg 2009

i-PrO

Me

435

Example 3, Asymmetric acyl Pictet–Spengler9

OHC NH2

N H

OTBDPS

N

N H

CH2Cl2/Et2O (3 : 1) Na2SO4, 23 oC, 2 h

OTBDPS

t-Bu S i-Bu2N

N H

O

N H

N

Ph

AcCl, 2,6-lutidine, Et2O −78 oC to −60 oC, 23 h

N H

NAc

OTBDPS 81% 2 steps 94% ee

Example 4, Oxa-Pictet–Spengler10 O

O CHO

O

OH

O

BF3•OEt2, CH2Cl2 0 oC to rt, 88%, 88% de

O O

O

O O

References Pictet, A.; Spengler, T. Ber. 1911, 44, 2030−2036. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (Review). Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202−9203. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43−46. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543−547. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177−180. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003, 14, 1309−1320. 8. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 469−479. (Review). 9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745−748. 10. Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74, 423−426. 1. 2. 3. 4. 5. 6. 7.

436

Pinacol rearrangement Acid-catalyzed rearrangement of vicinal diols (pinacols) to carbonyl compounds.

HO R R1

O

OH R2 R3

H R R

R2 3 1R

The most electron-rich alkyl group (more substituted carbon) migrates first. The general migration order: tertiary alkyl > cyclohexyl > secondary alkyl > benzyl > phenyl > primary alkyl > methyl >> H. For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-MeOAr > p-O2N-Ar HO R R1

R

H

HO R R1

H

HO R 1

OH R2 R3

alkyl

R2 R3

migration

OH2 R2 R3

− H2O

O

O

R R

R2 3 1R

H

R R

R2 3 1R

Example 14 OMe OMe MeO

MeO OH

OTBDMS OTBDMS

MeO

BF3•OEt2

CHO

MeO

H

OTBDMS

THF, 68% OH

OMe

OTBDMS OMe

Example 25 Ph OH OH N SO2Ph

1. MsCl, Et3N, CH2Cl2 0 oC, 10 min. 2. Et3Al, CH2Cl2, −78 oC 10 min., 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_202, © Springer-Verlag Berlin Heidelberg 2009

O Ph

N SO2Ph

437

Example 37 Ph

OH OH

Ph

O cat. TsOH

Ph

O Ph Ph

Ph

CDCl3 3:1

Example 49 OBn N

OBn N

O

O

BF3•OEt2 HO

R

OH

CH2Cl2, 0

oC

O

R R R R

= vinyl, 92% = allyl, 95% = furyl, 90% = prenyl, 94%

98% ee

R

References Fittig, R. Ann. 1860, 114, 54−63. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tetrahedron 1996, 52, 14147−14176. 3. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693−5706. 4. Pettit, G. R.; Lippert III, J. W.; Herald, D. L. J. Org. Chem. 2000, 65, 7438–7444. 5. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937−6940. 6. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143−7157. (Review). 7. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff, E. J. Org. Chem. 2004, 69, 2017−2023. 8. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263−3270. 9. Suzuki, K.; Takikawa, H.; Hachisu, Y.; Bode, J. W. Angew. Chem., Int. Ed. 2007, 46, 3252–3254. 10. Goes, B. Pinacol rearrangement. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review). 1. 2.

438

Pinner reaction Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine. O H+, H2O 1

R CN

R OH

HCl (g)

NH2 Cl

NH2

OR1

R

NH3, EtOH

R

R

protonation

H

NH

R

NH2•HCl

nucleophilic

R O: H 1

N:

OR1

R

NH2 Cl

addition

OR1

R

common intermediate NH2 Cl R

H

hydrolysis

O H2 N O H

OR1

H2O:

H

NH2 Cl

nucleophilic

OR1

R

OR1

R

OR1

R

NH2

HCl•H2N OR1

addition

R

R

NH2 H

H3N:

NH2•HCl

Example 12 O Ph

Ph

Ph N H

NH2

pyr., H2S N

N

Ph

NH

EtSH, HCl, CH2Cl2

N

O

0 oC, 10 min., 95%

4 h, 0 oC, 42%

O Ph

Ph

Example 22 O Ph

O

EtSH, HCl, CH2Cl2 N H

N

0 oC, 1 h, 85%

Ph

N H

SEt NH

O

pyr., H2S 2 h, 0 oC, 40%

Ph

SEt

N H

S

Example 36 O2 S

N

O2 S

MeOH, HCl OPh Et2O, 0 oC 90%

HCl•HN

OPh

OMe

O2 S

NaHCO3, Et2O −5 oC, 87−92%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_203, © Springer-Verlag Berlin Heidelberg 2009

HN

OPh

OMe

439

O2 S H2 N

O2 S

OPh MeO

OMe

O2 S

NH2 OPh

Ph

Me

HN

EtOH, rt 36 h, 78%

NH2

Me

OPh

NH2 Ph

Example 410 Cl N S

NC

N

HCl EtOH 95%

H2 N

S OEt

N

N NaHCO3

HN

S OEt

NH 4Cl 65%

H2 N Cl

S NH2

References (a) Pinner, A.; Klein, F. Ber. 1877, 10, 1889–1897. (b) Pinner, A.; Klein, F. Ber. 1878, 11, 1825. 2. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622–624. 3. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169–1170. 4. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643–645. 5. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789–794. 6. Fischer, M.; Troschuetz, R. Synthesis 2003, 1603–1609. 7. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331–2334. 8. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; Mayence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209–4216. 9. Li, J.; Zhang, L.; Shi, D.; Li, Q.; Wang, D.; Wang, C.; Zhang, Q.; Zhang, L.; Fan, Y. Synlett 2008, 233–236. 10. Racané, L.; Tralic-Kulenovic, V.; Mihalic, Z.; Pavlovic, G.; Karminski-Zamola, G. Tetrahedron 2008, 64, 11594–11602. 1.

440

Polonovski reaction Treatment of a tertiary N-oxide with an activating agent such as acetic anhydride, resulting in rearrangement where an N,N-disubstituted acetamide and an aldehyde are generated. R1 N O R

R2

O

R2

R

pyr., CH2Cl2

O acylation

R1 N

O R

O

R2

O

R1 N O R

(CH3CO)2O

H

R1 O N O R

2

H

R1 N R

R2 HOAc CH3CO2

CH3CO2

iminium ion O R1 R2 N: R O O

O O

R2

R1 N

O R

O

Ac2O R

O

R1 N

O R2 O

OAc

The intramolecular pathway is also operative: R1 N

R2

: O

R2 R O

R1 N R O O

R

R1 N

O R O

Example 11 (CH3CO)2O N

N O

100 oC

O

Example 22 O

O N

(CH3CO)2O

N

< 30 oC, 98%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_204, © Springer-Verlag Berlin Heidelberg 2009

2

H

H

441

Example 3, Iron salt-mediated Polonovski reaction9 Me O

Me O

O

H2O2 then

HO

H

N

codeine

O

2 M HCl Me

HO

Me O Cl N OH H Me

FeSO4

O

87%, 2 steps HO

H

NH

References Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190–1208. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377–4385. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135– 2146. 4. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45, 2683–2692. 5. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 6. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378–5381. 7. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68, 9847–9850. 8. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849–1854. 9. Thavaneswaran, S.; Scammells, P. J. Bioorg. Med. Chem. Lett. 2006, 16, 2868–2871. 10. Volz, H.; Gartner, H. Eur. J. Org. Chem. 2007, 2791–2801. 1. 2. 3.

442

Polonovski–Potier reaction A modification of the Polonovski reaction where trifluoroacetic anhydride is used in place of acetic anhydride. Because the reaction conditions for the Polonovski– Potier reaction are mild, it has largely replaced the Polonovski reaction. N (CF3CO)2O

N O

pyr., CH2Cl2

O

CF3

tertiary N-oxide O F3C

N

O

N O

O

CF3

acylation

CF3

H

H O

N O CF3CO2

CF3CO2

iminium ion N:

N

N F3 C

O O

CF3

CF3CO2

H O

O

O

CF3

CF3

enamine Example 12

N H

N

O

(CF3CO)2O, CH2Cl2, 0 oC

N

N H H

then, HCl, heat, 30% HO

HO

Example 25 O O H H HN

N

O OH

O H

(CF3CO)2O, pyr.

N

CH2Cl2, 0 oC, 65% F3C

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_205, © Springer-Verlag Berlin Heidelberg 2009

HN

O OH

H O

443

Example 38 O N N H Boc

H

Me

1.3 equiv m-CPBA

O

CH2Cl2, 0 oC, 94%

N N H Boc

O H HO

CN 1. TFAA, CH2Cl2, rt, 3 h 2. KCN, H2O, pH 4 0 oC, 30 min., then rt, 3 h

N N H Boc

Me

O

N

Me N H Boc

O H 22%

H

OH

25%

Example 410 O

H

HN

O

H 1. m-CPBA, DMF, 0 oC, 0.5 h, 80% N CH3 H 2. Ac2O, Et3N, DMF, 0 oC, 1 h

H

OH

N CH3 H

HN

References Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; de Rostolan, J.; Potier, P. J. Am. Chem. Soc. 1968, 90, 5622–5623. 2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem. Commun. 1972, 930–931. 3. Grierson, D. Org. React. 1990, 39, 85–295. (Review). 4. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277–296. 5. Kende, A. S.; Liu, K.; Brands, J. K. M. J. Am. Chem. Soc. 1995, 117, 10597–10598. 6. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39, 4251–4254. 7. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713–9720. 8. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291–3293. 9. Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037–5039. 10. Gazak, R.; Kren, V.; Sedmera, P.; Passarella, D.; Novotna, M.; Danieli, B. Tetrahedron 2007, 63, 10466–10478. 11. Nishikawa, Y.; Kitajima, M.; Kogure, N.; Takayama, H. Tetrahedron 2009, 65, 1608– 1617. 1.

444

Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate aminoacetal intermediate. OEt OEt CHO

H OEt

H2N

OEt

OEt H2N

N

N

OEt

:

OEt

OEt

condensation :N

H

imine formation

H

OH2

O

H

H : OEt

OEt

OEt

HOEt

OEt :

OEt

N

N

N

H OEt

OEt

H

H

N

N

N

Example 13 EtO

OEt

MeO

BF3•AcOH, (CF3CO)2O N

MeO

60−82 %

MeO N

MeO

Example 24 MeO OMe

H

OMe

TiCl4, CH2Cl2

O

N

−78 oC, 69 %

N Me

O

Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_206, © Springer-Verlag Berlin Heidelberg 2009

445

Example 39 OMe MeO

MeO

OMe N

MeO

Ns

6 N HCl, EtOH, dioxane

N

MeO

Ns

reflux, 30 min., 68%

Example 4, Bobbitt modification10 EtO

MeO MeO

H N

OEt

Br

OEt

H

OEt

MeO N

MeO

H

NaH, DMF

MeO 1. 5 M HCl, 12 h, rt 2. NaBH4, TFA, CH2Cl2 38% overall

MeO

N H

References (a) Pomeranz, C. Monatsh. 1893, 14, 116−119. Cesar Pomeranz (1860−1926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. (b) Fritsch, P. Ber. 1893, 26, 419−422. Paul Fritsch (1859−1913) was born in Oels, Silesia. He studied at Munich where he received his doctorate in 1884. Fritsch eventually became a professor at Marburg after several junior positions. 2. Gensler, W. J. Org. React. 1951, 6, 191−206. (Review). 3. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253−1259. 4. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248−3251. 5. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601−616. (Review). 6. GluszyĔska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359−2368. 7. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297−8303. 8. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Review). 9. Bracca, A. B. J.; Kaufman, T. S. Eur. J. Org. Chem. 2007, 5284−5293. 10. Grajewska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007, 18, 2910−2914. 1.

446

Schlittler–Müller modification Simple permutation where the amine and the aldehyde switch places for the two reactants in comparison to the Pomeranz–Fritsch reaction.

OEt OEt NH2

OHC

OEt

H N

N

OEt

R

R

R

Example 13 OMe R

OMe

OMe X

HN

OMe

R

N

Ts

Ts

H R

N

Ts

Example 24 OEt O

1. EtO H H2N

NH2

N

N

2. oleum, 30%

References 1. 2. 3. 4. 5.

Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914−924, 1119−1132. Guthrie, D. A.; Frank, A. W.; Purves, C. B. Can. J. Chem. 1955, 33, 729−742. Boger, D. L.; Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 3977−3980. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107−1109. Hudson, A. Pomeranz–Fritsch Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480−486. (Review).

447

Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation. O2CPh

I2 AgO2CPh

I

OH

O2CPh

I

I

I

OH

hydrolysis

SN2

SN2 O O2CHPh

Ph

cyclic iodonium ion intermediate O2CPh

O2CPh

SN2 O

O

O

neighboring group assistance OH

hydrolysis

OH

O2CPh

Ph

Example 15 O

AgOCOPh, I2 PhH, rt, 2 h, reflux, 10 h, 46%

Ph

F

O O

O

F

Ph

Example 29 O2C-C6H4-p-OMe

AgOCOPh, I2 CCl4, 74%

O

OAc

OH I O

O2C-C6H4-p-OMe

1. KOH, H2O 2. Ac2O, pyr.

AcO

OAc

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Prévost, C. Compt. Rend. 1933, 196, 1129–1131. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063–5070. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439–4443. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801–4805. Zajc, B. J. Org. Chem. 1999, 64, 1902–1907. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D. Tetrahedron 2000, 56, 1345–1348. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M. J. Org. Chem. 2000, 65, 8134–8138. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209–1212. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373–386.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_207, © Springer-Verlag Berlin Heidelberg 2009

448

Prins reaction The Prins reaction is the acid-catalyzed addition of aldehydes to alkenes and gives different products depending on the reaction conditions.

O R

H

H

O or

R

R

OH

O

or

OH

R

OH

O H

OH

H H2O

H

H

H

OH

H2O

H

R

OH

R

OH

R

the common intermediate

R

OH

H

R

H

OH

:B

H O O H

H

R

OH

R

O

H

H O

H

O

R

Example 15 Br OAc

SnBr4, CH2Cl2

O TsO

O

−78 oC, 84% OBn

TsO

OBn

Example 27 O (CH2O)n, Bi(OTf)3 AcO

CH3CN, rt, 10 h, 77%

AcO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_208, © Springer-Verlag Berlin Heidelberg 2009

O

449

Example 39 OBn OTBS TMSEO2C

O

O

HO

O O

O

Cl OBn OH

In(OTf)3, TMSCl, CH2Cl2 −78 to −40 ºC, 4 h, 42%

TMSEO2C

O

O

O O

O

Example 410

AcOH, BF3•OEt2

O OH OHC PhO2SO

OCH3

0 oC, CH2Cl2 X = OAc, 33% X = F, 48%

O

O

X O PhO2S

OCH3

References Prins, H. J. Chem. Weekblad 1919, 16, 1072−1023. Born in Zaandam, The Netherlands, Hendrik J. Prins (1889−1958) was not even an organic chemist per se. After obtaining a doctorate in chemical engineering, Prins worked for an essential oil company and then a company dealing with the rendering of condemned meats and carcasses. But he had a small laboratory near his house where he carried out his experiments in his spare time, which obviously was not a big distraction—for he rose to be the president-director of the firm he worked for. 2. Adam, D. R.; Bhatnagar, S. P. Synthesis 1977, 661−672. (Review). 3. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223−226. 4. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491−493. 5. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S. D. Org. Lett. 2002, 4, 3919−3922. 6. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodriguez-Lens, M. Synlett 2003, 345−348. 7. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun. 2005, 35, 1177−1182. 8. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485−3488. 9. Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939−941. 10. Bahnck, K. B.; Rychnovsky, S. D. J. Am. Chem. Soc. 2008, 130, 13177−13181. 1.

450

Pschorr cyclization The intramolecular version of the Gomberg−Bachmann reaction. CO2H

CO2H

NaNO2, HCl Cu

NH2

CO2H

N

H

H

O

N

− H2O

O

O H2O

N

− NO2

NH2

:

HO

O

O

N

O

N

O

CO2H

CO2H H N N

NH N O

CO2H H

H

N: N

O H

CO2H

CO 2H − H2O

OH2

Cu(0)

N2↑

Cu(I)

N2

H

CO2H

6-exo-trig

CO2H Cu(I) Cu(0)

radical cyclization

H

H

Example 17 O

O

O

O

O

O

O

O

O

1. NaNO2, HCl−H2O−HOAc 0 to 5 oC, 2 h NH2 S

2. CuSO4, HOAc, reflux 2 h, 86%

S

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_209, © Springer-Verlag Berlin Heidelberg 2009

6:1

S

451

Example 28 O

O

N N

NH2

NaNO2, HCl

N N

5 to 20 oC, 64%

Example 310 O

O hv (350 nM) Br

MeCN, N2

O

34%

O

62%

References Pschorr, R. Ber. 1896, 29, 496−501. Robert Pschorr (1868−1930), born in Munich, Germany, studied under von Baeyer, Bamberger, Knorr, and Fischer. He became an assistant professor in 1899 at Berlin where he discovered the phenanthrene synthesis. During WWI, Pschorr served as a major in the German Army. 2. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405−406. 3. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196−201. 4. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656−2657. 5. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359−1469. (Review). 6. Karady, S.; Cummins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer, P. G.; Marcune, B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett. 2003, 5, 1175−1178. 7. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427−5433. 8. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; Lemière, G. L. F.; Riedl, Z.; Hajós, G.; Van der Driessche, B.; Dommisse, R. A.; Mátyus, P. Tetrahedron 2003, 59, 5919−5926. 9. Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemière, G. L. F.; TapolcĞanyi, P.; Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123−1139. (Review). 10. Moorthy, J. N.; Samanta, S. J. Org. Chem. 2007, 72, 9786−9789. 1.

452

Pummerer rearrangement The transformation of sulfoxides into α-acyloxythioethers using acetic anhydride.

R

O 1 S

R2

Ac2O

R1

R2

S

OAc

O O

O

O O O

O

R

O 1 S

acyl transfer

R2

R1

O S

AcO

R

1

O S

R2 H

R2 AcO

HOAc R1

S

R2

R1

S

R

2

R1

R2

S

OAc AcO

Example 12 1. Me2C(OMe)2, H+ 2. m-CPBA, CH2Cl2, −20 oC

OH BnO

O

OAc

BnO

SPh 3. Ac2O, NaOAc, reflux, 6 h 81%

OH

SPh O

Example 27 MeO

MeO N

N

CO2Et

TMSOTf, DIPEA

MeO Ph

S

O

N

N

MeO

O

Bn

CO2Et PhS

CH2Cl2, −20 C 88%, dr = 2:1 o

N

N Bn

Example 38 MeO

O

MeO

N

O SEt CO2Me

MeO CSA, PhMe

H MeO

reflux, 88%

Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_210, © Springer-Verlag Berlin Heidelberg 2009

MeO2C

N

O SEt Br

O

453

Example 49

Bn

Bn N

O

O S

Ac2O, pyr., DMAP CH2Cl2, rt, 91%

Ph

Bn

Bn N Ph

O S OAc

References Pummerer, R. Ber. 1910, 43, 1401−1412. Rudolf Pummerer, born in Austria in 1882, studied under von Baeyer, Willstätter, and Wieland. He worked for BASF for a few years and in 1921 he was appointed head of the organic division of the Munich Laboratory, fulfilling his long-desired ambition. 2. Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune, S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J. J. Org. Chem. 1982, 47, 1373−1378. 3. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157−406. (Review). 4. Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 1353−1378. (Review). 5. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175−203. (Review). 6. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851−862. (Review). 7. Gámez Montaño, R.; Zhu, J. Chem. Commun. 2002, 2448−2449. 8. Padwa, A.; Danca, M. D.; Hardcastle, K.; McClure, M. J. Org. Chem. 2003, 68, 929. 9. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317. 10. Ahmad, N. M. Pummerer rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 334−352. (Review). 1.

454

Ramberg–Bäcklund reaction Olefin synthesis via α-halosulfone extrusion. X R

R1

Base

S O O

R

O S O↑

1

R

:B X R

R

backside

H X

R1

S O O

S O O

R1

displacement

R1

R

R1

SO2 S O

extrusion

O S O↑ R

O

episulfone intermediate Example 14 H KOt-Bu, THF S H O2

Br

H

−15 oC to rt, 71%

Example 25

H

Br

KOt-Bu, THF/HOt-Bu

SO 2CH2Br

0 oC to rt, 0.5 h, 65%

Example 36 O

O

O O H O2S Cl

O

1. 2.2 eq. KOt-Bu, 10 eq. HMPA DME, 70 oC, 5 min., 82% 2. 6 N HCl/THF (1:10, v/v), rt, 4 h, 85%

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_211, © Springer-Verlag Berlin Heidelberg 2009

OH O

O H O

O

455

Example 4, in situ chlorination7 TMSO

O2S

O

TMSO

HO 1. t-BuOK, t-BuOH CCl4, rt, 65% 2. TsOH, H2O, EtOH rt, 95%

O

HO

References Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 1−50. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209−216. (Review). Paquette, L. A. Org. React. 1977, 25, 1−71. (Review). Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090−1100. Block, E.; Aslam, M.; Eswarakrishnan, V.; Gebreyes, K.; Hutchinson, J.; Iyer, R.; Laffitte, J. A.; Wall, A. J. Am. Chem. Soc. 1986, 108, 4568−4580. 6. Boeckman, R. K., Jr.; Yoon, S. K.; Heckendorn, D. K. J. Am. Chem. Soc. 1991, 113, 9682−9784. 7. Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1994, 116, 7459−7460. 8. Taylor, R. J. K. Chem. Commun. 1999, 217−227. (Review). 9. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357−475. (Review). 10. Li, J. J. Ramberg–Bäcklund olefin synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 386−404. (Review). 11. Pal, T. K.; Pathak, T. Carbohydrate Res. 2008, 343, 2826−2829. 12. Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem. 2009, 74, 2271−2277. 1. 2. 3. 4. 5.

456

Reformatsky reaction Nucleophilic addition of organozinc reagents generated from α-haloesters to carbonyls.

O

OR2

Br R

R

1

O

OR2

Br

OR2 R1

O

O

Zn(0)

nucleophilic R1

R

oxidative addition or electron transfer

O

HO R

Zn

ZnBr addition

OR2 O

BrZnO R

OR2 R1

H2O, hydrolysis during workup

O

HO R

OR2 R1

O

Example 14 OTBDMS

OTBDMS BrCH2CO2Me

Ph S

N Boc

Ph

MeO2C N Boc

Zn, THF, reflux, 71%

Example 26 O

O Zn, THF O 60 oC

Br

MeO

O O

HO O MeO

HCl THF, rt, 10 h 92%

O MeO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_212, © Springer-Verlag Berlin Heidelberg 2009

457

Example 3, Boron-mediated Reformatsky reaction8 O

O

O H

I Me

OP O O

H OH H

BEt3, tol. H

OP O

−78 oC, quant.

P = TBS

H

Me

O

single diastereomer

Example 4, SmI2-mediated Reformatsky reaction9 OTBDPS

OTBDPS n-Bu O

O

Me H

O

OSiEt3 Br Me

OSiEt3 CHO O

1. SmI2, THF, −78 oC 2. Martin sulfurane, CH2Cl2 72%, 2 steps

Me

O

H OSiEt3

OSiEt3

n-Bu

O Me

References Reformatsky, S. Ber. 1887, 20, 1210−1211. Sergei Reformatsky (1860−1934) was born in Russia. He studied at the University of Kazan in Russia, the cradle of Russian chemistry professors, where he found competent guidance of a distinguished chemist, Alexander M. ZaƱtsev. Reformatsky then studied at Göttingen, Heidelberg, and Leipzig in Germany. After returning to Russia, Reformatsky became the Chair of Organic Chemistry at the University of Kiev. 2. Rathke, M. W. Org. React. 1975, 22, 423−460. (Review). 3. Fürstner, A. Synthesis 1989, 571−590. (Review). 4. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173−2174. 5. Fürstner, A. In Organozinc Reagents Knochel, P., Jones, P., Eds.; Oxford University Press: New York, 1999, pp 287−305. (Review). 6. Zhang, M.; Zhu, L.; Ma, X. Tetrahedron: Asymmetry 2003, 14, 3447−3453. 7. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325−9374. (Review). 8. Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426−427. 9. Moslin, R. M.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 15106−15107. 10. Cozzi, P. G. Angew. Chem., Int. Ed. 2007, 46, 2568−2571. (Review). 11. Ke, Y.-Y.; Li, Y.-J.; Jia, J.-H.; Sheng, W.-J.; Han, L.; Gao, J.-R. Tetrahedron Lett. 2009, 50, 1389−1391. 1.

458

Regitz diazo synthesis Synthesis of 2-diazo-1,3-diketones or 2-diazo-3-oxoesters using sulfonyl azides.

OR1

R O

O

OR1 O

O

proton

H N

N N SO2Tol N H OR1 O

O

N N

O

O

O

O H2 N S O

OR1

R

OR1 O

R

SO2Tol

R

transfer

Ts NH2

O

OR1

R

formation

O

N N:

O

O N N N S O

enolate

R

OR1

R

MeCN

:NEt3 H

N2

TsN3, Et3N

O

tosyl amide is the by-product When only one carbonyl is present, ethylformate can be used as an activating auxiliary:6−9 O

O

NaH, HCO2Et

OH

Et2O

:NEt3

O

O O

O

O

MsN3

N2

Et2O

O N N N S Me O

O

N N

N

SO2Me

H

H

N N N SO Me 2 H O

O

O HN S Me O O H

O

O N

N

O N2

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_213, © Springer-Verlag Berlin Heidelberg 2009

459

O O N N N S Me O

O

1,3-dipolar

N N N SO Me 2

cycloaddition

H OH

OH

O HN S Me O O H

O N2

Example 15 H N

O Ot-Bu O

O

O

SO2N3

O

Et3N, CH3CN

N2 Ot-Bu

0 oC, 5 h, 45%

O

O

Example 210 O

O

O N

O

O N H N

OTIPS

O N

CH3SO2N3 CH3CN, 84%

O

N2

O N H

OTIPS

N

References (a) Regitz, M. Angew. Chem., Int. Ed. 1967, 6, 733–741. (b) Regitz, M.; Anschütz, W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 9, 3171–3174. (c) Regitz, M. Synthesis 1972, 351–373. (Review). 2. Pudleiner, H.; Laatsch, H. Ann. 1990, 423–426. 3. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011–4030. 4. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252–9254. 5. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org. Chem. 2003, 68, 6153–6159. 6. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624–13628. 7. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241–3244. 8. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609–2614. 9. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967–3977. 10. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47–50. 1.

460

Reimer–Tiemann reaction Synthesis of o-formylphenol from phenols and chloroform in alkaline medium. OH

OH CHCl3

a.

CHO

3 KOH

2 H2O

Carbene generation: fast

Cl3C H

CCl2 Cl

H2O

OH

b.

3 KCl

− Cl−, slow α-elimination

:CCl2

Addition of dichlorocarbene and hydrolysis: OH

O

O H2O

O

H

O

Cl

OH H

Cl CHCl

CCl2

CCl2

OH

Cl

O

H

KOH

O

H

OH

O

CHO H

Example 1, Photo-Reimer–Tiemann reaction without base7 OH

O

CHCl2

hv (Hg lamp) CHCl3, 5 h, 48% CN

CN

Example 28 OH

OH CHO CHCl3, 6 eq. NaOH CO2H

NHBoc

2 eq. H2O, reflux 4 h, 64%

CO2H NHBoc

References 1. 2. 3. 4. 5. 6. 7. 8.

Reimer, K.; Tiemann, F. Ber. 1876, 9, 824–828. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685–4690. Neumann, R.; Sasson, Y. Synthesis 1986, 569–570. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609–616. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691–3694. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825–5828. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553–1555.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_214, © Springer-Verlag Berlin Heidelberg 2009

461

Reissert reaction Treatment of quinoline or isoquinoline with acid chloride and KCN gives quinaldic acid, aldehyde, and KCN.

O R

Cl

KCN

H2SO4

H CN

N

N

O R

O R Reissert Compound

NH3 H

N

CO2H

CN :

N

N

Cl

R

O

O

O

R

H

H CN

N

H

H

N

R

O N

R

H

Reissert compound H NH

N

NH

N: O

R

R

O

H

:

H

H

NH

N

O

H

O R H

H

N R H

O

N

O

O H

OH NH2

N R H

O

H

O

R

NH2

H

HO NH

H2O:

NH3 N

2

Example 13 O MeO

NaCN, H2O, CH2Cl2

Cl

MeO

N

H

NH2

H O

N

NH2

O

N

4.5 h, 95%

OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_215, © Springer-Verlag Berlin Heidelberg 2009

CO2H

462

O N

CN

MeO

30% H2SO4

MeO

H

O reflux, 1 h, 95%

MeO

MeO OMe

OMe

Example 2, Reissert compound from isoquinoline7 chiral Al catalyst TMSCN, CH2=CHOCOCl

N Br

CH2Cl2, −40 oC, 72 h, 53%

N

O

CN O Br 73% ee

Example 3, Reissert compound fron isoquinoline10

O Cl

O

N CN

N

N

O

CN

O

O O

1:1 TMS-CN, CH2Cl2 48 h, rt, 96%

Reissert compounds

References (a) Reissert, A. Ber. 1905, 38, 1603–1614. (b) Reissert, A. Ber. 1905, 38, 3415–3435. Carl Arnold Reissert was born in 1860 in Powayen, Germany. He received his Ph.D. In 1884 at Berlin, where he became an assistant professor. He collaborated with Tiemann. Reissert later joined the faculty at Marburg in 1902. 2. Popp, F. D. Adv. Heterocycl. Chem. 1979, 24, 187–214. (Review). 3. Schwartz, A. J. Org. Chem. 1982, 47, 2213–2215. 4. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63, 2244–2250. 5. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999, 297–303. 6. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801–6808. 7. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989–1999. 8. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337–340. 9. Kanai, M.; Kato, N.; Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491–1508. (Review). 10. Gibson, H. W.; Berg, M. A. G.; Clifton Dickson, J.; Lecavalier, P. R.; Wang, H.; Merola, J. S. J. Org. Chem. 2007, 72, 5759–5770. 11. Fuchs, C.; Bender, C.; Ziemer, B.; Liebscher, J. J. Heterocycl. Chem. 2008, 45, 1651– 1658. 1.

463

Reissert indole synthesis The Reissert indole synthesis involves base-catalyzed condensation of an onitrotoluene derivative with an ethyl oxalate, which is followed by reductive cyclization to an indole-2-carboxylic acid derivative.

CO2Et CO2Et

R NO2

CH3

CO2Et

B R

B

NO 2

O

H

O NO2

CH2

EtO

NO2

O

O

N H

CO2H

OH OEt CO2Et NO2

H

OEt

O

hydrolysis

CO2Et NO2

O

R

H

H

CO2H NO2

H

H

CO2H N H

CO H NH2 2

CO2H

CO2H

OH

N H

N H

Example 12 O MeO N

NO2

CO2Et CO2Et

KOEt 93%

CO2Et

MeO

H2, Pd/C

MeO

EtOH, 85%

N

NO2

N

N H

CO2Et

N H

CO2Et

Example 23

NO2

CO2Et CO2Et

KOEt, EtOH Et2O

CO2Et OK NO2

H2 (30 psi), PtO2 HOAc, 41−44%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_216, © Springer-Verlag Berlin Heidelberg 2009

464

Example 3, Furan ring as the masked carbonyl10

O

Ms NH

O HCl, EtOH

O

O Ph

reflux, 84%

Ms N O

O Ph

References Reissert, A. Ber. 1897, 30, 1030−1053. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530−3531. Noland, W. E.; Baude, F. J. Org. Synth. 1973; Coll. Vol. 567−571. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39, 3580−3583. 5. Cannon, J. G.; Lee, T.; Ilhan, M.; Koons, J.; Long, J. P. J. Med. Chem. 1984, 27, 386−389. 6. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami, Y. Synlett 2000, 1196−1198. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001, 42, 2031−2036. 8. Katayama, S.; Ae, N.; Nagata, R. J. Org. Chem. 2001, 66, 3474−3483. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 154−158. (Review). 10. Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D. Tetrahedron 2006, 63, 474−491. 1. 2. 3. 4.

465

Ring-closing metathesis (RCM)

Cy3P Cl Cl

Cy3P Ph Cl Ru Cl Mes N N Mes

Ph

Ru PCy3

F3C F3C F3C F3C

N Mo O O

Ph

Grubbs’ catalysts Schrock’s catalyst Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below. Generation of the real catalyst from the precatalysts: R

LnM

LnM CHR

the active catalyst

LnM CHR

[2 + 2]

LnM CHR

cycloreversion

cycloaddition [2 + 2]

MLn

MLn

CHR

cycloreversion L nM

cycloaddition

Catalytic cycle: LnM

LnM

[2 + 2]

LnM

cycloreversion

MLn

cycloaddition

[2 + 2]

MLn

cycloreversion

cycloaddition

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_217, © Springer-Verlag Berlin Heidelberg 2009

LnM

466

Example 13 10 mol% (PCy3)2Cl2Ru=CHPh O

O

0.3 eq. Ti(Oi-Pr)4 CH2Cl2, 40 oC, 93%

C11H23

O

O

C11H23

Example 25 Cy3P Ph Cl Ru Cl Mes N N Mes

E E

E

E

45 oC, 60 min., 100%

E = CO2Et Example 37 MesN Cl cat. =

O O

NMes Ru

O

Cl O

O

O

O

1. cat. PhH (0.07 mM) 80 oC, then air 2. 10% Pd/C, H2, EtOAc, rt 80−85%

OBn

OBn

Example 49

O

OBz H

O

5.4 mol%

Cy3P Ph Cl Ru Cl Mes N N Mes

O O

CH2Cl2, rt, 73%

H

5 mol%

Cy3P Ph Cl Ru Cl Mes N N Mes

CH2Cl2, rt, 93%, > 10:1 E:Z

OBz

O O

H

H OBz

467

Example 510

TBSO

O O O

O

O

15 mol% Grubbs II TBSO

O

O

toluene, 110 oC, 78%

single isomer

O TES

O

OTES

Example 612 1. 1 mol% N Mo

N Cl N

Ph

O Cl

N

TBSO PhH, rt, 1 h

N H

N H 2. H2, Pd/C, 81%, 96% ee

References Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875–3886. Richard Schrock is a professor at MIT. He shared the 2005 Nobel Prize in Chemistry with Robert Grubbs of Caltech and Yves Chauvin of Institut Français du Pétrole in France for their contributions to metathesis. 2. Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452. (Review). 3. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247–2250. 4. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781– 10787. 5. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2000, 41, 8635–8638. 6. Thiel, O. R. Alkene and alkyne metathesis in organic synthesis. In Transition Metals for Organic Synthesis (2nd Edn.), 2004, 1, pp 321–333. (Review). 7. Smith, A. B., III; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–14874. 8. Hoveyda, A.H.; Zhugralin, A. R. Nature 2007, 450, 243–251. (Review). 9. Marvin, C. C.; Clemens, A. J. L.; Burke, S. D. Org. Lett. 2007, 9, 5353–5356. 10. Keck, G. E.; Giles, R. L.; Cee, V. J.; Wager, C. A.; Yu, T.; Kraft, M. B. J. Org. Chem. 2008, 73, 9675–9691. 11. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem. Eur. J. 2008, 14, 5716–5726. (Review). 12. Sattely, E. S.; Meek, S. J.; Malcolmson, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 943–953. 1.

468

Ritter reaction Amides from nitriles and alcohols in strong acids. General scheme: O

H

R2 CN

R1 OH

R1

R2

N H

e.g.:

OH

H

O

H2SO4

OH

H3C CN

:N

E1

OH2

N H

H2O

H2O

N

nitrilium ion :OH2

OH2

N H

N

N

N

O

OH

H

Similarly: O

H2SO4 H3C CN

N H

H2O

Example 13 H

MeOCHN

OH

H

H2SO4

OC

Cr CO CO

MeCN 89%

OC

Cr CO CO

Example 24 CH3

N

CH3

t-BuOH, conc. H2SO4

CN

70−75 oC, 75 min., 97%

O

N HN

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_218, © Springer-Verlag Berlin Heidelberg 2009

469

Example 35 NO2 NO2 Pt electrode, E = 2.5 V CH3CN, LiClO4 O

H2O, 56%, dr 8:2

O O2N OH

O2N

N H

Example 46 fuming H2SO4, CH3CN, rt, 30 min., O

then H2O, 100 oC, 2 h, 77%

OH NH2

References (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045−4048. (b) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048−4050. 2. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 3. Top, S.; Jaouen, G. J. Org. Chem. 1981, 46, 78−82. 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem. 1989, 54, 2242−2244. 5. Le Goanvic, D; Lallemond, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001, 42, 5175−5176. 6. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906−5925. 7. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575−1577. 8. Concellón, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6, 4499−4501. 9. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005, 212−216. 10. Brewer, A. R. E. Ritter reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 471−476. (Review). 11. Baum, J. C.; Milne, J. E.; Murry, J. A.; Thiel, O. R. J. Org. Chem. 2009, 74, 2207−2209. 1.

470

Robinson annulation Michael addition of cyclohexanones to methyl vinyl ketone followed by intramolecular aldol condensation to afford six-membered α,β-unsaturated ketones.

O

O

O

base

R

R

methyl vinyl ketone (MVK) O

H

O

O enolate

R

Michael

O

isomerization

addition

formation

R

R

O

B: :B H B aldol

O

HO

O

addition

O

O

− H2 O

H

dehydration R

R

R

Example 1, Homo-Robinson7

NaOMe

MVK, AcOH, BF3•OEt2 −20 oC, 97%

TMSO

O

O

1.5 equiv Et2Zn 1.1 equiv CH2I2

2.5 equiv LDA, TMSCl THF, −78 oC

98%

O

TMSO

Et2O, 0 oC

1. 2.5 equiv FeCl3, 0 oC 2. NaOAc, reflux 40% for 4 steps

TMSO

O

Example 28 O

O

3 equiv TfOH, P4O10 CH2Cl2, microwave 40 oC, 8 h, 57%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_219, © Springer-Verlag Berlin Heidelberg 2009

O

471

Example 3, Double Robinson-type cyclopentene annulation9 O

OH 10 equiv

CO2R

0.1 equiv FeCl3•6H2O CH2Cl2, 60 oC, 2 d

RO2C OH

O RO2C

O

O conc. H2SO4 0 oC, 1 h

CO2R then rt, 16 h

O

CO2R

RO2C

O

O

Example 410 O

O

O CN

DBU, tol., reflux, 20 h,16%

NC

References Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285–1288. Robert Robinson used the Robinson annulaton in his total synthesis of cholesterol. Here is a story told by Derek Barton about Robinson and Woodward: “By pure chance, the two great men met early in a Monday morning on an Oxford train station platform in 1951. Robinson politely asked Woodward what kind of research he was doing these days; Woodward replied that he thought that Robinson would be interested in his recent total synthesis of cholesterol. Robinson, incensed and shouting ‘Why do you always steal my research topic?’, hit Woodward with his umbrella.”—An excerpt from Barton, Derek, H. R. Some Recollections of Gap Jumping, American Chemical Society, Washington, D.C., 1991. 2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem. 2000, 65, 8093–8096. 4. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S.; Liu, H.-J. Synlett 2001, 214–217. 5. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137–140. 6. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739–741. 7. Yun, H.; Danishefsky, S. J. Tetrahedron Lett. 2005, 46, 3879–3882. 8. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057–5061. 9. Zhang, Y.; Christoffers, J. Synthesis 2007, 3061–3067. 10. Jahnke, A.; Burschka, C.; Tacke, R.; Kraft, P. Synthesis 2009, 62–68. 1.

472

Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles. R2

R2

− H2O

HN

N

R3

R1

R1

OO

R3

O

R1, R2, R3 = alkyl, aryl, heteroaryl R2

H

H R2 N R3

N R1

R3

R1

OO

O

R2

− H2O

N R1

OH

R3

O

Example 13 O H

O

H N

O

Ph3P, I2, Et3N

H CbzHN

O

H

55%

O

N

O

O

CbzHN

Example 24 OTIPS O MeO

OMe H N

O H

N O

HO

OH 1. Dess−Martin, CH2Cl2 2. Ph3P, BrCCl2CCl2Br 3. DBU, CH3CN 4. TBAF, THF 42%

O

OMe O OMe H

N

N

O (+)-hennoxazole A

Example 3, Halogen effect9 H N O

O N H

2 equiv PPh3

O

CCl4, MeCN reflux, 97%

N N

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_220, © Springer-Verlag Berlin Heidelberg 2009

R

473

H N O

O N H

2 equiv PPh3

O

CBr4, MeCN reflux, 68%

N N

Br

Example 410

N O TBDPSO

O

CHO N H

OTBS

1. PPh3, C2Br2Cl4, CH2Cl2 2,6-di-tert-butylpyridine NaHCO3, CH2Cl2, 0 oC 2. Et3N, MeCN, 0 oC to rt 89% for 2 steps

N O TBDPSO

O

OTBS N

References (a) Robinson, R. J. Chem. Soc. 1909, 95, 2167−2174. (b) Gabriel, S. Ber. 1910, 43, 134−138. (c) Gabriel, S. Ber. 1910, 43, 1283−1287. 2. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York, 1986; pp 1−342. (Review). 3. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604−3606. 4. Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558−559. 5. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org. Lett. 2002, 4, 2665−2668. 6. Nicolaou, K. C.; Rao, P. B.; Hao, J.; Reddy, M. V.; Rassias, G.; Huang, X.; Chen, D. Y.-K.; Snyder, S. A. Angew. Chem., Int. Ed. 2003, 42, 1753−1758. 7. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623−2632. 8. Brooks, D. A. Robinson–Gabriel Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249−253. (Review). 9. Yang, Y.-H.; Shi, M. Tetrahedron Lett. 2005, 46, 6285–6288. 10. Bull, J. A.; Balskus, E. P.; Horan, R. A. J.; Langner, Martin; Ley, Steven V. Angew. Chem., Int. Ed. 2006, 45, 6714−6718. 1.

474

Robinson−Schöpf reaction 1,4-Diketone condensations with primary amines to give tropinones.

CO2H

N

CHO NH2

2 CO2↑

O

2 H2O

CHO CO2H

O

H NH2:

HN:

H

− H2O

imine

O

HO2C

CO2H

OH

O

formation

N CHO

CHO

CHO O

O HO2C

HO2C

CO2H

O

CO2H − H2O

H

HO2C

CO2H

:N

:N H H

N OH

O

hemiaminal O

N

H O

HO2C

N decarboxylation

CO2↑ HO2C

O

N

OH

N

N CO2↑

O H

O

O

O

OH

Example 15

OH NH2

OMe O KCN, citric acid, H2O, rt, 24−48 h

Ph

MeO

Ph H

NC

then EtOH, reflux, 96 h

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_221, © Springer-Verlag Berlin Heidelberg 2009

N

O

475

Example 29 O CHO CHO

CO2H NH2

OH

O

N THF, rt 72 h, 51%

CO2H

OH

References Robinson, R. J. Chem. Soc. 1917, 111, 762–768. Paquette, L. A.; Heimaster, J. W. J. Am. Chem. Soc. 1966, 88, 763–768. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765–4769. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105, 7754–7755. 5. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175–6178. 6. Villacampa, M.; Martínez, M.; González-Trigo, G.; Söllhuber, M. M. J. Heterocycl. Chem. 1992, 29, 1541–1544. 7. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med. Chem. Lett. 1992, 2, 519–522. 8. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115– 3116. 9. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52, 1350–1352. 10. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175–5177. 1. 2. 3. 4.

476

Rosenmund reduction Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned palladium catalyst. Without this poisoning, the resulting aldehyde may be further reduced to the corresponding alcohol. O R

O

H2 Cl

Pd Pd

R

Pd−BaSO4

H

Pd Pd H H

Pd Pd H H

H Pd H

H H

O R

O

Pd(0) Cl

oxidative addition

O R

R

H Pd H Pd

Cl

ligand exchange

O

reductive Pd

H

Pd(0) elimination

R

H

Example 14 H2/Pd or Pd/BaSO4 2,6-dimethylpyridine, THF

O R

Cl

O R

or H2/Pd−C/quinoline−S, PhH 74−97%

H

Example 26 NBoc2

NBoc2

Me2N Cl

HO

CO2t-Bu

CO2t-Bu

Cl O

O

NBoc2

H2, 5% Pd/C 2,6-lutidine

H

THF, 2 h, 78%

CO2t-Bu O

Example 39 O

1. SOCl2, cat. DMF, reflux, 4 h OH

2. H2, 5% Pd/C, EtOAc, 53%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_222, © Springer-Verlag Berlin Heidelberg 2009

477

O H

References Rosenmund, K. W. Ber. 1918, 51, 585–594. Karl Wilhelm Rosenmund was born in Berlin, Germany in 1884. He was a student of Otto Diels and received his Ph.D. In 1906. Rosenmund became professor and director of the Pharmaceutical Institute in Kiel in 1925. 2. Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362–377. (Review). 3. Tsuji, J.; Ono, K.; Kajimoto, T. Tetrahedron Lett. 1965, 6, 4565–4568. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767–768. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem. 1983, 48, 4436–4438. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405– 410. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226–232. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416–424. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851–4858. 10. Ancliff, R. A.; Russell, A. T.; Sanderson, A. J. Chem. Commun. 2006, 3243–3245. 1.

478

Rubottom oxidation α-Hydroxylation of enolsilanes. OSiR3

O 1. m-CPBA

OH

2. K2CO3, H2O

Ar Ar

O R3SiO

O O H

‡

R3Si

O

O

Prilezhaev

R3SiO

O

epoxidation

O

O

H

H

The “butterfly” transition state R3Si

:O

H O

O

SiR3 OH

O K2CO3, H2O

OH

hydrolysis

Example 12

N

2.5 eq m-CPBA ClCH2CH2Cl

OSiMe3 CO2Me

O N

OH CO2Me

0 oC to rt, 1 h, 80%

Example 23 1. m-CPBA, NaHCO3, pentane, 0 oC

TMSCl, NaI O

Et3N, rt, 91% OTMS

OH

2. aq. K2CO3, 0 oC, 20 h, 80% O

Example 34

TMSO

OTBS O

m-CPBA TMSO

TMSO TMSO

OTBS

O SiO2

63%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_223, © Springer-Verlag Berlin Heidelberg 2009

HO TMSO

OTBS

479

Example 45 Me

Me H Me

H O

H Me

1. LDA, TMSCl 2. m-CPBA, NaHCO3 3. K2CO3, MeOH 72%

H

Me

H HO O

H Me

References Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 15, 4319−4322. George Rubottom discovered the Rubottom oxidation when he was an assistant professor at the University of Puerto Rico. He is now a grant officer at the National Science Foundation. 2. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563−2366. 3. Jauch, J. Tetrahedron 1994, 50, 12903−12912. 4. Crimmins, M. T.; Al-awar, R. S.; Vallin, I. M.; Hollis, W. G., Jr.; O’Mahoney, R.; Lever, J. G.; Bankaitis-Davis, D. M. J. Am. Chem. Soc. 1996, 118, 7513–7528. 5. Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B. Tetrahedron Lett. 1997, 38, 195–198. 6. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org. Chem. 2004, 69, 2454−2460. 7. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143−151. (Review). 8. He, J.; Tchabanenko, K.; Adlington, R. M.; Cowley, A. R.; Baldwin, J. E. Eur. J. Org. Chem. 2006, 4003−4013. 9. Wolfe, J. P. Rubottom oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 282−290. (Review). 10. Wang, H.; Andemichael, Y. W.; Vogt, F. G. J. Org. Chem. 2009, 74, 478−481. 1.

480

Rupe rearrangement Acid-catalyzed rearrangement of tertiary α-acetylenic (terminal) alcohols, leading to the formation of α,β-unsaturated ketones rather than the corresponding α,βunsaturated aldehydes. Cf. Meyer−Schuster rearrangement.

OH

O H+ , H2 O

H OH

OH2

H

− H2 O

− H

dehydration

H2O:

H

:OH

protonation H

O H

H

tautomerization

H H

Example 14 O

conc. H2SO4 OH

CHCl3, HOAc, reflux, 1 h

Example 28 O OH HCO2H, reflux

Me

CH3

Me

15 min., 42%

Example 39 O H3C OH H H O

H

H3 C

A-252C H+ resin EtOAc, reflux

H

4 h, 78%

H O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_224, © Springer-Verlag Berlin Heidelberg 2009

481

References Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429−438. (Review). Hasbrouck, R. W.; Anderson Kiessling, A. D. J. Org. Chem. 1973, 38, 2103−2106. Baran, J.; Klein, H.; Schade, C.; Will, E.; Koschinsky, R.; Bäuml, E.; Mayr, H. Tetrahedron 1988, 44, 2181−2184. 5. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389–7392. 6. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997, 62, 2505–2511. 7. Yadav, J. S.; Prahlad, V.; Muralidhar, B. Synth. Commun. 1997, 27, 3415−3418. 8. Takeda, K.; Nakane, D.; Takeda, M. Org. Lett. 2000, 2, 1903–1905. 9. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc. Res. Dev. 2002, 6, 216−219. 10. Mullins, R. J.; Collins, N. R. Meyer–Schuster Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 305−318. (Review). 1. 2. 3. 4.

482

Saegusa oxidation Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis. Me3Si

O

O

0.5 Pd(OAc)2 Me

0.5 p-benzoquinone benzene, rt, 3 h, 91%

Me

The mechanism is similar to that of the Wacker oxidation (page 564). AcO

AcO Pd(II) OAc Me3Si

Me3Si

O:

O

O Pd(II) OAc

Me

OSiMe3

Me

Me

O

O

O Pd(II) OAc

H

β-hydride

Pd

elimination

H Me

HOAc

Pd(0)

OAc Me

Me

Regenerating the Pd(II) oxidant: OH

O Pd(0)

Pd(OAc)2

2 HOAc OH

O

Larock reported regeneration of the Pd(II) oxidant using oxygen:4 O2

Pd(0)

Pd

O O

HOAc HOOPdOAc

O OSiMe3

HOOSiMe3

Pd(II)(OAc)2

Example 13 OMe

OMe O

O

O Me3SiCl, Et3N

O H H

O

O

O

TMSO

CH3OCH2CH2OCH3 rt, 3 h, 74%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_225, © Springer-Verlag Berlin Heidelberg 2009

H H

O

O

483

OMe O

Pd(OAc)2, p-benzoquinone

O

O H

CH3CN, rt, 60 oC, 53% H

O

O

Example 28 O

LDA, TBSCl

O

HMPA−THF −78 to 0 oC, 93%

O

O

O

Pd(OAc)2, O2

O OTBS

O

DMSO, 80 oC 48 h, 77%

O

Example 310 H Me

O

Me

OTES

Pd(OAc)2, DMSO

O

Me

0 oC to rt, 12 h, 81% O

Me

References Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011–1013. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5350–5356. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun. 1990, 20, 989–997. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423–2426. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed. 1999, 38, 2015–2016. The authors proposed a sandwiched Pd(II) as a possible alternative pathway. 6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217–3220. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596–7597. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343, 618–623. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831–836. 10. Angeles A. R; Waters, S. P.; Danishefsky S. J. J. Am. Chem. Soc. 2008, 130, 13765– 13770. 1. 2.

484

Sakurai allylation reaction Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi–Sakurai reaction. The allylsilane will add to the carbonyl compound directly if the electrophile (carbonyl group) is not part of an α,βunsaturated system (Example 2), giving rise to an alcohol. O O

TiCl4

SiMe3

TiCl4 O

:

complexation

O

O

Cl TiCl3

TiCl3

Michael addition SiMe3

SiMe3

Cl

The β-carbocation is stabilized by the β-silicon effect O

TiCl3

silicon cleavage

O H2O

Me3Si Cl

workup

Example 12 TMS

EtAlCl2, Tol. 0 oC, 50%

O

O

Example 26 O

OH CHO

Br

SiMe3

TiCl4, CH2Cl2

O Br

rt, 10 min., 67% OTIPS

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_226, © Springer-Verlag Berlin Heidelberg 2009

9:1 dr OTIPS

485

Example 39 SiMe3 H

Me H

OPMB H3C

Ba(OH)2•8H2O

BF3•OEt2

OPMB

H

o OC(O)CO2Me −78 C, 4 h H

OHC

H

CO2Et

OH

o

CO2Et

0 C, 2 h, 62%

CHO H

O

O

H Me

OPMB

OC(O)CO2Me

H

Example 410 HO H

H

H O

H O

SiMe3 BnN O

BnN

NBn OH

BF3•OEt2, CH2Cl2 rt, 64%

NBn

O

References Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295–1298. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615–3618. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymmetry 2001, 12, 301–307. 4. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744–8752. 5. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185–3196. 6. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155–13164. 7. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591–8603. 8. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394–396. 9. Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.; Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 6361–6363. 10. Norcross, N. R.; Melbardis, J. P.; Solera, M. F.; Sephton, M. A.; Kilner, C.; Zakharov, L. N.; Astles, P. C.; Warriner, S. L.; Blakemore, P. R. J. Org. Chem. 2008, 73, 7939– 7951. 1. 2. 3.

486

Sandmeyer reaction Haloarenes from the reaction of a diazonium salt with CuX. ArN2

CuX

Y

Ar

X

X = Cl, Br, CN

e.g.: CuCl ArN2

N2↑

Cl

Ar

CuCl2

Ar Cl

CuCl

Example 14 Cl

Cl

Cl N2 Cl Cl

1. FeCl3

DMSO, rt N2

2. CuCl2 81%

Cl

Cl

CuCl4

97% Cl

2

Example 27 CF3

CF3

CF3

1. H2SO4 NH2

CuCN, NaCN

2. NaNO2

N

N

Na2CO3, 50%

CN

Cl

Cl

Cl

Example 38 OMe

OMe OH

NaNO2, CuBr 55%

H2 N

OH Br

Example 49

O

NO2

O N H

N O

1. HOAc, H2O, H2SO4 reflux, 2 h 2. NaNO2, 0 oC 3. CuCN, 50 oC 50−58%

O

NC

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_227, © Springer-Verlag Berlin Heidelberg 2009

NO2

N O

487

References Sandmeyer, T. Ber. 1884, 17, 1633. Traugott Sandmeyer (1854−1922) was born in Wettingen, Switzerland. He apprenticed under Victor Meyer and Arthur Hantzsch although he never took a doctorate. He later spent 31 years at the company J. R. Geigy, which is now part of Novartis. 2. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645–647. 3. Merkushev, E. B. Synthesis 1988, 923–937. (Review). 4. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39, 9567–9570. 5. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc., Perkin Trans. 2 2002, 1135–1150. 6. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573–583. 7. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059– 1064. 8. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437–2439. 9. LaBarbera, D. V.; Bugni, T. S.; Ireland, C. M. J. Org. Chem. 2007, 72, 8501–8505. 10. Gehanne, K.; Lancelot, J.-C.; Lemaitre, S.; El-Kashef, H.; Rault, S. Heterocycles 2008, 75, 3015–3024. 1.

488

Schiemann reaction Fluoroarene formation from arylamines. Also known as the Balz−Schiemann reaction.

Δ

ArN2 BF4

HO

N

H2O

N

O

N

H N

:

Ar

N

BF3

HO

N O

O

Ar

Δ

Ar N N

N2↑

F

H2O

O:

O

NH2

H2O

N

Ar

N

N2↑

ArN2 BF4

Ar

O

O

H

OH

N

N

N

O

N

O

:

O :

Ar

HBF4 O

HBF4

HNO2

Ar NH2

N

Ar

Ar

F BF3

OH2

N

F

BF3

Example 14 F

NH2 N

N F

N

NaNO2, HBF4, H2O

N

N

−10 to 0 oC, 25% F N N R R = 2,3-5-tri-O-acetyl-β-D-ribofuranose

N R

Example 2, Photo-Schiemann reaction6 F HN

NHBoc N

F

1. HBF4 2. NaNO2

HN

3. hv

F

F N

HN

N 8%

36%

Example 3, Photo-Schiemann reaction8 H2N HN

CO2Et N

NO+BF4− [bmim][BF4]

BF4−N2+ HN

CO2Et N

hv

F

[bmim][BF4] 0 oC, 24 h, 56%

HN

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_228, © Springer-Verlag Berlin Heidelberg 2009

CO2Et N

489

Example 410 NH2 S

CO2Me

N2+BF4−

NaNO2 HBF4 93%

S

CO2Me

F

160−200 oC sand, 67%

S

CO2Me

References Balz, G.; Schiemann. G. Ber. 1927, 60, 1186−1190. Günther Schiemann was born in Breslau, Germany in 1899. In 1925, he received his doctorate at Breslau, where he became an assistant professor. In 1950, he became the Chair of Technical Chemistry at Istanbul, where he extensively studied aromatic fluorine compounds. 2. Roe, A. Org. React. 1949, 5, 193−228. (Review). 3. Sharts, C. M. J. Chem. Educ. 1968, 45, 185−192. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396−1399. 5. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31−34. 6. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107, 147−152. 7. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693−720. 8. Heredia-Moya, J.; Kirk, K. L. J. Fluorine Chem. 2007, 128, 674−678. 9. Gribble, G. W. Balz-Schiemann reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 552−563. (Review). 10. Pomerantz, M.; Turkman, N. Synthesis 2008, 2333−2336. 1.

490

Schmidt rearrangement The Schmidt reactions refer to the acid-catalyzed reactions of hydrazoic acid with electrophiles, such as carbonyl compounds, tertiary alcohols and alkenes. These substrates undergo rearrangement and extrusion of nitrogen to furnish amines, nitriles, amides or imines.

R

O

HN3

O 1

R

2

R2

H+

N H

N2 ↑

R1

N

N O R1

O

H R2

R1

H

HN3

N

HO N3 R1

R2

N

H

H2O N

HO N

R2

R

1

R

R1

2

R2

azido-alcohol R1

− H2O

R1

:

N N N

N2↑

migration

:

R2

R1 N

R2 H2 O

nitrilium ion intermediate (Cf. Ritter intermediate) R1

HO H

N

O tautomerization R2

2

R

Example 1, A classic example3 O CO2Et

H N

NaN3 MeSO3H 21%

CO2Et

O

Example 25 O NaN3, H2SO4

H N

CHCl3, 92%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_229, © Springer-Verlag Berlin Heidelberg 2009

O

N H

R1

491

Example 3, Intramolecular Schmidt rearrangement6 OH

OH

TfOH, CH2Cl2 N

0 oC, 79%

O

O

N3

Example 4, Intramolecular Schmidt rearrangement8 N3 O

H O

H O

TiCl4

N H

82% Et

O

Et

Example 5, Intermolecular Schmidt rearrangement9 O NC

O N

HO2C

NaN3, CHCl3

HO2C

NH

H N

O

N

N

conc. H2SO4 84% OMe

OMe

OMe

0%

References (a) Schmidt, K. F. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (1887−1971) collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. (b) Schmidt, K. F. Ber. 1924, 57, 704−706. 2. Wolff, H. Org. React. 1946, 3, 307−336. (Review). 3. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667−2573. 4. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316−4318. 5. Johnson, P. D.; Aristoff, P. A.; Zurenko, G. E.; Schaadt, R. D.; Yagi, B. H.; Ford, C. W.; Hamel, J. C.; Stapert, D.; Moerman, J. K. Bioorg. Med. Chem. Lett. 2003, 13, 4197−4200. 6. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475−5481. 7. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260−11261. 8. Iyengar, R.; Schidknegt, K.; Morton, M..; Aubé, J. J. Org. Chem. 2005, 70, 10645−10652. 9. Amer, F. A.; Hammouda, M.; El-Ahl, A. A. S.; Abdel-Wahab, B. F. Synth. Commun. 2009, 39, 416−425. 10. Wu, Y.-J. Schmidt reactions. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 353−372. (Review). 1.

492

Schmidt’s trichloroacetimidate glycosidation reaction Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phenols.

HN O

O

cat. NaH AcO

CCl3

OH

OAc OCH3

Cl3CCN

AcO

O

O

HO Ar

OAc OCH3

BF3•OEt2

AcO

Ar O

OAc OCH3

trichloroacetimidate N O AcO

O

CCl3

H H

O

deprotonation

BF3•OEt2

O

H2↑

OAc

AcO

OCH3

OAc OCH3

BF3•OEt2 HN

CCl3 neighboring

O

O

AcO CH3O

O

O

group assistance

H O Ar :

Ar O

O Cl3C

NH2

O

O

O

AcO CH3O

O

AcO

OAc OCH3

Example 15 HN O AcO

I

CCl3 O

OAc OCH3

I

CO2Me

HO

OMe

BF3•OEt2, 4 Å MS CH2Cl2, −50 oC, 95%

O

CO2Me OMe

O

OMe AcO

OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_230, © Springer-Verlag Berlin Heidelberg 2009

OAc OCH3

493

Example 27

BnO

OH

O

BnO BnO

AcO

BnO O

NH

BF3•OEt2 CH2Cl2/hexane −20 oC, 68%

CCl3

BnO BnO

O O AcO

Example 39

PF6

OAc O

AcO AcO AcO

HO O

CCl3

AcO

N H2

NH

0.2 equiv TMSOTf, CH2Cl2, −15 oC, 5 min.

AcO AcO

t-Bu

PF6

OAc O

O t-Bu

PF6 O 40%

N H2

AcO

AcO AcO

O

O

N H2

O 30%

References (a) Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203−218. (b) Schmidt, R. R. Angew. Chem., Int. Ed. 1986, 25, 212−235. (Review). 2. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992, 114, 3134−3136. 3. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503−1531. (Review). 4. Nicolaou, K. C. Angew. Chem., Int. Ed. 1993, 32, 1377−1385. (Review). 5. Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7593−611. 6. Fürstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. 2002, 41, 2097−2101. 7. Yan, L. Z.; Mayer, J. P. J. Org. Chem. 2003, 68, 1161−1162. 8. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol. Chem. 2005, 3, 1501−1507. 9. Steinmann, A.; Thimm, J.; Thiem, J. Eur. J. Org. Chem. 2007, 66, 5506−5513. 10. Coutrot, F.; Busseron, E.; Montero, J.-L. Org. Lett. 2008, 10, 753−756. 1.

494

Shapiro reaction The Shapiro reaction is a variant of the Bamford−Stevens reaction. The former uses bases such as alkyl lithium and Grignard reagents whereas the latter employs bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. Consequently, the Shapiro reaction generally affords the less-substituted olefins (the kinetic products), while the Bamford−Stevens reaction delivers the more-substituted olefins (the thermodynamic products). R1 R

H N

2

N

Ts

E R3

R1

Bu R1

H N

N

R2 H Ts

R1 N

− N2

N

N R

N

Ts

3

Bu

R3

R2

R

2

then E

R3

R2 H

R1

2 n-BuLi

R1 E

R2

R1 R2

R3

R3

E R3

Example 12

NNHTs

MeLi, Et2O 2%

98%

Example 23 NNHTs MeLi, Et2O−PhH 75−80%

Example 37 O MeO

OTBDPS H H

H

H O

OMe

1. TsNHNH2, MeOH, THF

MeO

2. n-BuLi, THF, –78 °C to rt 3. aqueous workup 69%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_231, © Springer-Verlag Berlin Heidelberg 2009

OTBDPS H H

H

H O

OMe

495

Example 48

H

NHTris N

1. n-BuLi

O

3.

Me

Me Me O

O Ph

Me

O

H

2. MgBr2•OEt2 Me

Me HO

O Ph

Me Me 55% yield one diastereomer

References Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471–472. Robert H. Shapiro was an assistant professor at the University of Colorado. He was not given tenure despite getting a reaction named after him. 2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734–5735. 3. Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.; Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762−4763. 4. Shapiro, R. H. Org. React. 1976, 23, 405−507. (Review). 5. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55–59. (Review). 6. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1−83. (Review). 7. Grieco, P. A.; Collins, J. L.; Moher, E. D.; Fleck, T. J.; Gross, R. S. J. Am. Chem. Soc. 1993, 115, 6078–6093. 8. Tamiya, J.; Sorensen, E. J. Tetrahedron 2003, 59, 6921–6932. 9. Wolfe, J. P. Shapiro reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., eds, John Wiley & Sons: Hoboken, NJ, 2007, pp 405−413. 10. Bettinger, H. F.; Mondal, R.; Toenshoff, C. Org. Biomol. Chem. 2008, 6, 3000–3004. 1.

496

Sharpless asymmetric amino-hydroxylation Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectivity may be controlled by ligand. Nitrogen sources (X−NClNa) include: O

R

S

O

O

O

O

NClNa

BnO EtO

NClNa

NClNa

O NBrLi

TMS

NClNa

R = p-Tol; Me

R1 R

chiral ligand K2OsO2(OH)4

R

ClNaN−X t-BuOH, H2O

HO

R1 NHX

The catalytic cycle: OsO4

ClN−X

R1

R HO

O O Os N X O

NHX

L*

H2O

O O Os N X O L*

R O O Os N ON X X

R1 R1 R

L* R ClN−X

O O Os N O L* X

R1

R O O Os N O L* X

R1

Example 11b 5 mol% (DHQD)2PHAL 4 mol% K2OsO2(OH)4

O BnO

NClNa

O NH BnO

n-PrOH/H2O (1:1), 63% ee 51%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_232, © Springer-Verlag Berlin Heidelberg 2009

OH

497

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N

N

N N O

O

H O

O N

N

Example 22

CO2Et

BnOCONH2 NaOH, t-BuOCl (DHQD)2AQN

OH CO2Et

K2OsO2(OH)4 n-PrOH/H2O (1:1) BnO rt, 12 h, 45%, 87% ee

BnO

NHCbz

Example 36 F

F F

NaOH, urethane K2OsO2(OH)4 (DHQD)2PHAL

Me

1,3-dichloro-5,5-dimethyl hydantoin n-PrOH/H2O

Me

Me HN

OH OEt

O

HO EtO

NH O

F 1. Cs2CO2, MeOH 2. H2SO4

O

HN O

References 1.

(a) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544−2548. K. Barry Sharpless (USA, 1941−) shared the Nobel Prize in Chemistry in 2001 with Herbert William S. Knowles (USA, 1917−) and Ryoji Noyori (Japan, 1938−) for his work on chirally catalyzed oxidation reactions. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 2813−2817. (c) Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. 1997, 36, 2637−2640. (d) Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998, 2, 243−260. (Review). (e) Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379−8385. (f) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783−786.

498

2.

Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.; Jain, N. F.; Ramanjulu, J. M.; Braese, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602−2621. 3. Lohr, B.; Orlich, S.; Kunz, H. Synlett 1999, 1139−1141. 4. Boger, D. L.; Lee, R. J.; Bounaud, P.-Y.; Meier, P. J. Org. Chem. 2000, 65, 6770−6772. 5. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221−2223. 6. Barta, N. S.; Sidler, D. R.; Somerville, K. B.; Weissman, S. A.; Larsen, R. D.; Reider, P. J. Org. Lett. 2000, 2, 2821−2824. 7. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn., Ojima, I., Ed.; Wiley−VCH: New York, 2000, 399. (Review). 8. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 2733−2746. (Review). 9. Rahman, N. A.; Landais, Y. Cur. Org. Chem. 2000, 6, 1369−1395. (Review). 10. Nilov, D.; Reiser, O. Recent Advances on the Sharpless Asymmetric Aminohydroxylation. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds.; Wiley−VCH: Weinheim, Germany 2003, 118−124. (Review). 11. Bodkin, J. A.; Bacskay, G. B.; McLeod, M. D. Org. Biomol. Chem. 2008, 2544−2553. 12. Wong, D.; Taylor, C. M. Tetrahedron Lett. 2009, 50, 1273−1275.

499

Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands. AD-mix-β

HO (DHQD)2-PHAL

RS RL

RS

K2OsO2(OH)4

RM H

K2CO3, K3Fe(CN)6

RL (DHQ)2-PHAL

OH

RL H

RS R M H

HO

AD-mix-α

RM

OH

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine: N

N

N N O

O O

O N

N

The concerted [3 + 2] cycloaddition mechanism:5 O

O Os O O

O O Os O O L

O O Os O O L

L

O O Os O O L

[3 + 2]-like cycloaddition

hydrolysis

HO HO

Example 12 O

OH

EtO2C N3

K2OsO2(OH)4 (DHQD)2PHAL

OH

O

OH

EtO2C

K2CO3, MeSO2NH2 t-BuOH/H2O (1:1) rt, 12 h, 90% de

OH

N3

Example 24

CO2Et BnO

OH

1. AD-mix-β, MeSO2NH2 t-BuOH/H2O (1:1), rt, 12 h 2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee

CO2Et BnO

Nos = nosylate = 4-nitrobenzenesulfonyl

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_233, © Springer-Verlag Berlin Heidelberg 2009

ONos

500

The catalytic cycle: (the secondary cycle is shut off by maintaining a low concentration of olefin): R R O O O Os O O R

R

L

H2O

Secondary cycle low ee R R

R

OH

R

OH

low ee R R O O O Os O O

R

L R

NMM

NMO

O O Os L O O

H2O

R

OH

R

OH

R

Primary cycle high ee

L

R

high ee O

O Os O O

Example 39 OMe OH

OMe Me

CO2Et

O O

AD-mix-α t-BuOH/H2O (1:1) 93%, 97% ee

Me

CO2Et OH

O O

501

Example 410 K2OsO2(OH)4 (DHQD)2PHAL NMO acetone/H2O 89%

OH

OH

70% ee

References (a) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968−1970. (b) Wai, J. S. M.; Markó, I.; Svenden, J. S.; Finn, M. G.; Jacobsen, E. N.; Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 1123−1125. 2. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096−7699. 3. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483−2547. (Review). 4. Rao, A. V. R.; Chakraborty, T. K.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett. 1994, 35, 5043−5046. 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319−329. (Mechanism). 6. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1997, 119, 9907−9908. (Mechanism). 7. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024−2032. (Review, Nobel Prize Address). 8. Zhang, Y.; O’Doherty, G. A. Tetrahedron 2005, 61, 6337−6351. 9. Chandrasekhar, S.; Reddy, N. R.; Rao, Y. S. Tetrahedron 2006, 62, 12098−12107. 10. Ferreira, F. C.; Branco, L. C.; Verma, K. K.; Crespo, J. G.; Afonso, C. A. M. Tetrahedron: Asymmetry 2007, 18, 1637−1641. 11. Ramon, R.; Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2007, 18, 2797−2802. 12. Krishna, P. R.; Reddy, P. S. Synlett 2009, 209−212. 1.

502

Sharpless asymmetric epoxidation Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-iso-propoxide, and optically pure diethyl tartrate. R1

R

t-Bu−O−OH, Ti(Oi--Pr)4 OH

R2 R1

R

t-Bu−O−OH, Ti(Oi-Pr)4 OH

R2

L-(+)-diethyl tartrate

D-(−)-diethyl tartrate

R1 O R2

R OH

R1 O R2

R OH

The catalytic cycle:

Oi-Pr LnTi Oi-Pr

OH

O

t-Bu−O−OH O

OH LnTi

O O

t-Bu

* O

LnTi O O * t-Bu

O

LnTi O t-Bu

O * * Ln*Ti O O t-Bu

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_234, © Springer-Verlag Berlin Heidelberg 2009

* O L*n*Ti O O * t-Bu

503

The putative active catalyst and the transition state:

EtO O

CO2Et

EtO2C

OEt O

O Ti

Oi-Pr

O

Ti

i-PrO

O Ti

O

O

i-PrO

CO2Et

O

O

O

O

t-Bu

EtO2C Oi-Pr

Example 13 O Me OH crude: 88% yield, 92.3 % ee recrystallization: 73% yield, > 98% ee

Ti(Oi-Pr)4, 4 Å MS, (+)-DET Me

OH

t-BuOOH, CH2Cl2 −20 °C

Example 23 (−)-DIPT, Ti(Oi-Pr)4

O

OH

OH

TBHP, 3 Å MS 50−60%, 88−92% ee

Example 311 OEt

OH

O

L-(+)-DIPT, Ti(Oi-Pr)4 TBHP, EtOAc 89%, 98% ee

H

O

OH (R,R)

H

NH

(S,S)-reboxetine

Example 412 BnO BnO BnO

BnO D-(−)-DIPT, Ti(Oi-Pr)4

O BnO

OH

TBHP, 4 Å MS 70%, > 95% ee

BnO BnO

O BnO

O OH

504

References 1.

2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12. 13.

(a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974−5976. (b) Williams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430−6433. (c) Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106−113. Pfenninger, A. Synthesis 1986, 89−116. (Review). Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765−5780. Corey, E. J. J. Org. Chem. 1990, 55, 1693−1694. (Review). Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Ed,; Pergamon Press: New York, 1991; Vol. 7, Chapter 3.2. (Review). Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,; VCH: New York, 1993; Chapter 4.1, pp 103−158. (Review). Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1−299. (Review). Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I., ed.; Wiley-VCH: New York, 2000, 231−285. (Review). Palucki, M. Sharpless−Katsuki Epoxidation. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 50−62. (Review). Henegar, K. E.; Cebula, M. Org. Proc. Res. Dev. 2007, 11, 354−358. Pu, J.; Franck, R. W. Tetrahedron 2008, 64, 8618−8629. Knight, D. W.; Morgan, I. R. Tetrahedron Lett. 2009, 50, 35−38.

505

Sharpless olefin synthesis Olefin synthesis from the syn-oxidative elimination of o-nitrophenyl selenides, which may be prepared using o-nitrophenyl selenocyanate and Bu3P, among other methods. NO2 SeCN O

R

R

OH

R

Se NO2

Bu3P, THF, rt

R

O

H

:

Bu3P: NO2

NO2 Se

SN 2

CN

Se PBu 3

CN

NO2 Se

R

O

PBu3

R

O PBu3

Se NO2

NO2

O

R H

Se O

syn-elimination

Se R

OH

NO2

Example 13 OH H

H

1. Bu3P, o-O2NPhSeCN, THF, rt 2. CSA, PhH, rt to 70 oC

OH

H

H

3. m-CPBA, 2,4,6-collidine CH2Cl2, 0 oC, 42%

N

O

N H

MeO

Example 26 1. Bu3P, o-O2NPhSeCN THF, rt, 6 h, 97%

MeO O

O

O OH OH

MeO

OH

O 2. m-CPBA, Et3N, CH2Cl2, −78 oC 86%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_235, © Springer-Verlag Berlin Heidelberg 2009

O

O OH OH

506

Example 39

O

NO2 SeCN

O 1.

O

OH

O

O

O H HO

O

n-Bu3P, THF, rt, 78%

O

H OH OMe

2. aq. H2O2, THF, pyr. −40 oC to rt, 90%

H HO

H OMe

Example 410 NO2 SeCN 1.

HO H O H

H O

n-Bu3P, THF, rt O

2. aq. H2O2, THF, 40 oC 90% 2 steps

H

O

References (a) Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979−1982. (b) Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947−949. 2. (a) Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120−122. (b) Grieco, P. A.; Miyashita, M. Tetrahedron Lett. 1974, 1869−1871. (c) Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597−1599. (d) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485−1486. (e) Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210−5219. 3. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431−2449. 4. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1−296. (Review). 5. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741−4743. 6. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493−1507. 7. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004, 2905−2916. 8. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org. Chem. 2004, 69, 7294−7302. The authors observed the concurrent epoxidation of a tri-subsituted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process. 9. Paquette, L. A.; Dong, S.; Parker, G. D. J. Org. Chem. 2007, 72, 7135−7147. 10. Yokoe, H.; Yoshida, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 3504−3506. 1.

507

Simmons–Smith reaction Cyclopropanation of olefins using CH2I2 and Zn(Cu). CH2I2

Zn(Cu)

ICH2ZnI

Zn I CH2 I

ICH2ZnI Oxidative addition

Simmons−Smith reagent (ICH2)2Zn

2 ICH2ZnI

I

C H2

ZnI

I

ZnI2

ZnI ZnI2

Example 12 O

O Zn/Cu [from Zn and Cu(SO4)2] CH2I2, Et2O, reflux, 36 h, 90%

Example 2, An asymmetric version3 CONEt2 OH OH

(1 eq) OH

CONEt2

OH

6 eq Zn/Cu, 3 eq CH2I2 CH2Cl2, 0 oC, 15 h 78%, 94% ee

MeO

MeO

Example 3, Diastereoselective Simmons−Smith cyclopropanations of allylic amines and carbamates9 I

NBn2 Et2Zn, CH2I2, TFA CH2Cl2, rt, 1 h 92%, > 98% de

I

NBn2

Zn N

Ph Ph

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_236, © Springer-Verlag Berlin Heidelberg 2009

508

Example 410 O

O O

HO

HO 1. PhMe2SiH, RhCl(PPh3)3, 60 oC 2. Et2Zn, CH2I2, 0 oC 3. TsOH, MeOH 83%, 3 steps

H

H O

O O

O

References Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323−5324. Howard E. Simmons (1929−1997) was born in Norfolk, Virginia. He carried out his graduate studies at MIT under John D. Roberts and Arthur Cope. After obtaining his Ph.D. In 1954, he joined the Chemical Department of the DuPont Company, where he discovered the Simmons–Smith reaction with his colleague, R. D. Smith. Simmons rose to be the vice president of the Central Research at DuPont in 1979. His views on physical exercise were the same as those of Alexander Woollcot’s: “If I think about exercise, I know if I wait long enough, the thought will go away.” 2. Limasset, J.-C.; Amice, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1969, 3981−3990. 3. Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T. Bull. Chem. Soc. Jpn. 1997, 70, 207−217. 4. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844−5845. 5. Loeppky, R. N.; Elomari, S. J. Org. Chem. 2000, 65, 96−103. 6. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1−415. (Review). 7. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341−2350. 8. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737−2740. 9. Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E. Chem. Commun. 2007, 4029−4031. 10. Shan, M.; O’Doherty, G. A. Synthesis 2008, 3171−3179. 11. Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009, 131, 954−962. 1.

509

Skraup quinoline synthesis Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).

HO

H2SO4

OH OH

NH2

PhNO2

N

H HO

OH

H

HO

OH

OH

dehydration HO

OH2

CHO

HO

OH

glycerol H O H

CHO

H2O

dehydration

O

H

H

conjugate

H

H

addition :

N H

H2N

acrolein O

O

tautomerization

H

H

intramolecular

H :

N H

addition

N H

OH

OH

N H

N H

OH2 oxidation by

H dehydration

H

PhNO2, − H2

N H

N H

N

For an alternative mechanism, see that of the Doebner−von Miller reaction (page 196). Example 15 H2SO4, FeSO4 H3BO3, 80 %

F OH

F HO F

NH2

OH

F F

SO3H F NO2

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_237, © Springer-Verlag Berlin Heidelberg 2009

N

510

Example 26 O OH HO N

O

O

H2SO4, H3BO3 FeSO4•7H2O OH N

75 %

NH2

O

N

Example 3, A modified Skraup quinoline synthesis8 O H

HOAc, reflux

H MeO

MeS

SMe

NH2

8−10 h, 78%

MeO

N

SMe

References (a) Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (1850−1910) was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. (b) Skraup, Z. H. Ber. 1880, 13, 2086. 2. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80−99. (Review). 3. Bergstrom, F. W. Chem. Rev. 1944, 35, 77−277. (Review). 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269−1274. 5. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25−26. 6. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409−418. 7. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59, 813−819. 8. Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449−452. 9. Moore, A. Skraup Doebner–von Miller Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 488−494. (Review). 10. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668−1676. Mechanistic study using 13C-labelled α,β-unsaturated ketones. 11. Vora, J. J.; Vasava, S. B.; Patel, Asha D.; Parmar, K. C.; Chauhan, S. K.; Sharma, S. S. E-J. Chem. 2009, 6, 201−206. 1.

511

Smiles rearrangement Intramolecular nucleophilic aromatic rearrangement. General scheme: Z strong

X

X

Z

base

Y

YH

X = S, SO, SO2, O, CO2 YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R e.g.: NO2

O2 S

NO2

O2 S

OH

SNAr

O

OH

O2 NO2 S

O2S

O

NO2

O

spirocyclic anion intermediate (Meisenheimer complex) Example 17 O O

Br

O NH2 H2 N

O

NaOH, DMA

HO

O

O

O

NaOH, H2O

H2O, reflux HO

50 oC

O

59%, 3 steps

N H

H2N

Example 2, Microwave Smiles rearrangement9 N

O

N

NH2

K2CO3, 200 oC μW, NMP, 30 min. 90%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_238, © Springer-Verlag Berlin Heidelberg 2009

H N

O

N

N H

512

Example 310 I(OAc)2 MOMO

O

MOMO

O

O

O I

BnO

AcO

OMe OH 2 equiv Na2CO3 H2O, rt, 2 h

OMe OH

MOMO

OBn

O

O

o

DMF, 150 C 87% overall

I OMe O

OBn

References Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181−188. Samuel Smiles began his career at King’s College London as an assistant professor. He later became professor and chair there. He was elected Fellow of the Royal Society (FRS) in 1918. 2. Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99−215. (Review). 3. Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 69−74. (Review). 4. Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem. Soc., Perkin Trans. 1 2001, 1751−1757. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocycles 2001, 55, 741−752. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421−2425. 7. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629−3631. 8. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817−3820. 9. Bi, C. F.; Aspnes, G. E.; Guzman-Perez, A.; Walker, D. P. Tetrahedron Lett. 2008, 49, 1832−1835. 10. Jin, Y. L.; Kim, S.; Kim, Y. S.; Kim, S.-A.; Kim, H. S. Tetrahedron Lett. 2008, 49, 6835−6837. 1.

513

Truce−Smile rearrangement A variant of the Smiles rearrangement where Y is carbon: Z

Z Y

base

X

L YH

L XH

Example 16 CF3

CF3

CF3

N

N KH or NaH

O

N

O

O OMe CO2Me

MO

OM

OMe

CF3

CF3

N

N

O

OH

O

O

Example 27 N

NO2

N NaOH, H2O

O2S

EtOH, reflux

NO2

O2 S

O2S NO2

46%

41%

O

Example 38 O O 2N

K2CO3, DMF F

reflux, 73%

HO

O 2N O2 N

O

O

O

OH

H N

514

Example 410

HO O

F O

NO2

1. K2CO3, DMSO, rt, 85%

HO K2CO3, DMSO rt, 93%

O O2N

2. PTSA, acetone/H2O 50 oC, 98%

O

O

O O2N

O

NO2

References Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc. 1958, 80, 3625–3629. 2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276–2279. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782– 783. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett. 1982, 23, 437–438. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.; Düsler, E. N J. Org. Chem. 1986, 51, 130–135. 6. Erickson, W. R.; McKennon, M. J. Tetrahedron Lett. 2000, 41, 4541–4544. 7. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807– 8815. 8. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669–5672. 9. Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452–2458. (Review). 10. Snape, T. J. Synlett 2008, 2689–2691. 1.

515

Sommelet reaction Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine. Cf. Delépine amine synthesis (page 171). N Ar

X

N CHCl3

N N

Δ

X

N

Δ

N N

Ar

N

Ar

H2O

CHO

hexamethylenetetramine N X

N: Ar

SN2

N N N

X

N CH 3 Ar N N N

N CH 2 H N

:

N N

N

N N

Ar

Ar

N CH 3 Ar N N N O H

H :OH2

Ar

hydride transfer

N CH 3

CHO

N N

NH

hemiaminal The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion: X

N N N

N

H

N N

N CH 3 Ar N

Ar

Example 1

3

Br BnO

CHO 1. HMTA, CHCl3, reflux, 6 h

BnO

2. 50% HOAc/H2O, reflux, 3 h 40%

S

S

Example 24

NH2 OH

HMTA, HOAc/H2O (11:3) reflux, 4 h

CHO

then 4.5 HCl, reflux, 1.5 h 68%

OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_239, © Springer-Verlag Berlin Heidelberg 2009

516

Example 37

F

F

N

Cl F

N N

HOAc, H2O N

CHO

Δ, 62%

F

Example 48

Br

Br

Br

NBS, BPO CCl4, reflux, 15 h 38%

62%

CHO HMTA, H2O/EtOH (1:1) reflux, 4 h, 75%

References Sommelet, M. Compt. Rend. 1913, 157, 852−854. Marcel Sommelet (1877−1952) was born in Langes, France. He received his Ph.D. In 1906 at Paris where he joined the Faculté de Pharmacie after WWI and became the chair of organic chemistry in 1934. 2. Angyal, S. J. Org. React. 1954, 8, 197–217. (Review). 3. Campaigne, E.; Bosin, T.; Neiss, E. S. J. Med. Chem. 1967, 10, 270−271. 4. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847−853. 5. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett. 1985, 26, 5217−5220. 6. Kilenyi, S. N., in Encyclopedia of Reagents of Organic Synthesis, ed. Paquette, L. A., Wiley: Hoboken, NJ, 1995, Vol. 3, p. 2666. (Review). 7. Malykhin, E. V.; Shteingart, V. D. J. Fluorine Chem. 1998, 91, 19−20. 8. Karamé, I.; Jahjah, M.; Messaoudi, A.; Tommasino, M. L.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 1569−1581. 9. Göker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005, 13, 1707−1714. 10. Li, J. J. Sommelet reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 689−695. (Review). 1.

517

Sommelet–Hauser rearrangement [2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.

NH2

N

NH3 N

N

[2,3]-sigmatropic

N

NH3

H

rearrangement

NH2

ammonium ylide H NH2 aromatization N

N

H

Example 13 I DMF, reflux Ph

N

SiMe3

I

N

18 h, 94%

CsF, HMPA SiMe3

rt, 23 h, 86%

N

Example 24 Br N

N

CsF, HMPA SiMe3

AcO

AcO 10 oC, 0.5 h, 32%

AcO

46:54

Example 38

t-BuOK, THF N

−15 oC, 50%

Br

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_240, © Springer-Verlag Berlin Heidelberg 2009

N

N

518

Example 410 N

CO2R* t-BuOK, THF Br

CO2Me

−60 oC, 4 h 57%, > 20:1 de R* = (−)-8-phenylmenthyl

N

CO2R* CO2Me

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Sommelet, M. Compt. Rend. 1937, 205, 56–58. Shirai, N.; Sato, Y. J. Org. Chem. 1988, 53, 194–196. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767–2770. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034–5036. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687–1691. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188–5190. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113–2116. Hanessian, S.; Talbot, C.; Saravanan, P. Synthesis 2006, 723–734. Liao, M.; Peng, L.; Wang, J. Org. Lett. 2008, 10, 693–696. Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673–3680.

519

Sonogashira reaction Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot–Chodkiewicz coupling and Castro−Stephens reaction. The Castro– Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. R

X

PdCl2•(PPh3)2

R'

R

R'

CuI, Et3N, rt Ph3P

Cl

II

Pd

Ph3P

Cl CuC

CR'

Ph3P

HX-amine Cycle B'

ii

Ph3P

II

Pd

C

CR'

C

CR'

R

CH

ii

i

Ph3P

Pd0(PPh3)2

Ph3P CC

HX-amine

R'C

CuX

CH

Cycle A

iii

R'C

CCu

Cycle B

RX R'C

CuX

Ph3P

R'C

X

II

Pd

Ph3P

C

II

Pd

CR'

R

CR' iii

RC

i. oxidative addition ii. transmetallation iii. reductive elimination

CR'

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to the iminium ion at the same time:

PdCl2

H

NEt3

NEt2

NEt2

H PdCl2

H

Pd

Cl Cl

reductive

NEt2 Cl Cl

Pd

H

elimination

HCl

Pd(0)

Example 12

I N H

CO2Et

PdCl2•(Ph3P)2 CuI, Et3N 60 oC, 89%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_241, © Springer-Verlag Berlin Heidelberg 2009

N H

CO2Et

520

Example 23 Br

Br

SiMe3 N

Br

N

PdCl2•(Ph3P)2, CuI Et3N, rt, 65–74%

SiMe3

Example 38 OMe Pd(PPh3)4, CuI, [bmim][BF4] Et3N, 80 °C, 12 h, 11% I OMe OMe

OMe

OMe

BF4 N

MeO

MeO

N [bmim][BF4]

OMe

MeO

OMe

MeO OMe 9

Example 4

PMPO O PMPO O

OTf O O Cl

O TMS OTBDPS

MeO OMOM

O

OTBS

OTBS OH

OH Pd(PPh3)4, CuI, i-PrNEt2:DMF (1:1) > 83%

O O Cl

TMS OTBDPS

MeO OMOM

References (a) Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467−4470. Richard Heck also discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259−263. 2. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248−2252. 3. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959−7962. 4. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729−1731. 5. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411−1414. 6. Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; de Meijere, A., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, 319. (Review). 7. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839−9847. 8. Li, Y.; Zhang, J.; Wang, W.; Miao, Q.; She, X.; Pan, X. J. Org. Chem. 2005, 70, 3285−3287. 9. Komano, K.; Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc. 2007, 129, 14184−11186. 10. Gray, D. L. Sonogashira Reaction. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 100−133. (Review). 1.

521

Staudinger ketene cycloaddition [2 + 2]-Cycloaddition of ketene and imine to form β-lactam. Other coupling partners for ketenes include: olefin to give cyclobutanone and carbonyl to give βlactone. O

O

R1

X R3

R2

R3

R4

R4

R2 R1

O

O

X

R3 R4

X R1

X

X = NR; O; CHR

R3

R2

R4

R2 R1

puckered transition state: Example 16

PhO N

PhO

Cl

Ot-Bu p-Tol

O

O

O

Et3N, CH2Cl2 10 oC to rt, 24 h 88%

N

N O

Ot-Bu

N p-Tol

Example 27

O AcO N

O

Cl

Et3N, CH2Cl2 −78 oC to rt, 60%

N AcO

Example 39

O

CO2Et

O

COCl

O PMPN CHPMP Et3N, CH2Cl2 −40 oC to rt 15 h, 70%

PMP H

CO2Et O

PMP N

PMP N H PMP

O

CO2Et O

major

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_242, © Springer-Verlag Berlin Heidelberg 2009

O

O minor

522

Example 410

CO2t-Bu

MeO2C

N I Me

Cl

N S

CO2H

S

CO2t-Bu N

H

CO2t-Bu N

Ph

S

56 : 44

CH2PMP

O

S N

Ph

N O

C O

MeO2C

MeO2C

62%

N

CH2Cl2, Et3N

Ph C N CH2 PMP H

CO2t-Bu

MeO2C

H

CH2PMP

References Staudinger, H. Ber. 1907, 40, 1145−1146. Hermann Staudinger (Germany, 1881−1965) won the Nobel Prize in Chemistry in 1953 for his discoveries in the area of macromolecular chemistry. 2. Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987, 59, 485−492. (Review). 3. Snider, B. B. Chem. Rev. 1988, 88, 793−811. (Review). 4. Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159−646. (Review). 5. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545−3565. (Review). 6. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; Sancassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195−10201. 7. Banik, I.; Becker, F. F.; Banik, B. K. J. Med. Chem. 2003, 46, 12−15. 8. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611−3622. 9. Chincholkar, P. M.; Puranik, V. G.; Rakeeb, A.; Deshmukh, A. S. Synlett 2007, 2242−2246. 10. Cremonesi, G.; Dalla Croce, P.; Fontana, F.; La Rosa, C. Tetrahedron: Asymmetry 2008, 19, 554−561. 1.

523

Staudinger reduction Phosphazo compounds (e.g., iminophosphoranes) from the reaction of tertiary phosphine (e.g., Ph3P) with organic azides. X N3

PR3

N2

X N N N PR3

X N PR3

phosphazide

X N N N

X N N N PR3

X N N N PH2R3

:PR3

N PR3 N N X

phosphazide N PR3 N N X

N PR3 N N X

‡ H2O

X N PR3

N2

X NH2

O PR3

4-membered ring transition state Example 12 OMe

OMe O

Ph3P, THF

N3

N

Δ, 81%

OTBDMS

OTBDMS N

N

Example 23 CO2CH3 H O O

H

1. PPh3, THF

MeO

N3 O

O 2. NaBH4, MeOH O MeO 60%

H

H

Example 34 N3

Br

N Ts

O

H N O

N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_243, © Springer-Verlag Berlin Heidelberg 2009

Br

NH

CO2CH3

524

H N PBu3, toluene

O

N

reflux, 20 h, 82%

Br

N H

N Ts

Br

Example 48 N3 BnO BnO

O

1.1 eq. PMe3, 2.4 eq. Boc-ON

N3 N3 O AcO

N3

Tol., −78 to 10 oC

OAc

N3 BnO BnO

N3 37%

O N3 N3 O AcO

BnO BnO

O

42%

N3 NHBoc O N3 AcO OAc

NHBoc OAc

9

Example 5

F N

O N

O N3

NC R2

F

PPh3, H2O THF, 45 °C 78%

N

O N

O NH2

NC R2

References Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635−646. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 3. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721−2722. 4. Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1369−1371. 5. Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67, 9089−9092. 6. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281−1283. 7. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45, 1655−1657. 8. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7, 3061−3064. 9. Takhi, M.; Murugan, C.; Munikumar, M.; Bhaskarreddy, K. M.; Singh, G.; Sreenivas, K.; Sitaramkumar, M.; Selvakumar, N.; Das, J.; Trehan, S.; Iqbal, J. Bioorg. Med. Chem. Lett. 2006, 16, 2391−2395. 10. Iula, D. M. Staudinger reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 129−151. (Review). 1. 2.

525

Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and α,β-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for −CN. Also known as the Michael−Stetter reaction. Cf. Benzoin condensation. Cl

Ph N

HO

O

S

R CHO

O

R

NH3

O

Bn

Ph N

HO

N

deprotonation H

S

H

R1

R1 = HOCH2CH2CH2-

R

:NH3 Bn

Bn

N R1

Michael

N

OH H

S

R

OH

1

addition

S

R

R

:NH3

O

Bn N R

O

S

Bn

OH

S R

N

tautomerization

1

R1

O

O

R

O

Ph

Ph

NH4

N

HO

R

O

S

N

HO

S

O

S

Example 1, Intramolecular Stetter reaction2 Me

Me N CN

I

CN HO MeO2C

S 2.3 equiv

MeO2C o

TEA, i-PrOH, 80 C 67%

OHC

O

Example 23 Me HO OHC

O

CHO

O

Me N I S (cat.)

O

Et3N, EtOH, 80 oC, 56%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_244, © Springer-Verlag Berlin Heidelberg 2009

O O O

O

526

Example 35 O N

CO2Me H

N

HO

S

O

Cl

CO2Me

O

N

N

(cat.) Ph

O

N

Et3N, DMF, 100 ºC, 75%

Example 4, Sila-Stetter reaction9 Me O Ph

O Me Si Me Me

Ph

O

Br

30 mol% Ph

Et N

HO

S

4 equiv i-PrOH, DBU, THF, 77%

Ph

Ph Ph

O

References (a) Stetter, H.; Schreckenberg, H. Angew. Chem. 1973, 85, 89. Hermann Stetter (1917−1993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. (b) Stetter, H. Angew. Chem. 1976, 88, 695−704. (Review). (c) Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26. 2. Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284−1285. 3. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233−235. 4. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649−651. 5. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409−419. 6. Kobayashi, N.; Kaku, Y.; Higurashi, K. Bioorg. Med. Chem. Lett. 2002, 12, 1747−1750. 7. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284−6289. 8. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368−6378. 9. Mattson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org. Chem. 2006, 71, 5715−5724. 10. Cee, V. J. Stetter Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 576−587. (Review). 1.

527

Still–Gennari phosphonate reaction A variant of the Horner−Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins. O (CF3CH2O)2P

KN(SiMe3)2, 18-Crown-6 CO2CH3

O CF3CH2O P CF3CH2O

Ph

CO2CH3

then PhCH2CHO

O

O CF3CH2O P CF3CH2O

OMe H SiMe3

O OMe

H

Ph

O

N SiMe3 O OCH CF 2 3 O P OCH CF 2 3 H H CO2CH3 Ph

O OCH2CF3 P OCH CF 2 3 H CO2CH3

O H Ph

Ph

CO2CH3

erythro isomer, kinetic adduct Example 12

O (CF3CH2O)2P

KN(SiMe3)2, 18-Crown-6 −78 oC, THF, 30 min. CO2CH3

Ph

CO2CH3

then PhCH2CHO, 87%

Example 23 N

N O

F3CH2CO

P F3CH2CO

O

O

N

N

CO2Et

Me

F

OEt Sn(OSO2CF3)2, N-methylpiperidine CH2Cl2, 70%, E:Z = 96:4

F

Me

Example 34 OTBS F3CH2CO O

N

CH3

O

O

P F3CH2CO

S

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_245, © Springer-Verlag Berlin Heidelberg 2009

OEt

528

OTBS KHMDS, THF 18-crown-6, −78 oC, 1 h 89%, (Z)-isomer only

O N

EtO

CH3

S

Example 49

MeO O

O O O TBS TBS

NaH, THF 73%, Z:E 5:1

P(OCH2CF3)2 O

CHO

OTBS

O OPMB TBS

MeO O

O O O TBS TBS

OTBS

O OPMB TBS

References Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405−4408. W. Clark Still (1946−) was born in Augusta, Georgia. He was a professor at Columbia University. 2. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang, Z. Chem. Eur. J. 1995, 1, 467−494. 3. Sano, S. Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706–709. 4. Mulzer, J.; Mantoulidis, A.; Öhler, E. Tetrahedron Lett. 1998, 39, 8633–8636. 5. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535−9544. 6. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. 2001, 40, 3842−3846. 7. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221−2224. 8. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812−6815. 9. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494−5507. 10. Rong, F. Horner–Wadsworth–Emmons reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J.; Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 420−466. (Review). 1.

529

Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic halides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 325. Pd(0)

R1 Sn(R2)3

R X

oxidative R X

L2Pd(0)

R

addition

L

X Sn(R2)3

L Pd R R1

R R1

X Sn(R2)3

R1 Sn(R2)3

L Pd X L

transmetallation isomerization

reductive R R1

elimination

L2Pd(0)

Example 14 PhO2S

SnBu3 N SO2Ph

Cl

N

Br

Cl

N

NH2

PdCl2•(Ph3P)2, CuI THF, reflux, 92%

Cl

N

Cl

N

N

NH2

Example 25 (MeCN)2PdCl2

Cl TBDPSO

Me3Sn

Br

Cl TBDPSO

Cl

AsPh3, NMP 80 oC, 1.5 h, 55%

Cl

HCl Cl

HN

Cl

Zoloft

Example 3, π-Allyl Stille coupling8 Me OTBDPS SnMe3

Me

Me OAc

Me O

Me

Pd2(dba)3, LiCl i-Pr2NEt, NMP

Me

OTBDPS Me

35 °C, 1.5 h, 96%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_246, © Springer-Verlag Berlin Heidelberg 2009

O

Me

530

Example 49 I

Me OH

Me MeO

Me

O

OTBS

SnMe3

DMF, 32%

O

N MeHN

Pd(PPh3)4, CuTC

O

S

O

Me MeO Me OTBS

OH 18

O

Me

O

N O

MeHN

S

O

References (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636−3638. John Kenneth Stille (1930−1989) was born in Tucson, Arizona. He developed the reaction bearing his name at Colorado State University. At the height of his career, Stille unfortunately died of an airplane accident returning from an ACS meeting. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992−4998. (c) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508−524. 2. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 3. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235−1249. (Review on the intramolecular Stille reaction). 4. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507−4510. 5. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967−8976. 6. Mitchell, T. N. Organotin Reagents in Cross-Coupling Reactions. In Metal-Catalyzed Cross-Coupling Reactions (2nd edn.) De Meijere, A.; Diederich, F. eds., 2004, 1, 125−161. Wiley-VCH: Weinheim, Germany. (Review). 7. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245−2267. (Review). 8. Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 740−742. 9. Roethle, P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960−8961. 10. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review). 1.

531

Stille− Kelly reaction Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides using ditin reagents. Br

Me3Sn SnMe3 Br

Pd(Ph3P)4

OH

OH OH

OH

BrPd Br Br

Me3Sn Pd

Br

Pd(0)

Me3Sn SnMe3

oxidative addition

OH

OH

Br

transmetalation

OH

OH

OH

OH Me3Sn

Me3Sn Pd(0)

Br

reductive Pd(0) elimination

OH

PdBr

oxidative addition

OH OH

OH

Pd

reductive

transmetallation

Pd(0) OH

elimination

OH OH

OH

Example 1

6

I I N

I Cl

HO NaH, DMF, reflux, 89%

I

N O

Me3Sn SnMe3 PdCl2•(Ph3P)2 xylene, reflux, 92%

N O

References 1. 2. 3. 4. 5. 6. 7. 8.

Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161−164. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859−3862. Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Heterocycles 1997, 38, 4581−4582. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105−108. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505−1510. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201−2203. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58, 3021−3037. Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 133−162. (Review).

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_247, © Springer-Verlag Berlin Heidelberg 2009

532

Stobbe condensation Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of bases.

O R1

R

t-BuO

O OEt CO2Et

R

CO2Et

KOt-Bu

CO2Et

HOt-Bu

R1

enolate

H

R1

CO2Et

O

formation

R1

R

CO2Et

O

EtO O

aldol

OEt CO2Et

ring

H

O

R1

O R

CO2Et CO2H

R

addition

R

CO2Et lactonization

O EtO

CO2Et CO2

R

Ot-Bu opening

R1

O

H

CO2Et CO2H

R R1

R1

O

Example 1, Stobbe condensation and cyclization5 O

O CHO

O

CO2Me

1. t-BuOK, t-BuOH, reflux

CO2Me

2. Ac2O, NaOAc, reflux 84%

O

CO2Me O O

OAc

Example 2, Stobbe condensation6 O

O O

aq. NaOH, EtOH

CHO O

O

−10 oC, 5 h, 80−95%

O OH

O O

O

Example 3, Cyclization of the Stobbe product7 BnO2C

BnO2C CO2Et

CO2Et

NaOAc, Ac2O reflux, 57%

CO2H

OAc

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_248, © Springer-Verlag Berlin Heidelberg 2009

533

Example 4, Two sequential Stobbe condensations9 CO2Me

1. (CH2CO2Et)2, NaOMe, MeOH then aq. NaOH, 36% F

CHO

O O

I

O CHO

NaOMe, MeOH, 74%

CO2Me F

2. MeOH, H2O4, 94%

O

F

I CO2Me CO2H

References Stobbe, H. Ber. 1893, 26, 2312. Hans Stobbe (1860−1938) was born in Tiehenhof, Germany. He earned his Ph.D. In 1889 at the University of Leipzig where he became a professor in 1894. 2. Zerrer, R.; Simchen, G. Synthesis 1992, 922–924. 3. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556–1560. 4. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521–3524. 5. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416–4423. 6. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett. 2005, 46, 1009–1012. 7. Sato, A.; Scott, A.; Asao, T.; Lee, M. J. Org. Chem. 2006, 71, 4692–4695. 8. Kapferer, T.; Brückner, R. Eur. J. Org. Chem. 2006, 2119–2133. 9. Mizufune, H.; Nakamura, M.; Mitsudera, H. Tetrahedron 2006, 62, 8539–8549. 10. Lowell, A. N.; Fennie, M. W.; Kozlowski, M. C. J. Org. Chem. 2008, 73, 1911–1918. 1.

534

Strecker amino acid synthesis Sodium cyanide-promoted condensation of aldehyde, or ketone, with amine to afford α-amino nitrile, which may be hydrolyzed to α-amino acid. O R1

H2 N

H

NaCN

R2

AcOH

R2

HN R1

HN

H

R1

CN

H H

O H : H2N

O

R1

R2

HN

R1 R2

:

R1

H N H

H

NC

R2 CO2H

R2 HN

R

NH R2

1

N H

H2O:

R2 NH

R1

OH

iminium ion R2

HN

:OH2 NH2

R1 O

acidic amide

HN

hydrolysis

R1 HO

R2 H NH2

HN

R2

R1 HO

OH

HN

NH3

R1

O H

H

R2 CO2H

Example 1, Soluble cyanide source2 C8H17 C8H17

N

pyrrolidine, THF, 62%

NC

H H

H

H

O (EtO)2P CN

H

H

O

Example 23 Cl OHC

CN

NH S

O

Cl

N acetone cyanohydrin MgSO4, 45 oC toluene, 31%

N

S

S Plavix

Example 38 O Ph

NaCN, NH4Cl i-PrOH, NH4OH

O

CN Ph

NH2 Ph CN H 34%

35%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_249, © Springer-Verlag Berlin Heidelberg 2009

NH2 H

Cl

535

Example 49 Ph

F3C

NaCN, BnNH2 AcOH, MeOH

O O CF3

98%

Ph

F3C

O

CF3

CN HN Bn

References Strecker, A. Ann. 1850, 75, 27−45. Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1979, 20, 4663–4666. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43, 891–898. 4. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762–766. 5. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Organic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds.; Wiley−VCH: Weinheim, Germany, 2003, pp 187−193. (Review). 6. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029–2037. 7. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027–5029. 8. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613–2523. 9. Wrobleski, M. L.; Reichard, G. A.; Paliwal, S.; Shah, S.; Tsui, H-C.; Duffy, R. A.; Lachowicz, J. E.; Morgan, C. A.; Varty, G. B.; Shih, N-Y. Bioorg. Med. Chem. Lett. 2006, 16, 3859–3863. 10. Galatsis, P. Strecker amino acid synthesis. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 477−499. (Review). 11. Belokon, Y. N.; Hunt, J.; North, M. Tetrahedron: Asymmetry 2008, 19, 2804−2815. 1. 2. 3.

536

Suzuki–Miyaura coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic halides, triflates, etc. In the presence of a base (transmetallation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada coupling on page 325.

R X

oxidative

L2Pd(0)

addition transmetallation

L2Pd(0)

R1 B(R2)2

R X

R

L Pd X L

NaOR3 R1 B(R2)2

R3O B(R2)2

OR3 R1 B(R2)2

R

base L L Pd 1 R R

isomerization

R R1

NaOR3

reductive

R R1

L Pd X L

L2Pd(0)

elimination

Example 12 I CO2Me CO2Me

N CO2Et

Pd(OAc)2 Ph3P, K2CO3

O

CO2Me

B O

THF, MeOH 70 °C, 15 h, 80%

N CO2Et

CO2Me

Example 24 B(OH)2 I I

I N SEM

I

N TBS

N

I Pd(Ph3P)4, Na2CO3, 45%

N N SEM

N TBS

Example 3, Intramolecular Suzuki–Miyaura coupling8 OBn

OBn TBDMSO

TBDMSO

1.

O O

OMOM

BH

2

O O

2. H2O, CH2O 3. KHF2 Br

99%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_250, © Springer-Verlag Berlin Heidelberg 2009

BF3K

OMOM

Br

537

BnO OMOM

OH O

cat. Pd(PPh3)4, Cs2CO3

O

THF/H2O, reflux, 42%

Example 49 O O

B O

SnBu3

I

3

N H

OMe

cat. Pd2(dba)3, Ph3As DMF, 84%

I

O O

B O

N H

3

O

OH HO cat. PdCl2(dppf), Ph3As K3PO4 (aq), DMF, 71%

OMe

N H

OMe

References (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437−3440. (b) Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866–867. 2. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164–7168. 3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483. (Review). 4. (a) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998, 48, 1887–1901. (b) Kawaski, I.; Yamashita, M.; Ohta, S. Chem. Pharm. Bull. 1996, 44, 1831–1839. 5. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley−VCH: Weinhein, Germany, 1998, 49–97. (Review). 6. Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (Review). 7. Zapf, A. Coupling of Aryl and Alkyl Halides with Organoboron Reagents (Suzuki Reaction). In Transition Metals for Organic Synthesis (2nd edn.); Beller, M.; Bolm, C. eds., 2004, 1, 211−229. Wiley−VCH: Weinheim, Germany. (Review). 8. Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–10318. 9. Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007, 129, 3826–3827. 10. Wolfe, J. P.; Nakhla, J. S. Suzuki coupling. In Name Reactions for HomologationsPart I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 163−184. (Review). 1.

538

Swern oxidation Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2, DMSO, and quenching with Et3N. (COCl)2, DMSO CH2Cl2, −78 oC

OH R1

O

O

S

R

then Et3N

O

R2

Cl S

O O

Cl

Cl

Cl

R2

O 1

S

O

Cl

Cl O

CO2↑

S

O

H :O

CO↑

R1

Cl

R2

O

Cl S O H 1 R R2

H

:NEt3

S

O Et3N•HCl↓

R1 2 R

O

CH2 H

R1

R2

(CH3)2S↑

sulfur ylide Example 12 OMe OMe

H

H

O

1. (COCl)2, DMSO, −60 oC, 45 min

OH

2. Et3N, −60 oC, 15 min. then rt 81%

OH OMe OMe OH

OMe OMe O

OH

Example 23 Swern conditions

TMSCH2CH2O2C HO NC

O

Cl TMSCH2CH2O2C O NC

80%

O

O

Example 35 O

OH C11H23

C6H13 OSiMe2t-Bu

O

(COCl)2, DMSO

C11H23

then Et3N, 89%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_251, © Springer-Verlag Berlin Heidelberg 2009

C6H13 OSiMe2t-Bu

539

Example 47

OMe HO

OMe

OTBDPS N

O

(COCl)2, DMSO

N3

N3 OTBDPS

then Et3N, 85% N

References (a) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329−3331. (b) Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297−299. (c) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480−2482. 2. Ghera, E.; Ben-David, Y. J. Org. Chem. 1988, 53, 2972−2979. 3. Smith, A. B., III; Leenay, T. L.; Liu, H. J.; Nelson, L. A. K.; Ball, R. G. Tetrahedron Lett. 1988, 29, 49−52. 4. Tidwell, T. T. Org. React. 1990, 39, 297−572. (Review). 5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P. M.; Uskoviü, M. R. J. Org. Chem. 1991, 56, 4714−4718. 6. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998, 63, 2407−2409. (Odorless protocols). 7. Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Bakovec, J. M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123, 3239−3242. 8. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177−5179. (Another odorless protocols). 9. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed. 2005, 44, 2413−2416. 10. Ahmad, N. M. Swern oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 291−308. (Review). 11. Lopez-Alvarado, P; Steinhoff, J; Miranda, S; Avendano, C; Menendez, J. C. Tetrahedron 2009, 65, 1660−1672. 1.

540

Takai reaction Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide using CHI3 and CrCl2. O R

CHI3, CrCl2 H

I

R

THF

R I H

CrCl2

I

O

I H

I CrIIICl2

I

H

CrCl2

CrIIICl2 I CrIIICl2

H

R OCrIIICl2

Cl2CrIII

I

R

I

A radical mechanism was recently proposed10 I

I

I

H

I

I

O I

H

III

Cr I

CrII

R

H

H

I CrIII

CrII OCrIII

OCrIII R I

I H

R

I H

OCrIII CrIII

CrII

CrII

I

R

I

R

Example 12 CHI3, CrCl2 Ph

Ph

CHO

I

THF, 70%

OTBS

OTBS 20: 1 E:Z

Example 23 Et Et N Ni N

CHO N

Et

Et Et

Et

Et

Et

Et N

Et

Et

Et 25 equiv CrCl2 6 equiv CHI3

N

THF, rt, 3 h 75%

N

N Ni I

N Et

Et Et

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_252, © Springer-Verlag Berlin Heidelberg 2009

Et

541

Example 34

CHI3, CrCl2, 0 oC

OTES OHC

CO2Me

OTES I

THF, 50%

CO2Me

Example 4, A Br/Cl variant9 6 equiv CrCl2, 2 equiv CHBr3 OTHP

O

THF, 0 oC, 2.5 h, 67%

Br

Cl

OTHP

OTHP

1:1

Example 510 H

CO2Me

5.8 equiv anhydrous CrCl2 2 equiv CHI3

H

CO2Me

MOMO

MOMO H

CHO

1,4-dioxane−THF (6:1) 20 oC, 72 h, 88%

H

I

References Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159– 12169. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335–1345. 4. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717–8724. 5. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043–2046. 6. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533–3536. 7. Paterson, I.; Mackay, A. C. Synlett 2004, 1359–1362. 8. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569–571. 9. Gung, B. W.; Gibeau, C.; Jones, A. Tetrahedron: Asymmetry 2005, 16, 3107–3114. 10. Legrand, F.; Archambaud, S.; Collet, S.; Aphecetche-Julienne, K.; Guingant, A.; Evain, M. Synlett 2008, 389–393. 1. 2.

542

Tebbe’s reagent The Tebbe’s reagent, ȝ-chlorobis(cyclopentadienyl)(dimethylaluminium)-ȝmethylenetitanium, transforms a carbonyl compound to the corresponding exoolefin. H2 C

CH3 Al

Ti

CH3

Cl

Preparation:2,6 CH4↑ + Al(CH3)2Cl +

Cp2TiCl2 + 2 Al(CH3)3

Cp2Ti

Al(CH3 )2 Cl

Mechanism:3

Cp2Ti

Cl

Cl

[2 + 2]

Cp2Ti CH2

dissociation

Al(CH3)2

Cp2Ti CH2 R1

O

cycloaddition

R

Al(CH3)2

O

R1 R

retro-[2 + 2] cycloaddition

oxatitanacyclobutane

Cp2Ti O

R1

R

formation of the strong Ti=O is the driving force.

Example 1, Ketone2 O

Tebbe's reagent, Tol. CO2Et

CO2Et

then the ketone substrate, THF, 0 oC to rt, 30 min., 67%

Example 2, Double Tebbe4 Cp

H 2.5 eq

O

O H

O

Ti Cp

Al

H

Cl

THF, CH2Cl2 −40 to 25 °C, 69%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_253, © Springer-Verlag Berlin Heidelberg 2009

O

543

Example 3, Double Tebbe5 TBSO OHC

TBSO

3 equiv Tebbe's reagent in Tol. pyr., Tol./THF

OBn OTBS CHO

O OBn OTBS TBS

−78 oC to −15 oC, 2 h 86%

O OBn OTBS TBS

OBn OTBS

Example 4, N-Oxide6 Cp Ti Cp N O

Al Cl

THF, 0 oC to rt, 90%

N

Example 5, Amide11

N O

N

O

O

CF3

CF3

CF3

CF3

N

1. Tebbe's reagent 2. BH3, THF, H2O2, NaOH 75−95%

O

N

OH

O

References Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611−3613. Pine, S. H.; Pettit, R. J.; Geib, G. D.; Cruz, S. G.; Gallego, C. H.; Tijerina, T.; Pine, R. D. J. Org. Chem. 1985, 50, 1212–1216. 3. Cannizzo, L. F.; Grubbs, R. H. J. Org. Chem. 1985, 50, 2386–2387. 4. Philippo, C. M. G.; Vo, N. H.; Paquette, L. A. J. Am. Chem. Soc. 1991, 113, 2762−2764. 5. Ikemoto, N.; Schreiber, L. S. J. Am. Chem. Soc. 1992, 114, 2524–2536. 6. Pine, S. H. Org. React. 1993, 43, 1−98. (Review). 7. Nicolaou, K. C.; Koumbis, A. E.; Snyder, S. A.; Simonsen, K. B. Angew. Chem., Int. Ed. 2000, 39, 2529–2533. 8. Straus, D. A. Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, 2000. (Review). 9. Payack, J. F.; Hughes, D. L.; Cai, D.; Cottrell, I. F.; Verhoeven, T. R. Org. Syn., Coll. Vol. 10, 2004, p 355. 10. Beadham, I.; Micklefield, J. Curr. Org. Synth. 2005, 2, 231−250. (Review). 11. Long, Y. O.; Higuchi, R. I.; Caferro, T.s R.; Lau, T. L. S.; Wu, M.; Cummings, M. L.; Martinborough, E. A.; Marschke, K. B.; Chang, W. Y.; Lopez, F. J.; Karanewsky, D. S.; Zhi, L. Bioorg. Med. Chem. Lett. 2008, 18, 2967−2971. 12. Zhang, J. Tebbe reagent. In Name Reactions for Homolotions-Part I; Li, J. J., Corey, E. J., Eds., Wiley & Sons: Hoboken, NJ, 2009, pp 319−333. (Review). 1. 2.

544

TEMPO oxidation TEMPO = Tetramethyl pentahydropyridine oxide. 2,2,6,6-Tetramethylpiperidinyloxy is a stable nitroxyl radical, which serves in oxidations as catalyst O

NaOCl, cat. TEMPO R

OH KBr, NaHCO3, CH2Cl2

:

:

N O

N O

R

OH

1/2 NaOCl N O : HO

R

: O Cl O

NHAc N O

O H

R H R

H

N OH

O Cl

N O

:B

O R

O

Cl

OH

O

H R

O

R

O

Example 14 OH HO HO

NaOCl, cat. TEMPO O OMe OH

KBr, NaHCO3, CH2Cl2 55%

HO2C HO HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_254, © Springer-Verlag Berlin Heidelberg 2009

O OMe OH

545

Example 2, Trichloroisocyanuric/TEMPO Oxidation5 Cl N

O Cl R

OH

N

O N

Cl

O

O 0.01 mol equiv TEMPO 0.05 mol equiv NaBr acetone, aq. NaHCO3, rt 1−24 h, 75−100%

R

OH

Example 38 O

cat. TEMPO, 2 eq. 2,6-lutidine electrolysis in CH3CN/H2O (95:5) 95%

Example 410 OH

OH

Ormosil-TEMPO, NaOCl OH

Cl

CH3CN, NaHCO3, 5% 0 oC, 80%

CO2H Cl

“Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix doped with TEMPO References Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905–4908. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (Review). 3. Rychnovsky, S. D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310–312. 4. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551– 7553. 5. De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003, 45, 4999– 5001. 6. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381–6383. 7. Tashino, Y.; Togo, H. Synlett 2004, 2010–2012. 8. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487–2490. 9. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960–966. 10. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M. Org. Biomol. Chem. 2005, 3, 2389–2392. 11. Zhang, M.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem., Int. Ed. 2008, 47, 9730–9733. 1. 2.

546

Thorpe−Ziegler reaction The intramolecular version of the Thorpe reaction, which is base-catalyzed selfcondensation of nitriles to yield imines that tautomerize to enamine. CN CN CN

EtO

OEt NH2

HOEt

H

N H

N H OEt

N H OEt

N

CN

H CN

EtO

OEt

NH2

NH H OEt

Example 1, A radical Thorpe−Ziegler reaction2 H2 N

Bu3SnH, AIBN syringe pump

CN

CN

NC Br

PhH, 80 oC, 56%

Example 25 CN

N CN Ph

LDA, THF −78 oC to rt 2 h, 80%

NH2 CN N Ph

Example 38 N

O

N H

H N

S O

NH2 HN

KOH, EtOH Ph

reflux, 5 min., 80%

O

N H

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_255, © Springer-Verlag Berlin Heidelberg 2009

S

O

Ph

547

Example 49 NC

CN NH

NC Cl

CN

N

NH2

NC

CN CN

N

CN

Et3N, reflux 15 min., 91% OMe

OMe

OMe

References (a) Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726–1761. (b) Ziegler, K. et al. Ann. 1933, 504, 94–130. Karl Ziegler (1898−1973), born in Helsa, Germany, received his Ph.D. In 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization. 2. Curran, D. P.; Liu, W. Synlett 1999, 117–119. 3. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527– 1531. 4. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tetrahedron Lett. 2002, 43, 3225–3228. 5. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895–898. 6. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517–7520. 7. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245–1256. 8. Dotsenko, V. V.; Krivokolysko, S. G.; Litvinov, V. P. Monatsh. Chem. 2008, 139, 271–275. 9. Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M. ARKIVOC 2008, 180–190. 10. Miszke, A.; Foks, H.; Brozewicz, K.; Kedzia, A.; Kwapisz, E.; Zwolska, Z. Heterocycles 2008, 75, 2723–2734. 1.

548

Tsuji−Trost reaction The Tsuji–Trost reaction is the palladium-catalyzed substitution of allylic leaving groups by carbon nucleophiles. These reactions proceed via π-allylpalladium intermediates. R1

Pd(0) (catalytic) R

1

X

Nu

R1

Pd(II) X

base

Nu

2 π-allyl complex R1

Nu

R1

Pd(0)

R2

R1

R2 OR

X

Hard Nu Inversion of configuration

R2

Pd(0)

X

R1

Soft Nu

R2 Nu

Retention of configuration

R1 >> R2

X = OCOR, OCO2R, OCONHR, OP(O)(OR)2, OPh, Cl, NO2, SO2Ph, NR3X, SR2X, OH

The catalytic cycle: Pd(0) or Pd(II) precatalysts R1

Nu R1

X

LnPd(0) A R1

Nu

R1

LnPd(0)

B

D Nu

X LnPd(0)

π-allyl complex R1

+L Pd(II) L

L

A: Coordination B: Oxidative addition (Ionization)

R1 Pd(II)

−X C

L

X

C: Ligand exchange D: Substitution then reductive elimination

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_256, © Springer-Verlag Berlin Heidelberg 2009

549

Example 1, Allylic ether3 BnO

BnO O BnO

Pd2(dba)3, dppb

N N H

OPh

O

o

THF, 60–70 C 72%

BnO

α:β = 90:10

N N

Example 2, Allylic acetate3 NH2 N N H

OAc

AcO

N

NaH, Pd(Ph3P)4, DMF 60 oC, 18 h, 79%

NH2

N

N N

AcO

N N

Example 3, Allylic epoxide5 N N N H

O

N

HO

Pd(Ph3P)4, THF rt, 64 h, 35%

Example 4, Intramolecular Tsuji–Trost reaction6 O

O Bn N

10 mol% Pd(OAc)2 10 mol% n-Bu4NCl

NH2 OCO2Me S CO2Me

BnN

P(OEt)3, NaHCO3 DMF, 100 oC, 77%

NH

S CO2Me

Example 5, Intramolecular Tsuji–Trost reaction7 Me TESO

TESO

OTES

Me

O O

10 mol% Pd2(dba)3 THF (0.005 M) 40 oC, 80%

Me Ot-Bu

Me TMSO

OTES

OMe

O

O

O t-BuO

Me

O Me

OTMS

550

Example 6, Asymmetric Tsuji–Trost reaction8 BocO

O EtO2C

O I

O

O

O

2.5 mol% (dba)3Pd2•CHCl3 7.5 mol% ent-cat

O

EtO2C

I O

MeO

OH

30 mol% Bu4NCl CH2Cl2

MeO

O

H

O

89% yield, 95% ee

O

O NH HN

ent-cat = PPh2 Ph2P

References (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387−4388. (b) Tsuji, J. Acc. Chem. Res. 1969, 2, 144−152. (Review). 2. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.; Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 3. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481–2484. 4. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A. R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 5. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl. Chem. 1997, 34, 233−239. 6. Seki, M.; Mori, Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67, 5527−5536. 7. Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.; Sorenson, E. J. J. Am. Chem. Soc. 2003, 125, 5393−5407. 8. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090−3100. 9. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044−15045. 10. Fuchter, M. J. Tsuji–Trost Reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 185−211. (Review). 1.

551

Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. R2

O 1

R CO2H

3

2

R NH2

R N C

R CHO

R

N R1

H N

R3

O

isocyanide H N R1

O

O R2

O

HO H N 1 R2 R H

N R1 R CO2H

:

H :

R1 NH2

R2 H

R

C N

R2 H

R3

imine

O

R3 H N

R3 H N

O

:

R

N

R2

O

H N

O R1

O R

R2

R

R2

N

N R1

O

R1

Example 12 OMe

OMOM

C N

BnO O NH2

O O

I BocHN

OTBDPS

H

OMOM

NHPMP O

MeOH, Δ 1 h, 90%

O

CO2H

N

NHBoc

O

OMe O TBDPSO

O I

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_257, © Springer-Verlag Berlin Heidelberg 2009

OBn

R3

552

Example 25 O CO2H

HN

NH2

O2N O2S

C N

N OMe

OTBS

CHO

O2N

O2S N

MeOH, Δ

O

OO

61%

NHt-Bu

N HN

OMe

OTBS 7

Example 3

HO

O

O

O

NH2

CH3 CH3

O CH3

C

N

H3CO

OCH3 OCH3

OCH3 OCH3 TFE, rt

PMB O

NH

N 78%

O

O H3C

H

O

CH3 CH3

Example 48 O OH H3C TBSO CH3

H H2 N

H3C

H H OTBS OH

TBSO

O

O 2

NH2

(CH2O)n

N

C

553

Cy NH O O N H3 C HO CH3

H O

1. MeOH, rt. 2. TBAF, THF 54%, 2 Steps

H3C

H H OH N

HO

O

O

O HN Cy

References (a) Ugi, I. Angew. Chem., Int. Ed. 1962, 1, 8Ȃ21; (b) Ugi, I.; Offermann, K.; Herlinger, H.; Marquarding, D. Liebigs Ann. Chem. 1967, 709, 1–10.; (c) Ugi, I.; Kaufhold, G. Ann. 1967, 709, 11–28; (d) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review); (e) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Review); (f) Ugi, I. Pure Appl. Chem. 2001, 73, 187Ȃ191. (Review). 2. Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 6552−6554. 3. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596Ȃ597. 4. Multicomponent Reactions J. Zhu, H. Bienaymé, Eds.; Wiley-VCH, Weinheim, 2005. 5. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47Ȃ50. 6. Dömling, A. Chem. Rev. 2006, 106, 17Ȃ89. 7. Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007, 9, 3631Ȃ3634. 8. Rivera, D. G.; Pando, O.; Bosch, R.; Wessjohann, L. A. J. Org. Chem. 2008, 73, 6229Ȃ6238. 9. Bonger, K. M.; Wennekes, T.; Filippov, D. V.; Lodder, G.; van der Marel, G. A.; Overkleeft, H. S. Eur. J. Org. Chem. 2008, 3678Ȃ3688. 10. Williams, D. R.; Walsh, M. J. Ugi Reaction. In Name Reactions for HomologationsPart II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 786−805. (Review). 1.

554

Ullmann coupling Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls.

2

I

Cu

CuI2

Cu, single

Cu(II)I

I

Cu(I)I

electron transfer

SET

I Cu(II)I

CuI2

The overall transformation of PhI to PhCuI is an oxidative addition process. Example 13 NO2 NO2

Cu powder, DMF

N

N N

o

Cl

100−105 C, 4 h, 63%

O2N

Example 2, CuTC-catalyzed Ullmann coupling4 O S

N I

N

O Cu

NMP, rt, 88%

I

Example 35 OEt OMe O I MeO

OEt

Cu-bronze 210−220 οC 72%

O MeO MeO

OMe OMe O OEt

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_258, © Springer-Verlag Berlin Heidelberg 2009

555

Example 48

O

P(O)Ph2 I I P(O)Ph2

O

Cu, DMF

O

P(O)Ph2

O

P(O)Ph2

140 οC, 88%

O

P(O)Ph2

O

P(O)Ph2

70%

18%

Example 59 MeO MeO

O

I

Cu0, Pd(PPh3)4

PhHN

MOMO I

NCy

N

ο

DMF, 100 C 39%

MOMO PhHNOC

O N

References (a) Ullmann, F.; Bielecki, J. Ber. 1901, 34, 2174−2185. Fritz Ullmann (1875−1939), born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. (b) Ullmann, F. Ann. 1904, 332, 38−81. 2. Fanta, P. E. Synthesis 1974, 9−21. (Review). 3. Kaczmarek, L.; Nowak, B.; Zukowski, J.; Borowicz, P.; Sepiol, J.; Grabowska, A. J. Mol. Struct. 1991, 248, 189−200. 4. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312−2313. 5. Hauser, F. M.; Gauuan, P. J. F. Org. Lett. 1999, 1, 671−672. 6. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623−1626. 7. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265−556. (Review). 8. Qui, L.; Kwong, F. Y.; Wu, J.; Wai, H. L.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J Am. Chem. Soc. 2006, 128, 5955−5965. 9. Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255−3257. 10. Ahmad, N. M. Ullman coupling. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 255−267. (Review). 1.

556

van Leusen oxazole synthesis 5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC, also known as the van Leusen reagent) with aldehydes in protic solvents at refluxing temperatures.

O O S

N

O

NC

K2CO3

O

H MeOH, reflux

O O S

N

O O S

C

N

C

O O S

N

R

O

C

H B

R

O

H

N

Tos

Tos

+H

N

H

N

H

− TosH

O

O

R

R H

R

H

O B

Example 13 N O O O S

H

O H

NC

Pr N Pr

H

NaOMe MeOH, reflux 81%

HN

HN

Example 25

O

O EtO

H O

O S

O

NC K2CO3

EtO

DMF, 80%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_259, © Springer-Verlag Berlin Heidelberg 2009

O

N

Pr N Pr

557

Example 39 N O CHO TosMIC, K2CO3 OHC

CHO

MeOH, reflux 81%

O N O

N

Example 410 O CHO

O O

TosMIC, K2CO3 MeOH, reflux 4 h, 91%

O

N O

References (a) van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13, 2369–2381. (b) Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77–80. (c) Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793–796. (d) van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723–3726. 2. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 4973−4979. (Review). 3. Anderson, B. A.; Becke, L. M.; Booher, R. N.; Flaugh, M. E.; Harn, N. K.; Kress, T. J.; Varie, D. L.; Wepsiec, J. P. J. Org. Chem. 1997, 62, 8634–8639. 4. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633–5636. 5. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516–1524. 6. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S. Org. Lett. 2001, 3, 271–273. 7. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Res. Dev. 2002, 6, 677–681. 8. Brooks, D. A. van Leusen Oxazole Synthesis. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 254– 259. (Review). 9. Kotha, S.; Shah, V. R. Synthesis 2007, 3653–3658. 10. Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278–3280. 1.

558

Vilsmeier−Haack reaction The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.

O O

O

DMF, POCl3

CHO

100 oC, 24 h CHO

34%

Cl

O O PCl2

N

N

:

O

:

N

O P Cl Cl

H

Cl

Cl

H

4% O O PCl2 H

N

H

O Cl O PCl2

Vilsmeier–Haack reagent O

O:

N

H H

Cl

H

O

N

Cl

B

H N:

Cl

O

O O aqueous workup

:

:

H O H

H

HO

N

H CHO

N H

Example 12 OMe MeO

100 oC, 14 h, 98%

OH

OHC

DMF, POCl3

OMe MeO

Example 23 N

DMF, POCl3

N CHO

o

100 C, 83% N

Cl

N

Cl

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_260, © Springer-Verlag Berlin Heidelberg 2009

559

Example 39

CH3 100 oC, 20 h

N

N CH3

CH3

CHO

CHO

POCl3/DMF

CH3 Cl

CH3 OH

CH3 Cl

CH3 OH

N

OH CH3

65%

CH3 10%

N CH3

CH3

15%

Example 410 O 12 equiv POCl3/DMF

Cl

R

R

O

O

o

80−100 C, 31−71%

CHO Cl

12 equiv POCl3/DMF R

R O

120−135 oC, 39−78%

Cl

References Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662–2665. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 3122–3128. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392−396 (Review). 6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659. (Review). 8. Tasneem, Synlett 2003, 138–139. (Review of the Vilsmeier–Haack reagent). 9. Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.; Mohan, P. S. Eur. J. Med. Chem. 2007, 42, 1128–1136. 10. Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320. 11. Pundeer, R.; Ranjan, P.; Pannu, K.; Prakash, O. Synth. Commun. 2009, 39, 316–324. 1. 2. 3. 4.

560

Vinylcyclopropane−cyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate. R2

R2

Δ R1

R1

R2

R2

R2

R 2

R1

R1

R1

R1

Example 11 O CO2Me

O

340 oC, 2 h 50%

CO2Me

Example 22

SO2Ph

1. n-BuLi, THF−HMPT −78 to −30 oC 2. PhCH2Br P h

3. desulfonylation 77% overall yield

Example 39 H

O MOM O

H

N N MOM

O

O

N N MOM

AlCl3, CH2Cl2

O

H

MOM

O

H

H

H

O

O

N MOM

N MOM

O

MOM N O N MOM

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_261, © Springer-Verlag Berlin Heidelberg 2009

0 oC, 88%

O H O

H

561

Example 410

Me Me

O

CO2Me

Me

150 mol% MgI2 (0.2 M) CH3CN, 40 oC, 6 h, 75%

H

Me Me

O

CO2Me Me H

References Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc. Chim. Fr. 1981, 1−2, 57−64. 2. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579−4581. 3. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247−335. (Review). 4. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229−267. (Review). 5. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875−884. (Review). 6. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153−156. 7. Baldwin, J. E. Chem. Rev. 2003, 103, 1197−1212. (Review). 8. Wang, S. C.; Tantillo, D. J. J. Organomet. Chem. 2006, 691, 4386−4392. 9. Zhang, F.; Kulesza, A.; Rani, S.; Bernet, B.; Vasella, A. Helv. Chim. Acta 2008, 91, 1201−1218. 10. Coscia, R. W.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131, 2496−2498. 1.

562

von Braun reaction Different from the von Braun degradation reaction (amide to nitrile), the von Braun reaction refers to the treatment of tertiary amines with cyanogen bromide, resulting in a substituted cyanamide.

R

1

R N

R1

Br R

1

R2

NC Br R N:

CN N R R2

Br CN

Br

R2

R1

S N2

R CN N R2

R1

CN N R2

Br R

Example 14 CF3

CF3

CF3 Br-CN

O

Tol.

N

O

KOH

O N

CN

N H

MeOH/H2O

Prozac

Example 25 CO2Me

CO2Me CO2Me

CO2Me

Br-CN, THF, H2O

Br N CN

75%

N

Example 39 OTBS

OTBS

TBSO BrCN, CH2Cl2 Ph

N

reflux, 98%

Br

NC Ph

N

N

Br Ph

CN

References 1.

von Braun, J. Ber. 1907, 40, 3914−3933. Julius von Braun (1875−1940) was born in Warsaw, Poland. He was a Professor of Chemistry at Frankfurt.

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_262, © Springer-Verlag Berlin Heidelberg 2009

563

2. 3. 4. 5. 6. 7. 8. 9.

Hageman, H. A. Org. React. 1953, 7, 198−262. (Review). Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279−1300. (Review). Mody, S. B.; Mehta, B. P.; Udani, K. L.; Patel, M. V.; Mahajan, Rajendra N.. Indian Patent IN177159 (1996). McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200−204. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898−1904. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908−9917. Thavaneswaran, S.; McCamley, K.; Scammells, P. J. Nat. Prod. Commun. 2006, 1, 885−897. (Review). McCall, W. S.; Abad Grillo, T.; Comins, D. L. Org. Lett. 2008, 10, 3255−3257.

564

Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones, and aldehydes in certain cases. O

cat. PdCl2, H2O R

2 HCl + 0.5 O2

2 CuCl

H2O

2 CuCl2

R

CuCl2, O2

R

LnPdCl2

complexation

LnPd

HCl

reductive elimination

LnClPd

Cl

R

:

hydroxypalladation

H

:

LnPdHCl O

H

O hydride shift R

HCl

LnClPd

L = ligand or solvent

R H :O: H

Example 15 CO2H

O O2, 5% Pd(OAc)2

O

NaOAc, DMSO, 80%

Example 27 O

O O

O O

H

10% Pd(OAc)2, HClO4

H H

H

0.5 equiv benzoquinone CH3CN

H

O H

H H

O

H 45%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_263, © Springer-Verlag Berlin Heidelberg 2009

H H

H 35%

CHO

565

Example 39 O2, 20 mol% Cu(OAc)2 10 mol% PdCl2 O

O

O

DMA/H2O (7:1) 84%

O

O

Example 410 O O

O

O

5 eq. PdCl2, air

O

HO

DMF/H2O (7:1) 81%

O O

O O

O

O

O

HO

O

O

12 : 1 HO

O

O

O O

CHO

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

10. 11.

12.

13.

Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80−88. Tsuji, J. Synthesis 1984, 369−384. (Review). Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 4, 552. (Review). Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7, 449. (Review). Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298−5300. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 199−208. (Review). Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997, 53, 10733−10742. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C., eds.; Wiley−VCH: Weinheim, Germany. 1998, 2, 307−315. (Review). Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468−10477. Kobayashi, Y.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 4381−4384. Hintermann, L. Wacker-type Oxidations in Transition Met. Org. Synth. (2nd edn.) Beller, M.; Bolm, C., eds., Wiley−VCH: Weinheim, Germany. 2004, 2, pp 379−388. (Review). Li, J. J. Wacker−Tsuji oxidation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 309−326. (Review). Okamoto, M.; Taniguchi, Y. J. Cat. 2009, 261, 195−200.

566

Wagner–Meerwein rearrangement Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins. R1 R2

R

R

R1 R2

R

R

R1 R2

H

H 3 OH

H

H 3 OH

R1

R

R2

R3

R

R

R1 R2

− H2O

H 3 OH2

R H R

3

1,2-shift R1 R2 R

−H

H R 3

R1

R

R2

R3

Example 13 H3CO2C H3 C

OH Br

HN O N

CH3SO3H

N

O

H3CN

O

ClCH2CH2Cl 50 oC, 86%

OCH3 HN

OCH3

H3CO

H3C

CO2CH3 Br

HN O N

O

H3CN

N O

OCH3 HN

OCH3

H3CO

Example 2, Double Wagner–Meerwein rearrangement6 O

O

O OEt

HO

TFA, CH2Cl2 72 h, 76%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_264, © Springer-Verlag Berlin Heidelberg 2009

O OEt

567

Example 37 OH

O CH3 OTBS

HO MsO H BzO

OH Et2AlCl, CH2Cl2 −78 oC → rt 52%

O CH3 OTBS

O H BzO H

Example 49 BzO H H O

H3C

BzO H H

BF3•Et2O OBz CH3

benzene, 40%

O H3C

H

OBz CH3

References Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89–124. (Review). 3. Kinugawa, M.; Nagamura, S.; Sakaguchi, A.; Masuda, Y.; Saito, H.; Ogasa, T.; Kasai, M. Org. Proc. Res. Dev. 1998, 2, 344–350. 4. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162–7163. 5. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067–1074. 6. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015–6028. 7. Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 315–320. 8. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107–3110. 9. Michalak, K.; Michalak, M.; Wicha, J. Molecules 2005, 10, 1084–1100. 10. Mullins, R. J.; Grote, A. L. Wagner–Meerwein rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 373−394. (Review). 1. 2.

568

Weiss–Cook reaction Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione. The product is frequently decarboxylated. EtO2C

EtO2C O

R

aq. buffer

O O

R

O

EtO2C O H EtO2C

O EtO2C

EtO2C

H

R

O

R1

O

CO2Et

R1

EtO2C

R CO2Et O R1

O

O H CO2Et

HO

H CO2Et

EtO2C

R

O H EtO2C

R1

O

R CO2Et

R

1

EtO2C HO EtO2C

CO2Et

O

pH 5.6

O

O

MeO2C

CO2Me

MeO2C

CO2Me

86% MeO2C

Example 23 CO2CH3

1. pH = 8.3 2. HOAc/HCl, Δ

O CO2CH3

O

CHO

90%

O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_265, © Springer-Verlag Berlin Heidelberg 2009

O H

CO2Et OH

R1

O O

CO2Et

R

Example 12

MeO2C

OH

O

EtO2C

O R1

EtO2C

HO

CO2Et

R

CO2Et

EtO2C

R

O H EtO2C

R1

O H EtO2C

OH

EtO2C

EtO2C

EtO2C

1

R1

OH

H

R

EtO2C

H

O

OH

EtO2C

R

EtO2C

R

O

O

1

EtO2C

EtO2C

CO2Et

R

CO2Et

569

Example 34 O

CO2CH3 O

1. pH = 6.8 2. HOAc/HCl O

O

O

80% CO2CH3

Example 49 EtO2C Et

O

O Me

O EtO2C

NaHCO3

O

Et CO2Et O Me CO Et 2

H2O/MeOH rt, 24 h, 86%

O

EtO2C

EtO2C

CO2Et

CO2Et

EtO2C HO EtO2C

Et CO2Et OH Me CO Et 2

EtO2C HO EtO2C

Et CO2Et OH Me CO Et 2

References Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885–4887. Bertz, S. H.; Cook, J. M.; Gawish, A.; Weiss, U. Orga. Synth. 1986, 64, 27–38. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285–4288. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org Chem. 1983, 48, 139–141. 5. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665–3710. 6. Paquette, L. A.; Kesselmayer, M. A.; Underiner, G. E.; House, S. D.; Rogers, R. D.; Meerholz, K.; Heinze, J. J. Am. Chem. Soc. 1992, 114, 2644–2652. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43–54. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993, 49, 1511–1518. 9. Williams, R. V.; Gadgil, V. R.; Vij, As.; Cook, J. M.; Kubiak, G.; Huang, Q. J. Chem. Soc., Perkin Trans. 1 1997, 1425–1428. 10. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1 1997, 3471–3478. 1. 2. 3. 4.

570

Wharton reaction Reduction of α,β-epoxy ketones by hydrazine to allylic alcohols. R2 R1

NH2NH2 O

O

N2↑

H2O

R2 H

R2 R1

OH NH NH2

O

R2 tautomerization

R1

O

H2O

R1

N O hydrazone

:

O :NH2NH2

O

R2

HO

R2 R1

R1

Δ

H N

H N

H

:OH2 N

R1

N2↑

H

R2

HO

diazene

Example 15 OH

O O NH2NH2•H2O, MeOH N TEOC

H

HOAc, rt, 52%

N TEOC

H

Example 26 TBDMSO

TBDMSO CO2CH3

O

(dimethylamino)ethanol 32%

O

CO2CH3

NH2NH2•HCl, Et3N

Example 37 O O NH2NH2, KOH THF, reflux, 64% HO OH

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_266, © Springer-Verlag Berlin Heidelberg 2009

OH

571

OH

OH 91 : 9 HO

HO OH

OH

Example 48 O O TESO

O O

NH2NH2•H2O, MeOH HOAc, rt, 59%

TESO

O

OH

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9.

(a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615−3616. (b) Wharton, P. S. J. Org. Chem. 1961, 26, 4781−4782. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1−51. (Review). Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437−3444. (Review). Thomas, A. F.; Di Giorgio, R.; Guntern, O. Helv. Chim. Acta 1989, 72, 767−773. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003−2004. Yamada, K.-i.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666−3672. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem. 2000, 3247−3249. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031−2036. Li, J. J. Wharton reaction. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 152−158. (Review).

572

White Reagent O O Ph S · S Ph Pd(OAc)2 White Reagent

The White Reagent 1 is a highly versatile, commercially-available catalyst for allylic C–H oxidation which allows for the construction of useful C–O, C–N, and C–C bonds directly from relatively inert allylic C–H bonds (Figure 1).1–11 The White Reagent enables novel and predictable disconnections for the synthesis of complex molecules which can streamline their synthesis.2,4,7,8 Widely available αolefins undergo intra- and intermolecular C–H oxidation with remarkably high levels of chemo-, regio-, and stereoselectivity. Mechanistic studies provide evidence that the White Reagent promotes allylic C–H cleavage to generate πallylpalladium intermediate 2 which can then be functionalized with an oxygen, nitrogen or carbon nucleophile (Figure 1).3 Figure 1 H R O O Ph S · S Ph 1 Pd(OAc)2 (10 mol%) White Reagent

C −C CO2Me

R

R

NO2

C −N

C −O OC(O)R1

OC(O)R1

Pd(II)Ln

R

NR'2

R

2

R

OH

Ar O O

R NR'2

Common organic functionality such as Lewis basic phenol 3,3 acid-labile acetal 4, highly reactive aryl triflate 6,11 and depsipeptide 55 are well-tolerated under the mild reaction conditions (Figure 2). In all cases the products are isolated as one regioisomer and olefin isomer after column purification. Current state-of-the-art methods for constructing C–N bonds rely on functional group interconversions or C–C bond forming reactions using preoxidized materials. Allylic amination using the White Reagent can streamline the synthesis of nitrogen-containing molecules by reducing the functional group manipulations necessary for working with oxygenated intermediates. Allylic C–H amination was used to synthesize (–)-8, an intermediate in the synthesis of Lacosamine derivative 9 (Figure 3A).7 The C–H amination route to (–)-8 proceeded in half the total number of steps, no functional group manipulations, and 8

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_267, © Springer-Verlag Berlin Heidelberg 2009

573

comparable overall yield to the alternative C–O to C–N bond-forming route. Intermolecular C–H amination has also led to the construction of (+)deoxynegamycin analogue 12 in five less steps and improved overall yield compared to the alternative route relying on C–O substitution (Figure 3B).8 Figure 2 O O Ph S · S Ph 1 Pd(OAc)2 Nu (10 mol%) or + pro-nucleophile (NuH) (1.5−2.0 equiv) R conditions branched product (B)

H R

branched allylic C-H oxidation

Nu R linear product (L)

linear allylic C-H amination

OH

p-BrPhO2C O

BQ (2 equiv), dioxane, 43 oC

O O

CO2Me

N Ts OBn (+)-4, 63%, > 20:1 E:Z, > 20:1 L:B

O 3, 65% yield, > 20:1 B:L branched macrolactonization

Cr(salen)Cl (6 mol%), BQ (2 equiv), TBME, 45 oC

linear allylic C-H alkylation

O MeO2C BQ (2 equiv) CH2Cl2, 45 oC

N O Ph

CO2Me DMBQ (1.5 equiv), AcOH (0.5 equiv), dioxane:DMSO (4:1)

O NO2

TfO NH HN

OMe

O

O 5, 61% yield, 3:1 dr

6, 64% yield, > 20:1 E:Z, > 20:1 L:B

Figure 3 A.

O O

TBSO

H (+)-7

B. BocNH

TMSEO2C (−)-10

NHTs

O O Ph S · S Ph 1 O Pd(OAc)2 (10 mol%) O NTs PhBQ (1.05 equiv) THF, 50 oC, 72 h 78%, 9:1 dr crude TBSO (70% yield, (−)-8 1 isomer)

O O Ph S · S Ph 1 Pd(OAc)2 (10 mol%) Cr(salen)Cl (6 mol%)

BocNH

OMe steps Me

NHAc OH (−)-N-acetyl-O-methyl acosamine 9

BocNH

O

CbzNHTs (2 equiv) NTsCBz BQ (2 equiv.), TBME (+)-11 54%, 1 isomer

O

O

steps OTMSE

2 HBr

N H

N

NH2 CO2H (+)-deoxynegamycin analogue 12

Similarly, allylic C–H oxidation can streamline the construction of oxygenated compounds by reducing functional group manipulations necessary for working with bisoxygenated intermediates. For example, a chiral allylic C–H oxidation/enzymatic resolution sequence furnished bisoxygenated compound 14 in 97% ee and in 42% overall yield in just 3 steps from a commercially available

574

monooxygenated precursor, 11-undecenoic acid (Figure 4).10 Alternative routes to similar molecules require protection/deprotection sequences and use a kinetic resolution giving a maximum of 50% yield. Figure 4 O

H

O

1. (MeO)NMe

HO 7 undecenoic acid

CDI, DCM

MeO

N Me

H 7

13

2) 1 (10 mol%) (R,R)-Cr(salen)F (10 mol%)

O MeO

AcOH (1.1 equiv) BQ (2 equiv) 4 Å MS, EtOAc, rt 3) Novazyme 435

N Me

OAc 7

14 42% overall yield > 20:1 B:L, 97% ee

In addition to allylic C–H oxidation, the White Reagent also catalyzes intermolecular Heck arylations.6 Notably, the arylation uses electronically unbiased α-olefins and aryl boronic acids and occurs under acidic, oxidative conditions. A one-pot allylic C–H oxidation/vinylic C–H arylation reaction furnishes E-arylated allylic esters with high regio- and stereoselectivities (Figure 5). This three-component coupling can be used to rapidly synthesize densely functionalized products from inexpensive hydrocarbon feedstocks. N-Boc glylcine allylic ester 9 was synthesized in one step using commercially available olefin, amino acid, and boronic acid reagents. Compounds similar to 15 have been transformed into medicinally relevant dipeptidyl peptidase IV inhibitors.6 Figure 5 Branched allylic C−H esterification

H Me 7 1-undecene

O O Ph S · S Ph 1 Pd(OAc)2 (10 mol%) N-Boc-Gly (2 equiv) Me BQ (2 equiv) dioxane, 45 oC

Oxidative Heck O O 7

O

(4-Br)PhB(OH)2 NHBoc (1.5 equiv), 45 oC Me

O

NHBoc

7

15, 75% Br > 20:1 E:Z > 20:1 internal:terminal

Besides the one-pot process described above, the White Reagent catalyzes a chelate-controlled oxidative Heck arylation between a wide range of α-olefins and organoborane compounds in good yields and with excellent regioand stereoselectivities (Figure 6).9 Unlike other Heck arylation methods, no Pd–H isomerization is observed under the mild reaction conditions. Aryl boronic acids, styrenylpinacol boronic esters, and aryl potassium trifluoroborates (activated with boric acid) are all compatible with the general reaction conditions.

575

Figure 6 R'

X R n = 0−2

Ar

O O M M = B(OH) 2 Ph S · S Ph 1 Pd(OAc)2 = BF3K X (10 mol%) or R Ar AcOH (4 equiv) Bpin quinone (2 equiv) > 20:1 E:Z dioxane, rt, 4 h > 20:1 internal:terminal

α,β-unsaturated carbonyls

amino acids F

O

H N

BocHN

F

O CO2Me (+)-16, 60% free alcohols

Br

HO 18, 83%

N Boc

Ph

Bn (+)-17, 62% allylic amine NHBoc Ph (+)-19, 81%

References Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346–1347. Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett. 2005, 7, 223–226. Chen. M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970–6971. 4. Covell, D. J.; Vermeulen, N. A.; White, M. C. Angew. Chem. Int. Ed. 2006, 45, 8217– 8220. 5. Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am. Chem. Soc. 2006, 128, 9032–9033. 6. Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076–15077. 7. Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274–7276. 8. Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 129, 3316–3318. 9. Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 129, 11270– 11271. 10. Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448–6451. 11. Young, A. J.; White, M. C. J. Am. Chem. Soc. 2008, 129, 14090–14091. 1. 2. 3.

576

Willgerodt–Kindler reaction Conversion of a ketone to thioamide, with functional group migration. S

O

HNR2

Me

Ar

Ar

NR 2

n

TsOH, S8, Δ

n

thioamide

In Carmack’s mechanism,2 the most unusual movement of a carbonyl group from methylene carbon to methylene carbon was proposed to go through an intricate pathway via a highly reactive intermediate with a sulfur-containing heterocyclic ring. The sulfenamide serves as the isomerization catalyst. e.g.: S

O

HN

O N

TsOH, S8, Δ

thioamide

O

O

S S S S O

O

S S S S

NH

O

NH

N:

SH S N S S S S S S

O

N S

O

N S

SH S S S HS S

sulfenamide

O :

O

O

N :

O

N

N : S

S

N

S

N

N H

O

O

O

H

O

O

O N

N S

N S

thiirene

H

S H

N

H

:N

S

:N

N O

HN

O

O

O

S S N

O N

N

O

O

S8

N O

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_268, © Springer-Verlag Berlin Heidelberg 2009

577

Example 1, The Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:3 O

O HN

O

N

S8

O

S

O

1. H+ 2. CH3OH, H2SO4

OH O

O

3. NaH, CH3I 4. NaOH

Naproxen

Example 25 O

HN

S

O

N S8, microwave 4 min., 40%

O

Example 3, A domino annulation reaction under Willgerodt–Kindler conditions:10 O N

O Cl

O

HN

O

N S S

N

S8, 130 oC, 6 h, 15%

S S

46% N

N

26%

References (a) Willgerodt, C. Ber. 1887, 20, 2467−2470. Conrad Willgerodt (1841−1930), born in Harlingerode, Germany, was a son of a farmer. He worked to accumulate enough money to support his study toward his doctorate, which he received from Claus. He became a professor at Freiburg, where he taught for 37 years. (b) Kindler, K. Arch. Pharm. 1927, 265, 389−415. 2. Carmack, M.; Spielman, M. A. Org. React. 1946, 3, 83−107. (Review). 3. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203−205. 4. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319−1323. 5. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett. 1999, 40, 7549−7552. 6. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59−63. 7. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167−4169. 8. Purrello, G. Heterocycles 2005, 65, 411−449. (Review). 9. Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007, 2687−2690. 10. Kadzimirsz, D.; Kramer, D.; Sripanom, L.; Oppel, I. M.; Rodziewicz, P.; Doltsinis, N. L.; Dyker, G. J. Org. Chem. 2008, 73, 4644−4649. 1.

578

Wittig reaction Olefination of carbonyls using phosphorus ylides, typically the Z-olefin is obtained. O R1

R2

R1

Ph3P: R

R3

R1

R3

R4

R2

R4

Ph3P

Ph3P O

X

SN2

R1

Ph3P

X

R1 H

PPh3

R

R3 2

R

O

O R2 R3

O

Ph3P R

R

:B

2

R

[2 + 2]

1

cycloaddition

R1 R PPh3

betaine

R3 R

“puckered” transition state, irreversible and concerted R3

Ph3P O R

R

1

PPh3 O

3

2

R R oxaphosphetane

R

R1

2

R

Example 13 CHO

NaH, Et2O; then add CH2=CHPPh3+Br−

NHTs

DMF, reflux, 48 h, 50%

N Ts

Example 24 1.8 N NaOEt, EtOH PPh3

Cl HO

O

O

−30 oC to rt

CO2H CO2H 2-cis-4-cis-vitamin A acid

Accutane

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_269, © Springer-Verlag Berlin Heidelberg 2009

579

Example 35 H N

PhO O

N O t-BuO2C

H N

PhO

S

Tol., 70 oC

O PPh3

S

O

70%

N O

CO2t-Bu

Example 49 H

O

H

O O

H

H

EtS

O

H O

I O H H

H

O

H

H

O

PPh3

H

OTBS O

OTPS

EtS O

OTMS

H

1. n-BuLi, HMPA 2. PPTS, 75%

O

OTPS

TBSO H O

H

O

H

H

O O

EtS OTMS EtS

O

H O

O O H

H

H O H H

H

O

H

References Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318−1330. Georg Wittig (Germany, 1897−1987), born in Berlin, Germany, received his Ph.D. from K. von Auwers. He shared the Nobel Prize in Chemistry in 1981 with Herbert C. Brown (USA, 1912−2004) for their development of organic boron and phosphorous compounds. 2. Maercker, A. Org. React. 1965, 14, 270−490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146–3149. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982– 1983. 5. Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman, D. E.; Pfaendler, H. R.; Woodward, R. B. J. Am. Chem. Soc. 1978, 100, 8214–8222. 6. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1−30. (Review). 7. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863−927. (Review). 8. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1–157. (Review). 9. Nicolaou, K. C. Angew. Chem., Int. Ed. 1996, 35, 589–607. 10. Rong, F. Wittig reaction in. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 588−612. (Review). 1.

580

Schlosser modification of the Wittig reaction The normal Wittig reaction of nonstabilized ylides with aldehydes gives Z-olefins. The Schlosser modification of the Wittig reaction of nonstabilized ylides furnishes E-olefins instead.

PhLi

PhLi

Br Ph3P R

R

t-BuOH

R1 CHO

t-BuOK

R1

Br H Ph3P

Ph3P

H

Ph3P

R

H

R

R

R1

O

Ph

phosphorus ylide Ph3P OLi Br RH

Ph3P OLi Br

R1

R Li

R

t-BuOH

1

Ph

LiBr complex of β-oxo ylide These conditions allow for the erythreo betaine to interconvert to the threo betaine PPh3 Br LiO R

H

t-BuOH

R

H

LiBr

Ph3P O

t-BuOK

R1

R1

LiBr complex of threo betaine Example 16 Me Ph

O

I N

N EtO2C

O

5 equiv Et3P, DMF, rt, 30 min. O

then 0 oC, LDA, then

N

O

Ph

H Me

66%

N EtO2C

O

581

Example 210

O

PPh3Br PhLi, Bu2O/THF 66%

References (a) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. 1966, 5, 126. (b) Schlosser, M.; Christmann, K. F. Ann. 1967, 708, 1−35. (c) Schlosser, M.; Christmann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29−31. 2. van Tamelen, E. E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 2061−2062. 3. Parziale, P. A.; Berson, J. A. J. Am. Chem. Soc. 1991, 113, 4595−606. 4. Sarkar, T. K.; Ghosh, S. K.; Rao, P. S.; Satapathi, T. K.; Mamdapur, V. R. Tetrahedron 1992, 48, 6897−6908. 5. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5, 103−113. (Review). 6. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449−5452. 7. Panek, J. S.; Liu, P. J. Am. Chem. Soc. 2000, 122 11090−11097. 8. Duffield, J. J.; Pettit, G. R. J. Nat. Prod. 2001, 64, 472−479. 9. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2004, 4995−5002. 10. Kraft, P.; Popaj, K. Eur. J. Org. Chem. 2008, 4806−4814. 1.

582

[1,2]-Wittig rearrangement Treatment of ethers with bases, such as alkyl lithium, results in alcohols. R

O

2

R1

R2Li

R1

R

1

2

OH 1

The [1,2]-Wittig rearrangement is believed to proceed via a radical mechanism: Li

R2

R

O

R

R1

O

R1 R

cleavage

R1

OLi

R

Li

homolytic

R1

deprotonation

H

R

R1

O

R1

workup R

OLi

OH

Example 1, Aza [1,2]-Wittig rearrangement2 Ph

n-BuLi

N SnBu3 CH3

Ph

workup

N Li CH3

H N

Ph

83%

CH3

Example 23 t-BuLi O 58%

O

OH

O

Example 34

O

H

O

TMS

OTBDPS

O

n-BuLi, THF, ether 0 °C, 60%, > 98:2 dr

H

OH TMS

OTBDPS

Example 46 NOMe

NOMe 2 eq. LDA, THF O O

−78 oC, 82%

O

Example 58 J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_270, © Springer-Verlag Berlin Heidelberg 2009

OH

583

TBSO

OTBS O

TBSO

n-BuLi, THF Ph

TBSO

OH Ph

−20 to 0 oC, 32%

Example 69 N O

OMe

N

LDA, THF O

Ph

O −40 oC, 94%

OMe Ph OH

References 1 2 3 4 5 6 7 8 9 10

Wittig, G.; Löhmann, L. Ann. 1942, 550, 260–268. Peterson, D. J.; Ward, J. F. J. Organomet. Chem. 1974, 66, 209–217. Tsubuki, M.; Okita, H.; Honda, T. J. Chem. Soc., Chem. Commun. 1995, 2135–2136. Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317–3318. Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551–8552. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915–1916. Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783–1788. Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed. 2000, 39, 4502–4505. Miyata, O.; Asai, H.; Naito, T. Chem. Pharm. Bull. 2005, 53, 355–360. Wolfe, J. P.; Guthrie, N. J. [1,2]-Wittig Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 226−240. (Review).

584

[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as the Still−Wittig rearrangement. Cf. Sommelet−Hauser rearrangement. 2

3

1 1

X

2

1

[2,3]-sigmatropic

3

rearrangement

Y

X

2

Y

2

1

R R

R1

O

R2Li O

H R1 R2

R1 = alkynyl, alkenyl, Ph, COR, CN.

rearrangement

R

R

[2,3]-sigmatropic O

workup

R1

HO

R1

Example 12

KOt-Bu, HOt-Bu, THF O O

0 oC, 26 h, 22%

HO O

Example 23 LDA, THF, −78 oC; O

CO2H

TsO CO2H > 95% E

then TsCl, 87%

Example 35 H

H H

O N H O

O

1.5 equiv LiHMDS 5 equiv HMPA, THF

O

H N

HO H

−78 to −10 οC 67%

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_271, © Springer-Verlag Berlin Heidelberg 2009

O N

O

HO H

H

O H

94 : 6

585

Example 46 Me

Me

Me OSEM O

O

Me O

OSEM

n-BuLi

Me

THF-pentane 97% HO

Me

References Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521−3527. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084−2087. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22, 69−72. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105−209. (Review). 5. Kress, M. H.; Yang, C.; Yasuda, N.; Grabowski, E. J. J. Tetrahedron Lett. 1997, 38, 2633−2636. 6. Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962−5970. 7. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111−1113. 8. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahedron: Asymmetry 2000, 11, 4725−4736. 9. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913−2920. 10. Ahmad, N. M. [2,3]-Wittig Rearrangement. In Name Reactions for HomologationsPart II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 241−256. (Review). 1. 2. 3.

586

Wohl–Ziegler reaction The Wohl–Ziegler reaction is the reaction of an allylic or benzylic substrate with N-bromosuccinimide (NBS) under radical initiating conditions to provide the corresponding allylic or benzylic bromide. Conditions used to promote the radical reaction are typically radical initiators, light and/or heat; carbon tetrachloride (CCl4) is typically utilized as the solvent. Br

O

O

CCl4, reflux

R

Br N

R

HN

initiator O

O

Initiation: Δ NC

N N

CN

N2↑

homolytic cleavage

2

CN

Br

CN

2,2ƍ-azobisisobutyronitrile (AIBN) O

O N Br

N

CN

O

O

Propagation: O

O H abstraction

N

NH

H

O

O O

O

N Br

Br

N

O

O

The succinimidyl radical is now available for the next cycle of the radical chain reaction. Example 13 OAc

OAc NBS, CCl4 reflux, 30 min., 48%

AcO

OAc

:

OAc

O

O Br

AcO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_272, © Springer-Verlag Berlin Heidelberg 2009

AcO

O

587

Example 27 CO2Me

1.2 eq. NBS, 0.1 eq. AIBN

CO2Me

solvent free, 60 to 65 oC 89%

Br

Example 38 Br N

N

NBS, CCl4 reflux, 71%

N

N Br

Example 49 Br NBS, AIBN (cat) BocN O

CCl4, reflux, 2 h, 95%

BocN O

References Wohl, A. Ber. 1919, 52, 51−63. Alfred Wohl (1863−1939), born in Graudenz, Germany, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochschule in Danzig. 2. Ziegler, K.; Spath, A.; Schaaf, E.; Schumann, W.; Winkelmann, E. Ann. 1942, 551, 80−119. Karl Ziegler (1898−1973), born in Helsa, Germany, received Ph.D. in 1920 from von Auwers at the University of Marburg. He became the director of the MaxPlanck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943 and stayed there until 1969. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (1903−1979) for their work in polymer chemistry. The Ziegler−Natta catalyst is widely used in polymerization. 3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660−663. 4. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351−352. 5. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609−4612. 6. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R. Synlett 2002, 1089−1092. 7. Togo, H.; Hirai, T. Synlett 2003, 702−704. 8. Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Mendeleev Commun. 2004, 278−279. 9. Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 6310−6311. 10. Curran, T. T. Wohl–Ziegler reaction. In Name Reactions for Homologations-Part I; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 661−674. (Review). 1.

588

Wolff rearrangement Conversion of an α-diazoketone into a ketene. O

N2

R1

Δ

H2O

R1

O

R2

OH

CO2

C O R1

N2

R2

R2

α-diazoketone

R2

R1

ketene intermediate

Step-wise mechanism: N

N

N

O

N

R1

R2

R1

R2

R1

O

N2

O

C O R1

R2

R2

α-ketocarbene Treatment of the ketene with water would give the corresponding homologated carboxylic acid. Concerted mechanism: N O

N

R1

R2

N2

R1 C O R2

Example 12 O

O

Δ or hv H

O

O OEt

EtOH, dioxane (1:1) > 90%

N2

Example 23 O

N Me

CO2Me

N2

hv, MeOH

O

90%

O N Me

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_273, © Springer-Verlag Berlin Heidelberg 2009

589

Example 34

hυ

1. LiHMDS, TFEA N2

2. MsN3, Et3N O

CH3OH

O

O

OMe

Example 49 C5H11

C5H11 HN

N2 EtO2C

O

O Rh2Oct4

HN O CO2Et

EtO2C

C5H11CONH2 N Boc

N 55% Boc Wolff rearrangement

39%

O O

N Boc

N-H insertion

References Wolff, L. Ann. 1912, 394, 23−108. Johann Ludwig Wolff (1857−1919) earned his doctorate in 1882 under Fittig at Strasbourg, where he later became an instructor. In 1891, Wolff joined the faculty of Jena, where he collaborated with Knorr for 27 years. 2. Zeller, K.-P.; Meier, H.; Müller, E. Tetrahedron 1972, 28, 5831−5838. 3. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Ber. 1993, 126, 2357−2360. 4. Taber, D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998, 63, 7953−7956. 5. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2, 2177−2179. 6. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002, 2193−2256. (Review). 7. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125, 4478−4486. 8. Zeller, K.-P.; Blocher, A.; Haiss, P. Mini-Reviews Org. Chem. 2004, 1, 291−308. (Review). 9. Davies, J. R.; Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70, 5840−5851. 10. Kumar, R. R.; Balasubramanian, M. Wolff Rearrangement. In Name Reactions for Homologations-Part II; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2009, pp 257−273. (Review). 1.

590

Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.

O

NH2NH2 R1

R

R1

R

NaOH, reflux

HO O R

:

R

NH2 HO N H

1

R

R

N

1

:

R

NH2NH2

HO

H N R1 H

H

N

R1

N

O

H

H R1

R R

R

O

H

− N2

H

R1

Example 1, Huang Minlon modification, with loss of ethylene here5

O

NH2NH2•H2O NH2NH2•2HCl

KOH, 210 oC

130 oC

36%

Example 27 H2 N

O 80% NH2NH2•H2O toluene, microwave 20 min., 75%

MeO2C

N

MeO2C

KOH, microwave 30 min., 40%

MeO2C

Example 38 OH O 85% NH2NH2•H2O, KOH OH

H2O, 30 min., 165 oC, 87%

HO

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_274, © Springer-Verlag Berlin Heidelberg 2009

591

OH OH

OH OH O

H H H

H 1,5-hydride shift

HO

HO

Example 4, Huang Minlon modification10 N

OH Me NH2NH2•H2O diethylene glycol reflux, 4.75 h, 75%

HO

HO OMe

OMe

References (a) Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582−595. (b) Wolff, L. Ann. 1912, 394, 86. (c) Huang, Minlon J. Am. Chem. Soc. 1946, 68, 2487−2488. (d) Huang, Minlon J. Am. Chem. Soc. 1949, 71, 3301−3303. (The Huang-Minlon modification). 2. Todd, D. Org. React. 1948, 4, 378−422. (Review). 3. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734−1735. 4. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556−2557. 5. Lemieux, R. P.; Beak, P. Tetrahedron Lett. 1989, 30, 1353−1356. 6. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903−906. 7. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573−1592. 8. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67, 31−38. 9. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268−3272. 10. Pasha, M. A. Synth. Commun. 2006, 36, 2183−2187. 11. Song, Y.-H.; Seo, J. J. Heterocycl. Chem. 2007, 44, 1439−1443. 12. Shibahara, M.; Watanabe, M.; Aso, K.; Shinmyozu, T. Synthesis 2008, 3749−3754. 1.

592

Woodward cis-dihydroxylation Cf. Prévost trans-dihydroxylation. 1. I2, AgOAc HO OH

2. H2O, H+

I

I

I

I

SN2

SN2 : O

O

OAc

cyclic iodonium ion intermediate O

−H

O

O

neighboring group assistance protonation

HO O

O

H O

H2O:

:OH2 HO O O

O

hydrolysis

HO O

HO OH

HO O

H

H

Example 11 CH3 H3C O

H

CH3

I2, AgOAc HOAc, H2O

H3 C

23 → 95 °C 3.5 h

H

H

O

OR1 OR2

H

CH3 KOH, MeOH

H3C

23 °C, 71% overall O

H

H

OH OH

Example 26 OH H3 C

CH3 NBA, AgOAc, HOAc H

HO

23 °C, 75% H

MeO2C

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_275, © Springer-Verlag Berlin Heidelberg 2009

R1 = Ac, R2 = H R1 = H, R2 = Ac

593

OH H3 C

OH

CH3

H3C

CH3

H HO MeO2C

H

O O Me

HO MeO2C

H

H OAc Br

Br

References Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80, 209−211. Robert Burns Woodward (USA, 1917−1979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products. 2. Kirschning, A.; Plumeier, C.; Rose, L. Chem. Commun. 1998, 33−34. 3. Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.; Kirschning, A. Org. Lett. 1999, 1, 2101−2104. 4. Kirschning, A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett. 1999, 40, 8999−9002. 5. Muraki, T.; Yokoyama, M.; Togo, H. J. Org. Chem. 2000, 65, 4679−4684. 6. Germain, J.; Deslongchamps, P. J. Org. Chem. 2002, 67, 5269−5278. 7. Myint, Y. Y.; Pasha, M. A. J. Chem. Res. 2004, 333−335. 8. Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005, 7, 5071−5074. 9. Mergott, D. J. Woodward cis-dihydroxylation. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 327−332. (Review). 10. Burlingham, B. T.; Rettig, J. C. J. Chem. Ed. 2008, 85, 959−961. 1.

594

Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent). Cl O Cl

O

O

Cl

Cl O R

R

Cl OH

O

Et3N, CH2Cl2

O

HO R1 Cl

Cl

DMAP, Tol., reflux

O Cl O

O

R

O Cl Cl

R

O Cl

H

Cl

R1

Cl

N

:NEt3 O

O

Cl

:

Cl

R

O

O

Cl Cl O

R

Cl N

DMAP (dimethylaminopyridine) R O N

O

Cl

O

O

O

Cl R

O Cl

Cl

Cl

N

Cl

N N

R1 O: H

Steric hindrance of the chloro substituents blocks attack of the other carbonyl of the mixed anhydride intermediate. R O R1

O

O

N R

N

O

R1

Example 1, Intermolecular coupling5 OH

OMe I

CO2H

n-Bu3Sn

ODMT OMe

OTES

OMe I 2,4,6-trichlorobenzoyl chloride DMAP, Tol., Et3N rt, 24 h, 89%

O OTES

O

n-Bu3Sn

ODMT OMe

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_276, © Springer-Verlag Berlin Heidelberg 2009

595

Example 2, Intramolecular coupling7

O O

O

O

2,4,6-trichlorobenzoyl chloride Et3N, THF

HO CO2H

then DMAP, toluene, 62%

O O

O

O

O O

Example 3, Dimerization8 H H

H

H

BnO

O

Yamaguchi reagent

OH O

H

O

125 OH

oC,

O

O

O

O

6 h, 66% BnO

O

H H H

References (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989−1993. (b) Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943−944. 2. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977−8996. 3. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513−1516. 4. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39, 4314−4316. 5. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533−4537. 6. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214−2222. 7. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970−15971. 8. Smith, A. B. III.; Simov, V. Org. Lett. 2006, 8, 3315−3318. 9. Ahmad, N. M. Yamaguchi esterification. In Name Reactions for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; John Wiley & Sons: Hoboken, NJ, 2007, pp 545−550. (Review). 10. Wender, P. A.; Verma, V. A. Org. Lett. 2008, 10, 3331−3334. 11. Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769−772. 1.

596

Zincke reaction The Zincke reaction is an overall amine exchange process that converts N-(2,4dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.

NH2 N

Cl

O2N

R NH2

O2N

N R

Zincke salt

Cl NO2

NO2

:

H2 N R Cl

N

N

O2N

N H

O2N

R

N H

N H

O2 N

R ringopening

NO2

NO2

NO2

:

R NH2 NH

N

R

NH

H

O2N

O2N

N H

R 1,6-addition/elimination

NO2

NO2

R :

N H O2N

NH

N H

NH2

R

O2N

NO2 NO2

R

N H

H N

R

H R

R

6π electrocyclization

N R

N H

R

H N

N

H

cis-trans R

:

N R

H N

N R

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_277, © Springer-Verlag Berlin Heidelberg 2009

N H2

inversion

R

N R

Cl

597

Example 15 Et Cl NO2

Et

N

Acetone, Δ

Cl

O2N

NH2 OH

Ph

overnight (79%)

N NO2

NO2

Et n-BuOH, Δ

N

20 h, 86%

Cl Ph

OH

Example 26 NH2

Cl NO2 N

N

OH

N

OH

N

NO2

OH

Cl

H2O, Δ, 16 h

OEt

OH

EtO H N

CaCO3, H2O/THF (4:1) 20 oC, 3 days 25%, 2 steps

N

O

HO

Example 39 Cl

11

N

N Boc

NO2

CO2t-Bu

MeOH, reflux 89%

NO2

11

N O2 N

Cl

N Boc

CO2t-Bu 11 11

NH2

N

Cl

N 11

n-BuOH, heat, 61% NO2

N

N Boc

CO2t-Bu

598

Example 410 Cl NO2

N O2N

N

Cl

NO2

Me2NH then NaOH 58%

NO2 Zincke salt

Me2N

CHO

LiSnBu3 50−55%

Bu3Sn

CHO

Zincke aldehyde

References (a) Zincke, Th. Ann. 1903, 330, 361−374. (b) Zincke, Th.; Heuser, G.; Möller, W. Ann. 1904, 333, 296−345. (c) Zincke, Th.; Würker, W. Ann. 1905, 338, 107−141. (d) Zincke, Th.; Würker, W. Ann. 1905, 341, 365−379. (e) Zincke, Th.; Weisspfenning, G. Ann. 1913, 396, 103−131. 2. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665−1673. (Review). 3. Becher, J. Synthesis 1980, 589−612. (Review). 4. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423−3454. (Review). 5. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J. Org. Chem. 1997, 62, 729−735. 6. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251−9256. 7. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585−588. (Review). 8. Rojas, C. M. Zincke Reaction. In Name Reactions in Heterocyclic Chemistry; Li, J. J., Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, pp 355−375. (Review). 9. Shorey, B. J.; Lee, V.; Baldwin, J. E. Tetrahedron 2007, 63, 5587−5592. 10. Michels, T. D.; Rhee, J. U.; Vanderwal, C. D. Org. Lett. 2008, 10, 4787−4790. 1.

599

Subject Index A abnormal Beckmann rearrangement, 34 abnormal Chichibabin reaction, 108 abnormal Claisen rearrangement, 121 acetic anhydride, 54, 167, 204, 424, 440, 442, 452 2-acetamido acetophenone, 92 acetone cyanohydrin, 534 acetonitrile as a reactant, 168 α-acetylamino-alkyl methyl ketone, 167 acetylation, 311 acetylenic alcohols, 100 Į,ȕ-acetylenic esters, 225 acid chloride, 11, 461, 476 acid scavenger, 202 acid-catalyzed acylation, 296 acid-catalyzed alkyl group migration, 566 acid-catalyzed condensation, 131, 133 acid-catalyzed cyclization, 409 acid-catalyzed electrocyclic formation of cyclopentenone, 383 acid-catalyzed reaction, 490 acid-catalyzed rearrangement, 436, 480 acidic alcohol, 339 acidic amide hydrolysis, 534 acidic methylene moiety, 337 acid-labile acetal, 572 acid-mediated cyclization, 444 acid-promoted rearrangement, 190 acrolein, 30, 509 acrylic ester, 30 acrylonitrile, 30 activated hydroxamate, 332 activated methylene compounds, 315 activating agent, 440 activating auxiliary, 458 activating effect of a base, 536 activating group, 288, 351, 440 activation of the hydroxamic acid, 332 activation step, 325 α-active methylene nitrile, 254 acyclic mechanism, 159 acyl anhydride, 234 acyl azides, 162 acyl derivative, 432 N-acyl derivative, 162 ortho-acyl diarylmethanes, 66 acyl group, 234

acyl halide, 234 acyl malonic ester, 263 acyl transfer, 14, 322, 424, 452 2-acylamidoketones, 472 acylation, 8, 51, 234, 235, 296, 322, 332, 440 O-acylation, 332 acylbenzenesulfonylhydrazines, 334 acylglycine, 205 acylium ion, 234, 240, 253, 319 acyl-o-aminobiphenyls, 371 α-acyloxycarboxamide, 415 α-acyloxyketone, 14 α-acyloxythioether, 452 adamantane-like structure, 432 1,4-addition of a nucleophile, 355 addition of Pd-H, 373 cis-addition, 496 1,6-addition/elimination, 596 ADDP, 366 adduct formation, 365 adenosine, 370 aglycon, 221 AIBN, 22, 23, 24, 25, 200, 546, 586, 587 air oxidation, 194 Al(Oi-Pr)3, 345 alcohol activation, 365 aldehyde cyanohydrin, 229 Alder ene reaction, 1, 2, 111 Alder’s endo rule, 184 aldol addition, 470 aldol condensation, 3, 42, 107, 212, 238, 274, 284, 375, 424, 470 Algar–Flynn–Oyamada reaction, 6 alkali metal amide, 517 alkali metal, 44, 517 alkaline medium, 460 alkene, 1, 30, 236, 399, 417, 419, 430, 448, 490 alkenyl anilines, 281 alkenylation, 277 alkoxide-catalyzed oxidation, 404 alkoxide-catalyzed rearrangements, 214 alkoxy methylenemalonic ester, 263 α-alkoxycarbonyl phosphonate, 341 alkyl alcohol, 231 alkyl amine, 596 alkyl cation, 236 alkyl fluorosilane, 233 alkyl group migration, 566

J.J. Li, Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8_BM2, © Springer-Verlag Berlin Heidelberg 2009

600

alkyl halide, 171, 236, 247, 325, 357 O-allyl hydroxylamines, 350 alkyl lithium, 494, 582 alkyl migration, 319, 436 N-alkyl pyridinium, 596 O-alkylating agent, 343 alkylating agent, 236, 343 N-alkylation, 343 alkylation reaction, 203 alkyl-silane, 231 alkyne coordination, 198 alkyne insertion, 198 alkyne, 98, 100, 148, 198, 236, 257, 259, 419, 519 alkynyl copper reagent, 90, 98, 257, 519 alkynyl halide, 90 Allan–Robinson reaction, 8, 322 allenyl enyne, 382 all-trans-retinal, 88 allyl ether, 584 π-allyl Stille coupling, 529 allyl trimethylsilyl ketene acetal, 125 allylic acetate, 549 allylic alcohol, 100, 127, 363, 401, 406, 502, 570 allylic amination, 572 allylic amine, 426, 507 allylic bromide, 586 allylic carbamate, 507 allylic C–H amination, 572 allylic C–H cleavage, 572 allylic C–H oxidation, 572, 573, 574 allylic epoxide, 549 allylic ester enolate, 125 allylic ether, 549 allylic leaving group, 548 allylic substrate, 586 allylic sulfoxide, 363 allylic tertiary amine-N-oxides, 350 allylic transformation, 222 allylic transposition, 1 allylic trichloroacetamide, 406 allyloxycarbenium ions, 222 π-allylpalladium intermediate, 548, 572 allylsilane, 484 (R)-alpine-borane, 359, 360 aluminum chloride, 253 aluminum hydride, 100, 235 aluminum phenolate, 240 amalgamated zinc, 129

amide, 33, 102, 105, 123, 328, 379, 468, 490, 543562 amidine, 438 amination, 58, 80-82, 330, 572, 573 amine exchange, 596 amine-catalyzed rearrangements, 214 amino acid, 167, 534, 574, 575 α-amino acid, 167, 534 α-amino ketone, 238, 385 α-amino nitrile, 534 aminoacetal intermediate, 444 β-aminoalcohol, 177 gem-aminoalcohol, 330 o-aminobiphenyls, 371 β-aminocrotonate, 391 aminothiophene synthesis, 254 ammonia, 107, 270, 274, 276, 411 ammonium carbonate, 76 ammonium sulfite, 74 ammonium ylide intermediate, 517 amphotericin B, 89 aniline, 46, 81, 102, 131, 133, 194, 251, 263, 281, 373, 394, 509, 596 anilinomethylenemalonic ester, 263 anion-assisted Claisen rearrangement, 96 anionic oxy-Cope rearrangement, 138 p-anisyloxymethyl, 141 α-anomer, 222, 223 β-anomer, 320 anomeric center, 313 anthracenes, 66 AOM, 141 aprotic solvent, 16, 401 aralkyloxazole, 472 Arndt–Eistert homologation, 10 aromatic aldehyde, 229 aromatic solvent, 202 aromatization, 196, 234, 236, 517 Arthur C. Cope, 217 aryl aldehyde, 424 aryl boronic acid, 87, 102, 574 aryl diazonium salt, 262 aryl groups migrate intramolecularly, 393 aryl halide, 64, 80, 368, 531, 554 aryl hydrazine, 72 aryl migration, 36, 165 1,2-aryl migration, 215 aryl potassium trifluoroborate, 574 N-aryl pyridinium, 596

601

aryl–acetylene, 98 Ȧ-arylamino-ketone, 46 arylation, 102, 277, 332, 574 O-arylation, 332 arylboronates, 368 β-arylethylamine, 434 2-aryl-3-hydroxy-4H-1benzopyran-4ones, 6 arylhydrazone, 227 O-aryliminoethers, 105 3-arylindole, 46 aryllithium, 413 arylmethyl ether, 202 asymmetric [3+2]-cycloaddition, 144 asymmetric acyl Pictet–Spengler, 434 asymmetric aldol condensation, 212 asymmetric amino-hydroxylation, 496 asymmetric aza-Michael addition, 355 asymmetric Carroll rearrangement, 96 asymmetric Claisen rearrangement, 118 asymmetric construction of carbon– carbon bond, 351 asymmetric Diels–Alder reactions, 143 asymmetric dihydroxylation, 499 asymmetric epoxidation, 300, 502 asymmetric hydroboration, 71 asymmetric hydrogenation, 399 asymmetric intermolecular Heck reaction, 277 asymmetric Mannich reaction, 337, 338 asymmetric Mannich-type reaction, 337, 338 asymmetric Michael addition, 355 asymmetric Mukaiyama aldol reaction, 376 asymmetric Petasis reaction, 426 asymmetric reduction of ketones, 359 asymmetric reduction, 359, 399 asymmetric Robinson annulation, 271 asymmetric Simmons−Smith, 507 asymmetric Tsuji–Trost reaction, 550 α-attack, 6 β-attack, 6 aurone derivative, 7 aza [1,2]-Wittig rearrangement, 582 aza-Diels–Alder reaction, 187 aza-Grob fragmentation, 268 aza-Henry reaction, 284 azalactone, 167 aza-Myers−Saito reaction, 382 aza-Payne rearrangement, 421

aza-π-methane rearrangement, 192 azide, 52, 102, 162, 163, 458, 523 azido-alcohol, 52, 490 aziridine, 52, 146, 266 azirine intermediate, 385 N-aziridinyl imine, 16 azlactone, 204 2,2ƍ-azobisisobutyronitrile, 22, 24, 200, 586 1,1'-(azodicarbonyl)dipiperidine, 366 B backside displacement, 454 Baeyer–Villiger oxidation, 12, 70, 165 Baker–Venkataraman rearrangement, 14 Balz−Schiemann reaction, 488 Bamford–Stevens reaction, 16, 494 Barbier coupling reaction, 18 Bartoli indole synthesis, 20 Barton ester, 22 Barton nitrite photolysis, 26 Barton radical decarboxylation, 22 Barton–McCombie deoxygenation, 24 base-catalyzed condensation, 169, 463 base-catalyzed self-condensation, 546 base-induced cleavage, 273 base-mediated rearrangement, 332 base-promoted radical coupling, 262 base-sensitive aldehyde, 341 basic condition, 203, 337, 430 basic hydrogen peroxide conditions, 165 basic oxidation, 70 BaSO4-poisoned palladium catalyst, 476 Batcho–Leimgruber indole synthesis, 28 Baylis–Hillman reaction, 30 9-BBN, 359 Beckmann rearrangement, 33 Belluš–Claisen rearrangement, 117 benzaldehyde, 95, 108, 515 1,4-benzenediyl diradical formation, 40 benzil, 36 benzilate, 36 benzilic acid rearrangement, 36 benzoin condensation, 38, 525 p-benzoquinone, 391 benzothiazole, 309 benzyl halide, 171, 515, 586 benzyl reagent, 202 benzylation, 202, 203 benzylic bromide, 586 benzylic quaternary ammonium salt, 517

602

benzylic substrate, 586 Bergman cyclization, 40, 382 betaine, 578, 580 biaryl, 554 cis-bicyclo[3.3.0]octane-3,7-dione, 568 Biginelli pyrimidone synthesis, 42 biindolyl, 369 bimolecular elimination, 30 Birch reduction, 44 2,4-bis(4-methoxyphenyl)-1,3dithiadiphosphetane-2,4-disulfide, 328 bis(trifluoroethyl)phosphonate, 527 bis-acetylene, 90 bis-aryl halide, 531 1,4-bis(9-O-dihydroquinidine)phthalazine, 496, 499 Bischler indole synthesis, 46 Bischler–Möhlau indole synthesis, 46 Bischler–Napieralski reaction, 48 B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane, 359 bisoxygenated intermediate, 573 Blaise reaction , 50 Blum–Ittah aziridine synthesis, 52 boat-like, 117 Bobbitt modification, 445 N-Boc glylcine allylic ester, 574 Boekelheide reaction, 54 Boger pyridine synthesis, 56, 188 9-borabicyclo[3.3.1]nonane, 359, see also 9-BBN borane, 70, 87, 89, 143, 359, 360, 536, 574 Borch reductive amination, 58 boric acid, 574 Z-(O)-boron-enolate, 212 boron trifluoride etherate, 222 boronate, 87, 368 boronic acid-Mannich, 426 boronic acid, 87, 88, 102,426, 574 boron-mediated Reformatsky reaction, 457 boron-protected haloboronic acid, 87, 88 Borsche–Drechsel cyclization, 60 Boulton–Katritzky rearrangement, 62 Bouveault aldehyde synthesis, 64 Bouveault–Blanc reduction, 65 Br/Cl variant of the Takai reaction, 541 Bradsher reaction, 66 bromine/alkoxide for Hofmann rearrangement, 290

α-bromoacid, 282 bromodinitrobenzene, 347 N-bromosuccinimide, 586, see also NBS Brook rearrangement, 68 [1,2]-Brook rearrangement, 68, 69 [1,3]-Brook rearrangement, 68 [1,4]-Brook rearrangement, 68 [1,5]-Brook rearrangement, 69 Brown hydroboration, 70 BT, 309 Bu3P, 505 Bucherer carbazole synthesis, 72 Bucherer reaction, 74 Bucherer–Bergs reaction, 76 Büchner ring expansion, 78 Buchwald–Hartwig amination, 80, 102 t-BuLi, 69, 199, 390, 413, 414, 582 Burgess dehydrating reagent, 84, 339 Burke boronates, 87 butterfly transition state, 478 t-butyl peroxide, 502 C 13 C-labelled α,β-unsaturated ketone, 196 Cadiot–Chodkiewicz coupling, 90, 98, 519 calystegine, 220 camphorsulfonic acid, 203, see also CSA Camps quinoline synthesis, 92 Cannizzaro reaction, 94 carbazole, 60, 70, 72 carbene generation, 460 carbene mechanism, 428 carbene, 10, 112, 156, 198, 428, 460, 588 carbocation rearrangement, 176, 177 β-carbocation stabilization by the silicon group, 231 β-carbocation stabilizationby the βsilicon effect, 484 carbocyclization, 220 carbodiimide, 332, 370 carbon Ferrier reaction, 222 carbon monoxide, 253, 419 carbon nucleophile, 222, 484, 548, 572, see also C- nucleophile carbon tetrachloride, 586, see also CCl4 carbon–boron bond, 306, 328, 387, 430, 434, 436 carbonyl oxide, 161

603

carbonyl, 335, 399, 456, 484, 490, 542 ȕ-carbonyl sulfide derivative, 251 1,2-carbon-to-nitrogen migration, 162 carboxylic acid, 10, 22, 94, 202, 214, 282, 304, 415, 551 carboxylic amide derivative, 273 Carroll rearrangement, 96 Castro–Stephens coupling, 90, 98, 519 in situ Castro–Stephens reaction, 99 catalytic asymmetric enamine aldol, 271 catalytic asymmetric inverse-electrondemand Diels–Alder reaction, 187 catalytic cycle, 81, 143, 277, 288, 325, 399, 401, 465, 496, 500, 502, 529, 536, 548, 564 catalytic Pauson−Khand reaction, 419 CBS reagent, 143 3CC, 415 4CC, 551 C–C bond rotation, 277 CCl4, 97, 298, 319, 447, 455, 473, 516, 586, 587 Celebrex, 318 CH2I2, 470, 507, 508 CH3OTf, 202 chair-like, 117 Chan alkyne reduction, 100 Chan–Lam C–X coupling reaction, 102 Chantix, 211 Chapman rearrangement, 105, 393 Chapman-like thermal rearrangement, 106 chelate-controlled oxidative Heck arylation, 574 chemoselective tandem acylation of the Blaise reaction intermediate, 51 chemoselectivity, 572 CHI3, 540 Chichibabin pyridine synthesis, 107 chiral allylic C–H oxidation, 573 chiral auxiliary, 212, 351 chiral ligand, 496 chiral oxazoline, 351 chlorination, 332 in situ chlorination, 455 chloro substituent, 594 chloroammonium salt, 292 ȝ-chlorobis-(cyclopentadienyl)(dimethylaluminium)-ȝmethylenetitanium, 542 chlorodinitrobenzene, 347

chloroiminium salt, 558 α-chloromethyl ketones, 276 2-chloro-1-methyl-pyridinium iodide, 379 3-chloropyridine, 112 N-chlorosuccinimide, 150, see also NCS cholesterol, 321 chromium (VI), 304 chromium trioxide, 304 chromium trioxide-pyridine complex, 304 chromium variant of the Nicholas reaction, 395 Chugaev reaction, 110 Chugaev syn-elimination, 110 Ciamician–Dennsted rearrangement, 112 cinchona alkaloid ligand, 499 cinnamic acid synthesis, 424 Claisen condensation, 113, 182 Claisen isoxazole synthesis, 115 Claisen rearrangement, 16, 96, 117 para-Claisen rearrangement, 119 ortho-Claisen rearrangement product, 119 classical Favorskii rearrangement, 217 cleavage of primary carbon–boron bond, 308 Clemmensen reduction, 129 C–O bond fragmentation, 240 CO insertion, 198 CO, 198, 319 cobalt-catalyzed Alder-ene reaction, 2 Collins oxidation, 304 Collins–Sarett oxidation, 305 Combes quinoline synthesis, 131, 133 combinatorial Doebner reaction, 195 Comins modification, 64 complexation, 87, 234, 240, 296, 484, 564 concerted oxygen transfer, 300 concerted process, 113, 117, 137, 184, 268, 499, 578, 588 condensation, 3, 28, 38, 42, 43, 60, 92, 107, 113, 131, 133, 169, 182, 196, 204, 212, 225, 229, 238, 254, 255, 270, 274, 284, 286, 315, 375, 423, 434, 444, 463, 470, 474, 525, 532, 534, 546, 551 Aldol, 3, 424 Benzoin, 38 Claisen, 113 Darzens, 169

604

Dieckmann, 182 Guareschi–Thorpe, 270 Knoevenagel, 254, 255, 315 Stobbe, 532 conjugate addition, 42, 196, 355, 391, 509, see also Michael addition Conrad–Limpach reaction, 131, 133 coordination and deprotonation, 102, 345 coordination, 102, 198, 345, 404, 548 Cope elimination reaction, 135, 136 Cope rearrangement, 119, 137 copper catalyst, 257 Corey’s PCC, 304 Corey’s oxazaborolidine, 143 Corey’s ylide, 146 Corey–Bakshi–Shibata (CBS) reagent, 143 Corey–Claisen, 117 Corey–Fuchs reaction, 148 Corey–Kim oxidation, 150 Corey–Nicolaou double activation, 152 Corey–Nicolaou macrolactonization, 152 Corey–Seebach dithiane reaction, 154 Corey–Winter olefin synthesis, 156 Corey–Winter reductive elimination, 156 Corey−Chaykovsky reaction, 146 coumarin, 423 (−)-CP-263114, 304 Cp2TiMe2, 428 Cr(CO)3-coordinated hydroquinone, 198 Cr(IV), 304 CrCl2, 540 Criegee glycol cleavage, 159 Criegee mechanism of ozonolysis, 161 Criegee zwitterion, 161 Crimmins procedure for Evans aldol, 212 Crixivan, 301 cross-coupling, 87, 88, 102, 259, 288, 289, 299, 325, 389, 519, 529, 531, 536 cross-McMurry coupling, 335, 336 Cr−Ni bimetallic catalyst, 401 CSA, 203, 271, 412, 453, 505 Cu(III) intermediate, 90, 98 Cu(OAc)2, 102, 103, 259, 260, 299, 565 cupric acetate, 102 Curtius rearrangement, 162 CuTC-catalyzed Ullmann coupling, 554

cyanamide, 562 cyanide, 38 cyanoacetic ester, 270 cyanogen bromide, 562 cyanohydrins, 76 cyclic intermediate, 159 cyclic iodonium ion intermediate, 447, 592 cyclic mechanism, 159 cyclic thiocarbonate, 156 cyclic transition state, 345, 404 cyclization of the Stobbe product, 532 cyclization, 6, 40, 46, 60, 66, 115, 131, 133, 173, 196, 220, 227, 255, 263, 281, 371, 382, 383, 385, 400, 413, 417, 423, 434, 444, 450, 463, 532, 596 Bergman, 40 Borsche–Drechsel, 60 Ferrier carbocyclization, 220 Myers−Saito, 382 Nazarov, 383 Parham, 423 Pshorr, 450 [2+2] cycloaddition, 78, 300, 465, 521, 542, 578 [2+2+1] cycloaddition, 419 [3+2]-cycloaddition, 143, 499 [4+2]-cycloaddition reactions, 184 cyclobutane cleavage, 173 cyclobutanone, 521 cyclodehydration, 472 cyclo-dibromodi-ȝ-methylene(ȝtetrahydrofuran)trizinc, 403 cyclohepta-2,4,6-trienecarboxylic acid ester, 78 cyclohexadiene, 44 cyclohexanone phenylhydrazone, 60 cyclohexanone, 60, 220, 383, 419, 470 cyclopentene, 560 cyclopropanation, 112, 507 cyclopropane, 146, 192, 560 cyclopropanone intermediate, 214 cycloreversion, 465 C−C bond cleavage, 268 C−C bond migration, 176, 177 D Dakin oxidation, 165 Dakin–West reaction, 167 Danishefsky diene, 184 Darzens condensation, 169

605

DBU, 15, 170, 206, 285, 290, 333, 341, 342, 377, 386, 406, 407, 471, 472, 526, DCC, 23, 245, 370 de Mayo reaction, 173 DEAD, 223, 243, 248, 365, 366 decalin, 432 decarboxylation, 96, 263, 315, 332, 474, 568 dehydrating reagent, 339, 432 dehydration, 46, 108, 408, 470, 480, 509 dehydrative ring closure, 371 Delépine amine synthesis, 171, 515 demetallation, 395 Demjanov rearrangement, 175 deoxygenation, 24 (+)-deoxynegamycin, 573 deprotonation of nitroalkanes, 284 depsipeptide, 572 Dess–Martin oxidation, 179, 180, 472 desulfonylation, 560 desymmetrization, 95 Dewar intermediate, 119 (DHQ)2-PHAL, 499 (DHQD)2-PHAL, 496 diamide, 551 diaryl compound, 262 diastereomer, 311, 451, 495 diastereoselective glycosidation, 313 diastereoselective Simmons−Smith cyclopro-panation, 507 1,8-diazabicyclo[5.4.0]undec-7-ene, 341, see also DBU diazoacetic esters, 78 2-diazo-1,3-diketone, 458 α-diazoketone, 588 2-diazo-3-oxoester, 458 diazomethane, 10 diazonium salt, 177, 262, 302, 486 diazotization, 176, 177 diboron reagents, 368 dibromoolefin, 148 1,3-dicarbonyl compounds, 317 1,4-dicarbonyl derivative, 525 1,3-dicyclohexylurea, 370 dichlorocarbene, 112, 460 Dieckmann condensation, 182 Diels–Alder adduct, 184 Diels–Alder reaction, 56, 66, 143, 184, 185, 186, 187 diene, 44, 184, 186, 188, 192 1,4-diene, 192

dienone, 119 Dienone–phenol rearrangement, 190 dienophile, 56, 184, 186, 187 diethyl diazodicarboxylate, 365, see also DEAD diethyl succinate, 532 diethyl tartrate, 502 diethyl thiodiglycolate, 286 dihydroisoquinolines, 48 cis-dihydroxylation, 499 1,4-dihydropyridine, 274 diketone, 14, 131, 173, 270, 286, 408, 409, 411, 458, 474 α-diketone, 286 β-diketones, 14, 131 1,4-diketone, 408, 409, 411 1,4-diketone condensation, 474 1,5-diketone, 173 dimerization, 255, 257, 299 dimethylaminomethylating agent, 206 dimethylaminomethylation, 206 dimethylaminopyridine, 594, see also DMAP N,N-dimethylformamide dimethyl acetal, 28 dimethylmethylideneammonium iodide, 206 dimethylsulfide, 150 dimethylsulfonium methylide, 146 dimethylsulfoxonium methylide, 146 dimethyltitanocene, 428 dinitrophenyl, 67 diol, 156, 159, 203, 250, 436, diosgenin, 130 1,3-dioxolane-2-thione, 156 dipeptidyl peptidase IV inhibitor, 574 diphenyl 2-pyridylphosphine, 244 diphenylphosphoryl azide, 163, see also DPPA DIPT, 503 1,3-dipolar cycloaddition, 161, 458, 459 2,2ƍ-dipyridyl disulfide, 152 diradical, 40, 192, 382, 417, 560 N,N-disubstituted acetamide, 440 disubstituted azodicarboxylate, 365 3,4-disubstituted phenols, 190 4,4-disubstituted cyclohexadienone, 190 3,4-disubstituted thiophene-2,5dicarbonyl, 42, 286, 317, 525 di-tert-butylazodicarbonate, 244 dithiane, 154

606

ditin reagent, 531 di-vinyl ketone, 383 di-π-methane rearrangement, 192 2,4-dinitro-benzenesulfonyl chloride, 243 DMAP, 78, 103, 157, 158, 161, 167, 245, 380, 453, 594, 595 DMFDMA, 28 DMS, 150 DNP, 67 Doebner quinoline synthesis, 194 Doebner–von Miller reaction, 196, 509 domino annulation reaction under Willgerodt–Kindler conditions, 577 Dötz reaction, 198 double Chapman rearrangement, 106 double imine, 227 double Robinson-type cyclopentene annulation, 471 double Tebbe, 542, 543 double Wagner–Meerwein rearrangement, 566 Dowd–Beckwith ring expansion, 200 Dowtherm A, 134 DPE-Phos, 82 DPPA, 163, 164 DTBAD, 244 Dudley reagent, 202 E E/Z geometry control, 125 E1cB, 271, 339 E2, 30, 31, 424, 430 E2 anti-elimination, 430 E2 elimination, 424 E-allylic alcohols, 100 EAN, 316 E-arylated allylic ester, 574 EDDA, 315 EDG, 184 Eglinton coupling, 259 Ei, 84 electrocyclic formation, 383 electrocyclic ring closure, 198 electrocyclic ring opening, 78 electrocyclization, 40, 131, 133, 417, 596 electron transfer, 18, 44, 215, 266, 311, 335, 456, 554 electron-deficient heteroaromatics, 361 electron-donating substituent, 44, 184

electronically unbiased α-olefin, 574 electron-rich alkyl group, 436 electron-rich carbocycle, 558, 558 electron-rich ligands, 80 electron-withdrawing substituent, 44, 184, 347 electrophile, 30, 89, 146, 266, 325, 484, 490, 558 electrophilic site, 413 electrophilic substitution, 234, 296 elemental sulfur, 254, 408 elimination, 30, 80, 84, 90, 98, 102, 110, 135, 136, 156, 229 α-elimination, 460 β-elimination, 281, 339, 519 syn-elimination, 505 syn-β-elimination, 277 Emil Fischer, 222 enamine formation, 271, 274 enamine, 56, 107, 131, 442, 546 enantioselective aromatic Claisen rearrangement, 121 enantioselective borane reduction, 143 enantioselective cis-dihydroxylation, 499 enantioselective epoxidation, 502 enantioselective ester enolate-Claisen rear-rangement, 125 enantioselective Mukaiyama-aldol reaction, 4 enantiospecific Baker−Venkataraman rear-rangement, 14 ene reaction, 1, 110, 121, 140 enediyne, 40 ene-hydrazine, 227 enol, 96, 458 enol ether, 355, 377, 397 enol silane, 482 enolate, 3, 125, 182, 206, 212, 250, 274, 282, 355, 424, 458, 470, 532 enolates, enolsilylethers, 206 enolizable hydrogens for ketones, 217 enolizable α-haloketones, 214 enolization, 8, 42, 282, 322, 323, 337 enolsilane, 478 enone, 173, 323, 482 enophile, 1 enzymatic resolution, 573 episulfone intermediate, 454 epoxidation Corey−Chaykovsky, 146

607

Jacobsen–Katsuki, 300 Payne, 421 Prilezhaev, 478 Sharpless, 502 epoxide migration, 421 epoxide, 146, 300, 421, 478, 502 549 cis-epoxide, 300 trans-epoxide, 300 2,3-epoxy alcohol, 421 α,β-epoxy esters, 169 α,β-epoxy ketone, 570 α,β-epoxy sulfonylhydrazones, 208 1,2-epoxy-3-ol, 421 α,β-epoxyketones, 208 Erlenmeyer−Plöchl azlactone synthesis, 204 erythreo betaine, 580 erythro (kinetic adduct), Horner– Wadsworth–Emmons reaction, 294 erythro isomer, 527 Eschenmoser hydrazone, 16 Eschenmoser’s salt, 206, 337 Eschenmoser–Claisen amide acetal rearrangement, 123 Eschenmoser–Tanabe fragmentation, 208 Eschweiler–Clarke reductive alkylation of amines, 210, 330 6π-electrocyclization, 131, 133, 596 ester, 22, 26, 30, 50, 65, 78, 96, 103, 113, 115, 117, 125, 127, 133, 169, 214, 225, 240, 245, 263, 270, 286, 328, 343, 438, 525 esterification, 379, 574, 594 Et3O+BF4−, 343 Et3SiH, 245 ether formation, 202, 339, 366, 584 ethyl oxalate, 463 ethylammonium nitrate, 316 ethylenediamine diacetate, 315 ethylformate, 458 Evans aldol reaction, 212 Evans syn, 212 evolution of CO2, 167 EWG, 184 exo complex, 419 extrusion of dinitrogen, 162 extrusion of nitrogen, 56, 490 F Favorskii rearrangement, 214

Feist–Bénary furan synthesis, 218 Ferrier carbocyclization, 220 Ferrier glycal allylic rearrangement, 222 Ferrier I reaction, 222 Ferrier II Reaction, 220 Ferrier reaction, 222 Ferrier rearrangement, 222 Fiesselmann thiophene synthesis, 225 Fischer carbene, 198 Fischer indole synthesis, 60, 72, 227 Fischer oxazole synthesis, 229 flavone, 8 flavonol, 6 Fleming–Tamao oxidation, 231 Fleming−Kumada oxidation, 233 fluoride, 288 fluoroarene, 488 fluoro-Meisenheimer complex, 347 fluorous Corey−Kim reaction, 150 fluorous Mukaiyama reagent, 380 formal [2+2+1] cycloaddition, 419 formaldehyde, 210, 330 formamide acetal, 28 formic acid, 210, 330 o-formylphenol, 460 formylation, 64, 253 four-component condensation, 551 four-electron system, 1 four-membered titanium oxide ring intermediate, 428 fragmentation, 196, 208, 240, 268 Friedel–Crafts acylation reaction, 234 Friedel–Crafts alkylation reaction, 236 Friedel–Crafts reaction, 234 Friedländer quinoline synthesis, 238 Fries rearrangement, 240 ortho-Fries rearrangement, 241 Fries−Finck rearrangement, 240 Fukuyama amine synthesis, 243 Fukuyama reduction, 245 Fukuyama−Mitsunobu procedure, 243 functional group interconversion, 572 functional group migration, 576 furan ring as the masked carbonyl, 464 furan synthesis, 218, 409 fused pyridine ring, 263 G Gabriel amine synthesis, 249 Gabriel synthesis, 171, 246 Gabriel–Colman rearrangement, 250

608

Garner’s aldehyde, 266 Gassman indole synthesis, 251 Gattermann–Koch reaction, 253 Gewald aminothiophene synthesis, 254 Glaser coupling, 257, 299 glycerol, 509 glycidic ester, 169 glycol, 159, 222, 223, 225, 334, 591 glycosidation, 313, 320, 492 β-glycoside, 320 C-glycosidic product, 222 glycosyl acceptor, 313 Gomberg–Bachmann reaction, 262, 450 Gould–Jacobs reaction, 263 green Dakin–West reaction, 168 Grignard reaction, 18, 266 Grignard reagent, 16, 20, 266, 325, 490, 494 Grob fragmentation, 268 Grubbs’ catalyst, 78, 465, 467 Grubbs’ catalyst, intramolecular Buchner rea-ction, 78 Guareschi imide, 270 Guareschi–Thorpe condensation, 270 H [1,5]-H-atom shift, 121 Hajos–Wiechert reaction, 271 halfordinal, 230 Haller–Bauer reaction, 273 N-haloamines, protonated, 292 o-halo-aniline, 373 haloarene, 486 α-halocarbohydrate, 320 α-haloesters, 50, 169, 456 halogen effect, 472 α-halogenation, 282 halogen–lithium exchange, 413 α-haloketones, 171, 218 2-halomethyl cycloalkanones, 200 α-halosulfone, 454 Hantzsch 1,4-dihydropyridines, 274, 275 Hantzsch dihydropyridine synthesis, 274 Hantzsch pyrrole synthesis, 276 head-to-head alignment, 173 head-to-tail alignment, 173 Heck arylation, 574 Heck reaction, 277, 278, 280, 373, 574 Hegedus indole synthesis, 281 Hell–Volhard–Zelinsky reaction, 282 hemiaminal, 474, 515

(+)-hennoxazole, 472 Henry nitroaldol reaction, 284 heteroaryl Heck reaction, 280 heteroaryl recipient, 280 heteroaryllithium, 413 heteroarylsulfones, 309 hetero-Carroll rearrangemen, 96 hetero-Diels–Alder reaction , 56, 187 heterodiene addition, 187 heterodienophile addition, 187, 188 heteropoly acid catalyst, 168 hex-5-enopyranosides, 221 hexacarbonyldicobalt complex, 395, 419 hexacarbonyldicobalt-stabilized propergyl cation, 395 hexamethylenetetramine, 171, 172, 515 Hinsberg synthesis of thiophene derivative, 286 Hiyama cross-coupling reaction, 288 Hoch–Campbell aziridine synthesis, 266 Hofmann degradation, 290 Hofmann rearrangement, 290 Hofmann–Löffler–Freytag reaction, 292 homoallylic alcohol, 584 homocoupling, 258, 299, 335, 554 homo-Favorskii rearrangement, 215 homologated carboxylic acid, 588 homolysis, 215 homolytic cleavage, 22, 24, 26, 200, 292, 298, 334, 582, 586 homo-McMurry coupling, 335 homo-Robinson, 470 Horner–Wadsworth–Emmons reaction, 294, 341 Horner−Emmons reaction, 527 Hosomi–Sakurai reaction, 484 Hosomi−Miyaura borylation, 368 Houben–Hoesch synthesis, 296 Huang Minlon modification, 590, 591 Hunsdiecker–Borodin reaction, 298 hydantoin, 76, 102, 497 hydrazine, 72, 102, 227, 249, 317, 334, 570, 590 hydrazoic acid, 490 hydrazone, 16, 60, 208, 227, 302, 570 hydride, 94, 100, 210, 330, 345, 359, 373, 404, 482, 515, 564, 591 β-hydride elimination, 373, 482 hydride shift, 564, 591 hydride source, 210 hydride transfer, 94, 345, 359, 404, 515

609

hydro-allyl addition, 1 o-hydroxyaryl ketones, 8 hydrogen atom abstraction, 24 1,5-hydrogen abstraction, 26 1,5-hydrogen atom transfer, 292 hydrogen donor, 40, 274 hydrogenation, 399, 476 hydrogenolysis, 251 hydrolysis of iminium salt, 271 hydrolysis, 54, 162, 165, 231, 247, 266, 271, 282, 286, 296, 315, 385, 393, 438, 447, 456, 460, 463, 478, 499, 534, 592 hydropalladation, 564 hydroxamic acid, 332 hydroxide-catalyzed rearrangements, 214 ω-hydroxyl-acid, 152 hydroxylamine, 115, 349 N-hydroxyl amines, 135 α-hydroxylation, 478 4-hydroxy-3-carboalkoxyquinoline, 263 ȕ-hydroxycarbonyl, 3 2ƍ-hydroxychalcones, 6 5-hydroxylindole, 391 3-hydroxy-isoxazoles, 115 2-hydroxymethylpyridine, 54 β-hydroxy-β-phenylethylamine, 432 4-hydroxyquinoline, 263 β-hydroxysilane, 203, 430 3-hydroxy-2-thiophenecarboxylic acid deri-vatives, 225 hydrozinolysis, 62 hypohalite, 251, 290 I IBX, 179, 397 imide, 102, 270, 444, 474 imine, 58, 102, 107, 131, 490, 521, 546, 551 iminium formationhydrolysis, 315 iminium ion, 315, 330, 440, 442, 519, 534 imino ether, 438 iminochloride, 385 iminophosphorane, 523 indole, 20, 28, 46, 60, 72, 227, 251, 281, 373, 391, 463 indole synthesis, 227, 251, 281, 373, 391, 463 Bartoli, 20 Batcho–Leimgruber, 28

Bischler–Möhlau, 46 Fischer, 227 Gassman, 251 Hegedus, 281 Mori–Ban, 373 Nenitzescu, 391 Reissert, 463 indole-2-carboxylic acid, 463 Ing–Manske procedure, 249 Initiation, radical, 586 inositol, 220 insertion toward CH, 419 insertion, 198, 277, 280, 373, 419, 589 intercomponent interactions, 90 intermolecular addition, 361, 509 intermolecular aldol, 4 intermolecular Bradsher cycloaddition, 66, 67 intermolecular C–H amination, 573 intermolecular C–H oxidation, 572 intermolecular Friedel–Crafts acylation, 234 intermolecular Heck arylation, 280, 574 intermolecular Yamaguchi coupling, 594 internal acetylenes, 353 intramolecular acyl transfer, 424 intramolecular Alder-ene reaction, 1 intramolecular aldol condensation, 470 intramolecular Baylis–Hillman reaction, 31 intramolecular Boger pyridine synthesis, 56 intramolecular Bradsher cyclization, 66 intramolecular Büchner reaction, 78 intramolecular Cannizzaro reaction, 95 intramolecular C–H oxidation, 572 intramolecular condensation, 205 intramolecular cross-coupling, 531 intramolecular cyclization, 413 intramolecular Diels–Alder reaction, 184, 185 intramolecular ene reaction, 110 intramolecular Favorskii Rearrangement, 214 intramolecular Friedel–Crafts acylation, 234, 235 intramolecular Heck reaction, 278, 280, 285, 280, 373 intramolecular Horner–Wadsworth– Emmons, 295

610

intramolecular Houben−Hoesch reaction, 296 intramolecular mechanism, 304 intramolecular Michael addition, 356 intramolecular Minisci reaction, 362 intramolecular Mitsunobu reaction, 366 intramolecular Mukaiyama aldol reaction, 375 intramolecular Nicholas reaction using chromium, 396 intramolecular Nozaki–Hiyama–Kishi reaction, 401 intramolecular nucleophilic aromatic rearrangement, 511 intramolecular pathway, 440 intramolecular Pauson−Khand reaction, 419 intramolecular Schmidt rearrangement, 491 intramolecular SN2, 169 intramolecular Stetter reaction, 525 intramolecular Suzuki–Miyaura coupling, 536 intramolecular Thorpe reaction, 546 intramolecular transamidation, 331 intramolecular Tsuji–Trost reaction, 549 intramolecular Yamaguchi coupling, 594 inverse electronic demand Diels–Alder reaction, 186 cis-trans inversion, 596 inversion of configuration, 548 iododinitrobenzene, 347 iodosobenzene diacetate for Hofmann rear-rangement, 290 O-iodoxybenzoic acid, 179, 397 ionic liquid, 316, 343 ionic liquid-promoted interrupted Feist– Benary reaction, 218 ionic mechanism, 266 ipso attack, 347 ipso substitution, 231, 347 Ireland–Claisen (silyl ketene acetal) rearrangement, 125 iron salt-mediated Polonovski reaction, 441 irreversible fragmentation, 196 C-isocyanide, 415, 551 isocyanate intermediate, 76, 162, 290, 332 isoflavone, 8

isomerization, 229, 353, 421, 470 isoquinoline 1,4-diol, 250 isoquinoline, 48, 250, 432, 434, 444, 461, 462 3-isoxazolol, 115 5-isoxazolol, 115 J Jacobsen–Katsuki epoxidation, 300 Japp–Klingemann hydrazone synthesis, 60, 302 Johnson–Claisen (orthoester) rearrangement, 127 Jones oxidation, 304, 305 Julia olefination, 309 Julia–Kocienski olefination, 309, 311 K Kahne glycosidation, 313 Kazmaier–Claisen, 117 ketene, 10, 123, 125, 127, 521, 588 ketene acetal, 123, 125, 127 ketene cycloaddition, 521 N,O-ketene acetals, 123 α-ketocarbene, 588 α-ketocarbene intermediate, 10 keto-enol tautomerization, 96 β-ketoester, 50, 96, 113, 115, 133, 218, 274, 276, 302, 423 2-ketophenols, 240 4-ketophenols, 240 α-keto-phosphonate, 341 ketoximes, 266 ketyl, 65 Kharasch cross-coupling reaction, 325 kinetic product, 16, 294, 494, 527 kinetic resolution, 574 Kishner reduction, 1 Knoevenagel condensation, 254, 255, 315 Knorr pyrazole synthesis, 317, 411 Knorr thiophene synthesis, 328 Koch–Haaf carbonylation, 319 Koenig–Knorr glycosidation, 320 Kostanecki acylation reaction, 322 Kostanecki reaction, 8, 322 Kostanecki−Robinson reaction, 322 Kröhnke pyridine synthesis, 333 Kumada coupling, 288, 325, 529, 536

611

L lactam, 240, 328, 521 β-lactam, 521 lactone, 204, 328, 403, 521 azalactone, 167, 204 β-lactone, 521 lactonization, 532 larger counterion, 309 Lawesson’s reagent, 328, 408 lead tetraacetate for Hofmann rearrangement, 291 lead tetraacetate, 159 Lebel modification of the Curtius rearrangement, 164 less-substituted olefin, 494 Leuckart–Wallach reaction, 210, 330, 331 Lewis acid catalyst, 222 Lewis acid, 1, 212, 222, 234, 236, 240, 375, 377, 395, 423, 484, 492 Lewis acid-catalyzed aldol condensation, 375 Lewis acid-catalyzed Michael addition, 377 Lewis basic phenol, 572 LiBr complex, 580 ligand exchange, 80, 476, 548 Lipitor, 411 liquid ammonia, 44 long-lived radical, 26 Lossen rearrangement, 332 low-valent titanium, 335 L-phenylalanine, 271, 272 proline, 143, 271, 337, 338 LTA, 159 M macrolactonization, 152, 573 magnesium metal, 266 magnesium oxide, 202 maleimidyl acetate, 250 manganaoxetane intermediate, 300 Mannich base, 337 Mannich reaction, 206, 337, 426 Martin’s sulfurane dehydrating reagent, 339, 457 Masamune–Roush conditions, 341 masked carbonyl equivalent, 154 McFadyen–Stevens reduction, 334 McMurry coupling, 335 MCR, 42, 76

Me3O+BF4−, 343 Meerwein reagent, 343, 361 Meerwein’s salt, 343 Meerwein–Eschenmoser–Claisen rearrangement, 123 Meerwein–Ponndorf–Verley reduction, 345, 404 Me-IBX, 397 Meisenheimer complex, 243, 347, 511 [1,2]-Meisenheimer rearrangement, 349 [2,3]-Meisenheimer rearrangement, 350 Meisenheimer−Jackson salt, 347 Meldrum’s acid, 116 4-membered ring transition state, 523 Mes, 465 mesityl, 465 mesyl azide, 458 metal-methylation, 343 methoxycarbonylsulfamoyltriethylammonium hydroxide inner salt, 84 o-methyl-IBX, 397 methyl triflate, 202 methyl vinyl ketone, 470 methylenated ketones, 206 N-methylation, 344 N-methyliminodiacetic acid, 87 2-methylpyridine N-oxide, 54 Meyers oxazoline method, 351 Meyer–Schuster rearrangement, 353, 480 MgO, 202 Mg-Oppenauer oxidation, 404 Michael addition, 107, 271, 274, 323, 355, 377, 423, 470, 484, 525, see also conjugate addition Michaelis–Arbuzov phosphonate synthesis, 357 Michael−Stetter reaction, 525 microwave, 29, 33, 43, 47, 74, 210, 264, 298, 299, 334, 335, 356, 429, 470, 511, 577, 590 microwave Smiles rearrangement, 511 microwave-assisted Gould–Jacobs reaction, 264 microwave-assisted, solvent-free Bischler-indole synthesis, 47 microwave-Hunsdiecker−Borodin, 298 microwave-indued Biginelli condensation, 43 MIDA, 87

612

Midland reduction, 359 migration order, 12, 436 migration, 12, 36, 68, 162, 165, 175, 177, 203, 215, 319, 393, 421, 436, 490, 566, 576 1,3-migration of an aryl group from oxygen to sulfur, 393 migratory insertion, 277 Minisci reaction, 361 Mislow–Evans rearrangement, 363 Mitsunobu reaction, 243, 332, 365, 366 mixed anhydride, 205, 594 mixed orthoester, 127 Miyaura borylation, 368 Mn(III)salen, 300 Mn(III)salen-catalyzed asymmetric epoxidation, 300 modified Ireland–Claisen rearrangement, 126 modified Skraup quinoline synthesis, 509 Moffatt oxidation, 370 monooxygenated precursor, 574 more-substituted olefin, 494 Morgan–Walls reaction , 371 Mori–Ban indole synthesis, 373 Morita–Baylis–Hillman reaction, 30 morpholine-polysulfide, 255 MPS, 255 Mukaiyama aldol reaction, 4, 375, 375, 376 Mukaiyama Michael addition, 377 Mukaiyama reagent, 379, 380 multicomponent reactions, 42, 62 MVK, 470 MWI, 43 Myers−Saito cyclization, 382 N-(2,4-dinitrophenyl)pyridinium salt, 596 N naphthol, 72 β-naphthol, 74 β-naphthylamines, 74 Naproxen, 577 Nazarov cyclization, 383 NBS variant of Hofmann rearrangement, 290 NBS, 290, 298, 516, 586, 587 NCS, 100, 150, 151, 292 Neber rearrangement, 385

Nef reaction, 387 Negishi cross-coupling reaction, 325, 389 neighboring group assistance, 447, 492, 592 Nenitzescu indole synthesis, 391 Newman−Kwart reaction, 393 Nicholas reaction, 395 Nicholas-Pauson–Khand sequence, 395 nickel-catalyzed cross-coupling, 325, 389 Nicolaou dehydrogenation, 397 nifedipine, 274 nitrene, 162 nitrile, 2, 34, 50, 98, 254, 296, 438, 468,, 490, 534, 546, 562 nitrile-Alder-ene reaction, 2 nitrilium ion intermediate, 468, 490 nitrite ester, 26 2-nitroalcohol, 284 nitroaldol condensation, 284 nitroalkanes, 284 nitroarenes, 20 nitrobenzene, 371 4-nitrobenzenesulfonyl, 499 nitrogen nucleophile, 572 nitrogen radical cation, 292 nitrogen source, 496 nitronate, 284, 347, 387 nitronic acid, 284, 387 o-nitrophenyl selenide, 505 o-nitrophenyl selenocyanate, 505 nitroso intermediate, 20, 26, 102 o-nitrotoluene derivatives, 28, 463 non-enolizable ketone, 217, 273 nonstabilized ylide, 580 Nos, 499 nosylate, 499 Noyori asymmetric hydrogenation, 399 Nozaki–Hiyama–Kishi reaction, 401 nucleophile, 89, 154, 162, 222, 355, 365, 395, 484, 548, 572, 573 C-nucleophile, 222, see also carbon nucleophile O-nucleophile, 222 S-nucleophile, 222 nucleophilic addition, 50, 351, 438, 456, 456 nucleophilic radical, 361 Nysted reagent, 403

613

O octacarbonyl dicobalt, 419 odorless Corey−Kim reaction, 150 olefin, 16, 66, 70, 84, 110, 135, 146, 148, 156, 157, 173, 277, 294, 309, 319, 335, 339, 373, 454, 494, 499, 500, 505, 507, 521, 564, 566, 572, 574, 578, 580 α-olefin, 572, 574 cis-olefin, 294 E-olefin, 300, 309, 311, 580 exo-olefin, 542 trans-olefin, 294 (Z)-olefin, 300, 527, 578, 580 olefin ether, 66 olefin formation, 294, 454, 505 olefin silfide, 66 olefination, 156, 309, 311, 335, 403, 428, 430, 578 olefination of ketones and aldehydes, 403 oleum, 446 one-carbon homologation, 10 , 148 one-pot PCC–Wittig reactions, 306 Oppenauer oxidation, 404, 345 optically pure diethyl tartrate, 502 organic azide, 523 organoborane, 70, 536, 574 organocatalyst, 4, 274 organohalide, 266, 288, 325, 519, 529, 536 organolithium, 325 organomagnesium compounds, 266, 325, see also Grignard reagent organosilicon, 288 organostannane, 529 organozinc, 389, 456 Ormosil-TEMPO, 545 osmium catalyst, 499 osmium-mediated, 496, 499 O-substituted glycal derivatives, 222 O-sulfonylation, 332 Overman rearrangement, 406 oxaphosphetane, 578 oxa-Pictet–Spengler, 434 oxatitanacyclobutane, 542 oxazete intermediate, 105 oxazole, 229, 472, 556 5-oxazolone, 205 oxazoline intermediate, 167 oxa-π-methane rearrangement, 193 oxetane, 417

manganaoxetane, 300 γ-oximino alcohol, 26 oxidation, 70, 107, 194, 572 Baeyer–Villiger, 12 Collins–Sarett, 305 Corey–Kim, 150 Dakin, 165 Dess−Martin, 179 Étard, 129 Fleming–Tamao, 231 Hooker, 196 Jacobsen–Katsuki, 300 Jones, 304 Moffatt, 370 Oppenauer, 404 PCC, 306 PDC, 307 Prilezhaev, 323 Riley, 336 Rubottom, 378 Saegusa, 482 Sarett, 538 Swern, 402 Tamao−Kumada, 233 TEMPO, 544 Wacker, 564 oxidative addition, 80, 90, 98, 245, 277, 280, 288, 325, 368, 373, 389, 401, 456, 476, 507, 519, 529, 531, 536, 548, 554 syn-oxidative elimination, 505 oxidative cyclization, 6, 281 oxidative demetallation, 395 oxidative homo-coupling, 257, 299 N-oxide, 54, 135, 300, 349, 350, 440, 442, 543 oxide-coated titanium surface, 335 oxime, 33, 266, 385 oxirane, 52 oxo-Diels–Alder reaction, 187 4-oxoform, 263 oxonium ion, 313, 320, 343 β-oxo ylide, 580 oxy-Cope rearrangement, 137, 138, 140 oxygen nucleophile, 572 oxygen transfer, 300 oxygenated compound, 572, 573 P P2O5, 432 P4O10, 432 P4–t-Bu, 311

614

Paal thiophene synthesis, 408 Paal–Knorr furan synthesis, 409 Paal–Knorr pyrrole synthesis, 317, 411 palladation, 281, 564 palladium, 80, 98, 277, 288, 325, 368, 389, 476, 482, 519, 529, 531, 536, 548, 564, 572 palladium-catalyzed alkenylation, 277 palladium-catalyzed arylation, 277 palladium-catalyzed oxidation, 564 palladium-promoted reaction Buchwald–Hartwig amination, 80 Heck, 277 heteroaryl Heck, 280 Hiyama, 288 Kumada, 325 Miyaura borylation, 368 Mori–Ban indole, 373 Negishi, 389 Rosenmund reduction, 476 Saegusa, 482 Sonogashira, 519 Stille, 529 Stille–Kelly, 531 Suzuki–Miyaura, 536 Tsuji–Trost, 548 Wacker, 564 palladium-catalyzed substitution, 548 pancratistatin, 220 paniculide A, 220 paraffin, 134 Parham cyclization, 413, 415 Passerini reaction, 551 Paternò–Büchi reaction, 417 Pauson–Khand reaction, 395, 419, 420 Payne rearrangement, 421 Pb(OAc)4, 159 PCC oxidation, 304, 306 Pd(II) oxidant, 482 Pd(II) reduction to Pd(0), 519 Pd/C catalyst, 245 Pd/Cu-catalyzed cross-coupling, 519 PDC, 304, 307 Pd–H isomerization, 574 Pechmann coumarin synthesis, 423 pentacoordinate silicon intermediate, 68 peracid, 231 pericyclic reaction, 1 periodinane oxidation, 179, 180 Perkin reaction, 424

Petasis boronic acid-Mannich reaction, 426 Petasis reaction, 426 Petasis reagent, 428 Peterson elimination, 203 Peterson olefination, 430 Pfau−Platter azulene synthesis, 78 Pfitzner−Moffatt oxidation, 370 Ph3P, 52, 53, 99, 148, 149, 152, 223, 280, 288, 360, 365, 368, 373, 472, 519, 523, 536, 578 PhCuI, 554 phenanthridine cyclization, 371 β-phenethylamides, 48 phenol esters, 240 phenol, 102, 165, 190, 240, 296, 393, 423, 460, 492, 572 phenolic ether, 296 phenylhydrazine, 227 4-phenylpyridine N-oxide, 300 phenyltetrazolyl, 309 PhNO2, 509 phospha-Michael addition, 355 phosphate ester, 220 phosphazide, 523 phosphazo compound, 523 phosphite, 357 phosphonate synthesis, 357 phosphonate, 294, 341, 357, 527 phosphoric acid, 409 phosphorus oxychloride, 48, 49, 229, 235, 264, 371, 432, 558, 559, phosphorus pentoxide, 432 phosphorus ylide, 578, 580 [2+2]-photochemical cyclization, 173 photochemical decomposition, 292 photochemical rearrangement, 162 photo-Favorskii Rearrangement, 215 photo-Fries rearrangement, 241 photoinduced electrocyclization, 417 photolysis, 26, 192 photo-Reimer–Tiemann reaction without base, 460 photo-Schiemann reaction, 488 phthalimide, 247, 248, 249 Pictet–Gams isoquinoline synthesis, 432 Pictet–Spengler tetrahydroisoquinoline synthesis, 434 pinacol, 436, 574 pinacol rearrangement, 436 (1R)-(+)-α-pinene, 359

615

Pinner reaction, 438 piperidine, 292 pivalic acid, 411 PMB ethers, 202 PMB reagent, 202 PMB-protection, 203 Polonovski reaction, 440, 442 Polonovski–Potier rearrangement, 442 polyene skeleton, 89 polymer-support Hinsberg thiophene synthesis, 287 polymer-supported Mukaiyama reagent, 379 polyphosphoric acid, 34, 66, 332, see also PPA polysubstituted oxetane ring system, 417 Pomeranz–Fritsch reaction, 444, 446 potassium phthalimide, 247 PPA, 34, 66, 132, 134, 163, 164, 235, PPSE, 235 precatalyst, 465, 548 preoxidized material, 572 Prévost trans-dihydroxylation, 447, 592 Prilezhaev epoxidation, 478 primary alcohol, 304, 305, 339 primary amides, 290 primary amine, 171, 178, , 210, 243, 247, 290, 411, 474 primary cycle, 500 primary nitroalkane, 387 primary ozonide, 161 Prins reaction, 448 proline, 143, 271 (S)-(−)-proline, 271 propagation, 586 propargylated product, 395 protic acid, 33, 202, protic solvent, 16, 556 proton transfer, 38, 52, 131, 132, 133, 458 protonated heteroaromatic nucleus, 361 Pschorr cyclization, 450 PT, 309 puckered transition state, 521, 578 Pummerer rearrangement, 452 purine, 102 putative active catalyst, 502 PyPh2P, 244 PYR, 309 pyrazinone, 102 pyrazole, 317, 411

pyrazolone, 317 2-pyridinethione, 152 2-pyridone, 270 pyridinium chlorochromate, 304, see also PCC pyridinium dichromate, 304, see also PDC pyridium, 66 pyridone, 102 pyrimidine, 102 α-pyridinium methyl ketone salts, 323 pyrolysis, 156 pyrrole, 112, 276, 317, 411 pyrrolidine, 292 pyruvic acid, 194 Q quasi-axial bonds, 222 quasi-Favorskii rearrangement, 217 quinaldic acid, 461 quinoline, 92, 131, 133, 194, 196, 238, 263, 394, 461, 509, 510 quinolin-4-ones, 133 quinoline-4-carboxylic acid, 194 R racemization, 227, 273 radical, 22, 24, 26, 40, 44, 65, 129, 192, 200, 257, 262, 266, 292, 300, 335, 361, 382, 417, 450, 540, 544, 546, 560, 582, 586 radical anion, 44, 65, 129, 335 radical cation, 292 radical chain reaction, 586 radical coupling, 262 6-exo-trig radical cyclization, 450 5-exo-trig-ring closure, 182 radical decarboxylation, 22 radical initiating conditions, 586 radical intermediate, 300 radical mechanism, 257, 266, 540, 582 radical reactions Barton radical decarboxylation, 22 Barton–McCombie, 240 Barton nitrite photolysis, 26 Dowd–Beckwith ring expansion, 200 Gomberg–Bachmann, 262 McFadyen–Stevens reduction, 334 McMurry coupling, 335 TEMPO-mediated oxidation, 544 radical Thorpe−Ziegler reaction, 546

616

radical-based carbon–carbon bond formation, 361 radical-mediated ring expansion, 200 Ramberg–Bäcklund reaction, 454 Raney nickel, 251 Ra-Ni, 29, 155 rate-limiting step, 218 Rawal diene, 188 RCM, 465 real catalyst, 465 rearomatization, 196 rearrangement abnormal Claisen, 121 anionic oxy–Cope, 138 Baker–Venkataraman, 14 Beckmann, 33 Benzilic acid, 36 Boulton–Katritzky, 62 Brook, 68 Carrol, 96 Chapman, 105 Ciamician–Dennsted, 112 Claisen, 117 para-Claisen Cope, 119 Cope, 137 Curtius, 162 Demjanov, 175 Dienone–phenol, 190 Di-π-methane, 192 Eschenmoser–Claisen, 123 Favorskii, 214 Ferrier glycal allylic, 222 Fries, 240 Gabriel–Colman, 250 Hofmann, 290 Ireland–Claisen, 125 Johnson–Claisen, 127 Lossen, 332 [1,2]-Meisenheimer, 349 [2,3]-Meisenheimer, 350 Meyer–Schuster, 353 Mislow–Evans, 363 Neber, 385 Overman, 406 oxy-Cope, 140 Payne, 421 Pinacol, 436 Polonovski–Potier, 442 Pummerer, 452 Rupe, 480 quasi-Favorskii, 217

Schmidt, 490 siloxy-Cope, 141 Smiles, 511 Sommelet–Hauser, 513 Tiffeneau–Demjanov, 177 Truce−Smile, 513 Vinylcyclopropane−cyclopentene, 560 Wagner–Meerwein, 566 [1,2]-Wittig, 582 [2,3]-Wittig, 584 Wolff, 588 (S,S)-reboxetine, 503 Red-Al, 100 redox reaction, 94, 401 reducing agent, 210, 330, 274 reduction Birch, 44 Bouveault–Blanc, 65 CBS, 143 Chan alkyne, 100 Clemmensen, 129 Fukuyama, 245 ketones, 345 McFadyen–Stevens, 334 Meerwein–Ponndorf–Verley, 345 Midland, 359 Rosenmund, 476 Staudinger, 532 Wolff–Kishner, 590 1,4-reduction, 44 reduction of Pd(OAc)2 to Pd(0) using Ph3P, 373 reductive amination, 58, 330 reductive cyclization, 463 reductive elimination, 58, 80, 90, 98, 102, 156, 245, 277, 288, 325, 330, 368, 389, 419, 476, 519, 529, 531, 536, 548, 564 reductive Heck reaction, 278 reductive methylation, 210 Reformatsky reaction, 456 regeneration of Pd(0), 373 regioisomer, 173, 572 regioselectivity, 52, 496, 572 Regitz diazo synthesis, 458 Reimer–Tiemann reaction, 460 Reissert aldehyde synthesis, 461 Reissert compound from isoquinoline, 462 Reissert compound, 461

617

Reissert indole synthesis, 463 retention of configuration, 231, 548 retro-[1,4]-Brook rearrangement, 69 retro-[2+2] cycloaddition, 542 retro-aldol reaction, 173 retro-benzilic acid rearrangement, 36 retro-Bucherer reaction, 74 retro-Claisen condensation, 60, 113 retro-Cope elimination, 136 retro-Diels−Alder reaction, 56, 185 retro-Henry reaction, 284 reverse Kahne-type glycosylation, 314 reversible conjugate addition, 196 rhodium carbenoid, 78 ring expansion, 200 ring opening, 532, 596 6-oxo-trig ring formation, 322 ring-closing metathesis, 465 trisubstituted phosphine, 365 Ritter intermediate, 490 Ritter reaction, 468 Robinson annulation, 271, 470 Robinson–Gabriel synthesis, 472 Robinson–Schöpf reaction, 474 room temperature Buchwald–Hartwig amination, 81 Rosenmund reduction, 476 Rosenmund–von Braun synthesis of aryl nitrile, 98 rotation, 277, 430 rotaxane, 90 Rubottom oxidation, 478 Rupe rearrangement, 353, 480 ruthenium(II) BINAP-complex, 399 S Saegusa enone synthesis, 482 Saegusa oxidation, 397, 482 safe surrogate for cyanide, 525 Sakurai allylation reaction, 484 Sandmeyer reaction, 486 Sanger’s reagent, 347 saponification, 263 Sarett oxidation, 304, 305 Saucy–Claisen, 117 Schiemann reaction, 488 Schiff base, 133 Schlittler–Müller modification, 446 Schlosser modification of the Wittig reaction, 580 Schmidt rearrangement, 490

Schmidt’s trichloroacetimidate glycosidation reaction, 492 Schmittel cyclization, 382 Schönberg rearrangement, 393 Schrock’s catalyst, 465 secondary alcohol, 179, 304, 339, 404 secondary amine, 210, 243 secondary cycle, 500 secondary nitroalkane, 387 secondary ozonide, 161 secondary α-acetylenic alcohol, 353 seleno-Mislow-Evans, 363 semi-benzylic mechanism, 217 SET, 18, 44, 65, 129, 155, 266, 311, 554, 335, 397, 554 Shapiro reaction, 16, 494 Sharpless asymmetric amino hydroxylation, 496 Sharpless asymmetric dihydroxylation, 499 Sharpless asymmetric epoxidation , 502 Sharpless olefin synthesis, 505 1,3-shift, 353 Shioiri–Ninomiya–Yamada modification of Curtius rearrangement, 163 SIBX, 397 [1,2]-sigmatropic rearrangement, 349 [2,3]-sigmatropic rearranegment, 20, 251, 350, 363, 584 [3,3]-sigmatropic rearranegment, 60, 72, 96, 117, 119, 121, 123, 125, 127, 137, 138, 140, 141, 227, 406 sila-Stetter reaction, 525 sila-Wittig reaction, 430 silicon cleavage, 484 β-silicon effect, 484 siloxane, 102 α-silyloxy carbanions, 68 siloxy-Cope rearrangement, 141 silver carboxylate, 298 silver salt, 320 silver-catalyzed oxidative decarboxylation, 361 silyation, 332 α-silyl carbanion, 430 silyl enol ether, 375, 377, 397 α-silyl oxyanions, 68 [1,2]-silyl migration, 68 β-silylalkoxide intermediate Simmons–Smith reaction , 507 Simmons−Smith reagent, 507

618

single electron transfer, 18, 44, 65, 129, 155, 266, 311, 554, 335, see also SET single-electron process, 335 singlet diradical, 417 six-membered α,β-unsaturated ketone, 470 Skraup quinoline synthesis, 196, 509 Skraup type, 263 SMEAH, 100 SmI2-mediated Reformatsky reaction, 457 Smile reaction, 393 Smiles rearrangement, 511, 513 SN1, 313 SN2 inversion, 365 SN2 reaction, 52, 129, 148, 179, 229, 247, 249, 240, 292, 357, 363, 365, 578, 592 SNAr, 243, 347, 379 sodium amalgam, 311 sodium bis(2-methoxyethoxy)aluminum hydride, 100 sodium bisulfite, 72 sodium cyanide, 534 sodium hypochlorite for Hofmann rearrangement, 291 sodium tert-butoxide, 80 sodium, 65 solid-phase Cope elimination, 135 soluble cyanide source, 534 solvent-free Claisen condensation, 114 solvent-free Dakin oxidation, 165 Sommelet reaction, 171, 515 Sommelet–Hauser rearrangement, 251, 517, 584 Sonogashira reaction, 98, 519 (−)-sparteine, 213, 351 spirocyclic anion intermediate, 511 stabilized IBX, 397 stable nitroxyl radical, 544 stannane, 20, 102, 529, 531 statin side chain, 50 Staudinger ketene cycloaddition, 521 Staudinger reduction, 523 step-wise mechanism, 588 stereoselective conversion, 540 stereoselective oxidation, 231 stereoselective reduction, 100 stereoselectivity, 572 steric hindrance, 594 sterically-favored isomer, 419

Stetter reaction, 38, 525 Stille coupling, 529 Stille–Kelly reaction, 531 Still–Gennari phosphonate reaction, 527 Still−Wittig rearrangement, 584 Stobbe condensation and cyclization, 532 Stobbe condensation, 532 stoichiometric copper, 519 stoichiometric Pd(II), 281 Strecker amino acid synthesis, 534 strong acid, 319, 468, 598 styrenylpinacol boronic ester, 574 substituted hydrazine, 317 7-substituted indoles, 20 5-substituted oxazole, 556 2-substituted-quinolin-4-ol, 92 4-substituted-quinolin-2-ol, 92 substitution reactions, 351 succinimidyl radical, 586 sulfenamide, 576 sulfinate, 102 sulfonamides, 102 sulfone reduction, 309 sulfone, 30, 309, 311, 454 sulfonium ion, 251 sulfonyl azide, 458 sulfoxide activation, 313 sulfoxide, 313, 363, 452 sulfoximines, 102 sulfur ylide, 146, 538 sulfurane dehydrating reagent, 339, 340, 457 sulfur-containing heterocyclic ring, 576 sulfuric acid, 304 Suzuki, 298 Suzuki–Miyaura coupling, 102, 536 Swern oxidation, 150, 538 switchable molecular shuttles, 90 syn/anti, 377 syn-addition, 70 synchronized fashion, 515 T Takai reaction, 540 Tamao−Kumada oxidation, 233 d3-tamoxifen, 210 tautomerization, 74, 121, 133, 140, 167, 198, 227, 274, 353, 383, 408, 490, 509, 525, 570 TBABB, 377

619

TBAO, 239 TBTBTFP, 309 TDS, 141, 180 Tebbe olefination, 428, 542 Tebbe’s reagent, 428 TEMPO oxidation, 544 terminal acetylenic group, 353 terminal alkyne, 148, 299, 257, 519 tertiary alcohol, 84, 339, 490 tertiary amine, 30, 206, 349, 350, 562 tertiary amine N-oxide, 349 tertiary carbocation, 319 tertiary carboxylic acid formation, 319 tertiary N-oxide, 440, 442 tertiary phosphine, 523 tertiary α-acetylenic (terminal) alcohol, 480 tertiary α-acetylenic alcohols, 353 tetrahydrocarbazole, 60 tetrahydroisoquinoline, 434 tetramethyl pentahydropyridine oxide, 544 tetra-n-butylammonium bibenzoate, 377 1,1,3,3-tetramethylguanidine, 95 2,2,6,6-tetramethylpiperi-dinyloxy, 544 tetrazole, 309 Tf2O, 313, 314, 379 TFA, 14, 54, 287, 292, 354, 362, 375, 391, 415, 445, 507, 566 TFAA, 54, 262, 443 thermal aliphatic Claisen rearrangement, 16 thermal aryl rearrangement, 105 thermal Bamford–Stevens, 17 thermal decomposition, 292 thermal elimination, 110, 135 thermal rearrangement, 96, 162 thermal-catalyzed condensation, 133 thermal-mediated rearrangement, 332 thermodynamic adduct, 294 thermodynamic product, 16, 494 thermodynamic sink, 140 thermodynamically favored, 319 thermolysis, 62 thexyldimethylsilyl, 141, 180 thia-Fries rearrangement, 241 thia-Michael addition, 355 thiazolium catalyst, 525 thiazolium salt, 38 thiirane, 146 3-thioalkoxyindoles, 251

thioamide, 576 thiocarbonyl derivatives, 24, 328, 408 1,1ƍ-thiocarbonyldiimidazole, 156 thioglycolic acid derivatives, 225 thiol, 102, 245 thiophene, 17, 225, 254, 286, 287, 328, 329, 408 thiophene from dione, 328 thiophene synthesis, 225, 408 thiophene-2,5-dicarbonyls, 286 thiophenol, 393 Thorpe−Ziegler reaction, 546 three-component aminomethylation, 337 three-component condensation, 415 three-component coupling, 194, 426, 574 threo (thermodynamic adduct), Horner– Wadsworth–Emmons reaction, 294 threo betaine, 580 Ti(0), 335 Ti=O, 542 TiCl3/LiAlH4, 335 Tiffeneau–Demjanov rearrangement, 177 titanium tetra-iso-propoxide, 502 TMG, 95 TMSO-P(OEt)2, 358 p-tolylsulfonylmethyl isocyanide, 556 tosyl amide, 458 tosyl ketoxime, 385 trans-β-dimethylamino-2-nitrostyrene, 28 transannular aldol reaction, 4 transition state, 1, 309, 345, 404, 478, 503, 521, 523, 578, transmetallation, 102, 288, 325, 368, 389, 401, 519, 529, 531, 536, 536 trapping molecule, 90 Traxler–Zimmerman trasition state, 193 triacetoxyperiodinane, 179 trialkyl orthoacetate, 127 trialkyloxonium salts, 343 1,1,1-triacetoxy-1,1-dihydro-1,2benziodoxol-3(1H)-one, 179 1,2,4-triazine, 56 triazole intermediate, 458 trichloroacetimidate intermediate, 406, 492 2,4,6-trichlorobenzoyl chloride, 594 trichloroisocyanuric/TEMPO oxidation, 545

620

triethyloxonium tetrafluoroborate, 343 triflate, 202, 288, 325, 389, 529, 536, 572 trifluoroacetic anhydride, 54, 442, see also TFAA trifluorotoluene, 202 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane, 239 trimethyloxonium tetrafluoroborate, 343 trimethylphosphite, 156 trimethylsilyl chloride, 125 trimethylsilyl polyphosphate, 235 tri-O-acetyl-D-glucal, 222 1, 1,2,3-trioxolane, 161 2,4-trioxolane, 161 triphenylphosphine, 365, see also Ph3P triplet diradical, 417 n, π* triplet, 417 tropinone, 474 Truce−Smile rearrangement, 513 Tsuji–Trost allylation, 548 Two sequential Stobbe condensations, 532 U Ugi reaction, 415, 551 UHP, 12, 165 Ullmann coupling, 554 umpolung, 154 11-undecenoic acid, 574 α,β-unsaturation of aldehydes, 397 α,β-unsaturation of ketones, 397 α,β-unsaturated aldehyde, 480 γ,δ-unsaturated amides, 123 α,β-unsaturated carbonyl compounds, 353 γ,δ-unsaturated carboxylic acids, 125 α,β-unsaturated ester, 525 γ,δ-unsaturated ester, 127 2,3-unsaturated glycosyl derivatives, 222 5,6-unsaturated hexopyranose derivatives, 220 α,β-unsaturated ketone, 323, 480, 525 γ-unsaturated ketones, 96 α,β-unsaturated system, 355, 377, 484 urea, 12, 42, 102, 162, 165, 332, 370 urea-hydrogen peroxide complex, 12, 165

V van Leusen oxazole synthesis, 556 van Leusen reagent, 556 varenicine, 211 vicinal diol, 159, 436 Vilsmeier–Haack reaction, 558, 558 Vinyl azide, 162 vinyl boronic acid, 426 vinyl Grignard, 20 vinyl halide, 401 E-vinyl iodide, 540 vinyl ketones, 30, 470 vinyl sulfones, 30 N,O-vinylation, 102 vinylcyclopropane, 192, 560 vinylcyclopropane−cyclopentene rearrangement, 560 vinylic alkoxy pentacarbonyl chromium carbene, 198 vinylic C–H arylation, 574 vinylogous Mukaiyama aldol reaction, 375 2-cis-vitamin A acid, 578 von Braun degradation, 562 von Braun reaction, 562 W Wacker oxidation, 281, 482, 564 Wagner–Meerwein rearrangement, 566 Wagner–Meerwein shift, 331 Weinstock variant of the Curtius rearrangement, 163 Weiss–Cook reaction, 568 Wharton reaction, 570 White reagent, 572 Willgerodt–Kindler reaction, 576 Wittig reaction, 148, 294, 306, 430, 578, 580 Wittig reagent, 403 [1,2]-Wittig rearrangement, 582 [2,3]-Wittig rearrangement, 517, 584 Wohl–Ziegler reaction, 586 Wolff rearrangement, 40, 588 Wolff–Kishner reduction, 590 Woodward cis-dihydroxylation, 447, 592 X xanthate, 110 Xphos, 82, 83, 89, 369

621

Y Yamaguchi esterification, 594, 595 Yamaguchi reagent, 594, 595 ylidene-sulfur adduct, 254, 255 Z Zimmerman rearrangement, 192 zinc amalgam, 129 zinc-carbenoid, 129 zinc chloride, 371 zinc reagent, 389, 403, 456 Zincke anhydride, 598 Zincke reaction, 596 Zincke salt, 596, 598 Zn(Cu), 507 zwitterionic peroxide, 161