Name Reactions

Jie Jack Li

Name ReactionsA Collectionof Detailed Reaction Mechanisms

Third Expanded Edition

123

Jie Jack Li, Ph.D.

Pfizer Global Research and DevelopmentChemistry Department2800 Plymouth RoadAnn Arbor, MI 48105USAe-mail: jack.li@pfizer.com

3rd. expanded ed.

ISBN-10 3-540-30030-9 Springer Berlin Heidelberg New YorkISBN-13 978-3-540-30030-4 Springer Berlin Heidelberg New Yorke-ISBN 3-540-30031-7ISBN-10 3-540-40203-9 2nd ed. Springer Berlin Heidelberg New York

Library of Congress Control Number: 2006925628

This work is subject to copyright. All rights reserved, whether the whole or part of thematerial is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting, reproduction on microfilm or in any other way, and storage in databanks. Duplication of this publication or parts thereof is permitted only under the provisionsof the German Copyright Law of September 9, 1965, in its current version, and permissionfor use must always be obtained from Springer. Violations are liable for prosecution underthe German Copyright Law.

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© Springer-Verlag Berlin Heidelberg 2003, 2006Printed in Germany

The use of general descriptive names, registered names, trademarks, etc. in this publicationdoes not imply, even in the absence of a specific statement, that such names are exempt fromthe relevant protective laws and regulations and therefore free for general use.

Typesetting: By the AuthorProduction: LE-TEX, Jelonek, Schmidt & Vöckler GbR, LeipzigCoverdesign: KünkelLopka, Heidelberg

Printed on acid-free paper 2/3100 YL – 5 4 3 2 1 0

Dedicated to

Professor E. J. Corey

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 hesita-te 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” rearrange-ment, 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 reacti-ons”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original disco-verers, 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 ca-taloging 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 reacti-ons 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 “must-have” 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 La Jolla, March 2006

Preface

Confucius said: “Reviewing old knowledge while learning new old knowledge, is that not, after all, a pleasure?” Indeed, name reactions are not only the fruit of pioneering organic chemists, but also our contemporaries whose combined dis-coveries have resulted in organic chemistry today. Since publication of this book, Barry Sharpless and Ryoji Noyori, whose name reactions have been included since the first edition, went on to win the Nobel Prizes in 2001. Recently, Richard Schrock, Robert Grubbs, and Yves Chauvin shared the 2005 Nobel Prize in che-mistry for their contributions to metathesis, a name reaction that has been also in-cluded since the first edition. Therefore, I intend to keep up with the new devel-opments in the field of organic chemistry while retaining the collection of name reactions that have withheld test of time.

The third edition contains major improvements over the previous two editions. I have updated references. Each reaction is now supplemented with two to three representative examples in synthesis to showcase its synthetic utility. As Emil Fi-scher stated: “Science is not an abstraction; but as a product of human endeavor it is inseparably bound up in its development with the personalities and fortunes of those who dedicate themselves to it.” To that end, I added biographical sketches for most of the chemists who discovered or developed those name reactions. Furthemore, I have significantly beefed up the subject index to help the reader na-vigate the book more easily.

In preparing this manuscript, I have incurred many debts of gratitude to Prof. Reto Mueller of Switzerland, Prof. Robin Ferrier of New Zealand, and Prof. James M. Cook of the University of Wisconsin, Milwaukee; Dr. Yike Ni of California Institute of Technology, and Dr. Shengping Zheng of Columbia University for in-valuable suggestions. I also wish to thank Dr. Gilles Chambournier, Prof. Phil S. Baran of Scripps Research Institute and his students, Narendra Ambhaikar, Ben Hafensteiner, Carlos Guerrero, and Dan O’Malley, Prof. Brian M. Stoltz of Cali-fornia Institute of Technology and his students, Kevin Allan, Daniel Caspi, David Ebner, Andrew Harned, Shyam Krishnan, Michael Krout, Qi Charles Liu, Sandy Ma, Justin Mohr, John Phillips, Jennifer Roizen, Brinton Seashore-Ludlow, Na-thaniel Sherden, Jennifer Stockdill, and Carolyn Woodroofe for proofreading the final draft of the manuscript. Their knowledge and time have tremendously en-hanced the quality of this book. Any remaining errors are, of course, solely my own responsibility.

I welcome your critique.

Jack Li Ann Arbor, Michigan, March 2006

Table of Contents

Abbreviations .................................................................................................. XVIII

Alder ene reaction ................................................................................................... 1 Aldol condensation.................................................................................................. 3 Algar–Flynn–Oyamada reaction ............................................................................. 5 Allan–Robinson reaction......................................................................................... 8 Appel reaction ....................................................................................................... 10 Arndt–Eistert homologation.................................................................................. 12 Baeyer–Villiger oxidation ..................................................................................... 14 Baker–Venkataraman rearrangement .................................................................... 16 Bamberger rearrangement ..................................................................................... 18 Bamford–Stevens reaction .................................................................................... 20 Barbier coupling reaction ...................................................................................... 22 Bargellini reaction................................................................................................. 24 Bartoli indole synthesis ......................................................................................... 26 Barton radical decarboxylation ............................................................................. 28 Barton–McCombie deoxygenation........................................................................ 30 Barton nitrite photolysis ........................................................................................ 32 Barton–Zard reaction ............................................................................................ 34 Batcho–Leimgruber indole synthesis .................................................................... 36 Baylis–Hillman reaction........................................................................................ 39 Beckmann rearrangement...................................................................................... 41 Beirut reaction....................................................................................................... 43 Benzilic acid rearrangement.................................................................................. 45 Benzoin condensation ........................................................................................... 47 Bergman cyclization.............................................................................................. 49 Biginelli pyrimidone synthesis.............................................................................. 51 Birch reduction...................................................................................................... 53 Bischler–Möhlau indole synthesis......................................................................... 55 Bischler–Napieralski reaction ............................................................................... 57 Blaise reaction....................................................................................................... 59 Blanc chloromethylation ....................................................................................... 61 Blum aziridine synthesis ...................................................................................... 63 Boekelheide reaction............................................................................................. 65 Boger pyridine synthesis ....................................................................................... 67 Borch reductive amination .................................................................................... 69 Borsche–Drechsel cyclization ............................................................................... 71 Boulton–Katritzky rearrangement......................................................................... 73 Bouveault aldehyde synthesis ............................................................................... 75 Bouveault–Blanc reduction ................................................................................... 77 Boyland–Sims oxidation ....................................................................................... 79 Bradsher reaction .................................................................................................. 81 Brook rearrangement............................................................................................. 83 Brown hydroboration ............................................................................................ 85

XII

Bucherer carbazole synthesis ................................................................................ 87 Bucherer reaction .................................................................................................. 90 Bucherer–Bergs reaction....................................................................................... 92 Büchner–Curtius–Schlotterbeck reaction.............................................................. 94 Büchner method of ring expansion ....................................................................... 96 Buchwald–Hartwig C–N bond and C–O bond formation reactions...................... 98 Burgess dehydrating reagent ............................................................................... 100 Cadiot–Chodkiewicz coupling ............................................................................ 102 Camps quinolinol synthesis................................................................................. 104 Cannizzaro dispropotionation ............................................................................. 107 Carroll rearrangement ......................................................................................... 109 Castro–Stephens coupling................................................................................... 112 Chan alkyne reduction......................................................................................... 114 Chan–Lam coupling reaction .............................................................................. 116 Chapman rearrangement ..................................................................................... 118 Chichibabin pyridine synthesis ........................................................................... 120 Chugaev reaction................................................................................................. 123 Ciamician–Dennsted rearrangement ................................................................... 125 Claisen condensation........................................................................................... 127 Claisen isoxazole synthesis ................................................................................. 129 Claisen rearrangement......................................................................................... 131 Abnormal Claisen rearrangement............................................................... 133 Eschenmoser–Claisen amide acetal rearrangement.................................... 135 Ireland–Claisen (silyl ketene acetal) rearrangement .................................. 137 Johnson–Claisen (orthoester) rearrangement ............................................. 139 Clemmensen reduction........................................................................................ 141 Combes quinoline synthesis ................................................................................ 144 Conrad–Limpach reaction................................................................................... 147 Cope elimination reaction ................................................................................... 149 Cope rearrangement ............................................................................................ 151 Oxy-Cope rearrangement ............................................................................ 152 Anionic oxy-Cope rearrangement ............................................................... 153 Corey–Bakshi–Shibata (CBS) reduction............................................................. 154 Corey Chaykovsky reaction ............................................................................... 157 Corey–Fuchs reaction ......................................................................................... 160 Corey–Kim oxidation.......................................................................................... 162 Corey–Nicolaou macrolactonization................................................................... 164 Corey–Seebach dithiane reaction ........................................................................ 166 Corey–Winter olefin synthesis ............................................................................ 168 Criegee glycol cleavage ...................................................................................... 171 Criegee mechanism of ozonolysis....................................................................... 173 Curtius rearrangement......................................................................................... 175 Dakin oxidation................................................................................................... 177 Dakin–West reaction........................................................................................... 179 Danheiser annulation........................................................................................... 181 Darzens glycidic ester condensation ................................................................... 183

XIII

Davis chiral oxaziridine reagent.......................................................................... 185 Delépine amine synthesis .................................................................................... 187 de Mayo reaction................................................................................................. 189 Demjanov rearrangement .................................................................................... 191 Tiffeneau–Demjanov rearrangement........................................................... 193 Dess–Martin oxidation ........................................................................................ 195 Dieckmann condensation .................................................................................... 197 Diels–Alder reaction ........................................................................................... 199 Dienone–phenol rearrangement .......................................................................... 202 Di- -methane rearrangement .............................................................................. 204 Doebner quinoline synthesis ............................................................................... 206 Dötz reaction ....................................................................................................... 208 Dowd–Beckwith ring expansion ......................................................................... 210 Erlenmeyer Plöchl azlactone synthesis .............................................................. 212 Eschenmoser–Tanabe fragmentation .................................................................. 214 Eschweiler–Clarke reductive alkylation of amines ............................................. 216 Evans aldol reaction ............................................................................................ 218 Favorskii rearrangement and quasi-Favorskii rearrangement ............................. 220 Feist–Bénary furan synthesis .............................................................................. 222 Ferrier carbocyclization....................................................................................... 224 Ferrier glycal allylic rearrangement .................................................................... 227 Fiesselmann thiophene synthesis ........................................................................ 230 Fischer indole synthesis ...................................................................................... 233 Fischer oxazole synthesis .................................................................................... 235 Fleming–Tamao oxidation .................................................................................. 237 Tamao Kumada oxidation .......................................................................... 239 Friedel–Crafts reaction........................................................................................ 240 Friedländer quinoline synthesis........................................................................... 243 Fries rearrangement............................................................................................. 245 Fukuyama amine synthesis.................................................................................. 247 Fukuyama reduction............................................................................................ 249 Gabriel synthesis ................................................................................................. 251 Ing–Manske procedure................................................................................ 253 Gabriel–Colman rearrangement .......................................................................... 255 Gassman indole synthesis.................................................................................... 257 Gattermann–Koch reaction ................................................................................. 259 Gewald aminothiophene synthesis ...................................................................... 261 Glaser coupling ................................................................................................... 263 Eglinton coupling ........................................................................................ 265 Gomberg–Bachmann reaction............................................................................. 267 Gould–Jacobs reaction ........................................................................................ 269 Grignard reaction ................................................................................................ 271 Grob fragmentation ............................................................................................. 273 Guareschi–Thorpe condensation ......................................................................... 275 Hajos–Wiechert reaction..................................................................................... 277 Haller–Bauer reaction ......................................................................................... 279

XIV

Hantzsch dihydropyridine synthesis.................................................................... 281 Hantzsch pyrrole synthesis.................................................................................. 283 Heck reaction ...................................................................................................... 285 Heteroaryl Heck reaction ............................................................................ 287 Hegedus indole synthesis .................................................................................... 289 Hell–Volhard–Zelinsky reaction ......................................................................... 291 Henry nitroaldol reaction .................................................................................... 293 Hinsberg synthesis of thiophene derivatives ....................................................... 295 Hiyama cross-coupling reaction.......................................................................... 297 Hiyama–Denmark cross-coupling reaction ................................................. 299 Hofmann rearrangement...................................................................................... 302 Hofmann–Löffler–Freytag reaction .................................................................... 304 Horner–Wadsworth–Emmons reaction ............................................................... 306 Houben–Hoesch synthesis .................................................................................. 308 Hunsdiecker–Borodin reaction............................................................................ 310 Hurd–Mori 1,2,3-thiadiazole synthesis ............................................................... 312 Jacobsen–Katsuki epoxidation ............................................................................ 314 Japp–Klingemann hydrazone synthesis .............................................................. 316 Jones oxidation.................................................................................................... 318 Julia–Kocienski olefination................................................................................. 321 Julia–Lythgoe olefination.................................................................................... 323 Kahne–Crich glycosidation................................................................................. 325 Keck macrolactonization..................................................................................... 327 Knoevenagel condensation.................................................................................. 329 Knorr pyrazole synthesis..................................................................................... 331 Paal–Knorr pyrrole synthesis ...................................................................... 333 Koch–Haaf carbonylation ................................................................................... 335 Koenig–Knorr glycosidation............................................................................... 337 Kolbe–Schmitt reaction....................................................................................... 339 Kostanecki reaction............................................................................................. 341 Kröhnke pyridine synthesis................................................................................. 343 Kumada cross-coupling reaction......................................................................... 345 Lawesson’s reagent ............................................................................................. 348 Leuckart–Wallach reaction ................................................................................. 350 Lossen rearrangement ......................................................................................... 352 McFadyen–Stevens reduction ............................................................................. 354 McMurry coupling .............................................................................................. 356 MacMillan catalyst.............................................................................................. 358 Mannich reaction................................................................................................. 361 Marshall boronate fragmentation ........................................................................ 363 Martin’s sulfurane dehydrating reagent .............................................................. 365 Masamune–Roush conditions ............................................................................. 367 Meerwein–Ponndorf–Verley reduction............................................................... 369 Meisenheimer complex ....................................................................................... 371 [1,2]-Meisenheimer rearrangement..................................................................... 372 [2,3]-Meisenheimer rearrangement..................................................................... 374

XV

Meth–Cohn quinoline synthesis .......................................................................... 376 Meyers oxazoline method ................................................................................... 378 Meyer–Schuster rearrangement........................................................................... 380 Michael addition.................................................................................................. 382 Michaelis–Arbuzov phosphonate synthesis ........................................................ 384 Midland reduction ............................................................................................... 386 Mislow–Evans rearrangement............................................................................. 388 Mitsunobu reaction.............................................................................................. 390 Miyaura borylation.............................................................................................. 392 Moffatt oxidation ................................................................................................ 394 Montgomery coupling......................................................................................... 396 Morgan–Walls reaction ...................................................................................... 399 Pictet–Hubert reaction ................................................................................ 400 Mori–Ban indole synthesis.................................................................................. 401 Mukaiyama aldol reaction................................................................................... 403 Mukaiyama Michael addition.............................................................................. 405 Mukaiyama reagent ............................................................................................. 406 Myers Saito cyclization...................................................................................... 408 Nazarov cyclization............................................................................................. 410 Neber rearrangement ........................................................................................... 412 Nef reaction......................................................................................................... 414 Negishi cross-coupling reaction .......................................................................... 416 Nenitzescu indole synthesis ................................................................................ 418 Nicholas reaction................................................................................................. 420 Nicolaou dehydrogenation .................................................................................. 422 Nicolaou hydroxy-dithioketal cyclization ........................................................... 424 Nicolaou hydroxy-ketone reductive cyclic ether formation ................................ 426 Nicolaou oxyselenation ....................................................................................... 428 Noyori asymmetric hydrogenation...................................................................... 430 Nozaki–Hiyama–Kishi reaction .......................................................................... 432 Oppenauer oxidation ........................................................................................... 434 Overman rearrangement...................................................................................... 436 Paal thiophene synthesis...................................................................................... 438 Paal–Knorr furan synthesis ................................................................................. 440 Parham cyclization .............................................................................................. 442 Passerini reaction ................................................................................................ 444 Paternó–Büchi reaction ....................................................................................... 446 Pauson–Khand cyclopentenone synthesis ........................................................... 448 Payne rearrangement ........................................................................................... 450 Pechmann coumarin synthesis ............................................................................ 452 Perkin reaction .................................................................................................... 454 Petasis reaction.................................................................................................... 456 Peterson olefination............................................................................................. 458 Pictet–Gams isoquinoline synthesis .................................................................... 460 Pictet–Spengler tetrahydroisoquinoline synthesis ............................................... 462 Pinacol rearrangement......................................................................................... 464

XVI

Pinner reaction .................................................................................................... 466 Polonovski reaction............................................................................................. 468 Polonovski–Potier rearrangement ....................................................................... 470 Pomeranz–Fritsch reaction.................................................................................. 472 Schlittler–Müller modification.................................................................... 473 Prévost trans-dihydroxylation............................................................................. 475 Woodward cis-dihydroxylation................................................................... 476 Prins reaction ...................................................................................................... 478 Pschorr cyclization.............................................................................................. 480 Pummerer rearrangement .................................................................................... 483 Ramberg–Bäcklund reaction............................................................................... 485 Reformatsky reaction .......................................................................................... 487 Regitz diazo synthesis ......................................................................................... 489 Reimer–Tiemann reaction................................................................................... 492 Reissert aldehyde synthesis................................................................................. 494 Reissert indole synthesis ..................................................................................... 497 Ring-closing metathesis ...................................................................................... 499 Ritter reaction...................................................................................................... 501 Robinson annulation ........................................................................................... 503 Robinson–Gabriel synthesis................................................................................ 505 Robinson–Schöpf reaction .................................................................................. 507 Rosenmund reduction ......................................................................................... 509 Rubottom oxidation............................................................................................. 511 Rupe rearrangement ............................................................................................ 513 Saegusa oxidation ............................................................................................... 515 Sakurai allylation reaction................................................................................... 518 Sandmeyer reaction............................................................................................. 520 Schiemann reaction ............................................................................................. 522 Schmidt reaction ................................................................................................. 524 Schmidt’s trichloroacetimidate glycosidation reaction ....................................... 526 Shapiro reaction .................................................................................................. 529 Sharpless asymmetric amino hydroxylation........................................................ 531 Sharpless asymmetric epoxidation ..................................................................... 533 Sharpless asymmetric dihydroxylation ............................................................... 536 Sharpless olefin synthesis ................................................................................... 540 Simmons–Smith reaction ................................................................................... 543 Skraup quinoline synthesis.................................................................................. 545 Doebner–von Miller reaction ...................................................................... 547 Smiles rearrangement.......................................................................................... 549 Newman Kwart reaction ............................................................................ 551 Truce Smile rearrangement ........................................................................ 553 Sommelet reaction............................................................................................... 555 Sommelet–Hauser rearrangement ....................................................................... 557 Sonogashira reaction ........................................................................................... 559 Staudinger ketene cycloaddition ......................................................................... 561 Staudinger reduction ........................................................................................... 563

XVII

Sternbach benzodiazepine synthesis ................................................................... 565 Stetter reaction .................................................................................................... 567 Still–Gennari phosphonate reaction .................................................................... 569 Stille coupling ..................................................................................................... 571 Stille–Kelly reaction............................................................................................ 573 Stobbe condensation............................................................................................ 575 Stork enamine reaction........................................................................................ 577 Strecker amino acid synthesis ............................................................................. 579 Suzuki coupling................................................................................................... 581 Swern oxidation .................................................................................................. 583 Takai iodoalkene synthesis.................................................................................. 585 Tebbe olefination ................................................................................................ 587 Petasis alkenylation ..................................................................................... 587 TEMPO-mediated oxidation ............................................................................... 589 Thorpe Ziegler reaction...................................................................................... 592 Tsuji–Trost allylation .......................................................................................... 594 Ugi reaction......................................................................................................... 596 Ullmann reaction................................................................................................. 599 van Leusen oxazole synthesis ............................................................................. 601 Vilsmeier–Haack reaction ................................................................................... 603 Vilsmeier mechanism for acid chloride formation .............................................. 605 Vinylcyclopropane cyclopentene rearrangement ............................................... 606 von Braun reaction .............................................................................................. 608 Wacker oxidation ................................................................................................ 610 Wagner–Meerwein rearrangement ...................................................................... 612 Weiss–Cook reaction .......................................................................................... 614 Wharton oxygen transposition reaction............................................................... 616 Willgerodt–Kindler reaction ............................................................................... 618 Wittig reaction..................................................................................................... 621 Schlosser modification of the Wittig reaction ............................................ 622 [1,2]-Wittig rearrangement.................................................................................. 624 [2,3]-Wittig rearrangement.................................................................................. 626 Wohl–Ziegler reaction ........................................................................................ 628 Wolff rearrangement ........................................................................................... 630 Wolff–Kishner reduction..................................................................................... 632 Yamaguchi esterification..................................................................................... 634 Zincke reaction.................................................................................................... 637

Subject Index....................................................................................................... 641

XVIII

Abbreviations and Acronyms

polymer support A adenosine Ac acetyl AIBN 2,2’-azobisisobutyronitrile Alpine-borane® B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane Ar aryl B: generic base 9-BBN 9-borabicyclo[3.3.1]nonane [bimim]Cl•2AlCl3 1-butyl-3-methylimidazolium chloroaluminuminate

(a Lewis acid ionic liquid) BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl Bn benzyl Boc tert-butyloxycarbonyl t-Bu tert-butyl Bz benzoyl Cbz benzyloxycarbonyl m-CPBA m-chloroperoxybenzoic acid CuTC copper thiophene-2-carboxylate DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEAD diethyl azodicarboxylate

solvent heated under reflux (DHQ)2-PHAL 1,4-bis(9-O-dihydroquinine)-phthalazine (DHQD)2-PHAL 1,4-bis(9-O-dihydroquinidine)-phthalazine DIAD diisopropyl azodidicarboxylate DIBAL diisobutylaluminum hydride DIPEA diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMFDMA N,N-dimethylformamide dimethyl acetal DMS dimethylsulfide DMSO dimethylsulfoxide DMSY dimethylsulfoxonium methylide DMT dimethoxytrityl dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1’-bis(diphenylphosphino)ferrocene dppp 1,3-bis(diphenylphosphino)propane

XIX

DTBAD di-tert-butylazodicarbonate DTBMP 2,6-di-tert-butyl-4-methylpyridine E1 unimolecular elimination E2 bimolecular elimination E1cB 2-step, base-induced -elimination via carbanion EAN ethylammonium nitrate EDDA ethylenediamine diacetate ee enantiomeric excess Ei two groups leave at about the same time and bond to

each other as they are doing so. Eq equivalent Et ethyl EtOAc ethyl acetate HMDS hexamethyldisilazane HMPA hexamethylphosphoramide HMTTA 1,1,4,7,10,10-hexamethyltriethylenetetramine Imd imidazole KHMDS potassium hexamethyldisilazide LAH lithium aluminum hydride LDA lithium diisopropylamide LHMDS lithium hexamethyldisilazide LTMP lithium 2,2,6,6-tetramethylpiperidide M metal Mes mesityl Ms methanesulfonyl MVK methyl vinyl ketone NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMP 1-methyl-2-pyrrolidinone Nos nosylate (4-nitrobenzenesulfonyl) Nu nucleophile N-PSP N-phenylselenophthalimide N-PSS N-phenylselenosuccinimide PCC pyridinium chlorochromate PDC pyridinium dichromate Piv pivaloyl PMB para-methoxybenzyl PPA polyphosphoric acid PPTS pyridinium p-toluenesulfonate PyPh2P diphenyl 2-pyridylphosphine Pyr pyridine Red-Al sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) Salen N,N´-disalicylidene-ethylenediamine SET single electron transfer SM starting material

XX

SMEAH sodium bis(methoxy-ethoxy)aluminum hydride (Red-Al) SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution SNAr nucleophilic substitution on an aromatic ring TBABB tetra-n-butylammonium bibenzoate TBAF tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEA triethylamine TEOC trimethysilylethoxycarbonyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFP tri-2-furylphosphine THF tetrahydrofuran TIPS triisopropylsilyl TMEDA N,N,N’,N’-tetramethylethylenediamine TMG tetramethylguanidine TMP tetramethylpiperidine TMS trimethylsilyl TMSCl trimethylsilyl chloride TMSCN trimethylsilyl cyanide TMSI trimethylsilyl iodide TMSOTf trimethylsilyl triflate Tol toluene or tolyl Tol-BINAP 2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl TosMIC (p-tolylsulfonyl)methyl isocyanide Ts tosyl TsO tosylate UHP urea-hydrogen peroxide

1

Alder ene reaction

Addition of an enophile to an alkene via allylic transposition. Also known as hy-droallyl addition.

O

O

O

O

O

O enophile

OO

OO

O

OH

ene

reaction

Example 113

OH

NH2N KOH, Pt/Clay, 35%

(Kishner reduction)

O

H

OH

O

O

0 oC, CH2Cl2, 89%

(Alder ene reaction)

O

OOH

O

Example 214

NO

O

NO

HTol., reflux

5 h, 95%O

H

2

References

1. Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27. Kurt Alder (Germany, 1902 1958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 1876 1954) for development of the diene synthesis.

2. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). 3. Oppolzer, W. Angew. Chem. 1984, 96, 840. 4. Mackewitz, T. W.; Regitz, M. Synthesis 1998, 125 138. 5. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325 335. (Review). 6. Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595 1615. 7. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.;

Wiley VCH: New York, 2000, 543 568. (Review). 8. Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243. 9. Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198. 10. Shibata, T.; Takesue, Y.; Kadowaki, S.; Takagi, K. Synlett 2003, 268. 11. Suzuki, K.; Inomata, K.; Endo, Y. Org. Lett. 2004, 6, 409. 12. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-catalyzed Alder-ene Reaction. In

Modern Rhodium-Catalyzed Organic Reactions 2005, 151 172. (Book chapter). 13. Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70, 2862. 14. Pedrosa, R.; Andres, C.; Martin, L.; Nieto, J.; Roson, C. J. Org. Chem. 2005, 70, 4332.

3

Aldol condensation

Condensation of a carbonyl with an enolate or an enol. A simple case is addition of an enolate to an aldehyde to afford an alcohol, thus the name aldol.

R2 R3

OR1

OR

1. base

R1

O

RR3

OHR2

2.

R2R3

O

R1

OR R1

OR

H

B:

deprotonation condensation

R1

O

RR3

OR2

R1

O

RR3

OHR2acidic

workup

Example 13

OTMSO LDA, THF, then MgBr2, 110 oC, then

OHCO OBn

BnO OOTMS

OH O85% yield

4

Example 212

CO2HO OTBS

LDA, THF, 78 to 40 oC, then

aldehyde, 1 h, 83%, 3:2 de

H

O

CO2HO OTBS

HO

References

1. Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436. 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 a 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 is no longer considered synthetically useful, although the aldol reaction that Wurtz discovered in 1872 has become a staple in or-ganic synthesis.

2. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1 438. (Review). 3. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031, 1035. 4. Mukayama, T. Org. React. 1982, 28, 203 331. (Review). 5. Mukayama, T.; Kobayashi, S. Org. React. 1994, 46, 1 103. (Review on Tin(II)

enolates). 6. Saito, S.; Yamamoto, H. Chem. Eur. J. 1999, 5, 1959 1962. (Review). 7. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325 335. (Review). 8. Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432 440. (Review). 9. Nicolaou, K. C.; Ritzén, A.; Namoto, K. Chem. Commun. 2001, 1523. 10. Palomo, C.; Oiarbide, M.; García, J. M. Chem. Eur. J. 2002, 8, 36 44. (Review). 11. Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595 1601. (Review). 12. Wei, H.-X.; Hu, J.; Purkiss, D. W.; Paré, P. W. Tetrahedron Lett. 2003, 44, 949. 13. Bravin, F. M.; Busnelli, G.; Colombo, M.; Gatti, F.; Manzoni, L.; Scolastico, C. Syn-

thesis 2004, 353. 14. Mahrwald, R. (ed.) Modern Aldol Reactions, Wiley VCH: Weinheim, Germany,

2004. (Book).

5

Algar Flynn Oyamada Reaction

Conversion of 2’-hydroxychalcones to 2-aryl-3-hydroxy-4H-1benzopyran-4-ones (flavonols) by alkaline hydrogen peroxide oxidation.

OH

O

ArR1

R2

H2O2, NaOHO

O

R1

R2

Ar

OH

O

O

R1

R2

Ar

OH

OH

O

HO , H2O2

O

OO

-attack

O

OHO

OO

OHO

flavonol

A side reaction:

O

OO

-attack

then dehydration

O

Oaurone

6

Example 15

OH

O

1. PhCHO, NaOH, EtOH, rt

2. H2O2, 15 to 50 oC, 54%

O Ph

OOH

Example 25

OH

O

O

1.

OMe

CHO

, aq. NaOH, EtOH

2. aq. NaOH, 30% H2O2

47% for two steps

O O

OOH

OMe

References

1. Algar, J.; Flynn, J. P. Proc. Roy. Irish. Acad. 1934, 42B, 1. 2. Oyamada, T. J. Chem. Soc. Japan 1934, 55, 1256. 3. Oyamada, T. Bull. Chem. Soc. Jpn. 1935, 10, 182. 4. Wheeler, T.S. Rec. of Chem. Prog. 1957, 18, 133. (Review) 5. Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl. Chem. 1968, 5, 425. 6. Rao, A. V. S.; Rao, N. V. S. Current Science 1974, 43, 477. 7. Cullen, W. P.; Donnelly, D. M. X.; Keenan, A. K.; Kennan, P. J.; Ramdas, K. J. Chem.

Soc., Perkin Trans. 1 1975, 1671. 8. Wagner, H.; Farkas, L. In The Flavonoids; Harborne, J. B.; Mabry, T. J.; Mabry H.,

Eds.; Academic Press: New York, 1975; p 127. (Review). 9. Wollenweber, E. In The Flavonoids: Advances in Research; Harborne, J. B.; Mabry,

T. J., Eds; Chapman and Hall: New York, 1982; p 189. (Review). 10. Jain, A. C.; Gupta, S. M.; Sharma, A. Bull. Chem. Soc. Jpn. 1983, 56, 1267. 11. Prasad, K. J. Rajendra; Iyer, C. S. Rukmani; Iyer, P. R. Indian J. Chem., Sect. B 1983,

22B, 693.

7

12. Wollenweber, E. In The Flavonoids: Advances in Research since 1986; Harborne, J. B., Ed.; Chapman and Hall: New York, 1994, p 259. (Review).

13. Bennett, M.; Burke, A. J.; O'Sullivan, W. I. Tetrahedron 1996, 52, 7163. 14. Sobottka, A. M.; Werner, W.; Blaschke, G.; Kiefer, W.; Nowe, U.; Dannhardt, G.;

Schapoval, E. E. S.; Schenkel, E. P.; Scriba, G. K. E. Arch. Pharm. 2000, 333, 205. 15. Bohm, B. A.; Stuessy, T. F. Flavonoids of the Sunflower Family (Asteraceae);

Springer-Verlag: New York, 2001. (Review).

8

Allan–Robinson reaction

Synthesis of flavones or isoflavones.

R1 O R1

O O

R1CO2Na,

O

OR

R1OH

OR

OH

OR

enolization

OH

OR

H

R1

O

R1

O

O

R1CO2

acylation

OH

OH R1

O

R

enolization O2CR1

OR

OH R1

OCOR1

O

O2CR1

O

OR

OHR1

OHR

O: R1

O

H

H

O2CR1

O

O

R

R1

9

Example 16

OH

OOMe

OMe

HO

OMe

O

O O

MeO OMe

O

OOMe

OMe

HO

OMe

OMe

PhCO2Na, 170 180 oC

8 h, 45%

References

1. Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192. 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 chem-istry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the ar-row pushing approach to organic reaction mechanism. Robinson was also an accom-plished pianist. J. 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. 3. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405. 4. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037. 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. 7. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987,

35, 4465. 8. Horie, T.; Kawamura, Y.; Tsukayama, M.; Yoshizaki, S. Chem. Pharm. Bull. 1989,

37, 1216.

10

Appel reaction

The reaction between triphenylphosphine and tetrahalomethane (CCl4, CBr4)forms a salt known as Appel’s salt. Treatment of alcohols with Appel’s salt gives rise to the corresponding halides.

R R1

OH CX4, PPh3

R R1

X

X

X

XX

Ph3P X,

Ph3P:CX3

Appel’s salt

Ph3P X,

R R1

O

Ph3P XX3CH

X3CH

R R1

O

R R1

OPPh3

X

R R1

XPh3P O

Example 17

CBr4, PPh3

DMF, 24 h, 96%O

BnOBnO

AcOO

BnOBnO

AcO

OH Br

BnOBnO

11

Example 2, Appel’s salt is often used as a dehydrating agent8

CCl4, PPh3, Et3N

CH2Cl2, reflux, 5 h, 63%

NH

CO2Me

NHO

N

NN

N

CO2Me

References

1. Appel, R.; Kleinstueck, R.; Ziehn, K. D. Angew. Chem., Int. Ed. Engl. 1971, 10, 132. Rolf Appel was a professor at Anorganisch-Chemisches Institut der Universität in Bonn, Germany.

2. Appel, R.; Kleinstück, R.; Ziehn, K.-D. Chem. Ber. 1971, 104, 1335. 3. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (Review). 4. Beres, J.; Bentrude, W. G.; Parkanji, L.; Kalman, A.; Sopchik, A. E. J. Org. Chem.

1995, 50, 1271. 5. Lee, K. J.; Kim, S. Heon; K., Jong H. Synthesis 1997, 1461. 6. Lee, K.-J.; Kwon, H.-T.; Kim, B.-G. J. Heterocycl. Chem. 1997, 34, 1795. 7. Lim, J.-S.; Lee, K.-J. J. Heterocycl. Chem. 2002, 39, 975. 8. Nishida, Y.; Shingu, Y.; Dohi, H.; Kobayashi, K. Org. Lett. 2003, 5, 2377. 9. Cho, H. I.; Lee, S. W.; Lee, K.-J. J. Heterocycl. Chem. 2004, 41, 799.

12

Arndt–Eistert homologation

One carbon homologation of carboxylic acids using diazomethane.

R OH

O SOCl2

R Cl

O 1. CH2N2

OH

OR2. H2O, hv

R Cl

O

H2C N N

R Cl

O

NN

R

O

NN

H H

H2C N N

Cl

R

ON

N

R

ON

N N2

H H

CH3N2

hv

:OH2

C C OH

RR

O

:

H

-ketocarbene intermediate ketene intermediate

CH

R OH

OH

OH

OR

side reaction:

H3C N NCl CH3Cl N2

13

Example 110

CO2HBnO

BnOHN

Boc

1. ClCO2Et, Et3N, THF, 10 oC, 15 min

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

BnO

BnOHN

Boc

ON2

AgOBz, Et3N, MeOH/THF, dark

25 oC to rt, 3 h, 61%

BnO

BnOHN

Boc

CO2Me

References

1. Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. 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 diazome-thane 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. stu-dent. Eistert later joined I. G. Farbenindustrie, which became BASF after the Allies broke the conglomerate up after WWII.

2. Kuo, Y. C.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 899. 3. Podlech, J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 471. 4. Matthews, J. L.; Braun, C.; Guibourdenche, C.; Overhand, M.; Seebach, D. in Enanti-

oselective Synthesis of -Amino Acids Juaristi, E. ed. Wiley-VCH, New York, N. Y. 1997, pp 105 126. (Review).

5. Katritzky, A. R.; Zhang, S.; Fang, Y. Org. Lett. 2000, 2, 3789. 6. Cesar, J.; Sollner Dolenc, M. Tetrahedron Lett. 2001, 42, 7099. 7. Katritzky, A. R.; Zhang, S.; Hussein, A. H. M.; Fang, Y.; Steel, P. J. J. Org. Chem.

2001, 66, 5606. 8. Vasanthakumar, G.-R.; Babu, V. V. S. Synth. Commun. 2002, 32, 651. 9. 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.; Wy-vratt, M.J.; Fisher, M. H.; Meinke, P. T. Bioorg. Med. Chem. Lett. 2003, 13, 147.

10. Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman, M.; Mazaleyrat, J.-P. Tetrahedron: Asymmetry 2005, 16, 857.

14

Baeyer–Villiger oxidation

General scheme:

R1 R2

O HO

O R3

O

R1 O

OR2

HO R3

O

or H2O2

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:

O

HO

O

m-CPBAO

Cl

O

O

O

OCl

O

OH

H

:HOAc

AcO

HO

OClalkyl

migration

O

OO

OHO

O

Cl

15

Example 210

NHPh

OH O

O

m-CPBA,

CH2Cl2, rt NH

OOH

O

Ph

O

NH

OH O

O

m-CPBA,

CH2Cl2, rt NHO

OH O

O

References

1. v. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625. Adolf von Baeyer (1835 1917) was one of the most illustrious organic chemists in history. He contrib-uted in many areas of the field. The Baeyer-Drewson indigo synthesis made possible the commercialization of synthetic indigo. Baeyer’s other claim of fame is his synthe-sis of barbituric acid, named after his 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 to work with Adolf von Baeyer for eleven years.

2. Krow, G. R. Tetrahedron 1981, 37, 2697. 3. Krow, G. R. Org. React. 1993, 43, 251 798. (Review). 4. Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737. (Review). 5. Bolm, C.; Beckmann, O. Compr. Asymmetric Catal. I-III 1999, 2, 803. (Review). 6. Crudden, C. M.; Chen, A. C.; Calhoun, L. A. Angew. Chem., Int. Ed. 2000, 39, 2851. 7. Fukuda, O.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2001, 42, 3479. 8. Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481. 9. Kobayashi, S.; Tanaka, H.; Amii, H.; Uneyama, K. Tetrahedron 2003, 59, 1547. 10. Laurent, M.; Ceresiat, M.; Marchand-Brynaert, J. J. Org. Chem. 2004, 69, 3194. 11. Reetz, M. T.; Brunner, B.; Schneider, T.; Schulz, F.; Clouthier, C. M.; Kayser, M. M.

Angew. Chem., Int. Ed. 2004, 43, 4075.

16

Baker–Venkataraman rearrangement

Base-catalyzed acyl transfer reaction that converts -acyloxyketones to -diketones.

OOPh

O

baseOOH

Ph

O

OOPh

O

H

:B

O

OO

Ph

O

O

OPh

OO

Ph

O OOH

Ph

Oacyl

transfer

H+

workup

Example 17

NaH, THF

reflux, 2 h, 84%

O

O

NEt2O

OH

O

NEt2

O

Example 28

2.5 eq. NaH, PhMe, reflux, 2 h

then 6 eq. TFA, reflux, 1 h, 93%

O

MeOO

NEt2O

17

O O

MeOOH

References

1. Baker, W. J. Chem. Soc. 1933, 1381. Wilson Baker (1900 2002) was born in Run-corn, England. He studied chemistry at Manchester under Arthur Lapworth and at Ox-ford 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 re-tired in 1965 as the head of the School of Chemistry. Baker was a well-known chem-ist centenarian, spending 47 years in retirement!

2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the di-rector of the National Chemical Laboratory at Poona.

3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212. 4. Bowden, K.; Chehel-Amiran, M. J. Chem. Soc., Perkin Trans. 2 1986, 2039. 5. Makrandi, J. K.; Kumari, V. Synth. Commun. 1989, 19, 1919. 6. Reddy, B. P.; Krupadanam, G. L. D. J. Heterocycl. Chem. 1996, 33, 1561. 7. Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahe-

dron Lett. 1998, 39, 4995. 8. Kalinin, A. V.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4999. 9. Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43, 4515. 10. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2003, 4575.

18

Bamberger rearrangement

Acid-mediated rearrangement of N-phenylhydroxylamines to 4-aminophenols.

HN

OHH2SO4

H2O

NH2

HO

HN

OHH+ N

OH

H

H2O:

HH

NH2

OH

HH

HSO4

HSO4

NH2

HOH

NH2

HO

Example 15

NHOH

NH2

OH

HClO4, 40 oC

96%

References

1. Bamberger, E. Ber. Dtsch. Chem. Ges. 1894, 27, 1548. Eugen Bamberger (1857 1932) was born in Berlin. He taught in Munich and at ETH in Zurich. He in-troduced sodium and amyl alcohol as a reducing agent. Bamberger also engaged in a long (1894 1900) and acrimonious controversy with Arthur Hantzsch on the structure of diazo-compounds.

2. Shine, H. J. in Aromatic Rearrangement Elsevier: New York, 1967, pp 182 190. (Re-view).

3. Buckingham, J. Tetrahedron Lett. 1970, 11, 2341.

19

4. Sone, T.; Tokuda, Y.; Sakai, T.; Shinkai, S.; Manabe, O. J. Chem. Soc., Perkin Trans. 2 1981, 298.

5. Fishbein, J. C.; McClelland, R. A. J. Am. Chem. Soc. 1987, 109, 2824. 6. Zoran, A.; Khodzhaev, O.; Sasson, Y. J. Chem. Soc., Chem. Commun. 1994, 2239. 7. Tordeux, M.; Wakselman, C. J. Fluorine Chem. 1995, 74, 251. 8. Fishbein, J. C.; McClelland, R. A. Can. J. Chem. 1996, 74, 1321. 9. Naicker, K. P.; Pitchumani, K.; Varma, R. S. Catal. Lett. 1999, 58, 167. 10. Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143. 11. Qiu, X.; Jiang, J.-J.; Wang, X.-Y.; Shen, Y.-J. Youji Huaxue 2005, 25, 561.

20

Bamford–Stevens reaction

The Bamford Stevens reaction and the Shapiro reaction share a similar mechanis-tic 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 re-agents. As a result, the Bamford Stevens reaction furnishes more-substituted ole-fins as the thermodynamic products, while the Shapiro reaction generally affords less-substituted olefins as the kinetic products.

R2

N

HN

Ts

R3

R1

R2

R3

R1

HNaOMe

R2

NN

TsR3

R1 H

H

MeO

R2

NN

TsR3

R1

H

:

R2

N

R3

R1

H N

In protic solvent:

N2R2

N

R3

R1

H NR2

N

R3

R1

H N

HHS

R2

R3

R1

HR2

H

R3

R1

HS

SHR3

R2

R1

H

In aprotic solvent:

N2R2

N

R3

R1

H N

R2

N

R3

R1

H N

21

R2

R3

R1

HR3

R2

R1

HR2

R3

R1

R2

R3

R1

H

H2O:

Example 1, thermal Bamford–Stevens5

Me3Si Ph

NN Ph Tol., 145 oC

sealed tube, 65%

Me3Si Ph

E : Z = 90 : 10

Example 29

ON NHTs

t-BuOK, t-BuOH

reflux, 83% OOt-Bu

References

1. Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735. Thomas Stevens (1900 2000), a chemist centenarian, was born in Renfrew, Scotland. He and his stu-dent W. R. Bamford published this paper at the University of Sheffield, UK. Stevens also contributed to another name reaction, the McFadyen Stevens reaction (page 354).

2. Shapiro, R. H. Org. React. 1976, 23, 405 507. (Review). 3. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55 59. (Review on the

Shapiro reaction). 4. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1 83. (Review). 5. Sarkar, T. K.; Ghorai, B. K. J. Chem. Soc., Chem. Commun. 1992, 17, 1184. 6. Nickon, A.; Stern, A. G.; Ilao, M. C. Tetrahedron Lett. 1993, 34, 1391. 7. Olmstead, K. K.; Nickon, A. Tetrahedron 1998, 54, 12161. 8. Olmstead, K. K.; Nickon, A. Tetrahedron 1999, 55, 7389. 9. Chandrasekhar, S.; Rajaiah, G.; Chandraiah, L.; Swamy, D. N. Synlett 2001, 1779. 10. May, J. A.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 12426. 11. Zhu, S.; Liao, Y.; Zhu, S. Org. Lett. 2004, 6, 377.

22

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. Grig-nard reaction.

R1 R2

O R3X, MR1 R2

OH

RR M

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 trans-fer pathway.

Generation of the Grignard reagent,

R3 XSET-1

R X MMX

R R MSET-2

R M

Ionic mechanism,

R MgX

O

R OMgX

R2R1R2

R1

R OH

R2R1H

Single electron transfer mechanism,

R MgX

OR2

R1 OR2

R1

MgXR

R OMgX

R2R1

R OH

R2R1H

23

Example 18

OO

BrSm, THF, rt

20 min. 70%

OHO

Example 211

Ph

NHCO2Et

O

BrZn, THF, aq. NH4Cl

0 oC, 82%, 95% de

Ph

NHCO2Et

OH

References

1. Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110. 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. 3. Molle, G.; Bauer, P. J. Am. Chem. Soc. 1982, 104, 3481. 4. Moyano, A.; Pericás, M. A.; Riera, A.; Luche, J.-L. Tetrahedron Lett. 1990, 31, 7619.

(Theoretical study). 5. Alonso, F.; Yus, M. Rec. Res. Dev. Org. Chem. 1997, 1, 397. (Review). 6. Russo, D. A. Chem. Ind. 1996, 64, 405. (Review). 7. Curran, D. P.; Gu, X.; Zhang, W.; Dowd, P. Tetrahedron 1997, 53, 9023. 8. Basu, M. K.; Banik, B. Tetrahedron Lett. 2001, 42, 187. 9. Sinha, P.; Roy, S. Chem. Commun. 2001, 1798. 10. Lambardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C. Tetrahedron 2004, 60, 11725. 11. Resende, G. O.; Aguiar, L. C. S.; Antunes, O. A. C. Synlett 2005, 119.

24

Bargellini reaction

Synthesis of hindered morpholinones or piperazinones from ketones (such as ace-tone) and 2-amino-2-methyl-1-propanol or 1,2-diaminopropanes.

ONH2

XH

X = O, NRNaOH, CHCl3

CH2Cl2, BnEt3NCl

HN

X O

H CCl3HO

deprotonationO

CCl3

O

CCl2Cl

NH2

XH

O

ClCl

:HN

Cl OHXCl

H

HN

Cl OHX

HN

X O

Example 12

ONH2

NHNaOH, CHCl3

CH2Cl2, BnNEt3Cl

HN

N O

HN

N

O

67% 15%

25

Example 26

HN

OO

H2N

HO

1. NaOH, CHCl3, acetone

2. CSA, toluene, 66%

References

1. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329. 2. Lai, J. T. J. Org. Chem. 1980, 45, 754. 3. Lai, J. T. Synthesis 1981, 754. 4. Lai, J. T. Synthesis 1984, 122. 5. Lai, J. T. Synthesis 1984, 124. 6. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J. Org. Chem. 1998,

63, 6363. 7. Cvetovich, R. J.; Chung, J. Y. L.; Kress, M. H.; Amato, J. S.; Zhou, G.; Matty, L.;

Tsay, F. R.; Li, Z. Abstracts of Papers, 226th ACS National Meeting, New York, NY, United States, September 7 11, 2003 (2003), ORGN-078.

26

Bartoli indole synthesis

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

NH

RNO2

1.

2. H2O+

MgBr

R

R

NO

O

BrMg

R

NO

OMgBr

OMgBr

[3,3]-sigmatropic

rearrangementR

NO

MgBrRN

O

BrMg

nitroso intermediate

RNMgBr

O

H

N

R

OMgBrH+

workup

H

BrMg

NH

RNH

R

OH2+

H

Example 13

NO2NH

1.

2. aq. NH4Cl, 67%

40 oC, THF

MgBr (3 eq)

27

Example 28

BrNO2

MeMgCl

THF, 40 oC

67%NH

Me

Br

References

1. Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc., Perkin Trans. 1 1978,892. 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.

3. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129. 4. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin

Trans. 2 1991, 657. Mechanistic studies. 5. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc.,

Perkin Trans. 1 1991, 2757. 6. Dobson, D. R.; Gilmore, J.; Long, D. A. Synlett 1992, 79. 7. Dobbs, A. P.; Voyle, M.; Whittall, N. Synlett 1999, 1594. 8. Dobbs, A. J. Org. Chem. 2001, 66, 638. 9. Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143. 10. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179. 11. Knepper, K.; Braese, S. Org. Lett. 2003, 5, 2829. 12. Li, J.; Cook, J. M. Bartoli indole synthesis In Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 100 103. (Review). 13. Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163 178. (Review).

28

Barton radical decarboxylation

Radical decarboxylation via the corresponding thiocarbonyl derivatives of the car-boxylic acids.

R Cl

ON

HO

S

R O

O

N

SAIBN, R

Hn-Bu3SnH

Barton ester

N N CNNC CNN2 2homolyticcleavage

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3Sn CNH

R O

O

N

S

SnBu3

N

SBu3Sn

R O

O

Bu3SnRHCO2 SnBu3HR

Example 13

CO2H

H

OAc H

OAc

1. (COCl)2

2.

NNaO

S

OO

NS

29

S

H

OAc

N98%

1. m-CPBA, 78 oC

2. 100 oC, 78%

H

OAc

Example 211

HO2C OTBDPS

Ph N

S

O

2

Bu3P, THF, PhH

OTBDPS

Ph

OO

N

S

OTBDPS

Me3SiH, AIBN

PhH, 80 oC, 75% Ph

References

1. Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983,939. Derek Barton (United Kingdom, 1918 1998) studied under Ian Heilbron at Im-perial 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 at Austin.

2. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675. 3. Barton, D. H. R.; Bridon, D.; Zard, S. Z.; Fernandaz-Picot, I. Tetrahedron 1987, 43,

2733. 4. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30,

7111. 5. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 6. Gawronska, K.; Gawronski, J.; Walborsky, H. M. J. Org. Chem. 1991, 56, 2193. 7. Eaton, P. E.; Nordari, N.; Tsanaktsidis, J.; Upadhyaya, S. P. Synthesis 1995, 501. 8. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189. 9. Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 3519. 10. Materson, D. S.; Porter, N. A. Org. Lett. 2002, 4, 4253. 11. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68,

9255. 12. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford,

UK, 2003. (Book). 13. 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.

30

Barton–McCombie deoxygenation

Deoxygenation of alcohols by means of radical scission of their corresponding thiocarbonyl derivatives.

O S

S n-Bu3SnH, AIBN

PhH, refluxR2

R1

HR2

R1

n-Bu3SnSMe C SO

N N CNNC CNN22

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3Sn CNH

O S

S

n-Bu3Sn

O S

S

R2

R1

R2

SnBu3R1

O S

Sn-Bu3Sn-scission

R2

R1

HR2

R1

n-Bu3Sn H n-Bu3Snhydrogen atom

abstractionR2

R1

n-Bu3SnSMe

O S

Sn-Bu3Sn

C SO

Example 15

OO

O

O

O

O

AIBN, , 74%

(CH2)4Bu2SnH

SPh

31

OO

O

O

O

Example 29

O

O

O O

OH

OBn 1. NaH, CS2, MeI, 80%

2. Bu3SnH, AIBN, 70%

O

O

O O

OBn

References

1. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. Stuart McCombie, a Barton student, now works at Schering Plough.

2. Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. 3. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949. 4. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925. 5. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41,

3377. 6. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763. 7. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192. 8. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492. 9. Gómez, A. M.; Moreno, E.; Valverde, S.; López, J. C. Eur. J. Org. Chem. 2004, 1830.

32

Barton nitrite photolysis

Photolysis of a nitrite ester to a -oximino alcohol.

O

OO

OAc

NOCl

O

HOO

OAc

NO

h

O

O

OAc

N

HO OHH

O N Cl

O

HOO

OAc

HCl

O

OO

OAc

NO

1,5-hydrogen

abstraction

O

OO

OAc

H

hhomolytic

cleavageON•

O

O

OAc

N

O OHHO N

O

HOO

OAc

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

33

O

O

OAc

NHO OHH

tautomerization

Example11

O

OAcH

HO1. NOCl, CH2Cl2, 20 oC, 100%

2. Irradiation at 350 nM

5 h, PhH, 0 oC, 50%

O

OAcH

NHO HO

References

1. Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. J. Am. Chem. Soc. 1960,82, 2640. 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 sat-isfying piece of work.

2. Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1960, 82, 2641. 3. Barton, D. H. R.; Beaton, J. M. J. Am. Chem. Soc. 1961, 83, 4083. 4. Kabasakalian, P.; Townley, E. J. Am. Chem. Soc. 1962, 84, 2723. 5. Barton, D. H. R.; Lier, E. F.; McGhie, J. M. J. Chem. Soc., C 1968, 1031. 6. Suginome, H.; Sato, N.; Masamune, T. Tetrahedron 1971, 27, 4863. 7. Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. J. Chem. Soc., Perkin

Trans. 1 1979, 1159. 8. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). 9. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (Review). 10. Herzog, A.; Knobler, C. B.; Hawthorne, M. F. Angew. Chem., Int. Ed. 1998, 37, 1552. 11. Anikin, A.; Maslov, M.; Sieler, J.; Blaurock, S.; Baldamus, J.; Hennig, L.; Findeisen,

M.; Reinhardt, G.; Oehme, R.; Welzel, P. Tetrahedron 2003, 59, 5295. 12. Suginome, H. CRC Handbook of Organic Photochemistry and Photobiology 2nd edn.

2004, 102/1 102/16. (Review).

34

Barton–Zard reaction

Base-induced reaction of nitroalkenes with alkyl -isocyanoacetates to afford pyr-roles.

NO2

R2R1

C=NCH2CO2R3NH

CO2R3

Base

R1 = H, alkyl, arylR2 = H, alkylR3 = Me, Et, t-BuBase = KOt-Bu, DBU, guanidine bases

R2 R1

Example 1

C=NCH2CO2R3

BaseNO2 N

HCO2R

C=N CO2R

N

C=N CO2R

H

B O

O

Michael additionBH

BH

CN

N

CO2RN

O2N

CO2R

O O

H

N

O2N

CO2R

HNO2

N CO2R NH

CO2R[1,5]

35

Example 25

O2N

CNCH2CO2Et

NH

CO2EtDBU, THFrt, 8 h, 75%

Example 37

N

NO2

SO2Ph

CNCH2CO2Et

N NH

CO2EtPhO2S

DBUTHF, rt, 20 h

85%

References

1. Barton, D. H. R.; Zard, S. Z. J. Chem. Soc., Chem. Commun. 1985, 1098. Samir Z. Zard, a Barton student, emigrated from Lebanon to the UK in 1975. He is a professor at CNRS and École Polytechnique in France.

2. van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337.

3. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587. 4. Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1991, 70, 68. 5. Ono, N.; Hironaga, H.; Ono, K.; Kaneko, S.; Murashima, T.; Ueda, T.; Tsukamura, C.;

Ogawa, T. J. Chem. Soc., Perkin Trans. 1 1996, 417. 6. Murashima, T.; Fujita, K.; Ono, K.; Ogawa, T.; Uno, H.; Ono, N. J. Chem. Soc.,

Perkin Trans. 1 1996, 1403. 7. Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem. Commun. 1996, 1909. 8. Uno, H.; Ito, S.; Wada, M.; Watanabe, H.; Nagai, M.; Hayashi, A.; Murashima, T.;

Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 4347. 9. Murashima, T.; Tamai, R.; Nishi, K.; Nomura, K.; Fujita, K.; Uno, H.; Ono, N. J.

Chem. Soc., Perkin Trans. 1 2000, 995. 10. Fumoto, Y.; Uno, H.; Tanaka, K.; Tanaka, M.; Murashima, T.; Ono, N. Synthesis

2001, 399. 11. Lash, T. D.; Werner, T. M.; Thompson, M. L.; Manley, J. M. J. Org. Chem. 2001, 66,

3152. 12. Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira, M. L.

G. Org. Prep. Proc. Int. 2001, 33, 411. (Review). 13. Murashima, T.; Nishi, K.; Nakamoto, K.; Kato, A.; Tamai, R.; Uno, H.; Ono, N. Het-

erocycles 2002, 58, 301. 14. Gribble, G. W. Barton Zard Reaction in Name Reactions in Heterocyclic Chemistry,

Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 70 78. (Review).

36

Batcho–Leimgruber indole synthesis

Condensation of o-nitrotoluene derivatives with formamide acetals, followed by reduction of the trans- -dimethylamino-2-nitrostyrene to furnish indole deriva-tives.

NO2

R

DMF, NO2

R

NN

R1

R2CH

OR3

OR3R1

R2

1. Pd/C, H2

2. 5% HClNH

R

Example 1

NO2 DMF, NO2

NMe2DMFDMA

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

Pd/C, H2

NH

NMeO

MeON

MeO +OMe

37

CH2

N

HCH2

NO

OO

O

NMeO +

OMe

NO2

NMe2MeO

H NO2

NMe2MeOH

NH2

NMe2[H]

reduction

:

NH

NMe2

NH

NH

H

NMe2

NHMe2

Example 25

NO2 NO2

NMe2

CO2H CO2Me1. MeI, NaHCO3

2. Me2NCH(OMe)2 DMF, 80%, 2 steps

NH

CO2Me

Pd/C, H2, PhH, 82%

38

Example 314

NO2NO2

NMe2

OBn OBnMe2NCH(OMe)2

pyrrolidine

DMF, 110 oC

3 h, 95%

NO2

OBn

15 : 1

NH

OBn

Ni, NH2NH2

THF, MeOH96%NO2

NMe2

OBn

References

1. Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemis-try: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at Hoffmann La Roche in Nutley, NJ, USA.

2. Leimgruber, W.; Batcho, A. D. US 3732245 1973.3. Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675. 4. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London,

1970. (Review). 5. Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3550. 6. Maehr, H.; Smallheer, J. M. J. Org. Chem. 1981, 46, 1752. 7. Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. 8. Gupton, J. T.; Lizzi, M. J.; Polk, D. Synth. Commun. 1982, 12, 939. 9. Repke, D. B.; Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. 10. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195. (Review). 11. Clark, R. D.; Repke, D. B. J. Heterocycl. Chem. 1985, 22, 121. 12. Feldman, P. L.; Rapoport, H. Synthesis 1986, 735. 13. Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am. Chem. Soc. 1982, 104, 7622. 14. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106. 15. Toste, F. D.; Still, I. W. J. Org. Prep. Proced. Int. 1995, 27, 576. 16. Coe, J. W.; Vetelino, M. G.; Bradlee, M. J. Tetrahedron Lett. 1996, 37, 6045. 17. Grivas, S. Current Org. Chem. 2000, 4, 707. 18. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomolecular Chem. 2004, 2, 160. 19. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis in Name Reactions in Hetero-

cyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005,104 109. (Review).

20. Batcho, A. D.; Leimgruber, W. Org. Synth. 1984, 63, 214.

39

Baylis–Hillman reaction

Also known as Morita–Baylis–Hillman reaction, and occasionally known as Rauhut–Currier reaction. It is a carbon carbon bond-forming 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, -alkoxycarbonyl ketones, aldimines, and Michael acceptors.

General scheme:

R1 R2

X EWG catalytic

tertiary amineR2 EWG

XHR1

X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2,CH2=CHCO2Me

Example 1:

PhPh H

OO

NN

OOH

Ph H

OO

NN

:N

N

Oconjugate

addition

aldol

NN

O

Ph

OH

NN

O

Ph

O

H

40

Ph

OOH

NN

E2 (bimolecular elimination) mechanism is also operative here:

NN

O

PhE2

OH

H

Ph

OOHN

NN

N

:

2

Example 210

H

O O

OMe

Cl

NN

OMe

OOH

ClMeOH, rt, 8 h, 79%

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 at Celanese Corp. USA.

2. Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. 3. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (Review). 4. Ciganek, E. Org. React. 1997, 51, 201. (Review). 5. Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406. 6. Yu, C.; Hu, L. J. Org. Chem. 2002, 67, 219. 7. Wang L.-C.; Luis A. L.; Agapiou K.; Jang H.-Y.; Krische M. J. J. Am. Chem. Soc.

2002, 124, 2402. 8. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. 9. Shi, M.; Li, C.-Q.; Jiang, J.-K. Tetrahedron 2003, 59, 1181. 10. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338. 11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147.

A novel mechanism involving a hemiacetal intermediate is proposed.

41

Beckmann rearrangement

Acid-mediated isomerization of oximes to amides.

In protic acid:

R1 R2

NOH

NH

R2

O

R1H

R1 R2

NOH

R1 R2

NOH2H

the substituent trans to the leaving group migrates

:OH2

N

R2

R1

NR1

R2

: N

R2 O

R1

H

H

N

R2 OH

R1

HN

R2 O

R1H+ tautomerization

With PCl5:

R1 R2

NOH

NH

R2

O

R1PCl5

R1 R2

NO

H

PCl4Cl

R1 R2

NOPCl4HCl:

the substituent trans to the leaving group migrates

42

:OH2

N

R2

R1

NR1

R2

: N

R2 O

R1

H

H

N

R2 OH

R1

HN

R2 O

R1H+ tautomerization

Example 112

NHO

NOH

PPA

21%

PPA

72%

HN O

NH

O

PPA = polyphosphoric acid

References

1. 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 addi-tion to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions.

2. Mazur, R. H. J. Org. Chem. 1961, 26, 1289. 3. Chatterjea, J. N.; Singh, K. R. R. P. J. Indian Chem. Soc. 1982, 59, 527. 4. Gawley, R. E. Org. React. 1988, 35, 1 420. (Review). 5. Catsoulacos, P.; Catsoulacos, D. J. Heterocycl. Chem. 1993, 30, 1. 6. Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000, 41, 7235. 7. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31,

2047. 8. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12, 387. 9. Sharghi, H.; Hosseini, M. Synthesis 2002, 1057. 10. Chandrasekhar, S.; Copalaiah, K. Tetrahedron Lett. 2003, 44, 755. 11. Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J. Tetrahedron Lett. 2004, 45,

3369. 12. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067. 13. Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671. 14. Fernández, A. B.; Boronat, M.; Blasco, T.; Corma, A. Angew. Chem., Int. Ed. 2005,

44, 2370.

43

Beirut reaction

Synthesis of quinoxaline-1,4-dioxides from benzofurazan oxide.

NO

NO

CO2Et

Ph

O

ON

NO

O

Ph

O

Et3N

EtOH CO2Et

NO

NO

CO2Et

Ph

O

OCO2Et

Ph

O

O

HEt3N:

NO

NO

CO2Et

Ph

O

O NO

N

O

CO2Et

Ph

O

OH

:

N

N

O

O

CO2EtN

N

O

O

CO2Et

OH

:NEt3

Ph

O

HPh

O

Example 13

O

OEt

O

H3CN

ONO

N

N

CH3

O

OEt

O

O

morpholine,

0 oC, 10 h, 82%

44

Example 27

NO

NO O O

Ph NH

PhN

N

Ph

O

O

O

NH

Phsilica gel

MeOH, 90%

References

1. Haddadin, M. J.; Issidorides, C. H. Heterocycles 1976, 4, 767. The authors named the reaction after the city where it was discovered, Beirut, the capital of Lebanon.

2. Gaso, A.; Boulton, A. J. In Advances in Heterocyclic Chem.; Vol. 29, Katritzky, A. R.; Boulton, A. J., eds.; Academic Press: New York, 1981, 251. (Review).

3. Vega, A. M.; Gil, M. J.; Fernández-Alvarez, E. J. Heterocycl. Chem. 1984, 21, 1271 4. Atfah, A.; Hill, J. J. Chem. Soc., Perkin Trans. 1 1989, 221. 5. Haddadin, M. J.; Issidorides, C. H. Heterocycles 1993, 35, 1503. 6. El-Abadelah, M. M.; Nazer, M. Z.; El-Abadla, N. S.; Meier, H. Heterocycles 1995, 41,

2203. 7. Takabatake, T.; Miyazawa, T.; Kojo, M.; Hasegawa, M. Heterocycles 2000, 53, 2151. 8. Panasyuk, P. M.; Mel’nikova, S. F.; Tselinskii, I. V. Russ. J. Org. Chem. 2001, 37,

892. 9. Turker, L.; Dura, E. Theochem 2002, 593, 143. 10. Tinsley, J. M. Beirut reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.;

Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 504 509. (Review).

45

Benzilic acid rearrangement

Rearrangement of benzil to benzylic acid via aryl migration.

ArAr

O

OKOH

ArOH

OH

O

Ar

ArAr

O

O

OH

ArO

O

ArOH

ArOH

OH

O

ArAr

OOH

O

ArH+

acidic

workup

ArOH

O

O

Ar

Final deprotonation of the carboxylic acid drives the reaction forward.

Example 13

O

H3C

H3C

H

H

H

OO

KOH, MeOH/H2O

130 140 oC, 3 h, 32%

O

H3C

H3C

H

H

H

CO2H

OH

References

1. Liebig, J. Ann. 1838, 27. Justus von Liebig (1803 1873) pursued his Ph.D. in organic chemistry in Paris under the tutelage of Joseph Louis Gay-Lussac (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.

46

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

2. Zinin, N. Justus Liebigs Ann. Chem. 1839, 31, 329. 3. Georgian, V.; Kundu, N. Tetrahedron 1963, 19, 1037. 4. Trost, B. M.; Hiemstra, H. Tetrahedron 1986, 42, 3323. 5. Rajyaguru, I.; Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2 1987, 1819. 6. Askin, D.; Reamer, R. A.; Jones, T. K.; Volante, R. P.; Shinkai, I. Tetrahedron Lett.

1989, 30, 671. 7. Toda, F.; Tanaka, K.; Kagawa, Y.; Sakaino, Y. Chem. Lett. 1990, 373. 8. Robinson, J. M.; Flynn, E. T.; McMahan, T. L.; Simpson, S. L.; Trisler, J. C.; Conn,

K. B. J. Org. Chem. 1991, 56, 6709. 9. Hatsui, T.; Wang, J.-J.; Ikeda, S.-y.; Takeshita, H. Synlett 1995, 35. 10. Fohlisch, B.; Radl, A.; Schwetzler-Raschke, R.; Henkel, S. Eur. J. Org. Chem. 2001,

4357.

47

Benzoin condensation

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

Ar H

O

CN ArAr

O

OHcat.

Ar H

O

CN Ar H

O

CN

Ar

OH

CN

Ar

HO NC

O

OH

Ar

Ar

Hproton

transfer

NCOH

O

Ar

Ar

HAr

ArO

OH

CNproton

transfer

Example 111

CHO

CH3

O

N

S

CH3

HO Br

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

O

OHCH3

Example 211

O

ON

S

CH3

HO Br

Et3N, DMF, 60 oC, 24 h, 90%

48

OO

OOH

O2 (air)

References

1. Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. 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. Ide, W. S.; Buck, J. S. Org. React. 1948, 4, 269 304. (Review). 3. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407 496. (Review). 4. Kluger, R. Pure Appl. Chem. 1997, 69, 1957. 5. Demir, A. S.; Dunnwald, T.; Iding, H.; Pohl, M.; Muller, M. Tetrahedron: Asymmetry

1999, 10, 4769. 6. Davis, J. H., Jr.; Forrester, K. J. Tetrahedron Lett. 1999, 40, 1621. 7. White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124. 8. Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743. 9. Duenkelmann, P.; Kolter-Jung, D.; Nitsche, A.; Demir, A. S.; Siegert, P.; Lingen, B.;

Baumann, M.; Pohl, M.; Mueller, M. J. Am. Chem. Soc. 2002, 124, 12084. 10. Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003, 125, 8432. 11. Enders, D.; Niemeier, O. Synlett 2004, 2111. 12. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326 1328. (Review).

49

Bergman cyclization

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

hydrogen donor

or

hv

Helectrocyclization

reversibleH

enediyne 1,4-benzenediyl diradical

Example 114

S

S

DMF, 180 oC, 24 h, 60%S

SS

S Ph

Ph S

S Ph

Ph

Example 215

N

N

H3Chv

THF, 45%

N

N

H3C

References

1. Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. Robert G. Bergman (1942 ) is a professor at the University of California, Berkeley.

2. Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (Review). 3. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. 4. Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.

50

5. McMahon, R. J.; Halter, R. J.; Fimmen, R. L.; Wilson, R. J.; Peebles, S. A.; Kuczkowski, R. L.; Stanton, J. F. J. Am. Chem. Soc. 2000, 122, 939.

6. Rawat, D. S.; Zaleski, J. M. Chem. Commun. 2000, 2493. 7. Clark, A. E.; Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 2650. 8. Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119. 9. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem.

2002, 67, 1453. 10. Eshdat, L.; Berger, H.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2002, 124, 3822. 11. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205. (Review). 12. Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68, 2234. 13. Basak A.; Mandal S.; Bag S. S. Chem. Rev. 2003, 103, 4077. (Review). 14. Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. Engl.

2005, 44, 592. 15. Zhao, Z.; Peacock, J. G.; Gubler, D. A.; Peterson, M. A. Tetrahedron Lett. 2005, 46,

1373.

51

Biginelli pyrimidone synthesis

One-pot condensation of an aromatic aldehyde, urea, and ethyl acetoacetate in the acidic ethanolic solution and expansion of such a condensation thereof. It belongs to a class of transformations called multicomponent reactions (MCRs).

R CHOO

O O

H2N NH2

O

NHHN

OO

O

R

HCl, EtOH

R

O

O O

HO

aldol

addition

H

O

O OH

H

enolization

H

O

O O

R OH

H

HO

O O

R OH

H

H+

O

O O

R OH2

H

OH

O

O

HN R

O NH2

conjugate

additionNH2H2N

O

O

O O

R :

H

:

O

O

O

NH

RO

H2N

H

HN NH

O

HO R

O OH

H+

52

HN NH

O

H2O R

O OH

H2OH+

NHHN

OO

O

R

Example9

O O

O H

H2N

O

NH2+ +MeO

OMe

NH

NH

O

EtOH, , 2.5 h

OMe

MeOOCCeCl3 7H2O

95%

.

References

1. Biginelli, P. Ber. Dtsch. Chem. Ges. 1891, 24, 1317. Pietro Biginelli was at Lab. chim. della Sanita pubbl. Roma, Italy.

2. Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 8741. 3. Kappe, C. O. Tetrahedron 1993, 49, 6937. (Review). 4. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. (Review). 5. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043. (Review). 6. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075. 7. Lu, J.; Bai, Y. Synthesis 2002, 466. 8. Perez, R.; Beryozkina, T.; Zbruyev, O. I.; Haas, W.; Kappe, C. O. J. Comb. Chem.

2002, 4, 501. 9. Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68, 587. 10. Kappe, C. O.; Stadler, A. Org. React. 2004, 68, 1 116. (Review). 11. Limberakis, C. Biginelli Pyrimidone Synthesis In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 509 520. (Review).

53

Birch reduction

The Birch reduction is the 1,4-reduction of aromatics to their corresponding cyclohexadie-nes by alkali metals (Li, K, Na) dissolved in liquid ammonia in the presence of an alcohol.

Benzene ring bearing an electron-donating substituent:

ONa, liq. NH3

ROH

O

O O

H

H

H OR

single electron

transfer (SET)

O

radical anion

OO

H

HH e

O

H

HH

H OR

Benzene ring with an electron-withdrawing substituent:

CO2HNa, liq. NH3

CO2H

e

H

CO2CO2HCO2e

radical anion

54

H NH2H

CO2 CO2HCO2

H H

H

Example 18

ON

O

OMe

OMe

1. Na, NH3, THF 78 oC

2. MeI, 98%, 30:1 drO

N

O

OMe

OMeExample 214

N

Na, NH3, THF

78 oC, quant.N

References

1. Birch, A. J. J. Chem. Soc. 1944, 430. Arthur Birch (1915 1995), an Australian, de-veloped the “Birch reduction” at Oxford University during WWII in Robert Robin-son’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs.

2. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1 334. (Review). 3. Birch, A. J. Pure Appl. Chem. 1996, 68, 553. (Review). 4. Schultz, A. G. Chem. Commun. 1999, 1263. 5. Ohta, Y.; Doe, M.; Morimoto, Y.; Kinoshita, T. J. Heterocycl. Chem. 2000, 37, 751. 6. Labadie, G. R.; Cravero, R. M.; Gonzalez-Sierra, M. Synth. Commun. 2000, 30, 4065. 7. Guo, Z.; Schultz, A. G. J. Org. Chem. 2001, 66, 2154. 8. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett.

2001, 42, 5841. 9. Yamaguchi, S.; Hamade, E.; Yokoyama, H.; Hirai, Y.; Shiotani, S. J. Heterocycl.

Chem. 2002, 39, 335. 10. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611 642. (Review). 11. Jiang, J.; Lai, Y.-H. Tetrahedron Lett. 2003, 44, 1271. 12. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 1443 1451. (Review). 13. Zvilichovsky, G.; Gbara-Haj-Yahia, I. J. Org. Chem. 2004, 69, 5490. 14. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054.

55

Bischler–Möhlau indole synthesis

3-Arylindoles from the cyclization of -arylamino-ketones and anilines.

OH2N

Br

O

NH N

H

O

H2N

BrO

NH

: SN2 :

H

NHO

H

dehydration

N

H H

H H

NH

56

Example 15

NH2

OO

BrNaHCO3, EtOH

reflux, 4 h

NH O

O230 250 oC

silicone oil, 10 15 min

35 80%

NH

O

Example 29

N

OTBS

O

F

NH2N NH2

OMe

DME, H2SO4

reflux, 53%NH2N

OMe

NH

N

F

References

1. Möhlau, R. Ber. Dtsch. Chem. Ges. 1881, 14, 171. 2. Bischler, A.; Fireman, P. Ber. Dtsch. Chem. Ges. 1893, 26, 1346. 3. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, p 164.

(Book). 4. Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971,

2606. 5. The Chemistry of Heterocyclic Compounds, Indoles (Part 1), Houlihan, W. J., ed.;

Wiley & Sons: New York, 1972. (Review). 6. Bigot, P.; Saint-Ruf, G.; Buu-Hoi, N. P. J. Chem. Soc., J. Chem. Soc., Perkin 1 1972,

2573. 7. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852. 8. Coic, J. P.; Saint-Ruf, G. J. Heterocycl. Chem. 1978, 15, 1367. 9. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763.

57

Bischler–Napieralski reaction

Dihydroisoquinolines from -phenethylamides using phosphorus oxychloride.

HN O

R

POCl3 N

R

HN O

R

PCl

OClCl

HN O

RPOCl2

Cl

N

R OPOCl2

HH

Cl

NH

OPOCl2

R

N

R O

H N

RP

O

ClCl

+ HCl + POCl

OHCl +

Example 16

NCO2Me

BnMeO POCl3

P2O5, 96%N

OBn

MeO

58

Example 210

O

OHN O

MeOOMe

OMe

POCl3

toluene, 95%

O

ON

MeOOMe

OMe

References

1. Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903. Augustus Bis-chler (1865 1957) was born in South 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. Fodor, G.; Nagubandi, S. Heterocycles 1981, 15, 165. 3. Rozwadowska, M. D. Heterocycles 1994, 39, 903. 4. Sotomayor, N.; Dominguez, E.; Lete, E. J. Org. Chem. 1996, 61, 4062. 5. Doi, S.; Shirai, N.; Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 2217. 6. Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 1998, 39, 6609. 7. Sanchez-Sancho, F.; Mann, E.; Herradon, B. Synlett 2000, 509. 8. Ishikawa, T.; Shimooka, K.; Narioka, T.; Noguchi, S.; Saito, T.; Ishikawa, A.; Yama-

zaki, E.; Harayama, T.; Seki, H.; Yamaguchi, K. J. Org. Chem. 2000, 65, 9143. 9. Miyatani, K.; Ohno, M.; Tatsumi, K.; Ohishi, Y.; Kunitomo, J.-I.; Kawasaki, I.; Ya-

mashita, M.; Ohta, S. Heterocycles 2001, 55, 589. 10. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron

2001, 57, 8297. 11. Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 2002,

116. 12. Wolfe, J. P. Bischler–Napieralski Reaction In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 376 385. (Re-view).

59

Blaise reaction

-Ketoesters from nitriles and -haloesters using Zn.

R CNBr CO2R2

R1

1. Zn, THF, reflux

2. H3O+

CO2R2

R1R

O

R

Br CO2R2

R1

Zn(0)

R1

N

nucleophilic

addition

OR2

OZnBr

CO2R2

R1R

NHH

workup

H2O:CO2R2

R1R

NZnBr

H2O H

CO2R2

R1R

O

CO2R2

R1R

OH2N H

H2O H

Example 1, preparation of the statin side chain10

Cl CNOTMS

Br CO2t-Bu

1. cat. Zn, THF, reflux

2. H3O+, 85%Cl

OH OCO2t-Bu

60

Example 211

Zn, MeSO3H

THF, reflux, 2.5 hN

F CN

Cl ClBr CO2Et

HCl, 72%

N

F

Cl Cl

HN

OEt

OZnBr

N

F

Cl Cl

O

OEt

O

References

1. Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478, 978. Blaise was at Insti-tut Chimique de Nancy, France.

2. Hannick, S. M.; Kishi, Y. J. Org. Chem. 1983, 48, 3833. 3. Krepski, L. R.; Lynch, L. E.; Heilmann, S. M.; Rasmussen, J. K. Tetrahedron Lett.

1985, 26, 981. 4. Beard, R. L.; Meyers, A. I. J. Org. Chem. 1991, 56, 2091. 5. Syed, J.; Forster, S.; Effenberger, F. Tetrahedron: Asymmetry 1998, 9, 805. 6. Narkunan, K.; Uang, B.-J. Synthesis 1998, 1713. 7. Erian, A. W. J. Prakt. Chem. 1999, 341, 147. 8. Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Eur. J. Med. Chem. 2001, 36,

303. 9. Creemers, A. F. L.; Lugtenburg, J. J. Am. Chem. Soc. 2002, 124, 6324. 10. Shin, H.; Choi, B. S.; Lee, K. K.; Choi, H.-W.; Chang, J. H.; Lee, Kyu W.; Nam, D.

H.; Kim, N.-S. Synthesis 2004, 2629. 11. 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.

61

Blanc chloromethylation

Lewis acid-promoted chloromethyl group installation onto the aromatics rings with 1,3,5-trioxane and HCl.

HClZnCl2 Cl

H2OO

O O

1,3,5-trioxane

H+H H

OH

O

O O

HO

HHOH+ H+

H2OCl

OH2

ClSN2

Example 112

CH3

NH3Cl

O

O

(OCH2)n, HCl, PhCl

20 oC, 2 h, 71%

CH3

NH3Cl

O

O

Cl

References

1. Blanc, G. Bull. Soc. Chim. Fr. 1923, 33, 313. Gustave Louis Blanc (1872 1927), born in Paris, France, studied under Charles Friedel in Paris. He developed the chloro-methylation of aromatic hydrocarbons while he was a director at the Intendance mili-taire aux Invalides.

62

2. Fuson, R. C.; McKeever, C. H. Org. React. 1942, 1, 63. (Review). 3. Olah, G.; Tolgyesi, W. S. In Friedel Crafts and Related Reactions vol. II, Part 2,

Olah, G., Ed.; Interscience: New York, 1963, pp 659 784. (Review). 4. Franke, A.; Mattern, G.; Traber, W. Helv. Chim. Acta 1975, 58, 283. 5. Sekine, Y.; Boekelheide, V. J. Am. Chem. Soc. 1981, 103, 1777. 6. Mallory, F. B.; Rudolph, M. J.; Oh, S. M. J. Org. Chem. 1989, 54, 4619. 7. Witiak, D. T.; Loper, J. T.; Ananthan, S.; Almerico, A. M.; Verhoef, V. L.; Filppi, J.

A. J. Med. Chem. 1989, 32, 1636. 8. De Mendoza, J.; Nieto, P. M.; Prados, P.; Sanchez, C. Tetrahedron 1990, 46, 671. 9. Tashiro, M.; Tsuge, A.; Sawada, T.; Makishima, T.; Horie, S.; Arimura, T.; Mataka,

S.; Yamato, T. J. Org. Chem. 1990, 55, 2404. 10. Miller, D. D.; Hamada, A.; Clark, M. T.; Adejare, A.; Patil, P. N.; Shams, G.;

Romstedt, K. J.; Kim, S. U.; Intrasuksri, U.; et al. J. Med. Chem. 1990, 33, 1138. 11. Ito, K.; Ohba, Y.; Shinagawa, E.; Nakayama, S.; Takahashi, S.; Honda, K.; Nagafuji,

H.; Suzuki, A.; Sone, T. J. Heterocycl. Chem. 2000, 37, 1479. 12. Harms, A.; Ulmer, E.; Kovar, K.-A. Archiv. Pharmazie 2003, 336, 155.

63

Blum aziridine synthesis

Ring opening of oxiranes using azide is followed by Staudinger reduction of the intermediate azido alcohol to give aziridines.

R2R1

ONaN3 R1

R2

N3

OH R2R1

HNPPh3

Staudinger

R2R1

O SN2 R1

R2

N3

OHN3

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

R1

R2

HON N N :PPh3

R1

R2

HON N N PPh3

N N N PR3

R1

R2

HOPR3N

N NX

N2

NPR3

R1

R2

OH

NPR3

HOR2

R1

NHR3P:O

R1

R2

R2R1

HNproton

transfer R2O

NHR1

PPh3

64

Example 13

OTrO

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

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

HN OTr

Example 25

OTBSO NaN3, NH4Cl, MeOH

reflux, 4 h, 50%

OTBSOH

N3

OTBSN3

OH

Ph3P, CH3CN

reflux, 99%OTBS

NH

References

1. Ittah, Y.; Sasson, Y.; Shahak, I.; Tsaroom, S.; Blum, J. J. Org. Chem. 1978, 43, 4271. Jochanan Blum is a professor at The Hebrew University in Jerusalem, Israel.

2. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211. 3. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639. 4. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649. 5. Oh, K.; Parson, P. J.; Cheshire, D. Synlett 2004, 2771. 6. Serafin, S. V.; Zhang, K.; Aurelio, L.; Hughes, A. B.; Morton, T. H. Org. Lett. 2004,

6, 1561.

65

Boekelheide reaction

Treatment of 2-methylpyridine N-oxide with trifluoroacetic anhydride gives rise to 2-hydroxymethylpyridine.

N

O

TFAA

NOH

TFAA, trifluoroacetic anhydride

NO

F3C O CF3

O O

acyl

transfer

NO

CF3

O

H

O2CCF3

NO

CF3

O

NOHN

O CF3

O

hydrolysis

Example 16

NN

O

Ac2O, CH2Cl2

reflux, 1 h, 90% NNOAc

Example 29

NO

OtBu

N

OtBu

OH

1. TFAA, CH2Cl2

2. Na2CO3, 3 h 89%

66

References

1. Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286. Virgil Boekelheide (1919 2003) was a professor at the University of Oregon.

2. Boekelheide, V.; Harrington, D. L. Chem. Ind. 1955, 1423. 3. Boekelheide, V.; Lehn, W. L. J. Org. Chem. 1961, 26, 428. 4. Katritzky, A. R.; Lagowski, J. M. Chemistry of the Heterocylic N-Oxides Academic

Press, NY, 1971. (Review). 5. Bell, T. W.; Firestone, A. J. Org. Chem. 1986, 51, 764. 6. Newkome, G. R.; Theriot, K. J.; Gupta, V. K.; Fronczek, F. R.; Baker, G. R. J. Org.

Chem. 1989, 54, 1766. 7. Goerlitzer, K.; Schmidt, E. Arch. Pharm. 1991, 324, 359. 8. Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011 1049. (Review). 9. Fontenas, C.; Bejan, E.; Haddon, H. A.; Balavoine, G. G. A. Synth. Commun. 1995,

25, 629. 10. Goerlitzer, K.; Bartke, U. Pharmazie 2002, 57, 804. 11. Higashibayashi, S.; Mori, T.; Shinko, K.; Hashimoto, K.; Nakata, M. Heterocycles

2002, 57, 111. 12. Galatsis, P. Boekelheide Reaction In Name Reactions in Heterocyclic Chemistry, Li, J.

J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 340 349. (Review).

67

Boger pyridine synthesis

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

O

NH

N NN

N

O

HN

: NOH

H

H2O

NNN

N

Hetero-Diels-Alder

reaction

NN

NN

:B

N

Retro-Diels-Alder

reaction, N2 NN

H

Example 14

NN

NEtO2C

EtO2C

CO2EtN O+

NEtO2C

EtO2C

CO2EtCHCl3, 60 oC

26 h, 92%

68

References

1. Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179. Dale Boger is a professor at the Scripps Research Institute.

2. Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem. 1982, 47, 895. 3. Boger, D. L. Tetrahedron 1983, 39, 2869 2939. (Review). 4. Boger, D. L. Chem. Rev. 1986, 86, 781 793. (Review). 5. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1987, 66, 142. 6. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 451 512. (Review). 7. Golka, A.; Keyte, P. J.; Paddon-Row, M. N. Tetrahedron 1992, 48, 7663. 8. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 5259 5288. (Review). 9. Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 6099 6138. (Review). 10. Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379 471. (Re-

view). 11. Rykowski, A.; Olender, E.; Branowska, D.; Van der Plas, H. C. Org. Prep. Proced.

Int. 2001, 33, 501. 12. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2003, 44, 693. 13. Galatsis, P. Boger Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.;

Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 323 339. (Review).

69

Borch reductive amination

Reduction (often using NaCNBH3) of the imine formed by an amine and a car-bonyl to afford the corresponding amine—basically, reductive amination.

H

R1 R2

O

R3

HN

R4 N

R1 R2

R4R3

H

R1 R2

O

R3

HN

R4

R1 R2

OH

N:R4R3

N

R1 R2

R4R3N

R1 R2

R4R3

HH

Example 14

CH3

O

NH2

1. TiCl4, Et3N, CH2Cl2, rt, 48 h

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

CH3

HN

70

Example 25

5 N HCl, NaCNBH3

MeOH, rt, 72 h, 75%O O

NH2

N

References

1. Borch, R. F. J. Am. Chem. Soc. 1969, 91, 3996. Richard F. Borch was born in Cleve-land, Ohio. He 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. 3. Borch, R. F.; J. Chem. Soc., Perkin I 1984, 717. 4. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547. 5. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638. 6. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171. 7. Lewin, G.; Schaeffer, C.; Hocquemiller, R.; Jacoby, E.; Leonce, S.; Pierre, A.; Atassi,

G. Heterocycles 2000, 53, 2353.

71

Borsche–Drechsel cyclization

Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fisher indole synthesis.

NH

N

HCl

NH

[3,3]-sigmatropic

rearrangementNH

N

H

H+NH

NH

H+

NHNH2

H

NHNH

NH

NH2

H

H+NH

Example 18

NH2

H3CO

O

HO

CH3HCl, NaNO2, AcONa

H2O, MeOH, 54%

72

NHN

H

N

H3COO

CH3

HOAc, HCl, reflux

10 min., 44% O

CH3

H3CO

References

1. Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 2. Borsche, W.; Feise, M. Ber. Dtsch. Chem. Ges. 1904, 20, 378. 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. Borsche and his colleague at Frankfurt, Julius von Braun, both suf-fered under the Nazi regime for their independent minds.

3. Atkinson, C. M.; Biddle, B. N. J. Chem. Soc. (C) 1966, 2053. 4. Bruck, P. J. Org. Chem. 1970, 35, 2222. 5. Gazengel, J. M.; Lancelot, J. C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1990, 27,

1947. 6. Abramovitch, R. A.; Bulman, A. Synlett 1992, 795. 7. Murakami, Y.; Yokooa, H.; Watanabe, T. Heterocycles 1998, 49, 127. 8. Lin, G.; Zhang, A. Tetrahedron 2000, 56, 7163. 9. Ergun, Y.; Bayraktar, N.; Patir, S.; Okay, G. J. Heterocycl. Chem. 2000, 37, 11. 10. Rebeiro, G. L.; Khadilkar, B. M. Synthesis 2001, 370.

73

Boulton–Katritzky rearrangement

Rearrangement of one five-membered heterocycle into another under thermolysis.

NA

BD

XY

ZH

YX

NZ

AB

DH

Example 17

N:H

NO

N

Ph

N

NO

N

Ph

150 oC H H+

NN N

HPh

O

Example 211

NN

OF3C

Ph

ONH2NH2, DMF

rt, 1 h NN

OF3C

N

Ph

NH2

NNNH

PhNHF3C

O

5%

N

NH

NF3C

PhN

HO

92%

74

NN

OF7C3

Ph

ONH2NH2, DMF

rt, 1 h

NNNH

PhNHF7C3

O

24%

N

NH

NF7C3

PhN

HO

70%

References

1. Boulton, A. J.; Katritzky, A. R.; Hamid, A. M. J. Chem. Soc. (C) 1967, 2005. Alan Katritzky, a professor at the University of Florida, is best known for his series Ad-vances of Heterocyclic Chemistry, now in its 87th volume.

2. Ruccia, M.; Vivona, N.; Spinelli, D. Adv. Heterocyl. Chem. 1981, 29, 141. (Review). 3. Butler, R. N.; Fitzgerald, K. J. J. Chem. Soc., Perkin Trans. 1 1988, 1587. 4. Takakis, I. M.; Hadjimihalakis, P. M.; Tsantali, G. G. Tetrahedron 1991, 47, 7157. 5. Takakis, I. M.; Hadjimihalakis, P. M. J. Heterocycl. Chem. 1992, 29, 121. 6. Vivona, N.; Buscemi, S.; Frenna, V.; Cusmano, C. Adv. Heterocyl. Chem. 1993, 56,

49.7. Katayama, H.; Takatsu, N.; Sakurada, M.; Kawada, Y. Heterocycles 1993, 35, 453. 8. Rauhut, G. J. Org. Chem. 2001, 66, 5444. 9. Crampton, M. R.; Pearce, L. M.; Rabbitt, L. C. J. Chem. Soc., Perkin Trans. 2 2002,

257. 10. Pena-Gallego, A.; Rodriguez-Otero, J.; Cabaleiro-Lago, E. M. J. Org. Chem. 2004, 69,

7013. 11. Buscemi, S.; Pace, A.; Piccionello, A. P.; Macaluso, G.; Vivona, N.; Spinelli, D.;

Giorgi, G. J. Org. Chem. 2005, 70, 3288.

75

Bouveault aldehyde synthesis

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

R X

1. M

2. DMF

3. H+R CHO

R XM

R M Me2NR

O MH+

R CHO

Me2N H

O

A modification by Comins:7

H

O N NLi LiO N

H

N

n-BuLi

ortho-lithiation

N

LiO

N

1. RX, X = Br, I

2. H3O+

H

O

R

Example 16

BrLi, DMF, THF, 10 oC

ultrasound 5 min, 85%

CHO

76

References

1. Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306, 1322. Louis Bouveault (1864 1909) was born in Nevers, France. He devoted his short yet very productive life to teaching and to working in science.

2. Maxim, N.; Mavrodineanu, R. Bull. Soc. Chim. Fr. 1935, 2, 591. 3. Maxim, N.; Mavrodineanu, R. Bull. Soc. Chim. Fr. 1936, 3, 1084. 4. Smith, L. I.; Bayliss, M. J. Org. Chem. 1941, 6, 437. 5. Sicé, J. J. Am. Chem. Soc. 1953, 75, 3697. 6. Pétrier, C.; Gemal, A. L.; Luche, J. L. Tetrahedron Lett. 1982, 23, 3361. 7. Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078. 8. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1791. 9. Einhorn, J.; Luche, J. L. Tetrahedron Lett. 1986, 27, 1793. 10. Denton, S. M.; Wood, A. Synlett 1999, 55. 11. Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466.

77

Bouveault–Blanc reduction

Reduction of esters to the corresponding alcohols using sodium in an alcoholic solvent.

R OEt

O Na, EtOHR OH

R OEt

OOEtsingle-electron

transfer (SET) R OEt

O H

e ketyl (radical anion)

R OEt

OH

R OEt

OH

OEtH

OEt

R OEt

OH e

OEt

R H

O H

R H

O e

R H

OHR H

OH

OEtH

R OHe

Example 18

OEt

OOH

Na, Al2O3t-BuOH, Tol.

reflux, 6 h, 66%

References

1. Bouveault, L.; Blanc, G. Compt. Rend. 1903, 136, 1676. 2. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666. 3. Ruehlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H.

J. Organomet. Chem. 1971, 27, 327. 4. Castells, J.; Grandes, D.; Moreno-Manas, M.; Virgili, A. An. Quim. 1976, 72, 74.

78

5. Sharda, R.; Krishnamurthy, H. G. Indian J. Chem., Sect. B 1980, 19B, 405. 6. Banerji, J.; Bose, P.; Chakrabarti, R.; Das, B. Indian J. Chem., Sect. B 1993, 32B, 709. 7. Seo, B. I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993,

23, 15. 8. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959. 9. Schopohl, Matthias C.; Bergander, Klaus; Kataeva, Olga; Froehlich, Roland; Waldvo-

gel, Siegfried R. Synthesis 2003, 2689.

79

Boyland–Sims oxidation

Oxidation of anilines to phenols using alkaline persulfate.

NR2K2S2O8

aq. KOH

NR2

OSO3 K+H+

NR2

OH

NR2

O OS SOO

OO

O

O ipso-attackSO4

OR2NS

O

O

O

OR2NS

O

O

O

: OR2NS

O

O

O

H

:

OR2NS

O

O

O

H

NR2

OSO3 K+

OH

Another pathway is also operative:

OR2NS

O

O

O NR2

OSO3 K+R2NO

SO

OO

HOH

E2

80

Example 13

NH2

K2S2O8

aq. KOH

NH2

OSO3 K+

NH2

OSO3 K+

OSO3 K+

50-55%

References

1. Boyland, E.; Manson, D.; Sims, P. J. Chem. Soc. 1953, 3623. Eric Boyland and Peter Sims were at the Royal Cancer Hospital in London, UK.

2. Boyland, E.; Sims, P. J. Chem. Soc. 1954, 980. 3. Behrman, E. J. J. Am. Chem. Soc. 1967, 89, 2424. 4. Krishnamurthi, T. K.; Venkatasubramanian, N. Indian J. Chem., Sect. A 1978, 16A,

28.5. Behrman, E. J.; Behrman, D. M. J. Org. Chem. 1978, 43, 4551. 6. Srinivasan, C.; Perumal, S.; Arumugam, N. J. Chem. Soc., Perkin Trans. 2 1985, 1855. 7. Behrman, E. J. Org. React. 1988, 35, 421 511. (Review). 8. Behrman, E. J. J. Org. Chem. 1992, 57, 2266.

81

Bradsher reaction

Anthracenes from ortho-acyl diarylmethanes via acid-catalyzed cyclodehydration.

R

O R

HBr

CH3CO2H

anthracene

R

O

H+

R

OH

R

H+

OHR HO

H

RR OH2

H

H+

Example5

Br

O

Br

HBr, CH3CO2H

150 oC, 7 h, 21%

References

1. Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486. Charles K. Bradsher was a profes-sor at Duke University.

2. Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451.

82

3. Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786. 4. Bradsher, C. K.; Sinclair, E. F. J. Org. Chem. 1957, 22, 79. 5. Vingiello, F. A.; Spangler, M. O. L.; Bondurant, J. E. J. Org. Chem. 1960, 25, 2091. 6. Brice, L. K.; Katstra, R. D. J. Am. Chem. Soc. 1960, 82, 2669. 7. Saraf, S. D.; Vingiello, F. A. Synthesis 1970, 655. 8. Ashby, J.; Ayad, M.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1 1974, 1744. 9. Nicolas, T. E.; Franck, R. W. J. Org. Chem. 1995, 60, 6904. 10. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837.

83

Brook rearrangement

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

SiR3

OH

R1R2

RLi

Li

O

R1R2

SiR3

SiR3

OR1

R2

R

H

SiR3

OR1

R2

R1R2

SiR3

O

pentacoordinate silicon intermediate

H

OPh

Ph

SiPh3OPh

Ph

SiPh3

H OH

workup

Example 111

t-BuMe2SiCN

O

Ph

1. 4 eq. NaHMDS, 78 to 15 oC

2. PhCH2Br, 10 oC, 75%

t-BuMe2SiOCN

Ph Ph

84

Example 214

PhBrt-BuLi, Et2O

78 oC

PhLi

Me3Si Ph

O

78 oC to rt, 30 min.

then NH4Cl, H2O, 44%

Ph

OPh

SiMe3

References

1. Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. Adrian G. Brook (1924 ) was born in Toronto, Canada. He is a professor in Lash Miller Chemical Laboratories, Univer-sity of Toronto, Canada.

2. Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (Review). 3. Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147. (Review). 4. Takeda, K.; Nakatani, J.; Nakamura, H.; Yosgii, E.; Yamaguchi, K. Synlett 1993, 841. 5. Fleming, I.; Ghosh, U. J. Chem. Soc., Perkin Trans. 1 1994, 257. 6. Takeda, K.; Takeda, K.; Ohnishi, Y. Tetrahedron Lett. 2000, 41, 4169. 7. Sumi, K.; Hagisawa, S. J. Organomet. Chem. 2000, 611, 449. 8. Moser, W. H. Tetrahedron 2001, 57, 2065. (Review). 9. Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031. 10. Takeda, K.; Haraguchi, H.; Okamoto, Y. Org. Lett. 2003, 5, 3705. 11. Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973. 12. Matsumoto, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Org. Lett. 2004, 6, 4367. 13. Tanaka, K.; Takeda, K. Tetrahedron Lett. 2004, 45, 7859. 14. Clayden, J.; Watson, D. W.; Chambers, M. Tetrahedron 2005, 61, 3195. 15. Nahm, M. R.; Xin, L.; Potnick, J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew.

Chem., Int. Ed. Engl. 2005, 44, 2377.

85

Brown hydroboration

Addition of boranes to olefins, followed by basic oxidation of the organoborane adducts, resulting in alcohols.

R1. R'2BH

2. H2O2, NaOHR

OH

RB

HR'

R' syn-

additionR

B

H

R'

R'

O OHR

BH

R'R'

RB

H

O

R'OH

R' Baeyer Villiger-

like reaction

RO

BR'

R'

O OH

ROHR

OB

OR'

OR'

OH B(OH)3

Example 12

H

H

H

H

1. BH3•SMe3, THF

2. NaOOH

H

H

H

H 35% 40%

H

H

H

H

OH HO

86

Example 213

OMe

OMeNO2

MeO

OBn

HO

Me

BH3•SMe3, NaOOH

THF, 85%, dr 8-11:1

OMe

OMeNO2

MeO

OBn

HO

Me

HO

Example 314

Ph1. Pyridine•BH3, I2, CH2Cl2, 2 h

2. H2O2, NaOH, MeOH, 92% Ph

OH PhOH

15:1

References

1. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552. 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. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120. 3. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1131. 4. Streitwieser, A., Jr.; Verbit, L.; Bittman, R. J. Org. Chem. 1967, 32, 1530. 5. Herz, J. E.; Marquez, L. A. J. Chem. Soc. (C) 1971, 3504. 6. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents Academic Press: New York,

1972. (Review). 7. Brewster, J. H.; Negishi, E. Science 1980, 207, 44. (Review). 8. Brown, H. C.; vara Prasad, J. V. N. Heterocycles 1987, 25, 641. 9. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1,

95 121. (Review). 10. Hayashi, T. Comprehensive Asymmetric Catalysis I III 1995, 1, 351 364. (Review). 11. Morrill, T. C.; D’Souza, C. A.; Yang, L.; Sampognaro, A. J. J. Org. Chem. 2002, 67,

2481. 12. Hupe, E.; Calaza, M. I.; Knochel, P. Tetrahedron Lett. 2001, 42, 8829. 13. Carter K. D; Panek J. S. Org. Lett. 2004, 6, 55. 14. Clay, J. M.; Vedejs, E. J. Am. Chem. Soc. 2005, 127, 5766.

87

Bucherer carbazole synthesis

Carbazoles from naphthols and aryl hydrazines promoted by sodium bisulfite.

OH

NHNH2

NaHSO3

NH

OHH+

OHH

OSO2H

OHHHH+

OSO2H

OHH

OSO2H

:NH2NHPh

H+

OSO2H

NHNHPh

H:B

HH

OSO2H

NHNHPhOH

H+

NHNH

[3,3]-sigmatropicrearrangement

H+

88

NH

NH2H NHNH2H H+

NH

Example 13

OH

NHNH2CO2H

NH

NaHSO3, NaOH, , 130 oC

several days, 46%

Example 24

H2NHN

1) aq. NaHSO3,OH

NH2) H

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. Hans Th. Bucherer (1869 1949) was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career.

2. Bucherer, H. T.; Seyde, F. J. Prakt. Chem. 1908, 77, 403. 3. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369. 4. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1. 5. Friedländer, P. Chem. Ztg. 1916, 40, 918. 6. Fuchs, W.; Niszel, F. Chem. Ber. 1927, 60, 209. 7. Drake, N. L. Org. React. 1942, 1, 105. (Review). 8. Buu-Hoï, N. P.; Hoán, N.; Khôi, N. H. J. Org. Chem. 1949, 14, 492. 9. Buu-Hoï, N. P.; Royer, R.; Eckert, B.; Jacquignon, P. J. Chem. Soc. 1952, 4867. 10. Zander, M.; Franke, W. Chem. Ber. 1963, 96, 699. 11. Seeboth, H.; Bärwolff, D.; Becker, B. Justus Liebigs Ann. Chem. 1965, 683, 85. 12. Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. 13. Thang, D. C.; Can, C. X.; Buu-Hoï, N. P.; Jacquignon, P. J. Chem. Soc., Perkin Trans.

1 1972, 1932.

89

14. Robinson, B. The Fischer Indole Synthesis, Wiley-Interscience, New York, 1982.(Book).

15. Hill, J. A.; Eaddy, J. F. J. Labeled. Compd. Radiopharm. 1994, 34, 697. 16. Pischel, I.; Grimme, S.; Kotila, S.; Nieger, M.; Vögtle, F. Tetrahedron: Asymmetry

1996, 7, 109.

90

Bucherer reaction

Transformation of -naphthols to -naphthylamines using ammonium sulfite.

OH NH2(NH4)2SO3•NH3

H2O, 150 oC

OH+

OHH

OSO2NH4

OHHH+

OSO2NH4

HH

O

OSO2NH4

:NH3

OSO2NH4

NH2

OH

tautomerization

OSO2NH4

NH2

H

NH2H+

OSO2NH4

NH2

OH2

H

Example2

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

OH NH2NH3, (NH4)2SO3, H2O, rt

microwave 30 min. 93%

References

1. Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. 2. Drake, N. L. Org. React. 1942, 1, 105. (Review). 3. Reiche, A.; Seeboth, H. Justus Liebigs Ann. Chem. 1960, 638, 66. 4. Seeboth, H.; Reiche, A. Justus Liebigs Ann. Chem. 1964, 671, 77.

91

5. Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p166. (Re-view).

6. Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. 7. Gruszecka, E.; Shine, H. J. J. Labelled. Compd. Radiopharm. 1983, 20, 1257. 8. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539. 9. Cañete, A.; Meléndrez, M. X.; Saitz, C.; Zanocco, A. L. Synth. Commun. 2001, 31,

2143.

92

Bucherer–Bergs reaction

Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2CO3] or from cyanohydrins and ammo-nium carbonate. It belongs to the category of multiple component reaction (MCR).

R1

R2O

KCN

(NH4)2CO3NH

HNR1

R2

O

O

(NH4)CO2 2 NH3 + CO2 + H2O

NC

CNR1OH

R2

H3N

R1

R2O

: R1NH2

R2N

C O

:

O

cyanohydrin

HNR1

R2

OH

O

N

:

O

NR1

R2

O

HN

H

NH

HNR1

R2

O

O

:

NH2

NR1

R2

O

COH+

isocyanate intermediate

Example 110

N

CH3O

CH3O

O

KCN, (NH4)2CO3

48 h, 60 oC, 83%

93

N

CH3O

CH3ON

CH3O

CH3OH H

HN

NH HNNHO

O

O

OExample 211

O

O

O

H

HHCO2Et

KCN, (NH4)2CO3

EtOH/H2O, 70 oC, 50%

O

O

H

HHCO2Et

NHHN

O

O

References

1. Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Ger-many.

2. Bucherer, H. T., Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 69. 3. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291. (Mechanism). 4. E. Ware, Chem. Rev. 1950, 46, 403. (Review). 5. Wieland, H. et al., in Houben Weyl's Methoden der organischen Chemie, Vol. XI/2,

1958, p 371. 6. Chubb, F. L.; Edward, J. T.; Wong, S. C. J. Org. Chem. 1980, 45, 2315.7. Rousset, A.; Laspéras, M.; Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2649. 8. Bowness, W. G.; Howe, R.; Rao, B. S. J. Chem. Soc., Perkin Trans. 1 1983, 2649. 9. Haroutounian, S. A.; Georgiadis, M. P.; Polissiou, M. G. J. Heterocycl. Chem. 1989,

26, 1283. 10. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992,

27, 61. 11. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron:

Asymmetry 1997, 8, 511. 12. Mic vá, J.; Steiner, B.; Kóoš, M.; Langer, V.; Gyepesova, D. Synlett 2002, 1715. 13. Li, J. J. Bucherer–Bergs Reaction In Name Reactions in Heterocyclic Chemistry, Li, J.

J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 266 274. (Review).

94

Büchner–Curtius–Schlotterbeck reaction

Reaction of carbonyl compounds with aliphatic diazo compounds to deliver ho-mologated ketones.

R2 N2

H

R O

R1

RR1

R2

O

R2 N2

HR O

R1

R2 N

H

N

R2 N

H

N

nucleophilic

addition

R1

R

O

R2

rearrangementN2

R2 ONN

R1

H R

Example 13

O

Cl

O

O

CH2N2

Et2OO

N2CH2

O

OH3C

O

O

OH3C

ClHCl

Example 26

Ph H

NC CN CH2N2, Et2O

rt, 100% Ph CH3

NC CN

95

Ph CH3

O33% aq. NaOH

45 oC, 99%

References

1. Büchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges. 1885, 18, 2371. Eduard Büchner (Germany, 1860 1917) won the Nobel Prize in Chemistry in 1907 for biochemical studies and discovery of fermentation without cells.

2. Schlotterbeck, F. Ber. Dtsch. Chem. Ges. 1907, 40, 479. 3. Fried, J.; Elderfield, R. C. J. Org. Chem. 1941, 6, 577. 4. Gutsche, C. D. Org. React. 1954, 8, 364. (Review). 5. Bastús, J. B. Tetrahedron Lett. 1963, 955. 6. Kirmse, W.; Horn, K. Tetrahedron Lett. 1967, 1827.

96

Büchner method of ring expansion

Reaction of benzene with diazoacetic esters to give cyclohepta-2,4,6-trienecarboxylic acid esters. Cf. Pfau Platter azulene synthesis.

N2 CO2CH3

[Rh]CO2CH3

N2 CO2CH3

[Rh][Rh] CO2CH3N2

Rhodium carbenoid

[Rh]

CO2CH3

[Rh]

CO2CH3[2 + 2]

cycloaddition

CO2CH3

electrocyclic

ring opening

Example 17

H O

Rh2(OAc)4

CH2Cl2, 98%

ON2

Example 28

Br

ON2

I

cat. Rh2(OCOt-Bu)4, DMAP

Ac2O, CH2Cl2, 73%

I

OAc

References

1. Büchner, E. Ber. Dtsch. Chem. Ges. 1896, 29, 106. 2. Dev, S. J. Indian Chem. Soc. 1955, 32, 513. 3. von Doering, W.; Knox, L. H. J. Am. Chem. Soc. 1957, 79, 352.

97

4. Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431. (Review). 5. Anciaux, A. J.; Demonceon, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J.

Org. Chem. 1981, 46, 873. 6. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933. 7. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484. 8. Crombie, A. L; Kane, J. L. Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem. 2004, 69,

8652.

98

Buchwald–Hartwig C–N and C–O bond formation reactions

Direct Pd-catalyzed C–N and C–O bond formation from aryl halides and amines in the presence of stoichiometric amount of base.

Br

NH

NPd(OAc)2, dppf

NaOt-Bu, Tol.,

BrPd(0)

oxidative addition

Pd(II) Br NH

ligandexchange

HBr

NPd(II) N reductive

eliminationPd(0)

The C–O bond formation reaction follows a similar mechanistic pathway.7 9

Example 111

O Cl HN O

0.5 mol% Pd2(dba)2

1 mol% ligand

1.4 eq. NaOt-Bu, Tol.

100 oC, 24 h, 92%

O N O ligand =

PN

N

Ni-Bu

i-Bu

Ni-Bu

99

Example 212

CO2MeI

NH2Pd(OAc)2, Cs2CO3

DPE-Phos, Tol., 95 oC

95%OCF3

MeO2C HN

OCF3

DPE-Phos =O

PPh2 PPh2

References

1. Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969. John Hartwig earned his Ph.D. under Bergman and Anderson. He has moved from Yale University to the University of Illinois at Urbana-Champaign in 2006. Hartwig and Buchwald in-dependently discovered this chemistry.

2. Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. Steve Buchwald is a professor at MIT.

3. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. 4. Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. 5. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005. 6. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,

805. (Review). 7. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (Review). 8. Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615. (Review). 9. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (Review). 10. Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 975. 11. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135. 12. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737. 13. Li, C. S.; Dixon, D. D. Tetrahedron Lett. 2004, 45, 4257. 14. Gooßen, L. J.; Paetzold, J.; Briel, O.; Rivas-Nass, A.; Karch, R.; Kayser, B. Synlett

2005, 275.

100

Burgess dehydrating reagent

Burgess dehydrating reagent is efficient at generating olefins from secondary and tertiary alcohols where the first-order thermolytic Ei (during the elimination, the two groups leave at about the same time and bond to each other concurrently) mechanism prevails.

Reagen formation,

R1 CH3

R2OH

CH3O2C N S NEt3O

O

Burgess reagent

R1

R2 CH3O2C

HN

SO

O OHNEt3

N S ClO

OO

H3C OH

CH3O2C N S ClO

O

:NEt3

CH3O2C N S NEt3O

O

Reaction,

CH3O2C N S NEt3O

O

HNEt3OH

R1

R2

CH3

SN2

OSO2

NCO2CH3

R1

R2

H

R1

R2CH3O2C

HN

SO

O O

Ei HNEt3

Example 14

CH3O2C N S NEt3O

O

OH

tol., 95 oC, 2 h, 80%

101

OSO2

NCO2CH3

[SO3] NHCO2Me

Example 25

CH3O2C N S NEt3O

O

DMF, 80 oC, 18 h, 87%N

NHN

O

OH

N

NHN

O

Example 310

OSi

NOH 1.5 eq. Burgess, THF

reflux, 1 h, 97%

OSi

N

References

1. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. Edward M. Bur-gess earned his Ph.D. at MIT under George Büchi. He discovered the Burgess reagent at Georgia Institute of Technology, Atlanta, Georgia.

2. Burgess, E. M.; Penton, H. R.; Taylor, E. A., Jr. J. Am. Chem. Soc. 1970, 92, 5224. 3. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1972, 94, 6135. 4. Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973, 38, 26. 5. Stalder, H. Helv. Chim. Acta 1986, 69, 1887. 6. Claremon, D. A.; Phillips, B. T. Tetrahedron Lett. 1988, 29, 2155. 7. Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin Trans. 1

1998, 1015. 8. Lamberth, C. J. Prakt. Chem. 2000, 342, 518. 9. Burekhardt, S.; Svenja, B. Synlett. 2000, 559. 10. Miller, C. P.; Kaufman, D. H. Synlett 2000, 1169. 11. Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Reddy, M. V. Angew. Chem.,

Int. Ed. 2002, 41, 834. 12. Jose, B.; Unni, M. V. V.; Prathapan, S.; Vadakkan, J. J. Synth. Commun. 2002, 32,

2495.

102

Cadiot–Chodkiewicz coupling

Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. Castro Stephens reaction.

X Cu R2R1 R1 R2

X Cu R2oxidative

addition

XCu R2R1

R1

Cu(III) intermediate

reductive

eliminationCuX R1 R2

Example 16

OHBr

OH

cat. CuCl, NH2OH•HCl

EtNH2, MeOH, 0 40 oC, 70 80%

Example 211

TBS Br OH

TBS OHcat. CuCl, NH2OH•HCl

30% n-BuNH2, H2O, 92%

References

1. Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055. Paul Cadiot (1923 ) and Wladyslav Chodkiewicz (1921 ) are both French chemists.

2. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker: New York, 1969, 597 647. (Review).

3. Eastmond, R.; Walton, D. R. M. Tetrahedron 1972, 28, 4591. 4. Ghose, B. N.; Walton, D. R. M. Synthesis 1974, 890. 5. Hopf, H.; Krause, N. Tetrahedron Lett. 1985, 26, 3323.

103

6. Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.; Halazy, S. J. Med. Chem. 1995, 38, 3207.

7. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997,21, 739.

8. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54,11741.

9. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687. 10. Steffen, W.; Laskoski, M.; Collins, G.; Bunz, U. H. F. J. Organomet. Chem. 2001,

630, 132. 11. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841. 12. Utesch, N. F.; Diederich, F. Org. Biomol. Chem. 2003, 1, 237. 13. Utesch, N. F.; Diederich, F.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M. Helv. Chim.

Acta 2004, 87, 698.

104

Camps quinolinol 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)-substituted-quinolin-2-ol (3), or a mixture.

R1O

NH

OR2

R1

N

1 2

OH

R2NaOR

ROH

R1O

NH

OR2

R2

N

1 3

OH

R1

NaOR

ROH

R1O

NH

OR2

1

R1

NH

O

O

R2H

OR

R1

N

2

OH

R2

R1

NH

O

R2

OH

H

105

OR

R1O

NH

OR2

1

R2

NH

O

OR1

H

H R2

N

3

OH

R1

R2

NH

O

R1

HO

Example 11,2

69%

N OH

20%

N

OH

NH

O

NaOH, H2O

104 °C

O

Example 28

HN

O

O

N

Me

MeN

NOH

Me

MeNaOH

H2O, 90%

References

1. Camps, R. Chem. Ber. 1899, 32, 3228. Rudolf Camps worked under Professor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany.

2. Camps, R. Arch. Pharm. 1899, 237, 659. 3. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345. 4. Elderfield, R. C.; Todd, W. H.; Gerber, S. Heterocyclic Compounds Vol. 6, R. C.

Elderfield, ed. Wiley and Sons, New York, 1957, 576. (Review).

106

5. Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110.

6. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641. 7. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Hete-

rocycl. Chem. 2000, 37, 241.8. Pflum, D. A. Camps Quinolinol Synthesis in Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 386 389. (Re-view).

107

Cannizzaro disproportionation

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

R H

O OH

R OH

OR OH2

R H

O

OH

OH

R H

OHO

R H

OO

Pathway A:

hydride

transfer R O

OR OR H

O

R OH

OHH

R OHR O

O

Final deprotonation of the carboxylic acid drives the reaction forward.

Pathway B:

hydride

transfer R O

OR O

R H

O

R O

OH

R OH

O

R OHacidic

workup

108

Example 111

CHOKOH powder

100 oC, 5 min

solvent-free

CO2HOH

Example 213

CHOOH

NNa

H

THF, 0 oC, 5 h, 76%

OHN

References

1. Cannizzaro, S. Justus Liebigs Ann. Chem. 1853, 88, 129. 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 in-terests brought Cannizzaro to the Italian Senate and he later became its vice president.

2. Geissman, T. A. Org. React. 1944, I, 94. (Review). 3. Hazlet, S. E.; Stauffer, D. A. J. Org. Chem. 1962, 27, 2021. 4. Hazlet, S. E.; Bosmajian, G., Jr.; Estes, J. H.; Tallyn, E. F. J. Org. Chem. 1964, 29,

2034. 5. Sen Gupta, A. K. Tetrahedron Lett. 1968, 5205. 6. Swain, C. G.; Powell, A. L.; Sheppard, W. A.; Morgan, C. R. J. Am. Chem. Soc. 1979,

101, 3576. 7. Mehta, G.; Padma, S. J. Org. Chem. 1991, 56, 1298. 8. Sheldon, J. C.; et al. J. Org. Chem. 1997, 62, 3931. 9. Thakuria, J. A.; Baruah, M.; Sandhu, J. S. Chem. Lett. 1999, 995. 10. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381. 11. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. 12. Reddy, B. V. S; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32,

219. 13. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983. 14. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005,

7, 1331.

109

Carroll rearrangement

Thermal rearrangement of -ketoesters followed by decarboxylation to yield -unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of

the Claisen rearrangement (page 131).

OH

R1R1

R2O

O O base

O

R1

R1

R2OH CO2

OH

R1R1

R2O

O Obase

O

R1R1

O

O OR1R1

O

R1R1O

OR2

Oester

exchange H:B

O

O O

R1

R1

O

O O

R1

R1

anion-assisted

Claisen rearrangement

O

R1

R1

CO2

O

R1

R1 acidic

workup

110

Example 19

TESOH

O

O O2 eq. NaH, xylene

reflux, 96%

TESOH

O O

O Carroll

rearrangement

TESOH

O

CO2H

CO2

TESOH

O

Example 210

O

OO

OMeMeO

LDA, THF, 78 oC to rt

CCl4, reflux, 86%

OMeMeO

Me

O

HO2C

OMeMeO

Me

O

111

References

1. Carroll, M. F. J. Chem. Soc. 1940, 704. Michael F. Carroll worked at A. Boake, Rob-erts and Co. Ltd., in London, UK.

2. Carroll, M. F. J. Chem. Soc. 1941, 507. 3. Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722. 4. Gilbert, J. C.; Kelly, T. A. Tetrahedron 1988, 44, 7587. 5. Ziegler, F. E. Chem. Rev. 1988, 88, 1423. (Review). 6. Ouvrard, N.; Rodriguez, J.; Santelli, M. Tetrahedron Lett. 1993, 34, 1149. 7. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem., Int. Ed. Engl. 1995, 34,

2278. 8. Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Liebigs Ann. 1996, 1095. 9. Hatcher, M. A.; Posner, G. H. Tetrahedron Lett. 2002, 43, 5009. 10. Jung, M. E.; Duclos, B. A. Tetrahedron Lett. 2004, 45, 107. 11. Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 2603.

112

Castro–Stephens coupling

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

Cu RAr Xpyridine

refluxAr R

Ar X L3Cu R Cu RArX

L

L

Ar RCuX

XAr Cu

R

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

Ar X Cu Roxidative

additionAr

XCu R

Cu(III) intermediate

Ar Rreductive

eliminationCuX

Example7

O

I

Ocat. CuI, Ph3P, K2CO3

DMF, 120 oC, 37%

O

O

113

References

1. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. Castro and Stephens were in the Department of Nematology and Chemistry at University of California, Riverside.

2. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 3313. 3. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. 4. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299. 5. von der Ohe, F.; Brückner, R. New J. Chem. 2000, 24, 659. 6. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc.

2001, 123, 5407. 7. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487. 8. Rawat, D. S.; Zaleski, J. M. Synth. Commun. 2002, 32, 1489.

114

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 Li-AlH4.

R1

R

OHNaAlH2(OCH2CH2OCH3)2 in PhH

Et2O, heat, 20 h, 83% R R1

OH

R1

R

OHAlH2R2

R1

R

O

H2

Al

RR

H

R1

OAl

RR

R

H workup

R R1

OH

Example 13

OHLiAlH4

77%

OH

Example 24

Ph

OH

CO2Me

1.5 eq. Red-Al, 72 oC, 25 min.

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

78%

Ph

OH

CO2Me

I

115

References

1. Chan, K.-K.; Cohen, N.; De Noble, J. P.; Specian, A. C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497. Ka-Kong Chan was a chemist at Hoffmann La Roche, Inc., Nutley, NJ, USA.

2. 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.

3. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143. 4. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785. 5. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073.

116

Chan–Lam coupling reaction

N-Arylation of a wide range of NH substrates by reaction with boronic acid in the presence of cupric acetate and either triethylamine or pyridine at room tempera-ture. The reaction works even for poorly nucleophilic substrates such as aryla-mide.

X H

RB(OH)2, Cu(OAc)2

CH2Cl2, rt, Et3N or pyridineX = NR'2, OR"

RX

Example 11

NH

B(OH)2

Cu(OAc)2, pyridinert, 48 h, 74%

H3C

N CH3

Mechanism:

NHCu(OAc)2, pyridine

coordination anddeprotonation

CuIIL L

N OAc

Ph

pyridium acetate

B(OH)2H3C

transmetallation

CuIIL L

N

PhCH3

AcOB(OH)2

N CH3

reductive

elimination

117

Example 23

NH

O

S

Cl

CO2Me N O

S

Cl

CO2Me

B(OH)2

Cu(OAc)2, Et3N, MS 4 ÅCH2Cl2, rt, 48 h, 29%

References

1. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,39, 2933. Dominic M. T. Chan and Patrick Y. S. Lam were both chemists at DuPont Pharmaceuticals Company, Wilmington, DE, USA.

2. 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.

3. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55,12757.

4. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674.

5. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.2001, 42, 3415.

6. Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. 7. Combs, A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y. S. J. Comb. Chem.

2002, 4, 179. 8. Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetra-

hedron Lett. 2003, 44, 3863. 9. Quach, T. D.; Batey, R. A. Org. Lett. 2003, 5, 4397. 10. Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079.

118

Chapman rearrangement

Thermal aryl rearrangement of O-aryliminoethers to amides.

Ar OPh

NAr1

Ar NAr1

O

Ph

Ar O

N:Ar1

Ar NAr1

O

Ph

N

O

Ar1

Ar

SNAr

oxazete intermediate

Example 12

Cl

MeO2C

NaO

MeO

N Ph

ClNaOEt, EtOH/Et2O

0 oC to rt, 48 h

210 215 oC, 70 min

28% for 2 stepsMeO

N Ph

O

MeO2CCl

MeO

N

PhO

ClMeO2C

MeO

NH

ClHO2C

119

Example 24

Ph

O

N

Ph

Ph

300 oC

30 min., 87%

Ph

NPh

Ph O

References

1. Chapman, A. W. J. Chem. Soc. 1925, 127, 1992. Arthur William Chapman was born in 1898 in London, England. He was 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. 3. Schulenberg, J. W.; Archer, S. Org. React. 1965, 14, 1 51. (Review). 4. Relles, H. M. J. Org. Chem. 1968, 33, 2245. 5. Wheeler, O. H.; Roman, F.; Rosado, O. J. Org. Chem. 1969, 34, 966. 6. Shawali, A. S.; Hassaneen, H. M. Tetrahedron 1972, 28, 5903. 7. Kimura, M. J. Chem. Soc., Perkin Trans. 2 1987, 205. 8. Kimura, M.; Okabayashi, I.; Isogai, K. J. Heterocycl. Chem. 1988, 25, 315. 9. Farouz, F.; Miller, M. J. Tetrahedron Lett. 1991, 32, 3305. 10. Dessolin, M.; Eisenstein, O.; Golfier, M.; Prange, T.; Sautet, P. J. Chem. Soc., Chem.

Commun. 1992, 132. 11. Shohda, K.-I.; Wada, T.; Sekine, M. Nucleosides Nucleotides 1998, 17, 2199.

120

Chichibabin pyridine synthesis

Condensation of aldehydes with ammonia to afford pyridines.

3 R CHO NH3

N

RR

R

H3N:

RO

HR

NH2

H

H3N:

ROH

NH2

HR

NH

H

enamine imine

:NH3

RO

H

RO

H

HR

O

H

Aldol

condensation

RO

H

RH

OH

H

H2O RO

H

R

HN

R

:

Michael

addition

RO

RN

RH

RH

O

RNH

R

HH3N

: N

RR

R

OHH

H

N

RR

R

OHH

HN

RR

R

H

H

autoxidation

[O] N

RR

R

121

Example 14

N

CHO

N

ONH4OH, NH4OAc

250 oC, autoclave, 32%

N

N

N

N

Example 25

CHOO

NH4OAc, HOAc

reflux, 1 h, 68%

N

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 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.; Seven, R. P. J. Am. Chem. Soc. 1949, 71, 2629. 4. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182. 5. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200. 6. Herzenberg, J.; Boccato, G. Chem. Ind. 1950, 80, 248.

122

7. Levitt, L. S.; Levitt, B. W. Chem. Ind. 1963, 1621. 8. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825. 9. Shimizu, S.; Abe, N.; Iguchi, A.; Dohba, M.; Sato, H.; Hirose, K.-I. Microporous

Mesoporous Materials 1998, 21, 447. 10. Galatasis, P. Chichibabin (Tschitschibabin) Pyridine Synthesis In Name Reactions in

Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 308 309. (Review).

123

Chugaev elimination

Thermal elimination of xanthates to olefins.

ROH R

O S

S

1. CS2, NaOH

2. CH3I xanthate

R OCS CH3SH

RO S

S

HS

O

S

R

CH3SHR SO

SC SO

H

Example 16

OOHO

H

O

OHH

CS2, MeI, NaH

THF, rt, 2 h, 51%

OOO

H

O

OHH

S

S

124

dodecane, reflux (216 oC)

48 h, 74%

OO

H

O

OHH

Example 2, Chugaev syn-elimination is followed by an intramolecular ene reac-tion7

O

O N

OH

Cbz

CS2, MeI, NaH

THF, 92%

O

O N

O

Cbz

S

S

NaHCO3, diphenyl ether

reflux, 45 min. 72% N O

O

CbzReferences

1. Chugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332. Lev A. Chugaev (1873 1922) was born in Moscow, Russia. He was a Professor of Chemistry at Petrograd, a posi-tion 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 to 5 a.m.

2. Chande, M. S.; Pranjpe, S. D. Indian J. Chem. 1973, 11, 1206. 3. Kawata, T.; Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1973, 21, 604. 4. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467. 5. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615. 6. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org.

Chem. 1999, 64, 9178. 7. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. 8. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4523.

125

Ciamician–Dennsted rearrangement

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

NH

N

ClCHCl3

NaOH

Cl3C H

OH

CCl2H2OCl

Cl:CCl2

carbene

NH

N

ClCCl2 N

ClCl

H

HO

Example 18

N

Cl2 eq. PhHgCCl3

PhH, 54%NH

126

Example 210

NH

NH

HNHN

N

N

N

N

Cla Clb

Cla

Clb

ClaClb

Cla

Clb

NaO2CCl3

26%

References

1. Ciamician, G. L.; Dennsted, M. Ber. Dtsch. Chem. Ges. 1881, 14, 1153. Giacomo Luigi Ciamician (1857 1922) was born in Trieste, Italy. After his Ph.D. training at Giessen, Germany, Ciamician carried out most of his work at the University of Bolo-gna, Italy. Ciamician is considered the father of modern organic photochemistry.

2. Cantor, P. A.; VanderWerf, C. A. J. Am. Chem. Soc. 1958, 80, 970. 3. Krauch, H.; Kunz, W. Chemiker-Ztg. 1959, 83, 815. 4. Vogel, E. Angew. Chem., Int. Ed. 1960, 72, 4. 5. Wynberg, H. Chem. Rev. 1960, 60, 169. (Review). 6. Wynberg, H. and Meijer, E. W. Org. React. 1982, 28, 1. (Review). 7. Josey, A. D.; Tuite, R. J.; Snyder, H. R. J. Am. Chem. Soc. 1960, 82, 1597. 8. Parham, W. E.; Davenport, R. W.; Biasotti, J. B. J. Org. Chem. 1970, 35, 3775. 9. De Angelis, F.; Inesi, A.; Feroci, M.; Nicoletti R. J. Org. Chem. 1995, 60, 445. 10. Král, V.; Gale, P. A.; Anzenbacher, P. Jr.; K. Jursíková; Lynch, V.; Sessler, J. L. J.

Chem. Soc., Chem. Comm. 1998, 9. 11. Pflum, D. A. Ciamician–Dennsted Rearrangement In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 350 354. (Review).

127

Claisen condensation

Base-catalyzed condensation of esters to afford -keto esters.

OR1

O

Rbase

OR1

O

R

R2R2 OR3

OO

OR3R2

O

OR1

OR

OR1

OR

H

B:

deprotonation condensation

OR1

O

RR3O

OR2

OR1

O

RR2

O

Example 19

O Ph

O t-BuOK, solvent-free

90 oC, 20 min., 84%O Ph

OPh

O

Ph

Ph

Example 212

Cbz

HN CO2Me

PhO

t-BuO

Cbz

HN

Ph

O

O

Ot-Bu

3.5 eq. LDA, THF

45 to 50 oC

then H+, 97%

128

References

1 Claisen, R. L.; Lowman, O. Ber. Dtsch. Chem. Ges. 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.

2 Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266 302. (Review). 3 Thaker, K. A.; Pathak, U. S. Indian J. Chem. 1965, 3, 416. 4 Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1 203. (Review). 5 Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917. 6 Leijonmarck, H. K. E. Chem. Commun. Stockhol. 1992, 33, 1. (Review). 7 Kashima, C.; Takahashi, K.; Fukusaka, K. J. Heterocycl. Chem. 1995, 32, 1775. 8 Tanabe, Y.; Hamasaki, R.; Funakoshi, S. Chem. Commun. 2001, 1674. 9 Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. 10 Mogilaiah, K.; Kankaiah, G. Indian J. Chem., Sect. B 2002, 41B, 2194. 11 Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581. (Review). 12 Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447. 13 Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73. 14 Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838.

129

Claisen isoxazole synthesis

Cyclization of -keto esters with hydroxylamine to provide 3-hydroxy-isoxazoles (3-isoxazolols).

O O

R1

R2

OR

ON

R2 OH

R1

NH2OH

H2O

O O

R1

R2

OR

:NH2OH

O O

R1

R2

NH

OH

O

R1

R2

NH

OHORO

ON

R2 OH

R1ONH

R2 O

R1

HO ONH

R2 O

R1

H2O

3-isoxazolol

A side reaction:

HON O

R1

R2

OR

OHO O

R1

R2

OR NH2OH

:NH2OH

H

N O

R1

R2

OR

ON

R2 R1

O

H2OO:H

ON

R1

R2

ORO H

5-isoxazolone

130

Example20

O O

OMe

ON

OHNH2OH-HCl, NaOH, MeOH

50 oC, 2 h

then 85 oC, 1 h, 65%

References

1. Claisen, L; Lowman, O. E. Ber. Dtsch. Chem. Ges. 1888, 21, 784. 2. Claisen, L.; Zedel, W. Ber. 1891, 24, 140. 3. Hantzsch Ber. 1891, 24, 495. 4. Barnes, R.A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York,

1957; Vol. 5, p 474 ff. (Review). 5. Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Am-

sterdam, 1957; Vol. 4a, p. 345ff. (Review). 6. Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 41. 7. Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 51. 8. Katritzky, A.R.; Oksne, S.; Boulton, A. J. Tetrahedron 1962, 18, 777. 9. Katritzky, A. R.; Oksne, S. Proc. Chem. Soc. 1961, 387. 10. Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chem. Fr. 1970, 2685. 11. Cocivera, M.; Effio, A.; Chen, H. E.; Vaish, S. J. Am. Chem. Soc. 1976, 98, 7362. 12. Jacobsen, N.; Kolind-Andersen, H.; Christensen, J. Can. J. Chem. 1984, 62, 1940. 13. Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf, T. I. J. Org. Chem. 1986,

51, 4037. 14. Krogsgaard-Larsen, K.; Sorensen, U. S. Org. Prep. Proc. Int. 2001, 33, 515. 15. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65, 1003. 16. Chen, B.-C. Heterocycles, 1991, 32, 529. 17. McNab, H. Chem. Soc. Rev. 1978, 7, 345. (Review). 18. Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A.B.; Krogsgaard-Larsen, K.; Falch,

E. J. Med. Chem. 1995, 38, 3287. 19. Frølund, B.; Tagmose, L.; Liljefors, T.; Stensbøl, T. B.; Engblom, C.; Kristiansen, U.;

Krogsgaard-Larsen, K. J. Med. Chem. 2000, 43, 4930. 20. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Niel-

sen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051.

21. Brooks, D. A. Claisen Isoxazole Synthesis In Name Reactions in Heterocyclic Chemis-try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 220 224. (Re-view).

131

Claisen rearrangements

The Claisen, Johnson–Claisen, Ireland–Claisen, para-Claisen rearrangements, 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.

O

R

O

R

O

R, [3,3]-sigmatropic

rearrangement

1 23

1 23

1 23

1 23

Example 17

O

BnO

BnO O

BnO

BnOO

O O

n-decane/toluene 5:1

180 oC, 70%

O

OBn

BnOO

OBnBnO

O

O

O

Example 28

O

O

Et2AlCl, hexanes

78 oC, 81%

O

OH

References

1. Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. 2. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1 252. (Review).

132

3. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-mon, 1991, Vol. 5, 827 873. (Review).

4. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 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. 8. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E. M. Tetrahedron Lett. 2005,

46, 2457.

133

Abnormal Claisen rearrangement

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

O OH

O [3,3]-sigmatropicrearrangement

"normal Claisen"

O

H

tautomerization

OHOH

OH

ene

reaction

[1,5]-H-atom

shift

Example 14

OMeMeO

O

CHOMeO

PhNEt2

180 oC

40%

OMeO

MeO

CHO

OMe

kodsurenin M

134

Example 25

O (R)-(+)-BINOL-Me•FeCl3

CH2Cl2, 78 oC, 76%

OH

Example 36

OO

O

Tol. 180 oC

24 h, 65%

OO

O

References

1. Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B. S., ed.; Wiley-Interscience: New York, 1971, pp 177 236. (Review).

2. Shah, R. R.; Trivedi, K. N. Curr. Sci. 1975, 44, 226. 3. Kilenyi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591. 4. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. 5. Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131. 6. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tet-

rahedron Lett. 2001, 42, 4561. 7. Puranik, R.; Rao, Y. J.; Krupadanam, G. L. D. Indian J. Chem., Sect. B 2002,

41B, 868.

135

Eschenmoser–Claisen amide acetal rearrangement

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

NMe2

OMeMeO

NMe2

OMeOMe

R R1

O:

R R1

OH

OMeMe2NH

R R1

OH

NMe2: OMeH

NMe2

OMe

R R1

O

NMe2

R R1

[3,3]-sigmatropic

rearrangement

CONMe2

Example 17

O PhF3C

OH

CH3C(OMe)2NMe2

PhH, 100 oC, 2 h, 60%

ONMe2

PhCF3 O

Example 29

HO CO2Me

5 eq. CH3C(OMe)2NMe2

xylene, reflux, 48 h, 50%

CO2Me

NMe2

O

136

References

1. Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Justus Liebigs Ann. Chem. 1961, 641,1.

2. Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425. 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.

3. Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta 1969,52, 1030.

4. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Perga-mon, 1991, Vol. 5, 827 873. (Review).

5. Coates, B.; Montgomery, D.; Stevenson, P. J. Tetrahedron Lett. 1991, 32, 4199. 6. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 7. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81. 8. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43 50. (Review). 9. Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279. 10. Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett 2002, 411. 11. Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N.; Aviyente, V.; Neier,

R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68, 572. 12. Castro, A. M. M. Chem. Rev. 2004, 104, 2939 3002. (Review). 13. Gilbert, M. W.; Galkina, A.; Mulzer, J. Synlett 2004, 2558.

137

Ireland–Claisen (silyl ketene acetal) rearrangement

Rearrangement of allyl trimethylsilyl ketene acetal, prepared by reaction of allylic ester enolates with trimethylsilyl chloride, to yield -unsaturated carboxylic a-cids. 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

OLDA, then

Me3SiClO

OSiMe3

O

OSiMe3

H+ CO2H, [3,3]-sigmatropic

rearrangement

Example 13

O

N

O

Bn

TIPSOTf, Et3N

PhH, rt, 62%NBn

CO2TIPS

Example 2, a modified Ireland–Claisen rearrangement10

O

F

FO

F

HOF

F

O

F

BBr3, Et3N, PhMechiral ligand

78 to rt, 79%, > 99% ee

138

Example 314

O

OO

OPMP

KHMDS, TMSCl, THF

78 to 25 oC, 1 h, 81% O

CO2MePMPO

References

1. Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897. Also J. Am. Chem. Soc. 1976, 98, 2868. 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. Cha, J. K.; Lewis, S. C. Tetrahedron Lett. 1984, 25, 5263. 3. Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026. (Enantioselective variant

of the Ireland–Claisen rearrangement). 4. Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17 29. (Review). 5. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. 6. Mohamed, M.; Brook, M. A. Tetrahedron Lett. 2001, 42, 191. 7. Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh, M. C. J. Org. Chem.

2002, 67, 2042. 8. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron

2002, 58, 2905 2928. (Review). 9. Khaledy, M. M.; Kalani, M. Y. S.; Khuong, K. S.; Houk, K. N.; Aviyente, V.; Neier,

R.; Soldermann, N.; Velker, J. J. Org. Chem. 2003, 68, 572. 10. 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.

11. Höck, S.; Koch, F.; Borschberg, H.-J. Tetrahedron: Asymmetry 2004, 15, 1801. 12. Hutchison, J. M.; Hong, S.-p.; McIntosh, M. C. J. Org. Chem. 2004, 69, 4185. 13. Gilbert, J. C.; Yin, J.; Fakhreddine, F. H.; Karpinski, M. L. Tetrahedron 2004, 60, 51. 14. Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46,

3465.

139

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 to give a mixed orthoester. The orthoester loses ethanol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearran-gement to give a -unsaturated ester.

R R1

OH CH(OR2)3

H+

R R1

OH

OR2R2OH

R R1

OH

OR2:B:

R R1

O

OR2

[3,3]-sigmatropic

rearrangement R R1

CO2R2

Example 12

ClOH

ClOTBS

CH3C(OCH3)3, TsOH

170 oC, 55%OMe

Cl

OTBS

ClO

Example 27

N

OMe

OH

CH3C(OCH3)3cat. CH3CH2CO2H

reflux, 77%

N

OMe

OMe

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. 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 Wiscon-

140

sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department.

2. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C. An-gew. Chem., Int. Ed. 1998, 37, 2085.

3. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713. 4. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem.

2003, 122, 237. 5. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063. 6. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089. 7. 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. Bio-org. Med. Chem. Lett. 2005, 15, 1647.

141

Clemmensen reduction

Reduction of aldehydes and ketones to the corresponding methylene compounds using amalgamated zinc and hydrogen chloride.

R R1

O Zn(Hg)

HCl R R1

HH

The zinc-carbenoid mechanism:6

Ph CH3

O

Ph CH3

OZn(Hg), HCl

SET

ZnCl

radical anion

Ph CH3

Zn

Ph CH3

OZnCl

ZnZinc-carbenoid

Ph CH3

HH+

H

The radical anion mechanism:

Ph CH3

O Zn(Hg)

HCl Ph CH3

HH

Ph CH3

O e; H+

Ph CH3

OZnCl

H

Zn(Hg), HCl

SETPh CH3

O ZnCl

radical anion

H+Ph CH3

OZnCl

H

H

Cl

SN2Ph CH3

H

Cl

142

Ph CH3

H

Ph CH3

HHe; H+e

Example 18

Zn(Hg), HCl

MeOH, reflux, 1 hOH

OHO

OH

O

OH18% 67%

Example 210

Zn(Hg), HCl

Et2O, 5 oC, 57%N

OH

HPh

N

H

HPhO O

References

1. Clemmensen, E. Ber. Dtsch. Chem. Ges. 1913, 46, 1837. 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 (now part of Pfizer) as a research chemist for 14 years, where he discovered the reduction of car-bonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corpora-tion in Newark, New York.

2. Martin, E. L. Org. React. 1942, 1, 155 209. (Review). 3. Brewster, J. H. J. Am. Chem. Soc. 1954, 76, 6361. 4. Vedejs, E. Org. React. 1975, 22, 401 422. (Review). 5. Elphimoff-Felkin, I.; Sarda, P. Tetrahedron Lett. 1983, 24, 4425. 6. Burdon, J.; Price, R. C. Chem. Commun. 1986, 893. 7. Talpatra, S. K.; Chakrabarti, S.; Mallik, A. K.; Talapatra, B. Tetrahedron 1990, 46,

6047. 8. Martins, F. J. C.; Viljoen, A. M.; Coetzee, M.; Fourie, L.; Wessels, P. L. Tetrahedron

1991, 47, 9215. 9. Ni, Y.; Kim, H. S.; Wilson, W. K.; Kisic, A.; Schroepfer, G. J., Jr. Tetrahedron Lett.

1993, 34, 3687. 10. Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Chem. Soc., Perkin Trans. 1 1996, 1113. 11. Cheng, L.; Ma, J. Org. Prep. Proc. Int. 1995, 27, 224.

143

12. Kappe, T.; Aigner, R.; Roschger, P.; Schnell, B.; Stadlbauer, W. Tetrahedron 1995,51, 12923.

13. Kohara, T.; Tanaka, H.; Kimura, K.; Fujimoto, T.; Yamamoto, I.; Arita, M. Synthesis2002, 355.

14. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69, 789.

144

Combes quinoline synthesis

Acid-catalyzed condensation of anilines and -diketones to assemble quinolines. Cf. Conrad-Limpach reaction.

NH2 R1 R2

O O H2SO4

N R1

R2

NH2:

O

R1

H

R2

ONH2

OHR1

O

R2 proton

transfer

NH

OH2

:R1

O

R2

N R1

O

R2

NH

R1

O

R2

imine

H+

NH

R1

R2

OH

:

NH

R1

R2

O

enamine

H+

NH

R1

R2OH

N R1

H R2OH

H+

145

N R1

R2

NH

R1

R2OH H

:

HN R1

R2

An electrocyclization mechanism is also possible:

:

NH

R1

R2

OH

N R1

R2

OH

6 -electrocyclization

N R1

R2HO

N R1

R2

H

proton

transferN R1

HOH2

R2

Example 110

NH

NH2

MeOO O

PPA, 110 °C

NH

MeO

N

35%

Example 211

NH

NH2

CO2Et

O

Ph

O

cat. p-TsOH, 220 °Cneat, 38%

NH

CO2Et

N

Ph

146

References

1. 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.

2. Roberts, E. and Turner, E. J. Chem Soc. 1927, 1832. (Review). 3. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., ed., Wiley & Sons,

New York, 1952, vol. 4, 36–38. (Review). 4. Popp, F. D. and McEwen, W. E. Chem. Rev. 1958, 58, 321–401. (Review). 5. Coscia, A. T.; Dickerman, S. C. J. Am. Chem. Soc. 1959, 81, 3098. 6. Claret, P. A.; Osborne, A. G. Org. Prep. Proced. Int. 1970, 2, 305. 7. Born, J. L. J. Org. Chem. 1972, 37, 3952. 8. Jones, G. In Chemistry of Heterocyclic Compounds, Jones, G., ed.; Wiley & Sons,

New York, 1977, Quinolines Vol. 32, pps.119–125. (Review). 9. Ruhland, B.; Leclerc, G. J. Heterocycl. Chem. 1989, 26, 469. 10. Alunni-Bistocchi, G.; Orvietani, P., Bittoun, P., Ricci, A.; Lescot, E. Pharmazie 1993,

48, 817. 11. El Ouar, M.; Knouzi, N.; Hamelin, J. J. Chem. Research (S) 1998, 92. 12. Curran, T. T. Combes Quinoline Synthesis In Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 390 397. (Re-view).

147

Conrad–Limpach reaction

Thermal or acid-catalyzed condensation of anilines with -ketoesters leads to qui-nolin-4-ones. Cf. Combes quinoline synthesis.

NH2 NH

OEt

O OPh2O

260 oC

O

NH2

EtO2C

O

NH

CO2Et

OH

: :

H2Oproton

transfer

N

CO2Et

N

OEtHO 6 electron

electrocyclization

tautomerize

Schiff base

HOEt

N

HO

H OEtN

H OEtO

H

NH

O

proton

transfer N

OH

Example 13

N

NH2CHCl3, HCl (cat.)

60%OEt

O O

148

N

HN

CO2Et

N

N

OH

Ph2O, reflux

60%

Example 212

NH2

NO2

CO2MeHO

OMeO2C

2HCl, MeOH

64%

+O2N

NH

CO2Me

NHPhNO2MeO2C

Dowtherm A

250 °C, 55% NH

HN

CO2Me

O2NO

NO2

References

1. Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20, 944. Max Conrad (1848 1920), born in Munich, Germany, was a professor of the University of Würz-burg, 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. 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. Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; et al. J. Med. Chem. 1968, 11, 1218. 7. Perche, J. C.; Saint-Ruf, G. J. Heterocycl. Chem. 1974, 11, 93. 8. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York,

1977, Quinolines, Vol 32, 137–151. (Review). 9. Barker, J. M.; Huddleston, P. R.; Jones, A. W.; Edwards, M. J. Chem. Res., (S) 1980,

4.10. Guay, V.; Brassard, P. J. Heterocycl. Chem. 1987, 24, 1649. 11. Deady, L. W.; Werden, D. M. J. Org. Chem. 1987, 52, 3930. 12. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077. 13. Hormi, O. E. O.; Peltonen, C.; Heikkila, L. J. Org. Chem. 1990, 55, 2513. 14. Billah, M.; Buckley, G. M.; Cooper, N; et al. Bioorg. Med. Chem. 2002, 12, 1617. 15. Curran, T. T. Conrad–Limpach Reaction In Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 398 406. (Re-view).

149

Cope elimination reaction

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

NO

H

R2R3RR1 R2

R3

R1

R

N

OH

NO

H

R2 R3RR1

R2

R3

R1

R

N

OH

Ei

Example 17

OO

N

OH

m-CPBA, CHCl3

rt, 67%

OO

N

OH

OH

OO

HON

OH

150

Example 211

N

CN

Om-CPBA, CH2Cl2

rt, 100%

NOO

NC H

NOH O

CN

References

1. Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929. 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. (Re-

view). 5. Vidal, T.; Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 5959. 6. Gravestock, M. B.; Knight, D. W.; Malik, K. M. A.; Thornton, S. R. J. Chem. Soc.,

Perkin 1 2000, 3292. 7. Sammelson, R. E.; Kurth, M. J. Tetrahedron Lett. 2001, 42, 3419. 8. Bagley, M. C.; Tovey, J. Tetrahedron Lett. 2001, 42, 351. 9. Remen, L.; Vasella, A. Helv. Chim. Acta 2002, 85, 1118. 10. Garcia Martinez, A.; Teso Vilar, E.; Garcia Fraile, A.; de la Moya Cerero, S.; Lora

Maroto, B. Tetrahedron: Asymmetry 2002, 13, 17. 11. 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.

151

Cope rearrangement

The Cope, oxy-Cope, and anionic oxy-Cope rearrangements belong to the cate-gory of [3,3]-sigmatropic rearrangements. Since it is a concerted process, the ar-row pushing here is only illustrative. Cf. Claisen rearrangement.

R R R, [3,3]-sigmatropic

rearrangement

Example 15

O OTMS

CO2Me 100 oC, 12 h

84%

CO2Me

TMS

Example 28

CO2Me

CO2MeO

dioxane, Et3N, 60 oC

22 h, 1 bar, 92%O

CO2Me

CO2Me

References

1. Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. 2. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103 124. (Review). 3. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1 252. (Review). 4. Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds., Per-

gamon, 1991, Vol. 5, 785 826. (Review). 5. Chou, W.-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658. 6. Davies, H. M. L. Tetrahedron 1993, 49, 5203 5223. (Review). 7. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815 824. (Review). 8. Von Zezschwitz, P.; Voigt, K.; Lansky, A.; Noltemeyer, M.; De Meijere, A. J. Org.

Chem. 1999, 64, 3806. 9. Nakamura, H.; Yamamoto, Y. In Handbook of Organopalladium Chemistry for Or-

ganic Synthesis 2002, 2, 2919 2934. (Review). 10. Clive, D. L. J.; Ou, L. Tetrahedron Lett. 2002, 43, 4559. 11. Hrovat, D. A.; Brown, E. C.; Williams, R. V.; Quast, H.; Borden, W. T. J. Org. Chem.

2005, 70, 2627.

152

Oxy-Cope rearrangement

ROH

ROH, [3,3]-sigmatropic

rearrangement

ROH

R

Otautomerize

Example 12

PhMe2Si

PhMe2SiO O

O

t-Bu

O

1. 170 oC

2. p-TsOH-H2O

65 75%

O

O

t-Bu

O

PhMe2SiOOHC

Example 24

OH Oxylene, Ace® tube

225 oC, 24 h, 49%

References

1. Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609 626. (Review). 2. Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850. 3. Schneider, C. Synlett 2001, 1079 1091. (Review on siloxy-Cope rearrangement). 4. DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley,

M. Org. Biomol. Chem. 2003, 1, 4423.

153

Anionic oxy-Cope rearrangement

ROH

ROKKH

THF

, [3,3]-sigmatropic

rearrangement

ROK H2O

ROK

ROH

R

Otautomerize

Example 11

OH KH, THF, rt

then H2O, 88%

O

Example 26

OHNaH, THF, reflux

22 h, 88%

O

References

1. Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37,3967.

2. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319. 3. Paquette, L. A. Tetrahedron 1997, 53, 13971 14020. (Review). 4. Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519. 5. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron

Lett. 2002, 43, 3633. 6. Gentric, L.; Hanna, I.; Huboux, A.; Zaghdoudi, R. Org. Lett. 2003, 5, 3631.

154

Corey–Bakshi–Shibata (CBS) reduction

Enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines.

O OHN B

O

PhPhH

H

cat.

BH3, THF, rt, 97% ee

RL RS

O

N BO

PhPhH

H

N BO

PhPhH

H

BH3

H3B

NB

O

PhPhH

OH2BH

H

RL

RS

N B

O

PhPhH

OH2BH

H

RSRL

BH3

N BO

PhPhH

HH3B

H OBH2

RS RL

H O

RS RL

BH

2

H2O H OH

RS RL

The catalytic cycle is shown on the next page.

155

The catalytic cycle:

RL RS

O

N BO

PhPhH

H

N BO

PhPhH

H

BH3

H3B

RL RS

OBH2

N BO

PhPhH

OH2B

RS

RLBH3

N BO

PhPhH

OH2BH

H

RL

RS

H

Example 19

SO2C6H4CH3-pO

O

0.1 eq. (S)-CBS1.0 eq. i-Pr(Et)NPh•BH3

THF, rt, syringe pump1.5 h, 98%, 97% ee

SO2C6H4CH3-pOH

ON B

O

PhPhH

CH3

(S)-CBS =

Example 214

O

O

OO

BH3•SMe2, cat. (R)-CBS

CH2Cl2, 30 oC, 84%, > 99% ee

HO

O

OO

156

References

1. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. Elias J. Corey (1928 ) was born in Methuen, Massachusetts. After earning his Ph.D. at MIT from John Sheehan at age 22, he began his independent academic career at the Univer-sity of Illinois in 1950 and moved to Harvard University in 1959. Corey won the No-bel Prize in Chemistry in 1990 for development of novel methods for the synthesis of complex natural compounds and retrosynthetic analysis. He is still carrying out active research at Harvard. Prof. Corey has been a consultant to Pfizer for more than 50 years.

2. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.1987, 109, 7925.

3. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. 4. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1992, 3, 1583. 5. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. 6. 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. 7. Itsuno, S. Org. React. 1998, 52, 395 576. (Review). 8. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986 2012. (Review). 9. Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043. 10. de Koning, C. B.; Giles, R. G. F.; Green, I. R.; Jahed, N. M. Tetrahedron Lett. 2002,

43, 4199. 11. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086. 12. Fu, X.; McAllister, T. L.; Thiruvengadam, T. K.; Tann, C.-H.; Su, D. Tetrahedron

Lett. 2003, 44, 801. 13. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495. 14. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652.

157

Corey Chaykovsky reaction

The Corey Chaykovsky reaction entails the reaction of a sulfur ylide, either di-methylsulfoxonium 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.

R R1

X

R R1

X

X = O, CH2, NR2, S, CHCOR3,

CHCO2R3, CHCONR2, CHCN

3H3C

SCH3

CH2

1 2

H3CSCH3

CH2

O

4

1 or 2

H3CS

CH2CH3

O

R R1

O

H3CS

CH3

O

O R1

R

H3CS

CH2CH3

O R R1

O

H3CS

CH3

O R

OR1

H3CS

CH3

O

O R1

R

Example 112

CHOR20

Ph2S

BF4

R20OKOH, DMSO, rt, 62%

158

Example 214

N

O

O

Cl

F

(CH3)3S(O)+I , NaH, DMSO

60 oC, 3.5 h, 79%

N

O

O

Cl

F

References

1 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867. Michael Chaykovsky last published from Prospect Pharma, USA

2 Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 4, 169. 3 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1640. 4 Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. 5 Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides Academic Press: New York, 1975. (Re-

view). 6 Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978.

(Review). 7 Johnson, C. R. Aldrichimica Acta 1985, 18, 3 10. (Review). 8 Gololobov, Y. G.; Nesmeyanov, A. N., Iysenko, V. P.; Boldeskul, I. E. Tetrahedron

1987, 43, 2609 2651. (Review). 9 Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Perga-

mon: Oxford, 1991, Vol. 1, pp 820 825. (Review). 10 Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette,

L. A., Ed.; Wiley: New York, 1995, pp 2139 41. (Review).11 Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A.,

Ed.; Wiley: New York, 1995, 2159 65. (Review). 12 Corey, E. J.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Li, D.; Song, X. J. Am. Chem.

Soc. 1997, 119, 1277. 13 Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341 2372. (Review). 14 Vacher, B.; Bonnaud, B.; Funes, P.; et al. J. Med. Chem. 1999, 42, 1648. 15 Shea, K. J. Chem. Eur. J. 2000, 6, 1113 1119. (Review). 16 Saito, T.; Sakairi, M.; Akiba, D. Tetrahedron Lett. 2001, 42, 5451. 17 Mae, M.; Matsuura, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2002, 43, 2069.

159

18 Chandrasekhar, S.; Narasihmulu, Ch.; Jagadeshwar, V.; Reddy, K. V. Tetrahedron Lett. 2003, 44, 3629.

19 Li, J. J. Corey Chaykovsky Reaction In Name Reactions in Heterocyclic Chemistry,Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 1 14. (Review).

160

Corey Fuchs reaction

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

R CHOCBr4, PPh3

Zn Br

Br

H

R n-BuLiR H

:PPh3Br3C Br CBr3 Br PPh3

SN2

CBr3

Br PPh3

Br

PPh3

SN2 BrBr

Br

SN2

Br

Br

H

RO PPh3

R H

O

Br2 PPh3

Br

BrWittig reaction (see page 621 for the mechanism)

Br2 Zn ZnBr2

Br

Br

H

R

Bu

R BrBu

R HRacidic

workup

Example 13

OHC

OMe

OTBS

OO

CBr4, Ph3P, CH2Cl2

rt, 35 min., 90%

161

2.0 eq. THF•BH3, THF, 15 oC, 26 h

then CH3OH, 3 N NaOH, 30% H2O2

rt, 2 h, 85%

OMe

OTBS

OO

Br

Br

3.0 eq. n-BuLi/hexanes, THF

78 oC, 1 h; rt, 1 h, 99%

OMe

OTBS

OO

OHExample 28

CHOOTBS

1. CBr4, Ph3P, Zn, CH2Cl2

2. n-BuLi, then NH4Cl, 90%

OTBS

References

1 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769. 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.

3 Gilbert, A. M.; Miller, R.; Wulff, W. D. Tetrahedron 1999, 55, 1607. 4 Muller, T. J. J. Tetrahedron Lett. 1999, 40, 6563. 5 Serrat, X.; Cabarrocas, G.; Rafel, S.; Ventura, M.; Linden, A.; Villalgordo, J. M. Tetra-

hedron: Asymmetry 1999, 10, 3417. 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. 7 Falomir, E.; Murga, J.; Carda, M.; Marco, J. A. Tetrahedron Lett. 2003, 44, 539. 8 Zeng, X.; Zeng, F.; Negishi, E.-i. Org. Lett. 2004, 6, 3245. 9 Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4527.

162

Corey–Kim oxidation

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

R1 R2

OH

R1 R2

ONCS, DMS

then NEt3NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide.

SN

O

O

Cl:

ClSN

O

O

R1 R2

:OH

R1 R2

OS

H

H:NEt3N

O

O

S

Cl

NH

O

O

Cl

R1 R2

O

R1

OS

(CH3)2S

HR2

Et3N·HCl

Example 1, fluorous Corey Kim reaction5

NO2

OH

C6F13S

NCS, toluene, 25 oC, 2 h

then Et3N, 86%

NO2

CHO

163

Example 2, odorless Corey Kim reaction8

NO

0.5 eq. NCS, CH2Cl2, 40 oC, 2 h

then Et3N, 40 oC to rt, 8 h

OH

D

S

O

NO

S D

45%86%

References

1 Corey, E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. 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. 3 Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099. 4 Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604. 5 Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865. 6 Nishide, K.; Ohsugi, S.-I.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett.

2002, 43, 5177. 7 Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node,

M. Tetrahedron 2003, 59, 8393. 8 Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green

Chem. 2004, 6, 142.

164

Corey–Nicolaou macrolactonization

Macrolactonization of -hydroxyl-acid using 2,2’-dipyridyl disulfide. Also known as Corey–Nicolaou double activation method.

OH

OH

O

n

SS

N

N

Ph3P On

O

SS

NN

Ph3P:S

PPh3

NHS NH

OH

O

O

n

SPPh3

NS

H

OH

O

O

n

PPh3

NH

OH

O

O

n

PPh3

S

N

O PPh3

NH

S

OO n

On

O

NH

S

O n

NH

S

O2-pyridinethione

165

Example 13

N

OHO

O

HO2C

PhPh H (2-pyr-S)2, PPh3

CHCl3, , 75%

N

HOO

O

O

PhPh

Example 26

OH

OH OMOM

O

O O(2-pyr-S)2, PPh3

AgClO4, , 33%

O

O

HOOH

OH

Dowex, MeOH

58%

References

1. Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614. 2. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). 3. Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117. 4. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475. 5. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169. 6. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780. 7. Lu, S.-F.; O'yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62,

8400. 8. Sasaki, T.; Inoue, M.; Hirama, M. Tetrahedron Lett. 2001, 42, 5299.

166

Corey–Seebach reaction

Dithiane as a nucleophile, serving as a masked carbonyl equivalent. This is an ex-ample of umpolung.

SH

SH

CH2(OMe)2

Et2O•BF3 S

S1. BuLi

2. Cl-(CH2)4-I80%

S

S

Cl

HgCl2, 50 oC

50%

OHC

Cl

S

S

HH

Bu

S

S

ClI

S

S

Cl

Example 16

CHO

SS

Ph

n-BuLi, THF

0 oC, 30 min. 99%

S S

Ph

HO

Ph

PhI(O2CCCl3)2

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

HO O

167

Example 28

O CHO SSPh

n-BuLi, THF, 78 to 0 oC

OOH

SS

Ph

References

1. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075, 1077. Dieter Seebach is a professor at ETH in Zürich, Switzerland.

2. Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. 3. Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300. 4. Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. 5. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. 6. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37,

307. 7. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518. 8. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454. 9. Bräuer, M.; Weston, J.; Anders, E. J. Org. Chem. 2000, 65, 1193.

168

Corey–Winter olefin synthesis

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

R

R1

OH

OH

N N

S

NN

R

R1 O

OS

P(OMe)3R

R1

H

H

R

R1

OH

OH

N N

S

NN

:

R

R1

O

OH

NS

N

NN

H

R

R1 OH

O

Imd

S R

R1 O

O

ImdS

R

R1 O

OS

:P(OMe)3R

R1 O

OS P(OMe)3

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

S P(OMe)3

R

R1 O

OP(OMe)3

R

R1 O

O

P(OMe)3

S

:P(OMe)3

R

R1

H

H O

OP(OMe)3 C OO P(OMe)3

169

A mechanism involving a carbene intermediate can also be drawn and is sup-ported by pyrolysis studies:

:P(OMe)3R

R1 O

OS

R

R1 O

OS P(OMe)3

S P(OMe)3

R

R1 O

O:P(OMe)3

R

R1

H

H

R

R1 O

OP(OMe)3

O

OP(OMe)3 :P(OMe)3 C OO

Example 17

O

OMOM

HO

HO CF3

N OMe Imd2CS, toluene

reflux, 79%

O

OMOMCF3

N OMeO

OS

P(OMe)3

92%

O

OMOM

N OMe

F3C

One olefin isomer Example 211

HO

HO

TBSOH

H

OMe

OAcCSCl2, DMAP

CH2Cl2, rt, 96%

170

O

O

TBSOH

H

OMe

OAcS

TBSOH

H

OMe

OAc(EtO)3P

reflux, 76%

References

1. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677. Roland A. E. Winter is at Ciba Specialty Chemicals Corporation, USA.

2. Horton, D.; Tindall, C. G., Jr. J. Org. Chem. 1970, 35, 3558. 3. Hartmann, W.; Fischler, H.-M.; Heine, H.-G. Tetrahedron Lett. 1972, 13, 853. 4. Block, E. Org. React. 1984, 30, 457. (Review). 5. Dudycz, L. W. Nucleosides Nucleotides 1989, 8, 35. 6. Carr, R. L. K.; Donovan, T. A., Jr.; Sharma, M. N.; Vizine, C. D.; Wovkulich, M. J.

Org. Prep. Proced. Int. 1990, 22, 245. 7. Kaneko, S.; Nakajima, N.; Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron 1998,

54, 5485. 8. Crich, D.; Pavlovic, A. B.; Wink, D. J. Synth. Commun. 1999, 29, 359. 9. Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J. Org. Chem. 2001, 66,

4180. 10. Saito, Y.; Zevaco, T. A.; Agrofoglio, L. A. Tetrahedron 2002, 58, 9593. 11. Araki, H.; Inoue, M.; Katoh, T. Synlett 2003, 2401.

171

Criegee glycol cleavage

Vicinal diol is oxidized to the two corresponding carbonyl compounds using Pb(OAc)4, lead tetraacetate (LTA).

R2 R4

OHHO

R1 R3 Pb(OAc)4

R1 R2

O

R3 R4

OPb(OAc)2 2 HOAc

Pb(OAc)3AcO

R2 R4

OHHO

R1 R3HOAc

R2 R4

OHO

R1 R3

(AcO)2Pb

OAc

R2 R4

R1 R3

O

Pb

O

OAcAcO

R1 R2

O

R3 R4

OPb(OAc)2HOAc

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

O:

OH

H Pb(OAc)3

O

O HOAc

O

O

Pb(OAc)2

O

O

AcO

H

PbII(OAc)2

O

O

HOAc

172

Example 17

N

OPh

CO2Et

OH

OH Pb(OAc)4, K2CO3

PhH, 0 oC, 80%

N

O

CO2Et

O

H

Example 29

HPhO2S

OHHO

HPb(OAc)4, CH2Cl2, K2CO3

15 oC to rt, 1 h, then

Ph3P=CHCO2Me, CH3CN, 80%

HPhO2S

CO2MeH

E:Z = 10:1

References

1 Criegee, R. Ber. Dtsch. Chem. Ges. 1931, 64, 260. 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, 2003.4 Danielmeier, K.; Steckhan, E. Tetrahedron: Asymmetry 1995, 6, 1181. 5 Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999, 1, 941. 6 Lautens, M.; Stammers, T. A. Synthesis 2002, 1993. 7 Hartung, I. V.; Eggert, U.; Haustedt, L. O.; Niess, B.; Schäfer, P. M.; Hoffmann, H. M.

R. Synthesis 2003, 1844. 8 Gaul, C.; Njardarson, J. T.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 6042. 9 Gorobets, E.; Stepanenko, V.; Wicha, J. Eur. J. Org. Chem. 2004, 783. 10 Mori, K.; Rikimaru, K.; Kan, T.; Fukuyama, T. Org. Lett. 2004, 6, 3095.

173

Criegee mechanism of ozonolysis

O3 OO

O

OO

O OO

O:1,3-dipolar

cycloaddition

primary ozonide (1,2,3-trioxolane)

OO

OO

O

O

1,3-dipolar

cycloaddition

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

Example 114

HO

HO

O3, EtOAc, 78 oC, then

Ac2O, Et3N, DMAP,

78 oC to rt, 75%

O

OH

H

O OAc

Example 215

O3, CH2Cl2

70 oC

O

CHOMe

O

O

O

MeOH

quant. CO2Me

CO2Me

References

1. Criegee, R.; Wenner, G. Justus Liebigs Ann. Chem. 1949, 564, 9. 2. Criegee, R. Rec. Chem. Prog. 1957, 18, 111. 3. Criegee, R. Angew. Chem. 1975, 87, 765. 4. Klopman, G.; Joiner, C. M. J. Am. Chem. Soc. 1975, 97, 5287. 5. Bailey, P. S.; Ferrell, T. M. J. Am. Chem. Soc. 1978, 100, 899.

174

6. Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363. 7. Wojciechowski, B. J.; Pearson, W. H.; Kuczkowski, R. L. J. Org. Chem. 1989, 54,

115. 8. Bunnelle, W. H. Chem. Rev. 1991, 91, 335 362. (Review). 9. Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 79 83. (Review). 10. Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675. 11. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757. 12. Anglada, J. M.; Crehuet, R.; Maria Bofill, J. Chem. Eur. J. 1999, 5, 1809. 13. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377. 14. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150. 15. Schank, K.; Beck, H.; Pistorius, S. Helv. Chim. Acta 2004, 87, 2025.

175

Curtius rearrangement

Thermal or photochemical rearrangement of acyl azides into amines via isocy-anate intermediates. While the thermal rearrangement is a concerted process, the photochemical rearrangement goes through a nitrene intermediate.

The thermal rearrangement:

R Cl

O NaN3

R N3

O

R N C ON2

H2OR NH2 CO2

R Cl

O

R N

O

N3N NR N3

O

R Cl

N3O

R N

O

N NN2

R N C O

:OH2

H+

isocyanate intermediate

R NH2 CO2R

HN O

O

H

:B

The photochemical rearrangement:

R N

O

N NN2

h

R N:

O

nitrene

R N

O

R N C O R NH2 CO2

176

Example 19

O

O O

CO2MeHO2C DPPA, Et3N, t-BuOH

80 oC, 16 h, 64%

O

OO

CO2MeBocHN

Example 211

OOCO2H

EtO(CO)Cl, then NaN3

EtOH, PhH, reflux, 55% OONHCO2Et

References

1. Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023. 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 de-rivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and com-posed music.

2. Chen, J. J.; Hinkley, J. M.; Wise, D. S.; Townsend, L. B. Synth. Commun. 1996, 26,617.

3. am Ende, D. J.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Org. Process Res. Dev.1998, 2, 382.

4. Braibante, M. E. F.; Braibante, H. S.; Costenaro, E. R. Synthesis 1999, 943. 5. Migawa, M. T.; Swayze, E. E. Org. Lett. 2000, 2, 3309. 6. El Haddad, M.; Soukri, M.; Lazar, S.; Bennamara, A.; Guillaumet, G.; Akssira, M. J.

Heterocycl. Chem. 2000, 37, 1247. 7. Moore, J. D.; Sprott, K. T.; Hanson, P. R. J. Org. Chem. 2002, 67, 8123. 8. Mamouni, R.; Aadil, M.; Akssira, M.; Lasri, J.; Sepulveda-Arques, J. Tetrahedron

Lett. 2003, 44, 2745. 9. 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. 10. Kedrowski, B. L. J. Org. Chem. 2003, 68, 5403. 11. Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455. 12. Holt, J.; Andreassen, T.; Bakke, J. M.; Fiksdahl, A. J. Heterocycl. Chem. 2005, 42,

259.

177

Dakin oxidation

Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen per-oxide conditions. Cf. Baeyer–Villiger oxidation.

HO CHOH2O2, NaOH

45 50 oCHO OH HCO2H

OO

H

HOH

OHO

O

HO

HO

aryl

migration

OHO

H OHO

hydrolysisHO OH

O

OH

HO2CHHO OHHO O CHO2

Example 16

OBnCHO

NHCO2t-Bu

CO2H

2.5 eq. 30% H2O2

4% (PhSe)2, CH2Cl2, 18 h

OBnO

NHCO2t-Bu

CO2H

CHONH3, MeOH, 1 h

78%

OBnOH

NHCO2t-Bu

CO2H

178

Example 27

HO

CHO urea-hydrogen peroxide (UHP)

solvent-free, 55 oC, 3 h, 83% HO

OH

References:

1. Dakin, H. D. J. Am. Chem. Soc. 1909, 42, 477. Henry D. Dakin (1880 1952) was born in London, England. During WWI, he invented his hypochlorite solution (Da-kin’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. 3. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740. 4. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett.

1993, 34, 7401. 5. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado,

L. A. Synth. Commun. 1995, 25, 2121. 6. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. 7. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189. 8. Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synth. Commun. 1999,

29, 3781. 9. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg.

Med. Chem. Lett. 2001, 11, 51.

179

Dakin West reaction

The direct conversion of an -amino acid into the corresponding -acetylamino-alkyl methyl ketone, via oxazoline (azalactone) intermediates. The reaction pro-ceeds in the presence of acetic anhydride and a base such as pyridine with the evo-lution of CO2.

R CO2H

NH2

Ac2O R

NHAc

O

CO2

R CO2H

NH2

O

OO

R

HN

O

OH

O

OO

AcO

R

NH

OOH

OH+

:

H

NO

R OHO

H

NO

RO OH

O

NO

RO

H

O

OH

AcO H

H

oxazolone (azalactone) intermediate

HN O

RO

O

O

H N OH

RO

H

R

NHAc

OCO2 tautomerization

Example 112

Me CO2H

NH2

Me

NHAc

Me

OAc2O, AcOH, Et3N

DMAP, 50 oC, 14 h, > 90%

180

Example 214

NH

OBn

O OOHO

Ac2O, pyr.

90 oC, 2 h, 58%NH

OBn

O OO Me

References:

1. Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Da-kin and Rudolf West, a clinician, reported on the reaction of -amino acids with acetic anhydride to give -acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and -phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an op-portunity to be immortalized by a name reaction.

2. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1927, 74, 689. 3. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1928, 79, 95. 4. Cornforth, J. W.; Elliott, D. F. Science 1950, 112, 534. 5. Allinger, N. L.; Wang, G. L.; Dewhurst, B. B. J. Org. Chem. 1974, 39, 1730. 6. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91. (Review). 7. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. 8. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Com-

mun. 1998, 641. 9. Kawase, M.; Okada, Y.; Miyamae, H. Heterocycles 1998, 48, 285. 10. Kawase, M.; Hirabayashi, M.; Kumakura, H.; Saito, S.; Yamamoto, K. Chem. Pharm.

Bull. 2000, 48, 114. 11. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4,

. (Review). 12. Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581. 13. Orain, D.; Canova, R.; Dattilo, M.; Klöppner, E.; Denay, R.; Koch, G.; Giger, R.

Synlett 2002, 1443. 14. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.

Org. Chem. 2003, 68, 2623. 15. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105.

181

Danheiser annulation

Trimethylsilylcyclopentene annulation from an -unsaturated ketone and trimethylsilylallene in the presence of a Lewis acid.

O

SiMe3

O

SiMe3

TiCl4, CH2Cl2

75 oC, 82%

OCl3Ti

Cl Cl

SiMe3

OCl3Ti

SiMe3

OCl3Ti

SiMe3

1,2-shift of

silyl group

Transition State

Cl

OCl3Ti

SiMe3

O

SiMe3

182

Example 17

SiMe3TiCl4, CH2Cl2

78 oC

O

OMeO

O

OMe

O

OMe

O

Me3Si

O

OMeO

OH

48% 6% 15%

Example 28

O

SiMe3TiCl4, CH2Cl2

75 oC, 91%

O

Me3Si

H

H

O

Me3Si

H

H

(1:1)

References

1. Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1981, 103, 1604. Rick L. Danheiser earned his Ph.D. at Harvard under E. J. Corey. He is a professor at MIT.

2. Danheiser, R. L.; Carini, D. J.; Fink, D. M.; Basak, A. Tetrahedron 1983, 39, 935. 3. Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233. 4. Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem. 1986, 51, 3870. 5. Danheiser, R. L.; Tsai, Y.-M.; Fink, D. M. Org. Synth. 1988, 66, 1. 6. Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. J. Org. Chem. 1992, 57, 6094. 7. Engler, T. A.; Agrios, K.; Reddy, J. P.; Iyengar, R. Tetrahedron Lett. 1996, 37, 327. 8. Friese, J. C.; Krause, S.; Schäfer, H. J. Tetrahedron Lett. 2002, 43, 2683.

183

Darzens glycidic ester condensation

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

R CO2Et

X

R1 R2

O OEtO

R1

R2 CO2EtR

R

XH

OEt

R

XR1 R2

O

OEt

OOEt

O

R2 RO

R1

XCO2Et

OR1

R2 CO2EtR

intramolecular

SN2

Example 14

OCl CO2Et

OCO2Et+

t-BuOK, t-BuOH

10°C, 85–95%

Example 29

H3C Br

t-BuMe2Si

O LDA, THF, –78 °C then H3C

t-BuMe2Si

O OPh

H

H

66%, 90% dePhCHO, –90 °C

References

1 Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214. George Auguste Darzens (1867 1954) born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor.

2 Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review).

184

3 Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). 4 Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. 1963, 4, 459. 5 Bauman, J. G.; Hawley, R. C.; Rapoport, H. J. Org. Chem. 1984, 49, 3791. 6 Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis;

Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, vol. 2, pp 409–439. (Re-view).

7 Takahashi, T.; Muraoka, M.; Capo, M.; Koga, K. Chem. Pharm. Bull. 1995, 43, 1821. 8 Ohkata, K.; Kimura, J.; Shinohara, Y.; Takagi, R.; Hiraga, Y. Chem. Commun. 1996,

2411. 9 Enders, D.; Hett, R. Synlett 1998, 961. 10 Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga, Y.; Kojima,

S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 689. 11 Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc.,

Perkin Trans. 1 2000, 825. 12 Shinohara, Y.; Ohba, Y.; Takagi, R.; Kojima, S.; Ohkata, K. Heterocycles 2001, 55, 9. 13 Arai, A.; Suzuki, Y.; Tokumaru, K.; Shioiri, T. Tetrahedron Lett. 2002, 43, 833. 14 Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68,

2410. 15 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, 15 21. (Review).

185

Davis chiral oxaziridine reagents

Chiral N-sulfonyloxaziridines employed for asymmetric hydroxylation, etc.

ON

RSO2

Are.g.

SN

OO O

ClCl

ON

RSO2

ArR

R1

O

M

RR1

O

O M

ON

SO2R

Ar

RR1

O

M

RR1

O

O

N

Ar

RSO2

RR1

O

O M

Ar NSO2R

Example 12

ON

PhSO2

Ph

ON

OO

PhON

OO

Ph

OH

1. NaHMDS, THF, 78 oC

85%, 90% de

2. THF, 78 oC

3. camphor sulfonic acid, THF

186

Example 25

NaHMDS, THF, 78 oC

61%, 95% eePh

O

SN

OO O

ClCl

Ph

O

OH

References

1 Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J. Org. Chem. 1984, 49,3241. Franklin A. Davis developed this methodology while teaching at Drexel Uni-versity, now he is at Temple University.

2 Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc. 1985, 107, 4346. 3 Davis, F. A.; Billmers, J. M.; Gosciniak, D. J.; Towson, J. C.; Bach, R. D. J. Org.

Chem. 1986, 51, 4240. 4 Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703. (Review). 5 Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715. 6 Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919 934. (Review). 7 Davis, F. A.; Thimma Reddy, R.; Weismiller, M. C. J. Am. Chem. Soc. 1989, 111,

5964. 8 Davis, F. A.; Kumar, A.; Chen, B.-C. J. Org. Chem. 1991, 56, 1143. 9 Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J. J. Am. Chem. Soc. 1992, 114, 1428. 10 Tagami, K.; Nakazawa, N.; Sano, S.; Nagao, Y. Heterocycles 2000, 53, 771. 11 Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031. 12 Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React. 2003, 62, 1 356. (Re-

view).

187

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 amine and Sommelet reaction, where the product is aldehyde. The Delépine works well for active halides such as benzyl, allyl halides, and -halo-ketones.

Ar X NN

N

N

NN

N

NAr

X ArHX NH3

X

hexamethylenetetramine

[ArCH2-C6H12N4]+X + 3HCl + 6H2O

= ArCH2NH2•HX + 6CH2O + 3NH4Cl

NN

N:

N

NN

N

NAr

Ar X

SN2

X

:

NN

N

NAr

H2O:

NN

N

NAr

HO H

OCH2 N

NN

NAr

H

Ar NH3

X

Example 14

Br OH

O1. (CH2)6N4, NaHCO3 15 h, EtOH, H2O

2. HCl, EtOH, reflux, 15 h, 85% H2N OH

O

188

Example 28

NN

BrBr

hexamethylenetetramine

CH2Cl2, refux, 5 h, then

30 oC

NN

BrN4C6H12

+Br

conc. HCl, EtOH

reflux, 1 d78%, 2 steps

NN

BrNH2

References

1. Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 355; 1897, 17, 290. 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 chemis-try, and pharmacy.

2. Delépine, M. Compt. Rend. Acad. Sci. 1895, 120, 501. 1897, 124, 292. 3. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585. 4. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375. 5. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979,

512. 6. Blažzevi , N.; Kolnah, D.; Belin, B.; Šunji , V.; Kafjež, F. Synthesis 1979, 161. (Re-

view).7. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org.

Chem. 1990, 55, 1796. 8. Charbonnière, L. J.; Weibel, N.; Ziessel, R. Synthesis 2002, 1101.

189

de Mayo reaction

[2 + 2] Photochemical cyclization of enones with olefins is followed by a retro-aldol reaction to give 1,5-diketones.

O

OH

CO2Me h

OCO2Me

OH

O

O CO2Me

O

OH

h , [2 + 2]

cycloadditionCO2Me

O

OHCO2Me

head-to-tail alignment

retro-aldol

cyclobutane cleavage

O

O CO2Me

H O

O CO2Me

O

OH

CO2Me

Minor regioisomer:

O

CO2Me

OH

h , [2 + 2]

cycloaddition

O

OH

CO2Me

head-to-head alignment

retro-aldol

cyclobutane cleavage

O

O

H O

O

CO2Me CO2Me

O

O

CO2Me

H

190

Example 15

OPh

O

O

1. h , cyclohexane, 83%

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

O

Example 29

O

OH

h , MeOH

> 90%

O

HO

O

O

H

H

H

H

References

1. 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, Uni-versity of London. He later became a professor at the University of Western Ontario in London, Ontario, Canada, where he discovered the de Mayo reaction.

2. Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86,5570.

3. Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969,34, 794.

4. de Mayo, P. Acc. Chem. Res. 1971, 4, 49. (Review). 5. Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583. 6. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). 7. Pearlman, B. A. J. Am. Chem. Soc. 1979, 101, 6398. 8. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845. 9. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905. 10. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297 588. (Review). 11. Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939. 12. Blaauw, R. H.; Brière, J.-F.; de Jong, R.; Benningshof, J. C. J.; van Ginkel, A. E.;

Fraanje, J.; Goubitz, K.; Schenk, H.; Rutjes, F. P. J. T.; Hiemstra, H. J. Org. Chem.2001, 66, 233.

13. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603. 14. Kemmler, M.; Herdtweck, E.; Bach, T. Eur. J. Org. Chem. 2004, 4582.

191

Demjanov rearrangement

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

NH2

HNO2

OHOH

2 HON

OH+

H2ON

O

H2OON

OH

ON

ON

O

ON

ON

O

N N OHNO2

NH2

:

H

N N OH2

H+

:

H2O

N NN N OH

N2N OH

N

OH

H

: H+

N2

OH

OH

H

NN

:

H+or

Example 17

HNH2 NaNO2, AcOH/H2O

100 110 oC, 2 h, 61%

H OH

192

Example 29

O

NH2

NaNO2, 0 4 oC

0.25 M H2SO4/H2O

O

HO

O

OH

References

1. Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26. Nikolai J. Demjanov (1861 1938) was a Russian chemist.

2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157 188. (Review). 3. Kotani, R. J. Org. Chem. 1965, 30, 350. 4. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840. 5. Alam, S. N.; MacLean, D. B. Can. J. Chem. 1965, 43, 3433. 6. Cooper, C. N.; Jenner, P. J.; Perry, N. B.; Russell-King, J.; Storesund, H. J.; Whiting,

M. C. J. Chem. Soc., Perkin Trans. 2 1982, 605. 7. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289. 8. Uyehara, T.; Kabasawa, Y.; Furuta, T.; Kato, T. Bull. Chem. Soc. Jpn. 1986, 59, 539. 9. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649.

193

Tiffeneau–Demjanov rearrangement

Carbocation rearrangement of -aminoalcohols via diazotization to afford car-bonyl compounds through C C bond migration.

OH

NH2

NaNO2

H+

O

Step 1, Generation of N2O3

HON

OH+

H2ON

O

H2OON

OH

ON

ON

O

H+

Step 2, Transformation of amine to diazonium salt

ON

ON

OOH

NH2

OH

N:

HN OHONO

OH

N N OH2+

H+

:

H2O OH

NN

OH

N N OH

Step 3, Ring-expansion via rearrangement

ON2

OH H+O

NN H

:

Example 110

NH2

OHNaNO2, AcOH/H2O, 0 oC, 1 h

then reflux 1 h, 98%O

194

Example 212

SiMe3

HO NH2 NaNO2

AcOH

O O

SiMe3

SiMe3

72% 28%

References

1. Tiffeneau, M.; Weill, P.; Tehoubar, B. Compt. Rend. 1937, 205, 54. 2. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157. (Review). 3. Jones, J. B.; Price, P. J. Chem. Soc.,D. 1969, 1478. 4. Parham, W. E.; Roosevelt, C. S. J. Org. Chem. 1972, 37, 1975. 5. McKinney, M. A.; Patel, P. P. J. Org. Chem. 1973, 38, 4059. 6. Jones, J. B.; Price, P. Tetrahedron 1973, 29, 1941. 7. Dave, V.; Stothers, J. B.; Warnhoff, E. W. Can. J. Chem. 1979, 57, 1557. 8. Haffer, G.; Eder, U.; Neef, G.; Sauer, G.; Wiechert, R. Justus Liebigs Ann. Chem.

1981, 425. 9. Thomas, R. C.; Fritzen, E. L. J. Antibiotics 1988, 41, 1445. 10. Stern, A. G.; Nickon, A. J. Org. Chem. 1992, 57, 5342. 11. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649. 12. Chow, L.; McClure, M.; White, J. Org. Biomol. Chem. 2004, 2, 648.

195

Dess Martin periodinane oxidation

Oxidation of alcohols to the corresponding carbonyl compounds using triace-toxyperiodinane.

R1 R2

OHO

I

O

AcOOAc

OAc

R1 R2

O

OI

O

AcOO

OAc

OI

O

AcOOAc

OAc:OH

R1

H

R1R2R2 OAc

OI

O

OAcH

OO R1 R2

O

Example 19

OI

O

AcOOAc

OAc

O

OOOH

OCH2Cl2, 2 h, 67% O

OOO

O

Example 215

OI

O

AcOOAc

OAc

NaN3, CH2Cl20 oC, 3 h, 86%

N

CHO

N

N3

O

196

References

1. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. James Cullen (J. C.) Martin (1928 1999) had a distinguished career spanning 36 years both at the University of Il-linois 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 Har-vard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that led to his land-mark 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 de-hydration, page 365) and the Dess-Martin periodinane have found widespread applica-tion in synthetic organic chemistry. J. C. Martin and his student Daniel Dess devel-oped this methodology at the University of Illinois at Urbana. (Martin’s biography is kindly supplied by Prof. Scott E. Denmark).

2. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. 3. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. 4. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588 590. (Review). 5. Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760. 6. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622. 7. Jenkins, N. E.; Ware, R. W., Jr.; Atkinson, R. N.; King, S. B. Synth. Commun. 2000,

30, 947. 8. Promarak, V.; Burn, P. L. J. Chem. Soc., Perkin 1 2001, 14. 9. Bach, T.; Kirsch, S. Synlett 2001, 1974. 10. Wavrin, L.; Viala, J. Synthesis 2002, 326. 11. Wellner, E.; Sandin, H.; Pääkkönen, L. Synthesis 2003, 223. 12. Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575. 13. Bose, D. S.; Reddy, A. V. N. Tetrahedron Lett. 2003, 44, 3543. 14. Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111 124. (Review). 15. Deng, G.; Xu, B.; Liu, C. Tetrahedron 2005, 61, 5818.

197

Dieckmann condensation

The Dieckmann condensation is the intramolecular version of the Claisen conden-sation.

CO2Et

CO2Et NaOEt O

CO2Et

CO2Et O

OEtH O OEt

OOEt

enolate

formation

5-exo-trig

ring closure

OEt

CO2Et

OEtO O

CO2Et

Example 17

N

H OBn

OTBSO

MeO2CN

MeO2C

H OBn

OTBS

MeO2C

NaHMDS, THF

78 oC, 58%

Example 29

O

ON

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

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

MeO2C

ON

EtO2C

198

References

1. Dieckmann, W. Ber. Dtsch. Chem. Ges. 1894, 27, 102. Walter Dieckmann (1869 1925), born in Hamburg, Germany, studied with E. Bamberger at Munich. Af-ter serving as an assistant to von Baeyer in his private laboratory, he became a profes-sor 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. Toda, F.; Suzuki, T.; Higa, S. J. Chem. Soc., Perkin Trans. 1 1998, 3521. 4. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507. 5. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32,

563. 6. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403. 7. Rabiczko, J.; Urba czyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58,

1433. 8. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003,

68, 109. 9. de Sousa, A. L.; Pilli, R. A. Org. Lett. 2005, 7, 1617.

199

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 illus-trative.

Normal Diels–Alder reaction

EDGEWG

EDG

EWG

diene dienophile adduct

EDG = electron-donating group; EWG = electron-withdrawing group

Example 113

OMeCO2Et

Me3SiO

OMe

CO2EtH

Me3SiO

AcO

OAc

hydroquinone

180 oC, 1.5 h, 62%

Danishefsky diene Alder’s endo rule

OMe

CO2Et

AcO

OMe

CO2Et

Me3SiO AcO OSiMe3

EtO2C

4:1 -OMe : -OMeExample 217

O

O

F

Br4-BIPOL, AlMe3

CH2Cl2, rt, 8 h, 65%

O

OF

H

200

Inverse electronic demand Diels–Alder reaction

EWGEDG

EWG

EDG

diene dienophile adduct

Example 12

CO2Me CO2MeN N

Hetero-Diels–Alder reaction

Heterodiene addition to dienophile

N

SO2Ph

OEt

Ph

NSO2Ph

Ph OEtH

EtO2CEtO2C

N

SO2Ph

Ph

EtO2C OEt

Example 1, the Boger pyridine synthesis (see page 67)8

MeO

OMe

OMeMeO N

N NN

CO2Me

CO2Me

CHCl3, reflux

5 days, 65%

NN

N N

CO2Me

MeO2C

MeOMeO

MeO2C CO2Me

201

Heterodienophile addition to diene2

CO2Et

O

MeO

O

CO2EtMeOtoluene

110 oC, 60%

Example 2, using the Rawal diene9

OTBS

O

CO2MeMe

NMe2 CHCl3, 40 oC

71%

O

OMe

MeO2C

References

1. Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98. 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 ex-plicitly reserve for ourselves the application of the reaction developed by us to the so-lution of such problems.”

2. Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390. 3. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142. 4. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 315 399. (Review). 5. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 451 512. (Review). 6. Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;

Pergamon, 1991, Vol. 5, 401 449. (Review). 7. Wasserman, H. H.; DeSimone, R. W.; Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc.

1993, 115, 8457. 8. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418. 9. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321. 10. Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278. (Review). 11. Yli-Kauhaluoma, J. Tetrahedron 2001, 57, 7053. (Review). 12. Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42, 6231. 13. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478. 14. JØrgensen, K. A. Eur. J. Org. Chem. 2004, 2093. (Review). 15. Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (Review). 16. Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,

Int. Ed. 2002, 41, 1668. (Review). 17. Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J. Fluorine Chem.

2005, 126, 709.

202

Dienone–phenol rearrangement

Acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4-disubstituted phenols.

O

R R

H+

OH

R

R

O

R R

H+

OH

R

O

R R

H OH

R

RH RH

H+:

1,2-alkyl

shift

Example 14

O

O

O

50% aq. H2SO4

reflux, 80%

O

HO

O

Example 25

O OH

HO conc. H2SO4

Et2O, 95%

HO

References

1. Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 5568. (Re-view).

2. Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105.

203

3. Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824. 4. Hart, D. J.; Kim, A.; Krishnamurthy, R.; Merriman, G. H.; Waltos, A.-M. Tetrahedron

1992, 48, 8179. 5. Frimer, A. A.; Marks, V.; Sprecher, M.; Gilinsky-Sharon, P. J. Org. Chem. 1994, 59,

1831. 6. Oshima, T.; Nakajima, Y.-i.; Nagai, T. Heterocycles 1996, 43, 619. 7. Draper, R. W.; Puar, M. S.; Vater, E. J.; Mcphail, A. T. Steroids 1998, 63, 135. 8. Banerjee, A. K.; Castillo-Melendez, J. A.; Vera, W.; Azocar, J. A.; Laya, M. S. J.

Chem. Res., (S) 2000, 324. 9. Kumar, V. S.; Nagaraja, B. M.; Shashikala, V.; Seetharamulu, P.; Padmasri, A. H.;

Raju, B. D.; Rao, K. S. R. J. Mol. Catal. A: Chemical 2004, 223, 283. 10. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K.; Node, M. Tetrahedron 2004, 60,

4901.

204

Di- -methane rearrangement

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

R1R

R4 R3

R2h

R1RR2

R4R3

1,4-diene vinylcyclopropane

R1R

R4 R3

R2 hR1R

R4 R3

R2

diradical

R1RR2

R4R3

R1R

R4 R3

R2

diradical

Example 19

CN

CN

h , acetone

90%

CN

CN

Example 2, aza- -methane rearrangement2

h , acetophenone

benzene, 86%Ph

N OAcPh

Ph

PhN

OAc

205

References

1. Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc. 1966, 88, 183. Howard E. Zimmerman is a professor at the University of Wisconsin at Madison.

2. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc. Perkin Trans. I 1991, 223.

3. Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065. (Review). 4. Janz, K. M.; Scheffer, J. R. Tetrahedron Lett. 1999, 40, 8725. 5. Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365. 6. Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin 1 2000, 3791. 7. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341. 8. Ihmels, H.; Mohrschladt, C. J.; Grimme, J. W.; Quast, H. Synthesis 2001, 1175. 9. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365. 10. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org.

Chem. 2002, 526. 11. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155. 12. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44,

751. 13. Singh, V.; Vedantham, P.; Sahu, P. K. Tetrahedron 2003, 60, 8161. 14. Frutos, L. M.; Sancho, U.; Castano, O. J. Phys. Chem. A 2005, 109, 2993.

206

Doebner quinoline synthesis

Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid.

NH2 OHCN

CO2H

CO2H

O

NH2:

NH

OH2O

HH

:

H2O

CO2H

OH

N

H

H+

NH

O CO2H

N

CO2HHOH

HNH

CO2HH2O

HH+

B:

N

CO2H

NH

CO2H

air oxidation

2 H

H2O

207

Example 12

MeO

NH2

O

HO

CO2HNO2

MeO

N

CO2H

NO2EtOH, , 95%

Example 26

NH2CO2H

O H

O

N

CO2H

EtOH, reflux

3 h, 20%

References

1. Doebner, O. G. Justus Liebigs Ann. Chem. 1887, 242, 265. Oscar Gustav Doebner (1850 1907) was born in Meiningen, Germany. After studying under Liebig, he ac-tively 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.

2. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520. 3. Allen, C. F. H.; Spangler, F. W.; Webster, E. R. J. Org. Chem. 1951, 16, 17. 4. 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).

5. Jones, G. in Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125 131. (Review).

6. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396. 7. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119. 8. Pflum, D. A. Doebner Quinoline Synthesis In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 407 410. (Re-view).

208

Dötz reaction

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

R1 R2

(OC)5CrOR

RL RS

RL

RS

ORR1

OH

Cr(CO)3

R2

R1 R2

(OC)5CrOR

COOR

R1 R2

(OC)4Cralkyne

coordination

RSRL

OR

COOCOC CO

Cr

R2R1

RL RS

R1 R2

(OC)4CrOR

R3

alkyne insertion

Cr

R2R1

RS

RL

OR

COOC CO

COCO insertion electrocyclic

ring closure

Cr(CO)3

ORL

RS

ORR1

RL

RS

ORR1

OH

Cr(CO)3

tautomerizationR2

R2

209

Example 17

SeNO2

(OC)5CrOMe

1. THF, reflux

2. CAN, 22%

O

O

SeNO2

Example 211

BnO

MOMO MeO

Cr(CO)5

OMe

THF, 50 oC, 61%OH

MeOOMe

OMOM

BnO

References

1. Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644. Karl H. Dötz (1943 ) was a pro-fessor at the University of Munich in Germany.

2. Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Soc. 1981, 103, 7677. 3. Wulff, W. D. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., ed.; JAI

Press, Greenwich, CT; 1989; Vol. 1. (Review). 4. 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). 5. Torrent, M. Chem. Commun. 1998, 999. 6. Torrent, M.; Solá, M.; Frenking, G. Chem. Rev. 2000, 100, 439. (Review). 7. Caldwell, J. J.; Colman, R.; Kerr, W. J.; Magennis, E. J. Synlett 2001, 1428. 8. Jackson, T. J.; Herndon, J. W. Tetrahedron 2001, 57, 3859. 9. Solá, M.; Duran, M.; Torrent, M. The Dötz reaction: A chromium Fischer carbene-

mediated benzannulation reaction. In Computational Modeling of Homogeneous Ca-talysis Maseras, F.; Lledós, A. eds.; Kluwer Academic: Boston; 2002, 269 287. (Re-view).

10. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511. 11. White, J. D; Smits, H. Org. Lett. 2005, 7, 235.

210

Dowd Beckwith ring expansion

Radical-mediated ring expansion of 2-halomethyl cycloalkanones.

OBr

CO2CH3

Bu3SnH, AIBN

PhH, reflux

O

CO2CH3

N N CNNC CNN2 2homolyticcleavage

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H CN n-Bu3Sn CNH

SnBu3

OBr

CO2CH3

O

CO2CH3Bu3SnBr

O

CO2CH3

O

CO2CH3

SnBu3H

Bu3Sn

O

CO2CH3

211

Example 19

1.2 eq. Bu3SnH, cat. AIBN

Tol., reflux, 23 h

H

CO2EtH

I

O

H

H

H

CO2EtH

H

O

CO2Et86% 13%

O

References

1. Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493. Paul Dowd (1936 1996) was a professor at the University of Pittsburgh.

2. Beckwith, A. L. J.; O’Shea, D. M.; Gerba, S.; Westwood, S. W. J. Chem. Soc., Chem. Commun. 1987, 666. Athelstan L. J. Beckwith is a professor at University of Ade-laide, Adelaide, Australia.

3. Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110,2565.

4. Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77. 5. Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129. 6. Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847. 7. Bowman, W. R.; Westlake, P. J. Tetrahedron 1992, 48, 4027. 8. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091. (Review). 9. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525. 10. Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1998, 54, 8355. 11. Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E. Tetrahedron Lett. 1998, 39, 4059. 12. Hasegawa, E.; Yoneoka, A.; Suzuki, K.; Kato, T.; Kitazume, T.; Yanagi, K. Tetrahe-

dron 1999, 55, 12957. 13. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080. 14. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317. (Review). 15. Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171. 16. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691.

212

Erlenmeyer Plöchl azlactone synthesis

Formation of 5-oxazolones (or ‘azlactones’) by intramolecular condensation of acylglycines in the presence of acetic anhydride.

O

HN

R1 O

N

OR1

Ac2OCO2H

O

HN

R1

O

OH

O

O O

O

N

R1

O

O

H

O

mixed anhydride

AcO

O

N

OR12 AcOH

Example14

O

HN

PhCO2H

OO

H

O

O

N

OPh

O

O

NaOAc, Ac2O

110 oC, 69 73%

References

1. Plöchl, J. Ber. Dtsch. Chem. Ges. 1884, 17, 1616. 2. Erlenmeyer, E., Jr. Ann. 1893, 275, 1. 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.

3. Carter, H. E. Org. React. 1946, 3, 198 239. (Review). 4. Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150. (Review).

213

5. Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Het-erocyclic Chem; Katritzky, A. R. and Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp. 175 206. (Review).

6. Kumar, P.; Mishra, H. D.; Mukerjee, A. K. Synthesis 1980, 10, 836. 7. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995. (Review). 8. Mukerjee, A. K. Heterocycles 1987, 26, 1077. (Review). 9. Cornforth, J.; Ming-hui, D. J. Chem. Soc. Perkin Trans. I 1991, 2183. 10. Ivanova, G. G. Tetrahedron 1992, 48, 177. 11. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419. 12. Monk, K. A.; Sarapa, D.; Mohan, R. S. Synth. Commun. 2000, 30, 3167. 13. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 27. 14. Buck, J. S.; Ide, W.S. Org. Synth. Coll. 1943, 2, 55.15. Brooks, D. A. Erlenmeyer Plöchl Azlactone Synthesis in Name Reactions in Hetero-

cyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005,229 233. (Review).

214

Eschenmoser Tanabe fragmentation

Fragmentation of -epoxyketones via the intermediacy of -epoxy sulfonyl-hydrazones.

O

1. H2O2, OH

2. H2NNHSO2Ar, H+

3. OH

O

O

O OH

O

OOH

O

O

N

OH2NNHSO2Ar, H+

NH

SO2Ar

OH

N

O

N SO2Ar

NN SO2Ar

O

SO2Ar N2

O

Example 14

O

OAcO

Tol-SO2NHNH2CHCl3-AcOH (1:1)

rt, 5 h, 73%

215

AcO

O

Example 27

Me

MeOO

1. TsNHNH2, rt

2. 55 oC, 2 h, 50% O

Me

Me

References

1. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708. Albert 2. 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.

3. Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron Lett. 1967, 3943. 4. Felix, D.; Müller, R. K.; Horn, U.; Joos, R.; Schreiber, J.; Eschenmoser, A. Helv.

Chim. Acta 1972, 55, 1276. 5. Batzold, F. H.; Robinson, C. H. J. Org. Chem. 1976, 41, 313. 6. Covey, D. F.; Parikh, V. D. J. Org. Chem. 1982, 47, 5315. 7. 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. 8. Dai, W.; Katzenellenbogen, J. A. J. Org. Chem. 1993, 58, 1900. 9. Abad, A.; Arno, M.; Agullo, C.; Cuñat, A. C.; Meseguer, B.; Zaragoza, R. J. J. Nat.

Prod. 1993, 56, 2133. 10. Mück-Lichtenfeld, C. J. Org. Chem. 2000, 65, 1366.

216

Eschweiler–Clarke reductive alkylation of amines

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

R NH2 CH2O HCO2H R N

formic acid is the hydrogen source as a reducing agent

R NH2

O

: R NOH2

H

H

H

HR N

OH

H

H+

R NH O

HO C OO

R NH

:

OH

H

H

R NOH2:H+

R NH O

HO

R NC OO H R NH+

Example 17

NH

OO Pd/C/Na2SO4, H2 40 bar

EtOAc, 100 oC, 98%

N O

217

Example 211

H3C

ONHCH3

DCOD, DCO2D, DMSO

microwave (120 W), 1-3 min.

d3-tamoxifen

H3C

ON

CD3

CH3

References

1 Eschweiler, W. Chem. Ber. 1905, 38, 880. Wilhelm Eschweiler (1860 1936) was born in Euskirchen, Germany.

2 Clarke, H. T.; Gillespie, H. B.; Weisshaus, S. Z. J. Am. Chem. Soc. 1933, 55, 4571. Hans T. Clarke (1887 1927) was born in Harrow, England.

3 Moore, M. L. Org. React. 1949, 5, 301. (Review). 4 Pine, S. H.; Sanchez, B. L. J. Org. Chem. 1971, 36, 829. 5 Bobowski, G. J. Org. Chem. 1985, 50, 929. 6 Alder, R. W.; Colclough, D.; Mowlam, R. W. Tetrahedron Lett. 1991, 32, 7755. 7 Fache, F.; Jacquot, L.; Lemaire, M. Tetrahedron Lett. 1994, 35, 3313. 8 Bulman Page, P. C.; Heaney, H.; Rassias, G. A.; Reignier, S.; Sampler, E. P.; Talib, S.

Synlett 2000, 104. 9 Torchy, S.; Barbry, D. J. Chem. Res. Synop. 2001, 292. 10 Rosenau, T.; Potthast, A.; Röhrling, J.; Hofinger, A.; Sixta, H.; Kosma, P. Synth.

Commun. 2002, 32, 457. 11 Harding, J. R.; Jones, J. R.; Lu, S.-Y.; Wood, R. Tetrahedron Lett. 2002, 43, 9487. 12 Chen, F.-L.; Sung, K. J. Heterocycl. Chem. 2004, 41, 697.

218

Evans aldol reaction

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

ON

OO

1. Bu2BOTf, R3N

2. PhCHO, 78 oC

ON

OO

Ph

OH

ON

OO

H

R3N:

Bu2B OTf

Z-(O)-boron enolate

formation

ON

OOB

BuBu

PhCHO

ON

OO

Ph

O

O

BO Bu

Bu

Ph

HN

O

OH aldol

condensationH

BBuBu

ON

OO

Ph

OH

workup

Example 17

ON

OOMeO

N OMeCO2Me

219

TiCl4, DIPEA

CH2Cl2 78 oC, 1.5 h

then rt, overnight, 52%

ON

OO

NMeO2C

OMe

Example 213

OTES

O

NO

S

Bn

O

OBn

1 eq. Bu2BOTf, 1.1 eq. Et3N

PhMe, 0.15 M, 50 to 30 oC

2 h, 72%

NO

S

Bn

O

OBn

OTESOH

References

1. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. David Ev-ans is a professor at Harvard University.

2. Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876. 3. Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996, 37, 8023. 4. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3. (Review). 5. Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591. 6. Lu, Y.; Schiller, P. W. Synthesis 2001, 1639. 7. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56,

7411. 8. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem 2001, 66, 8463. 9. Matsushima, Y.; Itoh, H.; Nakayama, T.; Horiuchi, S.; Eguchi, T.; Kakinuma, K. J.

Chem. Soc., Perkin 1 2002, 949. 10. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13, 675. 11. Hein, J. E.; Hultin, P. G. Synlett 2003, 635. 12. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett.

2003, 5, 329. 13. Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem 2004, 69, 2569.

220

Favorskii rearrangement and quasi-Favorskii rearrangement

Favorskii rearrangement Transformation of enolizable -haloketones to esters, carboxylic acids, or amidesvia alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.

OR

OCl

O OR

enolizable -haloketone

OR

OCl

OClH

HOR

O ORORO

Cl

cyclopropanone intermediate

O ORH OR HOR

O OR

OR

Example 1, homo-Favorskii rearrangement3

OTsO 1.96 eq. NaOH

dioxane/H2O

90 oC, 3 h, 86%

H

O

51:40:9

O O

221

Quasi-Favorskii rearrangement

Br

O OH

Br

OHO

CO2H

non-enolizable ketone

Example 111

Br

O

Li

THF, 78 to 30 oC, 90% O

References

1. Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533. Aleksei E. Favorskii (1860 1945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he be-came a professor in 1900.

2. Favorskii, A. E. J. Prakt. Chem. 1913, 88, 658. 3. Wenkert, E.; Bakuzis, P.; Baumgarten, R. J.; Leicht, C. L.; Schenk, H. P. J. Am. Chem.

Soc. 1971, 93, 3208. 4. Chenier, P. J. J. Chem. Educ. 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. Gambacorta, A.; Turchetta, S.; Bovicelli, P.; Botta, M. Tetrahedron 1991, 47, 9097. 7. Dhavale, D. D.; Mali, V. P.; Sudrik, S. G.; Sonawane, H. R. Tetrahedron 1997, 53,

16789. 8. Braverman, S.; Cherkinsky, M.; Kumar, E. V. K. S.; Gottlieb, H. E. Tetrahedron 2000,

56, 4521. 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. Zhang, L.; Koreeda, M. Org. Lett. 2002, 4, 3755. 11. Harmata, M.; Wacharasindhu, S. Org. Lett. 2005, 7, 2563. (quasi-Favorskii rear-

rangement).

222

Feist–Bénary furan synthesis

-Haloketones react with -ketoesters in the presence of base to fashion furans.

OEt

O O

ClO

O

CO2Et

Et3N, 0 °C, 52 h

54 57%

ClOCO2Et

O

H CO2Et

O

Et3N: Et3N H

rate-determining

step

O

CO2EtHO

O

OHCl

HCO2Et

:NEt3

Et3N H

O

CO2EtH2O

:

O

CO2Et

O

CO2Et

H

Et3N:

Example 14,5

+

O

OOEt

O O

ClOCH3

OH3CO2C

O

OCH3

KOH, MeOH

57%

Example 26

223

OEt

O O

HCl

O+

O

CO2Et

pyridine, rt to 50 °C, 4 h

then rt, overnight, 86%

References

1. Feist, F. Ber. Dtsch. Chem. Ges. 1902, 35, 1537. 2. Bénary, E. Ber. Dtsch. Chem. Ges. 1911, 44, 489. 3. Bisagni, É.; Marquet, J.-P.; André-Louisfert, J.; Cheutin, A.; Feinte, F. Bull. Soc.

Chim. Fr. 1967, 2796. 4. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756. 5. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317. 6. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147. 7. 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).

8. Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990,20, 1923.

9. 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).

10. 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).

11. Calter, M.; Zhu, C. Org. Lett. 2002, 4, 205. 12. Calter, M.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209. 13. Shea, K. M. Feist–Bénary Furan Synthesis In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 160 167. (Re-view).

224

Ferrier carbocyclization

This process (also known as the “Ferrier II Reaction”) has proved to be of consid-erable 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 com-pounds of interest in biological and medicinal chemistry.1,2

While attempting to find a route from carbohydrates to functionalized cyclopentanes (and hence prostaglandins), Robin Ferrier converted alkene 1 to the standard product of methoxymercuration, but was unable to proceed to cyclopen-tanes by causing C-6 of the C-6-mercurated product to displace the tosyloxy group from C-2. However, hydroxymercuration of 1 with mercury(II) chloride in reflux-ing aqueous acetone afforded the unstable hemiacetal 2 from which aldehydoke-tone 3 and hence the hydroxyketone 4 were formed spontaneously, the latter crys-tallizing in 83% yield on cooling of the solution.3 The high yield can be increased to 89% by addition of a trace of acetic acid,4 and even higher yields have been re-ported in similar examples. Catalytic amounts of mercury(II) trifluoroacetate5 and sulfate6 can promote the reaction, and chelation control has been held responsible for the high stereoselectivity usually observed, the favored epimers having the trans-relationship between the hydroxyl groups at the new chiral centers and the substituents at C-3.1,2

General examples:

O

OMe

BzOBzO

TsO

O

OMe

BzOBzO

TsO

HgCl

+ OBzOBzO

HgCl

HO

1 2

HgCl2, Me2CO, H2O

reflux, 4.5 h OMeOTs

BzOBzO

O

HgCl

OTs O OH

BzOBzO

TsO

O

4383%3

BzOO

BzOOH

BzO

OBzOBzO

O

OBz

BzOBzO OBz

OBz

OMe

BzOO

OH

BzO

OBz

OBzO

OMeBzOBzO

BzO

OOH

OBz83%6

93%4 80%6

225

More complex products

O

OMe

BzO

OBzO

O

OMe

BzO

AcOAcO

OH

OBzO

AcOAcO

75%7

O

OMeO

OC6H4OMe(p)O

OC6H4OMe(p)

OH

86% (2:1)8

OAcOAc

OH

AcOAcO

83%7

O

O

O

Complex bioactive compounds made following the application of the reaction

O

OH

OO NH

O

O

OH O

HOH

OHH

OHHO

NHHOHO

HOHO

Paniculide A9 Pancratistatin10 Calystegine B211

Modified hex-5-enopyranosides and reactions

OH

BnOBnO

BnO

HOOAc

a,b85%14

O

OMe

BnOBnO

BnO

OAc

O

OMe

BnOBnO

BnO

OMe

BnOBnO

OMe

BnOBnO

BnO

HO OBn

O

Hc

d

79%13

98%13

a, Hg(OCOCF3)2, Me2CO, H2O, 0 oC; b, NaBH(OAc)3, AcOH, MeCN, rt; c, i-Bu3Al, 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).

226

References

1. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779 2831. (Review). 2. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277 291 (Review). 3. Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455. 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 Pro-fessor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand.

4. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413. 5. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118. 6. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231. 7. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett.

1991, 17. 8. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711. 9. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55,

3855. 10. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195. 11. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443. 12. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem. Int. Ed. Engl. 1997, 36, 493. 13. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471. 14. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883. 15. Estevez, V. A.; Prestwich, E. D. J. Am. Chem. Soc. 1991, 113, 9885.

227

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 2,3-unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Fer-rier 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 illus-trated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and C-nucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most com-mon. Allyloxycarbenium ions are involved as intermediates, high yields of prod-ucts are obtained, and glycosidic compounds with quasi-axial bonds (as illus-trated) predominate (commonly in the , -ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1

OAcO

AcO

AcOO

OAc

AcO +

i) HOCH2CCH6

ii) HSPh7

iii)

+ Lewis acid

4

O

RAcO

R = i) OCH2CCH6

ii) SPh7

iii)4

OAc

General examples4

OAcOAcO

OAc SnBr4, C6H14, EtOAc

rt, 5 min, 94%

OAcO

OAc

H

228

More complex products made directly from the corresponding glycols:

OH

O

O

OH

OH O

O

O

AcO

O

Ph

AcOOAc

EtOO O

O

OMe

In PhCOCH2CO2Et,

BF3.OEt2,

rt, 15 min,

(81% -anomer).9

OO NHC(O)CCl3

In benzene, BF3.OEt2,

5 oC, 10 min, (67%,

-anomer).8

By spontaneous sigmatropic

rearrangement of the glycal

3-trichloroacetimidate made

with NaH, Cl3CCN,

(78% anomer).10

Products formed without acid catalysts

OHO O OMe OAcO O

DDQ DEAD, Ph3P-anomer)11 (88%, mainly )12

C-3 leaving group of glycal:

Promoter:

hydroxy acetoxy

OO

O

O

O

O

OO

O

N-iodonium dicollidine perchlorate

(65%, mainly )13

pent-4-enoyloxy

229

Modified glycals and their reactions:

OOBn

BnOOAc

OBn

OOBn

BnO

O

O

O

O

Ph

O

O

O

PhN

NH

N

N

ClI

N

NH

N

N

Me

, reflux MeNO2,AgNO3, Na2CO3

6 h (58%, 15

++

OH

BF3•OEt2, CH2Cl2, 0oC

(70%, mainly 14

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 su-pervisor, who suggested her experiment, then found that simple alcohols at high tem-peratures 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, 175. (Review). 3. Fischer, E. Chem. Ber. 1914, 47, 196. 4. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans.

1 1990, 1995. 5. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581. 6. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999. 7. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org.

Chem. 1990, 55, 1979. 8. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Liebigs Ann. Chem. 1991, 509. 9. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68. 10. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36.

4311. 11. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35. 3661. 12. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc.,

Chem. Commun. 1993, 704. 13. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60,

3851. 14. Booma, C.; Balasubramanian, K. K. Tetraherdron Lett. 1993, 34, 6757. 15. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996. 16. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667. 17. Ferrier, R. J. J. Chem. Soc.1964, 5443.

230

Fiesselmann thiophene synthesis

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

CO2Me

O

OMeHSMeO2C

NaOMeS

CO2Me

OH

MeO2C

MeO2C

O

OMeS

+OCH3

O

O

OMeS

OH3CO

O

OMeHS

S

MeO2C

MeO2C O

OMeS

OOMe

SS

CO2Me

MeO2C

MeO2C

OMe

O

SS

CO2MeMeO2C

OMe

ONaOMe

O

OMeHS

O

MeOH

OMe

231

SS

CO2Me

O

OCH3

MeO2C

OMe

O S

MeO2C

OMe

CO2MeO

SCO2Me

S

MeO2C

CO2Me

SCO2Me

H

H

O HOMe

OMe

S

MeO2C

CO2Me

OHS

MeO2C

CO2MeH

O

MeO

Example 16

N Cl

CN

O

OEtHS N S

NH2

CO2Et

NaH, DMSO, 89%

Example 28

CN

S CO2Me

NH2

HSCH2CO2Me

NaOMe, 68%

References

1. Fiesselmann, H.; Schipprak, P. Chem. Ber. 1954, 87, 835; Fiesselmann, H.; Schipprak, P.; Zeitler, L. Chem. Ber. 1954, 87, 841; Fiesselmann, H.; Pfeiffer, G. Chem. Ber.1954, 87, 848; Fiesselmann, H.; Thoma, F. Chem. Ber. 1956, 89, 1907; Fiesselmann, H.; Schipprak, P. Chem. Ber. 1956, 89, 1897.

2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88 125. (Review).

232

3. Nicolaou, K. C.; Skokotas, G.; Furuya, S.; Suemune, H.; Nicolaou, D. C. Angew. Chem. Int. Ed. Engl. 1990, 29, 1064.

4. Mullican, M. D.; Sorenson, R. J.; Connor, D. T.; Thueson, D. O.; Kennedy, J. A.; Con-roy, M. C. J. Med. Chem. 1991, 34, 2186.

5. Ram, V. J.; Goel, A.; Shukla, P. K.; Kapil, A. Bioorg. Med. Chem. Lett. 1997, 7, 3101. 6. Showalter, H. D. H.; Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D.

W. J. Med. Chem. 1999, 42, 5464. 7. Shkinyova, T. K.; Dalinger, I. L.; Molotov, S. I.; Shevelev, S. A. Tetrahedron Lett.

2000, 41, 4973 8. Redman, A. M.; Johnson, J. S.; Dally, R.; Swartz, S.; et al. Bioorg. Med. Chem. Lett.

2001, 11, 9. 9. Migianu, E.; Kirsch, G. Synthesis, 2002, 1096. 10. 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, 184 192. (Review).

233

Fischer indole synthesis

Cyclization of arylhydrazones to indoles.

NH

N

R2R1

NH

NH2

O

R2R1

NH

R2

R1

NH3

H

phenylhydrazine phenylhydrazone

NH

N

R2R1

H

H+NH

NH2

R2R1

[3,3]-sigmatropic

rearrangement

protonation ene-hydrazine

N H2

NH2

R2R1

N H

NH2

R2R1

H

H+

tautomerization

double imine

NH

R2

R1

NH3

NH

H

R2R1

NH3N

H

H H

R2R1

NH2

Example 18,12

NH

N

O

Ph

O

N NH

NH2+

234

NH

N

HN

N

1) neat, 160 oC, 24 h

2) NH2NH2, 120 oC, 12 h

71%

Example 213

NHNH2

O

CNCO2Et

AcOH, 5 h

57%

NH

CNCO2Et

References

1. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241. 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.

2. Fischer, E.; Hess, O. Ber. Dtsch. Chem. Ges. 1884, 17, 559. 3. Shriner, R. L.; Ashley, W. C.; Welch, E. Org. Synth. 1955, Coll. Vol. 3, 725. 4. Robinson, B. Chem. Rev. 1963, 63, 373 401. (Review). 5. Robinson, B. Chem. Rev. 1969, 69, 227 250. (Review). 6. Ishii, H. Acc. Chem. Res. 1981, 14, 275 283. (Review). 7. Robinson, B. The Fisher Indole Synthesis, John Wiley & Sons, New York, NY, 1982.

(Book). 8. Hughes, D. L. Org. Prep. Proc. Int. 1993, 25, 607-632. (Review). 9. Bosch, J.; Roca, T.; Armengol, M.; Fernández-Forner, D. Tetrahedron 2001, 57, 1041. 10. Pete, B.; Parlagh, G. Tetrahedron Lett. 2003, 44, 2537. 11. Li, J.; Cook, J. M. Fischer Indole Synthesis In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 100 103. (Re-view).

235

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.

R2CHON

OR2

R1

etherH2O HCl

HClR1 CN

OH

O R2

H

:N

H+

Cl

R1

OH

NHR1

OH

Cl

NHO

R1

Cl

R2OH

ON

Cl

R2

R1

SN2H

NH2O

R1

Cl

R2OH

HCl

isomerizationO

N

Cl

R2

R1

H eliminationO

N

R2

R1

HCl

Example 16

H3CNH2

OH

O CHO

TsOH, Tol.

reflux

N

OCH3HN

OCH3

O

POCl3, 80 85 oC

15 min., 40%

236

Example 210

SOCl2, ether

dry HCl gas

HO

CN

OH

HO

ClNH

Cl

N

O

dry HCl gas, 16.5%

N

OH

N

CHO

halfordinal

References

1. Fischer, E. Ber. 1896, 29, 205. 2. Ingham, B. H. J. Chem. Soc. 1927, 692. 3. Minovici, S.; Nenitzescu, C. D.; Angelescu, B. Bull Soc. Chem. Romania 1928, 10,

149; Chem. Abstracts 1929, 23, 2716. 4. Ladenburg, K.; Folkers, K.; Major, R. T. J. Am. Chem. Soc. 1936, 58, 1292. 5. Wiley, R. H. Chem. Rev. 1945, 37, 401 442. (Review). 6. Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1949, 1028. 7. Cornforth, J. W. In Heterocyclic Compounds 5; Elderfield, R. C. Ed.; Wiley & Sons:

New York, 1957, 5, 309 312. (Review). 8. Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2, 85; Austr. J. Chem. 1964, 17,

119. 9. Brossi, A.; Wenis, E. J. Heterocyclic Chem. 1965, 2, 310. 10. Onaka, T. Tetrahedron Lett. 1971, 4393. 11. Brooks, D. A. Fisher Oxazole Synthesis in Name Reactions in Heterocyclic Chemistry,

Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 234 236. (Review).

237

Fleming Kumada oxidation

Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols us-ing peracids.

R R1

SiMe2Ph1. HX2. ArCO3H, base

3. hydrolysis R R1

OH

retention of configuration

R R1

Si H+

R R1

SiX

Hipso

substitution

the -carbocation is stabilized by the silicon group

R R1

SiO

O

Ar

OHX

R R1

SiX H

:OO

Ar

O

ArCO2

R R1

OSi

OO Ar

O

R R1

OSiO

H

OO Ar

O

:ArCO2

R R1

OSi

HO

O Ar

O

:

R R1

OSi

O

O

O

O

Ar

R R1

OSi

OO Ar

O

O

238

R R1

OSiO

OO

Ar

OHO

R R1

OSiO

OO

O

Ar hydrolysis

OH

R R1

O

R R1

OHHO

O

Ar

Example 17

NBoc

OO O

(EtO)2PhSi

OH

OTBS

C8H18 m-CPBA, KHF2, DMF

0 to 25 oC, 55 70%

NBoc

OO O

HO

OH

OTBS

C8H18

Example 212

SiMe2(OMe)MeO2C

CO2Me

KF, KHCO3THF-MeOH

30% H2O2, 77%

OHMeO2C

CO2Me

239

Tamao Kumada oxidation15

Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the Fleming Kumada oxidation.

RSi

R

FF KF, H2O2

KHCO3, DMF2 ROH

RSi

R

FF

F

R SiRF

F

F

HO

OH

R SiRF

F

FO

HOH

SiRF

F

FO

HOH

R

:

O SiRF

F

FR

O SiOF

F

FRR

2 ROH

References

1. Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29. 2. Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229. 3. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57 576. (Review). 4. Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599. 5. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112. 6. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613. 7. 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. 8. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337. 9. Rubin, M.; Schwier, T.; Gevorgyan, V. J. Org. Chem. 2002, 67, 1936. 10. Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281. 11. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572. 12. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron

2004, 60, 4205. 13. Sanganee, M. J.; Steel, P. G.; Whelligan, D. K. Org. Biomol. Chem. 2004, 2, 2393. 14. Ko, C. H.; Jung, D. Y.; Kim, M. K.; Kim, Y. H. Synlett 2005, 304. 15. Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120.

240

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.

R Cl

O

AlCl3

R

O

HCl

AlCl3complexation

R Cl:

O

R Cl

O:AlCl3

AlCl4

O

R

RO

electrophilic

substitution

acylium ion

R

OH

aromatization

R

OClAlClCl

ClAlCl3

HCl

Example 116

F

AlCl3, CH2Cl288%

OF

FN N

Cl

O

F

CHOCHO

241

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.

AlCl3RCl:

RCl

AlCl3AlCl4 R

R

RH

aromatization

ClAlClCl

Cl

HCl

alkyl cation

Example 27

O O

O Br

O

SnCl4, CH2Cl2

0 oC, 1 h, 84%

O

OO

O

References

1. Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392. 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, Mas-sachusetts. 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

242

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 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 reac-tions.

2. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533. 3. Gore, P. H. Chem. Ind. 1974, 727. 4. Chevrier, B.; Weiss, R. Angew. Chem., Int. Ed. Engl. 1974, 13, 1. 5. Schriesheim, A.; Kirshenbaum, I. Chemtech 1978, 8, 310 314. (Review). 6. Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241. 7. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahe-

dron Lett. 1999, 40, 4437. 8. Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett.

2001, 3, 1005. 9. Fleming, I. Chemtracts: Org. Chem. 2001, 14, 405. (Review). 10. Metivier, P. Friedel-Crafts Acylation In Friedel-Crafts Reaction Sheldon, R. A.; Bek-

kum, H. eds., Wiley-VCH: New York. 2001, pp161 172. (Review). 11. 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, pp550 556. (Review).

12. Le Roux, C.; Dubac, J. Synlett 2002, 181. 13. Sefkow, M.; Buchs, J. Org. Lett. 2003, 5, 193. 14. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. Engl. 2004, 43,

550 556. (Review). 15. Fakhraian, H.; Zarinehzad, M.; Ghadiri, H. Org. Prep. Proced. Int. 2005, 37, 377. 16. Ba Sappa; Mantelingu, K.; Sadashira, M. P.; Rangappa, K. S. Indian J. Chem. B. 2004,

43, 1954.

243

Friedländer quinoline synthesis

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

CHO

NH2

RR1

O OH

N

R

R1

NH2

RR1

O

H

HO

RR1

O

H

OAldol

condensation

R

NH2

R1

O

:

NH2

R

COR1

OH

HOH

N

R

N

R

R1R1OH

H

HO

Example 15

CHO

NH2 O N

NBn NBnNaOMe, EtOH

reflux, 3 h, 90%

244

Example 215

NHBoc

O

HO N

N O

OBn

N

OBn

OAcOH, 100 °C

88%

References

1. Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572. 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, 181–191. (Review).

4. Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37. (Review). 5. Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka,

H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522. 6. Thummel, R. P. Synlett 1992, 1. 7. Riesgo, E. C.; Jin, X.; Thummel, R. P. J. Org. Chem. 1996, 61, 3017. 8. Mori, T.; Imafuku, K.; Piao, M.-Z.; Fujimori, K. J. Heterocycl. Chem. 1996, 33, 841. 9. Ubeda, J. I.; Villacampa, M.; Avendaño, C. Synthesis 1998, 1176. 10. Bu, X.; Deady, L. W. Synth. Commun. 1999, 29, 4223. 11. Strekowski, L.; Czarny, A.; Lee, H. J. Fluorine Chem. 2000, 104, 281. 12. Chen, J.; Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.; Baguley, B. C.;

Denny, W. A. Bioorg. Med. Chem. 2000, 8, 2461. 13. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org.

Chem. 2001, 66, 400. 14. Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3,

1101; and 2002, 4, 1243. 15. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601. 16. Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider,

P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467. 17. 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).

245

Fries rearrangement

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

O R

O

AlCl3

OHOH

O R

R

O

and/or

O R

O:

AlCl3

complexation C O bond

fragmentation

OAlCl3

O

R

O R

OCl3Al

aluminum phenolate, acylium ion

O

R

OOAlCl3

O

R

H

OH

R

OH+

OAlCl3

O R

OH

O R

O

HR

O

H+

246

Example 111

OMe

O

O

Br

Br

ZrCl4, PhCl

160 oC, 3 h, 63%

OH O OH

Br Br

Example 212

OAc

O

O

10% Bi(OTf)3, PhMe

110 oC, 15 h, 64%

OAc

OH O

References

1. Fries, K.; Finck, G. Ber. Dtsch. Chem. Ges. 1908, 41, 4271. Karl Theophil Fries (1875 1962) was born in Kiedrich near Wiesbaden on the Rhine. He earned his doc-torate 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.

2. Martin, R. Bull. Soc. Chim. Fr. 1974, 983 988. (Review). 3. Martin, R. Org. Prep. Proced. Int. 1992, 24, 369-435. (Review). 4. Trehan, I. R.; Brar, J. S.; Arora, A. K.; Kad, G. L. J. Chem. Educ. 1997, 74, 324. 5. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem.

2000, 65, 4712. 6. Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 1979. 7. Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001,

2221. 8. Kozhevnikova, E. F.; Derouane, E. G.; Kozhevnikov, I. V. Chem. Commun. 2002,

1178. 9. Clark, J. H.; Dekamin, M. G.; Moghaddam, F. M. Green Chem. 2002, 4, 366. 10. Sriraghavan, K.; Ramakrishnan, V. T. Tetrahedron 2003, 59, 1791. 11. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982. 12. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794. 13. Easwaramurthy, M.; Ravikumar, R.; Lakshmanan, A. J.; Raju, G. J. Indian J. Chem.,

Sect. B 2005, 44B, 635.

247

Fukuyama amine synthesis

Transformation of a primary amine to a secondary amine using 2,4-dinitro-benzenesulfonyl chloride and an alcohol. Also known as Fukuyama Mitsunobu procedure.

SO2Cl

NO2

NO2

R1

HN

R2

S

NO2

NO2

CO2H1. R1NH2, pyr.

2. R2OH, PPh3, DEAD

3. HSCH2CO2HSO2

R1NH2

SO2

NO2

NO2

Cl SO2NHR1

NO2

NO2

SO2NR1R2

NO2

NO2R2OH, PPh3

DEAD

:

H+

See page 390 for mechanism of the Mitsunobu reaction.

SO2NR1R2

NO2

NO2

S CO2HH

:

SNAr

NO2

NO2

SO2SHO2C

H+

NR1R2

Meisenheimer complex

R1

HN

R2

S

NO2

NO2

CO2H

SO2

248

Example 19

OH

SO2

NO2

H2NPyPh2P, DTBAD

CH2Cl2, 84%

PyPh2P = diphenyl 2-pyridylphosphine; DTBAD = di-tert-butylazodicarbonate

SO2

NO2

HN K2CO3, PhSH

CH3CN, 80% NH2

References

1. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. Tohru Fu-kuyama moved to the University of Tokyo from Rice University in 1995.

2. Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T. Tetrahedron Lett. 1997, 38,5831.

3. Yang, L.; Chiu, K. Tetrahedron Lett. 1997, 38, 7307. 4. Piscopio, A. D.; Miller, J. F.; Koch, K. Tetrahedron Lett. 1998, 39, 2667. 5. Bolton, G. L.; Hodges, J. C. J. Comb. Chem. 1999, 1, 130. 6. Lin, X.; Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309. 7. Amssoms, K.; Augustyns, K.; Yamani, A.; Zhang, M.; Haemers, A. Synth. Commun.

2002, 32, 319. 8. 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. 9. Guisado, C.; Waterhouse, J. E.; Price, W. S.; JØrgensen, M. R.; Miller, A. D. Org.

Biomol. Chem. 2005, 3, 1049. 10. Olsen, C. A.; Witt, M.; Hansen, S. H.; Jaroszewski, J. W.; Franzyk, H. Tetrahedron

2005, 61, 6046.

249

Fukuyama reduction

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

R SEt

O Et3SiH, Pd/C

THF, rt R H

O

Path A:

Pd(0)

oxidativeaddition

R PdSEt

O

R SEt

O Et3SiH

Et3Si SEt

R H

Oreductive

elimination

Pd(0)R Pd

HO

Path B:

Et3SiH Pd(0) Et3SiPdH

R SEt

O Et3SiPdHR SEt

OSiEt3

PdH Pd(0)

R H

O

Et3Si SEtR SEt

OSiEt3

Example 11

CO2Me

COSEtO O

OEt3SiH, 10% Pd/C

acetone, rt, 92%

CO2Me

CHOO O

O

250

Example 23

HO2C CO2MeNHBoc

EtSH, DCC, DMAP

CH3CN, rt, 1 h, > 70%

CO2MeNHBoc

EtS

O

Et3SiH, 10% Pd/C

acetone, rt, 30 min., >74%CO2Me

NHBoc

H

O

References

1. Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112, 7050. 2. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451. 3. Fujiwara, A.; Kan, T.; Fukuyama, T. Synlett 2000, 1667. 4. Tokuyama, H.; Yokoshima, S.; Lin, S.-C.; Li, L.; Fukuyama, T. Synthesis 2002, 1121. 5. Evans, D. A.; Rajapakse, H. A.; Stenkamp, D. Angew. Chem., Int. Ed. 2002, 41, 4569. 6. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 4048. 7. Kimura, M.; Seki, M. Tetrahedron Lett. 2004, 45, 3219. (Possible mechanisms were

proposed in this paper). 8. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477.

251

Gabriel synthesis

Synthesis of primary amines using potassium phthalimide and alkyl halides.

N

O

O

K+

1. R X

2. OH

H2N RCO2H

CO2H

N

O

O

K+

R X

SN2 N

O

O

Rhydrolysis

OH

N

O

R

OHO

HN

OR

OO

HOH

OH

CO2HN

RO OH

H2N RCO2

CO2

252

Example 110

NK

O

O

Br CO2Et

DMF, 90 oC, 3 h, 77%

N

O

O

CO2Et

N

O

O

O OO

6 M HCl, reflux

14 h, 93% HCl•H2N

O OHO

References

1. Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224. 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. Press, J. B.; Haug, M. F.; Wright, W. B., Jr. Synth. Commun. 1985, 15, 837. 3. Slusarska, E.; Zwierzak, A. Justus Liebigs Ann. Chem. 1986, 402. 4. Han, Y.; Hu, H. Synthesis 1990, 122. 5. Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1991, 24, 285–289. (Review). 6. Toda, F.; Soda, S.; Goldberg, I. J. Chem. Soc., Perkin Trans. 1 1993, 2357. 7. Khan, M. N. J. Org. Chem. 1996, 61, 8063. 8. Lávová, M.; Chovancová, J.; Veverková, E.; Toma, Š. Tetrahedron 1996, 52, 14995. 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. 10. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Labelled. Compd. Radiopharm. 2002,

45, 569.

253

Ing–Manske procedure

A variant of Gabriel amine synthesis where hydrazine is used to release the amine from the corresponding phthalimide:

N

O

O

K+1. RX

2. NH2NH2

H2N RNHNH

O

O

N

O

O

K+

R X

SN2N

O

O

R

:NH2NH2

N

O

R

NHNH2O

NHNH2

O

NHRO

:

NHNH

O

O NH

H2N RNHNH

O

OR

Example6

NPht

NPht

1. NH2NH2•H2O, THF, reflux, 8 h

2. Pd/C, H2, THF, 95%, 2 steps

NH2

NH2

254

References

1. Ing, H. R.; Manske, R. H. F. J. Chem. Soc. 1926, 2348. 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.

2. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228. 3. Khan, M. N. J. Org. Chem. 1995, 60, 4536. 4. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615. 5. Khan, M. N. J. Org. Chem. 1996, 61, 8063. 6. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167. 7. Ariffin, A.; Khan, M. N.; Lan, L. C.; May, F. Y.; Yun, C. S. Synth. Commun. 2004, 34,

4439.

255

Gabriel–Colman rearrangement

Reaction of the enolate of a maleimidyl acetate to provide isoquinoline 1,4-diol.

GN

ROO

G = CO, SO2

ArNaOR

ROHG

NH

OH O

RAr

N

O

O

OMe

N

OOR

OR

OMeO

NOMe

O

OR

O HN

O

OO

OMe

NH

O

O

R

O

N

OH

OH

R

O

NH

O

R

OOO

Example11

SN

Oi-PrOO

OO S

NH

OO

OH O

Oi-Pr4 equiv i-PrONa

i-PrOH, reflux5 min., 85%

256

References

1. Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 980. 2. Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 2630. 3. Gabriel, S.; Colman, J. Chem. Ber. 1902, 35, 1358. 4. Allen, C. F. H. Chem. Rev. 1950, 47, 275 305. (Review). 5. Hauser, C.R. and Kantor, S. W. J. Am. Chem. Soc. 1951, 73, 1437. 6. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons.,

New York, N.Y., 1952, 378. (Review). 7. Albert, A. and Hampton, A. J. Chem. Soc. 1952, 4985. 8. Koelsch, C. F.; Lindquist, R. M. J. Org. Chem. 1956, 21, 657. 9. Hill, J. H. M.; J. Org. Chem. 1965, 30, 620. (Mechanism). 10. Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14, 1171. 11. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281. 12. Schapira, C. B.; Abasolo, M. I.; Perillo, I. A. J. Heterocycl. Chem. 1985, 22, 577. 13. Groutas, W. C.; Chong, L. S.; Venkataraman, R.; Epp, J. B.; Kuang, R.; Houser-

Archield, N.; Hoidal, J. R. Bioorg. Med. Chem. 1995, 3, 187. 14. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980. 15. Pflum, D. A. Gabriel Colman Rearrangement In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 416 422. (Review).

257

Gassman indole synthesis

The Gassman indole synthesis involves a one-pot process in which a hypohalite, a -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 re-moved by hydrogenolysis or Raney nickel.

NHCl

SR

O

Et3N

NH

R

S

NH2

t-BuOCl

NHCl

SR

OSN2

Et3N

NH

S

O

RH

:

:

sulfonium ion

NH

OS

R

HEt3N:

H

NH

S

O

R[2,3]-sigmatropic

rearrangement(Sommelet-Hauser)

NEt3

NH

S

NH

R

S

OHR

N

SHEt3N:

: R

H

Example 11

NH2

1) t-BuOCl

S CH3

O3) Et3N, 69%

NH

Me

S

2)

258

Example 21

NH2

1) t-BuOCl

3) Et3N

N2)

SCH3

OSCH3

LiAlH4, Et2O

NH

0 oC, 48% overall

References

1. Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc. 1974, 96, 5495. Paul G. Gassman (1935 1993) was a professor at the University of Minnesota (1974 1993).

2. Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508. 3. Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96,

5512. 4. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621. 5. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Naka-

gawa, K. Chem. Pharm. Bull. 1990, 38, 2459. 6. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc.

1990, 112, 8197. 7. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am.

Chem. Soc. 1992, 114, 1438. 8. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696. 9. 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, 128 131. (Review).

259

Gattermann–Koch reaction

Formylation of arenes using carbon monoxide and hydrogen chloride in the pres-ence of aluminum chloride under high pressure.

HClCOAlCl3

Cu2Cl2

CHO

:C O

:::C O:

AlCl3 :C OAlCl3

:

HClCl

:C OAlCl3

: C OAlCl3

:Cl

H+

Cl H

OAlCl3 O

H

AlCl4Cl H

OCl3Al

: :

acylium ion

AlCl3

CHOHCHO

AlCl4

O

H

Cl

CHOHCl AlCl3

Example, a more practical variant4

OH

HO

Zn(CN)2, AlCl3

HCl (g), 0 oC;

OH

HO

NH2

Cl

orcinol

260

H2O, 0 to 100 oC

95%

OH

HO

CHO

References

1. Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622. 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.

2. Crounse, N. N. Org. React. 1949, 5, 290 300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 37 72. (Review). 4. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. Tetrahedron: Asymmetry

1990, 1, 187. 5. Tanaka, M.; Fujiwara, M.; Ando, H. J. Org. Chem. 1995, 60, 2106. 6. Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. Chem. Commun. 1996, 159. 7. Tanaka, M.; Fujiwara, M.; Xu, Q.; Souma, Y.; Ando, H.; Laali, K. K. J. Am. Chem.

Soc. 1997, 119, 5100. 8. Tanaka, M.; Fujiwara, M.; Xu, Q.; Ando, H.; Raeker, T J. J. Org. Chem. 1998, 63,

4408. 9. Kantlehner, W.; Vettel, M.; Gissel, A; Haug, E.; Ziegler, G.; Ciesielski, M.; Scherr,

O.; Haas, R. J. Prakt. Chem. 2000, 342, 297. 10. Doana, M. I.; Ciuculescu, A.; Bruckner, A.; Pop, M.; Filip, P. Rev. Roum. Chim. 2002,

46, 345.

261

Gewald aminothiophene synthesis

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

R

R1

O CO2R2

CNS8

Base

S

CO2R2

NH2R1

R

O

R1

R

CN

OOR2

HB: CN

OOR2 Knoevenagel

condensationBH

R

R1

CN

O OR2

H

:B

BHNC

O

OR2

RR1

HO

H

:BNC

O

OR2

RR1

HO

R

R1

CN

O OR2

R

R1

O OR2

SS

SS

S SSS

SS S

N

6

:

BH

S

CO2R2

NH2R1

R

S7S

R2O2C

NH

R1

R

HSS

S SS

SS B

262

Example 18

N

NH3C CH3

CO2Et

CNS

CO2Et

NH2

N

S8+

morpholine

82%

Example 213

O

O O CO2Et

CN+

St-BuO2C NH2

CO2EtMeS8, EtOH, morpholine

60 oC, 5 h, 74%

References

1. Gewald, K. Z. Chem. 1962, 2, 305. 2. Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94. 3. Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. 4. Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 2712. 5. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. Engl. 1967, 6, 294 306. (Review). 6. Gewald, K. Chimia 1980, 34, 101 110. (Review). 7. Peet, N. P.; Sunder, S.; Barbuch, R. J.; Vinogradoff, A. P. J. Heterocycl. Chem. 1986,

23, 129. 8. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953. 9. Sabnis, R. W. Sulfur Reports 1994, 16, 1. (Review). 10. Guetschow, M.; Schroeter, H.; Kuhnle, G.; Eger, K. Monatsh. Chem. 1996, 127, 297. 11. Zhang, M.; Harper, R. W. Bioorg. Med. Chem. Lett. 1997, 7, 1629. 12. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36,

333. (Review). 13. Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger,

K. J. Med. Chem. 1999, 42, 5437. 14. Baraldi, P. G.; Zaid, A. N.; Lampronti, I.; Fruttarolo, F.; Pavani, M. G.; Tabrizi, M. A.;

Shryock, J. C.; Leung, E.; Romagnoli, R. Bioorg. Med. Chem. Lett. 2000, 10, 1953. 15. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41, 1597. 16. Buchstaller, H.-P.; Siebert, C. D.; Lyssy, R. H.; Frank, I.; Duran, A.; Gottschlich, R.;

Noe, C. R. Monatsh. Chem. 2001, 132, 279. 17. Hoener, A. P. F.; Henkel, B.; Gauvin, J.-C. Synlett 2003, 63. 18. Tinsley, J. M. Gewald Aminothiophene Synthesis In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 193 198. (Review).

263

Glaser coupling

Oxidative homo-coupling of terminal alkynes using copper catalyst in the pres-ence of oxygen.

HCuCl, O2

NH4OH, EtOH

H CuClBase

Cu(I)

O2Cu(II) Cu(I)

dimerization

Example 11

Cu2

O2

NH4OH, EtOH90%

Example 2, homo-coupling2

HO

Cu, NH4Cl

O2, 90% HO OH

References

1. Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. 2. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583. 3. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556. 4. Li, J.; Jiang, H. Chem. Commun. 1999, 2369. 5. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.

(Review). 6. Setzer, W. N.; Gu, X.; Wells, E. B.; Setzer, M. C.; Moriarity, D. M. Chem. Pharm.

Bull. 2001, 48, 1776.

264

7. Kabalka, G. W.; Wang, L.; Pagni, R. M. Synlett 2001, 108. 8. Youngblood, W. J.; Gryko, D. T.; Lammi, R. K.; Bocian, D. F.; Holten, D.; Lindsey, J.

S. J. Org. Chem. 2002, 67, 2111. 9. Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Gayathri, K. U.; Prasad, A. R. Tetrahe-

dron Lett. 2003, 44, 6493. 10. Moriarty, R. M.; Pavlovic, D. J. Org. Chem. 2004, 69, 5501. 11. Wang, L.; Yan, J.; Li, P.; Wang, M.; Su, C. J. Chem. Res. 2005, 112.

265

Eglinton coupling

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

R HCu(OAc)2

pyridine/MeOHR R

RR Hpyridine

NH

CuAcO OAc

R Cu OAc

R R

R

dimerizationR

Example 1, homo-coupling6

Cu(OAc)2, pyridine

MeOH, 1.5 h, 68%

NNC

Cl

NNC

Cl

NCN

Cl

Example 2, cross-coupling4

Ph

SPh

CO2Me

Cu(OAc)2pyridine/MeOH (1:1)

rt, 72%

266

Ph

SPh

CO2Me

References

1. Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737. Geoffrey Eglinton (1927 ) was born in Cardiff, Wales.

2. Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614. 3. Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225. (Review). 4. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104,

5558. 5. Altmann, M.; Friedrich, J.; Beer, F.; Reuter, R.; Enkelmann, V.; Bunz, U. H. F. J. Am.

Chem. Soc. 1997, 119, 1472. 6. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B

1997, 36B, 123. 7. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632. 8. Müller, T.; Hulliger, J.; Seichter, W.; Weber, E.; Weber, T.; Wübbenhorst, M. Chem.

Eur. J. 2000, 6, 54. 9. Märkl, G.; Zollitsch, T.; Kreimeier, P.; Prinzhorn, M.; Reithinger, S.; Eibler, E. Chem.

Eur. J. 2000, 6, 3806. 10. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem.,

Int. Ed. 2001, 40, 3402. 11. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632.

(Review). 12. Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4, 2533.13. Xu, G.-L.; Zou, G.; Ni, Y.-H.; DeRosa, M. C.; Crutchley, R. J.; Ren, T. J. Am. Chem.

Soc. 2003, 125, 10057.

267

Gomberg–Bachmann reaction

Base-promoted radical coupling between an aryl diazonium salt and an arene to form a diaryl compound.

N2O

O

OH

OH

N N

N N

N NOH

Ph

: N NPh

ONN

Ph

ON2

ONN

Ph

O

OH

ONN

Ph

OHNN

Ph

Example 14

N2O

O

O

O

BF4 KOAc, 18-C-6

rt, 55%

O

O

268

Example 25

N

N N

N

NH2

MeOONO

PhH, TFAA, reflux2 d, 33%

N

N N

N

MeO

References

1. Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339. 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 Uni-versity of Michigan as the Moses Gomberg Professor of Chemistry.

2. DeTar, D. F.; Kazimi, A. A. J. Am. Chem. Soc. 1955, 77, 3842. 3. Eliel, E. L.; Saha, J. G.; Meyerson, S. J. Org. Chem. 1965, 30, 2451. 4. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G.

W. J. Org. Chem. 1984, 49, 1594. 5. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859. 6. Gurczynski, M.; Tomasik, P. Org. Prep. Proced. Int. 1991, 23, 438. 7. Hales, N. J.; Heaney, H.; Hollinshead, J. H.; Sharma, R. P. Tetrahedron 1995, 51,

7403. 8. Lai, Y.-H.; Jiang, J. J. Org. Chem. 1997, 62, 4412.

269

Gould–Jacobs reaction

The Gould–Jacobs reaction is a sequence of the following reactions: a. condensa-tion of an aniline 1 with either alkoxy methylenemalonic ester or acyl malonic es-ter 2 providing the anilidomethylenemalonic ester 3; b. cyclization of 3 to the 4-hydroxy-3-carboalkoxyquinoline 4; c. saponification to form acid 5, and d. decar-boxylation to give the 4-hydroxyquinoline 6.

NH2

+CO2RRO2C

OR''R' NH

R'

CO2Rheat

R''OH

N

CO2ROH

R'

RO2C

N

CO2H

OH

R'

HO

N

OH

R'

R = alkylR' = alkyl, aryl, or HR'' = alkyl or H

1 2 3

4 5 6

NH2

EtO2C

OEt NH2

heatEtO2C

OEt

O

OEt

OEt

O H

EtOH

NH

CO2Et

OEtO

NH

CO2Et

OEtO H

N

CO2EtO

N

electrocylization

6

CO2EtO H

EtOH

270

N

CO2EtOH

tautomerization

Example 113

O

NH

EtO2C CO2EtPh2O, reflux

75%, 10:1

N N

OO CO2Et

OHOH

CO2Et

References

1. Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc. 1939, 61, 2890. 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 Rockefeller Institute for Medical Research where he discovered the Gould–Jacobs reaction with his colleague Walter A. Jacobs.

2. Baker, R. H., Lappin, G. R., Albisetti, C. J., Riegel, B. J. Am. Chem. Soc. 1946, 68,1267.

3. Jones, G. In Heterocyclic Compounds, Quinolines Vol. 32, chapter 2, pp 146 150, 158, 159. (Review).

4. Reitsema, R. H. Chem. Rev. 1948, 53, 43. (Review). 5. Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New

York, 1952, vol. 4, pps. 38 41. (Review). 6. Price, C. C., Snyder, H. R., Bullitt, O. H., Kovacic, P. J. Am. Chem. Soc. 1947, 69,

374. 7. Briehl, H., Lukosch, A., Wentrup, C. J. Org. Chem. 1984, 49, 2772. 8. Ouali, M. S., Vaultier, M., Carrie, R. Tetrahedron 1980, 36, 1821. 9. Horvath, G., Hermecz, I., Gorvath, A., Pongor-Csakvari, M., Pusztay, L. J. Hetero-

cycl. Chem. 1985, 22, 481. 10. Agui, H., Komatsu, T., Nakagome, T. J. Heterocycl. Chem. 1975, 12, 557. 11. Sabnis, R. W., Rangnekar, D. W. J. Heterocycl. Chem. 1991, 28, 1105. 12. Suzuki, N., Tanaka, Y., Dohmori, R. Chem. Pharm. Bull. 1979, 27, 1. 13. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110. 14. Hayakawa, I., Suzuki, N., Suzuki, K., Tanaka, Y. Chem. Pharm. Bull. 1984, 32, 4914. 15. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med.

Chem. 1995, 38, 950. 16. Leyva, E., Monreal, E., Hernandez, A. J. Fluorine Chem. 1999, 94, 7. 17. Dave, C. G.; Joshipura, H. M. Indian J. Chem., Sect. B 2002, 41B, 650. 18. 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).

271

Grignard reaction

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

R XMg(0)

R MgXR1 R2

O

R OH

R2R1

Formation of the Grignard reagent:

Mg Mg

R X

Mg Mg

R X

single electron

transfer

Mg Mg

R MgBr

R MgX

Grignard reaction, ionic mechanism:

R OMgX

R2R1R2

R1

R MgX

OR2

R1

R MgX

O

Radical mechanism,

R MgX

OR2

R1

OR2

R1

MgX

R

R OMgX

R2R1

R OH

R2R1H

272

Example 16

OMeMeO

MeOOMe

N

O

Ph

OMe

OO

Br

OO

MeO

MeOOMe

N

O Ph

MeO

OO

OO

+Mg

65%

Example 24

EtMgBr

reflux, tol./ether, 76%NOH

NH

H

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

References

1. Grignard, V. C. R. Acad. Sci. 1900, 130, 1322. 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. (Re-view).

3. Ashby, E. C.; Laemmle, J. T. Chem. Rev. 1975, 75, 521. (Review). 4. Sasaki, T.; Eguchi, S.; Hattori, S. Heterocycles 1978, 11, 235. 5. Lasperas, M.; Perez-Rubalcaba, A.; Quiroga-Feijoo, M. L. Tetrahedron 1980, 36,

3403. 6. Meyers, A. I.; Flisak, J. R.; Aitken, R. A. J. Am. Chem. Soc. 1987, 109, 5446. 7. Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New York, 2000. (Book). 8. Holm, T.; Crossland, I. In Grignard Reagents Richey, H. G., Jr., Ed.; Wiley: New

York, 2000, Chapter 1, pp 1 26. (Review). 9. Toda, N.; Ori, M.; Takami, K.; Tago, K.; Kogen, H. Org. Lett. 2003, 5, 269. 10. Shinokubo, H.; Oshima, K. Eur. J. Org. Chem. 2004, 2081 2091. (Review). 11. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733 763. (Review).

273

Grob fragmentation

C C bond cleavage primarily via a concerted process involving a five atom sys-tem. General scheme:

Y X

:

Y X

X = OH2+, OTs, I, Br, Cl; Y = O , NR2

Example 1

OMOM

OH

MsO

OMOM

O

MsONaH

15-crown-5

O

OMOM

Example 2, aza-Grob fragmentation7

N O

S

15 eq. NaBH4, THF

70 oC, 31 h, 53%NH

OHSH

274

Example 312

OH

OTs

NaH, DMSO, 40 oC, 1 h;

then tosylate, 40 oC, 1 h

52%MeO

OMeO

References

1. Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594. 2. Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1. 3. French, L. G.; Charlton, T. P. Heterocycles 1993, 35, 305. 4. Harmata, M.; Elahmad, S. Tetrahedron Lett. 1993, 34, 789. 5. Armesto, X. L.; Canle L., M.; Losada, M.; Santaballa, J. A. J. Org. Chem. 1994, 59,

4659. 6. Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215. 7. Hu, W.-P.; Wang, J.-J.; Tsai, P.-C. J. Org. Chem. 2000, 65, 4208. 8. Molander, G. A.; Le Huerou, Y.; Brown, G. A. J. Org. Chem. 2001, 66, 4511. 9. Paquette, L. A.; Yang, J.; Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542. 10. Barluenga, J.; Alvarez-Perez, M.; Wuerth, K.; Rodriguez, F.; Fananas, F. J. Org. Lett.

2003, 5, 905. 11. Tada, N.; Miyamoto, K.; Ochiai, M. Chem. Pharm. Bull. 2004, 52, 1143. 12. Khripach, V. A.; Zhabinskii, V. N.; Fando, G. P.; et al. Steroids 2004, 69, 495.

275

Guareschi–Thorpe condensation

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

O

O

R

R

CN

OR1O

NH3

NH

RCN

R O

CN

OR1O

H3N:CN

OR1O

H2NCN

OH2N

HH3N:

R1OH

H

CN

R OCN

OH2N

O

R

O

RNH2O

OHR

H :NH3

HO

H3N H

NH

RCN

R O

CN

R ONH2O

R

: NH

R

CN

R OOH

H

H3N:

H3N H

H2O

Example7

O CO2Et

CN NH3

NH

CNNC

O O

+

Guareschi imide

75%

276

References

1. Guareschi, I. Mem. Reale Accad. Sci. Torino 1896, II, 7, 11, 25. 2. Baron, H.; Renfry, F. G. P.; Thorpe, J. F. J. Chem. Soc. 1904, 85, 1726. 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 Col-lege.

3. Vogel, A. I. J. Chem. Soc. 1934, 1758. 4. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384. 5. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960. 6. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946. 7. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem.

1982, 47, 1445. 8. Collins, D. J.; Jones, A. M. Aust. J. Chem. 1989, 42, 215. 9. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. 10. Narsaiah, B.; Sivaprasad, A.; Venkataratnam, R. V. Org. Prep. Proced. Int. 1993, 25,

116. 11. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1995, 34B, 348. 12. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1998, 37B, 988. 13. Al-Omran, F.; El-Khair, A. A. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem.,

Sect. B 2001, 40B, 608. 14. Galatsis, P. Guareschi Thorpe Pyridine Synthesis In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 307 308. (Review).

277

Hajos–Wiechert reaction

Asymmetric Robinson annulation catalyzed by (S)-( )-proline.

O

OO

cat. NH

HO2CH

O

O CH3CN

O

O

O

H

Michael

addition

O

OO

NH

HO2CH

enamine formation

O

ON

HCO2

catalytic asymmetric

enamine aldol

O

ON

CO2 N

H H

CO2

:

O

NOH

CO2

H2O: hydrolysis

of iminium salt

O

NOH

CO2

HO

:

O

O

O

OOH

H

B:

O

OOH

E1cB

278

Example 11

O

OO

3 mol% (S)-proline

CH3CN, 100%, 93.4% ee

O

O

Example 29

O

OO

O

O

L-phenylalanine, PPTS

DMSO, 50 oC, 24 h

sonication, 97%, 93% eeOBz OBz

References

1. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Hajos and Parrish were chemists at Hoffmann-La Roche.

2. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. 3. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv.

Chim. Acta 1978, 61, 3108. 4. Agami, C. Bull. Soc. Chim. Fr. 1988, 499. 5. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. 6. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. 7. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. 8. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. 9. Shigehisa, H.; Mizutani, T.; Tosaki, S.-y.; Ohshima, T.; Shibasaki, M. Tetrahedron

2005, 61, 5057.

279

Haller–Bauer reaction

Base-induced cleavage of non-enolizable ketones leading to carboxylic amide de-rivative and a neutral fragment in which the carbonyl group is replaced by a hy-drogen.

R R5O

R2 R3R1 R4

NaNH2

PhH, reflux

RNH2

O

R2R1

H R5

R3R4

non-enolizable ketone

R R5O

R2 R3R1 R4

NH2

R R5

R2 R3R1 R4

NH2O

RNH2

O

R2R1

R5

R3R4H R5

R3R4

Example 14

O

t-BuOK, t-BuOH

43%

CO2H

Example 212

O

PhLiHNC6H13

10 mol% LDA, THF

0 oC to rt., 5 h, 86%Ph

O

HN C6H13

280

References

1. Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824. 2. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399. 3. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044. 4. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167. 5. Muir, D. J.; Stothers, J. B. Can. J. Chem. 1993, 71, 1290. 6. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279. 7. Mehta, G.; Reddy, K. S.; Kunwar, A. C. Tetrahedron Lett. 1996, 37, 2289. 8. Mehta, G.; Reddy, K. S. Synlett 1996, 229. 9. Mittra, A.; Bhowmik, D. R.; Venkateswaran, R. V. J. Org. Chem. 1998, 63, 9555. 10. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399 1422. (Review). 11. Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287. 12. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983.

281

Hantzsch dihydropyridine synthesis

Dihydropyridine from the condensation of aldehyde, -ketoester and ammonia.

R H

O CO2Et

R1O

NH3

NH

RCO2EtEtO2C

R1 R1

R H

O

CO2Et

R1O

enolate

formationCO2Et

R1OHH3N:

HH3N:

R1O

R

OH

CO2EtH CO2Et

R1O

R:NH3aldol

condensationR1O

R

OH

CO2Et

CO2Et

R1O

:NH3enamine

formation

CO2Et

R1HOH2N:

H2O

H3N:CO2Et

R1

H

H2N

CO2Et

R1H2N

:

Michael

addition

EtO2C

R1

R

O

CO2Et

R1

N

REtO2C

OR1

H

tautomerization

H2N HCO2Et

R1

NH2

REtO2C

O R1H2N H

H

:NH3

282

N

RCO2EtEtO2C

R1HOR1

H

H

H3N:

NH

RCO2EtEtO2C

R1 R1

Example 16

H

OCO2Et

O

NH3

NH

CO2EtEtO2C

NO2

NO2

nifedipine

References

1. Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1 83. 2. Bottorff, E. M.; Jones, R. G.; Kornfeld, E. C.; Mann, M. J. J. Am. Chem. Soc. 1951,

73, 4380. 3. Berson, J. A.; Brown, E. J. Am. Chem. Soc. 1955, 77, 4444. Marsi, K. L.; Torre, K. J. Org. Chem. 1964, 29, 3102. 5. Meyers, A. I.; Sircar, J. C.; Singh, S. J. Heterocycl. Chem. 1967, 4, 4616. Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 5787. Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc.,

Perkin Trans. 1 1986, 753. 8. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1986, 42, 5729. 9. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. 10. Sainai, J. B.; Shah, A. C.; Arya, V. P. Indian J. Chem. B. 1995, 34B(1), 17.11. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J.

Heterocycl. Chem. 1995, 32, 831. 12. Goerlitzer, K.; Heinrici, C.; Ernst, L. Pharmazie 1999, 54, 35. 13. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077. 14. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67,

3499. 15. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 304 307. (Review).

283

Hantzsch pyrrole synthesis

Reaction of -chloromethyl ketones with -ketoesters and ammonia to assemble pyrroles.

O

Cl

CO2Et

O NH

CO2EtNH3

CO2Et

O

:NH3enamine

formation

CO2Et

HOH2N:

H3N:CO2EtH

H2N

CO2Et

H2N

H2O

CO2Et

H2N

ClO

HN

OHCl

HCO2Et

:NH3:

H2OH3N H

N

CO2Et

HN

Cl CO2Et

:

H

HH3N: NH

CO2Et

Example 15

O

Br

F3C

CO2MeH2N NH

CO2Me

DME, 87 140 oC

2.5 h, 60%F3C

284

Example 28

OCl

CO2Et

ONH

CO2EtNH3, EtOH

48 h, 48%

References

1. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. 2. Hort, E. V.; Anderson, L. R. Kirk-Othmer Encycl. Chem. Technol.; 3rd Ed.; 1982, 19,

499. (Review). 3. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. 4. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332, 143. 5. Kameswaran, V.; Jiang, B. Synthesis 1997, 530. 6. Trautwein, A. W.; Sü muth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381. 7. 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). 8. Matiychuk, V. S.; Martyak, R. L.; Obushak, N. D.; Ostapiuk, Yu. V.; Pidlypnyi, N. I.

Chem. Heterocyclic Compounds 2004, 40, 1218.

285

Heck reaction

Palladium-catalyzed coupling between organohalides or triflates with olefins.

R XPd(0)

ZZ

R

X = I, Br, OTf, Cl, etc.Z = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc.

Pd(0)

Z

ZR

R Pd(II) X

R Pd(II) X

Z

Pd

ZH

RH

X

PdH X

R X

oxidativeaddition

coordination

insertion(cis)

cis- -elimination

Example 17

Cl

MeO

O

O

MeO

O

O

1.5% Pd2(dba)3, 6% P(t-Bu)3

1.1. eq. Cs2CO3, dioxane

120 oC, 24 h, 82%

286

Example 26

N

N

HO

I

OTBS

HN

N

O

HOTBS

0.3 eq. Pd(OAc)2

Bu4NCl, DMF, K2CO3

70 oC, 3 h, 74%

References

1. Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518. Richard Heck dis-covered 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 difficul-ties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida.

2. Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (Review). 3. Heck, R. F. Org. React. 1982, 27, 345. (Review). 4. Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985.

(Book). 5. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,

University Science Books: Mill Valley, CA, pp 103 113. (Book). 6. Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685. 7. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. 8. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009 3066. (Review). 9. Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (Review). 10. Link, J. T. Org. React. 2002, 60, 157 534. (Review). 11. Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945 2963. (Review). 12. Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd

edn.) 2004, 1, 271 305. (Review). 13. Oestreich, M. Eur. J. Org. Chem. 2005, 783 792. (Review).

287

Heteroaryl Heck reaction

Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl re-cipient.

N

SI

Pd(Ph3P)4, Ph3P, CuI

Cs2CO3, DMF, 140 oCN

S

N

SI

Pd(0)

oxidative addition

Pd(II)Iinsertion

N

SN

S

Pd(II)H

B:I

Cs2CO3

CsI CsHCO3Pd(0)

Example 13

N

N Cl

N

ON

NN

O

Pd(Ph3P)4, KOAcDMA, reflux, 65%

Example 22

O

Br

NN

N

BuN

NN

BuO

Pd(OAc)2, NaHCO3

n-Bu4NCl, DMA

150 oC, 24 h, 83%

288

References

1. Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.; Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951.

2. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915 3. Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Koma-

tsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocy-cles 1992, 33, 257.

4. Proudfoot, J. R. et al. J. Med. Chem. 1995, 38, 1406. 5. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn.

1998, 71, 467. 6. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; 2000, Pergamon:

Oxford, p16. (Review).

289

Hegedus indole synthesis

Stoichiometric Pd(II)-mediated oxidative cyclization of alkenyl anilines to in-doles. Cf. Wacker oxidation.

NH2

PdCl2(CH3CN)2, THF

then, Et3N, 84%MeO2C NH

MeO2CCH3

NH2MeO2CPd

NH2MeO2CCl

ClPdCl2(CH3CN)2

palladation

precipitate

Et3N

NH2MeO2C

PdCl

Et3NCl

:

NH2

PdEt3N

Cl

Cl

MeO2C

– HCl

– "PdH"

H

NH

MeO2C

"PdH"

NH

MeO2C

PdLn

H

NH

MeO2CCH3

-elimination

CH3

Example 11

NH2

10 mol% (CH3CN)2PdCl2100 mol% benzoquinone

10 eq. Et3N, THF, reflux, 85%NH

CH3

290

Example 24

10 mol % (CH3CN)2PdCl2100 mol% benzoquinone

10 eq. LiCl, THF, reflux, 79%NHTs N

Br

Ts

Br

References

1. Hegedus, L. S.; Allen, G. F.; Waterman, E. L. J. Am. Chem. Soc. 1976, 98, 2674. Lou Hegedus is a professor at Colorado State University.

2. Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978,100, 5800.

3. Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215. 4. Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. 5. Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (Review). 6. Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70. 7. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587. 8. A ruthenium variant: Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124,

186. 9. Johnston, J. N. Hegedus Indole Synthesis In Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 135 139. (Re-view).

291

Hell–Volhard–Zelinsky reaction

-Bromination of carboxylic acids using Br2/PBr3.

ROH

OR

Br

O

Br

H2O ROH

O

Br

PBr3

Br2

-bromoacid

RO

O

P BrBr

Br

RO

OP

Br

Br

Br

RO

OP

Br

Br

BrH

enolization RBr

O

Br Br

RBr

O

O P Br H

Br

H

:OH2

ROH

O

BrR

Br

O

Br

RBr

O

OH

H+

Br

HB:

hydrolysis

Example 17

CO2H Cl2, cat. PCl3

97 oC, 6 h, 77%

CO2HCl

292

Example 28

CO2H

PBr3

Br2, 57%Br

CO2H

CO2HBr

H

References

1. Hell, C. Ber. Dtsch. Chem. Ges. 1881, 14, 891. 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.

2. Volhard, J. Justus Liebigs Ann. Chem. 1887, 242, 141. Jacob Volhard (1849 1909) was born in Darmstadt, Germany. He apprenticed under Liebig, Will, Bunsen, Hof-mann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing -bromo-acid during his research in thiophenes.

3. Zelinsky, N. A. Ber. Dtsch. Chem. Ges. 1887, 20, 2026. Nikolai D. Zelinsky (1861 1953) was born in Tyaspol, Russia. He studied at Göttingen under Victor Meyer, receiving his Ph.D. in 1889. Zelinsky returned to Russia and became a profes-sor at the University of Moscow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin.

4. Watson, H. B. Chem. Rev. 1930, 7, 173 201. (Review). 5. Sonntag, N. O. V. Chem. Rev. 1953, 52, 237 246. (Review). 6. Harwood, H. J. Chem. Rev. 1962, 62, 99 154. (Review). 7. Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964).8. Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427.9. Little, J. C.; Sexton, A. R.; Tong, Y.-L. C.; Zurawic, T. E. J. Am. Chem. Soc. 1969, 91,

7098. 10. Chatterjee, N. R. Indian J. Chem., Sect. B 1978, 16B, 730. 11. Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263. 12. Kolasa, T.; Miller, M. J. J. Org. Chem. 1990, 55, 4246. 13. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097. 14. Krasnov, V. P.; Bukrina, I. M.; Zhdanova, E. A.; Kodess, M. I.; Korolyova, M. A.

Synthesis 1994, 961. 15. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9621. 16. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059. 17. Stack, D. E.; Hill, A. L.; Diffendaffer, C. B.; Burns, N. M. Org. Lett. 2002, 4, 4487.

293

Henry nitroaldol reaction

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

R R1

OR2 NO2

NH NO2

OH

R2

RR1

NH

R2 N

H

R2 N

R R1

O

NH H

deprotonation:

O

OO

O

nitronate

NO2

OH

R2

RR1 N

H

nucleophilic

addition

Example 16

NO2

CHO

Amberlyst A-21 (basic)rt, 62%

NO2HO

294

Example 2, aza-Henry reaction14

N

Ph

PO

PhPh

NO2Ph

5 mol% TMG, 100 oC

0.1 mBar, 26 h

95%, anti:syn = 98:2

HN

Ph

PO

PhPh

NO2

Ph

References

1. Henry, L. Compt. Rend. 1895, 120, 1265. 2. Matsumoto, K. Angew. Chem. 1984, 96, 599. 3. Sakanaka, O.; Ohmori, T.; Kozaki, S.; Suami, T.; Ishii, T.; Ohba, S.; Saito, Y. Bull.

Chem. Soc. Jpn. 1986, 59, 1753. 4. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233. 5. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Per-

gamon, 1991, 2, 321 340. (Review). 6. Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749. 7. Bandgar, B. P.; Uppalla, L. S. Synth. Commun. 2000, 30, 2071. 8. Luzzio, F. A. Tetrahedron 2001, 57, 915. (Review). 9. Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861. 10. Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401. 11. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (Review on aza-Henry reac-

tion). 12. Risgaard, T.; Gothelf, K. V.; Jøgensen, K. A. Org. Biomol. Chem. 2003, 1, 153. 13. Ballini, R.; Bosica, G.; Livi, D.; Palmieri, A.; Maggi, R.; Sartori, G. Tetrahedron Lett.

2003, 44, 2271. 14. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.;

Ricci, A. J. Org. Chem. 2004, 69, 8168. 15. Chung, W. K.; Chiu, P. Synlett 2005, 55. 16. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed. Engl. 2005, 44, 3881.

295

Hinsberg synthesis of thiophene derivatives

Condensation of diethyl thiodiglycolate and -diketones under basic conditions, which provides 3,4-disubstituted thiophene-2,5-dicarboxylic acids upon hydrolysis of the crude ester product with aqueous acid.

O

O SO

EtO

O

OEt S

PhPh

O

OH

HO

O1.

NaOEt, EtOH2. H3O+

O

Ph

O

Ph

S

CO2Et

CO2Et

O

Ph

O

CO2EtS

EtO

O

Ph

S

OO

CO2Et

Ph

O

HO2C

S CO2Et

Ph

O

EtO

Ph

Ph

S

Ph Ph

CO2EtHO2C S

Ph Ph

HO2C CO2H

H+, H2O

reflux

296

Example 111

S

O

O

S

O

O

(CHO)3, NaOMe

MeOH, 59%

Example 215

S CNNCO

H3C

O

CH3

S

CH3H3C

NH2

O

NC

NaOH, MeOH

94%

References

1. Hinsberg, O. Ber. Dtsch. Chem. Ges. 1910, 43, 901. 2. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; Wiley-

Interscience: New York, 1985, 34 41. (Review). 3. Wynberg, H.; Zwanenburg, D. J. J. Org. Chem. 1964, 29, 1919. 4. Wynberg, H.; Kooreman, H. J. J. Am. Chem. Soc. 1965, 87, 1739. 5. Chadwick, D. J.; Chambers, J.; Meakins, G. D.; Snowden, R. L. J. Chem. Soc., Perkin

I, 1972, 2079. 6. Kumar, A.; Tilak, B. D. Indian J. Chem.1986, 25B, 880. 7. Miyahara, Y.; Inazu, T.; Yoshino, T. Chem. Lett. 1980, 397. 8. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187. 9. Huybrechts, L.; Buffel, D.; Freyne, E.; Hoornaert, G. Tetrahedron 1984, 40, 2479. 10. Miyahara, Y.; Inazu, T.; Yoshino, T. Tetrahedron Lett. 1984, 25, 415. 11. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177. 12. Vogel, E. Pure Appl. Chem. 1990, 62, 557. 13. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem. Int. Ed. Engl. 1990, 29, 675. 14. Rangnekar, D. W.; Mavlankar, S. V. J. Heterocycl. Chem. 1991, 28, 1455. 15. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223. 16. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gissel-

brecht, J. P. Angew. Chem. Int. Ed. Engl. 1996, 35, 1520. 17. 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: Ho-boken, NJ, 2005, 199 206. (Review).

297

Hiyama cross-coupling reaction

Palladium-catalyzed cross-coupling reaction of organosilicons with organic hal-ides, triflates, etc. in the presence of an activating agent such as fluoride or hy-droxide (transmetalation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 345.

O BrMeO2C F3Si O

O

Pd(Ph3P)4, TBAF

THFOMeO2C O

O

F3Si O

O

FBu4N

nucleophilic

attack

F4Si O

O

Bu4NF4Si O

O

Bu4N

oxidative

additionO BrMeO2C Pd(Ph3P)4O PdMeO2C Br

F4Si O

O

O PdMeO2CCO2Me

trans"metal"lation

reductive

eliminationOMeO2C O

O

Pd(Ph3P)4

298

Example 11

S Si(Et)F2

S

I

MeO2C S

SMeO2C( 3-C3H5PdCl)2

DMF, KF, 100 oC

82%

Example 25

C5H11 Si(OMe)3

NBr

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

C5H11N

References

1. Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303. 2. Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. 3. Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1994, 35,

6507. 4. Mateo, C.; Fernandez-Rivas, C.; Echavarren, A. M.; Cardenas, D. J. Organometallics

1997, 16, 1997. 5. Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997, 1309. 6. Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich, F.; Stang,

P. J., Eds.; Wiley–VCH: Weinheim, Germany, 421–53. (Review). 7. Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 624, 372. 8. Hiyama, T. J. Organomet. Chem. 2002, 653, 58. 9. Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697. 10. Clarke, M. L. Adv. Synth. Cat. 2005, 347, 303. 11. Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Froehlich, J.; Kirchner, K. Or-

ganometallics 2005, 24, 3957.

299

Hiyama–Denmark cross-coupling reaction

A synthetically important and mechanistically distinct cross-coupling process of organosilanols has been developed. Unlike the Hiyama cross-coupling reaction of polychloro- and fluorosilanes that requires activation by fluoride ion, the Denmark process involves the simple deprotonation of an organosilanol to initiate the cou-pling. This variant has obvious advantages of avoiding incompatibility with fluo-ride (silicon protective groups and large-scale reactors).

Mechanistic study5

MeSi

Me

n-C5H11 O- M+

ArylPdL2X

MX

MeSi

Me

n-C5H11 OH

MH

C7H13Me2SiO

SiOK

Me Me

MeSi

Me

n-C5H11 O Pd

transmetalationL

LAryl

n-C5H11Pd n-C5H11

ArylAryl

L

L

Many organosilanol substrates and different bases have been demonstrated.

1. Alkenylsilanol (KOSiMe3)6

SiOH

MeMe

n-C5H11+

KOSiMe3 (2.0 eq.)

Pd(dba)2 (5 mol %)DME, 9 h, r.t.

CH2OTBSI

n-C5H11

CH2OTBS

80% (E: Z = 99.5/0.5)

300

2. Arylsilanol (Cs2CO3)7

Si

MeO

MeMe

OH +CO2Et

Br

MeO

CO2EtCs2CO3 + 3 H2O (2 equiv)

[(allyl)PdCl]2 (5 mol %)

dppb (10 mol %)

toluene, 90 oC

24 h, 90%

3. Arylsilanol (Ag2O)8

Si

MeO

MeMe

OH

MeOMe

Ag2O (1 equiv)

Pd(PPh3)4 (5 mol %)

THF, 60 oC, 36 h

69%

Aryl-I+

4. Alkynylsilanol (KOSiMe3)9

SiMe2OH

C5H11 CH2OHI

TMSOK (2 equiv), PdCl2(PPh3)2 (2.5 mol %)

DME, rt, 3 h, 84%

CH2OHC5H11

5. 2-Indolylsilanol (KOt-Bu)10

NBoc

SiMe Me

OHI CO2t-Bu+

301

NaOt-Bu (2.0 equiv)

NBoc

CO2t-Bu

CuI (1.0 equiv)toluene, rt, 84%

Pd2(dba)3•CHCl3 (5 mol%)

6. 4-Isoxazolylsilanol (NaOt-Bu)11

NOEt

PhSiMe

Me

HO

+I

NO2

NOEt

Ph

O2N

Pd2dba3•CHCl3(5 mol %)NaOtB-u (2.5 equiv)

Cu(OAc)2 (1.0 equiv)toluene, 40 ºC, 78%

7. 1,4-Bis-silyl-1,3-butadienes (KOSiMe3)12

I+

SiMe2Bn

MeOCO2Et

n-Bu4N+ F- (2.0 equiv)

Pd(dba)2 (2.5 mol%)

THF, rt, 1 h

90%

MeO

CO2Et

References

1. Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. Scott Denmark is a pro-fessor at the University of Illinois at Urbana-Champaign.

2. Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531. 3. Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75. 4. Denmark, S. E.; Sweis, R. F. Organosilicon Compounds in Cross-Coupling Reactions

In Metal-Catalyzed C-C and C-N Cross-Coupling Reactions; F. Diederich, A. deMei-jere, Eds. Wiley-VCH, 2004; Vol. 1; Chapt. 4.

5. Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876. 6. Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439. 7. Denmark, S. E.; Ober, M. H. Adv. Synth. Catal., 2004, 346, 1703. 8. Hirabayashi K.; Mori A.; Kawashima J.; Suguro M.; Nishihara Y.; Hiyama T. J. Org.

Chem. 2000, 65, 5342. 9. Denmark, S. E.; Tymonko, S. A. J. Org. Chem. 2003. 68, 9151. 10. Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6(20), 3649. 11. Denmark, S. E.; Kallemeyn, J. J. Org. Chem. 2005, 70, 2839. 12. Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127, 8004.

302

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 Hof-mann degradation reaction.

R NH2

OR N C O

H2OR NH2 CO2

Br2

NaOH

R NH

O

OH

Br BrH

R NH

O R N

O

H

Br

OH

R N

OBr

R NH2 CO2

N C OR

HN O

OH

R

OH OHisocyanate intermediate

Example 14

NH2

O2N

ONBS, DBU, MeOH

reflux, 25 min., 70%

HN

O2N

O

O

303

Example 29

NH2

O

OH

IOCOCF3

OCOCF3

CH3CN/H2O, 4.5 h, 100%

NH

O

OH

IO CF3

OPh

:

N

OH

CO

:

H

O

HN

O

References

1. Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1881, 14, 2725. 2. Grillot, G. F. Mech. Mol. Migr. 1971, 237. (Review). 3. Jew, S. S.; Park, H. G.; Park, H. J.; Park, M. S.; Cho, Y. S. Ind. Chem. Library 1991,

3, 147 53. (Review). 4. Jew, S.-s.; Kang, M.-h. Arch. Pharmacal Res. 1994, 17, 490. 5. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495. 6. Spanggord, R. J.; Clizbe, L. A. J. Labelled Compd. Radiopharm. 1998, 41, 615. 7. Monk, K. A.; Mohan, R. S. J. Chem. Educ. 1999, 76, 1717. (Review). 8. Togo, H.; Nabana, T.; Yamaguchi, K. J. Org. Chem. 2000, 65, 8391. 9. Yu, C.; Jiang, Y.; Liu, B.; Hu, L. Tetrahedron Lett. 2001, 42, 1449. 10. Keillor, J. W.; Huang, X. Org. Synth. 2002, 78, 234. 11. Lopez-Garcia, M.; Alfonso, I.; Gotor, V. J. Org. Chem. 2003, 68, 648. 12. Moriarty, R. M. J. Org. Chem. 2005, 70, 2893 2903. (Review).

304

Hofmann–Löffler–Freytag reaction

Formation of pyrrolidines or piperidines by thermal or photochemical decomposi-tion of protonated N-haloamines.

R1 NR2

Cl 1. H+,

NR1

R22. OH

R1 NR2

Cl H+

R1 NR2

ClH

homolyticcleavage

chloroammonium salt

R1 NR2

HClH

HN

R1R2

H

1,5-hydrogen

atom transfer

nitrogen radical cation

NH2R1

R1 NR2

ClH

R1N

R2H

NH2R1 ClR2

R2

NR1

R2NH

Cl R2R1

:SN2

NR1

R2H

OH OH

Example 16

N NNH N

NCS, ether, Et3N

then hv, (Hg0 lamp)

0 oC, 3.5 h in N2

100%

305

Example 23

O

H

H H

NH

1. NaOCl, 95%

2. TFA, hv, 87%3. NaOH, MeOH, 76%

O

H

H H

N

References

1. Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1879, 12, 984. 2. Löffler, K.; Freytag, C. Ber. Dtsch. Chem. Ges. 1909, 42, 3727. 3. Kerwin, J. F.; Wolff, M. E.; Owings, F. F.; Lewis, B. B.; Blank, B.; Magnani, A.;

Karash, C.; Georgian, V. J. Am. Chem. Soc. 1960, 82, 4117. 4. Wolff, M. E. Chem. Rev. 1963, 63, 55. (Review). 5. Furstoss, R.; Teissier, P.; Waegell, B. Tetrahedron Lett. 1970, 11, 1263. 6. Kimura, M.; Ban, Y. Synthesis 1976, 201. 7. Deshpande, R. P.; Nayak, U. R. Indian J. Chem., Sect. B 1979, 17B, 310. 8. Hammerum, S. Tetrahedron Lett. 1981, 22, 157. 9. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J.

Am. Chem. Soc. 1978, 100, 571. 10. Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337 422. (Review). 11. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (Review). 12. Madsen, J.; Viuf, C.; Bols, M. Chem. Eur. J. 2000, 6, 1140. 13. Togo, H.; Katohgi, M. Synlett 2001, 565. (Review). 14. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455. (Review). 15. Li, J. J. Hofmann–Löffler–Freytag Reaction In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 80 97. (Review).

306

Horner–Wadsworth–Emmons reaction

Olefin formation from aldehydes and phosphonates. Workup is more advanta-geous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water.

EtOP

OEt

OEtO

O NaH, then

RCHO

CO2Et

R EtOP

ONa

OEtO

EtOP

OEt

OEtO

O

H

HO R

HEtO

POEt

OEtO

O

EtOP

OEt

OEtO

O

O R

erythro (kinetic) or threo (thermodynamic)

PO

HR CO2Et

H

O

OEtOEt

HR CO2Et

HPO OEt

OEtO

R CO2Et

erythro, kinetic adduct

PO

HR H

CO2Et

O

OEtOEt CO2Et

RHR H

CO2EtPO OEt

OEtO

threo, thermodynamic adduct

307

Example 15

OCHO

OMe

EtOP

OEt

OEtO

O

NaH, THF, 91%

O

OMe

CO2Et

Example 28

CHOEtO

POEt

OEtO

O

KOH, THF, 95%

CO2Et

BnO BnO

References

1. Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499. 2. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. 3. Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30,

680. 4. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863 927. (Review). 5. Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem.

Soc. 1996, 118, 9509. 6. Ando, K. J. Org. Chem. 1997, 62, 1934. 7. Ando, K. J. Org. Chem. 1999, 64, 6815. 8. Nicolaou, K. C.; Boddy, C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R. J.; Natarajan, S.;

Jain, N. F.; Ramajulu, J. M.; Bräse, S.; Solomon, M. E. Chem. Eur. J. 1999, 5, 2602. 9. Reiser, U.; Jauch, J. Synlett 2001, 90. 10. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115. 11. Harusawa, S.; Koyabu, S.; Inoue, Y.; Sakamoto, Y.; Araki, L.; Kurihara, T. Synthesis

2002, 1072. 12. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron

Lett. 2003, 44, 1333. 13. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281.

308

Houben Hoesch reaction

Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.

OH

OH

RCN

HCl, AlCl3

OH

OH

R NH•HCl

OH

OH

R O

OH

OHR N:

AlCl3complexation

R N AlCl3

:

electrophilic

substitution

OH

OH

R NH•HCl

H2O:

O

OH

R NHH

H+

Cl

OH

OH

R O

hydrolysis

OH

OH

R ONH2

H

H+

Cl

Example 1, intramolecular Houben Hoesch reaction5

O

CN

OMe

OMe

1. ZnCl2, HCl(g), Et2O

2. H2O, reflux, 89%

O OMe

OMeO

309

Example 28

FPivO CN

OMe

OH

MeO

CO2Me

OH

SbCl5, 2-chloropropane

CH2Cl2, rt, 2 h, 95%

OPiv

MeO FOMe

OCO2Me

OH

NH

References

1. Hoesch, K. Ber. Dtsch. Chem. Ges. 1915, 48, 1122. 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 fam-ily business.

2. Houben, J. Ber. Dtsch. Chem. Ges. 1926, 59, 2878. 3. Amer, M. I.; Booth, B. L.; Noori, G. F. M.; Proenca, M. F. J. R. P. J. Chem. Soc.,

Perkin Trans. 1 1983, 1075. 4. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691. 5. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994,

35, 6347. 6. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117,

3037. 7. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751. 8. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294. 9. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36, 135.

310

Hunsdiecker Borodin reaction

Conversion of silver carboxylate to halide by treatment with halogen.

R O

OAg

X2R X CO2 AgX

R O

OAg

X X

AgXR O

OX

homolytic

cleavage

R XCO2XR O

OR

R O

OX

R O

O

Example 16

NBS, n-Bu4N+CF3CO2

ClCH2CH2Cl, 96%

CO2H

MeO

Br

MeO

Example 210

CO2H

HO

N

N

Cl

2 BF4

KBr, CH3CN, 82%

Br

HO

F"Select fluor"

References

1. Borodin, A. Justus Liebigs Ann. Chem. 1861, 119, 121. Aleksandr Porfirevi 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

311

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.

2. Hunsdiecker, H.; Hunsdiecker, C. Ber. Dtsch. Chem. Ges. 1942, 75, 291. Cläre Huns-diecker was the only woman to give a name reaction in this book. I hope there will be many more in future editions. Cläre Hunsdiecker was born in 1903 and educated in Cologne. She developed the bromination of silver carboxylate alongside her husband, Heinz.

3. Sheldon, R. A.; Kochi, J. K. Org. React. 1972, 19, 326. (Review). 4. Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979. 5. Crich, D. In Comprehensive Organic Synthesis; Trost, B. M.; Steven, V. L., Eds.; Per-

gamon, 1991, Vol. 7, 723 734. (Review). 6. Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998, 39, 699. 7. Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S. Tetrahedron 2000, 56, 2703. 8. De Luca, L.; Giacomelli, G.; Porcu, G.; Taddei, M. Org. Lett. 2001, 3, 855. 9. Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861. 10. Ye, C.; Shreeve, J. M. J. Org. Chem. 2004, 69, 8561.

312

Hurd–Mori 1,2,3-thiadiazole synthesis

Reaction of thionyl chloride with the N-acylated or tosyl hydrazone derivatives to provide the 1,2,3-thiadiazole in one step.

R1 = OR, NH2

HNN

O

R1

R2R3

SOCl2R1

NS

N

R2

NN

S

R2

R3

R1 = OR, NH2

HNN

Tos

R2R3

SOCl2

R1

NNH

R1

HNS

NX

OR1

NS

NO

R2

X

R2

ClSO

ClX

+

SH

R2Cl

O

X = Tos, COR1

R1

NS

NX

R2

+R1

NS

N

R2

SO2

Cl-

HCl

Example17

CN

NHNH2N

O

CN

SNN

SOCl2, CH2Cl2

rt, 6 h, 56%

313

References

1. Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359. 2. Meier, H.; Hanold, N. In Methoden der Organischen Chemie: Houben Weyl, Georg

Thieme: Stuttgart – New York, 1994; Vol. E8d, p.60. (Review). 3. Thomas, E. W. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Vol. Ed.;

Katrizky, A. R.; Rees, C. W.; Series Eds.; Pergamon Press: London, 1984; Vol. 6, Part 4B, p. 447. (Review).

4. Thomas, E. W. In Comprehensive Heterocyclic Chemistry II; Storr, R. C., Vol. Ed.; Katrizky, A. R.; Rees, C. W.; Scriven, E. F.; Series Eds.; Pergamon Press: London, 1996; Vol. 4, p. 289. (Review).

5. Stanetty, P.; Turner, M.; Mihovilovic, M. D. In Targets in Heterocyclic Systems 1999,3, 265–299. (Review).

6. Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J. J. Med. Chem.1985, 28, 442.

7. Lewis, G. S.; Nelson, P. H. J. Med. Chem. 1979, 22, 1214. 8. Fujita, M.; Nimura, K.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1995, 41,

2413. 9. Peet, N. P.; Sunder, S. J. Heterocycl. Chem. 1975, 12, 1191. 10. Zimmer, O.; Meier, H. Chem. Ber. 1981, 114, 2938. 11. Britton, T. C.; Lobl, T. J.; Chidester, C. G. J. Org. Chem. 1984, 49, 4773. 12. Fujita, M.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1993, 36, 33. 13. D'Hooge, B.; Smeets, S.; Toppet, S.; Dehaen, W. Chem. Commun. 1997, 1753. 14. Stanetty, P.; Kremslehner, M.; Vollenkle, H. J. Chem. Soc., Perkin Trans. 1 1998, 853;

Stanetty, P.; Kremslehner, M.; Jaksits, M. Pest. Sci. 1998, 54, 316. 15. Hu, Y.; Baudart, S.; Porco, J. A., Jr. J. Org. Chem. 1999, 64, 1049. 16. Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529. 17. Morzherin, Y. Y.; Glukhareva, T. V.; Mokrushin, V. S.; Tkachev, A. V.; Bakulev, V.

A. Heterocyclic Commun. 2001, 7, 173. 18. Hameurlaine, A.; Abramov, M. A.; Dehaen, W. Tetrahedron Lett. 2002, 43, 1015. 19. Sakya, S. M. Hurd–Mori 1,2,3-Thiadiazole Synthesis In Name Reactions in Heterocyc-

lic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 199 206. (Review).

314

Jacobsen–Katsuki epoxidation

Manganese-catalyzed asymmetric epoxidation of (Z)-olefins.

Ph CO2Me Ph CO2Me

O

N N

OO

Mn

t-Bu

t-Bu

Cl t-Bu

t-Bu

H H

NaOCl, aq. buffer, CH2Cl2

1. Concerted oxygen transfer (cis-epoxide):

R1R O

Mn(V)

R1R

O

Mn(V)

R1R

O

Mn(V)

R1R

O

2. Oxygen transfer via radical intermediate (trans-epoxide):

R1R O

Mn(V)

R1R

O

Mn(V)

R1R

O

R1R

OMn(V)

3. Oxygen transfer via manganaoxetane intermediate (cis-epoxide):

R1R O

Mn(V)

R1

R

O

Mn(V)

R1R

O

[2 + 2]

cycloaddition

R1

RMn(V)

O

315

Example5

cat, 4-phenylpyridine-N-oxide

NaOCl, CH2Cl2, 4 oC, 12 h

56%, 95 97% ee

CO2EtCO2Et

O

O

N

O

N

t-Bu

t-Bu t-Bu

t-BuMn

Clcat. =

H H

References

1. Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990,112, 2801.

2. Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31,7345.

2. Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055. 3. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296. 4. Schurig, V.; Betschinger, F. Chem. Rev. 1992, 92, 873. (Review). 5. Deng, Li; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320. 6. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim,

New York, 1993, Ch. 4.2. (Review). 7. Katsuki, T. Coord. Chem. Rev. 1995, 140, 189 214. (Review). 8. E. N. Jacobsen, in Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkin-

son, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995,vol 12, Chapter 11.1. (Review).

9. Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457. 10. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3. (Review). 11. 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). 12. Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH:

New York, 2000, 287. (Review). 13. Katsuki, T. Synlett 2003, 281. (Review). 14. Palucki, M. Jacobsen–Katsuki epoxidation In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 29 43. (Review).

316

Japp–Klingemann hydrazone synthesis

Hydrazones from -ketoesters and diazonium salts with the acid of base.

KOHArN2 Cl CO2R

O N CO2R

HN

Ar OH

O

Diazonium salt -keto-ester hydrazone

CO2R

O

HCO2R

O

OHdeprotonation

N N Arcoupling

CO2R

NN

Ar

O OHCO2R

O

NN

Ar

HO

N CO2R

HN

ArOH

O

N CO2RN

Ar

H

Example 16

SN

OONH2

Me

CO2Et

SN

OON

Me

CO2Et

N

ClNaNO2

conc. HCl, H2O0 oC

317

SN

OONH

N

CO2Et

NMe2Me NMe2

O

CO2Et

NaOAc (pH 3 4)0 to 50 oC

72%

Me

CO2Et

Example 29

OBn

N2+Cl

NH

OHO2C

0.5 N KOH, THF, rt, 1 h

then NH

O

N

HN

OBn

62% yield

References

1. Japp, F. R.; Klingemann, F. Justus Liebigs Ann. Chem. 1888, 247, 190. 2. Laduree, D.; Florentin, D.; Robba, M. J. Heterocycl. Chem. 1980, 17, 1189. 3. Strandtmann, M. v.; Cohen, Marvin P.; Shavel, J. Jr. J. Med. Chem. 1963, 6, 719. 4. Loubinoux, B.; Sinnes, J.-L.; O'Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60,

953. 5. Saha, C., Miss; Chakraborty, A.; Chowdhury, B. K. Indian J. Chem. 1996, 35B, 677. 6. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665. 7. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385. 8. Shawali, A. S.; Abdallah, M. A.; Mosselhi, M. A. N.; Farghaly, T. A. Heteroatom

Chem. 2002, 13, 136. 9. Dubash, N. P.; Mangu, N. K.; Satyam, A. Synth. Commun. 2004, 34, 1791.

318

Jones oxidation

The Collins/Sarett oxidation (chromium trioxide-pyridine complex), and Co-rey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxi-dations follow a similar pathway as the Jones oxidation. All these oxidants have a chromium (VI), normally yellow, which is reduced to Cr(IV), often green.

N 2

CrO3

Collins/Sarett

N 2

Cr2O7

H

CrO3ClN

H

PCC PDC

Jones oxidation

R1 R2

OH CrO3

H2SO4, acetone R1 R2

O

R1 R2

OH

:

CrO O

O

R1

OCr

R2

H

OH

OO

H

H

:OH2

R1 R2

OCr

O OH

OH

The intramolecular mechanism is also operative:

R1

OCr

R2

H

O

OHO

R1 R2

OCr

O OH

OH

319

Example 114

CO2t-Bu

OO

O

OO

OH

OH

1. Jones reagent acetone, 20 min.

2. HCO2H, rt, 1 h 96% 2 steps

CO2H

OO

O

OO

OH

O

( )-CP-263114

Example 215

HHO

OCO2Me

H

CrO3, H2SO4acetone/H2O

rt, 74%

HO

OCO2Me

H

Collins/Sarett oxidation5

O

O

OH

Ph

O

O8 eq CrO3•2Pyr

CH2Cl2, 15 min. 86%

O

O

CHO

Ph

O

O

PCC oxidation6

NEtO2C

OH 1.5 eq PCC, CH2Cl2

rt, 3 h, 75%N

EtO2CO

320

PDC oxidation7

S

S

OH

O

PDC, CH2Cl2

24 h, 68%

SCHO

SO

References

1. 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. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422. 3. Ratcliffe, R. W. Org. Syn. 1973, 53, 1852. 4. Andrieux, J.; Bodo, B.; Cunha, H.; Deschamps-Vallet, C.; Meyer-Dayan, M.; Molho,

D. Bull. Soc. Chim. Fr. 1976, 1975. 5. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995. 6. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14, 429. 7. Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230. 8. Gomez-Garibay, F.; Quijano, L.; Pardo, J. S. C.; Aguirre, G.; Rios, T. Chem. Ind.

1986, 827. 9. Glinski, J. A.; Joshi, B. S.; Jiang, Q. P.; Pelletier, S. W. Heterocycles 1988, 27, 185. 10. Turjak-Zebic, V.; Makarevic, J.; Skaric, V. J. Chem. Soc. (S) 1991, 132. 11. Luzzio, F. A. Org. React. 1998, 53, 1 222. (Review). 12. Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Rei-

der, P. J. Tetrahedron Lett. 1998, 39, 5323. (Catalytic CrO3 oxidation). 13. Caamano, O.; Fernandez, F.; Garcia-Mera, X.; Rodriguez-Borges, J. E. Tetrahedron

Lett. 2000, 41, 4123. 14. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825. 15. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett.

2001, 3, 251. 16. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313. 17. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2005, 44, 1275. 18. Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2005, 68, 5388.

321

Julia–Kocienski olefination

Modified one-pot Julia olefination to give predominantly (E)-olefins from het-eroarylsulfones and aldehydes. A sulfone reduction step is not required.

NNN N

SO2

R1

Ph

1. KHMDS

2. R2CHOR1

R2

NNN N

Ph

OH SO2

NNN N

SO2

R1

Ph

H

N(TMS)2

NNN N

SO2

R1

Ph

R2 H

O

NNN

NSO2

R1

Ph

R2O

NNN

NPh

K

SO2

OR2

R1

NNN

NPh

O R2

SR1O

O

R1R2

NNN

NPh

OH SO2

The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl):

R1R2

SO2PT

OK

O

R2H

HR1

SO2PT

322

Example 1, (BT = benzotriazole)4

SO2BT OHC OTIPS

OTIPSNaHMDS, DMF

78 oC to rt, 90% E:Z (78:22)

Example 26

O

O

OPiv

S S

N

O O

OOMe

OTBS

KHMDS, THF, 78 oC, 85%

O

O

OPiv

OMe

OTBS

References

1. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175. 2. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336. 3. Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993,

130, 856. 4. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327. 5. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morely, A. Synlett 1998, 26. 6. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans.

1 1999, 955. 7. Williams, D. R.; Brooks, D. A.; Berliner, M. P. J. Am. Chem. Soc. 1999, 121, 4924. 8. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365. 9. Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738. 10. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. 11. Compostella, F.; Franchin, L.; Panza, L.; Prosperi, D.; Ronchetti, F. Tetrahedron

2002, 58, 4425. 12. Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694. 13. Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem.

2004, 69, 7949. 14. Bedel, O.; Haudrechy, A.; Langlois, Y. Eur. J. Org. Chem. 2004, 3813. 15. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573. 16. Alonso, D. A.; Fuensanta, M.; Najera, C.; Varea, M. J. Org. Chem. 2005, 70, 6404.

323

Julia–Lythgoe olefination

(E)-Olefins from sulfones and aldehydes.

R SAr

OO

1. n-BuLi

2. R1CHOR

R1SO2Ar

OAc

Na(Hg)

CH3OHR

R1

3. Ac2O

R SAr

OO

H

n-Bu-deprotonation

R

SO2Ar

H O

R1 coupling

RR1

SO2Ar

O

O

O O

RR1

SO2Ar

OAc

RR1

SO2Ar

O

acetylation

O

O O

Na(Hg)

single electrontransfer (SET)

4 possible diastereomers

RR1

SO2Ar

OAc

Na(Hg)

single electrontransfer (SET)

RR1R

R1

OAcOAc

324

Example 13

SO2Ph

OHC

1. n-BuLi, THF, 78 oC

2.

3. Ac2O

4. Na(Hg)E:Z (99:1)

Example 24

NTEOC H

CHO

OTBSO

SO2PhLi

1. THF, 78 oC

2. Ac2O

3. 5% Na(Hg), 77%

NTEOC H

OTBSO

References

1. Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833. 2. Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1978, 834. 3. Kocienski, P. J.; Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1980, 1045. 4. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 5. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194. 6. Marko, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37, 2089. 7. Satoh, T.; Hanaki, N.; Yamada, N.; Asano, T. Tetrahedron 2000, 56, 6223. 8. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149. 9. Marko, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig, D.; Carballares,

S.; Dolan, S. Tetrahedron 2001, 57, 2609. 10. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453. 11. Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346. 12. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am.

Chem. Soc. 2002, 124, 1664. 13. D’herde, J. N. P.; De Clercq, P. J. Tetrahedron Lett. 2003, 44, 6657. 14. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 1064. 15. Pospisil, J.; Pospisil, T.; Marko, I. E. Org. Lett. 2005, 7, 2373.

325

Kahne–Crich glycosidation

Diastereoselective glycosidation of a sulfoxide at the anomeric center as the gly-cosyl acceptor. The sulfoxide activation is achieved using Tf2O.

O

PivO

PivOPivO

S

OPiv

Ph

OO

HOO

OPh

SPhN3

N

CH3

t-But-Bu

Tf2O, CH2Cl2, 78 to 30 oC

OOOPh

SPhN3

O

PivO

PivOPivO

OPiv

O

O

PivO

PivOPivO

S

OPiv

Ph

O

S O SF

F F

FFF

O

O

O

O

TfO O:

PivO

PivOPivO

S

OPiv

Ph

OTfSN1

PhS

OTf

OHO

OOPh

SPhN3

O

PivO

PivOPivO

OPiv

oxonium ion

326

OOOPh

SPhN3

O

PivO

PivOPivO

OPiv

O

Example 12

O OMOMOMOM

OMe OHBzO

O S(O)PhOBn

OBnOBn

Tf2O, DTBMP, CH2Cl2

70 to 50 oC, 38%O

OBnOBn

OBn

O OMOMOMOM

OMe OBzO

Example 26

OO

O OTBS

SPh

OPMBPh

OO

MeO

OTIPS

OHOTBS

Tf2O, DTBMP, CH2Cl2

78 to 0 oC, 67%

O

O

O

O

O

Ph

PMBOOTBS

MeO

OTIPSOTBS

References

1. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. 2. Yan, L.; Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem. Soc. 1994, 116,

6953. 3. Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239. 4. Gildersleeve, J.; Pascal, R. A.; Kahne, D. J. Am. Chem. Soc. 1998, 120, 5961. 5. Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435. 6. Crich, D.; Li, H. J. Org. Chem. 2000, 65, 3095. 7. 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, 801. 8. Crich, D.; Li, H.; Yao, Q.; Wink, D. J.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem.

Soc. 2001, 123, 5826. 9. Berkowitz, D. B.; Choi, S.; Bhuniya, D.; Shoemaker, R. K. Org. Lett. 2000, 2, 1149. 10. Crich, D.; Lim, L. B. L. Org. React. . 2004, 64, 115 251. (Review).

327

Keck macrolactonization

Macrolactonization of -hydroxyl acids using a combination of DCC, DMAP and DMAP HCl.

HO OH

O

n

DCC, DMAP

DMAP•HCl, CHCl3

O

O

n

N C NH+ N C N

Cy

CyH

O OH

OH

n

1,3-dicyclohexylcarbodiimide (DCC)

N

N

HN CyON

Cy O

OH

:n

H+

N

N

NCy

HN Cy

O O

OH

Hn

dimethylaminopyridine (DMAP)

N OH

O

n

N

:

H+

NH

NH

O

1,3-dicyclohexylurea

328

O

ON

N

H O

O

DMAP

n

n

Example 17

NHO2C

OH

HClOH

H

N-(3-methylaminopropyl)-N'-ethylcarbodiimide hydrochloride

DMAP, DMAP•HCl, CHCl3, THFreflux, 10 h, > 32%

NO

O

Cl

OH

H

halichlorine

H

References

1. Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394. 2. Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming, J. G.; Smith, J. D. J. Am. Chem.

Soc. 1994, 116, 9391. 3. Keck, G. E.; Sanchez, C.; Wager, C. A. Tetrahedron Lett. 2000, 41, 8673. 4. Tsai, C.-Y.; Huang, X.; Wong, C.-H. Tetrahedron Lett. 2000, 41, 9499. 5. Hanessian, S.; Ma, J.; Wang, W. J. Am. Chem. Soc. 2001, 123, 10200. 6. Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol.

Chem. 2003, 1, 104. 7. Christie, H. S.; Heathcock, C. H. PNAS 2004, 101, 12079.

329

Knoevenagel condensation

Condensation between carbonyl compounds and activated methylene compounds catalyzed by amines.

R CHO CH2(CO2R1)2

NH

RCO2R1

CO2R1

OHR

CO2H

CH(CO2R1)2

NH

H deprotonationNH2 CH(CO2R1)2:

NH

(CO2R1)2CH

R O

H iminium ion

formationR

H

NOH

:R N

H:

R

OHN

R

CO2R1

HCO2R1

NH

O OR1 hydrolysisO

OR1

OH:

H

NH2

R

O O

O

O

R

O O

O

OH

H+

H

R

OR1O

HO

OR1

OHO

workup

decarboxylationR

CO2HCO2R O

OH

H+

H

330

Example 17

NBoc

NCbzH

CHO O O

O O

EDDA, PhH, 60 oC

12 h, 84%

NBoc

NCbzHO O

O O

Meldrum's acid

Example 2, using ionic liquid ethylammonium nitrate (EAN) as solvent13

CHO

CO2Et

CN ethylammonium nitrate

rt, 10 h, 87%

CN

CO2Et

References

1. Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 2596. 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. (Review). 3. Van der Baan, J. L.; Bickelhaupt, F. Tetrahedron 1974, 30, 2447. 4. Green, B.; Khaidem, I. S.; Crane, R. I.; Newaz, S. S. Tetrahedron 1976, 31, 2997. 5. Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. J. Chem. Soc., Perkin Trans. 1

1989, 105. 6. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129. 7. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045. 8. Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869. 9. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001. 10. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Tsadjout, A. Synth. Commun.

2002, 32, 355. 11. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67, 4615. 12. Wada, S.; Suzuki, H. Tetrahedron Lett. 2003, 44, 399. 13. Hu, Yi; Chen, J.; Le, Z.-G.; Zheng, Q.-G. Synth. Comm. 2005, 35, 739.

331

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 333).

NHNH2

O

R1

R NN

R2

OR3

R

R1 R3

R2N

N

R1 R3

R2R

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.

NHNH2

O

R1

R NN

OR2

OR3

R

R1 R3

OH NN

R

R1 R3

O

RO

RO NH

NH

R

R

OH

OH

NH2NH2

NHN

R

RNHN

R

ROHAlternatively,

RO

RO

NR

R

NH2O

NH2NH2

NHN

R

RNHN

R

ROH

332

Example 15

MeO Me

OMe O MeNHNH2 NN

Me

MeHCl, H2O

84%

Example 213

Me

O

Me

EtO2CCF3, NaOMe, MeOH

reflux, 24 h, 94%

O

Me

CF3

O

NH

SH2NO

O

NH2 HCl N N

SH2N O

O

Me

CF3

EtOH, reflux, 46%

Celebrex

References

1 Knorr, L. Ber Dtsch. Chem. Ges. 1883, 16, 2597. Ludwig Knorr (1859 1921) was born near Munich, Germany. After studying under Volhard, Emil Fischer, and Bun-sen, he was appointed professor of chemistry at Jena. Knorr made tremendous contri-butions in the synthesis of heterocycles in addition to discovering the important pyra-zolone drug, pyrine.

2 Knorr, L. Ber Dtsch. Chem. Ges. 1884, 17, 546, 2032. 3 Knorr, L. Ber Dtsch. Chem. Ges. 1885, 18, 311. 4 Knorr, L., Justus Liebigs Ann. Chem. 1887, 238, 137. 5 Burness, D. M. J. Org. Chem. 1956, 21, 97. 6 Jacobs, T. L., in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York,

1957, 5, 45. (Review). 7 Houben-Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). 8 Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996, 37, 1003. 9 Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C.

W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). 10 Penning, T. D.; Talley, J. J.; et al. J. Med. Chem. 1997, 40, 1347. 11 Shen, D-M.; Shu, M.; Chapman, K. T. Org. Lett. 2000, 2, 2789. 12 Stanovnik, E.; Svete, J. in Science Of Synthesis, 2002, 12, 15; Ed. by Neier, R.;

Thieme. (Review). 13 Carpino, P. A.; Lefker, B. A.; Toler, S. M.; et al. Bioorg. Med. Chem. 2003,11, 581. 14 Sakya, S. M. Knorr Pyrazole Synthesis In Name Reactions in Heterocyclic Chemistry,

Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 292 300. (Review).

333

Paal–Knorr pyrrole synthesis

Reaction between 1,4-ketones and primary amines (or ammonia) to give pyrroles. A variation of the Knorr pyrazole synthesis (page 331).

RR1

O

O

R2 NH2NR2

R R1

RR1

O

OHHNRR1

O

O

R2H2N:

R2

slow

N

HO

R

OH

R1 NR2

R1HO

R

H H

R2

:

NR2

R R1

NR2

R1

H H

NR2

R1HO

R

H

:

R

Example 15

NF

CONHPh

OEtEtO

O

OF

CONHPh

H2N OEt

OEt

1 eq. pivalic acidTHF, reflux, 43%

334

N

CO2

F

HO

HO

Ca2+

2

O

HN

Lipitor

Example 27

O

N

OCl

F

NH4OAc

NH

N

F Cl

HOAc110 °C

90%

References

1. Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. 2. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Re-

view). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977,

pp 51 57, 74 79. (Review). 4. Chiu, P. K.; Sammes, M. P. Tetrahedron 1990, 46, 3439. 5. Browner, P. L.; Butler, D. E.; Deering, C. F.; Le, T. V.; Millar, A.; Nanninga, T. N.;

Roth, B. D. Tetrahedron Lett. 1992, 33, 2279, 2283. 6. Yu, S.-X.; Le Quesne, P. W. Tetrahedron Lett. 1995, 36, 6205. 7. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8,

2689. 8. Robertson, J.; Hatley, R. J. D.; Watkin, D. J. J. Chem. Soc., Perkin 1 2000, 3389. 9. Braun, R. U.; Zeitler, K.; Mueller, T. J. J. Org. Lett. 2001, 3, 3297. 10. Gorlitzer, K.; Fabian, J.; Frohberg, P.; Drutkowski, G. Pharmazie 2002, 57, 243. 11. Quiclet-Sire, B.; Quintero, L.; Sanchez-Jimenez, G.; Zard, Z. Synlett 2003, 75. 12. Gribble, G. W. Knorr and Paal Knorr Pyrrole Syntheses In Name Reactions in Het-

erocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005,79 88. (Review).

335

Koch–Haaf carbonylation

Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.

R OH CO, H2O

H+

CO2HR

R O:H

H+protonation R O

H

H

Ralkyl

migration

R :C O: RO

the tertiary carbocation is thermodynamically favored

ROH2

OR

O

:OH2

acylium ion

ROH

O

H+

Example 15

OHHCO2H, H2SO4

rt, 66%

CO2H

336

Example 27

HCO2H, H2SO4

CCl4, 5 oC, 95%

OH

CO2H

References

1. Koch, H.; Haaf, W. Justus Liebigs Ann. Chem. 1958, 618, 251. 2. Kell, D. R.; McQuillin, F. J. J. Chem. Soc., Perkin Trans. 1 1972, 2096. 3. Norell, J. R. J. Org. Chem. 1972, 37, 1971. 4. Booth, B. L.; El-Fekky, T. A. J. Chem. Soc., Perkin Trans. 1 1979, 2441. 5. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365. 6. Farooq, O.; Marcelli, M.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem. Soc. 1988, 110,

864. 7. Takahashi, Y. Synth. Commun. 1989, 19, 1945. 8. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem.

Soc. 1995, 117, 3615. 9. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed.

2000, 39, 2547. 10. Xu, Q.; Inoue, S.; Tsumori, N.; Mori, H.; Kameda, M.; Tanaka, M.; Fujiwara, M.;

Souma, Y. J. Mol. Catal. A: Chem. 2001, 170, 147. 11. Tsumori, N.; Xu, Q.; Souma, Y.; Mori, H. J. Mol. Catalysis A: Chem. 2002, 179, 271. 12. Mori, H.; Mori, A.; Xu, Q.; Souma, Y. Tetrahedron Lett. 2002, 43, 7871. 13. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070. 14. Haubein, N. C.; Broadbelt, L. J.; Schlosberg, R. H. Ind. Eng. Chem. Res. 2004, 43, 18.

337

Koenig–Knorr glycosidation

Formation of the -glycoside from -halocarbohydrate under the influence of sil-ver salt.

O

HAcO Br

OH

H

AcO

Ac

AcOROH

Ag2CO3

O

HAcO H

OH

OR

AcO

Ac

AcO

AgBr CO2 H2O

O:

HAcO Br

OH

H

AcO

Ac

AcO

Ag+

O

HAcO OH

AcO

AcOO:

oxonium ion

O

HAcO H

OH

OR

AcO

Ac

AcO-anomer is

favored

HO

R:

O

HAcO OH

AcO

AcOO

-anomer

Example 113

OMeO2C

PivO

Br

OPivOPiv

NO2

HON

N CF3

Ag2O, 10 eq. HMTTA

CH3CN, rt, 6 h, 41%

338

OMeO2C

PivO

O

OPivOPiv

NO2

NN CF3

Example 215

O

HAcO Br

OH

H

AcO

Ac

AcO

OMe

OH

OMe

Cd2CO3, Tol.

reflux, 6 h, 84%

O

HAcO OH

O

AcO

Ac

AcO

References

1. Koenig, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957. 2. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 243 83. (Review). 3. Schmidt, R. R. Angew. Chem. 1986, 98, 213. 4. Greiner, J.; Milius, A.; Riess, J. G. Tetrahedron Lett. 1988, 29, 2193. 5. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991,

113, 2092. 6. Li, H.; Li, Q.; Cai, M.-S.; Li, Z.-J. Carbohydr. Res. 2000, 328, 611. 7. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000,

65, 8758. 8. Josien-Lefebvre, D.; Desmares, G.; Le Drian, C. Helv. Chim. Acta 2001, 84, 890. 9. Seebacher, W.; Haslinger, E.; Weis, R. Monatsh. Chem. 2001, 132, 8397. 10. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc.,

Perkin Trans. 1 2002, 242. 11. Kroger, L.; Thiem, J. J. Carbohydrate Chem. 2003, 22, 9. 12. Somsak, L.; Kovacs, L.; Gyollai, V.; Osz, E. Chem. Commun. 1999, 591. 13. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004,

69, 1097. 14. Claffey, D. J.; Casey, M. F.; Finan, P. A. Carbohydrate Res. 2004, 339, 2433. 15. Wimmer, Z.; Pechova, L.; Saman, D. Molecules 2004, 9, 902.

339

Kolbe–Schmitt reaction

Carboxylation of sodium phenoxides with carbon dioxide, to give salicylic acid, the precursor to the synthesis of aspirin.

O NaCO2

pressure

OHCO2 Na H

OHCO2H

O NaCO2

complexation

NaO

NaO

O

O

H

O

Onucleophilic

addition

OHCO2

HOH

CO2Haromatization

Naworkup

Example 13

CO2, KHCO3

85 90 oC, 60%

OH

NH2

OH

NH2

HO2C

Example 2, the Marasse modification of the Kolbe–Schmitt reaction uses excess of anhydrous potassium carbonate in place of carbon dioxide4

OHCO2 K

OHK2CO3, 175 oC

1200 200 psi CO2

340

Example 3, the Jones modification of the Kolbe–Schmitt reaction employs sodium ethyl carbonate5

OH OHCO2 NaNaOCO2C2H5 C2H5OH

Salicylic acid is the precursor to the synthesis of aspirin:

HO

OH

salicylic acid

O

O

OH

aspirin

O

O90%

CH3CO2H(CH3CO2)2O

References

1. Kolbe, H. Justus Liebigs Ann. Chem. 1860, 113, 1125. Hermann Kolbe (1818 1884) was born in Elliehausen, Germany. In 1860, at Marburg University, he developed a reaction to synthesize salicylic acid by simply treating phenol with carbon dioxide un-der high pressure at 180 200 oC. Like Wöhler’s urea synthesis, Kolbe’s synthesis of acetic acid by treating trichloroacetic acid with potassium amalgam is considered one of the first total syntheses in organic chemistry. One of his students, Friedrich von Heyden, founded a company to profit from the Kolbe reaction with much financial success.

2. Schmitt, R. J. Prakt. Chem. 1885, 31, 397. 3. Erlenmeyer, H.; Prijs, B.; Sorkin, E.; Suter, E. Helv. Chim. Acta 1948, 31, 988. 4. Marasse, S. German Patent 73,279, 1893.5. Jones, J. I. Chem. Ind. 1957, 889. 6. Lindsey, A. S.; Jeskey, H. Chem. Rev. 1957, 57, 583. (Review). 7. Kunert, M.; Dinjus, E.; Nauck, M.; Sieler, J. Ber. 1997, 130, 1461. 8. Kosugi, Y.; Takahashi, K. Stud. Surf. Sci. Catal. 1998, 114, 487. 9. Kosugi, Y.; Rahim, M. A.; Takahashi, K.; Imaoka, Y.; Kitayama, M. Appl. Or-

ganomet. Chem. 2000, 14, 841. 10. Rahim, M. A.; Matsui, Y.; Kosugi, Y. Bull. Chem. Soc. Jpn. 2002, 75, 619.

341

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 (acyla-tion) reaction:

O

O OOH

O

O

O

R R R O O

R

1 2 3

O

O

O

O

O

O

O

R

R

OO

R

OR H

acyl

transferH

:

O

O

O

R

H

O

O

O

Renolization 6-exo-trig

ring closure

O O

R

O O

OH

H2O

O O

OHHR

:B R

Example 15

H O

O OOH

O O

OEt

O

O O

OEt

HCO2Na, rt, 15 h, 76%

342

Example 213

O O

O

HO

O

O O

O

O

O

NaOAc, Ac2O, reflux

62 %

References

1. von Kostanecki, S.; Rozycki, A. Ber. Dtsch. Chem. Ges. 1901, 34, 102. 2. Hauser, C. R.; Swamer, F. W.; Adams, J. T. Org. React. 1954, 8, 59. (Review). 3. Cook, D.; McIntyre, J. S. J. Org. Chem. 1968, 33, 1746. 4. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715. 5. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599. 6. Okumura, K.; Kondo, K.; Oine, T.; Inoue, I. Chem. Pharm. Bull. 1974, 22, 331. 7. Wagner, H.; Farkas, L. In The Flavanoids; Harborne, J. B.; Mabry, T. J.; Mabry H.,

eds.; Academic Press: New York, 1975; p 127. (Review). 8. Ahluwalia, V. K. Indian J. Chem., Sect. B 1976, 14B, 682. 9. Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Het-

erocyclic Compounds, Weissberger, A. and Taylor, E. C., eds.; Wiley & Sons: New York, 1977, vol. 31, p.495. (Review).

10. Looker, J. H.; McMechan, J. H.; Mader, J. W. J. Org. Chem. 1978, 43, 2344. 11. Stanton, J. In Comprehensive Organic Chemistry-The Synthesis and Reactions of Or-

ganic Compounds; Sammes, P. G., ed.; Pergamon Press: New York, 1979, vol.4; p. 659. (Review).

12. Iyer, P. R.; Iyer, C. S. R.; Prasad, K. J. R. Indian J. Chem., Sect. B 1983, 22B, 1055. 13. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303. 14. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Ya. A.

Chemistry of Heterocyclic Compounds 2003, 39, 96. 15. Limberakis, C. Kostanecki Robinson Reaction In Name Reactions in Heterocyclic

Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 521 535. (Review).

343

Kröhnke pyridine synthesis

Pyridines from -pyridinium methyl ketone salts and -unsaturated ketones.

RN

O

Br

R1 R2

O

NH4OAc, HOAcNR R2

R1

RN

O

Br

R1 R2

OH

H+

enolizationR

NO

H Br

Michael

addition

AcO

ON

RBr

R2

O HR1

ON

RBr

R2

O R1

H

H+

O

R

R2

O R1

:NH3

O

R

R2

R1HO

H2N:

O

R

R2

HNR1

HOAc

The ketone is more reactive than the enone

NR2

R1

OHR

H H+

AcO

NR2 R

R1

344

Example 12

N

Ph O

+

O

Ph

Ph NPh Ph

PhNH4OAcAcOH

90%

Example 210

N

N

N

N

NN

N

N

N

N

N

O

O

O

N

NH4OAcAcOH

81%

References

1. Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690. 2. Kröhnke, F.; Zecher, W. Angew. Chem. Intl. Ed. 1962, 1, 626. 3. Kröhnke, F. Synthesis 1976, 1 24. (Review). 4. Chatterjea, J. N.; Shaw, S. C.; Singh, J. N.; Singh, S. N. Indian J. Chem., Sect. B 1977,

15B, 430. 5. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103,

3584, 3585. 6. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850. 7. Constable, E. C.; Ward, M. D.; Tocher, D. A. J. Chem. Soc., Dalton Trans. 1991,

1675. 8. Constable, E. C.; Chotalia, R. J. Chem. Soc., Chem. Commun. 1992, 65. 9. Markovac, A.; Ash, A. B.; Stevens, C. L.; Hackley, B. E., Jr.; Steinberg, G. M. J. Het-

erocycl. Chem. 1977, 14, 19. 10. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774. 11. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589. 12. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045. 13. Cave, G. W. V.; Raston, C. L. J. Chem. Soc. Perkin Trans. 1 2001, 3258. 14. 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).

345

Kumada cross-coupling reaction

The Kumada cross-coupling reaction (also occasionally known as the Kharasch cross-coupling reaction) is a nickel- or palladium-catalyzed cross-coupling reac-tion of a Grignard reagent with an organic halide, triflate, etc.

R XPd(0)

R R1R1 MgX MgX2

PdL

L X

R R1 MgXR X L2Pd(0)

transmetallationisomerization

oxidative

addition

MgX2 PdL

R R1

LR1R

reductive

eliminationL2Pd(0)

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 cycle as shown on the next page. There are slight variations for the Hiyama and Suzuki re-actions, for which an additional activation step is required for the transmetalation to occur.

The catalytic cycle:

LnPd(II) R1Mtransmetallation

R1

LnPd(II)R1

LnPd(0)R1R1reductive

elimination

346

L2Pd(0)

PdL

L X

PdL

R R1

R

L

XR

R1R

transmetallation and isomerization

reductiveelimination

oxidativeaddition

R1M

MX

Example 12

O SBr MgBr

Pd(dppf)Cl2, Et2O

–30 oC to rt, 5 h, 98%

O

S

Example 24

N Br PdCl2•(dppb)THF, rt, 87%

Br N MgBrN

NBr

S MgBr

PdCl2•(dppb)THF, reflux, 98%

N

N

S

347

References

1. Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Naka-jima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958.

2. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919. 3. Kalinin, V. N. Synthesis 1992, 413. 4. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737. 5. Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). 6. Park, M.; Buck, J. R.; Rizzo, C. J. Tetrahedron 1998, 54, 12707. 7. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889. 8. Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353. 9. Li, G. Y. J. Organomet. Chem. 2002, 653, 63. 10. Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150. 11. Banno, T.; Hayakawa, Y.; Umeno, M. J. Organomet. Chem. 2002, 653, 288. 12. Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68, 1190. 13. Phan, N. T. S.; Brown, D. H.; Styring, P. Green Chem. 2004, 6, 526. 14. Mans, D. M.; Pearson, W. H. J. Org. Chem. 2004, 69, 6419. 15. Shao, L.-X.; Shi, M. Org. Biomol. Chem. 2005, 3, 1828. 16. Semeril, D.; Lejeune, M.; Jeunesse, C.; Matt, D. J. Mol. Cat. A: Chem. 2005, 239, 257.

348

Lawesson’s reagent

2,4-Bis-(4-methoxyphenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide, trans-forms the carbonyl groups of ketones, amides and esters into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.

NH

O

SPS P

OO

S

SNH

SLawesson's reagent

NH

OSPS P

OO

S

S

2 O PS

S

:

O PO

S

NH

S

NH

SO PO

SS H

N O PS

O

Example 14

Lawesson's reagent

(Me2N)2C=S

xylene, 160 oC, 47%

OH

HO

OMe

O

OH

HS

OMe

S

349

Example 24

N

O

MeO2C H Lawesson's

reagent, 95%

N

S

MeO2C H

References

1. Lawesson, S. O.; Perregaad, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I. Bull. Soc. Chim. Belg. 1977, 86, 679.

2. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885. 3. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061. (Review). 4. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. Angew. Chem., Int. Ed. Engl. 1989, 27,

1362. 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 6. Luheshi, A. B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett.

1990, 31, 123. 7. Luo, Y.; He, L.; Ding, M.; Yang, G.; Luo, A.; Liu, X.; Wu, T. Heterocycl. Commun.

2001, 7, 37. 8. He, L.; Luo, Y.; Li, K.; Ding, M.; Luo, A.; Liu, X.; Wu, T.; Cai, F. Synth. Commun.

2002, 32, 1415. 9. Ishii, A.; Yamashita, R.; Saito, M.; Nakayama, J. J. Org. Chem. 2003, 68, 1555.

350

Leuckart–Wallach reaction

Amine synthesis from reductive amination of a ketone and an amine in the pres-ence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler–Clarke reductive alkylation of amines.

R1

R2O

R4HN

R3HCO2H

NR2

R1

R4

R3

CO2 H2O

R1

R2O:N

R3H

NHO

R1

R2R3

R4

R4

H N

HO

R1

R2R3

R4

:

HH

-aminoalcohol

HCO2HN

R2

R1

R4

R3H2O N

R1 R3

HHO

R4

O

R2

iminium ion intermediate reduction

NR2

R1

R4

R3

NH

R1

H

R3

R4R2H+

CO2

Example 15

HCO2H

60 oC, 57%CHO

HN

O

NO

Example 27

O

OHCN

HCO2H, H2O

190 oC, autoclave

16 h, 75%

N

351

References

1. Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341. 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, chem-istry 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. Justus Liebigs Ann. Chem. 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. 1948, 5, 301. (Review). 4. Staple, Ezra; Wagner, E. C. J. Org. Chem. 1949, 14, 559. 5. DeBenneville, P. L.; Macartney, J. H. J. Am. Chem. Soc. 1950, 72, 3073. 6. Lukasiewiecz, A. Tetrahedron 1963, 19, 1789. (Mechanism). 7. Bach, R. D. J. Org. Chem. 1968, 33, 1647. 8. Doorenbos, N. J.; Solomons, W. E. Chem. Ind. 1970, 1322. 9. Ito, K.; Oba, H.; Sekiya, M. Bull. Chem. Soc. Jpn. 1976, 49, 2485. 10. Musumarra, G.; Sergi, C. Heterocycles 1994, 37, 1033. 11. Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002,

67, 8685.

352

Lossen rearrangement

Treatment of O-acylated hydroxamic acids with base provides isocyanates.

R1 NH

O R2O

O

OHR1 N C O

H2OR1 NH2 CO2

R1 NO R2

O

O

OH

R1 NO R2

O

O

H

R1 N C O

:OH2

R2CO2

HO H

isocyanate intermediate

R1 NH2 CO2R1

HN O

OH

:B

decarboxylation

Example 16

Br

Cl

OEtO2C

HN

OCO2Et

Et3N, H2O Br

NC

O

EtOH, H2O

50% Br

NH2

353

Example 28

N

NHN

OAcO

OOMeMeO

DBU, THF, H2O

reflux, 1 h

N

NN

OOMeMeO

CO

N

NH2N

OOMeMeO

References

1. 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. 1974, 86, 419. 3. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735. 4. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485. 5. Zalipsky, S. Chem. Commun. 1998, 69. 6. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291. 7. Needs, P. W.; Rigby, N. M.; Ring, S. G.; MacDougall, A. J. Carbohydr. Res. 2001,

333, 47. 8. Ohmoto, K.; Yamamoto, T.; Horiuchi, T.; Kojima, T.; Hachiya, K.; Hashimoto, S.;

Kawamura, M.; Nakai, H.; Toda, M. Synlett 2001, 299.

354

McFadyen–Stevens reduction

Treatment of acylbenzenesulfonylhydrazines with base delivers the corresponding aldehydes.

R NH

HN

SO2Ar

OBase

R H

O

R N

HN

SO2Ar

O

R NN

O

H

B:

H

N2R

Ohomolytic

cleavage R H

O

H

Example 19

K2CO3, MeOH

reflux, 1 h, 75%H

OO2N

NHHN

SO2

OO2N

Example 211

NH

NO

NHNHTs

ONaCO3, glass powder

ethylene glycol

microwave (450 W)90%

NH

NO

H

O

355

References

1. McFadyen, J. S.; Stevens, T. S. J. Chem. Soc. 1936, 584. Thomas S. Stevens (1900 )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 Glas-gow, 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. 3. Sprecher, M.; Feldkimel, M.; Wilchek, M. J. Org. Chem. 1961, 26, 3664. 4. Jensen, K. A.; Holm, A. Acta. Chem. Scand. 1961, 15, 1787. 5. Babad, H.; Herbert, W.; Stiles, A. W. Tetrahedron Lett. 1966, 2927. 6. Graboyes, H.; Anderson, E. L.; Levinson, S. H.; Resnick, T. M. J. Heterocycl. Chem.

1975, 12, 1225. 7. Eichler, E.; Rooney, C. S.; Williams, H. W. R. J. Heterocycl. Chem. 1976, 13, 841. 8. Nair, M.; Shechter, H. J. Chem. Soc., Chem. Commun. 1978, 793. 9. Dudman, C. C.; Grice, P.; Reese, C. B. Tetrahedron Lett. 1980, 21, 4645. 10. Manna, R. K.; Jaisankar, P.; Giri, V. S. Synth. Commun. 1998, 28, 9. 11. Jaisankar, P.; Pal, B.; Giri, V. S. Synth. Commun. 2002, 32, 2569.

356

McMurry coupling

Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. Single-electron process.

R1

R2O

R2

R1

R2

R11. TiCl3, LiAlH4

2. H2OTiO

Ti(III)Cl3 LiAlH4 Ti(0)

R1

R2O :Ti(0)

single electron

transfer

homocoupling

R1

R2 R2R1

O OTi Ti

radical anion intermediate

R1

R2 R2R1

O O

Ti Ti

R1

R2 R2R1

O O

Ti Ti

R2

R1

R2

R1

O O

Ti Ti

oxide-coated titanium surface

Example 112

MeO2S

O

OZn, TiCl4, reflux

4.5 h, 75%, >99% Z

OH

357

OHMeO2S

Example 213

CHOSZn, TiCl4, THF,110 oC

microwave (10 W), 10 min.

87%

SS

References

1. McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708. 2. McMurry, J. E. Chem. Rev. 1989, 89, 1513 1524. (Review). 3. Ephritikhine, M. Chem. Commun. 1998, 2549. 4. Hirao, T. Synlett 1999, 175. 5. Yamato, T.; Fujita, K.; Tsuzuki, H. J. Chem. Soc., Perkin Trans. 1 2001, 2089. 6. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett.

2002, 43, 3645. 7. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843. 8. Kowalski, K.; Vessieres, A.; Top, S.; Jaouen, G.; Zakrzewski, J. Tetrahedron Lett.

2003, 44, 2749. 9. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035. 10. Ephritikhine, M.; Villiers, C. in Modern Carbonyl Olefination Takeda, T. ed., Wiley-

VCH: Weinheim, Germany, 2004, 223 285. (Review). 11. Rajakumar, P.; Gayatri Swaroop, M. Tetrahedron Lett. 2004, 45, 6165. 12. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513. 13. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491.

358

MacMillan catalyst

Highly enantioselective and general asymmetric organocatalytic Diels-Alder reac-tion using -amino acid-derived imidazolidinones (of type 1) as catalysts. The first generation of MacMillan catalyst (1) has been employed in a variety of or-ganocatalytic enantioselective reactions. Typical examples are: Diels-Alder reac-tion;1 nitrone cycloaddition,2 pyrrole Friedel Crafts reaction,3 indole addition,4

vinylogous Michael addition;5 -chlorination;6 hydride addition;7 cyclopropana-tion;8 -fluorination.9 The second generation of MacMillan catalyst (2) was used to catalyze 1,4-addition of C-nucleophiles employing various indoles.

HX

N

NH

Me

Ph

O

Me

Me

O+

imidazolidinone 1

5 mol% (1)

23 oC

82%, 94% ee(endo/exo 14:1)

CHO

O

N

NPh

O Me

+Me

Me

HX

N

NH

Me

Ph

O

Me

Me

H NN

Ph

MeMe

Me

O

+

dienophile

diene

CHO

359

N

R2

R3

R1

R4 O

N

NH

O

imidazolidinone 2

20 mol% 2, CH2Cl2-i-PrOH

87 to 50 oC

N

R2

R3

R1

O

R4 H

70 94% yield89 97% ee

Example 111

O

NBn

Bn

O

20 mol% 2

90%, 90% ee

O

NBn

Bn

O

Example 210

O

BocHN

1. 20 mol% 2

2. NaBH4, MeOHN

Br

360

N NH

BrBoc

OH

78% yield90% ee

N NH

BrMe

( )-flustramine B

References

1. Ahrendt, K.; Borths, C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 2. Jen, W.; Wiener, J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. 3. Paras, N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. 4. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. 5. Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,

1192. 6. Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108. 7. Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32. 8. Kunz, R. K; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. 9. Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826. 10. Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Nat.

Acad. Sci. USA, 2004, 101, 5482. 11. Kim, S.-G.; Kim, J.; Jung, H. Tetrahedron Lett. 2005, 46, 2437.

361

Mannich reaction

Three-component aminomethylation from amine, formaldehyde and a compound with an acidic methylene moiety.

H H

O

RNH

RR1

R2

O H+

N R2R

R R1

O

H H

O

R

HN

H+

R

N HR

R

OH

N HR

R

OH2:

NR

R

H

:

When R = H, the +Me2N=CH2 salt is known as Eschenmoser’s salt

R1

R2

O H+

enolizationN R2R

R R1

O

NR

R

R1

R2

OH

The Mannich reaction can also operate under basic conditions:

R1

R2

O

H

B:

enolate

formationN R2R

R R1

O

NR

R

R1

R2

O

Mannich Base

Example 1, asymmetric Mannich reaction4

ONH2

O

OHC

NO2

362

35 mol% (L)-proline

DMSO, rt, 50%, 94% ee

HN

O

O

NO2

Example 2, asymmetric aza-Mannich reaction13

No-Ts

OHN

O

O

In(Oi-Pr)3, ligand

MS 5 Å, THF, rt, 80%

NHo-Ts

OHN

O

O

References

1. Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647. 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. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045. 3. Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235. 4. List, B. J. Am. Chem. Soc. 2000, 122, 9336. 5. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. 6. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221. (Review). 7. Vicario, J. L.; Badía, D.; Carrillo, L. Org. Lett. 2001, 3, 773. 8. Martin, S. F. Acc. Chem. Res. 2002, 35, 895 904. (Review). 9. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851 862.

(Review). 10. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851 862.

(Review). 11. Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580 591. (Re-

view). 12. Córdova, A. Acc. Chem. Res. 2004, 37, 102 112. (Review). 13. Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2005, 44,

4365.

363

Marshall boronate fragmentation

Marshall boronate fragmentation is a variation of the Grob fragmentation (page 273) category.

OMs

BH3 SMe2

NaOMe

OMs

OMs

H2BH

OMe

BH3 SMe2

HH2B

OMs

OMe

Example 15

OH

OMs1. BH3 SMe2, THF, 0 oC to rt, 3 h

2. NaOMe, MeOH, rt, overnight

68%

OH

364

Example 26

1. BH3 SMe2, THF, 0 oC to rt, 3 h

2. NaOMe, MeOH, rt, overnight

11%

OMs

OAc

OH

References

1. Marshall, J. A.; Huffman, W. F. J. Am. Chem. Soc. 1970, 92, 6358. 2. Marshall, J. A. Synthesis 1971, 229. (Review). 3. Wharton, P. S.; Sundin, C. E.; Johnson, D. W.; Kluender, H. C. J. Org. Chem. 1972,

37, 34. 4. Minnaard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. Tetrahedron 1994, 50, 4755. 5. Zhabinskii, V. N.; Minnard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem.

1996, 61, 4022. 6. Minnard, A. J.; Stork, G. A.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 1997,

62, 2344.

365

Martin’s sulfurane dehydrating reagent

Dehydrates secondary and tertiary alcohols to give olefins, but forms ethers with primary alcohols. Cf. Burgess dehydrating reagent.

OHPh2S O HOC(CF3)2Ph

Ph2S[OC(CF3)2Ph]2

Ph2SOC(CF3)2Ph

OC(CF3)2Ph

H OtBu

HOC(CF3)2Ph O

Ph2SOC(CF3)2Ph

:The alcohol is acidic

OPh2S

OC(CF3)2Ph protonation

:H OC(CF3)2Ph

OC(CF3)2Ph

OPh2S

OC(CF3)2PhH

OH

Ph2S OC(CF3)2Ph

Ph2S O HOC(CF3)2Ph-elimination

E1cB

Example 19

O

OMeO

O

O

O

O

OMe

BzOOBn

OBn OH

OPMB

Martin's sulfurane

Et3N, CHCl3, 50 oC

85%

366

O

OMeO

O

O

O

O

OMe

BzOOBn

OBn

OPMB

Example 210

OO

OMe

MeO

CO2MeHO

TBSO

1.5 eq. Martin's sulfurane

CH2Cl2, rt, 24 h, 84% OO

OMe

MeO

TBSO

CO2Me

References

1. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339, 2341. J. C. Martin was a professor at the University of Illinois at Urbana, where he discovered the Martin’s sul-furane dehydrating reagent. Martin also developed the Dess Martin periodinane oxi-dation (page 195) with his student Daniele Dess.

2. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327. 3. Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977,

57, 22. 4. Bartlett, P. D.; Aida, T.; Chu, H.-K.; Fang, T.-S. J. Am. Chem. Soc. 1980, 102, 3515. 5. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347. 6. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807. 7. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317. 8. Rao, P. N.; Wang, Z. Steroids 1997, 62, 487. 9. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J.

Angew. Chem., Int. Ed. Engl. 1999, 38, 3340. 10. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; White-

head, R. C. Synlett 2002, 358. 11. Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. 12. 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. 13. Begum, L.; Box, J. M.; Drew, M. G. B.; Harwood, L. M.; Humphreys, J. L.; Lowes, D.

J.; Morris, G. A.; Redon, P. M.; Walker, F. M.; Whitehead, R. C. Tetrahedron 2003,59, 4827.

367

Masamune–Roush conditions

Applicable to base-sensitive aldehydes and phosphonates for the Horner–Wadsworth–Emmons reaction

(EtO)2POEt

O OCHO

AcO

-keto or -alkoxycarbonyl phosphonate required

N

N

LiCl, CH3CNAcO

CO2Et

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

(EtO)2POEt

O O

N

N

H

:

deprotonation

(EtO)2POEt

O O LiCl

chelation

AcO

(EtO)2POEt

O OLi

O

HAcO O

EtO2C P

O

OEtOEt

AcOCO2Et

AcO

EtO2C

O

P(OEt)2

O

368

Example 16

OOOMe

MeO

MOMO

OHOO

7

(EtO)2(O)P

OOOMe

MeO

MOMO

OO7

LiCl, Hunig base

MeCN, rt, 14 h, 58%

Example 27

CHOBocNO

Ph

N

O

O

O

Ph

(EtO)2(O)P

Li, DBU, CH3CN, rt, 67%

NBocN

O

Ph

O

O

O

Ph

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.

2. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703. 3. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035. 4. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 6389. 5. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. 6. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123. 7. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Red-

shaw, S.; Watson, W. Synlett 2004, 679.

369

Meerwein–Ponndorf–Verley reduction

Reduction of ketones to the corresponding alcohols using Al(Oi-Pr)3 in isopropanol.

R1 R2

O

R1 R2

OH OAl(Oi-Pr)3

HOi-Pr

R1 R2

O

Al(Oi-Pr)3

coordination

H OAlO

Oi-Pr

Oi-Pr

R1

R2

:

cyclic transition state

hydride

transfer

O

R1

R2 H

OAl

Oi-Pri-PrO

H+

R1 R2

OO Al(Oi-Pr)2

R1 R2

OH

Example 12

O

OH

H

MeO2CH

Al(Oi-Pr)3

HOi-Pr, 90%

OHH

O

O H

H

H

370

Example 212

Br3C H

OOH

Ph

Br3C

O

Ph

OAl

O

CH2Cl2, rt, 2.5 h, 58%

O

References

1. Meerwein, H.; Schmidt, R. Justus Liebigs Ann. Chem. 1925, 444, 221. 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.

2. Woodward, R. B.; Bader, F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1.

3. Ashby, E. C. Acc. Chem. Res. 1988, 21, 414. (Review). 4. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007.

(Review). 5. Aremo, N.; Hase, T. Tetrahedron Lett. 2001, 42, 3637. 6. Campbell, E. J.; Zhou, H.; Nguyen, S. T. Angew. Chem., Int. Ed. Engl. 2002, 41, 1020. 7. Faller, J. W.; Lavoie, A. R. Organometallics 2002, 21, 2010. 8. Nishide, K.; Node, M. Chirality 2002, 14, 759. 9. Jerome, J. E.; Sergent, R. H. Chem. Ind. 2003, 89, 97. (Review). 10. Sominsky, L.; Rozental, E.; Gottlieb, H.; Gedanken, A.; Hoz, S. J. Org. Chem. 2004,

69, 1492. 11. Fukuzawa, S.-i.; Nakano, N.; Saitoh, T. Eur. J. Org. Chem. 2004, 2863. 12. Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A.; Maruoka, K. Org. Biomol. Chem. 2004, 2,

3312.

371

Meisenheimer complex

Also known as Meisenheimer Jackson salt, the stable intermediate for certain SNAr reactions.

FNO2

NO2

RNH2

SNAr

NHNO2

NO2

R

Sanger’s reagent

FNO2

NO2

:R NH2

NO2

NO2SNAr, slow,

rate-determining step

FHNR

ipso attack ipso substitution

NHNO2

NO2

R

NO2

NO2

Ffast

FNHR

Meisenheimer complex (Meisenheimer Jackson salt)

Example 110

Ph CN

NO2

CO2Ett-BuOK, DMF/THF

70 oC, argon

NCO2Et

O O

HNC

Ph

372

Example 213

OHNO2O2N

NO2

N C N

CH2Cl2

argon, rt, 3 h2

NOO

O2N NO2N

N

N

O Ni-Pri-Pr

H

15.5%

NO2N

NO2

NH

O

15.8%

NO2

The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and iodo-dinitrobenzene—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.

References

1. Meisenheimer, J. Justus Liebigs Ann. Chem. 1902, 323, 205. 2. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181. (Review). 3. Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147. (Review). 4. Terrier, F. Chem. Rev. 1982, 82, 77. (Review). 5. Buncel, E.; Dust, J. M.; Manderville, R. A. J. Am. Chem. Soc. 1996, 118, 6072. 6. Sepulcri, P.; Goumont, R.; Hallé, J.-C.; Buncel, E.; Terrier, F. Chem. Commun. 1997,

789. 7. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614. 8. Weiss, R.; Schwab, O.; Hampel, F. Chem. Eur. J. 1999, 5, 968. 9. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org.

Chem. 1999, 64, 4572. 10. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099. 11. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548. 12. Kim, H.-Y.; Song, H.-G. Appl. Microbiol. Biotech. 2003, 61, 150. 13. Al-Kaysi, R. O.; Guirado, G.; Valente, E. J. Eur. J. Org. Chem. 2004, 3408.

373

[1,2]-Meisenheimer rearrangement

[1,2]-Sigmatropic rearrangement of tertiary amine N-oxides to hydroxylamines:

R2N

O

R1

R2N

OR

R1R

Example 15

O

O N

35% H2O2, CHCl3/MeOH, rt, 15 h

then PtO2, rt, 4.5 h

O

O NO

O

O

NO

THF, reflux, 1 h

64%, 2 steps

Example 26

N

N

N

O

O

Om-CPBA

CH2Cl2, 50%

N

N

N

O

O

OO

POCl3

100 oC, 66%

N

N

N

O

O

OCl

References

1. Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. 2. [1,2]-Sigmatropic rearrangement, Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.;

Roy, S. K. Tetrahedron 1970, 26, 4319. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). 4. Molina, J. M.; El-Bergmi, R.; Dobado, J. A.; Portal, D. J. Org. Chem. 2000, 65, 8574. 5. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996,

52, 14563. 6. Williams, E. J.; Kenny, P. W.; Kettle, J. G.; Mwashimba, P. G. Tetrahedron Lett.

2004, 45, 3737.

374

[2,3]-Meisenheimer rearrangement

[2,3]-Sigmatropic rearrangement of allylic tertiary amine-N-oxides to give O-allyl hydroxylamines:

NO

RR R

N

O

R1

23

1

2 1

2

1

23

Example 17

N

ON

PhSO2

Ph

Et2O, rt, 48 h48%, 61% de

NO

Example 28

NO

OHO

Bn

m-CPBA

CH2Cl2, 100%

NO

OHO

BnHO

Al2O3 (alumina)

MeOH

NO

OHO

BnO

CDCl3, rt

67%, 65% deN

OO OHO

Bn

375

References

1. Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. 2. [2,3]-Sigmatropic rearrangement, Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem.

1976, 41, 303. 3. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). 4. Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R.

Chem. Pharm. Bull. 1994, 42, 475. 5. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279. 6. Enders, D.; Kempen, H. Synlett 1994, 969. 7. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322. 8. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tet-

rahedron: Asymmetry 2000, 11, 4227. 9. Mucsi, Z.; Szabó, A.; Hermecz, I.; Kucsman, Á.; Csizmadia, I. G. J. Am. Chem. Soc.

2005, 127, 7615.

376

Meth–Cohn quinoline synthesis

Conversion of acylanilides into 2-chloro-3-substituted quinolines by the action of Vilsmeier’s reagent in warmed phosphorus oxychloride (POCl3) as solvent.

N

R2

O

H

N

R2

Cl

DMF, POCl3R1R1

N O

H

PO

ClClCl:

N O

H

PCl2

O

Cl

SN2

N O

Cl

PCl2

O

H

: N H

Cl O PCl2

O

Vilsmeier–Haack reagent

N

R2

OR1

HN

R2

R1

Cl

POCl3

N

R2

R1

HCl

NMe

MeCl

HN

R2

R1

Cl

(Me)2N

ClOPOCl2

N

R2

R1

Cl

R2 = H

377

Example 15

N

Me

OH

N

CHO

Cl

DMF, POCl3

75 oC, 16.5 h, 68%

Example 25

S NH

O

Me

NS Cl

DMF (1 equiv.), POCl3(3 equiv.), (CH2Cl)2

, 4 h, 79%

References

1. Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 2045; 2. Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 3111. 3. Meth-Cohn, O.; Tarnowski, B. Tetrahedron Lett. 1980, 21, 3721. 4. Meth-Cohn, O; Rhouati, S.; Tarnowski, B.; Robinson, A. J. Chem. Soc., Perkin Trans.

1 1981, 1537. 5. Meth-Cohn, O; Narine, B.; Tarnowski, B. J. Chem. Soc., Perkin Trans. 1 1981, 1520. 6. Meth-Cohn, O.; Tarnowski, B. Adv. Heterocycl. Chem. 1982, 31, 207. (Review). 7. Marson, C. M. Tetrahedron 1992, 48, 3659. (Review). 8. Meth-Cohn, O. Heterocycles 1993, 35, 539. (Review). 9. Swahn, B.-M.; Claesson, A.; Pelcman, B.; Besidski, Y.; Molin, H.; Sandberg, M. P.;

Berge, O.-G. Bioorg. Med. Chem. Lett. 1996, 6, 1635. 10. Swahn, B.-M.; Andersson, F.; Pelcman, B.; Söderberg, J.; Claesson, A. J. Labelled.

Compd. Radiopharm. 1997, 39, 259. 11. Ali, M. M.; Sana, S.; Tasneem; Rajanna, K. C.; Saiprakash, P. K. Synth. Comm. 2002,

32, 1351. 12. Moore, A. J. Meth–Cohn quinoline synthesis In Name Reactions in Heterocycl. Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 443 450. (Re-view).

378

Meyers oxazoline method

Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nu-cleophilic addition and substitution reactions that lead to the asymmetric construc-tion of carbon-carbon bonds.

N

O Ph

OMe N

O Ph

OMeR

1) LDA

2) R-X

N

O Ph

OMe

H

N(i-Pr)2

ON

Li

Ph

OMe

H3C

H

ONLi

Ph

OMe

H

H3C

XR

O

N

Ph

OMe

H

H3C

R

Example 18

N

O Ph

OMe

TMSO Br

1) LDA

2)

3) LDA

4) Me2SO4

N

O Ph

OMe

H

TMSO

H3O+

O

O

66% yield70% ee

379

Example 212

NO

PhOMe

Li

I

OO

NO

Ph OMeOO

1)

2)

99% yield

References

1. Meyers, A. I.; Knaus, G.; Kamata, K. J. Am. Chem. Soc. 1974, 96, 268. While Albert I. Meyers was an assistant professor at Wayne State University, neighboring pharma-ceutical 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. Meyers is currently Professor Emeritus at Colorado State University.

2. Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508. 3. Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 1333. 4. Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266. 5. Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186. 6. Meyers, A. I.; Mihelich, E. D. Angew. Chem. Int. Ed. 1976, 15, 270. (Review). 7. Meyers, A, I. Acc. Chem. Res. 1978, 11, 375–381. (Review). 8. Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45,

2792. 9. Meyers, A. I., Lutomski, K. A. in Asymmetric Synthesis, Morrison, J. D. ed. Vol III,

part B, Chapter 3, Academic Press, 1983. (Review). 10. Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). 11. Meyers, A. I.; Barner, B. A. J. Org. Chem. 1986, 51, 120. 12. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607. 13. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). 14. Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). 15. Wolfe, J. P. Meyers Oxazoline Method In Name Reactions in Heterocycl. Chemistry,

Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 237 248. (Review).

380

Meyer–Schuster rearrangement

The isomerization of secondary and tertiary -acetylenic alcohols to -unsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is ter-minal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement.

R

OHR

R1

H+, H2O

R R1

R O

R

OHR

R1

H+

R

OH2R

R1

E1

:OH2

R

R

R1

R •

R

R1

R •

R

R1

OH

H+

R R1

R Otautomerization

Example 18

POP

OPO

O

TMSO

O O

O PO

OTMSOTMS

PhSOH

ClCH2CH2Cl, 83 oC, 30 min.PhS

6%

PhS

O

54%

381

Example 210

OO

O

HOOEt

10% H2SO4

THF, rt, 1.5 h

OO

O

CO2Et

OO

O

CO2EtHO

70%21%

References

1. Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. 1922, 55, 819. 2. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). 3. Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli, M. D. J. Org. Chem. 1977,

42, 3403. 4. Cachia, P.; Darby, N.; Mak, T. C. W.; Money, T.; Trotter, J. Can. J. Chem. 1980, 58,

1172. 5. Andres, J.; Cardenas, R.; Silla, E.; Tapia, O. J. Am. Chem. Soc. 1988, 110, 666. 6. Tapia, O.; Lluch, J. M.; Cardenas, R.; Andres, J. J. Am. Chem. Soc. 1989, 111, 829. 7. Omar, E. A.; Tu, C.; Wigal, C. T.; Braun, L. L. J. Heterocycl. Chem. 1992, 29, 947. 8. Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka, T. J. Org. Chem.

1995, 60, 4798. 9. Lorber, C. Y.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 853. 10. Crich, D.; Natarajan, S.; Crich, J. Z. Tetrahedron 1997, 53, 7139. 11. Chihab-Eddine, A.; Daich, A.; Jilale, A.; Decroix, B. J. Heterocycl. Chem. 2000, 37,

1543.

382

Michael addition

Conjugate addition of a carbon-nucleophile to an -unsaturated system.

Example 1

O

NaCH(CO2Et)2

ONa

CO2Et

CO2Et

O

CO2Et

CO2Et

acidic

workup

Example 2

OR2CuX

O

R

O O

R

conjugate

addition

O

R

H+workup

CuR

R

Example 34

ON

OH2S, NaOMe

MeOH, 75%

ON

O

HS

383

Example 43

N Si(Me)2Ph

O

OCPh3

O

N Si(Me)2Ph

O

OCPh3

O Ph

PhMgBr, CuBr•DMS

ether, THF, 55 oC

92%, 92% de

References

1. 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 women or-ganic 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. Fleming, I.; Kindon, N. D. J. Chem. Soc., Chem. Commun. 1987, 1177. 3. Hunt, D. A. Org. Prep. Proced. Int. 1989, 21, 705. 4. D’Angelo, J.; Desmaële, D.; Dumas, F.; Guingant, A. Tetrahedron: Asymmetry 1992,

3, 459. 5. Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135 631. (Review). 6. Hoz, S. Acc. Chem. Res. 1993, 26, 69. (Review). 7. Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1010. (Review). 8. Itoh, T.; Shirakami, S. Heterocycles 2001, 55, 37. 9. Cai, C.; Soloshonok, V. A.; Hruby, V. J. J. Org. Chem. 2001, 66, 1339. 10. Sundararajan, G.; Prabagaran, N. Org. Lett. 2001, 3, 389. 11. Eilitz, U.; Le mann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003,

14, 189.

384

Michaelis Arbuzov phosphonate synthesis

Phosphonate synthesis from the reaction of alkyl halides with phosphites.

General scheme:

(R1O)3P R2 X R2 P

O

OR1

OR1

R1 X

R1 = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I

For instance:

CH3BrBrO

OP

OCH3O

CH3O

O

O(CH3O)3P

BrO

CH3

O

(CH3O)3P:

Br

PO

CH3O

CH3O

O

OCH3

CH3SN2

PO

CH3O

CH3O

O

OCH3Br

SN2

Example 13

Br

Br (EtO)3P, Tol.

145 oC, 4 h, 70%

P(OEt)2

O

385

Example 213

PO

BnO

BnOCl (BnO)3P

140 oC

8 h, 92%

PO

BnO

BnOPO

OBn

OBn

Example 314

O

FF

F Br (EtO)3P, NiCl2

100 oC, 72 h, 10%

O

FF

F PO

OEtOEt

References

1. Michaelis, A.; Kaehne, R. Ber. 31, 1048 (1898). 2. Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. 3. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559. 4. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. Engl.

1973, 12, 91. (Review). 5. Saady, M.; Lebeau, L.; Mioskowski, C. Tetrahedron Lett. 1995, 36, 5183. 6. Kato, T.; Tejima, M.; Ebiike, H.; Achiwa, K. Chem. Pharm. Bull. 1996, 44, 1132. 7. Waschb sch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727. 8. Griffith, J. A.; McCauley, D. J.; Barrans, R. E., Jr.; Herlinger, A. W. Synth. Commun.

1998, 28, 4317. 9. Kiddle, J. J.; Gurley, A. F. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 160, 195. 10. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393. 11. Nifantiev, E. E.; Khrebtova, S. B.; Kulikova, Y. V.; Predvoditelv, D. A.; Kukhareva,

T. S.; Petrovskii, P. V.; Rose, M.; Meier, C. Phosphorus, Sulfur Silicon Relat. Elem.2002, 177, 251.

12. Battaggia, S.; Vyle, J. S. Tetrahedron Lett. 2003, 44, 861. 13. Erker, T.; Handler, N. Synthesis 2004, 668. 14. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125, 1317. 15. Kadyrov, A. A.; Silaev, D. V.; Makarov, K. N.; Gervits, L. L.; Röschenthaler, G.-V. J.

Fluorine Chem. 2004, 125, 1407.

386

Midland reduction

Asymmetric reduction of ketones using Alpine-borane®.Alpine-borane® = B-isopinocampheyl-9-borabicyclo[3.3.1]nonane.

R1

O

R

Alpine-borane

neatR1

OH

R

BH

THF

reflux

B

(1R)-(+)- -pinene 9-BBN (R)-Alpine-borane

9-BBN = 9-borabicyclo[3.3.1]nonane

R1

O

R

BH

OR1

R

B

R1

O

R

B H2O2, NaOH

workupR1

OH

R

hydride

transfer

Example 16

BnOO

H

(R)-Alpine-borane, THF

10 oC to rt, 95%, 88% ee

387

BnOOH

H

Example 27

TBSO

O

OPMB(R)-Alpine-borane

22 oC, 6 kbar, 82%

80% de

TBSO

OH

OPMB

References

1. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979,101, 2352. M. Mark Midland was a professor at the University of California, River-side.

2. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc.1980, 102, 867.

3. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531. 4. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606. 5. Singh, V. K. Synthesis 1992, 605. (Review). 6. Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721. 7. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891.

388

Mislow–Evans rearrangement

[2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol.

R SAr

O ArS

O

R

P(OCH3)3HO

R

SAr

OAr

SO

R

:P(OCH3)3

R [2,3]-sigmatropic

rearrangement1

2

31

21

1

22

3

O

R

SN2Ar

SP(OCH3)3

H+ HO

R

Example 16

O

TBSOCHO

O

TBSOOMePhS

NaIO4dioxane/H2O

50%

Example 211

OO

OMe

MeOOTBS

SPh

O

(EtO)3P, EtOH

reflux, 16 h, 98%

OO

OMe

MeOOTBS

OH

References

1. Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100. 2. Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956. 3. Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672.

389

4. Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147. (Review). 5. Masaki, Y.; Sakuma, K.; Kaji, K. Chem. Pharm. Bull. 1985, 33, 2531. 6. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936. 7. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077. 8. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682. 9. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23. 10. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334. 11. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341. 12. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem. Int. Ed. 2005, 44, 3485.

390

Mitsunobu reaction

SN2 inversion of an alcohol by a nucleophile using diethyl azodicarboxylate (DEAD) and triphenylphosphine.

R1 R2

OH

R1 R2

Nu

DEAD, PPh3

NuH

:PPh3

N NCO2Et

EtO2C N NEtO2C

CO2Et

Ph3P

adduct

formation

H Nu

Diethyl azodicarboxylate (DEAD)

R1 R2

O PPh3 + N NCO2Et

HEtO2C

H

R1 R2

:OH

N NEtO2C

CO2Et

Ph3P

H

alcohol

activation

R1 R2

O PPh3

R1 R2

NuO PPh3

Nu

+SN2

reaction

Example 14

OHO

O CO2HO2N

DEAD, PPh3, Tol.

30 to 0 oC, 1 h, 90%

4-O2NPhCOOO

O

391

Example 23

O

OAcOAc

OAc

CH2OAc

OH

PhCO2H

DIAD, PPh3, THF

50 oC to rt, 2 h, 80%

O

OAcOAc

OAc

CH2OAc

O2CPh

2:1

References

1. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380. 2. Mitsunobu, O. Synthesis 1981, 1. (Review). 3. Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813. 4. Kocie ski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin

Trans. 1, 1987, 2183. 5. Hughes, D. L. Org. React. 1992, 42, 335 656. (Review). 6. Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127. (Review). 7. Barrett, A. G. M.; Roberts, R. S.; Schroeder, J. Org. Lett. 2000, 2, 2999. 8. Racero, J. C.; Macias-Sanchez, A. J.; Herandez-Galen, R.; Hitchcock, P. B.; Hanson,

J./ R.; Collado, I. G. J. Org. Chem. 2000, 65, 7786. 9. Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 41, 8285. 10. Charette, A. B.; Janes, M. K.; Boezio, A. A. J. Org. Chem. 2001, 66, 2178. 11. Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751. 12. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855. 13. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261.

392

Miyaura borylation

Palladium-catalyzed reaction of aryl halides with diboron reagent to produce aryl-boronates. Also known as Hosomi Miyaura borylation.

Ar IO

BOO

BO Pd(0)

base

OB

OAr

Ar I L2Pd(0)oxidative

additionPd

L

L I

Ar

OB

OOB

O base OB

OOB

O

base

PdL

L I

transmetallation

Ar

OB

OI

reductive

elimination

PdL

Ar B

L

O

O OB

OAr L2Pd(0)

Example 111

OB

OOB

OPh

BO

OPh

OAc O

CuCl, LiCl, KOAc, DMF, 92%

O

Example 212

OB

OOB

O

NCbz

3% (Ph3P)2PdCl2, 6% Ph3P

1.5 eq. K2CO3, dioxane, 90 oC

85%

NCbz

OTfBO

O

393

References

1. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457 2483. (Review). 3. Suzuki, A. J. Organomet. Chem. 1995, 576, 147. (Review). 4. Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477. 5. Willis, D. M.; Strongin, R. M. Tetrahedron Lett. 2000, 41, 8683. 6. Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 126. 7. Todd, M. H.; Abell, C. J. Comb. Chem. 2001, 3, 319. 8. Giroux, A. Tetrahedron Lett. 2003, 44, 233. 9. Arterburn, J. B.; Bryant, B. K.; Chen, D. Chem. Commun. 2003, 1890. 10. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885. 11. Ramachandran, P. V.; Pratihar, D.; Biswas, D.; Srivastava, A.; Reddy, M. V. R. Org.

Lett. 2004, 6, 481. 12. Occhiato, E. G.; Lo Galbo, F.; Guarna, A. J. Org. Chem. 2005, 70, 7324.

394

Moffatt oxidation

Oxidation of alcohols using DCC and DMSO, also known as “Pfitzner Moffatt oxidation”.

R1 R2

OH

R1 R2

ODCC

DMSO, HXDCC, 1,3-dicyclohexylcarbodiimide

N C N N C N

OS

HH+

R1 R2

:OH

HN C N

OS

H

NH

NH

O

1,3-dicyclohexylurea

R1 R2

OS

H

HH

X

R1 R2

OS

H

R1 R2

O(CH3)2S

Example 13

OH

OH

DCC, DMSO, PhNH+CF3CO2

PhH, rt, 70%

O

O

395

Example 210

O

O O

A OH

DCC, DMSO, Cl2CHCO2H

rt, 90 min., 90%

O

O O

A CHO

A = adenosine

References

1. Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027. 2. Harmon, R. E.; Zenarosa, C. V.; Gupta, S. K. J. Org. Chem. 1970, 35, 1936. 3. Schobert, R. Synthesis 1987, 741. 4. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167. 5. Tidwell, T. T. Org. React. 1990, 39, 297 . (Review). 6. Gordon, J. F.; Hanson, J. R.; Jarvis, A. G.; Ratcliffe, A. H. J. Chem. Soc., Perkin

Trans. 1, 1992, 3019. 7. Krysan, D. J.; Haight, A. R.; Lallaman, J. E. Org. Prep. Proced. Int. 1993, 25, 437. 8. Wnuk, S. F.; Ro, B.-O.; Valdez, C. A.; Lewandowska, E.; Valdez, N. X.; Sacasa, P.

R.; Yin, D.; Zhang, J.; Borchardt, R. T.; De Clercq, E. J. Med. Chem. 2002, 45, 2651. 9. Adak, A. K. Synlett 2004, 1651. 10. Wang, M.; Zhang, J.; Andrei, D.; Kuczera, K.; Borchardt, R. T.; Wnuk, S. F. J. Med.

Chem. 2005, 48, 3649.

396

Montgomery coupling

Oxidative nickel-catalyzed coupling of aldehydes and alkynes to generate allylic alcohols. Intermolecular and intramolecular examples are both effective, and the transmetalating agent (MR4) may be an organosilane, organoborane, organozinc, or alkenylzirconium.1 5

R1

O

H

R3 MR4

Ni(COD)2, LR1

OH R4

R3+

R2

R2

R1, R3 = alkyl or aryl

R2, R4 = alkyl, aryl, or H

The mechanism was proposed to involve the formation of a nickel metallacycle by the oxidative cyclization of Ni(0) with the aldehyde and alkyne, followed by conversion of the metallacycle to product by a transmetalation/reductive elimina-tion sequence. If R4 possesses a -hydrogen, then -hydride elimination after the transmetalation step generates the product with R4 = H in some instances. The mechanism was shown to be ligand dependent, and the mechanism depicted below is undoubtedly oversimplified.4

OR3

R2R1 H

LnNi

LnNi

O

R1 R2

R3MR4

LnNi

R4

R3

R2

MO

R1R1

OM R4

R3

R2

R4 lacks -H

R1

OM H

R3

R2

LnNi

H

R3

R2

MO

R1

R4 = HR4 = EtH2C CH2

397

Example 16

CH3 CH3

OO

N

HH3C OBn

O

H3C

H

CH3 CH3

OO

N

HH3C OBn

OSiEt3

H3C

Et3SiH

Ni(COD)2PBu3

93 %(single diast.)

Example 27

N

CH3

O

HC6H13

ZrCp2Cl

Ni(COD)2

ZnCl2

NH

OH

H3C

C6H13

+

69 %

Example 38

H

O

Ph

O

O

O

Me

Me

PhMe

Me

Ni(COD)2, PBu3

Et3B Ph

PhMe

O

OMe

MeHO

O

Me 44 %(>10:1 dr)

398

Example 49

O

O

OR2

R1

O

O

R2O

R1

or

O

O

R1O

HNi(COD)2, ligand

reducing agent

reducing agentligand yield (ratio)

PMe3

N N ArAr :

Ar = 2,6 di-isopropylphenyl

Et3B

Et3SiH

89 % (4.5:1)

93 % (1:5)

A number of related processes involving alternate -systems including enones, dienes, and allenes have been reported.10

References

1. Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. 2. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. 3. Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. 4. Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. 5. Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. 6. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950. 7. Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743. 8. Colby, E. A.; O'Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998. 9. Knapp-Reed, B.; Mahandru, G. M.; Montgomery, J. J. Am. Chem. Soc. 2005, 127,

13156. 10. Montgomery, J. Angew. Chem. Int. Ed. 2004, 43, 3890. (Review).

399

Morgan–Walls reaction

Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.

R1

NHRO POCl3

R1

NR

R1

NHOR

PCl ClCl

O

:R1

NHOR

POCl2

R1

NHOPOCl2R

:

R1

NR

H HOPOCl2

Example 110

O2N NO2

HNO

CN

nitrobenzene, POCl3

SnCl4, 98%

O2N NO2

N

CN

400

Pictet–Hubert reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250 300 °C.

R1

NHRO ZnCl2

R1

NR

250 300 oC

Example 27

N

OH

N

ZnCl2, 250 300 oC

80%

References

1. Pictet, A.; Hubert, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1182. 2. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1931, 2447. 3. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225. 4. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423. 5. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664. 6. Nagarajan, K.; Shah, R. K. Indian J. Chem. 1972, 10, 450. 7. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 1279. 8. Sivasubramanian, S.; Muthusubramanian, S.; Ramasamy, S.; Arumugam, N. Indian J.

Chem., Sect. B 1981, 20B, 552. 9. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1988, 31, 774. 10. 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. 11. Holsworth, D. D. Pictet–Hubert Reaction In Name Reactions in Heterocycl. Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465 468. (Re-view).

401

Mori Ban indole synthesis

Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare in-dole.

N

Br

Ac

CO2Me

Pd(OAc)2, Ph3P

NaHCO3, DMF, 130 oC,N

CO2Me

Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P:

Pd OAcAcO

Pd OAcPh3P:PPh3

AcO

Pd(0) O PPh3

OO PPh3

O

O O

AcO

Mori Ban indole synthesis:

N

Br

Ac

CO2Me

Pd(0)

NAc

CO2MePdLn

Br

oxidativeaddition

insertion

N

PdBrLn

Ac

MeO2C

H PdBrLnHNAc

CO2Me-hydride

elimination

402

HNAc

CO2MePdBrLn

N

CO2Me

Ac

-hydride

elimination

addition

of PdH

Regeneration of Pd(0):

H PdBrLn NaHCO3 Pd(0) NaBr H2O CO2

Example 11

I

NH

NH

MePd(OAc)2

Et3N, MeCNsealed tube

110 °C, 87%Example 212

Br

NCOCF3

SO2NHMe

Br

N

Cbz NHBr

NSO2NHMe

Cbz

Pd(OAc)2, Bu4NCl

Et3N, DMF heat, DME, 76%

References

1. Mori Ban indole synthesis, (a) Mori, M.; Chiba, K.; Ban, Y. Tetrahedron Lett. 1977,12, 1037; (b) Ban, Y.; Wakamatsu, T.; Mori, M. Heterocycles 1977, 6, 1711.

2. 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; (b) Amatore, C.; Carre, E.; M’Barki, M. A. Organometallics 1995, 14, 1818; (c) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009; (d) Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375.

3. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289. 4. Li, J. J. J. Org. Chem. 1999, 64, 8425. 5. 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. 6. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721. 7. Bosch, J.; Roca, T.; Armengol, M.; Fernandez-Forner, D. Tetrahedron 2001, 57, 1041.

403

Mukaiyama aldol reaction

Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether.

R CHO R1

OSiMe3

R2Lewis

acidR R2

OH

R1

O

R1

O

R2 R R2

OH

R1

O

R H

O

SiMe3

X SiMe3

LAX

Example 114

N

O

Bn

OTBDMS

N

O

OHCBoc

BF3•OEt2, DTBMP

CH2Cl2, 78 to 50 oC, 93%NBn

OH

N

O

BocO

O

Example 215

OSiMe3

OO

CHO

CN

1. PhCO2H, rt

2. TFA, 60%O

OO

NC

OH

404

References

1. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. 2. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. 3. Langer, P.; Koehler, V. Org. Lett. 2000, 2, 1597. 4. Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett. 2000, 41, 103. 5. Delas, C.; Blacque, O.; Moise, C. Tetrahedron Lett. 2000, 41, 8269. 6. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125. 7. Kumareswaran, R.; Reddy, B. G.; Vankar, Y. D. Tetrahedron Lett. 2001, 42, 7493. 8. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A.

A. J. Chem. Soc., Perkin Trans. 1 2002, 1344. 9. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161. 10. Muñoz-Muñiz, O.; Quintanar-Audelo, M.; Juaristi, E. J. Org. Chem. 2003, 68, 1622. 11. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Re-

actions. In Modern Aldol Reactions Mahrwald, R. (ed.), 2004, 25 68. (Review). 12. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590 5614. (Review). 13. Li, H.-J.; Tian, H.-Y.; Wu, Y.-C.; Chen, Y.-J.; Liu, L.; Wang, D.; Li, C.-J. Adv. Synth.

Cat. 2005, 347, 1247. 14. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7,

2795. 15. Acocella, M. R.; Massa, A.; Palombi, L.; Villano, R.; Scettri, A. Tetrahedron Lett.

2005, 46, 6141.

405

Mukaiyama Michael addition

Lewis acid-catalyzed Michael addition of silyl enol ether to -unsaturated sys-tem.

R1

OSiMe3

R2Lewis

acidR

O

R

OR1

R2

O

Example 14

O

OMe

OSiMe3

1. 0.1 mol% TBABB, THF, 3 h

2. 1 N HCl, THF, 0 oC, 0.5 h

87%

O

O

O

TBABB = tetra-n-butylammonium bibenzoate

Example 27

OMe

OSiMe3O1. neat DBU, rt, 24 h

2. 1 N HCl, THF, 68%

O

O

O

References

1. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. 2. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. 3. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 5590 5614. (Review). 4. Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047. 5. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada,

T. J. Org. Chem. 2003, 68, 10046. 6. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075. 7. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507. 8. Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637.

406

Mukaiyama reagent

Mukaiyama reagent such as 2-chloro-1-methyl-pyridinium iodide for esterification or amide formation.

General scheme:

R1CO2H R2OH

NXR3

Y

R1 OR2

O

NOR3

base

X = F, Cl, Br

Example 13

O CO2HHO

F4BN Br

O

OOBu3N, CH2Cl2

NO N BF4Br

O

O BrO

O

O

:

H

SNAr

H+

NBu3

NO

O

O OBn

Br

HO

NO

O

O

Bn

:

BF4 BF4

NOBn

OO O

:

H+NHO

BF4

407

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.4

Example 2, polymer-supported Mukaiyama reagent8

OOH

N Cl

Tf2O, CH2Cl2, 16 h, rt

ON

Cl

TfO

1.25 mmol/g

NH

CO2H

NHBocO

NH2

O

polymer-supportedMukaiyama reagent

Et3N, CH2Cl2, rt16 h, 88%

NH

NHBoc

OO

NH

O

References

1. Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045. 2. Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635. 3. Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707. 4. For amide formation, see: Huang, H.; Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1984,

1465. 5. Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402. 6. Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540. 7. Folmer, J. J.; Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998, 63, 8170. 8. Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579. 9. Mashraqui, S. H.; Vashi, D.; Mistry, H. D. Synth. Commun. 2004, 334, 3129. 10. Donati, D.; Morelli, C.; Taddei, M. Tetrahedron Lett. 2005, 46, 2817.

408

Myers Saito cyclization

Cf. Bergman cyclization and Schmittel cyclization.

hydrogen atom donor

or

hv•

•

Hreversible

allenyl enyne diradical

H

Example 16

Ph

Ph

H

PhH, reflux

96 h, 40%Ph Ph

409

Example 2, aza-Myers Saito reaction16

Ph

N CDCl3

10 oC, 12 h

NCHO

Ph

N

Ph

MeOH

0 oC, 14 h

OMe

References

1. Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. 2. Saito, K.; Watanabe, T.; Takahashi, K. Chem. Lett. 1989, 2099. 3. Saito, I.; Nagata, R.; Yamanaka, H.; Murahashi, E. Tetrahedron Lett. 1990, 31 2907. 4. Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369. 5. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975. 6. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38,

6177. 7. Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew. Chem.,

Int. Ed. 1998, 37, 1960. 8. Ferri, F.; Bruckner, R.; Herges, R. New J. Chem. 1998, 22, 531. 9. Cramer, C. J.; Squires, R. R. Org. Lett. 1999, 1, 215. 10. Bruckner, R; Suffert, J. Synlett 1999, 657 679. (Review). 11. Kim, C.-S.; Diez, C.; Russell, K. C. Chem. Eur. J. 2000, 6, 1555. 12. Cramer, C. J.; Kormos, B. L.; Seierstad, M.; Sherer, E. C.; Winget, P. Org. Lett. 2001,

3, 1881. 13. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem.

2002, 67, 1453. 14. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124, 1823. 15. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871. 16. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059. 17. Schmittel, M.; Mahajan, A. A.; Bucher, G. J. Am. Chem. Soc. 2005, 127, 5324.

410

Nazarov cyclization

Acid-catalyzed electrocyclic formation of cyclopentenone from di-vinyl ketone.

OH+

O

O

H+

Oprotonation

H HO

H

O

tautomerization

OH

Example 12

NCO2Me

O

SiMe3

ZrCl4, (CH2Cl)2

60 oC, 36 h, 76%NCO2Me

H O

H

Example 2, cyclization of in situ generated di-vinyl ketone12

H3PO4, 60 65 oC

6 h, 65%

O

References

1. Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (1900 1957) discovered this reaction in 1942 in Russia.

2. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 2821. 3. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1 158. (Review).

411

4. Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.; Hitono, Y. Tetrahedron2000, 56, 6441.

5. Giese, S.; Kastrup, L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970. 6. Kim, S.-H.; Cha, J. K. Synthesis 2000, 2113. 7. Giese, S.; West, F. G. Tetrahedron 2000, 56, 10221. 8. Fernández M., A.; Martin de la Nava, E. M.; González, R. R. Tetrahedron 2001, 57,

1049. 9. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124, 14328. 10. Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171.

412

Neber rearrangement

-Aminoketone from tosyl ketoxime and base.

R1

R2

NOTs

1. KOEt

2. H2OR1 R2

NH2

O

TsOH

ketoxime -aminoketone

deprotonation

R2

NOTs

cyclizationH

R2

NOTs

R1EtOR1

TsOH N

R2R1

:OH2 hydrolysisH+

azirine intermediate

R1 R2NH2

O

HN

R2R1

O H

Example 15

N

Br

TsO

1. EtOH, HCl (g)

2. Na2CO3, 92%Br

OEtEtONH2

413

Example 215

N

N

N

TsON

MeO

OSEM

OMe

N

Br

Ts

1. KOH, H2O, EtOH, 0 oC, 3 h

2. 6 N HCl, 60 oC, 10 h, 96%

3. K2CO3, THF, H2O, 10 min.

N

N

HN

O

MeO

O

OMe

N

Br

Ts

H2N

References

1. Neber, P. W.; v. Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449, 109. 2. O’Brien, C. Chem. Rev. 1964, 64, 81. (Review). 3. Kakehi, A.; Ito, S.; Manabe, T.; Maeda, T.; Imai, K. J. Org. Chem. 1977, 42, 2514. 4. Friis, P.; Larsen, P. O.; Olsen, C. E. J. Chem. Soc., Perkin Trans. 1 1977, 661. 5. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329. 6. Corkins, H. G.; Storace, L.; Osgood, E. J. Org. Chem. 1980, 45, 3156. 7. Hyatt, J. A. J. Org. Chem. 1981, 46, 3953. 8. Parcell, R. F.; Sanchez, J. P. J. Org. Chem. 1981, 46, 5229. 9. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996,

118, 8491. 10. Oldfield, M. F.; Botting, N. P. J. Labelled Compounds Radio. 1998, 41, 29. 11. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144 146, 351. 12. Banert, K.; Hagedorn, M.; Liedtke, C.; Melzer, A.; Schoffler, C. Eur. J. Org. Chem.

2000, 257. 13. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363. 14. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640. 15. Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970.

414

Nef reaction

Conversion of a primary or secondary nitroalkane into the corresponding carbonyl compound.

R1 R2

NO2

R1 R2

O1/2N2O 1/2H2O

1. NaOH

2. H2SO4

R1 R2

NO O

H

H+

R1 R2

NO O

HO

H2O

nitronate

R1 R2

NHO O

OH

HR1 R2

NO

OH

H2O + H+H+

R1 R2

NHO OH

:OH2

nitronic acid

R1 R2

OHNO 1/2N2O 1/2H2O

R1 R2

NHO

OH

R1 R2

O

Example 17

O

NO2

1. NaOH, EtOH, 0 oC, 30 min.

2. 3 M HCl, 20 oC, 12 h, 68%

O

O

415

Example 211

H

HONO2

1. 2 M NaOH, MeOH

2. ice-cooled KMnO4 45% H

HOO

References

1. Nef, J. U. Justus Liebigs Ann. Chem. 1894, 280, 263. John Ulrich Nef (1862 1915) was born in Switzerland and emmigrated 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 Univer-sity, and the University of Chicago. The Nef reaction was discovered at Clark Univer-sity 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 . (Review). 3. Hwu, J. R.; Gilbert, B. A. J. Am. Chem. Soc. 1991, 113, 5917. 4. Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Epifano, F.; Rosati, O. Synth. Com-

mun. 1998, 28, 3057. 5. Adam, W.; Makosza, M.; Saha-Moeller, C. R.; Zhao, C.-G. Synlett 1998, 1335. 6. Shahi, S. P.; Vankar, Y. D. Synth. Commun. 1999, 29, 4321. 7. Thominiaux, C.; Rousse, S.; Desmaele, D.; d’Angelo, J.; Riche, C. Tetrahedron:

Asymmetry 1999, 10, 2015. 8. Capecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin 1 2000, 2681. 9. Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett. 2002, 43, 5233. 10. Petrus, L.; Petrusova, M.; Pham-Huu, D.-P.; Lattova, E.; Pribulova, B.; Turjan, J.

Monatsh. Chem. 2002, 133, 383. 11. Chung, W. K.; Chiu, P. Synlett 2005, 55.

416

Negishi cross-coupling reaction

Palladium-catalyzed cross-coupling reaction of organozinc reagents with organic halides, triflates, etc. It is compatible with many functional groups including ke-tones, esters, amines, and nitriles. For the catalytic cycle, see the Kumada cou-pling on page 345.

R X R1 ZnXPd(0)

R R1 ZnX2

R1 ZnX

R X L2Pd(0) transmetallationisomerization

oxidative

additionPd

L

L X

R

ZnX2 PdL

R R1

LR1R

reductive

eliminationL2Pd(0)

Example 15

N

I

O

HO

O

O

O

Ph

Ph

N

CH2CO2Et

O

HO

O

O

O

Ph

Ph

BrZnCH2CO2Et, Pd(Ph3P)4

HMPA/(CH2OCH3)2 (1:1)3.5 h, 40%

Example 26

BnOZnI

O

NHTrtBnO

IO

NHTrt

activated

Zn/Cu couple

417

N

N

I

Boc

CO2t-Bu

NHBoc

NHTrt

N

NBoc

CO2t-Bu

NHBoc

BnO

O

PdCl2(Ph3P)2, DMA

40 oC, 79%

References

1. Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596. 2. Negishi, E.-I. et al. J. Org. Chem. 1977, 42, 1821. 3. Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (Review). 4. Erdik, E. Tetrahedron 1992, 48, 9577. (Review). 5. De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Hetero-

cycl. Chem. 1993, 30, 1245 6. Evans, D. A.; Bach, T. Angew. Chem., Int. Ed. Engl, 1993, 32, 1326. 7. Negishi, E.-I.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; 1998, Diederich,

F.; Stang, P. J. eds.; Wiley–VCH: Weinheim, Germany, pp 1–47. (Review). 8. Yus, M.; Gomis, J. Tetrahedron Lett. 2001, 42, 5721. 9. Lutzen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292. 10. Fang, Y.-Q.; Polson, M. I. J.; Hanan, G. S. Inorg. Chem. 2003, 42, 5. 11. Arvanitis, A. G.; Arnold, C. R.; Fitzgerald, L. W.; Frietze, W. E.; Olson, R. E.; Gilli-

gan, P. J.; Robertson, D. W. Bioorg. Med. Chem. Lett. 2003, 13, 289. 12. Ma, S.; Ren, H.; Wei, Q. J. Am. Chem. Soc. 2003, 125, 4817.

418

Nenitzescu indole synthesis

5-Hydroxylindole from condensation of p-benzoquinone and -aminocrotonate.

N

CO2R3

O

O

H

HN

CO2R3

R2R2R1

HO

R1

O

O

H

HN

CO2R3

R2

R1

:

HO

OR1

conjugate

addition NR2

CO2R3

H

H+

H+

N

CO2R3

R2

HO

R1 N

CO2R3

R2

HO

R1

H

OH

Example 17

NH

HNBn

O

O

O1. aetone, rt, 48 h2. 20% TFA, CH2Cl2 86%

N

ONH2

Bn

HO

Example 28

N

CO2CH3

O

O

H

HN

CO2CH3 HOCH3NO2, rt

95%

419

References

1. Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37. 2. Allen, Jr. G. R. Org. React. 1973, 20, 337. (Review). 3. Patrick, J. B.; Saunders, E. K. Tetrahedron Lett. . 1979, 4009. 4. Bernier, J. L.; Henichart, J. P. J. Org. Chem. 1981, 46, 4197. 5. Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa, T.; Tomioka, S.; Kasai,

M. J. Chem. Soc., Perkin Trans. 1 1995, 2677. 6. Mukhanova, T. I.; Panisheva, E. K.; Lyubchanskaya, V. M.; Alekseeva, L. M.;

Sheinker, Y. N.; Granik, V. G. Tetrahedron 1997, 53, 177. 7. Ketcha, D. M.; Wilson, L. J.; Portlock, D. E. Tetrahedron Lett. 2000, 41, 6253. 8. Brase, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. Lett. 2002, 10, 2415. 9. Lyubchanskaya, V. M.; Savina, S. A.; Alekseeva, L. M.; Shashkov, A. S.; Granik, V.

G. Mendeleev Commun. 2004, 73. 10. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert, A.; Kucklaender, U. Tetra-

hedron 2005, 61, 9129.

420

Nicholas reaction

Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives propargylated product.

R1

R4

OR2

R31. Co2(CO)8

2. H+ or Lewis acid

1. NuH

2. [O]R1

R4

NuR3

R1

R4

OR2

R3

(CO)4Co Co(CO)3

CO

CO

R1

R3OR2

Co(CO)3(CO)3Co

CO

R4

CO

R1

R3O

Co(CO)3(CO)3Co

R4 R2H

R1

R3OR2

Co(CO)3(CO)3Co

R4

+ H+SN1

R1

R3

Co(CO)3(CO)3Co

R4R1

R3

Co(CO)3(CO)3Co

R4Nu

[O]

demetallation

NuH

propargyl cation intermediate (stabilized by the hexacarbonyldicobalt com-plex).

C OO R1

R3

Co(CO)2(CO)3Co

R4Nu R1

R4

NuR3

Example 1, chromium variant of the Nicholas reaction5

1. HBF4·Et2O, CH2Cl2, 60 oC

2. 5 eq. X, CH2Cl2, 60 oC, 86%

HN NO

CO2n-Bu

OH

Cl

Cr(CO)3X =

421

N N

Cl

OCO2n-Bu

Cr(CO)3

N N

Cl

OCO2H

2HCl

Zyrtec

Example 2, intramolecular Nicholas reaction using chromium11

OAc

Cr(CO)3BF3•OEt2, CH2Cl2

0 oC, 3.5 h, 49% Cr(CO)3

References

1. Nicholas, K. M. J. Organomet. Chem. 1972, C21, 44. 2. Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 4163. 3. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. (Review). 4. Roth, K. D. Synlett 1992, 435. 5. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. 6. Diaz, D.; Martin, V. S. Tetrahedron Lett. 2000, 41, 743. 7. Guo, R.; Green, J. R. Synlett 2000, 746. 8. Green, J. R. Curr. Org. Chem. 2001, 5, 809 826. (Review). 9. Teobald, B. J. Tetrahedron 2002, 58, 4133 4170. (Review). 10. Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625. 11. Ding, Y.; Green, J. R. Synlett 2005, 271. 12. Crisostomo, F. R. P.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett. 2005,

46, 2829.

422

Nicolaou dehydrogenation

, -Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of IBX (o-iodoxybenzoic acid), alternative to Saegusa oxidation (page 515).1

R1

O

R3

R2

IO

O

OHO

IBX = o-iodoxybenzoic acid R1

O

R3

R2

A SET mechanism has also been proposed.2 Additionally, silyl enol ethers are also viable substrates.3

R1

O

R3

R2

R1

HO

R3

R2 IO

O

O

HOtautomerization

R1

O

R3

R2IOHO

O OH

H

R1

O

R3

R2

Example 11

H

OH

H H

H

OH

H H

IBXfluorobenzene

DMSO

65 °C, 24 h80%

423

Example 24

O

OH

H

TBSO

MeO2C CO2Me

O

OH

H

TBSO

MeO2C CO2Me

IBX

DMSO–Tol.80 °C, 3 h, 52%

e. g.310

NMe

NO

MeO

H

H

H

HO

IBX

Tol., DMSO70 °C

NMe

NO

MeO

H

H

H

H

O

References

1. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. 2. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993. 3. Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew. Chem., Int.

Ed. 2002, 41, 996. 4. Ohmori, N. J. Chem. Soc., Perkin Trans. 1 2002, 755. 5. Shimokawa, J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem.,

Int. Ed. 2004, 43, 1559. 6. Zhang, D.-H.; Cai, F.; Zhou, X.-D.; Zhou, W.-S. Org. Lett. 2003, 5, 3257. 7. Hayashi, Y.; Yamaguchi, J.; Shoji, M. Tetrahedron 2002, 58, 9839. 8. Miyazawa, N.; Ogasawara, K. Synlett 2002, 1065. 9. Smith, N. D.; Hayashida. J.; Rawal, V. H. Org. Lett. 2005, 7, 4309. 10. Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339. 11. Nagata, H.; Miyazawa, N.; Ogasawara, K. Org. Lett. 2001, 3, 1737. 12. Herzon, S. B.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 5342.

424

Nicolaou hydroxy-dithioketal cyclization

Two step synthesis of medium-ring ethers through the intermediacy of thionium ions followed by sulfide reduction.

EtSEtS 1. NCS, AgNO3,

SiO2, 2,6-lut.

2. Ph3SnH, AIBN

OH

H

OH

The mechanism is analogous to the hydroxy-ketone cyclization except that the mixed ketal is isolable. It can be reductively cleaved using Ph3SnH/AIBN:

EtSEtS

Cl N

O

O

Ag

NO3

EtSEtS

HO

Cl

OH

thioniumformation OH

EtSOEtS

H

SnPh3

homolyticreduction

OH

H

OH

H

425

e. g. 11

O

OH

OHHEtS

EtS

O

OO

H

H

H1. AgNO3, NCS, SiO2 2,6-lut., 3 Å MS 5 min, 95%

2. Ph3SnH, AIBN, toluene, 110 °C, 95%

Example 2, carbocyclization is also possible3:

NH

N

H

H

EtS

EtS

OAc

H

HN

N

H

EtS

H OAcH

H

AgNO3, 3 Å MSSiO2, 2,6-lut., NCS

CH3CN, 44%

Example 3, the cyclizations tolerate ordinary acetals5:

O

O

O

H

OPiv

H

HOH

EtSEtS

Ph

1. AgClO4, NaHCO3 SiO2, 3 Å MS CH3NO2, 25 °C 4 h, 74%

2. Ph3SnH, AIBN toluene, 110 °C 3 h, 95%

O

O

O

H

OPiv

H

HO

PhH

References

1. Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc. 1986, 108, 2468. 2. Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999, 64, 9416. 3. Shin, K.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 3765. 4. Trost, B. M.; Nübling, C. Carbohydrate Res. 1990, 202, 1. 5. Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Wallace, P.

A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.; Yang, Z. Chem. Eur. J. 1999, 5, 599. 6. Nicolaou, K. C.; Gunzner, J. L.; Shi, G.-Q.; Agrios, K. A.; Gärtner, P.; Yang, Z.

Chem. Eur. J. 1999, 5, 646.

426

Nicolaou hydroxy-ketone reductive cyclic ether formation

Acid-catalyzed conversion of a ketone with a pendant hydroxyl group into a cyclic ether with net reduction of the carbonyl.

OPhOHO PhH H

Et3SiH, TMSOTf

CH2Cl2, 0 °C15 min., 90%

The mechanism involves hemiketal formation followed by reduction of the oxocarbonium group:

PhOHO

TMS OTf

silylation;hemiketal

formationO

HPh

OTMS

OH Ph

TES H

O PhH H

Example 11

O

O

OBnO

BnO

H

H H

H

H

O

O

HOH

HTMSOTf, MePh2SiH

CH2Cl2, 0 °C, 2 h, 62%

O

O

O

O

OHHMeH

BnO

HBnO

H H MeH H

427

e. g. 22

O

OO

OBz

OMTM

OBn

H

TfOH, EtMe2SiH

CH2Cl2, CH3CN,50 to 20 °C,

1 h, 81%

O

O

H

O

H H

OBz

OBn

References

1. Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989, 111, 4136. 2. Smith, A. B.; Cui, H. Helv. Chim. Acta 2003, 86, 3908. 3. Watanabe, K.; Suzuki, M.; Murata, M.; Oishi, T. Tetrahedron Lett. 2005, 46, 3991. 4. Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.;

Suzuki, T. Tetrahedron Lett. 2004, 45, 7011. 5. González, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099. 6. Alvarez, E.; Pérez, R.; Rico, M.; Rodríguez, R. M.; Martín, J. D. J. Org. Chem. 1996,

61, 3003.

428

Nicolaou oxyselenation

Activation of alkenes towards nucleophilic attack by a variety of nucleophiles em-ploying N-phenylselenophthalimide or N-phenylselenosuccinimide as an electro-philic source of the phenylseleno group.

N

O

O

Se N

O

O

Se

N-PSP = N-phenylselenophthalimide N-PSS = N-phenylselenosuccinimide

Se

OH

N-PSP

CH2Cl2,H2O, 89%

The reagent may require acid activation depending on the type of transforma-tion being attempted. The mechanism parallels that of halohydrin formation using an electrophilic source of halide in an aqueous medium:

N

O

O

SePh

selenoniumformation

Se

N

O

ONu M

Markovnikov

addition

Nu

Se+ N

O

O

M

429

Example 13

MeO

O

O

BnO

OH

MeO OO

BnO

O

HPhSe

N-PSP, CSA

CH2Cl2, rt2 h, 60%

Example 2, in addition to oxyselenide formation, carbo- and heteroseleno cycliza-tion, N-PSP can be used to generate selenides from alcohols and selenol esters from carboxylic acids, respectively, in the presence of a stoichiometric amount of n-Bu3P.6

OO

OTBDPS

OH

OO

OTBDPS

SePh

N-PSP, n-Bu3P

CH2Cl2, 25 to 20 °C3 h, 73%

References

1. Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc.1979, 101, 3704.

2. Chrétien, F.; Chapleur, Y. J. Org. Chem. 1988, 53, 3615. 3. Kühnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643. 4. Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125, 7822. 5. Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Dan-

ishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. 6. Grieco, P. A.; Jaw, J. Y.; Claremon, D. A.; Nicolaou, K. C. J. Org. Chem. 1981, 46,

1215. 7. Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. Tetrahedron 1985, 41, 4835.

430

Noyori asymmetric hydrogenation

Asymmetric reduction of carbonyl via hydrogenation catalyzed by ruthenium(II) BINAP complex.

R OR1

O O H2

(R)-BINAP-Ru R OR1

OH O

(R)-BINAP-Ru =

PPh2

PPh2

RuCl2L2

[RuCl2(binap)(solv)2]H2

HCl

[RuHCl(binap)(solv)2]

The catalytic cycle:

R

OR1

O

O

[RuHCl(binap)(solv)2]

(binap)ClHRu

R

OR1

O

O(binap)ClRu

H+

[RuCl(binap)(solv)2]+

R OR1

OH O

solv

R OR1

O O

solv

H2

H+, solv

HH

431

Example 12

OH

Ru((S)-BINAP(CF3CO2)2

30 atm H2, rt, 96% ee

OH

Example 23

O

Br

Ru((R)-BINAP(Cl)2

100 atm H2, rt, 92% ee

OH

Br

References

1. Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, Ma.; Ohta, T.; Takaya, H. J. Am. Chem. Soc. 1986, 108, 7117. Ryoji Noyori (Japan, 1938 ) and Herbert 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.

2. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; nnn J. Am. Chem. Soc. 1987, 109, 1596.

3. Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, Hi.Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. et al. J. Am. Chem. Soc. 1988, 110, 629.

4. Noyori, R.; Ohkuma, T.; Kitamura, H.; Takaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856.

5. Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1991, 781. 6. King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,

6689. 7. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New

York, 1994, chapter 2. (Review). 8. Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; Mcnamara, J. M.; Grabowski, E. J. J.; Rei-

der, P. J. Tetrahedron Lett. 1995, 36, 7379. 9. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9,

2015. 10. Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40. 11. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (Review, Nobel Prize Address). 12. Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693. 13. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733.

432

Nozaki–Hiyama–Kishi reaction

Cr Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.

RBr R1 CHO

CrCl2, NiBr2

DMSO SMe2R R1

OH

RBr

NiBr2

SMe2

reductionNi(0)

oxidativeaddition

RNi(II) Br

R1 CHO

RCr(III)Cl2

nucleophilicaddition

CrCl2 CrCl3

Ni(0)Ni(II)

Transmetalation and then reduction by Me2S

R R1

OCrCl2

R R1

OHhydrolysisCrCl2X

The catalytic cycle:7

X

OCrX2

R

OSiMe3

R

2 CrX2 2 CrX3

RCHO

Me3SiX

MnMnX2

CrX2

433

Example 18

AcOCHO

OTHPI OTBDPS

AcOOTBDPS

OTHP

OH

10 eq CrCl2, cat. NiCl2

DMSO, 25 oC, 12 h, 80%

Example 212

4 eq CrCl20.008 eq NiCl2

DMF, rt, 15 h35%

O

OOHC

OOTf

O

O

OOH

References

1. Okude, C. T.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179. Hitosi Nozaki and T. Hiyama are professors at the Japanese Academy.

2. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983,24, 5281. Kazuhiko Takai was Prof. Nozaki’s student during the discovery of the re-action and is a professor at Okayama University.

3. Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. Yo-shita Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin.

4. Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048.

5. Wessjohann, L. A.; Scheid, G. Synthesis 1991, 1. (Review). 6. Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999. 7. The catalytic cycle: Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. 8. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565. 9. Boeckman, R. K., Jr.; Hudack, R. A., Jr. J. Org. Chem. 1998, 63, 3524. 10. Fürstner, A. Chem. Rev. 1999, 99, 991 1046. (Review). 11. Kuroboshi, M.; Tanaka, M.; Kishimoto, S. Goto, K.; Mochizuki, M.; Tanaka, H. Tet-

rahedron Lett. 2000, 41, 81. 12. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiem-

stra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250. 13. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem. Int.

Ed. 2003, 42, 1032. 14. Takai, K. Org. React. 2004, 64, 253 612. (Review).

434

Oppenauer oxidation

Alkoxide-catalyzed oxidation of secondary alcohols.

OR1 R2

OH Al(Oi-Pr)3

R1 R2

O OH

O

R1 R2

OH

Al(Oi-Pr)2

coordinationR1 R2

OOHAl(Oi-Pr)2

Oi-Pr

:

O

H

OAl

R1R2

Oi-Pri-PrO

H O

AlO

Oi-Pr

Oi-PrR1

R2

cyclic transition state

hydride

transfer R1 R2

O OH

Example 1, magnesium Oppenauer oxidation3

OOH 1. EtMgBr, i-Pr2O

2. PhCHO, 60%

Example 212

(i-PrO)2AlO2CCF3p-O2N-Ph-CHO

PhH, rt, 24 h, 70%

OH

OH

O

OH

435

References

1. Oppenauer, R. V. Rec. Trav. Chim. 1937, 56, 137. 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. (Review). 3. Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769. 4. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007. 5. Almeida, M. L. S.; Kocovsky, P.; Bäckvall, J.-E. J. Org. Chem. 1996, 61, 6587. 6. Akamanchi, K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997, 38, 6925. 7. Raja, T.; Jyothi, T. M.; Sreekumar, K.; Talawar, M. B.; Santhanalakshmi, J.; Rao, B.

S. Bull. Chem. Soc. Jpn. 1999, 72, 2117. 8. Nait Ajjou, A. Tetrahedron Lett. 2001, 42, 13. 9. Schrekker, H. S.; de Bolster, M. W. G.; Orru, R. V. A.; Wessjohann, L. A. J. Org.

Chem. 2002, 67, 1975. 10. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669. 11. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601. 12. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819. 13. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C. Byrne, B.; Karras, M. Tetrahedron Lett. 2004,

45, 3313.

436

Overman rearrangement

Stereoselective transformation of allylic alcohol to allylic trichloroacetamide via trichloroacetimidate intermediate.

R R1

OH cat. NaH

Cl3CCNR R1

O

CCl3

HN

R R1

HN O

CCl3

or Hg(II) or Pd(II)

trichloroacetimidate

R R1

OH

HH2

R R1

O

N CCl3

R R1

OH

R R1

O

CCl3

N

R R1

O

CCl3

HN

R R1

HN O

CCl3, [3,3]-sigmatropic

rearrangement

Example 113

O

O

O

O

OH

HO

Cl3CCN, DBU

CH2Cl2, 78 oC

O

O

O

O

OH

OCl3C

HN

437

K2CO3, p-xylene

reflux, 90%, 2 steps

O

O

O

O

OH

HN

O

Cl3C

Example 214

K2CO3, p-xylene

reflux, 77%

O

TBDMSO

OCl3C

NHO

O

TBDMSO

ONHCl3C

O

References

1. Overman, L. E. Acc. Chem. Res. 1971, 4, 49. (Review). 2. Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. 3. Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. 4. Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.; Kawai, T.; Goto, T. Tetrahedron

Lett. 1990, 31, 3327. 5. Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527. 6. Toshio, N.; Masanori, A.; Norio, O.; Minoru, I. J. Org. Chem. 1998, 63, 188. 7. Cho, C.-G.; Lim, Y.-K.; Lee, K.-S.; Jung, I.-H.; Yoon, M.-Y. Synth. Commun. 2000,

30, 1643. 8. Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R. Tetrahedron: Asymmetry 2000, 11,

1585. 9. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863. 10. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151. 11. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927. 12. O’Brien, P.; Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523. 13. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2004, 433. 14. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401. 15. Ramachandran, P. V.; Burghardt, T. E.; Reddy, M. V. R. Tetrahedron Lett. 2005, 46,

2121.

438

Paal thiophene synthesis

Thiophene synthesis from addition of a sulfur atom to 1,4-dicarbonyl compounds and subsequent dehydration.

H3C CH3

O O SH3C

CH3

P2S5, tetralin, 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 348.

O

H3CCH3

O

S

H3CCH3

X

X = O or SP2S5

SH

H3CCH3

X

tautomerization

S

CH3

XHH3C

H

SCH3

H3CH2X

Example 14

O

PhO

NLawesson's reagent

110 ºC, 10 min, 82%

S NPh

439

Example 28

PhO

O

Ph

Ph

O Ph

O

SS

Ph

Ph Ph

Ph

Lawesson's reagentchlorobenzene, reflux, 36 h

69%

References

1. Paal, C. Chem. Ber. 1885, 18, 251. 2. Paal, C. Chem. Ber. 1885, 18, 367. 3. Campaigne, E.; Foye, W. O. J. Org. Chem. 1952, 17, 1405. 4. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.-

O. Chem. Lett. 1983, 809. 5. Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1992, 57, 1722. 6. Johnson, M. R.; Miller, D. C.; Bush, K.; Becker, J. J.; Ibers, J. A. J. Org. Chem. 1992,

57, 4414. 7. Freeman, F.; Lee, M. Y.; Lu, H.; Rodriguez, E.; Wang, X. J. Org. Chem. 1994, 59,

3695. 8. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4208. 9. Hemperius, M. A.; Lengeveld, B. M. W.; van Haave, J. A. E. H.; Janssen, R. A. J.

Sheiko, S. S.; Spatz, J. P.; Möller, M.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120,2798.

10. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409.

11. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66,7283.

12. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925. 13. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis In Name Reactions in Het-

erocyclic Chemistry, Li, J. J.; Corey, E. J. Eds., Wiley & Sons: Hoboken, NJ, 2005,207 217. (Review).

440

Paal–Knorr furan synthesis

Acid-catalyzed cyclization of 1,4-ketones to form furans.

RR3

O

O OR R3

cat. H+R2

R1

R1 R2

or P2O5

RR3

O

OR1

H+

:

R2

O R3

R1 R2

RHO

:

H+

H3O+

OR R3

R1 R2

OR R3

R2R1

H

Example 110

O

O

OTsOH

toluene, reflux

Cl

N

F

ClF

N

Example 214

O

n-Bu

98%

n-Bu

O

O

OMe

MeO

OMe

p-TsOH

toluene

MeO OMe

MeO

441

References

1. Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. 2. Knorr, L. Ber. Dtsch. Chem. Ges. 1885, 18, 299 3. Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. 4. Haley, J. F., Jr.; Keehn, P. M. Tetrahedron Lett. 1973, 4017. 5. 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. Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301. 7. Truel, I.; Mohamed-Hachi, A.; About-Jaudet, E.; Collignon, N. Synth. Commun. 1997,

27, 1165. 8. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive

Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Per-gamon: New York, 1996; Vol. 2, 351 393. (Review).

9. Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longman: Singapore, 1997; 211. (Re-view).

10. de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8,2689.

11. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 83 84. (Review).

12. Stauffer, F.; Neier, R. Org. Lett. 2000, 2, 3535. 13. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge,

2000; 308-309. (Review). 14. Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.;

Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838. 15. 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).

16. Shea, K. M. Paal–Knorr Furan Synthesis In Name Reactions in Heterocyclic Chemis-try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168 181. (Re-view).

442

Parham cyclization

Annulation of aryl halides with ortho side chains bearing a pendant electrophilic moiety via treatment with an organolithium reagent, involving halogen-metal ex-change and subsequent nucleophilic cyclization to form 4- to 7-membered rings.

ICH3O

CH3ON

ONEt2

2.2 eq. t-BuLi

THF, 78 oC rt

CH3O

CH3ON

O

ICH3O

CH3ON

ONEt2

halogen-metal

exchange I

LiCH3O

CH3ON

Et2N O

CH3O

CH3ON

CH3O

CH3ON

OOEt2N

cyclization

The fate of the second equivalent of t-BuLi:

I

HI

Example 19

2 eq. n-BuLi

THF, 78 oC

2.5 h, 83%

I

MeOOMe

N

O

O

N

MeO

MeOO

443

Example 216

O Br

N OMe

O

PMB

t-BuLi, THF, 100 oC

Ar, 30 min., 55%

ON

O

PMB

References

1. Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394. William E. Par-ham was a professor at Duke University.

2. Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184. 3. Bradsher, C. K.; Hunt, D. A. Org. Prep. Proced. Int. 1978, 10, 267. 4. Bradsher, C. K.; Hunt, D. A. J. Org. Chem. 1981, 46, 4608. 5. Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. (Review). 6. Quallich, G. J.; Fox, D. E.; Friedmann, R. C.; Murtiashaw, C. W. J. Org. Chem. 1992,

57, 761. 7. Couture, A.; Deniau, E.; Grandclaudon, P. J. Chem. Soc., Chem. Commun. 1994,

1329. 8. 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).

9. Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997,62, 2080.

10. Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2000, 41, 5211. 11. Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2001, 1267. 12. Ardeo, A.; Collado, M. I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in

Heterocyclic Systems Vol. 5; Atanassi, O., Spinelli, D., Eds.; Italian Society of Chem-istry: Rome, 2001; p 393. (Review).

13. Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59. (Review). 14. Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275. (Review). 15. González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69,

3875. 16. Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Org. Biomol.

Chem. 2005, 3, 2305.

444

Passerini reaction

Three-component condensation (3CC) of carboxylic acids, C-isocyanides, and carbonyl compounds to afford -acyloxycarboxamides. Cf. Ugi reaction.

R1 N CR2 R3

OR4 CO2H R1

HN

O R4

O

R3R2 O

isocyanide

O

R4 O

OH

CNR1

OO

ON

R1

R4

R3R2

HR2

R3

R2 R3

OR4 CO2H

R1

HN

O R4

O

R3R2 OO

ON

R1

R3R2O

R4

H

H+

acyl

transfer

Example 15

CHO

CN

HOAc, THF

rt, 93%HN

O

Et

AcO

445

Example 23

MeO

MeO

OMe

OMe

OMeOMe

Ts

CN TFA, PhH

rt, 2 h, 93%

MeO

MeO

OMe HN

O

Ts

OMe

OMe

References

1. Passerini, M. Gazz. Chim. Ital. 1921, 51, 126, 181. Mario Passerini (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.

2. Ferosie, I. Aldrichimica Acta 1971, 4, 21. (Review). 3. Barrett, A. G. M.; Barton, D. H. R.; Falck, J. R.; Papaioannou, D.; Widdowson, D. A.

J. Chem. Soc., Perkin Trans. 1 1979, 652. 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. 6. Ziegler, T.; Kaisers, H.-J.; Schlomer, R.; Koch, C. Tetrahedron 1999, 55, 8397. 7. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985. 8. Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett. 2000, 2, 2769. 9. Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301. 10. Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631. 11. Basso, A.; Banfi, L.; Riva, R.; Piaggio, P.; Guanti, G. Tetrahedron Lett. 2003, 44,

2367. 12. Banfi, L.; Riva, R. Org. React. 2005, 65, 1 140. (Review).

446

Paternó–Büchi reaction

Photoinduced electrocyclization of a carbonyl with an alkene to form polysubsti-tuted oxetane ring systems

R R1

O hvO

RR1

oxetane

R R1

O hv

R R1

O

n, * triplet

O

RR1

O

RR1

O

RR1

triplet diradical singlet diradical

Example 14

Me

PhO

O

O

PhMe

O

O

O

O

OH

*ROOCh , C6H6, 99%

Ph H

Example 26

O

Ph Ph

i-Pr

SMe

(E/Z = 6/1)

+

h , C6H6

73%

OPh

Ph

i-Pr

SMe

447

References

1. Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341. Emaubuele Paternó (1847 1935) was born in Palermo, Sicily, Italy.

2. Büchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76, 4327. 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. Paterno in 1909. Büchi died of heart failure while hiking with his wife in his native Switzerland.

3. Jones, G. In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1981, pp 1. (Review).

4. Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217. 5. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum

Press: New York, 1984, pp 425. (Review). 6. Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964. 7. 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). 8. Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70. (Re-

view). 9. Fleming, S. A.; Gao, J. J. Tetrahedron Lett. 1997, 38, 5407. 10. Hubig, S. M.; Sun, D.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2 1999, 781. 11. D'Auria, M.; Racioppi, R.; Romaniello, G. Eur. J. Org. Chem. 2000, 3265. 12. Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6, 3838. 13. Bach, T. Synlett 2000, 1699. 14. Abe, M.; Tachibana, K.; Fujimoto, K.; Nojima, M. Synthesis 2001, 1243. 15. D'Auria, M.; Emanuele, L.; Poggi, G.; Racioppi, R.; Romaniello, G. Tetrahedron

2002, 58, 5045. 16. Griesbeck, A. G. Synlett 2003, 451. 17. Liu, C. M. Paternó–Büchi Reaction In Name Reactions in Heterocyclic Chemistry, Li,

J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 44 49. (Review).

448

Pauson Khand cyclopentenone synthesis

Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide medi-ated by octacarbonyl dicobalt.

O

toluene, 60 80 oC

4 6 d, 60%

O

O

Co(CO)3Co(CO)3

HCo2(CO)8

Co(CO)3Co(CO)3

H

H(CO)4Co Co(CO)3

CO CO Co(CO)3

Co(CO)3

H

OC

CO

hexacarbonyldicobalt complex

Co(CO)3Co(CO)2

H

CO OOCO

insertiontowards CH

(CO)3Co

(CO)3Co H

HH

O

exo complex sterically-favored isomer

O(CO)3Co H

(CO)3Co

OO

(CO)3Co HO

(CO)3Co

CO

insertion

reductive elimination

Co2(CO)6

O

O

449

Example 16

benzene, 65 oC

16 h, 23%

Co2(CO)8OO

O

O

O

Example 2, a catalytic version9

NTs

5 mol% Co2(CO)8

20 mol% P(OPh)3

3 atm CO, DME

120 oC, 48 h, 94%

NTs O

References

1. Khand, I. U.; Knox, G. R.; Pauson, P. L.; 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.

2. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977.

3. Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (M), 1977, 153. 4. Pauson, P. L. Tetrahedron 1985, 41, 5855. (Review). 5. Schore, N. E. Chem. Rev. 1988, 88, 1081. (Review). 6. Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organometal. Chem.

1988, 356, 213. 7. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost,

B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). 8. Schore, N. E. Org. React. 1991, Vol. 40, pp 1 90. (Review). 9. Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159. 10. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (Review). 11. Son, S. U.; Lee, S. I.; Chung, Y. K. Angew. Chem., Int. Ed. 2000, 39, 4158. 12. Kraft, M. E.; Fu, Z.; Boñaga, L. V. R. Tetrahedron Lett. 2001, 42, 1427. 13. Muto, R.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4143. 14. Areces, P.; Durán, M. Á.; Plumet, J.; Hursthouse, M. B.; Light, M. E. J. Org. Chem.

2002, 67, 3506. 15. Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68, 1376. 16. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2005, 433.

450

Payne rearrangement

Base-promoted isomerization of 2,3-epoxy alcohols. Also known as epoxide mi-gration.

OHO

aq. NaOH

R

OH

O

R

OO

HOH

OOR R

R

O

O

SN2 H+

workup R

OH

O

Example 12

TrOHO

O

HOOTr

NaOMe, MeOH

reflux, 1 h, 84%

TrO

HOOTr

OOH

Example 23

BzOCO2Me

OBzOTs K2CO3, MeOH

rt, 2 h, 98% CO2Me

OH

O

References

1. Payne, G. B. J. Org. Chem. 1962, 27, 3819. 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. 3. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.;

Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436, 3663. 4. Page, P. C. B.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1, 1990,

1375. 5. Konosu, T.; Miyaoka, T.; Tajima, Y.; Oida, S. Chem. Pharm. Bull. 1992, 40, 562. 6. Dols, P. P. M. A.; Arnouts, E. G.; Rohaan, J.; Klunder, A. J. H.; Zwanenburg, B. Tet-

rahedron 1994, 50, 3473.

451

7. Ibuka, T. Chem. Soc. Rev. 1998, 27, 145. (Review). 8. Bickley, J. F.; Gillmore, A. T.; Roberts, S. M.; Skidmore, J.; Steiner, A. J. Chem. Soc.,

Perkin Trans. 1 2001, 1109. 9. Tamamura, H.; Hori, T.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2002, 577. 10. Hanson, R. M. Org. React. 2002, 60, 1 156. (Review). 11. Tamamura, H.; Kato, T.; Otaka, A.; Fujii, N. Org. Biomol. Chem. 2003, 1, 2468. 12. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073. 13. Bilke, J. L.; Dzuganova, M.; Froehlich, R.; Wuerthwein, E.-U. Org. Lett. 2005, 7,

3267.

452

Pechmann coumarin synthesis Lewis acid-mediated condensation of phenol with -ketoester to produce cou-marin.

OH

R OEt

O O AlCl3O

R

O

O:H EtO

R

O

OO

R

OO

OEtAlCl3

O O

ROH

:

Michael

addition

O O

O

RH

H+

O OO

R

O

R OH

HO O

R OH

H

HH+

Example 111

OH

OEt

O O

[bimim]Cl•2AlCl3130 oC, 35 min., 90%

O OHO HO

[bimim]Cl•2AlCl3 = 1-Butyl-3-methylimidazolium chloroaluminuminate (a Lewis acid ionic liquid)

453

Example 214

OH

OH

OEt

O O

BiCl3, 75 oC, 2 h, 66%

OH

O O

O O

References

1. v. Pechmann, H.; Duisberg, C. Ber. Dtsch. Chem. Ges. 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. Hirata, T.; Suga, T. Bull. Chem. Soc. Jpn. 1974, 47, 244. 3. Chaudhari, D. D. Chem. Ind. 1983, 568. 4. Holden, M. S.; Crouch, R. D. J. Chem. Educ. 1998, 75, 1631. 5. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151. 6. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem.

1992, 57, 399. 7. Biswas, G. K.; Basu, K.; Barua, A. K.; Bhattacharyya, P. Indian J. Chem., Sect. B

1992, 31B, 628. 8. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38. 9. Sugino, T.; Tanaka, K. Chem. Lett. 2001, 110. 10. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285. 11. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152. 12. Shockravi, A.; Heravi, M. M.; Valizadeh, H. Phosphorus, Sulfur Silicon Relat. Elem.

2003, 178, 143. 13. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997. 14. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231.

454

Perkin reaction

Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

Ar CHO Ac2OAcONa

Ar O

OAc O O OH

H2O Ar OH

O

cinnamic acid

O

O O

HOAc

enolate

formation

O

O O

H Ar

O

aldol

condensation

Ar O

O Ointramolecular

acyl transfer

O

Ar O

O O

O

Ar O

O O O

O

H

OH

Ar O

O O

O

H

O

O O

acyl

transfer

Ar O

OE2

elimination

O

OAc

Ac2O

Ar O

O

O

OHOO

Ar Ar OH

OHOAc

455

Example 19

CHO

MeO

MeO

MeOCO2H

Ac2O, Et3N, 90 oC

5 h, 66%

MeO

MeO

H

CO2H

MeO

Example 210

ClF2C

PhO

Ac2O,

AcONa, 46%

ClF2C

Ph CO2H

References

1. Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (1838 1907), born in London, England, studied under 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. Pohjala, E. Heterocycles 1975, 3, 615. 3. Poonia, N. S.; Sen, S.; Porwal, P. K.; Jayakumar, A. Bull. Chem. Soc. Jpn. 1980, 53,

3338. 4. Gaset, A.; Gorrichon, J. P. Synth. Commun. 1982, 12, 71. 5. Kinastowski, S.; Nowacki, A. Tetrahedron Lett. 1982, 23, 3723. 6. Koepp, E.; Voegtle, F. Synthesis 1987, 177. 7. Brady, W. T.; Gu, Y.-Q. J. Heterocycl. Chem. 1988, 25, 969. 8. Pálinkó, I.; Kukovecz, A.; Török, B.; Körtvélyesi, T. Monatsh. Chem. 2001, 131,

1097. 9. Solladié, G.; Pasturel-Jacopé, Y.; Maignan, J. Tetrahedron 2003, 59, 3315. 10. Sevenard, D. V. Tetrahedron Lett. 2003, 44, 7119.

456

Petasis reaction

Allylic amine from the three-component reaction of a vinyl boronic acid, a car-bonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction.

H R3

O

R1NH

R2

(HO)2BR4 N

R2

R1

R3

R4

H R3

O

R1

NHR2

NR2

R1

R3

OH

(HO)2BR4

NR2

R1

R3

R4

NR2

R1

R3

OB(OH)2

R4

H

Example 15

PhB

OH

OHO

C5H11

OHPh N

H

EtOH, rt

84%, 99% de PhC5H11

NPh

OH

457

Example 27

HO

HO

CHO

OMe

(HO)2BMeNHBn, EtOH, rt

24 h, 72%, 99% de

HO N

OMe

HO

MeBn

References

1. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. 2. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. 3. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. 4. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. 5. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969. 6. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471. (Review). 7. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149. 8. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahe-

dron 2005, 46, 3053. 9. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009.

458

Peterson olefination

Alkenes from -silyl carbanion and carbonyl compounds. Also known as sila-Wittig reaction.

R1 R2

O

R3

HSiR3M+

R1

HO

R3

SiR3R2 H

acid or

base R2

R1

R3

H

Basic conditions:

R1 R2

O

R3

HSiR3M+ R2

O

R3

SiR3R1 H

-silylalkoxide intermediate

R2 R3R1 H

SiR3O

R2

R1

R3

Hsyn-

elimination

Acidic conditions:

R2

HO

R3

SiR3R1 H rotation

R2

HO

SiR3

R3

R1 HH+

-hydroxysilane

R2

R1

H

R3

R2

H2O

SiR3

R3

R1 H E2 anti-

elimination:OH2

Example 110

PhO2S TBS

F 1. n-BuLi, Et2O, 78 oC

2. benzophenone, 63%PhO2S

FPh

Ph

459

Example 212

N

(t-BuO)Ph2Si CN

1. KHMDS, THF, 78 oC

2. N88% yield92:8 Z:ECHO

CN

References

1. Peterson, D. J. J. Org. Chem. 1968, 33, 780. 2. Ager, D. J. Synthesis 1984, 384 98. (Review). 3. Ager, D. J. Org. React. 1990, 38, 1 . (Review). 4. Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764 770.

(Review). 5. Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron Lett. 2001, 42, 6125. 6. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195 .

(Review). 7. Ager, D. J. Science of Synthesis 2002, 4, 789 809. (Review). 8. Adam, W.; Ortega-Schulte, C. M. Synlett 2003, 414. 9. Murai, T.; Fujishima, A.; Iwamoto, C.; Kato, S. J. Org. Chem. 2003, 68, 7979. 10. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81. 11. Suzuki, H.; Ohta, S.; Kuroda, C. Synth. Commun. 2004, 34, 1383. 12. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917. 13. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl

Olefination Takeda, T. (ed.), Wiley-VCH: Weinheim, Germany, 2004, 18 103. (Re-view).

14. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485.

460

Pictet–Gams isoquinoline synthesis

The isoquinoline framework is derived from the corresponding acyl derivatives of -hydroxy- -phenylethylamines. Upon exposure to a dehydrating agent such as

phosphorus pentaoxide, or phosphorus oxychloride, under reflux conditions and in an inert solvent such as decalin, isoquinoline frameworks are formed.

P2O5, decalin

reflux4

3

1HN

OH

O

RN

R

1

3

4

P2O5 actually exists as P4O10, an adamantane-like structure.

HN

OH

R

O

P O PO

O O

O

: HN

OH

R

OP

O

O

N

R

OH

: P O PO

O O

O

NH

R OPO2

OH

:

H

N

RN

R

OPO2

H

461

Example 110

N O

OH

Cl

H

P2O5

o-dichlorobenzene 80%

N

Cl

Example 27

O NH

O

HN

O

HN

HO

OHOH

POCl3, P4O10, decalin

180 oC, 6 h, 14%

N

N

N

Reference

1. Pictet, A.; Gams, A. Ber. Dtsch. Chem. Ges. 1909, 42, 1973, 2943. Amé Pictet (1857 1937), born in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids.

2. Kulkarni, S. N.; Nargund, K. S. Indian J. Chem., B 1967, 5, 294. 3. Ardabilchi, N.; Fitton, A. O.; Frost, J. R.; Oppong-Boachie, F. Tetrahedron Lett. 1977,

18, 4107. 4. 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. 5. Ardabilchi, N.; Fitton, A. O. J. Chem. Soc. (S) 1979, 310. 6. Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30, 1581. 7. Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994, 35, 9697. 8. Poszávácz, L.; Simig, G. J. Heterocycl. Chem. 2000, 37, 343. 9. Poszávácz, L.; Simig, G. Tetrahedron 2001, 57, 8573. 10. Manning, H. C.; Goebel, T.; Marx, J. N.; Bornhop, D. J. Org. Lett. 2002, 4, 1075. 11. Holsworth, D. D. Pictet–Gams Isoquinoline Synthesis In Name Reactions in Hetero-

cyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005,457 465. (Review).

462

Pictet–Spengler tetrahydroisoquinoline synthesis

Tetrahydroisoquinolines from condensation of -arylethylamines and carbonyl compounds followed by cyclization.

NH2NH

R2 H

O HCl

R2

R1O

R1O

R1O

R1O

NH2H

R2

OR1O

R1O :

N

R1O

R1O HOH

R2

+ H+H

N

R1O

R1O HR2

N:

R1O

R1O HOH2

R2

H2O

NH

R2

R1O

R1OH

NH

R2

R1O

R1OH

NH

R2

R1O

R1O

Example 112

NHMe

i-PrO

i-PrOMeO

i-PrO

i-PrOMeO

NMe

(CH2O)n

aq. HCl, EtOH

75%

463

Example 29

NO

O

S

O

O

OAcOMe

HO

MeONH2

+

NO

O

S

O

OAcO

Me

NH

HO

MeOsilica gel

dry EtOH

80%

References

1. Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030. 2. Hudlicky, T.; Kutchan, T. M.; Shen, G.; Sutliff, V. E.; Coscia, C. J. J. Org. Chem.

1981, 46, 1738. 3. Miller, R. B.; Tsang, T. Tetrahedron Lett. 1988, 29, 6715. 4. Rozwadowska, M. D. Heterocycles 1994, 39, 903. 5. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (Review). 6. Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. 7. Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611. 8. Kang, I.-J.; Wang, H.-M.; Su, C.-H.; Chen, L.-C. Heterocycles 2002, 57, 1. 9. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43. 10. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543. 11. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177. 12. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003,

14, 1309. 13. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis In Name Reactions in Hetero-

cyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005,469 479. (Review).

464

Pinacol rearrangement

Acid-catalyzed rearrangement of vicinyl diols (pinacols) to carbonyl compounds.

R1

HO

R3

OHR R2 H+

RR2

O

R1R3

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

R1

HO

R3

OHR R2 H+

R1

HO

R3

OH2R R2

H2O

RR2

O

R1R3RR2

O

R1R3

H

H+alkyl

migration

HO

R3R R2

R1

Example 112

Ph

OH

OH

NSO2Ph

1. MsCl, Et3N, CH2Cl2 0 oC, 10 min.

2. Et3Al, CH2Cl2, 78 oC

10 min., 90%N

SO2Ph

OPh

Example 214

Ph OH

OHPh

cat. TsOH

CDCl3

Ph Ph

O OPh

Ph

3:1

465

References

1. Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54. 2. Toda, F.; Shigemasa, T. J. Chem. Soc., Perkin Trans. 1 1989, 209. 3. Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112. 4. Paquette, L. A.; Lord, M. D.; Negri, J. T. Tetrahedron Lett. 1993, 34, 5693. 5. Jabur, F. A.; Penchev, V. J.; Bezoukhanova, C. P. J. Chem. Soc., Chem. Commun.

1994, 1591. 6. Patra, D.; Ghosh, S. J. Org. Chem. 1995, 60, 2526. 7. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tet-

rahedron 1996, 52, 14147. 8. Bach, T.; Eilers, F. J. Org. Chem. 1999, 64, 8041. 9. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693. 10. Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000, 39, 937. 11. Rashidi-Ranjbar, P.; Kianmehr, E. Molecules 2001, 6, 442. 12. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937. 13. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143 7157. (Review). 14. Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff,

E. J. Org. Chem. 2004, 69, 2017. 15. Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005, 3263.

466

Pinner reaction

Transformation of a nitrile into an imino ether, which can be converted to either an ester or an amidine.

R CN R1 OHHCl (g)

R OR1

NH2 ClH+, H2O

NH3, EtOH

R OR1

O

R NH2•HCl

NH2

R1 O R OR1

NH2 Cl

R N:

H+R NH nucleophilic

addition

protonation

H

:

common intermediate

R OR1

NH2 Cl

R OR1

Ohydrolysis

H2O:

H+

R OR1

OH2N H

R OR1

NH2 Cl

R NH2•HCl

NH2

H3N:R NH2

OR1HCl•H2N

H+

nucleophilic

addition

H

Example 13

Ph NH

O Ph

N

EtSH, HCl, CH2Cl2

0 oC, 10 min., 95%

N O

NHPh

Ph

pyr., H2S

4 h, 0 oC, 42%

N O

NH2Ph

Ph

467

Example 23

Ph NH

O

N

EtSH, HCl, CH2Cl2

0 oC, 1 h, 85%

pyr., H2S

2 h, 0 oC, 40%Ph N

H

OSEt

NH

NH

O PhSEt

S

References

1. Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10, 1889. 2. Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1878, 11, 1825. 3. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622. 4. Wagner, G.; Horn, H. Pharmazie 1975, 30, 353. 5. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169. 6. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643. 7. Neugebauer, W.; Pinet, E.; Kim, M.; Carey, P. R. Can. J. Chem. 1996, 74, 341. 8. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789. 9. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331. 10. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; May-

ence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209.

468

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.

(CH3CO)2O

pyr., CH2Cl2R2 N

O

R1

R

RNR1

OR2 H

O

R2 NO

R1

R

O

O O

acylation

CH3CO2

R2 NO

R1

RH

O

CH3CO2

R2 NR1

R R2 N:R1

RO O

O

O O

HOAc

iminium ion

RNR1

OR2 H

OR2 NR

O

OR1

O

OAc

The intramolecular pathway is also possible:

R2 NR

O O

R1

:

RNR1

OR2 H

O

ON

R2

RR1

O

469

Example 11

NO

(CH3CO)2O

100 oC

N

O

Example 22

O

(CH3CO)2O

< 30 oC, 98%

N N

O

References

1. Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190. 2. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377. 3. Volz, H.; Ruchti, L. Ann. 1972, 763, 184. 4. Hayashi, Y.; Nagano, Y.; Hongyo, S.; Teramura, K. Tetrahedron Lett. 1974, 15, 1299. 5. M’Pati, J.; Mangeney, P.; Langlois, Y. Tetrahedron Lett. 1981, 22, 4405. 6. Lounasmaa, M.; Koskinen, A. Tetrahedron Lett. 1982, 23, 349. 7. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135. 8. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45, 2683. 9. Grierson, D. Org. React. 1990, 39, 85. (Review). 10. Lounasmaa, M.; Jokela, R.; Halonen, M.; Miettinen, J. Heterocycles 1993, 36, 2523. 11. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378. 12. McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J. J. Org. Chem. 2003, 68,

9847. 13. Nakahara, S.; Kubo, A. Heterocycles 2004, 63, 1849.

470

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 O(CF3CO)2O

pyr., CH2Cl2

N

O CF3 tertiary N-oxide

N O

F3C O CF3

O O

acylation

N OCF3

OH

CF3CO2

N

H

CF3CO2

N:

CF3OF3C

OO iminium ion enamine

N

O CF3

N

O CF3

HCF3CO2

471

Example 12

NH

NNH

N

H

O(CF3CO2)2O, CH2Cl2, 0 oC

then, HCl, heat, 30%HOHO

Example 25

N

HN O

O

H

H

OHO

N

HN O

O

H

H

OH

OF3C

(CF3CO2)2O, pyr.

CH2Cl2, 0 oC, 65%

References

1. Ahond, A.; Cavé, A.; Kan-Fan, C.; Husson, H.-P.; cle Rostolan, J.; Potier, P. J. Am. Chem. Soc. 1968, 90, 5622.

2. Husson, H.-P.; Chevolot, L.; Langlois, Y.; Thal, C.; Potier, P. J. Chem. Soc., Chem. Commun. 1972, 930.

3. Grierson, D. Org. React. 1990, 39, 85. (Review). 4. Lewin, G.; Poisson, J.; Schaeffer, C.; Volland, J. P. Tetrahedron 1990, 46, 7775. 5. Kende, A. S.; Liu, K.; Jos Brands, K. M. J. Am. Chem. Soc. 1995, 117, 10597. 6. Sundberg, R. J.; Gadamasetti, K. G.; Hunt, P. J. Tetrahedron 1992, 48, 277. 7. Lewin, G.; Schaeffer, C.; Morgant, G.; Nguyen-Huy, D. J. Org. Chem. 1996, 61, 9614. 8. Renko, D.; Mary, A.; Guillou, C.; Potier, P.; Thal, C. Tetrahedron Lett. 1998, 39,

4251. 9. Suau, R.; Nájera, F.; Rico, R. Tetrahedron 2000, 56, 9713. 10. Thomas, O. P.; Zaparucha, A.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3291.

472

Pomeranz–Fritsch reaction

Isoquinoline synthesis via acid-mediated cyclization of the appropriate ami-noacetal intermediate.

CHOH2N

OEt

OEt

NOEt

OEt

H+

N

H2NOEt

OEt

H

O

:

NOEt

OEt

OH2

H

condensation:

NOEt

OEtH

:

N

OEt

OEt

H+

:imine

formation

N N

OEtOEt

HOEt

NN

OEtH

H

H+

473

Example 15

N

EtO OEt

N

MeO

MeO

MeO

MeO

BF3, (CF3CO)2O

60 82 %

Example 212

N

O

OMeH

Me

TiCl4, CH2Cl2

N

O Me

MeO OMe

78 oC, 69 %

Schlittler–Müller modification

OHC OEt

OEtNH2

R

NOEt

OEt

H+

N

R R

Example 37

NH2H2N

EtOO

H

OEt

i)

ii) oleum NN30 %

474

References

1. Pomeranz, C. Monatsh. 1893, 14, 116. Cesar Pomeranz (1860 1926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemis-try.

2. Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419. 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.

3. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914, 1119. 4. Gensler, W. J. Org. React. 1951, 6, 191. (Review). 5. Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253. 6. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974,

2185, 2190. 7. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107. 8. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248. 9. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601. (Review). 10. Katritzky, A. R.; Yang, Z.; Cundy, D. J. Heteroat. Chem. 1994, 5, 103. 11. Schlosser, M.; Simig, G.; Geneste, H. Tetrahedron 1998, 54, 9023. 12. Poli, G.; Baffoni, S. C.; Giambastiani, G.; Reginato, G. Tetrahedron 1998, 54, 10403. 13. Gluszy ska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359. 14. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron

2001, 57, 8297. 15. Hudson, A. Pomeranz–Fritsch Reaction In Name Reactions in Heterocyclic Chemis-

try, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480 486. (Re-view).

475

Prévost trans-dihydroxylation

Cf. Woodward cis-dihydroxylation.

I2

AgO2CPh

O2CPh

O2CPh

hydrolysisOH

OH

I I I

O2CPh

SN2

cyclic iodonium ion intermediate

O O

Ph

O2CPh

SN2I

O

SN2

O

Phneighboring group assistance

O2CPh

O2CPh

hydrolysisOH

OH

Example 18

FFO

OO

Ph

AgOCOPh, I2

PhH, rt, 2 h, reflux, 10 h, 46%

Ph

O

476

Example 212

AgOCOPh, I2

CCl4, 74%

O2C-C6H4-p-OMe

O

O2C-C6H4-p-OMe

O

OHI 1. KOH, H2O

2. Ac2O, pyr.

OAc

O

OAcAcO

Woodward cis-dihydroxylation13

Cf. Prévost trans-dihydroxylation.

1. I2, AgOAc

2. H2O, H+ OHHO

I I I

OAc

SN2

cyclic iodonium ion intermediate

O OSN2

H2O:

O O

OH

H+I

OO:

neighboring group assistance

OHO

O

:OH2

OHO

O

protonation

H

477

OHO

HO OOHHO

hydrolysis

H

References

1. Prévost, C. Compt. Rend. 1933, 196 1129. 2. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063. 3. Campi, E. M.; Deacon, G. B.; Edwards, G. L.; Fitzroy, M. D.; Giunta, N.; Jackson, W.

R.; Trainor, R. J. Chem. Soc., Chem. Commun. 1989, 407. 4. Prasad, K. J. R.; Subramaniam, M. Indian J. Chem., Sect. B 1994, 33B, 696. 5. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439. 6. Deota, P. T.; Singh, V. J. Chem. Res. (S), 1996, 258. 7. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801. 8. Zajc, B. J. Org. Chem. 1999, 64, 1902. 9. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D.; Welzel, P. Tetrahedron 2000, 56,

1345. 10. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M.; Amin, S. J. Org. Chem. 2000,

65, 8134. 11. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209. 12. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373. 13. Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209. Robert Burns

Woodward (USA, 1917 1979) won the Nobel Prize in Chemistry in 1953 for his syn-thesis of natural products.

478

Prins reaction

Addition of alkene to formaldehyde.

H+

RH H

O

H2O R OH

OH

R OHor or

O O

R

H+

RH H

O H2O

R OH

OHH H

OH

R OH

the common intermediate

H+

R OHR OH

H

:B

O O

RH H

O

R O

O

R OH

H

H

H

H+

Example 18

O

TsO

OAc

OBn

SnBr4, CH2Cl2

78 oC, 84%

O

TsO

Br

OBn

479

Example 210

AcO

(CH2O)n, Bi(OTf)3

CH3CN, rt, 10 h, 77% AcO

OO

References

1. Prins, H. J. Chem. Weekblad 1919, 16, 64, 1072. Hendrik J. Prins (1889 1958), born in Zaandam, The Netherlands, was not even an organic chemist per se. After obtain-ing 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. El Gharbi, R.; Delmas, M. Synthesis 1981, 361. 4. Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.;

Wurster, J. A. Org. Lett. 2000, 2, 223. 5. Yadav, J. S.; Reddy, B. V. S.; Kumar, G. M.; Murthy, C. V. S. R. Tetrahedron Lett.

2001, 42, 89. 6. Cho, Y. S.; Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.; Chang, M. H.

Org. Lett. 2002, 4, 2025. 7. Davis, C. E.; Coates, R. M. Angew. Chem., Int. Ed. 2002, 41, 491. 8. Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky, S.D. Org. Lett. 2002, 4, 3919. 9. Braddock, D. C.; Badine, D. M.; Gottschalk, T.; Matsuno, A.; Rodrihuez-Lens, M.

Synlett 2003, 345. 10. Sreedhar, B.; Swapna, V.; Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun.

2005, 35, 1177. 11. Aubele, D. L.; Wan, S.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485.

480

Pschorr cyclization

The intramolecular version of the Gomberg Bachmann reaction.

NH2

CO2HNaNO2, HCl

Cu

CO2H

HON

OH+

H2ON

O

H2OON

OH

ON

ON

O

ON

ON

O

H+NO2

NH2

CO2H

: NH

CO2H

NO

H+ H2O

N:

CO2H

NOH2

+

N

CO2H

NOH

H

N2

CO2HCu(0)

CO2H

Cu(I)

H

N2

CO2H

6-exo-trig

radical cyclization H

481

Cu(I)

H+ Cu(0)

CO2H

Example 110

O

NH2

S

OO

1. NaNO2, HCl-H2O-HOAc

0 to 5 oC, 2 h

2. CuSO4, HOAc, reflux

2 h, 86%

O

S

OOO

S

OO

6:1

Example 211

NN

O

NH2 NaNO2, HCl

5 to 20 oC, 64%

NN

O

482

References

1. Pschorr, R. Ber. Dtsch. Chem. Ges. 1896, 29, 496. 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. Kametani, T.; Fukumoto, K. J. Heterocycl. Chem. 1971, 8, 341. 3. Kupchan, S. M.; Kameswaran, V.; Findlay, J. W. A. J. Org. Chem. 1973, 38, 405. 4. Daidone, G.; Plesia, S.; Fabra, J. J. Heterocycl. Chem. 1980, 17, 1409. 5. Buck, K. T.; Edgren, D. L.; Blake, G. W.; Menachery, M. D. Heterocycles 1993, 36,

2489. 6. Wassmundt, F. W.; Kiesman, W. F. J. Org. Chem. 1995, 60, 196. 7. Qian, X.; Cui, J.; Zhang, R. Chem. Commun. 2001, 2656. 8. Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,

1359 1469. (Review). 9. 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. 10. Xu, Y.; Qian, X.; Yao, W.; Mao, P.; Cui, J. Bioorg. Med. Chem. 2003, 11, 5427. 11. Tapolcsányi, P.; Maes, B. U. W.; Monsieurs, K.; et al. Tetrahedron 2003, 59, 5919. 12. Mátyus, P.; Maes, B. U. W.; Riedl, Z.; Hajós, G.; Lemière, G. L. F.; Tapolc anyi, P.;

Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123-1139. (Review).

483

Pummerer rearrangement

The transformation of sulfoxides into -acyloxythioethers using acetic anhydride.

R1 S R2O Ac2O R1 S R2

OAc

R1 S R2O

AcO

O

OO

R1 S R2O

O

HR1 S R2

O

OOO

acyl

transfer

AcO

R1 S R2

OAcR1 S R2 R1 S R2

AcO

HOAc

Example 12

Ph2HCOSPh

OH

OH

1. m-CPBA, CH2Cl2, 78 oC

2. Ac2O, NaOAc, , 93%

Ph2HCOSPh

OH

OH

OAc

Example 213

BnN SBn

Ph

O OAc2O, pyr., DMAP

CH2Cl2, rt, 91%Bn

N SBn O

OAcPh

484

References

1. Pummerer, R. Ber. Dtsch. Chem. Ges. 1910, 43, 1401. 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. Masamune, S.; Sharpless, K. B. et al. J. Org. Chem. 1982, 47, 1373. 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. Kita, Y. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120 & 121, 145 164. (Re-

view). 6. Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175 203. (Review). 7. Marchand, P.; Gulea, M.; Masson, S.; Averbuch-Pouchot, M.-T. Synthesis 2001, 1623. 8. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851 862.

(Review). 9. Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003, 68,

929. 10. Matsuda, H.; Fujita, J.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashimoto, K. Tetrahe-

dron Lett. 2003, 44, 4089. 11. Fujita, J.; Matsuda, H.; Yamamoto, K.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashi-

moto, K. Tetrahedron 2004, 60, 6829. 12. Ruano, J. L.; Alemán, J.; Aranda, M. T.; Arévalo, M. J.; Padwa, A. Org. Lett. 2005, 7,

19. 13. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317.

485

Ramberg–Bäcklund reaction

Olefin synthesis via -halosulfone extrusion.

SO O

R R1

XBase

R

R1

S OO

SO O

R R1

X HS

O OX R1

R backside

displacement

:B

R

R1

S OOS

O O

SO2

extrusion

R R1

episulfone intermediate

Example 14

SO2

H

HBr

KOt-Bu, THF

15 oC to rt, 71%

H

Example 25

HSO2CH2Br

Br KOt-Bu, THF/HOt-Bu

0 oC to rt, 0.5 h, 65%

486

References

1. Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 50. 2. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209 216. (Review). 3. Paquette, L. A. Org. React. 1977, 25, 1 71. (Review). 4. Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090. 5. Block, E.; Aslam, M.; Eswarakishnan, V. et al. J. Am. Chem. Soc. 1986, 108, 4568. 6. Braverman, S.; Zafrani, Y. Tetrahedron 1998, 54, 1901. 7. Taylor, R. J. K. Chem. Commun. 1999, 217 227. (Review). 8. MaGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060. 9. McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197. 10. Murphy, P. V.; McDonnell, C.; Hämig, L.; Paterson, D. E.; Taylor, R. J. K. Tetrahe-

dron: Asymmetry 2003, 14, 79. 11. Wei, C.; Mo, K.-F.; Chan, T.-L. J. Org. Chem. 2003, 68, 2948. 12. Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357 475. (Review).

487

Reformatsky reaction

Nucleophilic addition of organozinc reagents generated from -haloesters to car-bonyls.

R R1

OBr

OR2

O

Zn OR2

O

HO

R1R

R R1

O

BrOR2

O

Zn(0)

oxidative addition orelectron transfer

OR2

OZnBr

OR2

O

BrZnO

R1Rnucleophilic

addition

H2O, hydrolysis

during workup

OR2

O

HO

R1R

Example 15

NS

Boc

Ph

OTBDMS

BrCH2CO2Me

Zn, THF, reflux, 71% NBoc

Ph

OTBDMS

MeO2C

Example 211

MeO

O

OBr

O Zn, THF

60 oC

MeO

HO O

O

MeO

O

OHCl

THF, rt, 10 h92%

488

References

1. Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. 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 dis-tinguished chemist, Alexander M. Za tsev. 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. Gaudemar, M. Organometal. Chem. Rev., A 1972, 8, 183. (Review). 3. Rathke, M. W. Org. React. 1975, 22, 423 460. (Review). 4. Fürstner, A. Synthesis 1989, 571 590. (Review). 5. Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173. 6. Fürstner, A. In Organozinc Reagents Knochel, P.; Jones, P. eds.; Oxford University

Press: New York, 1999, pp 287 305. (Review). 7. Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc.,

Perkin Trans. 1 2000, 825. 8. Kurosawa, T.; Fujiwara, M.; Nakano, H.; Sato, M.; Yoshimura, T.; Murai, T. Steroids

2001, 66, 499. 9. Ocampo, R.; Dolbier, W. R., Jr.; Abboud, K. A.; Zuluga, F. J. Org. Chem. 2002, 67,

72. 10. Obringer, M.; Colobert, F.; Neugnot, B.; Solladié, G. Org. Lett. 2003, 5, 629. 11. Zhang, M.; Zhu, L. Tetrahedron: Asymmetry 2003, 14, 3447. 12. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 9325 9374. (Review). 13. Scherkenbeck, T.; Siegel, K. Org. Proc. Res. Dev. 2005, 9, 216. 14. Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymmetry 2005, 16,

1913. 15. Cozzi, P. G.; Rivalta, E. Angew. Chem., Int. Ed. 2005, 44, 3600.

489

Regitz diazo synthesis

Synthesis of 2-diazo-1,3-dicarbonyl or 2-diazo-3-ketoesters using sulfonyl azide.

R OR1

O O

TsN3, Et3N

MeCN

R OR1

O O

N2

Ts NH2

R OR1

O O

H enolate

formation R OR1

O O

SNNNO

O

:NEt3

R OR1

O O

HNN

NSO2Tol

R OR1

O O

NN

HN

SO2Tolproton

transfer:

SH2NO

OR OR1

O O

NN

tosyl amide is the by-product

When only one carbonyl is present, ethylformate can be used as an activating auxiliary:6 9

ONaH, HCO2Et

Et2O

O

OHMsN3

Et2O

ON2

490

:NEt3O

OH O

O

MeSNNNO

O

ONN O

NSO2Me

H

O

NNN

SO2Me

H O

ON2MeSHN

O

OOH

ON

N

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide:

O

NNN

SO2Me

H OH

O

OH

MeSNNN

O

O1,3-dipolar

cycloaddition

ON2MeSHN

O

OOH

Example 110

O HN

OSO2N3O

Ot-Bu

O

491

Et3N, CH3CN

0 oC, 5 h, 45%

O

O

Ot-Bu

O

N2

Example 26

N NH

OTIPSO O O O

N

CH3SO2N3

CH3CN, 84%

N NH

OTIPSO O O O

NN2

References

1. Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733. 2. Regitz, M.; Anschütz, W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 3171. 3. Regitz, M. Synthesis 1972, 351–373. (Review). 4. Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077. 5. Taber, D. F.; Schuchardt, J. L. Tetrahedron 1987, 43, 5677. 6. Pudleiner, H.; Laatsch, H. Justus Liebigs Ann. Chem. 1990, 423. 7. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112,

4011. 8. Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Chem.

Commun. 1991, 646. 9. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252. 10. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org.

Chem. 2003, 68, 6153. 11. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624. 12. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241. 13. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609. 14. Rowlands, G. J.; Barnes, W. K. Tetrahedron Lett. 2004, 45, 5347. 15. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967. 16. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47.

492

Reimer–Tiemann reaction

Synthesis of o-formylphenol from phenols and chloroform in alkaline medium.

OH

CHCl3

OH

3 KClCHO3 KOH 2 H2O

a. Carbene generation:

Cl3C H

OH

CCl2H2O

Cl -elimination

Cl slow:CCl2

fast

b. Addition of dichlorocarbene and hydrolysis:

OH

H2O CCl2

KOHO O

CCl2

H

OHO Cl

H

O Cl

HOHO

CHClCl

OHCHO

O O

H

H

Example 1, photo Reimer–Tiemann reaction without base8

CN

OH

hv (Hg lamp)

CHCl3, 5 h, 48%

CN

OCHCl2

493

Example 29

OH

NHBoc

CO2H

CHCl3, 6 eq. NaOH

2 eq. H2O, reflux4 h, 64%

OH

NHBoc

CO2H

CHO

References

1. Reimer, K.; Tiemann, F. Ber. Dtsch. Chem. Ges. 1876, 9, 824. Karl L. Reimer (1845 1883) was born in Leipzig, Germany. He interrupted his study to serve in the Bohemian War in 1866. After the war, Reimer returned to his study and obtained his Ph.D. in 1871. He held several jobs but at the end had to resign because of poor health. The discovery of the Reimer–Tiemann reaction was the beginning of his short-lived career in organic chemistry. Johann K. F. Tiemann (1848 1899) was born in Rübeland, Germany. He was a student and a big fan of W. Hofmann, from whom Tiemann received his Ph.D. in 1871. Tiemann then became a Professor of Chemistry at Berlin.

2. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). 3. Smith, K. M.; Bobe, F. W.; Minnetian, O. M.; Hope, H.; Yanuck, M. D. J. Org. Chem.

1985, 50, 790. 4. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685. 5. Neumann, R.; Sasson, Y. Synthesis 1986, 569. 6. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609. 7. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691. 8. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825. 9. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553.

494

Reissert aldehyde synthesis

Aldehyde synthesis from the corresponding acid chloride, quinoline, and KCN.

R Cl

O N

KCNN

O R

CNH

H2SO4

R H

O

N CO2HNH3

N N

O R

CNH

:

R O

Cl N

O R

H

CNH+

Reissert compound

N

R O

H

NH

N:

OR

NHH

:

H+N

OR

NH

H

HO

H

N

OR

NHH

H+

N

OR H

NH2

OHN

OR H

NH2

O H

495

R H

O

NO

NH2

H3O+N

O

NH2

H

H2O:

NH3

N CO2HN

O

NH2HO

H

Example 14

Cl

O

MeO

MeO

OMeN

NaCN, H2O, CH2Cl2

4.5 h, 95%

H

O

MeO

MeO

OMe

N CN

OMeO

OMeMeO

30% H2SO4

reflux, 1 h, 95%

Example 210

N

Br

chiral Al catalyst

TMSCN, CH2=CHOCOCl

CH2Cl2, 40 oC, 72 h, 53%

N

Br

CN

O

O

73% ee

496

References

1. Reissert, A. Ber. Dtsch. Chem. Ges. 1905, 38, 1603, 3415. 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. McEwen, W. E.; Hazlett, R. N. J. Am. Chem. Soc. 1949, 71, 1949. 3. Popp, F. D. Adv. Heterocyclic Chem. 1979, 24, 187. (Review). 4. Schwartz, A. J. Org. Chem. 1982, 47, 2213. 5. Fife, W. K.; Scriven, E. F. V. Heterocycles 1984, 22, 2375. 6. Popp, F. D.; Uff, B. C. Heterocycles 1985, 23, 731. 7. Lorsbach, B. A.; Bagdanoff, J. T.; Miller, R. B.; Kurth, M. J. J. Org. Chem. 1998, 63,

2244. 8. Perrin, S.; Monnier, K.; Laude, B.; Kubicki, M.; Blacque, O. Eur. J. Org. Chem. 1999,

297. 9. Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123,

6801. 10. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989. 11. Sieck, O.; Schaller, S.; Grimme, S.; Liebscher, J. Synlett 2003, 337.

497

Reissert indole synthesis

The Reissert indole synthesis involves base-catalyzed condensation of an o-nitrotoluene derivative with an ethyl oxalate, which is followed by reductive cy-clization to an indole-2-carboxylic acid derivative.

NO2

CO2EtCO2Et

NO2

CO2Et

O+

BR R

NH

CO2HH

R H+

CH2

NO2

EtO

OEtO

OCH3

NO2

B

H

NO2

OH

OEtCO2Et NO2

CO2Et

Ohydrolysis

NO2CO2H

O H

NH2CO2H

OH

NH

CO2H

OH

H

NH

CO2H

498

Example 13

N

MeO

NO2

CO2EtCO2Et

KOEt

93%

N

MeO

NO2

N

MeO

NH

CO2Et

H2, Pd/C

EtOH, 85%

CO2EtO

Example 25

NO2

CO2EtCO2Et

KOEt, EtOH

Et2O, 76%+

NO2

CO2Et

OK

H2 (30 psi), PtO2

HOAc, 42% NH

CO2Et

References

1. Reissert, A. Ber. 1897, 30, 1030. 2. Julian, P. C.; Meyer, E. W.; Printy, S. C. Heterocyclic Compounds; : New York, 1962;

p 18. (Review). 3. Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530. 4. Brown, R. K. In Indoles, Part 1; Houlihan, W. J. Ed.; Wiley & Sons: New York, 1972;

pp 397 413. (Review). 5. Noland, W. E.; Baude, F. J. Org. Synth.; Ed, Baumgarten, H. E.; Wiley & Sons: New

York, 1973; p. 567. 6. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39,

3580. 7. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001,

42, 2031. 8. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami,

Y. Synlett 2000, 1196. 9. Li, J.; Cook, J. M. Reissert Indole Synthesis In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 154 158. (Re-view).

499

Ring-closing metathesis (RCM)

PhRu

Ph

P(cy)3ClCl

(Cy)3P N

MoO

O Ph

F3CF3C

F3CF3C

PhRu

ClCl

(Cy)3P

N NMes Mes

Grubbs’ reagents Schrock’s reagent Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below.

Generation of the catalyst from the precatalysts:

CHRLnM LnM

the real catalyst

CHRLnM[2 + 2]

cycloaddition

LnM CHR

[2 + 2]

cycloaddition

cycloreversionCHR MLn

MLncycloreversion

LnM

Catalytic cycle:

LnM

LnM[2 + 2]

cycloaddition

LnMcycloreversion

500

[2 + 2]

cycloaddition

MLn

MLncycloreversion

LnM

Example 14

OO C11H23OO C11H23

10 mol% (PCy3)2Cl2Ru=CHPh

0.3 eq. Ti(Oi-Pr)4

CH2Cl2, 40 oC, 93%

Example 29

PhRu

ClCl

(Cy)3P

N NMes MesEE

45 oC, 60 min. 100%

EE

E = CO2EtReferences

1. Schrock R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875. 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 Petrole 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. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. 4. Scholl, M.; Tunka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,

2247. 5. Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153. 6. Renaud, J.; Graf, C.-D.; Oberer, L. Angew. Chem., Int. Ed. 2000, 39, 3101. 7. Lane, C.; Snieckus, V. Synlett 2000, 1294. 8. Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781. 9. Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.; van der Marel, G. A.; van Boom, J. H.

Tetrahedron Lett. 2000, 41, 8635. 10. Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. 11. Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155. 12. van Otterlo, W. A. L.; Ngidi, E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron

Lett. 2003, 44, 311.

501

Ritter reaction

Amides from nitriles and alcohols in strong acids.

General scheme:

R1 OH R2 CNH+

R1

NH

R2

O

e.g.:

H3C CNOHH2SO4

H2O NH

O

Similarly:

H3C CNH2SO4

H2O NH

O

OHH3O+

OH2

:N

H2OE1

N

N

:OH2

nitrilium ion

NH

O

N

OH2 H+

N

OH

502

Example 14

N

CH3

CN

t-BuOH, conc. H2SO4

70 75 oC, 75 min., 97%N

CH3

O

HN

Example 28

O

fuming H2SO4, CH3CN, rt, 30 min.,

then H2O, 100 oC, 2 h, 77%

OH

NH2

References

1. Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. 2. Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048. 3. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). 4. Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem.

1989, 54, 2242. 5. Djaidi, D.; Leung, I. S. H.; Bishop, R.; Craig, D. C.; Scudder, M. L. J. Chem. Soc.,

Perkin 1 2000, 2037. 6. Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R. Synthesis 2000, 1709. 7. Le Goanric, D.; Lallemand, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001,

42, 5175. 8. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906. 9. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575. 10. Reddy, K. L. Tetrahedron Lett. 2003, 44, 1453. 11. Janin, Y. L.; Decaudin, D.; Monneret, C.; Poupon, M.-F. Tetrahedron 2004, 60, 5481. 12. Concellén, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett.

2004, 6, 4499. 13. Penner, M.; Taylor, D.; Desautels, D.; Marat, K.; Schweizer, F. Synlett 2005, 212.

503

Robinson annulation

Michael addition of cyclohexanones to methyl vinyl ketone followed by in-tramolecular aldol condensation to afford six-membered -unsaturated ketones.

O

R

O baseO

R methyl vinyl ketone (MVK)

O

R

O

H

B:

O

R

enolate

formation

Michael

addition

isomerization O

R

O

aldol

addition

H BO

RO

O

R

H2O

dehydrationO

R

HOH

:B

Example11

OO 3 TfOH, P4O10

CH2Cl2, microwave

40 oC, 8 h, 57%

O

504

References

1. Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285. 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 cho-lesterol. 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, DC, 1991.

2. Gawley, R. E. Synthesis 1976, 777–794. (Review). 3. Bui, T.; Barbas, C. F., III Tetrahedron Lett. 2000, 41, 6951. 4. Jansen, B. J. M.; Hendrikx, C. C. J.; Masalov, N.; Stork, G. A.; Meulemans, T. M.;

Macaev, F. Z.; de Groot, A. Tetrahedron 2000, 56, 2075. 5. Guarna, A.; Lombardi, E.; Machetti, F.; Occhiato, E. G.; Scarpi, D. J. Org. Chem.

2000, 65, 8093. 6. Tai, C.-L.; Ly, T. W.; Wu, J.-D.; Shia, K.-S,; Liu, H.-J. Synlett 2001, 214. 7. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137. 8. Liu, H.-J.; Ly, T. W.; Tai, C.-L.; Wu, J.-D. et al. Tetrahedron 2003, 59, 1209. 9. Kawanami, H.; Ikushima, Y. Tetrahedron Lett. 2004, 45, 5147. 10. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739. 11. Jung, M. E.; Maderna, A. Tetrahedron Lett. 2005, 46, 5057.

505

Robinson–Gabriel synthesis

Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.

HNR3R1

R2

O

N

R3R1

R2

O O

H2O

R1, R2, R3 = alkyl, aryl, heteroaryl

O

N R3

R1

R2

OH

NR3R1

R2

O O

HH

O

N

R3R1

R2H2O

Example 19

O

OTIPS

MeO

H

HN

O

HOO

N

O

O

OH

OMe H

NOMe

N

O

R

O

1. Dess-Martin, CH2Cl22. Ph3P, BrCCl2CCl2Br

3. DBU, CH3CN4. TBAF, THF 42% (+)-hennoxazole A

506

Example 28

O

N

O

O

CbzHN

H

O

HN

O

O

O

CbzHN

HH

Ph3P, I2, Et3N

55%

References

1. Robinson, R. J. Chem. Soc. 1909, 95, 2167. 2. Gabriel, S. Chem. Ber. 1910, 43, 134, 1283. 3. Wiley, R. H.; Borum, O. H. J. Am. Chem. Soc. 1948, 70, 2005. 4. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. 5. Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38, 2407. 6. Meguro, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Chem. Pharm.

Bull. 1986, 34, 2840. 7. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York,

1986; pp 1 342. (Review). 8. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. 9. Wipf, P. Lim, S. J. Am. Chem. Soc. 1995, 117, 558. 10. Brain, C. T.; Paul, J. M. Synlett 1999, 10, 1642. 11. Yokokawa, F.; Asano, T.; Shioiri, T. Org Lett 2000, 2, 4169. 12. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org Lett 2002, 4, 2665. 13. 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. 14. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J.

Org. Chem. 2003, 68, 2623. 15. Brooks, D. A. Robinson–Gabriel Synthesis in Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249 253. (Re-view).

507

Robinson Schöpf reaction

Tropinone synthesis.

CHO

CHONH2

CO2H

CO2H

O

N

O

2 CO2 2 H2O

CHO

O

HNH2:

CHO

OH

HN:

CHO

N

HO2C CO2H

OH

imine

formation

H2O

HO2C CO2HO

NHH

O

:

HO2C CO2HO

N

OH

:

hemiaminal

HO2C CO2HO

N

H

H2O

N

OHO2C

O

OH

CO2

N

OHO2C H

decarboxylation

508

N

OO

OH

N

O H

N

O

CO2

Example7

CO2H

CO2H

ONH2

CHO

OH

CHO

THF, rt, 72 h, 51%

OH

O

N

References

1. Robinson, R. J. Chem. Soc. 1917, 111, 762. 2. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765. 3. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105,

7754. 4. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175. 5. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med.

Chem. Lett. 1992, 2, 519. 6. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115. 7. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52,

1350. 8. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175.

509

Rosenmund reduction

Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned pal-ladium catalyst. Without poison, the resulting aldehyde may be further reduced to alcohol.

R Cl

O H2

Pd BaSO4 R H

O

Pd Pd

H H H HPd Pd

H HPd Pd Pd HH

R Cl

O Pd(0)

oxidativeaddition

R Pd

OCl

Pd HH

ligand exchange

R H

OPd(0)

R Pd

OH

reductive

elimination

Example 16

HOCO2t-Bu

O

N(Boc)2

Cl

Me2N

ClCO2t-Bu

O

N(Boc)2

H2, 5% Pd/C2,6-lutidine

THF, 2 h, 78%

HCO2t-Bu

O

N(Boc)2

510

Example 29

OH

O 1. SOCl2, cat. DMF, reflux, 4 h

2. H2, 5% Pd/C, EtOAc, 53%

H

O

References

1. Rosenmund, K. W. Ber. Dtsch. Chem. Ges. 1918, 51, 585. 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 Insti-tute 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, 4565. 4. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767. 5. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem.

1983, 48, 4436. 6. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405. 7. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226. 8. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416. 9. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851.

511

Rubottom oxidation

-Hydroxylation of enolsilanes.

OSiR31. m-CPBA

2. K2CO3, H2O

OOH

R3SiO O HO

O

Ar

Prilezhaev

epoxidationO

R3SiOH

OO

Ar

OO

R3Si

The “butterfly” transition state

OO

R3Si

H+H O

OH

SiR3

OOHK2CO3, H2O

hydrolysis

Example 15

N

OSiMe3

CO2Me

2.5 eq m-CPBA

ClCH2CH2Cl

0 oC to rt, 1 h, 80%

N

OOH

CO2Me

512

Example 210

O

TMSCl, NaI

Et3N, rt, 91%OTMS

1. m-CPBA, NaHCO3, pentane, 0 oC

2. aq. K2CO3, 0 oC, 20 h, 80%O

OH

References

1. Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 4319. George Rubottom discovered the Rubottom oxidation when he was an assistant pro-fessor at the University of Puerto Rico. He is now a grant officer at the National Sci-ence Foundation.

2. Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77, C19. 3. Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427. 4. Rubottom, G. M.; Gruber, J. M.; Boeckman, R. K., Jr.; Ramaiah, M.; Medwid, J. B.

Tetrahedron Lett. 1978, 4603. 5. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563. 6. Paquette, L. A.; Lin, H.-S.; Coghlan, M. J. Tetrahedron Lett. 1987, 28, 5017. 7. Hirota, H.; Yokoyama, A.; Miyaji, K.; Nakamura, T.; Takahashi, T. Tetrahedron Lett.

1987, 28, 435. 8. Gleiter, R.; Krämer, R.; Irngartinger, H.; Bissinger, C. J. Org. Chem. 1992, 57, 252. 9. Johnson, C. R.; Golebiowski, A.; Steensma, D. H. J. Am. Chem. Soc. 1992, 114, 9414. 10. Jauch, J. Tetrahedron 1994, 50, 12903. 11. Gleiter, R.; Staib, M.; Ackermann, U. Liebigs Ann. 1995, 1655. 12. Xu, Y.; Johnson, C. R. Tetrahedron Lett. 1997, 38, 1117. 13. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org.

Chem. 2004, 69, 2454. 14. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143 151. (Review).

513

Rupe rearrangement

Acid-catalyzed rearrangement of tertiary -acetylenic (terminal) alcohols, leading to the formation of -unsaturated ketones rather than the corresponding -unsaturated aldehydes. Cf. Meyer Schuster rearrangement.

H+, H2OOH O

H+OH OH2 H2O

dehydration H

H+ H+ protonationH

H

H2O:

tautomerization

OH

H

OH:

H+

Example 16

OH

conc. H2SO4

CHCl3, HOAc, reflux, 1 h

O

Example 210

O

H3C

H

H

H

OHA-252C H+ resin

EtOAc, reflux

4 h, 78%O

H3C

H

H

O

514

References

1. Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. 2. Hennion, G. F.; Davis, R. B.; Maloney, D. E. J. Am. Chem. Soc. 1949, 71, 2813. 3. Schmidt, C.; Thazhuthaveetil, J. Tetrahedron Lett. 1970, 2653. 4. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). 5. Hasbrouck, R. W.; Kiessling, A. D. J. Org. Chem. 1973, 38, 2103. 6. Apparu, M.; Glenat, R. Tetrahedron 1988, 41, 2181. 7. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389. 8. An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R. W. J. Org. Chem. 1997,

62, 2505. 9. Strauss, C. R. Aust. J. Chem. 1999, 52, 83–96. (Review). 10. Weinmann, H.; Harre, M.; Neh, H.; Nickisch, K.; Skötsch, C.; Tilstam, U. Org. Proc.

Res. Dev. 2002, 6, 216.

515

Saegusa oxidation

Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis.

O

Me

O

Me

Me3Si0.5 Pd(OAc)2

0.5 p-benzoquinonebenzene, rt, 3 h, 91%

The mechanism is similar to that of the Wacker oxidation (page 610).

O:

Me

Me3Si Pd(II) OAcAcOO

Me

Me3Si

Pd(II) OAc

AcO

O

OSiMe3

O

MeH

Pd(II) OAc -hydride

elimination

O

Me

PdH

OAc

O

Me

Pd(0) HOAc

Regenerating the Pd(II) oxidant:

Pd(0) 2 HOAc

O

O

OH

OH

Pd(OAc)2

516

Larock reported regeneration of the Pd(II) oxidant using oxygen:4

Pd(0) O2O

PdO

HOAcHOOPdOAc

OSiMe3

O

HOOSiMe3 Pd(II)(OAc)2

Example 13

OMeO

OO

H

HO O

Me3SiCl, Et3N

CH3OCH2CH2OCH3rt, 3 h, 74%

OMeO

OTMSO

H

HO O

Pd(OAc)2, p-benzoquinone

CH3CN, rt, 60 oC, 53%

OMeO

OO

H

HO O

Example 28

O

O

O

O

O

OTBS

LDA, TBSCl

HMPA-THF

78 to 0 oC, 93%

O

O

O

Pd(OAc)2, O2

DMSO, 80 oC

48 h, 77%

517

References

1. Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011. 2. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54,

5350. 3. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun.

1990, 20, 989. 4. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett.

1995, 36, 2423. 5. Porth, S.; Bats, J. W.; Trauner, D.; Giester, G.; Mulzer, J. Angew. Chem., Int. Ed.

1999, 38, 2015. The authors proposed sandwiched Pd(II) as a possible alternative pathway.

6. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217. 7. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. 8. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343,

618. 9. Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P. J. Org. Chem. 2002, 67, 831.

518

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 com-pound directly if it is not part of an -unsaturated system (Example 2), giving rise to an alcohol.

OSiMe3

TiCl4

O

O

SiMe3

TiCl4

complexation OTiCl3:

Cl

SiMe3

silicon

cleavage

OTiCl3

Cl

Michael

addition

The -carbocation is stabilized by the silicon atom

OOTiCl3

H2O

workupMe3Si Cl

Example 12

TMS

O

EtAlCl2, Tol.

0 oC, 50% O

519

Example 214

OBr

OTIPS

CHOSiMe3

TiCl4, CH2Cl2

rt, 10 min., 67%

OBr

OTIPS

OH

9:1 dr

References

1. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295. 2. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615. 3. Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570. 4. Markó, I. E.; Mekhalfia, A.; Murphy, F.; Bayston, D. J.; Bailey, M.; Janousek, Z.; Do-

lan, S. Pure Appl. Chem. 1997, 69, 565. 5. Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.; Varchi, G.

Tetrahedron: Asymmetry 1998, 9, 2979. 6. Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 1999, 64,

4233. 7. Sugita, Y.; Kimura, Y.; Yokoe, I. Tetrahedron Lett. 1999, 40, 5877. 8. Wang, M. W.; Chen, Y. J.; Wang, D. Synlett 2000, 385. 9. Organ, M. G.; Dragan, V.; Miller, M.; Froese, R. D. J.; Goddard, J. D. J. Org. Chem.

2000, 65, 3666. 10. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymme-

try 2001, 12, 301. 11. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744. 12. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185. 13. Nosse, B.; Chhor, R. B.; Jeong, W. B.; Böhm, C.; Reiser, O. Org. Lett. 2003, 5, 941. 14. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155. 15. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591. 16. Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem. Commun. 2005, 394.

520

Sandmeyer reaction

Haloarenes from the reaction of a diazonium salt with CuX.

ArN2 YCuX

Ar X X = Cl, Br, CN

e.g.:

ArN2 ClCuCl

Ar Cl

ArN2 ClCuCl

Ar ClCuCl2ArN2 CuCl

Example 15

N2

Cl

Cl

Cl1. FeCl3

2. CuCl2

N2

Cl

Cl

CuCl4

2

DMSO, rt

97%Cl

Cl

Cl

Example 211

CF3

ClNH2

1. H2SO4

2. NaNO2

CF3

ClN

N

CuCN, NaCN

Na2CO3, 50%

CF3

ClCN

References

1. Sandmeyer, T. Ber. Dtsch. Chem. Ges. 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 firm J. R. Geigy, which is now part of Novartis.

2. Galli, C. J. Chem. Soc., Perkin Trans. 2 1984, 897.

521

3. Suzuki, N.; Azuma, T.; Kaneko, Y.; Izawa, Y.; Tomioka, H.; Nomoto, T. J. Chem. Soc., Perkin Trans. 1 1987, 645.

4. Merkushev, E. B. Synthesis 1988, 923–927. (Review). 5. Obushak, M. D.; Lyakhovych, M. B.; Ganushchak, M. I. Tetrahedron Lett. 1998, 39,

9567. 6. Hanson, P.; Lövenich, P. W.; Rowell, S. C.; Walton, P. H.; Timms, A. W. J. Chem.

Soc., Perkin Trans. 2 1999, 49. 7. Chandler, S. A.; Hanson, P.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem.

Soc., Perkin Trans. 2 2001, 214. 8. Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,

Perkin Trans. 2 2002, 1126. 9. Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,

Perkin Trans. 2 2002, 1135. 10. Daab, J. C.; Bracher, F. Monatsh. Chem. 2003, 134, 573. 11. Nielsen, M. A.; Nielsen, M. K.; Pittelkow, T. Org. Proc. Res. Dev. 2004, 8, 1059.

522

Schiemann reaction

Fluoroarene formation from arylamines. Also known as the Balz Schiemann re-action.

ArN2 BF4Ar NH2 HNO2 HBF4 Ar F N2 BF3

HBF4HO

NO H2O

NO:

H2O N OHO

NO

ON

ON

O

ArNH2

Ar

HN

NO Ar

NN

OH:

ON

ON

O:

H2OArN

NOH2

H+

Ar N N:

ArN2 BF4 ArN2 Ar F BF3F BF3

Example 14

N

N N

N

F

NH2NaNO2, HBF4, H2O

10 to 0 oC, 25%

N

N N

N

F

F

R R

Example 210

HN N

F NHBoc 1. HBF42. NaNO2

3. hvHN N

F F

HN N

F

36% 8%

523

References

1. Balz, G.; Schiemann. G. Ber. Dtsch. Chem. Ges. 1927, 60, 1186. 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. (Review). 4. Montgomery, J. A.; Hewson, K. J. Org. Chem. 1969, 34, 1396. 5. Matsumoto, J.-i.; Miyamoto, T.; Minamida, A.; Nishimura, Y.; Egawa, H.; Nishimura,

H. J. Heterocycl. Chem. 1984, 21, 673. 6. Corral, C.; Lasso, A.; Lissavetzky, J.; Alvarez-Insua, A. S.; Valdeolmillos, A. M. Het-

erocycles 1985, 23, 1431. 7. Tsuge, A.; Moriguchi, T.; Mataka, S.; Tashiro, M. J. Chem. Res., (S) 1995, 460. 8. Saeki, K.-i.; Tomomitsu, M.; Kawazoe, Y.; Momota, K.; Kimoto, H. Chem. Pharm.

Bull. 1996, 44, 2254. 9. Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31. 10. Dolensky, B.; Takeuchi, Y.; Cohen, L. A.; Kirk, K. L. J. Fluorine Chem. 2001, 107,

147. 11. Gronheid, R.; Lodder, G.; Okuyama, T. J. Org. Chem. 2002, 67, 693.

524

Schmidt reaction

Conversion of ketones to amides using HN3 (hydrazoic acid).

R1 R2

ON2

R2 NH

OR1

HN3

H+

R1 R2

O H+

R1 R2

OH

HN3

R1 R2

N3HO

R1 R2

NHON

N

R1 R2

NHON

N

azido-alcohol

H+

NR2

R1

N N

R1 R2

NH2ON

NH2O

migration

:

R1

NR1

N2

H2O

:

R2

NR2

R1HOH+

nitrilium ion intermediate (Cf. Ritter intermediate)

R2 NH

OR1tautomerization

Example 1, a classic example11

CO2EtO

NaN3

MeSO3H35%

HN CO2Et

O

525

Example 2, a variant15

OH

O

N3

TfOH, CH2Cl2

0 oC, 79%N

O

OH

References

1. Schmidt, K. F. Z. 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.

2. Schmidt, K. F. Ber. Dtsch. Chem. Ges. 1924, 57, 704. 3. Wolff, H. Org. React. 1946, 3, 307. (Review). 4. Richard, J. P.; Amyes, T. L.; Lee, Y.-G.; Jagannadham, V. J. Am. Chem. Soc. 1994,

116, 10833. 5. Kaye, P. T.; Mphahlele, M. J. Synth. Commun. 1995, 25, 1495. 6. Krow, G. R.; Szczepanski, S W.; Kim, J. Y.; Liu, N.; Sheikh, A.; Xiao, Y.; Yuan, J. J.

Org. Chem. 1999, 64, 1254. 7. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144-146, 351. 8. Mphahlele, M. J. J. Chem. Soc., Perkin Trans. 1 1999, 3477. 9. Iyengar, R.; Schildknegt, K.; Aubé, J. Org. Lett. 2000, 2, 1625. 10. Pearson, W. H.; Hutta, D. A.; Fang, W.-k. J. Org. Chem. 2000, 65, 8326. 11. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667. 12. Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081. 13. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316. 14. Cristau, H.-J.; Marat, X.; Vors, J.-P.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3179. 15. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475. 16. Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260.

526

Schmidt’s trichloroacetimidate glycosidation reaction

Lewis acid-promoted glycosidation of trichloroacetimidates with alcohols or phe-nols.

O

OAcOCH3

AcO

OHO

OAcOCH3

AcO

O

HN CCl3

cat. NaH

Cl3CCN

trichloroacetimidate

HO Ar

BF3 OEt2

O

OAcOCH3

AcO

OAr

O

OAcOCH3

AcO

OH

HO

OAcOCH3

AcO

O

N CCl3

H2deprotonation

O

OAcOCH3

AcO

O

HN CCl3

O

OAcH3CO

AcO

OH

O

OAcOCH3

AcO

O

N CCl3

527

O

OCH3O

AcO

O

HN CCl3

BF3 OEt2

BF3 OEt2

O

neighboring

group assistance

O

NH2Cl3C

O

CH3OAcO O

OO

OAcOCH3

AcO

OArO Ar

H

:

Example 15

O

OAc

OCH3

AcO

O

HN CCl3

I CO2Me

OMeOMe

HO

O

OAc

OCH3

AcO

OBF3 OEt2, 4 Å MS

CH2Cl2, 50 oC, 95%

I CO2Me

OMeOMe

528

Example 27

O

BnO AcO

BnO

BnO

O

CCl3

NH

OH

BF3•OEt2CH2Cl2/hexane

20 oC, 68%

OO

BnO AcO

BnO

BnO

References

1. Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203. 2. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (Review). 3. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am.

Chem. Soc. 1992, 114, 3134. 4. Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503 1531. (Review). 5. Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1993, 32, 1377. 6. Weingart, R.; Schmidt, R. R. Tetrahedron Lett. 2000, 41, 8753. 7. Furstner, A.; Jeanjean, F.; Razon, P. Angew. Chem., Int. Ed. Engl. 2002, 41, 2097. 8. Yan, L. Z.; Mayer, J. P. Org. Lett. 2003, 5, 1161. 9. Roy, S.; Sarkar, S. K.; Mukhopadhyay, B.; Roy, N. Indian J. Chem., Sect. B 2005,

44B, 130. 10. Harding, J. R.; King, C. D.; Perrie, J. A.; Sinnott, D.; Stachulski, A. V. Org. Biomol.

Chem. 2005, 3, 1501.

529

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 re-action generally affords the less-substituted olefins as the kinetic products, while the Bamford Stevens reaction delivers the more-substituted olefins as the thermo-dynamic products.

R2

N

HN

Ts

R3

R1

2 n-BuLi R2

R3

R1

E+R2

R3

R1

E

R2

NN

Ts

R3

R1 H

H

Bu

R2

NN

Ts

R3

R1

H

Bu

R2

R3

R1

R2

NN

R3

R1

N2 E+R2

R3

R1

E

Example 13

NNHTsMeLi, Et2O-PhH

75 80%

Example 22

NNHTs MeLi, Et2O

98% 2%

530

References

1. Shapiro, R. H.; Duncan, J. H.; Clopton, J. C. J. Am. Chem. Soc. 1967, 89, 471. Robert H. Shapiro was a professor at the University of Colorado.

2. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734. 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. 4. Casanova, J.; Waegell, B. Bull. Soc. Chim. Fr. 1975, 922. 5. Shapiro, R. H. Org. React. 1976, 23, 405 507. (Review). 6. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55. (Review). 7. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 1 83. (Review). 8. Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915. 9. Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919. 10. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J. Synlett 2000, 547. 11. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J.; Zarecki, A. J. Org. Chem.

2001, 65, 6994. 12. Tormakangas, O. P.; Toivola, R. J.; Karvinen, E. K.; Koskinen, A. M. P. Tetrahedron

2002, 58, 2175. 13. Alvarez, R.; Dominguez, M.; Pazos, Y.; Sussman, F.; de Lera, A. R. Chem. Eur. J.

2003, 9, 5821. 14. Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem., Int. Ed.

Engl. 2005, 44, 1221. 15. Girard, N.; Hurvois, J.-P.; Moinet, C.; Toupet, L. Eur. J. Org. Chem. 2005, 2269.

531

Sharpless asymmetric amino hydroxylation

Osmium-mediated cis-addition of nitrogen and oxygen to olefins. Regioselectiv-ity may be controlled by ligand. Nitrogen sources (X NClNa) include:

SNClNa

R O

O

R = p-Tol; MeEtO NClNa

OBnO NClNa

O

NClNa

OTMS NBrLi

O

R1

R

chiral ligandK2OsO2(OH)4

ClNaN Xt-BuOH, H2O

R1

HO

R

NHX

The catalytic cycle:

R1

R

R1

HO

R

NHX

OsO4 ClN X

OsO

OO

N X

OsO

OO

N XL*

OsO

OO

NL*

X

R

R1OsO

OO

NL*

X

R

R1

OsO

OO

NN X

R

R1

X

L*

ClN X

L*

H2O

532

Example 14

5 mol% (DHQD)2PHAL4 mol% K2OsO2(OH)4

n-PrOH/H2O (1:1), 63% eeBnO NClNa

O NH OHBnO

O

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine (page 536).

Example 29

CO2Et

BnO

CO2Et

BnO

OH

NHCbz

BnOCONH2NaOH, t-BuOCl(DHQD)2AQN

K2OsO2(OH)4n-PrOH/H2O (1:1)

rt, 12 h, 45%, 87% ee

References

1. Herranz, E.; Sharpless, K. B. J. Org. Chem. 1978, 43, 2544. 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.

2. Mangatal, L.; Adeline, M. T.; Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Tetrahe-dron 1989, 45, 4177.

3. Engelhardt, L. M.; Skelton, B. W.; Stick, R. V.; Tilbrook, D. M. G.; White, A. H. Aust. J. Chem. 1990, 43, 1657.

4. Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. 5. Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2637. 6. Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998, 2, 243. (Review). 7. Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8279. 8. Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783. 9. Nicoloau, K. C.; Li, H.; Boddy, C. N. C.; Ramajulu, J. M.; Yue, T.-Y.; Natarajan, S.;

Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. 10. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221. 11. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn.,

Ojima, I., ed.; Wiley VCH: New York, 2000, 399. (Review). 12. Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 2733 2746. (Review). 13. Nilov, D.; Reiser, O. Recent Advances on The Sharpless Asymmetric Aminohydroxyla-

tion. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds., Wiley-VCH: Weinheim, Germany 2003, 118 124. (Review).

14. Lindstroem, U. M.; Ding, R.; Hidestal, O. Chem. Commun. 2005, 1773.

533

Sharpless asymmetric epoxidation

Enantioselective epoxidation of allylic alcohols using t-butyl peroxide, titanium tetra-iso-propoxide, and optically pure diethyl tartrate.

R1 R

R2OH

t-Bu O OH, Ti(Oi-Pr)4

L-(+)-diethyl tartrate

R1 R

R2OH

O

R1 R

R2OH

t-Bu O OH, Ti(Oi-Pr)4

D-( )-diethyl tartrate

R1 R

R2OH

O

The putative active catalyst, E = CO2Et:2

O

Ti

O

Ti

i-PrOi-PrO

Oi-Pr

OOEt

O

EtO2C

O

E

O

EtO

Oi-Pr

The transition state:

OOTi

OO

EtO2C CO2Et

t-Bu

O

534

The catalytic cycle:

LnTiOiPr

OiPr

OH tBu O OH

LnTiO

O

OtBu

LnTiO

tBu

O

LnTi OO

OtBu

LnTi OO

OtBu

*

**

***

LnTiO

O

tBu

O

*

*

OHO

Example 15

OHMeTi(O-iPr)4, 4 Å MS, (+)-DET

t-BuOOH, CH2Cl220 °C

OHO

Mecrude: 88% yield, 92.3 % ee

recrystallization: 73% yield, > 98% ee

535

Example 25

OH( )-DIPT, Ti(Oi-Pr)4

TBHP, 3 Å MS50 60%, 88 92% ee

OHO

References

1. Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. 2. Williams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc.

1984, 106, 6430. 3. Rossiter, B. E. Chem. Ind. 1985, 22(Catal. Org. React.), 295. (Review). 4. Pfenninger, A. Synthesis 1986, 89. (Review). 5. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J.

Am. Chem. Soc. 1987, 109, 5765. 6. Corey, E. J. J. Org. Chem. 1990, 55, 1693 1694. (Review). 7. 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). 8. Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106. 9. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,;

VCH: New York, 1993; Chapter 4.1, pp 103 158. (Review). 10. Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). 11. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1 299. (Review). 12. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I.,

ed.; Wiley-VCH: New York, 2000, 231 285. (Review). 13. Black, P. J.; Jenkins, K.; Williams, J. M. J. Tetrahedron: Asymmetry 2002, 13, 317. 14. Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry 2003, 14, 629. 15. Palucki, M. Sharpless Katsuki Epoxidation In Name Reactions in Heterocyclic Chem-

istry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 50 62. (Review).

536

Sharpless asymmetric dihydroxylation

Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the pres-ence of cinchona alkaloid ligands.

RL

RMRS

H

AD-mix-

AD-mix-

K2OsO2(OH)4

K2CO3, K3Fe(CN)6

(DHQD)2-PHAL

(DHQ)2-PHAL

OHHO

RS RL HRM

HO OH

HRMRSRL

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N

HO

N

O

NNO

N

N

O

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:

NO

N

O

NNO

N

N

O

The concerted [3 + 2] cycloaddition mechanism:

LOs

O

OO

OOsO

OO

LO

OsO

OO

LO

537

[3 + 2]-like

cycloadditionOsO

OO

LO

hydrolysis HO

HO

The catalytic cycle is shown on page 539 (the secondary cycle is shut off by main-taining a low concentration of olefin):

Example 13

EtO2CO

OH

N3

K2OsO2(OH)4(DHQD)2PHAL

K2CO3, MeSO2NH2t-BuOH/H2O (1:1)rt, 12 h, 90% de

EtO2CO

OH

N3

OH

OH

Example 29

CO2Et

BnO

1. AD-mix- , MeSO2NH2

t-BuOH/H2O (1:1), rt, 12 h

2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee

CO2Et

BnO

OH

ONos

Nos = nosylate = 4-nitrobenzenesulfonyl

References

1. Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968.

2. 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.

3. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096. 4. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,

2483 2547. (Review). 5. Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (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. (Mechanism).

538

7. Rouhi, A. M. A Reaction under Scrutiny, in Chem. Eng. News 1997, November 3, 23. (Review, Mechanism).

8. Bolm, C.; Gerlach, A. Eur. J. Org. Chem. 1998, 21. 9. Nicoloau, K. C.; Li, H.; Boddy, C. N. C.; Ramajulu, J. M.; Yue, T.-Y.; Natarajan, S.;

Chu, X.-J.; Bräse, S.; Rübsam, F. Chem. Eur. J. 1999, 5, 2584. 10. Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863. 11. Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem. 2000, 65, 3143. 12. Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; Beller, M. Tetrahedron Lett. 2000,

41, 8083. 13. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (Review, Nobel Prize Ad-

dress). 14. Moitessier, N.; Henry, C.; Len, C.; Postel, D.; Chapleur, Y. J. Carbohydrate Chem.

2003, 22, 25. 15. Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. J. Org. Chem. 2003, 68,

1736. 16. Junttila, M. H.; Hormi, O. E. O. J. Org. Chem. 2004, 69, 4816. 17. McNamara, C. A.; King, F.; Bradley, M. Tetrahedron Lett. 2004, 45, 8527. 18. Zhang, Y.; O'Doherty, G. A. Tetrahedron 2005, 61, 6337. 19. Hoevelmann, C. H.; Muniz, K. Chem. Eur. J. 2005, 11, 3951.

539

R

R

LH2O

OHR

OHR

low ee

OsO

O

R

R

LO O

LR

R

OsOO

OO

OsOO

OO O

RR

H2O

OHR

OHR

high ee

OsOO

OO O

RR

R R

NMONMM

L

Secondary cyclelow ee

Primary cyclehigh ee

The catalytic cycle of the Sharpless dihydroxylation

540

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.

OHR

SeCNNO2

Bu3P, THF, rt

SeR

NO2

OR

OR

SeNO2

Bu3P:

CN

H

:

SeNO2

PBu3SN2

CN

SeR

NO2

SeNO2

OR PBu3

O PBu3

SeR

NO2

OSe

R

NO2H O

RSe

NO2

syn-elimination OH

541

Example 19

OH

OH H

H

N

MeO

1. Bu3P, o-O2NPhSeCN, THF, rt

2. CSA, PhH, rt to 70 oC

3. m-CPBA, 2,4,6-collidine

CH2Cl2, 0 oC, 42%

OH

H

NH

Example 213

1. Bu3P, o-O2NPhSeCN

THF, rt, 6 h, 97%

2. m-CPBA, Et3N,

CH2Cl2, 78 oC

86%

OOO

MeO

OH

OH

OH

OOO

MeO

OH

OH

References

1. Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979. 2. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120. 3. Grieco, P. A.; Miyashita, M. Tetrahedron Lett. 1974, 1869. 4. Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947. 5. Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597. 6. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.

542

7. Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210. 8. Meade, E. A.; Krawczyk, S. H.; Townsend, L. B. Tetrahedron Lett. 1988, 29, 4073. 9. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431. 10. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1 296. (Review). 11. Krief, A.; Laval, A.-M. Bull. Soc. Chim. Fr. 1997, 134, 869 874. (Review). 12. Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741. 13. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493. 14. Siebum, A. H. G.; Woo, W. S.; Raap, J.; Lugtenburg, J. Eur. J. Org. Chem. 2004,

2905. 15. Blay, G.; Cardona, L.; Collado, A. M.; Garcia, B.; Morcillo, V.; Pedro, J. R. J. Org.

Chem. 2004, 69, 7294. The authors observed the concurrent epoxidation of a trisubsi-tuted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process.

543

Simmons–Smith reaction

Cyclopropanation of olefins using CH2I2 and Zn(Cu).

CH2I2 Zn(Cu) ICH2ZnI

CH2 ICH2ZnII IZn, Oxidative

addition Simmons Smith reagent

2 ICH2ZnI (ICH2)2Zn ZnI2

ZnI2CH2

ZnIIZnII

Example 12

OZn/Cu [from Zn and Cu(SO4)2]

CH2I2, Et2O, reflux, 36 h, 90%

O

Example 2, asymmetric version13

MeO

OH

CONEt2

OHOH

CONEt2

(1 eq)

6 eq Zn/Cu, 3 eq CH2I2CH2Cl2, 0 oC, 15 h

78%, 94% ee

MeO

OH

544

References

1. Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. 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 exer-cise 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. 3. Kaltenberg, O. P. Wiad. Chem. 1972, 26, 285. 4. Takai, K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994, 59, 2671. 5. Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tet-

rahedron 1995, 51, 12013. 6. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844. 7. Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 2479. 8. Kaye, P. T.; Molema, W. E. Synth. Commun. 1999, 29, 1889. 9. Loeppky, R. N.; Elomart, S. J. Org. Chem. 2000, 65, 96. 10. Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto,

Y. J. Org. Chem. 2001, 66, 81. 11. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1 415. (Review). 12. Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341. 13. Mahata, P. K.; Syam Kumar, U. K.; Sriram, V.; Ila, H.; Junjappa, H. Tetrahedron

2003, 59, 2631. 14. Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632. 15. Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737.

545

Skraup quinoline synthesis

Quinoline from aniline, glycerol, sulfuric acid and oxidizing agent (e.g. PhNO2).

NH2

HO OH

OH

H2SO4

PhNO2 N

HO OHOH

H+

HO OHOH2

Hdehydration

HO OH

glycerol

HOCHO

H+H2O

CHO

H

dehydrationOHC

acrolein

NH2

H+

:

O

Hconjugate

additionNH

O

NH

O

H+

HH+

NH

OH

intramolecular

additionNH

OHH

NH

OH

H+

:

N

dehydration

NH

OH2

H

NH

oxidation by

PhNO2 H2

For an alternative mechanism, see that of the Doebner von Miller reaction (page 547).

546

Example 19

OHHO OH+

F

F

F

NH2

F

F

F

N

NO2

SO3H

H2SO4, FeSO4

H3BO3, 80 %

Example 210

N O

O

NH2

OHHO OH+

N O

O

N

H2SO4, H3BO3

FeSO4•7H2O

75 %

References

1. 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 Vi-enna.

2. Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086. 3. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80. (Review). 4. Bergstrom, F. W. Chem. Rev. 1944, 35, 152 153. (Review). 5. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. 6. Takeuchi, I.; Hamada, Y.; Hirota, M. Chem. Pharm. Bull. 1993, 41, 747. 7. Fujiwara, H.; Okabayashi, I. Chem. Pharm. Bull. 1994, 42, 1322. 8. Fujiwara, H. Heterocycles 1997, 45, 119. 9. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25. 10. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409. 11. Theoclitou, M.-E.; Robinson, L. A. Tetrahedron Lett. 2002, 43, 3907. 12. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U.; Tetrahedron 2003, 59, 813. 13. 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).

547

Doebner–von Miller reaction

Doebner–von Miller reaction is a variant of the Skraup quinoline synthesis (page 545). Therefore, the mechanism for the Skraup reaction is also operative for the Doebner–von Miller reaction. An alternative mechanism shown below is based on the fact that the preformed imine (Schiff base) also gives 2-methylquinoline:

NH2 NOHC

HCl or

ZnCl2

NH2:

NH

OH

H

OH2

:

NH N

NH

N

:

N

NPh

H

[2 + 2]

cycloaddition

:

H+

NH

N

N

NH

H

B:

NH

NH

NH

HN

:

548

NH

NHHN

Ph:

HNPh

air oxidation

2 H NExample 17

N CO2Me

NH2

MeO2C CO2Me

O TsOH, CH2Cl2

reflux, 24 h

CO2Me

Example 28

NHAc

FH

ON

F

F F

Me

6 N HCl, Tol.

100 °C, 2 h, 70%

References

1. Doebner, O.; von Miller, W. Ber. Dtsch. Chem. Ges. 1883, 16, 2464. 2. Schindler, O.; Michaelis, W. Helv. Chim. Acta 1970, 53, 776. 3. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599. 4. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. 5. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 1996, 377. 6. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39, 5133. 7. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem.

Lett. 1999, 9, 2607. 8. 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.

9. Matsugi, M.; Tabusa, F.; Minamikawa, J.-i. Tetrahedron Lett. 2000, 41, 8523. 10. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731. 11. Kavitha, J.; Vanisree, M.; Subbaraju, G. V. Indian J. Chem., Sect. B 2001, 40B, 522. 12. Li, X.-G.; Cheng, X.; Zhou, Q.-L. Synth. Commun. 2002, 32, 2477. 13. 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).

549

Smiles rearrangement

Intramolecular nucleophilic aromatic rearrangement. General scheme:

X

YH

Z

Y

XZ

strong

base

X = S, SO, SO2, O, CO2

YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2Re.g.:

O2S

OH

OH

O

NO2 NO2O2S

O2S

OH

OH

NO2 O2S

O

NO2

SNAr

O

NO2O2S

O

O2S

NO2

spirocyclic anion intermediate (Meisenheimer complex)

550

Example8

O

HO NaOH, DMA

BrNH2

O O

OH2N

O

NaOH, H2O

50 oC

O

NH

HO

O

H2O, reflux

59%, 3 steps

O

H2N

References

1. Evans, W. J.; Smiles, S. J. Chem. Soc. 1935, 181. 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. 5. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocy-

cles 2001, 55, 741. 6. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421. 7. Kumar, G.; Gupta, V.; Gautam, D. C.; Gupta, R. R. Heterocyclic Commun. 2002, 8,

447. 8. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629. 9. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817.

551

Newman Kwart reaction

Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 549).

OH

Cl NMe2

SO NMe2

S

SHS NMe2

O

hydrolysis

Mechanism:

O S

NMe2

S NMe2

O

O

SMe2N

Example 18

OH

OH

Cl NMe2

S

NaH, DMF

85 oC, 1 h, 45%

O

OH

NMe2

S

275 oC, 0.8 mmHg

55%

S

OH

NMe2

O

552

Example 29

O

OH

1. Br2, CH2Cl2, 5 to 20 oC, 90 min.

2. CH2Cl2, 20 oC, 16 h, 37.4%

Cl NMe2

S

O

OBr

Me2N

S

dimethylaniline

218 oC, 7 h, 65.7%

O

SBr

Me2N

O

1. KOH, MeOH, reflux, 2 h

2. MeI, K2CO3, 90%

O

SBr

References

1. Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410. 2. Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980. 3. Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604. 4. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetra-

hedron 1997, 53, 6073. 5. Lin, S.; et al. Org. Prep. Proc. Int. 2000, 32, 547. 6. Ponaras, A. A.; Zairn, Ö. in Encyclopedia of Reagents for Organic Synthesis, Paquette,

L. A. (ed.), Wiley & Sons: New York, 1995, 2174. (Review). 7. Kane, V. V.; Gerdes, A.; Grahn, W.; Ernst, L.; Dix, I.; Jones, P. G.; Hopf, H. Tetrahe-

dron Lett. 2001, 42, 373. 8. Albrow, V.; Biswas, K.; Crane, A.; Chaplin, N.; Easun, T.; Gladiali, S.; Lygo, B.;

Woodward, S. Tetrahedron: Asymmetry 2003, 14, 2813. 9. 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. 10. Kusch, D. Speciality Chemicals Magazine 2004, 23, 41. (Review).

553

Truce Smile rearrangement

Smiles rearrangement where Y is carbon:

X

YHL

Y

XHL

Z Z

base

Example 16

N

O

CF3

CO2Me

KH or NaH

N

O

CF3

OMeMO

N

CF3

OM

O

OMe

OO

N

CF3

OOH

N

CF3

554

Example 28

N

O2S

ONO2

NaOH, H2O

EtOH, reflux

N

O2S

NO2

O2S

HN

NO2

41% 46%

Example 39

F

O2N K2CO3, DMF

reflux, 73%HO

O

OO2N

O OHO2N O

References

1. Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc.1958, 80, 3625.

2. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276. 3. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782. 4. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett.1982, 23, 437. 5. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S. J. Org. Chem. 1986, 51, 130. 6. Erickson, W. R.; McKennon, M. J.; Tetrahedron Lett. 2000, 41, 4541. 7. Hirota, T.; Tomita, K.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S.; Heterocycles

2001, 55, 741. 8. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807. 9. Mitchell, L. H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669.

555

Sommelet reaction

Transformation of benzyl halides to the corresponding benzaldehydes with the aide of hexamethylenetetramine.

Ar X NN

N

N

NN

N

NAr

X

ArCHO

H2OCHCl3 hexamethylenetetramine

NN

N:

N

NN

N

NAr

X

Ar X

SN2

NN

N

N CH3Ar

:OH2

NN

N

N CH2 H

Ar: hydride

transfer

NN

N

N CH3Ar

O H

H+Ar

CHON

NNH

N CH3

hemiaminal

The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion:

NN

N

NH

X

Ar

NN

N

N CH3Ar

556

Example9

NN

N

N

Cl

F

F

HOAc, H2O

, 62%

CHO

F

F

References

1. Sommelet, M. Compt. Rend. 1913, 157, 852. 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. Le Henaff, P. Annals Chim. Phys. 1962, 367.3. Zaluski, M. C.; Robba, M.; Bonhomme, M. Bull. Soc. Chim. Fr. 1970, 1445. 4. Smith, W. E. J. Org. Chem. 1972, 37, 3972. 5. Simiti, I.; Chindris, E. Arch. Pharm. 1975, 308, 688. 6. Stokker, G. E.; Schultz, E. M. Synth. Commun. 1982, 12, 847. 7. Armesto, D.; Horspool, W. M.; Martin, J. A. F.; Perez-Ossorio, R. Tetrahedron Lett.

1985, 26, 5217. 8. Simiti, I.; Oniga, O. Monatsh. Chem. 1996, 127, 733. 9. Malykhin, E. V.; Steingarts, V. D. J. Fluorine Chem. 1998, 91, 19. 10. Liu, X.; He, W. Huaxue Shiji 2001, 23, 237.

557

Sommelet–Hauser rearrangement

[2,3]-Wittig rearrangement of benzylic quaternary ammonium salts upon treatment with alkali metal amides via the ammonium ylide intermediates.

N NH2NH3N

N

NH2

NH3H

N [2,3]-sigmatropic

rearrangement

ammonium ylide

NN

H

aromatization

H NH2

Example 15

Ph N SiMe3 IDMF, reflux

18 h, 94%

N SiMe3

I CsF, HMPA

rt, 23 h, 86% N

558

Example 26

N SiMe3

Br CsF, HMPA

10 oC, 0.5 h, 32%AcO

NAcOAcO

N

46:54

References

1. Sommelet, M. Compt. Rend. 1937, 205, 56. 2. Pine, S. H. Tetrahedron Lett. 1967, 3393. 3. Wittig, G. Bull. Soc. Chim. Fr. 1971, 1921. 4. Robert, A.; Lucas-Thomas, M. T. J. Chem. Soc., Chem. Commun. 1980, 629. 5. Shirai, N.; Sato, Y. J. Org. Chem. Soc. 1988, 53, 194. 6. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767. 7. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034. 8. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687. 9. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188. 10. Endo, Y.; Uchida, T.; Shudo, K. Tetrahedron Lett. 1997, 38, 2113.

559

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 R'PdCl2 (PPh3)2

CuI, Et3N, rtR R'

IIPd

Ph3P

Ph3P

Cl

Cl

R'C CCuCuC CR' II

R'C CH

PdPh3P

Ph3P

X

RRX

CuXCuX R'C CH

IIIIPd

Ph3P

Ph3P

C

C

CR'

CR' PdPh3P

Ph3P

C

R

CR'

R'C CC CR'

RC CR'

HX-amine

Pd0(PPh3)2

HX-amine

Cycle A

Cycle BCycle B'ii

iii

iii

iiii. oxidative additionii. transmetalationiii. reductive elimination

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to imin-ium ion at the same time:

NEt3PdCl2

NEt2HH

PdCl2

NEt2

PdH Cl

Cl

NEt2 ClCl Pd H

reductive

eliminationHCl Pd(0)

560

Example 13

NH

I

CO2Et

PdCl2•(Ph3P)2

CuI, Et3N

60 oC, 89% NH

CO2Et

Example 25

N Br

SiMe3

NSiMe3

BrBr

PdCl2•(Ph3P)2, CuIEt3N, rt, 65–74%

References

1. Sonogashira K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467. Richard Heck discovered the same transformation using palladium but without the use of copper: J. Organomet. Chem. 1975, 93, 259.

2. McCrindle, R.; Ferguson, G.; Arsenaut, G. J.; McAlees, A. J.; Stephenson, D. K. J. Chem. Res. (S) 1984, 360.

3. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36,2248.

4. Rossi, R. Carpita, A.; Belina, F. Org. Prep. Proc. Int. 1995, 27, 129. 5. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959. 6. Campbell, I. B. In Organocopper Reagents; Taylor, R. J. K. Ed.; IRL Press: Oxford,

UK, 1994, 217. (Review). 7. Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. 8. Dai, W.-M.; Wu, A. Tetrahedron Lett. 2001, 42, 81. 9. Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114. 10. Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654. 11. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411. 12. Balova, I. A.; Morozkina, S. N.; Knight, D. W.; Vasilevsky, S. F. Tetrahedron Lett.

2003, 44, 107. 13. Garcia, D.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2004, 6, 4175. 14. Li, P.; Wang, L.; Li, H. Tetrahedron 2005, 61, 8633. 15. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839.

561

Staudinger ketene cycloaddition

[2 + 2] Cycloaddition of ketene and imine to form -lactam. Other coupling part-ners for ketene also include: olefin to give cyclobutanone and carbonyl to give -lactone.

O

R1 R2

X

R4R3

XO

R1

R2R3R4

X = NR; O; CHR

puckered transition state:

O

R1 R2

XO

R1

R2R3R4

XR4

R3

Example 18

p-TolN

NOt-Bu

OPhO

Cl

O

Et3N, CH2Cl210 oC to rt, 24 h

88%

N

PhOO

Ot-Bu

O N p-Tol

Example 29

AcOCl

O

Et3N, CH2Cl278 oC to rt, 88%

N N

AcO

O

562

References

1. Staudinger, H. Ber. Dtsch. Chem. Ges. 1907, 40, 1145. Hermann Staudinger (Ger-many, 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. Venturini, A.; Gonzalez, Jr. J. Org. Chem. 2002, 67, 9089. 6. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 3545 3565. (Review). 7. Hevia, E.; Perez, J.; Riera, V.; Miguel, D.; Campomanes, P.; Menendez, M. I; Sordo,

T. L.; Garcia-Granda, S. J. Am. Chem. Soc. 2003, 125, 3706. 8. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; San-

cassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195. 9. Becker, F. F.; Banik, I.; Banik, B. K. J. Med. Chem. 2003, 46, 505. 10. Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Tetrahedron 2004, 60, 93. 11. Botman, P. N. M.; David, O.; Amore, A.; Dinkelaar, J.; Vlaar, M.; Goubitz, K.;

Fraanje, J.; Schenk, H.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem., Int. Ed.2004, 43, 3471.

12. Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org. Chem. 2005, 70, 334. 13. Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. Lett. 2005, 13, 3611.

563

Staudinger reduction

Phosphazo compounds (e.g. iminophosphoranes) from the reaction of tertiary phosphine (Example Ph3P) with organic azides.

N3XPR3 X N N N PR3

N2X N PR3

phosphazide

NX N N :PR3X N N N PR3X N N N PR3

phosphazide

PR3NN N

X

PR3NN N

X

PR3NN N

X

4-membered ring transition state

N2 X N PR3

H2OX NH2 O PR3

Example 17

N

OMeO

OTBDMS

N3Ph3P, THF

, 81%

N

OMe

OTBDMS

N

564

Example 212

O

N3

BnOBnO

N3O

N3

AcOOAc

N3

1.1 eq. PMe3, 2.4 eq. Boc-ON

Tol., 78 to 10 oC

O

N3

BnOBnO

N3O

N3

AcOOAc

NHBoc

37% O

N3

BnOBnO

N3O

NHBoc

AcOOAc

N3

42%

References

1. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. 2. Leffler, J. E.; Temple, R. D. J. Am. Chem. Soc. 1967, 89, 5235. 3. Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437. 4. Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353. 5. Velasco, M. D.; Molina, P.; Fresneda, P. M.; Sanz, M. A. Tetrahedron 2000, 56, 4079. 6. Balakrishna, M. S.; Abhyankar, R. M.; Walawalker, M. G. Tetrahedron Lett. 2001, 42,

2733. 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. 8. Conroy, K. D.; Thompson, A. Chemtracts 2002, 15, 514. 9. Venturini, A.; Gonzalez, Jr. J. Org. Chem. 2002, 67, 9089. 10. Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281. 11. Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Molina, P. Tetrahedron Lett. 2004, 45,

1655. 12. Li, J.; Chen, H.-N.; Chang, H.; Wang, J.; Chang, C.-W. T. Org. Lett. 2005, 7, 3061.

565

Sternbach benzodiazepine synthesis

Treatment of quinazoline 3-oxide with amines gives the rearrangement product,

1,4-benzodiazepine.

Cl N

N

HN

O

chlordiazepoxide (Librium)

N

N

Cl

Cl

O

CH3NH2

quinazoline 3-oxide

N

N

Cl

Cl

O

H2N :

N

N

Cl

Cl

OCH3NH2

concerted

slow step

Cl N

N

HN

O

chlordiazepoxide (Librium)

Cl N

HN

HN

O

566

A step-wise mechanism is also possible:

N

N

Cl

Cl

O

H2N :

Cl N

N

HN

OH

Cl:

Cl N

N

HN

O

chlordiazepoxide (Librium)

References

1. Sternbach, L. H.; Kaiser, S.; Reeder, E. J. Am. Chem. Soc. 1960, 82, 475. 2. Sternbach, L. H.; Archer, G.; Reeder, E. J. Org. Chem. 1963, 28, 3013. 3. Stempel, A.; Reeder, E.; Sternbach, L. H. J. Org. Chem. 1965, 30, 4267. (Mechanism). 4. Sternbach, L. H. Angew. Chem., Int. Ed. 1971, 10, 34. (Review). 5. Sternbach, L. H. In The Benzodiazepines, Garattini, S.; Mussini, E.; Randall, L. O.

eds., Raven Press: New York, 1973, pp1 26. (Review). 6. Sternbach, L. H. In The Benzodiazepines: From Molecular Biology to Clinical Prac-

tice, Costa, Erminio, ed.; Raven Press: New York, 1983, pp 1 20. (Review).

567

Stetter reaction

1,4-Dicarbonyl derivatives from aldehydes and -unsaturated ketones. The thi-azolium catalyst serves as a safe surrogate for CN. Also known as the Mi-chael Stetter reaction. Cf. Benzoin condensation.

R CHOO

N

S

PhHO

NH3R

O

O

N

S

PhHO

H

:NH3

deprotonation N

S

Bn

R1

R

OH

R1 = HOCH2CH2CH2-

O

N

S

Bn

R1 OH

RH

B

N

S

Bn

R1 OH

R

N

S

Bn

R1

R

OH

O

tautomerizationMichael

addition

N

S

Bn

R1

R

O

O

R

O

O

N

S

PhHO N

S

PhHONH4

+

568

Example 14

O CHOOHCO

N

SHO

I

(cat.)

Et3N, EtOH, 80 oC, 56%

OOO

OO

Example 211

N

NO

H

O

CO2Me

N

S

Ph

HO

Cl

Et3N, DMF, 100 ºC, 75%

(cat.)

N

N

O

O

CO2Me

References

1. Stetter, H. Angew. Chem. 1973, 85, 89. Hermann Stetter (1917 1993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany.

2. Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639. 3. Castells, J.; Dunach, E.; Geijo, F.; Lopez-Calahorra, F.; Prats, M.; Sanahuja, O.; Villa-

nova, L. Tetrahedron Lett. 1980, 21, 2291. 4. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233. 5. Ho, T. L.; Liu, S. H. Synth. Commun. 1983, 13, 1125. 6. Phillips, R. B.; Herbert, S. A.; Robichaud, A. J. Synth. Commun. 1986, 16, 411. 7. Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26. 8. Ciganek, E. Synthesis 1995, 1311. 9. Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899. 10. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649. 11. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.;

Nagai, M. J. Med. Chem. 2000, 43, 409. 12. Kobayashi, N.; Kaku, Y.; Higurashi, K.; Yamauchi, T.; Ishibashi, A.; Okamoto, Y.

Bioorg. Med. Chem. Lett. 2002, 12, 1747. 13. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. 14. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368.

569

Still–Gennari phosphonate reaction

A variant of the Horner Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.

(CF3CH2O)2P CO2CH3

O KN(SiMe3)2, 18-Crown-6

then PhCH2CHO

CO2CH3Ph

CF3CH2OP

OMe

OCF3CH2O

O

H CF3CH2OP

OMe

OCF3CH2O

O

O

H

NSiMe3

SiMe3 Ph

PO

HCO2CH3

H

O

OCH2CF3

OCH2CF3

PhH

CO2CH3

H

PO OCH2CF3

OCH2CF3O

Pherythro isomer, kinetic adduct

CO2CH3Ph

Example 13

(CF3CH2O)2P CO2CH3

O

KN(SiMe3)2, 18-Crown-6

78 oC, THF, 30 min.

then PhCH2CHO, 87%

CO2CH3Ph

570

Example 212

MeOP(OCH2CF3)2

O O OTBS TBS

O O

OTBS

CHOOTBS

OPMB

NaH, THF

73%, Z:E 5:1

OTBS

OTBS

OPMB

MeO

O O OTBS TBS

O

References

1. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405. W. Clark Still (1946 ) was born in Augusta, Georgia. He was a professor at Columbia University.

2. Ralph, J.; Zhang, Y. Tetrahedron 1998, 54, 1349. 3. Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; LaGreca, S.; Tsuri, T.; Yue, E. W.; Yang,

Z. Angew. Chem., Int. Ed. Engl. 1994, 33, 2187. 4. Mulzer, J.; Mantoulidis, A.; Ohler, E. Tetrahedron Lett. 1998, 39, 8633. 5. Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669. 6. White, J. D.; Blakemore, P. R.; Browder, C. C. et al. J. Am. Chem. Soc. 2001, 123,

8593. 7. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.

2001, 123, 9535. 8. Mulzer, J.; Ohler, E. Angew. Chem., Int. Ed. Engl. 2001, 40, 3842. 9. Beaudry, C. M.; Trauner, D. Org. Lett. 2002, 4, 2221. 10. Sano, S.; Yokoyama, K.; Shiro, M.; Nagao, Y. Chem. Pharm. Bull. 2002, 50, 706. 11. Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002, 67, 6812. 12. Paterson, I.; Lyothier, I. J. Org. Chem. 2005, 70, 5494.

571

Stille coupling

Palladium-catalyzed cross-coupling reaction of organostannanes with organic hal-ides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 345.

R X R1 Sn(R2)3Pd(0)

R R1 X Sn(R2)3

R XR1 Sn(R2)3

L2Pd(0)transmetalationisomerization

oxidative

additionPd

L

L X

R

X Sn(R2)3 PdL

R R1

LR1R

reductive

eliminationL2Pd(0)

Example 16

N

N

NH2

Cl

ClN

N

NH2

BrCl

Cl PdCl2•(Ph3P)2, CuITHF, reflux, 92%

NSnBu3

SO2Ph

NPhO2S

Example 27

TBDPSO Br

(MeCN)2PdCl2

AsPh3, NMP

80oC, 1.5 h, 55%

Me3Sn Cl

Cl

TBDPSO Cl

Cl HCl

HN Cl

Cl

Zoloft

572

References

1. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. 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.

2. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992. 3. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. 4. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 5. For an excellent review on the intramolecular Stille reaction, see, Duncton, M. A. J.;

Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235. (Review). 6. Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507. 7. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967. 8. Nakamura, H.; Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 3208. 9. Heller, M.; Schubert, U. S. J. Org. Chem. 2002, 67, 8269. 10. Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968. 11. Samuelsson, L.; Langstrom, B. J. Labelled Comd. Radiopharm. 2003, 46, 263. 12. 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).

13. Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245 2267. (Review).

573

Stille Kelly reaction

Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides us-ing ditin reagents.

OH

OH

Br

BrMe3Sn SnMe3

Pd(Ph3P)4

OH

OH

OHOH

Br

Br

OHOH

Br

BrPd

Me3Sn SnMe3Pd(0)

oxidativeaddition

transmetalation

OHOH

Br

Me3Sn

OHOH

Br

PdMe3Sn

reductive

eliminationPd(0)

Pd(0)

oxidativeaddition

OHOH

PdBr

Me3Sn

transmetalation

OHOH

OHOH

Pdreductive

eliminationPd(0)

574

Example8

N

Cl

I HO

I

N

O

I I

NaH, DMF, reflux, 89%

Me3Sn SnMe3

PdCl2•(Ph3P)2xylene, reflux, 92%

N

O

References

1. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161. 2. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859. 3. Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles 1993, 36, 2597. 4. Iyoda, M.; Miura, M.i; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Hetero-

cycles 1997, 38, 4581. 5. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105. 6. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505. 7. Fukuyama, Y.; Yaso, H.; Mori, T.; Takahashi, H.; Minami, H.; Kodama, M. Heterocy-

cles 2001, 54, 259. 8. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201. 9. Olivera, R.; SanMartin, R.; Tellitu, I.; Dominguez, E. Tetrahedron 2002, 58, 3021.

575

Stobbe condensation

Condensation of diethyl succinate and its derivatives with carbonyl compounds in the presence of a base.

R R1

O

CO2Et

CO2EtR

R1

CO2EtCO2H

KOt-Bu

HOt-Bu

R

R1

O

CO2Et

enolate

formation

aldol

addition

O

OEtH

t-BuO

CO2Et

O

OEt

O

CO2EtRR1

OEtO

O

RR1

EtO O

CO2Etlactonization

O

RR1 CO2Et

O

H

Ot-Bu

R

R1

CO2EtCO2

H+ R

R1

CO2Et

CO2Hring

opening

Example 112

CO2Me

CO2Me

1. t-BuOK, t-BuOH, reflux

2. Ac2O, NaOAc, reflux 84%

OCHO

OO

O

OO

CO2Me

OAc

576

Example 213

O

O

CHO

O

O

O

aq. NaOH, EtOH

10 oC, 5 h, 88%

O

O

O

O

OH

References

1. Stobbe, H. Ber. Dtsch. Chem. Ges. 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. El-Rayyes, N. R.; Al-Salman, Mrs. N. A. J. Heterocycl. Chem. 1976, 13, 285. 3. Baghos, V. B.; Nasr, F. H.; Gindy, M. Helv. Chim. Acta 1979, 62, 90. 4. Welch, W. M.; Harbert, C. A.; Koe, K. B.; Kraska, A. R. US 4536518 (1985).5. Zerrer, R.; Simchen, G. Synthesis 1992, 922. 6. Baghos, V. B.; Doss, S. H.; Eskander, E. F. Org. Prep. Proced. Int. 1993, 25, 301. 7. Moldvai, I.; Temesvari-Major, E.; Balazs, M.; Gacs-Baitz, E.; Egyed, O.; Szantay, C.

J. Chem. Res., (S) 1999, 3018. 8. Moldvai, I.; Temesvari-Major, E.; Gacs-Baitz, E.; Egyed, O.; Gomory, A.; Nyulaszi,

L.; Szantay, C. Heterocycles 2001, 53, 759. 9. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556. 10. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521. 11. Moldvai, I.; Temesvari-Major, E.; Incze, M.; Platthy, T.; Gacs-Baitz, E.; Szantay, C.

Heterocycles 2003, 60, 309. 12. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416. 13. Mahajan, V. A.; Shinde, P. D.; Borate, H. B.; Wakharkar, R. D. Tetrahedron Lett.

2005, 46, 1009.

577

Stork enamine reaction

A variant of the Robinson annulation, where bulky amines such as pyrrolidine are used, making the conjugate addition to methyl vinyl ketone (MVK) take place at the less hindered side of two possible enamines.

O NH N

O O

methyl vinyl ketone (MVK)

O conjugate

addition

N: N O isomerization

N

O

O

N

H

B:O

Example 17

Br

O

F

NH

PhH, 4 Å MSreflux Br

F

NH

O

PhH, reflux, 12 h

578

BrF

N

O

H2O, reflux

1 h, 55%Br

F

O

O

Example 28

NNH

O

CH3O

Ph NH

1. , PhH, reflux

2. MVK, cat. hydroquinone PhH, reflux3. NaOAc, HOAc, H2O

NNH

O

CH3O

Ph

O

H

NNH

CH3O

Ph

O

H

17%22%

References

1. Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc. 1954, 76, 2029. Gilbert J. Stork (1921 ) was born in Brussels, Belgium. Being Jewish, he immigrated to the US due to rising antisemitism. He earned his Ph.D. at Wisconsin in 1945 and later be-came an assistant professor at Harvard. Since he was not awarded tenure in 1953, Stork moved to Columbia University where he has taught ever since.

2. Singerman, G.; Danishefsky, S. Tetrahedron Lett. 1964, 5, 2249. 3. Enamines: Synthesis, Structure, and Reactions; Cook, A. G., Ed.; Dekker: New York,

1969, 514. (Review). 4. Autrey, R. L.; Tahk, F. C. Tetrahedron 1968, 24, 3337. 5. Hickmott, P. W. Tetrahedron 1982, 38, 1975. (Review). 6. Hammadi, M.; Villemin, D. Synth. Commun. 1996, 26, 2901. 7. Bridge, C. F.; O'Hagan, D. J. Fluorine Chem. 1997, 82, 21. 8. Li, J. J.; Trivedi, B. K.; Rubin, J. R.; Roth, B. D. Tetrahedron Lett. 1998, 39, 6111. 9. Yehia, N. A. M.; Polborn, K.; Muller, T. J. J. Tetrahedron Lett. 2002, 43, 6907.

579

Strecker amino acid synthesis

Sodium cyanide-promoted condensation of aldehyde and amine to afford -amino nitrile, which may be hydrolyzed to -amino acid.

R1 H

O

H2NR2

R1 CN

HNR2

H+

R1 CO2H

HNR2

NaCN

AcOH

:

R1 H

O

H2NR2

NC

:

R1

HNH

R1 NH

H+

R2O

R2

HH

iminium ion

H2O:

R1

HNR2

H+N R1

HNR2

NH

OH

tautomerization

R1

HNR2

NH2

O

:OH2

H+

R1

HNR2

NH2

HO OH

acidic amide

hydrolysis

H+

R1

HNR2

NH3

HO OH

R1 CO2H

HNR2

580

Example 16

NH

S

acetone cyanohydrin

MgSO4, 45 oC, toluene, 31%

CHOCl

N

S

ClCN

N

S

ClO O

Plavix

Example 213

Ph

ONaCN, NH4Cl

i-PrOH, NH4OH

PhNH2

CNH

PhCN

NH2

H34% 35%

References

1. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27. 2. Chakraborty, T. K.; Hussain, K. A; Reddy, G. V. Tetrahedron 1995, 51, 9179. 3. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118,

4910. 4. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. Amino Acids 1996, 11, 259. 5. Mori, A.; Inoue, S. Compr. Asymmetric Catal. I-III 1999, 2, 983. (Review). 6. Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43,

891. 7. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000,

122, 762. 8. Ding, K.; Ma, D. Tetrahedron 2001, 57, 6361. 9. Matsumoto, K.; Kim, J. C.; Hayashi, N.; Jenner, G. Tetrahedron Lett. 2002, 43, 9167. 10. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Or-

ganic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds., Wiley-VCH: Weinheim, Germany, 2003, pp 187 193. (Review).

11. Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15,2029.

12. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. 13. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613.

581

Suzuki coupling

Palladium-catalyzed cross-coupling reaction of organoboranes with organic hal-ides, triflates, etc. in the presence of a base (transmetalation is reluctant to occur without the activating effect of a base). For the catalytic cycle, see Kumada cou-pling on page 345.

R XNaOR3

R1 B(R2)2 R1RL2Pd(0)

R X L2Pd(0)oxidative

additionPd

L

L X

R

NaOR3

addition of base

R1 B(R2)2 R1 B(R2)2

OR3

PdL

L X

R transmetalation

isomerizationR1 B(R2)2

OR3

PdL

R R1

LR1R

reductive

eliminationL2Pd(0)R3O B(R2)2

Example 11

N

CO2Me

CO2Me

I

CO2Et

OB

O

+

Pd(OAc)2

Ph3P, K2CO3THF, MeOH

70 °C, 15 h, 80%N

CO2Me

CO2Me

CO2Et

582

Example 24

N

N

I

I

SEMN

TBS

N

N

I

I

SEM

I

N

B(OH)2

TBS

Pd(Ph3P)4, Na2CO3, 45%

References

1. Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164. 2. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457 2483. (Review). 3. Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J.,

Eds.; Wiley VCH: Weinhein, Germany, 1998, 49–97. (Review). 4. Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles

1998, 48, 748 5. Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). 6. Li, J. J. Alkaloids: Chem. Biol. Perspect. 1999, 14, 437. (Review). 7. Groger, H. J. Prakt. Chem. 2000, 342, 334. 8. Franzen, R. Can. J. Chem. 2000, 78, 957. 9. LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555. 10. Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org.

Chem. 2002, 67, 1802. 11. Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. 12. Zapf, A. Coupling of Aryl and Alkyl Halides With Organoboron Reagents (Suzuki Re-

action). In Transition Metals for Organic Synthesis (2nd edn), Beller, M.; Bolm, C. eds., 2004, 1, 211 229. Wiley-VCH: Weinheim, Germany. (Review).

13. Leadbeater, N. E. Chem. Commun. 2005, 2881.

583

Swern oxidation

Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2,DMSO, and quenching with Et3N.

R1 R2

OH

R1 R2

O(COCl)2, DMSO

CH2Cl2, 78 oC

then Et3N

ClCl

O

O

OS

ClO

O

OS

Cl

ClO

O

SCl O

CO2 COSCl

R1 R2

:OH

Cl

R1 R2

OS

H

H:NEt3

R1 R2

OEt3N HCl (CH3)2S

R1

OS

R2H

sulfur ylide

Example 15

C6H13

OSiMe2t-Bu

OH

C11H23 (COCl)2, DMSO

then Et3N, 89%

C6H13

OSiMe2t-Bu

O

C11H23

584

Example 211

N

OMeO

OTBDPS

N3

N

OMeHO

OTBDPS

N3 (COCl)2, DMSO

then Et3N, 85%

References

1. Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329. 2. Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297. 3. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. 4. Tidwell, T. T. Org. React. 1990, 39, 297. (Review). 5. Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P.

M.; Uskovi , M. R. J. Org. Chem. 1991, 56, 4714 6. Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099. 7. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998,

63, 2407. (odorless protocol). 8. Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal, K. T.

Tetrahedron Lett. 1999, 40, 4593. 9. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1999, 40,

5161. 10. Dupont, J.; Bemish, R. J.; McCarthy, K. E.; Payne, E. R.; Pollard, E. B.; Ripin, D. H.

B.; Vanderplas, B. C.; Watrous, R. M. Tetrahedron Lett. 2001, 42, 1453. 11. 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. 12. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett.

2002, 43, 5177. (New odorless protocols). 13. Firouzabadi, H.; Hassani, H.; Hazarkhani, H. Phosphorus, Sulfur Silicon Related Ele-

ments 2003, 178, 149. 14. Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green

Chem. 2004, 6, 142. 15. Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.-i. Angew. Chem., Int. Ed.

Engl. 2005, 44, 2413.

585

Takai iodoalkene synthesis

Stereoselective conversion of an aldehyde to the corresponding E-vinyl iodide us-ing CHI3 and CrCl2.

R H

O

RI

CHI3, CrCl2

THF

CrCl2HI

II H

I

CrIIICl2

ICrCl2

R

HO

HCrIIICl2

CrIIICl2

ICl2CrIII

I

RCrIIICl2

RI

A radical mechanism is recently proposed10

I

I

H

I

CrII

CrIIII

I

H

I

CrII

R H

O

HI

CrIIII

RI

OCrIII

I

CrII

H

RIR

IOCrIII

CrII

HR

IOCrIII

CrIII

586

Example 12

CHI3, CrCl2

THF, 70%PhOTBS

CHO

PhOTBS

I20: 1E:Z

Example 25

CO2MeOHC

OTES CHI3, CrCl2, 0 oC

THF, 50%

CO2Me

OTES

I

References

1. Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408. 2. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159. 3. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335. 4. Solsona, J. G.; Romea, P.; Urpi, F. Org. Lett. 2003, 5, 4681. 5. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717. 6. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043. 7. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533. 8. Paterson, I.; Mackay, A. C. Synlett 2004, 1359. 9. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891. 10. Concellón, J. M.; Bernad, P. L.; Méjica, C. Tetrahedron Lett. 2005, 46, 569.

587

Tebbe olefination

Transformation of a carbonyl compound to the corresponding exo-olefin using Tebbe’s reagent.

Cp2TiCl

Al(CH3)2R R1

O

Tebbe’s reagent

R R1 Cp2Ti O ClAl(CH3)2

Cp2TiCl2transmetalation Cp2Ti

CH3

H -hydride

abstraction2 Al(CH3)3

titanocene dichloride

Cp2Ti CH2

Cl Al(CH3)2

coordinationCp2Ti

ClAl(CH3)2CH4

titanocene methylidene Tebbe’s reagent

Cp2Ti CH2

Cl Al(CH3)2Cp2Ti

ClAl(CH3)2

O

dissociation

RR1

R R1Cp2Ti O

[2 + 2]

cycloaddition

Cp2Ti CH2

OR

R1

retro-[2 + 2]

cycloaddition

oxatitanacyclobutane formation of the strong Ti=O is the driving force.

Petasis alkenylation

The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefina-tion reactions with ketones and aldehydes. 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 four-membered titanium ox-ide ring intermediate.9

588

Example 13

Tebbe's reagent, Tol.

then 1,

THF, 0 oC to rt, 30 min., 67%

O

CO2Et CO2Et

1

Example 24

MeO

MeO

Br

O 1. Cp2TiCl2, AlMe3, Tol, 3 d

2. 2, THF, 40 oC, 30 min.

then 0 oC, 1.5 h; rt, 1 h, 93%2

MeO

MeO

Br

References

1. Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611. 2. Chou, T. S.; Huang, S. B. Tetrahedron Lett. 1983, 24, 2169. 3. 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. 4. Winkler, J. D.; Muller, C. L.; Scott, R. D. J. Am. Chem. Soc. 1988, 101, 4831. 5. Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392. 6. Schioett, B.; Joergensen, K. A. J. Chem. Soc., Dalton Trans. 1993, 337. 7. Pine, S. H. Org. React. 1993, 43, 1 98. (Review). 8. Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc. 1996, 118,

1565. 9. Hughes, D. L.; Payack, J. F.; Cai, D.; Verhoeven, T. R.; Reider, P. J. Organometallics

1996, 15, 663. 10. Godage, H. Y.; Fairbanks, A. J. Tetrahedron Lett. 2000, 41, 7589. 11. Hartley, R. C.; McKiernan, G. J. J. Chem. Soc., Perkin 1 2002, 2763 2793. (Review). 12. Jung, M. E.; Pontillo, J. Tetrahedron 2003, 59, 2729.

589

TEMPO-mediated oxidation

R OHNaOCl, cat. TEMPO

KBr, NaHCO3, CH2Cl2 R OH

O

TEMPO = tetramethyl pentahydropyridine oxide:

N

NHAc

O

N

NHAc

O

1/2 NaOCl

N

NHAc

O

N

NHAc

O

N

NHAc

ON

NHAc

O

OCl

::

:

N

NHAc

O

N

NHAc

ON

NHAc

OH

590

N

NHAc

O

HO R

:

N

NHAc

O O

H RH

NAcHN O

:BR H

O

OCl

R

OH

OCl

R O

O

R O

OH

Example 17

NaOCl, cat. TEMPO

KBr, NaHCO3, CH2Cl255%

HOO

HOOH

OMe

OH

HOO

HOOH

OMe

HO2C

Example 210

cat. TEMPO, 2 eq. 2,6-lutidine

electrolysis in CH3CN/H2O (95:5)95%

O

591

Example 312

Ormosil-TEMPO, NaOCl

CH3CN, NaHCO3, 5%

0 oC, 80%Cl

OHOH

Cl

CO2H

OH

“Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix doped with TEMPO

References

1. Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905. 2. Yamaguchi, M.; Miyazawa, T.; Takata, T.; Endo, T. Pure Appl. Chem. 1990, 62, 217. 3. Adams, G. W.; Bowie, J. H.; Hayes, R. N.; Gross, M. L. J. Chem. Soc., Perkin Trans.

2 1992, 897. 4. de Nooy, A. E.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153. (Review). 5. Rychnovsky, S.D.; Vaidyanathan, R. J. Org. Chem. 1999, 64, 310. 6. Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V. Synthesis 2000, 1148. 7. Fabbrini, M.; Galli, C.; Gentili, P.; Macchitella, D. Tetrahedron Lett. 2001, 42, 7551. 8. Ciriminna, R.; Pagliaro, M. Tetrahedron Lett. 2004, 45, 6381. 9. Tashino, Y.; Togo, H. Synlett 2004, 2010. 10. Breton, T.; Liaigre, D.; Belgsir, E. M. Tetrahedron Lett. 2005, 46, 2487. 11. Chauvin, A.-L.; Nepogodiev, S. A.; Field, R. A. J. Org. Chem. 2005, 47, 960. 12. Gancitano, P.; Ciriminna, R.; Testa, M. L.; Fidalgo, A.; Ilharco, L. M.; Pagliaro, M.

Org. Biomol. Chem. 2005, 3, 2389.

592

Thorpe Ziegler reaction

The intramolecular version of the Thorpe reaction, which is base-catalyzed self-condensation of nitriles to yield imines that tautomerize to enamine.

CNCN OEt

CN

NH2HOEt

N

HEtO

N

N

NH OEt H

H OEt

OEt

CN

NH

CN

NH2

H

H OEt

EtO

Example 1, a radical Thorpe Ziegler reaction5

Br

CN

NC

Bu3SnH, AIBN

syringe pump

PhH, 80 oC, 56%

CNH2N

Example 210

NCN

Ph

CN LDA, THF

78 oC to rt

2 h, 80%NPh

CNNH2

593

References

1. Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726. 2. Ziegler, K. et al. Justus Liebigs Ann. Chem. 1933, 504, 94. Karl Ziegler (1898 1973),

born in Helsa, Germany, received his Ph.D. in 1920 from von Auwers at the Univer-sity of Marburg. He became the director of the Max-Planck-Institut für Kohlenfor-schung 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.

3. Rodriguez-Hahn, L.; Parra M., M.; Martinez, M. Synth. Commun. 1984, 14, 967. 4. Yakovlev, M. Yu.; Kadushkin, A. V.; Solov’eva, N. P.; Granik, V. G. Heterocyclic

Commun. 1998, 4, 245. 5. Curran, D. P.; Liu, W. Synlett 1999, 117. 6. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527. 7. Kovacs, L. Molecules 2000, 5, 127. 8. Gutschow, M.; Powers, J. C. J. Heterocycl. Chem. 2001, 38, 419. 9. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tet-

rahedron Lett. 2002, 43, 3225. 10. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895. 11. Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Org. Biomol.

Chem. 2003, 1, 547. 12. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517. 13. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245.

594

Tsuji Trost reaction

Palladium-catalyzed allylation using nucleophiles with allylic halides, acetates, carbonates, etc. via intermediate allylpalladium complexes, and typically with overall retention of stereochemistry.

O

BnO OPh

BnO

N

NH O

BnO N

BnO

N

Pd2(dba)3, dppb

THF, 60–70 oC72%

O

BnO OPh

BnOPd(0)Ln

coordination

O

BnO OPh

BnOPd(0)Ln

O

BnO

BnOPd(II)Ln

N

N

HO

BnO

BnOPd(II)Ln

-allyl complex

Pd(0)Ln

O

BnO N

BnO

NExample 14

OAcAcO

N

NH

NaH, Pd(Ph3P)4, DMF

60 oC, 18 h, 79%

NAcO

NN

N

NH2

NN

NH2

595

Example 27

N

NHO NHO

N

Pd(Ph3P)4, THFrt, 64 h, 35%

References

1. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. 2. Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (Review). 3. Godleski, S. A. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., eds.;

Vol. 4. Chapter 3.3. Pergamon: Oxford, 1991. (Review). 4. Saville-Stones, E. A.; Lindell, S. D.; Jennings, N. S.; Head, J. C.; Ford, M. J. J. Chem.

Soc., Perkin Trans. 1 1991, 2603. 5. Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett. 1992, 33, 2481. 6. Moreno-Mañas, M.; Pleixats, R. In Advances in Heterocyclic Chemistry; Katritzky, A.

R., ed.; Academic Press: San Diego, 1996, 66, 73. (Review). 7. Arnau, N.; Cortes, J.; Moreno-Mañas, M.; Pleixats, R.; Villarroya, M. J. Heterocycl.

Chem. 1997, 34, 233. 8. Tietze, L. F.; Nordmann, G. Eur. J. Org. Chem. 2001, 3247. 9. Sato, Y.; Yoshino, T.; Mori, M. Org. Lett. 2003, 5, 31. 10. Page, P. C. B.; Heaney, H.; Reignier, S.; Rassias, G. A. Synlett 2003, 22. 11. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.

596

Ugi reaction

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.

R3 N CR CO2H R1 NH2 R2 CHO isocyanide

R N

HN

O

R1

R2

OR3

R1 NH2

R2

H

O

: R2

H

HN

HO

R1: R2

H

N R1

imine

R O

HN

O N

R1

R3

:

R2

R CO2H

R

OO

R3NC

R2

H

N R1H

R N

HN

O

R1

R2

OR3O

NO

R

NR3

R2

R1

H+

597

Example 110

OO

NH2

OTBDPS

OMOMOMe

BnO

IBocHN

CO2H

H

O

O

NC

OO

N

OMOM NHPMP

O NHBoc

OMe

OBnI

MeOH,

1 h, 90%

TBDPSOO

Example 213

HN

OCO2H

OTBS

N

CHO

O2SO2N NH2

OMe

NC

HN

O

OTBS

NO2SO2N

ON

NHt-Bu

OMeOH,

61%

OMe

598

References

1. Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. 2. Skorna, G.; Ugi, I. Chem. Ber. 1979, 112, 776. 3. Hoyng, C. F.; Patel, A. D. Tetrahedron Lett. 1980, 21, 4795. 4. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.;

Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review). 5. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Review). 6. Ugi, I. Pure Appl. Chem. 2001, 73, 187. (Review). 7. Zimmer, R.; Ziemer, A.; Grunner, M.; Brüdgam, I.; Hartl, H.; Reissig, H.-U. Synthesis

2001, 1649. 8. Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167. 9. Baldoli, C.; Maiorana, S.; Licandro, E.; Zinzalla, G.; Perdicchia, D. Org. Lett. 2002, 4,

4341. 10. Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003, 44,

603. 11. Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.; Herdtweck, E.;

Doemling, A. Org. Lett. 2003, 5, 1047. 12. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596. 13. Oguri, H.; Schreiber, S. L. Org. Lett. 2005, 7, 47.

599

Ullmann reaction

Homocoupling of aryl halides in the presence of Cu or Ni or Pd to afford biaryls.

I2Cu

CuI2

I Cu(I)ICu(II)ICu, single

electron transfer SET

Cu(II)I

I

CuI2

The overall transformation of PhI to PhCuI is an oxidative addition process.

Example 15

N

NO2

Cl

Cu powder, DMF

100 105 oC, 4 h, 63%

N

NO2

N

O2N

Example 26

I

N

I

OSCu

O

NMP, rt, 88%

N

References

1. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174. 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.

2. Ullmann, F. Justus Liebigs Ann. Chem. 1904, 332, 38. 3. Fanta, P. E. Chem. Rev. 1946, 38, 139. (Review). 4. Fanta, P. E. Synthesis 1974, 9. (Review). 5. Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J.-P. Tetrahedron 1994, 50,

1153.

600

6. Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312. 7. Stark, L. M.; Lin, X.-F.; Flippin, L. A. J. Org. Chem. 2000, 65, 3227. 8. Belfield, K. D.; Schafer, K. J.; Mourad, W.; Reinhardt, B. A. J. Org. Chem. 2000, 65,

4475. 9. Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2000, 41, 4831. 10. Farrar, J. M.; Sienkowska, M.; Kaszynski, P. Synth. Commun. 2000, 30, 4039. 11. Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. 12. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org.

Lett. 2002, 4, 1623. 13. Hameurlaine, A.; Dehaen, W. Tetrahedron Lett. 2003, 44, 957. 14. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265 556. (Review).

601

van Leusen oxazole synthesis

5-Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures.

H

O

MeOH, refluxO

N

S NCO O

K2CO3

p-tolylsulfonylmethyl isocyanide (TosMIC)

S NO O

C

H

B

S NO O

C

O R

S NO O

C

ORO

NTos

R

+ H+

O

NH H

RO

NTos H

R

TosH

H

H

B

Example 17

S NCO O

HO

HN

NPr

PrH

602

MeOH, reflux

81%HN

NPr

PrH

NO

NaOMe

Example 210

OH

OEtO

O N

O

EtOS

NCOO

K2CO3

DMF, 80%

References

1. van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13,2369.

2. Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77. 3. Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979,

27, 793. 4. van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21,

3723. 5. 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). 6. Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. Tetrahedron Lett. 1996, 37,

8113; 7. 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. 8. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633. 9. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5637. 10. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.

Chem. 2000, 65, 1516. 11. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S. Or-

ganic Lett. 2001, 3, 271. 12. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Rec. Dev. 2002, 6,

677. 13. 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, 254 259. (Review).

603

Vilsmeier Haack reaction

The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. There-fore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.

O DMF, POCl3

100 oC, 24 h

OO

CHO

CHO

34% 4%

N O

H

PO

ClClCl:

N O

H

PCl2

O

Cl

SN2

N O

Cl

PCl2

O

H

: N H

Cl O PCl2

O

Vilsmeier–Haack reagent

O:

N H

Cl

O

Cl H

N

H

O

Cl H

N:B

:

aqueous

workup

O

HO HN

O

CHO

O

H N

HO

H

:

604

Example 13

N

NDMF, POCl3

100 oC, 83% N

N

CHO

Example 22

DMF, POCl3

100 oC, 14 h, 98%OH

OMeMeO

OMeMeO

OHC

References

1. Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119. 2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662. 3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. Jpn. 1985, 33, 3122. 4. 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. (Review). 7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 1. (Review). 8. Ali, M. M.; Tasneem; Rajanna, K. C.; Sai Prakash, P. K. Synlett 2001, 251. 9. Thomas, A. D.; Asokan, C. V. J. Chem. Soc., Perkin Trans. 1 2001, 2583. 10. Tasneem, Synlett 2003, 138. (Review of the Vilsmeier–Haack reagent).

605

Vilsmeier mechanism for acid chloride formation

Transformation of a carboxylic acid to the corresponding acid chloride using oxa-lyl chloride and catalytic amount of dimethyl formamide (DMF). It is a lot faster than without DMF, which generally needs reflux.

R Cl

O(COCl)2, cat. DMF

CH2Cl2, rtR OH

O

ClCl

O

O

Cl

N O

H

:

N O

H OCl

O

DMF oxalyl chloride

N O

Cl OCl

O

: N H

ClH ClCO2 CO

Vilsmeier–Haack reagent

N H

Cl

R O

OH

N O

Cl

R

O

:

H

NCHO

R Cl

OCl

N O

H

R

O

DMF recovered, therefore only catalytic amount is required

606

Vinylcyclopropane cyclopentene rearrangement

Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.

R1

R2

R1

R2

R1

R2

R1

R2

R1

R2

R1

R2

Example 15

O

CO2Me

340 oC, 2 h

50%

O CO2Me

Example 26

SO2Ph

1. n-BuLi, THF-HMPT

78 to 30 oC;

2. PhCH2Br

3. desulfonylation, 77% Ph

References

1. Neureiter, N. P. J. Org. Chem. 1959, 24, 2044. 2. Vogel, E. Angew. Chem. 1960, 72, 4. 3. Overberger, C. G.; Borchert, A. E. J. Am. Chem. Soc. 1960, 82, 1007, 4896. 4. Flowers, M. C.; Frey, H. M. J. Chem. Soc. 1961, 3547. 5. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc.

Chim. Fr. 1981, 57.

607

6. Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579. 7. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247 335. (Review). 8. Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229 267. (Review). 9. Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875 884.

(Review). 10. Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153. 11. Chuang, S.-C.; Islam, A.; Huang, C.-W.; Shih, H.-T.; Cheng, C.-H. J. Org. Chem.

2003, 68, 3811. 12. Baldwin, J. E. Chem. Rev. 2003, 103, 1197 1212. (Review). 13. Smart, B. E.; Krusic, P. J.; Roe, D. C.; Yang, Z.-Y. J. Fluorine Chem. 2004, 117, 199.

608

von Braun reaction

Treatment of tertiary amines with cyanogen bromide, resulting in a substituted cy-anamide and alkyl halides.

R1 NR2

R Br CN

R1 NR2

CNBr R

Cyanogen bromide (BrCN) is a counterattack reagent.

R1 NR2

RNC Br

:R1 N

R2

RCN

BrSN2

R1 NR2

CNBr R

Example 16

O

CF3

NCN

O

CF3

N

Br-CN

Tol.

O

CF3

NH

KOH, glycol

waterProzac

Example 27

N

CO2Me

CO2Me

Br-CN, THF, H2O

79% NCN

CO2Me

CO2Me

Br

609

References

1. von Braun, J. Ber. Dtsch. Chem. Ges. 1907, 40, 3914. Julius von Braun (1875 1940) was born in Warsaw, Poland. He was a Professor of Chemistry at Frankfurt.

2. Hageman, H. A. Org. React. 1953, 7, 198. (Review). 3. Fodor, G.; Abidi, S.-Y.; Carpenter, T. C. J. Org. Chem. 1974, 39, 1507. 4. Nakahara, Y.; Niwaguchi, T.; Ishii, H. Tetrahedron 1977, 33, 1591. 5. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279 1300. (Review). 6. Perni, R. B.; Gribble, G. W. Org. Prep. Proced. Int. 1980, 15, 297. 7. Verboom, W.; Visser, G. W.; Reinhoudt, D. N. Tetrahedron 1982, 38, 1831. 8. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200. 9. Cooley, J. H.; Evain, E. J. Synthesis 1989, 1. 10. Aguirre, J. M.; Alesso, E. N.; Ibanez, A. F.; Tombari, D. G.; Moltrasio Iglesias, G. Y.

J. Heterocycl. Chem. 1989, 26, 25. 11. Laabs, S.; Scherrmann, A.; Sudau, A.; Diederich, M.; Kierig, C.; Nubbemeyer, U.

Synlett 1999, 25. 12. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898. 13. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908.

610

Wacker oxidation

Palladium-catalyzed oxidation of olefins to ketones.

R

O

Rcat. PdCl2, H2O

CuCl2, O2

RPd

olefincomplexation

HOH :

R

PdCl2

Cl

Cl

R

OHPdCl

H

-hydrideelimination

HCl

nucleophilicattackR

OH

tautomerization

R

O

Pd(0)

PdH Cl

oxidation

HClreductive

elimination

Regeneration of Pd(II):

Pd(0) 2 CuCl2 PdCl2 2 CuCl

Regeneration of Cu(II):

CuCl2CuCl O2 H2O

611

Example 16

CO2HO2, 5% Pd(OAc)2

NaOAc, DMSO, 80%

O

O

Example 210

O2, 20 mol% Cu(OAc)210 mol% PdCl2

DMA/H2O (7:1) 84%

O O O O O

References

1. Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80. 2. Tsuji, J. Synthesis 1984, 369. (Review). 3. Miller, D. G.; Wayner, D. D. M. J. Org. Chem. 1990, 55, 2924. 4. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991,

Vol. 4, 552. (Review). 5. Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7,

449. (Review). 6. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298. 7. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994,

University Science Books: Mill Valley, CA, pp 199 208. (Review). 8. Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem.

1995, 60, 4678. 9. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C.,

eds., Wiley-VCH: Weinheim, Germany. 1998, 2, 307 315. (Review). 10. 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.

11. Gaunt, M. J.; Yu, J.; Spencer, J. B. Chem. Commun. 2001, 1844. 12. Barker, D.; Brimble, M. A.; McLeod, M.; Savage, G. P.; Wong, D. J. J. Chem. Soc.,

Perkin Trans. 1, 2002, 924. 13. Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4321. 14. Ho, T.-L.; Chang, M. H.; Chen, C. Tetrahedron Lett. 2003, 44, 6955. 15. Hintermann, L. Wacker-type Oxidations. In Transition Met. Org. Synth. (2nd edn.) Bel-

ler, M.; Bolm, C., eds., Wiley-VCH: Weinheim, Germany. 2004, 2, 379 388. (Re-view).

16. Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796.

612

Wagner–Meerwein rearrangement

Acid-catalyzed alkyl group migration of alcohols to give more substituted olefins.

R2 HR

R3

R1

OH

H+

R3

R

R2

R1

H+

R2 H

R

R3

R1

OHR2 H

R

R3

R1

OH2

H2O

R2 HR

R3

R1

H+

R2 HR1

R3R R3

R

R2

R1

Example 113

O

OEt

O

HOTFA, CH2Cl2

72 h, 76%

O

OEt

O

Example 214

OH

BrHBr, THF

0 oC, 10 min., 85%

References

1. Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. 2. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89. (Review). 3. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Fernandez, A. H.; De La Moya Cerero, S.;

Jimenez, F. M. Tetrahedron 1998, 54, 4607. 4. Birladeanu, L. J. Chem. Educ. 2000, 77, 858. 5. Kobayashi, T.; Uchiyama, Y. J. Chem. Soc., J. Chem. Soc., Perkin 1 2000, 2731. 6. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162.

613

7. Cerda-Garcia-Rojas, C. M.; Flores-Sandoval, C. A.; Roman, L. U.; Hernandez, J. D.; Joseph-Nathan, P. Tetrahedron 2002, 58, 1061.

8. Colombo, M. I.; Bohn, M. L.; Ruveda, E. A. J. Chem. Educ. 2002, 79, 484. 9. Román, L. U.; Cerda-Garcia-Rojas, C. M.; Guzmán, R.; Armenta, C.; Hernández, J.

D.; Joseph-Nathan, P. J. Nat. Products 2002, 65, 1540. 10. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Martinez-Ruiz, P. Tetrahedron 2003, 59,

1565. 11. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067. 12. Zubkov, F. I.; Nikitina, E. V.; Turchin, K. F.; Aleksandrov, G. G.; Safronova, A. A.;

Borisov, R. S.; Varlamov, A. V. J. Org. Chem. 2004, 69, 432. 13. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015. 14. Li, W.-D. Z.; Yang, Y.-R. Org. Lett. 2005, 7, 3107.

614

Weiss–Cook reaction

Synthesis of cis-bicyclo[3.3.0]octane-3,7-dione.

EtO2C

EtO2C

O

R1

RO

O

aq. bufferR

R1

OO

EtO2C

EtO2C

CO2Et

CO2Et

EtO2C

EtO2C

O O

OR

R1

EtO2C

EtO2C

OH

EtO2C

EtO2C

O OR1

OHR

H

OO

EtO2C

EtO2C

CO2Et

CO2Et

OOH

R

R1OH

EtO2CH

HEtO2C

H

R

R1

EtO2C

EtO2C

O OR1

OHR

H H

HO

EtO2C

EtO2CR1

R CO2Et

O

CO2Et

O

EtO2C

EtO2CR1

R CO2Et

O

CO2Et

HH

R

R1

OHO

EtO2C

EtO2C

CO2Et

CO2Et

R

R1

OHHO

EtO2C

EtO2C

CO2Et

CO2Et

615

Example 12

O CHO

1. pH = 8.32. HOAc/HCl,

90%O O

H

CO2CH3

CO2CH3

O

Example 23

O

O

CO2CH3

CO2CH3

O

1. pH = 6.82. HOAc/HCl

80%O O

Example 36

MeO2C

MeO2C

O

O O

pH 5.6

86%

O

CO2MeMeO2C O

MeO2C CO2Me

References

1. Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885. 2. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285. 3. Wrobel, J.; Takahashi, K.; Honkan, V.; Lannoye, G.; Bertz, S. H.; Cook, J. M. J. Org

Chem. 1983, 48, 139. 4. Gupta, A. K.; Fu, X.; Snyder, J. P.; Cook, J. M. Tetrahedron 1991, 47, 3665. 5. Reissig, H. U. Org. Synth. Highlights 1991, 121. (Review). 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. 7. Fu, X.; Cook, J. M. Aldrichimica Acta 1992, 25, 43. (Review). 8. Fu, X.; Kubiak, G.; Zhang, W.; Han, W.; Gupta, A. K.; Cook, J. M. Tetrahedron 1993,

49, 1511. 9. van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem. Soc., Perkin Trans. 1

1997, 3471. 10. Cadieux, J. A.; Buller, J. D.; Wilson, P. D. Org. Lett. 2003, 5, 3983.

616

Wharton oxygen transposition reaction

Reduction of -epoxy ketones by hydrazine to allylic alcohols.

OO

NH2NH2

OH

N2 H2O

OO

:NH2NH2O NH

OHNH2:

H2OO

N

tautomerization

ON

N

H:OH2

NH

H

H

N

O OH

+ H3O+

Example 15

O

NTEOC

O

H

NH2NH2•H2O, MeOH

HOAc, rt, 52%N

TEOC H

OH

617

Example 27

References 1. Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615. 2. Wharton, P. S. J. Org. Chem. 1961, 26, 4781. 3. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1. (Review). 4. Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 3437 3444. (Review). 5. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. 6. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem.

2000, 3247. 7. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031.

NH2NH2•H2O, MeOH

HOAc, rt, 59%

O

OTESO

O

O

OTESO

O

OH

618

Willgerodt–Kindler reaction

Conversion of ketones to the corresponding thioamide and/or ammonium salt.

O HN O

TsOH, S8,

N

S

O

thioamide

In Carmack’s mechanism,8 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:

SSS

S SSS

S

NHO

SS S

SS

SSH

SNO

NHO

sulfenamide

SN

O

NOHS S

SS

SSH

SNO

SNO

N

O

:

SN

O

N

O

SN

O

NO

H

thiirene

619

HNO

SN

O

SN

O

N

O

N

O

SN

O:

SN

O

N

O

:

N

O

N

O

N

S

O

S8

Example 1, the Willgerodt–Kindler reaction was a key operation in the initial syn-thesis of racemic Naproxen:6

O

O HN O

S8O

N

O

O

620

O

OH

O

1. H+

2. CH3OH, H2SO4

3. NaH, CH3I

4. NaOH naproxenExample 211

O HN ON

S

OS8, microwave4 min., 40%

References

1. Willgerodt, C. Ber. Dtsch. Chem. Ges. 1887, 20, 2467. 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 re-ceived from Claus. He became a professor at Freiburg, where he taught for 37 years.

2. Kindler, K. Arch. Pharm. 1927, 265, 389. 3. Carmack, M. Org. React. 1946, 3, 83. (Review). 4. Schneller, S. W. Int. J. Sulfur Chem. B 1972, 7, 155. 5. Schneller, S. W. Int. J. Sulfur Chem. 1973, 8, 485. 6. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.;

Fried, J. H. J. Med. Chem. 1970, 13, 203. 7. Schneller, S. W. Int. J. Sulfur Chem. 1976, 8, 579. 8. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319. 9. You, Q.; Zhou, H.; Wang, Q.; Lei, X. Org. Prep. Proced. Int. 1991, 23, 435. 10. Chatterjea, J. N.; Singh, R. P.; Ojha, N.; Prasad, R. J. Inst. Chem. (India) 1998, 70,

108. 11. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett.

1999, 40, 7549. 12. Moghaddam, F. M.; Ghaffarzadeh, M.; Dakamin, M. G. J. Chem. Res., (S) 2000, 228. 13. Poupaert, J. H.; Bouinidane, K.; Renard, M.; Lambert, D. M.; Isa, M. Org. Prep. Pro-

ced. Int. 2001, 33, 335. 14. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59. 15. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167. 16. Purrello, G. “Some aspects of the Willgerodt Kindler reaction and connected reac-

tions.” Heterocycles 2005, 65, 411 449. (Review).

621

Wittig reaction

Olefination of carbonyls using phosphorus ylides.

R X

R1

Ph3P Ph3PR

R1

H

Xbase

Ph3PR

R1R2 O

R3

Ph3P O R2

R3

R1

R

R X

R1Ph3P: Ph3P

R

R1

HSN2

:B

X

Ph3PR

R1

Ph3P O

R2R1

R3 R

[2 + 2]

cycloaddition

“puckered” transition state, irreversible and concerted

Ph3P O R2

R3

R1

R

Ph3P O

RR1 R2

R3

oxaphosphetane intermediate

Example 13

CHO

NHTs

NaH, Et2O; then add

CH2=CHPPh3+Br

DMF, reflux, 48 h, 50%NTs

622

Example 24

PPh3Cl

OHO O

2.0 N KOH, i-PrOH

30 oC, 1.5 h, 91.5%

CO2H

2-cis-4-cis-vitamin A acid

CO2H

Accutane

Schlosser modification of the Wittig reaction11 17

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.

R1 O

HPh3PR

Br PhLi PhLi t-BuOH

R1

R

t-BuOK

Br

Ph3PR

HH

Ph3PR

PhR1 O

HPh3PR

phosphorus ylide

Ph3P OLi

R R1H

Ph

Br

Ph3P OLi

R R1Li

Br

t-BuOH

LiBr complex of -oxo ylide

623

R1

RPh3P O LiBr

R1H

H

PPh3

RLiO

Brt-BuOH

t-BuOK

LiBr complex of threo-betaine

References

1. Wittig, G.; Schöllkopf, U. Ber. Dtsch. Chem. Ges. 1954, 87, 1318. 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 com-pounds.

2. Maercker, A. Org. React. 1965, 14, 270 490. (Review). 3. Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146. 4. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982 5. Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 1 30. (Review). 6. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863 927. (Review). 7. Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (Review). 8. Heron, B. M. Heterocycles 1995, 41, 2357. 9. Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049. 10. Blackburn, L.; Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 115. 11. Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1966, 5, 126. 12. Schlosser, M.; Christmann, K. F. Justus Liebigs Ann. Chem. 1967, 708, 35. 13. Schlosser, M.; Christmann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29. 14. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5,

103. (Review). 15. Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449. 16. Duffield, J. J.; Pettit, G. R. J. Nat. Products 2001, 64, 472.

624

[1,2]-Wittig rearrangement

Treatment of ethers with alkyl lithium results in alcohols.

R OR1 R2Li

R OH

R1

12

12

R OR1

Hdeprotonation

R OR1

R2

R O

R1[1,2]-sigmatropic

rearrangement R OH

R1workup

The radical mechanism is also possible as radical intermediates have been identi-fied.

Example 14

O

O

NOMe2 eq. LDA, THF

78 oC, 82% O

NOMe

OH

Example 25

TBSO O PhOTBS n-BuLi, THF

20 to 0 oC, 32%

TBSOPh

TBSO OH

625

References

1. Wittig, G.; Löhmann, L. Justus Liebigs Ann. Chem. 1942, 550, 260. 2. Tomooka, K.; Yamamoto, H.; Nakai, T. Justus Liebigs Ann. Chem. 1997, 1275. 3. Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551. 4. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915. 5. Tomooka, K.; Kikuchi, M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew.

Chem., Int. Ed. 2000, 39, 4502. 6. Katritzky, A. R.; Fang, Y. Heterocycles 2000, 53, 1783. 7. Kitagawa, O.; Momose, S.; Yamada, Y.; Shiro, M.; Taguchi, T. Tetrahedron Lett.

2001, 42, 4865. 8. Barluenga, J.; Fañanás, F. J.; Sanz, R.; Trabada, M. Org. Lett. 2002, 4, 1587. 9. Lemiègre, L.; Regnier, T.; Combret, J.-C.; Maddaluno, J. Tetrahedron Lett. 2003, 44,

373. 10. Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798. 11. Miyata, O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T. Tetrahedron 2004, 60, 3893. 12. Miyata, O.; Hashimoto, J.; Iba, R.; Naito, T. Tetrahedron Lett. 2005, 46, 4015.

626

[2,3]-Wittig rearrangement

Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as Still Wittig rearrangement. Cf. Sommelet Hauser rearrangement

XY

1

23

1

2X

Y

[2,3]-sigmatropic

rearrangement1

23

1

2

R2LiO R1R R1

R

OHR1 = alkynyl, alkenyl, Ph, COR, CN.

deprotonationO R1

R

HO

R

R1

R2

[2,3]-sigmatropic

rearrangement

workupR

O R1

R

HO R1

Example 13

O CO2H

LDA, THF

78 oC, 80% HO CO2H

74% E

Example 22

OO

KOt-Bu, HOt-Bu, THF

0 oC, 26 h, 22% HOO

627

References

1. Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521. 2. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084. 3. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22,

69.4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105 209. (Review). 5. Bertrand, P.; Gesson, J.-P.; Renoux, B.; Tranoy, I. Tetrahedron Lett. 1995, 36, 4073. 6. Maleczka, R. E., Jr.; Geng, F. Org. Lett. 1999, 1, 1111. 7. Tsubuki, M.; Kamata, T.; Nakatani, M.; Yamazaki, K.; Matsui, T.; Honda, T. Tetrahe-

dron: Asymmetry 2000, 11, 4725. 8. Itoh, T.; Kudo, K. Tetrahedron Lett. 2001, 42, 1317. 9. Pévet, I.; Meyer, C.; Cossy, J. Tetrahedron Lett. 2001, 42, 5215. 10. Anderson, J. C.; Skerratt, S. J. Chem. Soc., Perkin 1 2002, 2871. 11. Schaudt, M.; Blechert, S. J. Org. Chem. 2003, 68, 2913.

628

Wohl–Ziegler reaction

Radical-initiated allylic bromination using NBS, and catalytic AIBN as initiator or NBS under photolysis.

BrNBS, AIBN

CCl4, refluxInitiation:

N N CNNC CNN2 2homolyticcleavage

2,2’-azobisisobutyronitrile (AIBN)

N Br

O

O

N

O

O

CN CNBr

Propagation:

N

O

O

HH abstraction

NH

O

O

N Br

O

O

N

O

O

Br

The succinimidyl radical is now available for the next cycle of the radical chain reaction.

629

Example 13

AcO

OAc OAc

NBS, CCl4

reflux, 30 min., 48%

AcO

OAc O

Example 213

CO2Me 1.2 eq. NBS, 0.1 eq. AIBN

solvent free, 60 to 65 oC

89%

CO2Me

Br

References

1. Wohl, A. Ber. Dtsch. Chem. Ges. 1919, 52, 51. Alfred Wohl (1863 1939), born in Graudenz, Germany, received his Ph.D. from A. W. Hofmann. In 1904, he was ap-pointed Professor of Chemistry at the Technische Hochschule in Danzig.

2. Ziegler, K. et al. Justus Liebigs Ann. Chem. 1942, 551, 30. 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 Max-Planck-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 chemis-try. The Ziegler Natta catalyst is widely used in polymerization.

3. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660. 4. Wolfe, S.; Awang, D. V. C. Can. J. Chem. 1971, 49, 1384. 5. Ito, I.; Ueda, T. Chem. Pharm. Bull. 1975, 23, 1646. 6. Pennanen, S. I. Heterocycles 1978, 9, 1047. 7. Rose, U. J. Heterocycl. Chem. 1991, 28, 2005. 8. Greenwood, J. R.; Vaccarella, G.; Capper, H. R.; Mewett, K. N.; Allan, R. D.; Johns-

ton, G. A. R. THEOCHEM 1996, 368, 235. 9. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351. 10. Jeong, I. H.; Park, Y. S.; Chung, M. W.; Kim, B. T. Synth. Commun. 2001, 31, 2261. 11. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609. 12. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R.

Synlett 2002, 1089. 13. Togo, H.; Hirai, T. Synlett 2003, 702.

630

Wolff rearrangement

One-carbon homologation via the intermediacy of -diazoketone and ketene.

R2 NH2N2

R1 N2

OR1

HN

OR2C C O

H

R1

-diazoketone ketene intermediate

R1 N2

O

R1 N

ON

R1 NO

N

N2 R1 CH:

O alkyl

migration-ketocarbene

C C O

:NH2

R1

HN

R2H

R1

R2

H+ R1

HN

OR2

OH

H+

Treatment of the ketene with water would give the corresponding homologated carboxylic acid.

Example 12

H

O

N2

O or hv

EtOH, dioxane (1:1)> 90%

O

O O

Example 24

N

O

O

N2 hv, MeOH

90% NO

CO2Me

631

References

1. Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 25. Johann Ludwig Wolff (1857 1919) obtained 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. 3. Meier, H.; Zeller, K. P. Angew. Chem., Int. ed. Engl. 1975, 14, 32. 4. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Chem. Ber. 1993, 126, 2357. 5. Podlech, J.; Linder, M. R. J. Org. Chem. 1997, 62, 5873. 6. Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919. 7. Müller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837. 8. Lee, Y. R.; Suk, J. Y.; Kim, B. S. Tetrahedron Lett. 1999, 40, 8219. 9. Tilekar, J. N.; Patil, N. T.; Dhavale, D. D. Synthesis 2000, 395. 10. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2,

2177. 11. Xu, J.; Zhang, Q.; Chen, L.; Chen, H. J. Chem. Soc., Perkin Trans. 1 2001, 2266. 12. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002, 2193.

(Review). 13. Bogdanova, A.; Popik, V. V. J. Am. Chem. Soc. 2003, 125, 1456. 14. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003,

125, 4478. 15. Zeller, K.-P.; Blocher, A.; Haiss, P. “Oxirene participation in the Photochemical Wolff

Rearrangement” Mini-Reviews in Organic Chemistry 2004, 1, 291 308. (Review).

632

Wolff–Kishner reduction

Carbonyl reduction to methylene using basic hydrazine.

R R1

O NH2NH2

NaOH, refluxR R1

R R1

O

NH2NH2

R R1

NHHONH2

R R1

NN

H

HHO

HO

H

:

:

R R1

R R1

HO

HHO

HN

N R1

R

N2

Example 111

O

MeO2C

80% NH2NH2•H2O

toluene, microwave20 min., 75%

N

MeO2C

H2N

KOH, microwave

30 min., 40% MeO2C

Example 212

OOH

OH

HO

85% NH2NH2•H2O, KOH

H2O, 0.5 h, 165 oC, 87%

633

OHOH

HO

H

O

1,5-hydride shift

OHOH

HO

H

HH

References

1. Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582. 2. Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 86. 3. Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487. (the Huang-Minlon modification). 4. Todd, D. Org. React. 1948, 4, 378. (Review). 5. Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734. 6. Szmant, H. H. Angew. Chem., Int. Ed. Engl. 1968, 7, 120. 7. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556. 8. Akhila, A.; Banthorpe, D. V. Indian J. Chem. 1980, 19B, 998. 9. Bosch, J.; Moral, M.; Rubiralta, M. Heterocycles 1983, 20, 509. 10. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903. 11. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573. 12. Szendi, Z.; Forgó, P.; Tasi, G.; Böcskei, Z.; Nyerges, L.; Sweet, F. Steroids 2002, 67,

31.13. Bashore, C. G.; Samardjiev, I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125,

3268.

634

Yamaguchi esterification

Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).

R OH

OCl

OCl

Cl

Cl

Et3N, CH2Cl2

R O

O O Cl

Cl Cl

R1HO

DMAP, Tol., reflux R O

OR1

R O

OCl

OCl

Cl

Cl

H

:NEt3R O

O Cl

Cl Cl

ClO

R O

O O Cl

Cl ClN

N

O

O Cl

Cl Cl

OR

N

N

:

DMAP (Dimethylaminopyridine) Steric hindrance of the chloro sub-stituents blocks attack of the other carbonyl.

O

O Cl

Cl Cl

R N

O

NO:R1H

635

O N

N

ORR1

R O

OR1

Example 19

ICO2H

OTES

OMe

n-Bu3SnODMT

OMe

OH 2,4,6-trichlorobenzoyl chlorideDMAP, Tol., Et3N

rt, 24 h, 89%

I

OTES

OMe

n-Bu3SnODMT

OMe

O

O

636

Example 211

O O O

CO2H

O

HO

2,4,6-trichlorobenzoyl chlorideEt3N, THF

then DMAP, toluene, 62%

O O O

O

O

O

References

1. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.

2. Kawanami, Y.; Dainobu, Y.; Inanaga, J.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1981, 54, 943.

3. Bartra, M.; Vilarrasa, J. J. Org. Chem. 1991, 56, 5132. 4. Richardson, T. I.; Rychnovsky, S. D. Tetrahedron 1999, 55, 8977. 5. Berger, M.; Mulzer, J. J. Am. Chem. Soc. 1999, 121, 8393. 6. Paterson, I.; Chen, D. Y.-K.; Aceña, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513. 7. Hamelin, O.; Wang, Y.; Deprés, J.-P.; Greene, A. E. Angew. Chem., Int. Ed. 2000, 39,

4314. 8. Tian, Z.; Cui, H.; Wang, Y. Synth. Commun. 2002, 32, 3821. 9. Quéron, E.; Lett, R. Tetrahedron Lett. 2004, 45, 4533. 10. Mlynarski, J.; Ruiz-Caro, J.; Fürstner, A. Chem., Eur. J. 2004, 10, 2214. 11. Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc. 2004, 126, 15970. 12. Nakajima, N.; Ubukata, M. Heterocycles 2004, 64, 333.

637

Zincke reaction

The Zincke reaction is an overall amine exchange process that converts N-(2,4-dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.

NO2N

NO2

Cl R NH2

RN Cl

NH2

O2N

NO2

Zincke salt

NO2N

NO2

ClH2N R:

NO2N

NO2

NH2

RH

NO2N

NO2

NR

Hring-

opening

NHO2N

NO2

NR

H

NHO2N

NO2

NH

R

R

HN

HN

R

NH2

O2N

NO2

H2N R

638

H

RN

HN

R

cis-trans

inversionRN N

H

R

ring-

closureRN N

H

R H

RN N

H2

R:

RN Cl

Example 113

ClNO2

NO2

N

Et NNO2

NO2

Cl

Et

Acetone,

overnight (79%)

NH2

Ph

n-BuOH,

20 h (86%)

NCl

Et

OHPh

NNO2

NO2

Cl

Et

OH

Example 216

N N

ClNO2

NO2

OH OH

NH2

N N

ClH2O, , 16 h

OH

OH

639

OEt

N

H

O

HO

N

EtO

CaCO3, H2O/THF (4:1)

20 oC, 3 days

25%, 2 steps

References

1. Zincke, T. Justus Liebigs Ann. Chem. 1903, 330, 361. 2. Zincke, Th.; Heuser, G.; Möller, W. Justus Liebigs Ann. Chem. 1904, 333, 296. 3. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 338, 107. 4. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 341, 365. 5. Zincke, Th.; Weisspfenning, G. Justus Liebigs Ann. Chem. 1913, 396, 103. 6. Marvell, E. N.; Caple, G.; Shahidi, I. Tetrahedron Lett. 1967, 8, 277. 7. Marvell, E. N.; Caple, G.; Shahidi, I. J. Am. Chem. Soc. 1970, 92, 5641. 8. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665. (Review). 9. de Gee, A. J.; Sep, W. J.; Verhoeven, J. W.; de Boer, T. J. J. Chem. Soc., Perkin

Trans. 1 1974, 676. 10. Becher, J. Synthesis 1980, 589. (Review). 11. Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423. (Review). 12. Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org. Chem. 1996, 61, 9596. 13. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J.

Org. Chem. 1997, 62, 729. 14. Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.; Potier, P. J. Org. Chem. 1998, 63,

1767. 15. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. 16. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251. 17. Eda, M.; Kurth, M. J. J. Chem. Soc., Chem. Commun. 2001, 723. 18. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585. (Review). 19. Rojas, C. M. Zincke Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.;

Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 355 375. (Review).

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641

Subject index

AAbnormal Claisen rearrangement, 133 Accutane, 622 Acetone cyanohydrin, 580

-Acetylamino-alkyl methyl ketone, 179 O-Acylated hydroxamic acids, 352 Acetylation, 323, 468, 470

, -Acetylenic esters, 230 Acroleins, 39, 545 2-Acylamidoketones, 505 Acyl-o-aminobiphenyls, 399, 400 Acylanilides, 376 Acyl azide, 175 Acylbenzenesulfonylhydrazines, 354 Acyl halide, 240 Acrylic esters, 39 Acrylonitriles, 39 Acylium ion, 240, 245, 259, 335 Acyl oxazolidinone, 218

-Acyloxycarboxamides, 444 -Acyloxyketones, 16 -Acyloxythioethers, 483

Acyl transfer, 65, 341, 444, 483, 511 Intramolecular acyl transfer, 454 AD-mix- , 536 AD-mix- , 536 AIBN, 28, 30, 424, 628 Air oxidation, 206 Aldehyde cyanohydrins, 235 Alder’s endo rule, 199 Alder ene reaction, 1 Aldol condensation, 3, 120, 189, 218,

243, 281, 293, 403, 454, 503, 575 Algar–Flynn–Oyamada reaction, 5 Alkenylsilanol, 299 Alkyl alcohol, 237 Alkyl cation, 242 Alkyl migration, 14, 220, 464, 630 1,2-Alkyl shift, 202, 220, 335 Alkylsilanes, 237 Alkynylsilanol, 300 Allan–Robinson reaction, 8 Allylation, 518, 594

-Allyl complex, 594 O-Allyl hydroxylamines, 374 Allylic alcohol, 139, 388, 436, 533 Allylic amine, 456 Allylic sulfide, 388 Allylic tertiary amine-N-oxides, 374

Allylic transposition, 1 Allylic trichloroacetamide, 436 Allylsilanes, 518 Allyl trimethylsilyl ketene acetal, 137Alpine-borane®, 386, 387 Aluminum phenolate, 245 Amide, 41, 116, 118, 226, 279, 302,

348, 406, 407, 444, 501, 524, 558, 596

Amide acetal, 135 Amidine, 446 Amine synthesis, 247, 350 Aminoacetal, 472Amino acid, 179, 579

-Aminoalcohols, 350 -Aminoalcohols, 193

o-Aminobenzaldehyde, 243 -Aminocrotonate, 418

Amino hydroxylation, 531-Aminoketone, 412

2-Amino-2-methyl-1-propanol, 24-Amino nitrile, 579

4-Aminophenol, 18 Aminothiophene, 261 Ammonium ylide, 557 Aniline, 55, 79, 144, 147, 180, 257, 269,

289, 401, 546, 637 Anionic oxy-Cope rearrangement, 153

-Anomer, 337 Anomeric center, 325 Anomeric effect, 325 Anthracenes, 81 Appel reaction, 10 Appel’s salt, 10 Arndt–Eistert homologation, 12 Aromatization, 339, 557 Arylacetylene, 112Arylamides, 116 N-Arylation,116Aryl diazonium salt, 267

-Arylethylamines, 462 Aryl hydrazines, 87 Arylhydrazones, 233O-Aryliminoethers, 118 3-Arylindoles, 55 Aryl migration, 45, 177 Arylsilanol, 300 Aspirin, 340 Asymmetric aza-Mannich reaction, 362 Asymmetric hydroxylation, 185 Asymmetric epoxidation, 314

642

Asymmetric Mannich reaction, 361 Aurone, 6 Autoxidation, 48, 120 Aza-Grob fragmentation, 273 Aza-lactone, 179 Aza-Henry reaction, 294 Aza-Myers Saito reaction, 409 Aza- -methane rearrangement, 204 Azide, 63, 175, 489, 490, 564 Azido alcohol, 63 Aziridine, 63, 157, 272 Azirene, 412 2,2’-Azobisisobutyronitrile (AIBN), 28,

30, 210, 628

BBaeyer–Villiger oxidation, 14, 85 Baker–Venkataraman rearrangement, 16 Balz Schiemann reaction, 522 Bamberger rearrangement, 18 Bamford–Stevens reaction, 20 Barbier coupling reaction, 22 Bargellini reaction, 24 Bartoli indole synthesis, 26 Barton ester, 28 Barton–McCombie deoxygenation, 30 Barton nitrite photolysis, 32 Barton radical decarboxylation, 28 Barton–Zard reaction, 34 Batcho–Leimgruber indole synthesis, 36 Baylis–Hillman reaction, 39 9-BBN, 386 Beckmann rearrangement, 41 Beirut reaction, 43 1,4-Benzenediyl diradical, 49 Benzil, 45 Benzilic acid, 45 Benzilic acid rearrangement, 45 1,4-Benzodiazepine, 565 Benzofurazan oxide, 43 Benzoin, 47 Benzoin condensation, 47 1,4-Benzoquinone, 418 Benzotriazole, 322 Bergman cyclization, 49 Betaine, 623 cis-Bicyclo[3.3.0]octane-3,7-dione, 614 Biginelli pyrimidone synthesis, 51 Bimolecular elimination, 40 BINAP, 430 Birch reduction, 53

Bis-acetylene, 102Bischler–Möhlau indole synthesis, 55 2,4-Bis-(4-methoxyphenyl)-

[1,3,2,4]dithiadiphosphetane 2,4-disulfide, 348

Bischler–Napieralski reaction, 57 Bis(trifluoroethyl)phosphonate, 569 Blaise reaction, 59 Blanc chloromethylation, 61 Blum aziridine synthesis, 63 Boekelheide reaction, 65 Boger pyridine synthesis, 67, 200 Boranes, 85, 154, 386, 396, 582 Boronate fragmentation, 363 Borch reductive amination, 69 Borsche–Drechsel cyclization, 71 Boulton–Katritzky rearrangement, 73 Bouveault aldehyde synthesis, 75 Bouveault–Blanc reduction, 77 Boyland–Sims oxidation, 79 Bradsher reaction, 81

-Bromination, 291 -Bromoacid, 291

Brook rearrangement, 83 Brown hydroboration, 85 Bucherer carbazole synthesis, 87 Bucherer reaction, 90 Bucherer–Bergs reaction, 92 Büchner–Curtius–Schlotterbeck reac-

tion, 94 Büchner method of ring expansion, 96 Buchwald–Hartwig C–N bond and C–O

bond formation reactions, 98 Burgess dehydrating reagent, 100, 365 “Butterfly” transition state, 511

CCadiot–Chodkiewicz coupling, 102 Camps quinolinol synthesis, 104 Cannizzaro disproportionation, 107 Carbazole, 87 Carbene, 12, 169, 492, 630

-Carbocation, 237, 518 Carbocation rearrangement, 191, 193 Carbocyclization, 425 Carbonylation, 335 Carboxylation, 339 Carmack mechanism, 618–619 CAN, 209 Carroll rearrangement, 109 Castro–Stephens coupling, 112

643

3CC, 444, 456 4CC, 596 Celebrex, 332 Chan alkyne reduction, 114 Chan–Lam coupling reaction, 116 Chapman rearrangement, 118 Chichibabin pyridine synthesis, 120 Chlodiazepoxide, 565 Chloroammonium salt, 304 Chloroiminium salt, 603 Chloromethylation, 61 2-Chloro-1-methyl-pyridinium iodide,

4063-Chloropyridine, 125 Chugaev reaction, 123 Chromium-vinyl ketene, 208 Ciamician–Dennsted rearrangement, 125 Cinchona alkaloid, 536 Cinnamic acid, 454 Claisen condensation, 127, 197 Claisen isoxazole synthesis, 129 Claisen rearrangement, 131 anion-assisted, 109 Clemmensen reduction, 141 Collins oxidation, 318 Combes quinoline synthesis, 144 Comins modification of the Bouveault

aldehyde synthesis, 75 Concerted process, 151, 175 Conrad–Limpach reaction, 147 Cope elimination reaction, 149 Cope rearrangement, 151 Corey–Bakshi–Shibata (CBS) reduction,

154Corey Chaykovsky reaction, 157 Corey–Fuchs reaction, 160 Corey–Kim oxidation, 162 Corey–Nicolaou macrolactonization,

164Corey–Seebach dithiane reaction, 166 Corey’s ylide, 157 Corey–Winter olefin synthesis, 168 Counterattack reagent, 608 Coumarin, 452 Criegee glycol cleavage, 171 Criegee mechanism of ozonolysis, 173 Criegee zwitterion, 173 Cr Ni bimetallic catalyst, 432 Cu(III) intermediate, 102, 112 Curtius rearrangement, 175 Cyanohydrin, 92

Cyanamide, 608 Cyanoacetic ester, 275 Cyanogen bromide, 608 Cyclic ether, 426 Cyclic iodonium ion, 475, 476 Cyclic thiocarbonate, 168 Cyclization

Bergman, 49 Borsche–Drechsel, 71 Ferrier carbocyclization, 224 Myers Saito, 408 Nazarov, 410Nicolaou hydroxy-dithioketal, 424 Parham, 442

[2 + 2] Cycloaddition, 499, 547, 587, 621

[2 + 2 +1] Cycloaddition, 448 [3 + 2] Cycloaddition, 536 [4+2] Cycloaddition, 199, 314 Cycloalkanones, 210 Cyclobutanone, 561 Cyclohepta-2,4,6-trienecarboxylic acid

esters, 96 Cyclohexadienones, 202 Cyclohexanone phenylhydrazone, 71 Cyclopentene, 606 Cyclopentenone, 410, 448 Cyclopropanation, 125, 157, 358, 543

DDakin oxidation, 177 Dakin–West reaction, 179 Danheiser annulation, 181 Danishefsky diene, 199 Darzens glycidic ester condensation, 183 Davis chiral oxaziridine reagent, 185 DBU, 353, 367 DCC, 327, 395 DEAD, 249, 390 Decarboxylation, 28, 329, 352, 507 Dehydrating agent, 11, 100, 365, 460 Dehydrogenation, 422 Delépine amine synthesis, 187 de Mayo reaction, 189 Demetallation, 420 Demjanov rearrangement, 191 Deoxygenation, 30 Dess–Martin oxidation, 195, 505 DIAD, 391 1,2-Diaminopropanes, 24 Diastereomers, 323

644

Diazoacetates, 96 Diazo compounds, 94

-Diazoketone, 630 Diazomethane, 12 Diazonium salt, 193, 316, 520 Diazotization, 191, 193 Diboron reagent, 392 Dibromoolefin, 160 Di-tert-butylazodicarbonate, 248 Dichlorocarbene, 125, 492 1,3-Dicyclohexylurea, 327 Dieckmann condensation, 197 Diels–Alder reaction, 199 hetero-Diels Alder, 67 retro-Diels Alder, 67 Diene, 199, 200, 204, 358 Dienone–phenol rearrangement, 202 Dienophiles, 67, 199, 200, 358 Diethyl azodicarboxylate, 390 Diethyl succinate, 575 Diethyl tartrate, 533 Diethyl thiodiglycolate, 295 Dihydroisoquinolines, 57 Dihydropyridine, 281 Dihydroxylation, 475, 476, 536 Diketone, 16, 189, 245, 275, 295, 438,

440, 567 Dimerization, 265 Dimethylsulfide, 162 Dimethylsulfonium methylide, 157 Dimethylsulfoxonium methylide, 157 Dimethyltitanocene, 587 Di- -methane rearrangement, 204 2,4-Dinitrobenzenesulfonyl chloride,

153Diol, 168 1,3-Dioxolane-2-thione, 168 Diphenyl 2-pyridylphosphine, 248 1,3-Dipolar cycloaddition, 173, 490 Diradical, 49, 204, 408 Disproportionation reaction, 107 N,N-Disubstituted acetamide, 468 Dithiane, 166 Ditin, 573 Di-vinyl ketone, 410 DMFDMA, 36 DMS, 162 DMSY, 157 Doebner quinoline synthesis, 206 Doebner–von Miller reaction, 545 Dötz reaction, 208

Double imine, 233 Dowd–Beckwith ring expansion, 210 DPE-Phos, 99

EE1, 501 E1cB, 277, 365 E2, 40, 79, 100, 454, 458 Eglinton coupling, 265 Ei, 100, 149 Electrocyclic ring closure, 208, 410 Electrocyclic ring opening, 96 Electrocyclization, 49, 147, 269, 410 Photo-induced, 446 Electrophilic substitution, 240, 308

-Elimination, 285, 289, 365, 492 syn-Elimination, 540 Enamine, 67, 120, 144, 277, 281, 283,

470, 577, 592 Enediyne, 49 Ene reaction, 1, 133 Enol, 3 Enolizable -haloketone, 220 Enolization, 8, 197, 281, 291, 341, 343,

361, 454, 489, 503 Enolsilanes, 511, 515 Enones, 189, 515 Enophile, 1 Episulfone, 485 Epoxidation

Corey Chaykovsky, 157 Jacobsen–Katsuki, 314 Sharpless, 533

Epoxide, 157 Epoxide migration, 450 2,3-Epoxy alcohols, 450

-Epoxy esters, 183 -Epoxy ketones, 214, 616-Epoxy sulfonylhydrazones

Erlenmeyer Plöchl azalactone synthesis, 212

erythro, 306, 567 Eschenmoser–Claisen amide acetal rear-

rangement, 135 Eschenmoser’s salt, 361 Eschenmoser–Tanabe fragmentation,

214Eschweiler–Clarke reductive alkylation

of amines, 216 Ethyl acetoacetate, 51 Ethylammonium nitrate (EAN), 330

645

Ethyl oxalate, 497 Evans aldol reaction, 218 Evans chiral auxiliary, 218 5-Exo-trig-ring closure, 1976-Exo-trig-ring closure, 341, 480

FFavorskii rearrangement and quasi-

Favorskii rearrangement, 220 Feist–Bénary furan synthesis, 222 Ferrier carbocyclization, 224 Ferrier glycal allylic rearrangement, 227 Fiesselmann thiophene synthesis, 230 Fischer carbene, 208 Fischer indole synthesis, 233 Fischer oxazole synthesis, 235 Flavol, 5 Flavones, 8 Fleming–Tamao oxidation, 237 Fluoroarene, 522 Fluorous Corey Kim reaction, 162 Flustramine B, 360 Formamide acetals, 36 Formylation, 75, 259 Four-component condensation, 596 Friedel–Crafts reaction, 240 Friedländer quinoline synthesis, 243 Fries rearrangement, 245 Fukuyama amine synthesis, 247 Fukuyama reduction, 249 Furans, 222, 440

GGabriel–Colman rearrangement, 255 Gabriel synthesis, 251 Gassman indole synthesis, 257 Gattermann–Koch reaction, 259 Gewald aminothiophene synthesis, 261 Glaser coupling, 263 Glycals, 229 Glycidic esters, 183 Glycol, 228 Glycosidation, 325, 337, 526 Gomberg–Bachmann reaction, 267, 480 Gould–Jacobs reaction, 269 Grignard reaction, 20, 22, 271, 345, 529 Vinyl Grignard reagent, 26 Grob fragmentation, 273 Grubbs’ reagents, 499 Guareschi imide, 275 Guareschi–Thorpe condensation, 275

Guanidine bases, 34

HHajos–Wiechert reaction, 277 Halfordinal, 236 Halichlorine, 328 Haller–Bauer reaction, 279 N-Haloamines, 304

-Haloesters, 59, 183, 222, 489 Halogen-metal exchange, 442 Halohydrin, 428

-Haloketones, 222-Halosulfone extrusion, 485

Hantzsch dihydropyridine synthesis, 281 Hantzsch pyrrole synthesis, 283 Head-to-head alignment, 189 Head-to-tail alignment, 189 Heck reaction, 285 Hegedus indole synthesis, 289 Hell–Volhard–Zelinsky reaction, 291 Hemiaminal, 507, 555 Hemiketal, 426 Hennoxazole, 505 Henry nitroaldol reaction, 293 aza-Henry reaction, 294 Heteroaryl Heck reaction, 287 Heteroarylsulfones, 321 Hetero-Diels Alder, 67 Heterodiene, 201 Heterodienophile, 201 Hexacarbonyldicobalt, 420, 448 Hexamethylenetetramine, 187, 555 Hinsberg synthesis of thiophene deriva-

tives, 295 Hiyama cross-coupling reaction, 297 Hiyama–Denmark cross-coupling reac-

tion, 299 Hoch–Campbell aziridine synthesis, 272 Hofmann rearrangement, 302 Hofmann–Löffler–Freytag reaction, 304 Homolytic cleavage, 28, 32, 210, 304,

310, 354, 424, 628 Horner–Wadsworth–Emmons reaction,

306, 367 Hosomi Miyaura borylation, 392 Hosomi–Sakurai reaction, 518 Houben–Hoesch synthesis, 308 Intramolecular Houben Hoesch, 308 Hünig’s base, 368 Hunsdiecker–Borodin reaction, 310

646

Hurd–Mori 1,2,3-thiadiazole synthesis, 312

Hydantoin, 92 Hydrazine, 253, 331, 616, 632 Hydrazoic acid, 524 Hydrazone, 316

-Hydride elimination, 401, 515, 559, 610

Hydride transfer, 30, 107, 133, 369, 386, 555, 587, 633

Hydroboration, 85 Hydrogenation, 430, 509, 515 Hydrogen atom donor, 408 Hydroquinone, 208 Hydroxy-dithioketal cyclization, 424 3-Hydroxy-isoxazoles, 129 Hydroxy-ketone cyclization, 424 Hydroxylamine, 129

-Hydroxylation, 511 5-Hydroxylindole, 418 2’-hydroxychalcones, 5 2-Hydroxymethylpyridine, 654-Hydroxyquinoline, 269

-Hydroxysilane, 83 -Hydroxysilane, 458

Hypohalite, 257, 302

IIBX, 422-423 Imidazolidinones, 358 Imine, 69, 120, 144, 472, 507, 547, 592,

596Iminium ion, 329, 350, 358, 468, 470,

559, 579 Iminophosphoranes, 563 Indoles, 26, 36, 233, 257, 289, 359, 401 Indole-2-carboxylic acid, 497 2-Indolylsilanol, 300 Ing–Manske procedure, 253 Intramolecular Houben Hoesch reacti-

on, 308Intramolecular Nicholas reaction, 421Iodoalkene, 585 Iodonium ion, 475, 476 o-Iodoxybenzoic acid, 420-423Ipso, 79, 237, 371Ireland–Claisen (silyl ketene acetal)

rearrangement, 137 Isocyanide, 444, 596 Isocyanate, 92, 175, 302, 352

-Isocyanoacetates, 34

Isoflavones, 8 Isoquinoline, 206, 460, 462, 472 Isoquinoline 1,4-diol, 255 3-Isoxazolols, 129 5-Isoxazolone, 129 4-Isoxazolylsilanol, 301

JJacobsen–Katsuki epoxidation, 314 Japp–Klingemann hydrazone synthesis,

316Johnson–Claisen (orthoester) rearran-

gement, 139 Jones modification of the Kolbe–

Schmitt reaction, 340 Jones oxidation, 318 Julia–Kocienski olefination, 321 Julia–Lythgoe olefination, 323

KKahne–Crich glycosidation, 325 Keck macrolactonization, 327 Ketene, 12, 208, 561, 630 Ketene acetal, 139, 630 Ketocarbene, 12, 630

-Ketoesters, 316-Ketoesters, 59, 109, 127, 129, 281,

283, 452 1,4-Ketones, 438, 440-Ketoolefin, 109

Ketophenols, 245 Ketoximes, 272, 412 Ketyl (radical anion), 77 Kharasch cross-coupling reaction, 345 Kinetic products, 20 Kishner reduction, 1 Knoevenagel condensation, 261, 329 Knorr pyrazole synthesis, 331 Koch–Haaf carbonylation, 335 Koenig–Knorr glycosidation, 337 Kolbe–Schmitt reaction, 339 Kostanecki reaction, 341 Kröhnke pyridine synthesis, 343 Kumada cross-coupling reaction, 345

L-Lactam, 561 -Lactone, 561

Lactonization, 575 Lawesson’s reagent, 348, 438 Lead tetraacetate, 171

647

Leuckart–Wallach reaction, 350 Librium, 565 Lipitor, 334 Liquid ammonia, 53 Lossen rearrangement, 352

MMcFadyen–Stevens reduction, 354 McMurry coupling, 356 MacMillan catalyst, 358 Macrolactonization, 327 Magnesium Oppenauer oxidation, 434 Maleimidyl acetate, 255 Mannich base, 361 Mannich reaction, 361 Boronic acid-Mannich, 456 Petasis boronic acid-Mannich reacti-

on, 456 Markownikoff addition, 428 Marasse modification of the Kolbe–

Schmitt reaction, 339 Marshall boronate fragmentation, 363 Martin’s sulfurane dehydrating reagent,

365Masamune–Roush conditions, 367 MCRs, 51, 92 Meerwein–Ponndorf–Verley reduction,

369Meisenheimer complex, 247, 371, 549 Meisenheimer Jackson salt, 371 [1,2]-Meisenheimer rearrangement, 372 [2,3]-Meisenheimer rearrangement, 374 Meldrum’s acid, 330 Mesyl azide, 491 Metallacyclobutene, 208 Metallacyclopentenone, 208 Meth–Cohn quinoline synthesis, 376 2-Methylpyridine N-oxide, 65 Methyl vinyl ketone, 503, 577 Meyer–Schuster rearrangement, 380 Meyer’s oxazoline method, 378 Michael addition, 34, 120, 277, 281,

343, 382, 405, 418, 452, 518, 545, 567, 577

Michael Stetter reaction, 567 Michaelis–Arbuzov phosphonate syn-

thesis, 384 Microwave, 90, 504, 620, 632 Midland reduction, 386 Migratory aptitude, 14, 464 Mislow–Evans rearrangement, 388

Mitsunobu reaction, 247, 390 Miyaura borylation, 392 Moffatt oxidation, 394 Montgomery coupling, 396 Morgan–Walls reaction , 399 Morpholine, 44 Morpholinones, 24 Mori–Ban indole synthesis, 401 Morita–Baylis–Hillman reaction, 39 Mukaiyama aldol reaction, 403 Mukaiyama Michael addition, 405 Mukaiyama reagent, 406 Multi-component reactions, 51, 92 Myers Saito cyclization, 408

NNaphthol, 87, 90

-Naphthylamines, 90 Naproxen, 620 Nazarov cyclization, 410 NCS, 162 Neber rearrangement, 412 Nifedipine, 282 Nef reaction, 414 Negishi cross-coupling reaction, 416 Neighboring group assistance, 322, 358,

445, 475, 476, 527 Nenitzescu indole synthesis, 418 Newman Kwart reaction, 551 Nicholas reaction, 420 Nickel-catalyzed coupling, 396 Nicolaou dehydrogenation, 422 Nicolaou hydroxy-dithioketal cyclizati-

on, 424 Nicolaou hydroxy-ketone reductive cyc-

lic ether formation, 426 Nicolaou oxyselenation, 428 Nitrene, 175 Nitric oxide radical, 32 Nitrilium ion, 501, 524 Nitrite ester, 32 Nitroaldol reaction, 293 Nitroalkane, 412 Nitroalkene, 34 Nitroarenes, 26 Nitrogen radical cation, 304 Nitronates, 293, 414 Nitronic acid, 414 o-Nitrophenyl selenides, 540 Nitroso intermediate, 26, 32 o-Nitrotoluene, 36, 497

648

Non-enolizable ketone, 221, 279 Noyori asymmetric hydrogenation, 430 Nozaki–Hiyama–Kishi reaction, 432 Nucleophilic addition, 59, 94, 293, 297,

339, 378, 419, 428, 432, 466, 487, 610

OOctacarbonyl dicobalt, 448 Odorless Corey Kim reaction, 162 Olefin, 149, 189, 306, 321, 323, 335,

356, 371, 458, 485, 531, 540, 587, 610, 612

Olefin complexation, 610 Oppenauer oxidation, 434 Organoborane, 85, 581 Organosilanol, 299 Organosilicons, 297 Organostannanes, 571 Organozinc, 141, 396, 400, 416, 487 Orthoester, 139 Osmium, 531 Overman rearrangement, 436 Oxaborolidines, 154 Oxalyl chloride, 605 Oxaphosphetane, 621 Oxatitanacyclobutane, 587 Oxazete, 118 Oxaziridine, 185 Oxazoles, 235, 601 Oxazolidinone, 218 Oxazolines, 378 Oxazolone, 179 5-Oxazolone, 212 Oxetane, 446 Oxidation

Baeyer–Villiger, 14 Boyland–Sims, 79 Collins, 319 Corey–Kim, 162 Dakin, 177 Dess Martin, 109 Fleming-Tamao, 237 Jones, 318 Moffatt, 394 Oppenauer, 434 PCC, 319 PDC, 320 Prilezhaev, 511 Rubottom, 511

Sarett, 319 Swern, 583 Tamao Kumada, 238 Wacker, 424

Oxidative addition, 98, 102, 112, 249, 283, 287, 297, 345, 392, 401, 416, 432, 487, 509, 543, 559, 571, 573, 581, 599

syn-Oxidative elimination, 540 Oxidative homo-coupling, 263, 265N-Oxide, 149 Oximes, 41-Oximino alcohol, 32

Oxirane, 61 Oxonium ion, 325, 337 Oxy-Cope rearrangement, 152 Oxygen transfer, 314 Oxygen transposition, 616 Oxyselenation, 428 Oxyselenide, 429

PPaal–Knorr furan synthesis, 440 Paal–Knorr pyrrole synthesis, 333 Paal thiophene synthesis, 438 Palladation, 289, 610 Palladium-promoted reactions

Heck, 285 Heteroaryl Heck, 287 Hiyama, 297 Hiyama–Denmark, 299 Kumada, 345 Miyaura borylation, 392 Mori–Ban indole, 401 Negishi, 416 Saegusa, 515 Sonogashira, 559 Stille, 571 Stille–Kelly, 573 Suzuki, 581 Tsuji–Trost, 594 Wacker, 610

Parham cyclization, 442 Passerini reaction, 444 Paternò–Büchi reaction, 446 Pauson–Khand cyclopentenone synthe-

sis, 448 Payne rearrangement, 450 PCC, 319 PDC, 320 Pechmann coumarin synthesis, 452

649

Periodinane, 195 Perkin reaction, 454 Persulfate, 77 Pentacoordiante silicon intermediate, 83 Petasis alkenylation, 587 Petasis reagent, 587 Petasis reaction, 456 Peterson olefination, 458 Pfitzner Moffatt oxidation, 394Phenanthridine, 399, 400

-Phenethylamides, 57 Phenols, 202 Phenoxide, 339 L-Phenylalanine, 278 Phenylhydrazine, 233 Phenylhydrazone, 233 N-Phenylhydroxylamine, 16 4-Phenylpyridine N-oxide, 315 N-Phenylselenophthalimide, 428 N-Phenylselenosuccinimide, 428 Phenyltetrazolyl, 321 Phosphazide, 563 Phosphites, 384, 389 Phosphonates, 306, 367, 384 Phosphorus oxychloride, 57, 376, 399,

460Phosphorous pentaoxide, 460 [2 + 2] Photochemical cyclization, 189 Photochemical rearrangement, 175 Photo-induced electrocyclization, 446 Photolysis, 32 Photo Reimer–Tiemann, 492 Phthalimide, 253 Pictet–Gams isoquinoline synthesis, 460 Pictet–Hubert reaction, 400 Pictet–Spengler tetrahydroisoquinoline

synthesis, 462 Pinacol rearrangement, 464 (1R)-(+)- -Pinene, 386 Pinner reaction, 466 Piperazinones, 24 Piperidines, 304 Plavix, 580 Polonovski–Potier rearrangement, 470 Polonovski reaction, 468 Polyphosphoric acid, 42 Pomeranz–Fritsch reaction, 472 Potassium phthalimide, 251 PPA, 42 PPTS, 145 Precatalysts, 499

Prévost trans-dihydroxylation, 475 Prilezhaev epoxidation, 511 Primary ozonide, 173 Prins reaction, 478 Progesterone, 503 (L)-Proline, 362 (S)-( )-Proline, 277 Propargyl cation, 420 Pschorr cyclization, 480 Puckered transition state, 561, 621 Pummerer rearrangement, 483 Pyrazoles, 331 Pyrazolones, 331 Pyridine synthesis, 67, 120, 281, 343

-Pyridinium methyl ketone salts, 343 2-Pyridone, 275 2-Pyridinethione, 164 Pyrimidone, 51 Pyrroles, 34, 283, 331, 333 Pyrrolidines, 37, 304

QQuasi-Favorskii rearrangement, 221 Quinoline, 144, 243, 376, 494, 545, 547 Quinoline-4-carboxylic acid, 206 Quinoxaline-1,4-dioxide, 43Quinazoline 3-oxide, 565 Quinolinol, 104 Quinolin-4-ones, 147

RRadical anion, 53, 141, 356 Radical coupling, 267, 480 Radical decarboxylation, 28 Radical reactions

Barton radical decarboxylation, 28 Barton–McCombie, 30 Barton nitrite photolysis, 32 Dowd–Beckwith ring expansion, 210 Gomberg–Bachmann, 267 McFadyen–Stevens reduction, 354 McMurry coupling, 356 TEMPO-mediated oxidation, 590

Radical scission, 30 Radical Thorpe Ziegler reaction, 592 Ramberg–Bäcklund reaction, 485 Raney nickel, 257 Rauhut–Currier reaction, 39 Rearrangement

Abnormal Claisen, 131 Anionic oxy–Cope, 153

650

Baker–Venkataraman, 16 Bamberger, 18 Beckmann, 41 Benzilic acid, 45 Brook, 83 Carrol, 109 Chapman, 118 Claisen, 131 Cope, 151 Curtius, 175 Demjanov, 191

Dienone–phenol, 202 Di- -methane, 204 Eschenmoser–Claisen, 135 Favorskii, 220 Ferrier, 227 Fries, 245 Hofmann, 302Ireland–Claisen, 137Johnson–Claisen, 139 Lossen, 352 Meisenheimer, 372 Meyer–Schuster, 380 Mislow–Evans, 388 Neber, 412 Overman, 436 oxy-Cope, 152 Payne, 450 Pinacol, 464 Pummerer, 483 Rupe, 380, 513 Quasi-Favorskii, 221 Schmidt, 524 Smiles, 549 Sommelet–Hauser, 557 Tiffeneau–Demjanov, 193 Truce-Smile, 553 Wagner–Meerwein, 612 Wolff, 630

Red-Al, 114 Redox addition, 432 Redox reaction, 107 Reduction

Birch, 53 Bouveault–Blanc, 77 CBS, 154 Leuckart–Wallach reaction, 350 McFadyen–Stevens, 354 Meerwein–Ponndorf–Verley, 369 Midland, 386 Staudinger, 563

Wharton, 616 Wolff–Kishner, 632

Reductive amination, 69, 350 Reductive elimination, 96, 98, 102, 112,

116, 249, 345, 392, 416, 448, 509, 559, 571, 573, 581, 610

Reductive methylation, 216 Reductive olefination, 168 Reformatsky reaction, 487 Regitz diazo synthesis, 489 Reimer–Tiemann reaction, 492 photo Reimer–Tiemann, 492 Reissert aldehyde synthesis, 494 Reissert compound, 494 Reissert indole synthesis, 497 Retro-aldol reaction, 189 Retro-Diels Alder, 67 Reverse electronic demand Diels– Alder reaction, 199 Rhodium carbenoid, 96 Ring-closing metathesis, 499 Ring expansion, 193 Ritter reaction, 501 Robinson annulation, 277, 503 Robinson–Gabriel synthesis, 505 Robinson–Schöpf reaction, 507 Rosenmund reduction, 509 Rubottom oxidation, 511 Rupe rearrangement, 513 Ruthenium(II) BINAP complex, 430

SSaegusa enone synthesis, 515 Saegusa oxidation, 515 Sakurai allylation reaction, 518 Salicylic acid, 340 Sandmeyer reaction, 520 Sanger’s reagent, 371 Sarett oxidation, 319 Schiemann reaction, 522 Schiff base, 147, 547 Schlosser modification of the Wittig

reaction, 622 Schmidt reaction, 524 Schmidt’s trichloroacetimidate glycosi-

dation reaction, 526 Schrock’s reagent, 499

-Scission, 30 Secondary ozonide, 173 Selenides, 429 Selenol esters, 429

651

Selenonium, 428 Shapiro reaction, 529 Sharpless asymmetric amino hydroxyla-

tion, 531 Sharpless asymmetric epoxidation , 533 Sharpless asymmetric dihydroxylation,

536Sharpless olefin synthesis, 540 1,2-Shift of silyl group, 181 [1,2]-Sigmatropic rearrangement, 373, 624[2,3]-Sigmatropic rearrangement, 257,

374, 388, 557, 626 [3,3]-Sigmatropic rearrangement, 71, 87,

131, 133, 135, 139, 151, 152, 153, 233, 436

Silylation, 426 Silyl enol ether, 403, 405, 422 Silyl ester, 137 Silyl ether, 83 [1,2]-Silyl migration, 83 Silver carboxylate, 310 Simmons–Smith reaction, 543 Single electron transfer, 22, 53, 77, 323,

356, 422, 599 Singlet diradical, 446

-Silylalkoxide, 458 Skraup quinoline synthesis, 545 Sm, 23 SMEAH, 114 Smiles rearrangement, 549 SN1, 325 SN2, 61, 63, 141, 183, 187, 235, 251,

253, 257, 304, 376, 384, 388, 390, 390, 450, 471, 475, 476, 555, 603, 621

SNAr, 118, 120, 371, 406, 549 Sommelet–Hauser rearrangement, 557 Sommelet reaction, 555 Sonogashira reaction, 559 Spirocyclic anion, 549 Statin side chain, 59 Staudinger ketene cycloaddition, 561 Staudinger reduction, 63, 563 Stereoselective reduction, 114 Sternbach benzodiazepine synthesis, 565 Stetter reaction, 567 Still–Gennari phosphonate reaction, 569 Still Wittig rearrangement, 626 Stille coupling, 571 Stille–Kelly reaction, 573

Stobbe condensation, 575 Stork enamine reaction, 577 Strecker amino acid synthesis, 579 Succinimidyl radical, 628 Sulfenamide, 618 Sulfide reduction, 424 Sulfones, 323 Sulfonium ion, 257 Sulfonyl azide, 489N-Sulfonyloxaziridines, 185 Sulfoxide, 325 Sulfur, 261, 438, 618 Sulfur ylide, 157, 583 Suzuki coupling, 581 Swern oxidation, 583

TTakai iodoalkene synthesis, 585 Tamao Kumada oxidation, 239 Tamoxifen, 217 Tautomerization, 133, 179, 208, 233,

281, 380, 438, 513, 524, 567, 579, 610, 616

Tebbe olefination, 587 Tebbe’s reagent, 587 TEMPO-mediated oxidation, 589 Terminal alkyne, 160, 265 Tertiary amine, 608 Tertiary amine N-oxides, 373, 468, 470 Tertiary carbocation, 335 Tetrahydrocarbazole, 71 Tetrahydroisoquinolines, 462 Tetramethyl pentahydropyridine oxide,

589TFAA, 65, 470 Thermal aryl rearrangement, 118 Thermal Bamford-Stevens, 21 Thermal elimination, 123, 149 Thermal rearrangement, 109, 175 Thermodynamically favored, 335 Thermodynamic products, 20 Thermolysis, 73 1,2,3-Thiadiazole, 312 Thiamide, 618 Thiazolium, 47, 567 Thiirane, 157 Thiirene, 618 Thiocarbonyl, 28, 30 1,1’-Thiocarbonyldiimidazole, 168 Thioglycolic acid, 230 Thiol esters, 249

652

Thionium, 424 Thiophene, 230, 261, 295, 438 Thiophenol, 551 Thorpe Ziegler reaction, 592 Three-component coupling, 206, 444,

456 threo, 306 Tiffeneau–Demjanov rearrangement,

193Titanium tetra-iso-propoxide, 533 Titanocene methylidene, 587 Tosyl amide, 489 Tosyl hydrazone, 312 TosMIC, 601 p-Tolylsulfonylmethyl isocyanide, 601 Transmetalation, 116, 297, 299, 345,

416, 432, 559, 571, 573, 581, 587 Triacetoxyperiodinane, 195 1,2,4-Triazines, 67 Triazole, 490 Trichloroacetimidate, 436, 526 2,4,6-Trichlorobenzoyl chloride, 634 Trifluoroacetic anhydride, 65, 470 Trimethylphosphite, 168 Trimethylsilylallene, 181 Trimethylsilylcyclopentene, 181 1,3,5-Trioxane, 61 1,2,3-Trioxolane, 173 1,2,4-Trioxolane, 173 Triphenylphosphine, 10, 390, 401 n, * Triplet, 446 Triplet diradical, 446 Tropinone, 507 Truce Smile rearrangement, 553 Tsuji–Trost allylation, 594

UUgi reaction, 596 UHP, 178 Ullmann reaction, 599

-Unsaturated aldehydes, 513-Unsaturated ketone, 181, 343, 513

Urea, 51 Urea-hydrogen peroxide, 178

Vvan Leusen oxazole synthesis, 601 Vicinal diol, 171 Vilsmeier–Haack reaction, 603 Vilsmeier–Haack reagent, 376, 603, 605

Vilsmeier mechanism for acid chloride formation, 605

Vinylcyclopropane, 204 Vinylcyclopropane cyclopentene rear-

rangement, 606 Vinyl halides, 432 E-Vinyl iodide, 585 Vinyl ketones, 39 Vinyl sulfones, 39 von Braun reaction, 608

WWacker oxidation, 515, 610 Wagner–Meerwein rearrangement, 612 Weiss–Cook reaction, 614 Wharton oxygen transposition reaction,

616Willgerodt–Kindler reaction, 618 Wittig reaction, 621 Sila-Wittig reaction, 458 [1,2]-Wittig rearrangement, 624 [2,3]-Wittig rearrangement, 626, 557 Wohl–Ziegler reaction, 628 Wolff rearrangement, 630 Wolff–Kishner reduction, 632 Woodward cis-dihydroxylation, 476

XXanthate, 123

YYamaguchi esterification, 634 Yamaguchi reagent, 634

ZZimmerman rearrangement, 204 Zinc-carbenoid, 141 Zincke reaction, 637 Zincke salt, 637 Zoloft, 571 Zwitterionic peroxide, 173