Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications [3 ed.] 3540300317, 9783540300311

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Name Reactions

Jie Jack Li

Name Reactions A Collection of Detailed Reaction Mechanisms

Third Expanded Edition

123

Jie Jack Li, Ph.D. Pfizer Global Research and Development Chemistry Department 2800 Plymouth Road Ann Arbor, MI 48105 USA e-mail: jack.li@pfizer.com

3rd. expanded ed. ISBN-10 3-540-30030-9 Springer Berlin Heidelberg New York ISBN-13 978-3-540-30030-4 Springer Berlin Heidelberg New York e-ISBN 3-540-30031-7 ISBN-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 the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springer.com © Springer-Verlag Berlin Heidelberg 2003, 2006 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Typesetting: By the Author Production: LE-TEX, Jelonek, Schmidt & Vöckler GbR, Leipzig Coverdesign: 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 hesitate to point out that the names associated with “name reactions” are often not the actual inventors. For instance, the Arndt-Eistert reaction has nothing to do with either Arndt or Eistert, Pummerer did not discover the “Pummerer” rearrangement, and even the famous Birch reduction owes its initial discovery to someone named Charles Wooster (first reported in a DuPont patent). The list goes on and on… But does that mean we should ignore, boycott, or outlaw “named reactions”? Absolutely not. The above examples are merely exceptions to the rule. In fact, the chemists associated with name reactions are typically the original discoverers, contribute greatly to its general use, and/or are the first to popularize the transformation. Regardless of the controversial history underlying certain named reactions, it is the students of organic chemistry who benefit the most from the cataloging of reactions by name. Indeed, it is with education in mind that Dr. Jack Li has masterfully brought the chemical community the latest edition of Name Reactions. It is clear why this beautiful treatise has rapidly become a bestseller within the chemical community. The quintessence of hundreds of named reactions is encapsulated in a concise format that is ideal for students and seasoned chemists alike. Detailed mechanistic and occasionally even historical details are given for hundreds of reactions along with key references. This “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 discoveries 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 chemistry for their contributions to metathesis, a name reaction that has been also included since the first edition. Therefore, I intend to keep up with the new developments 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 Fischer 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 navigate 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 invaluable 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 California 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, Nathaniel Sherden, Jennifer Stockdill, and Carolyn Woodroofe for proofreading the final draft of the manuscript. Their knowledge and time have tremendously enhanced the quality of this book. Any remaining errors are, of course, solely my own responsibility. 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 CoreyChaykovsky 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-S-methane rearrangement .............................................................................. 204 Doebner quinoline synthesis ............................................................................... 206 Dötz reaction ....................................................................................................... 208 Dowd–Beckwith ring expansion ......................................................................... 210 ErlenmeyerPlöchl 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 TamaoKumada 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 MyersSaito 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 NewmanKwart reaction ............................................................................ 551 TruceSmile 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 ThorpeZiegler 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 Vinylcyclopropanecyclopentene 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 Ac AIBN Alpine-borane® Ar B: 9-BBN [bimim]Cl•2AlCl3 BINAP Bn Boc t-Bu Bz Cbz m-CPBA CuTC DABCO dba DBU DCC DDQ DEAD '   (DHQ)2-PHAL (DHQD)2-PHAL DIAD DIBAL DIPEA DMA DMAP DME DMF DMFDMA DMS DMSO DMSY DMT dppb dppe dppf dppp

adenosine acetyl 2,2’-azobisisobutyronitrile B-isopinocampheyl-9-borabicyclo[3.3.1]-nonane aryl generic base 9-borabicyclo[3.3.1]nonane 1-butyl-3-methylimidazolium chloroaluminuminate (a Lewis acid ionic liquid) 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl benzyl tert-butyloxycarbonyl tert-butyl benzoyl benzyloxycarbonyl m-chloroperoxybenzoic acid copper thiophene-2-carboxylate 1,4-diazabicyclo[2.2.2]octane dibenzylideneacetone 1,8-diazabicyclo[5.4.0]undec-7-ene 1,3-dicyclohexylcarbodiimide 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate solvent heated under reflux 1,4-bis(9-O-dihydroquinine)-phthalazine 1,4-bis(9-O-dihydroquinidine)-phthalazine diisopropyl azodidicarboxylate diisobutylaluminum hydride diisopropylethylamine N,N-dimethylacetamide 4-N,N-dimethylaminopyridine 1,2-dimethoxyethane N,N-dimethylformamide N,N-dimethylformamide dimethyl acetal dimethylsulfide dimethylsulfoxide dimethylsulfoxonium methylide dimethoxytrityl 1,4-bis(diphenylphosphino)butane 1,2-bis(diphenylphosphino)ethane 1,1’-bis(diphenylphosphino)ferrocene 1,3-bis(diphenylphosphino)propane

XIX

DTBAD DTBMP E1 E2 E1cB EAN EDDA ee Ei Eq Et EtOAc HMDS HMPA HMTTA Imd KHMDS LAH LDA LHMDS LTMP M Mes Ms MVK NBS NCS NIS NMP Nos Nu N-PSP N-PSS PCC PDC Piv PMB PPA PPTS PyPh2P Pyr Red-Al Salen SET SM

di-tert-butylazodicarbonate 2,6-di-tert-butyl-4-methylpyridine unimolecular elimination bimolecular elimination 2-step, base-induced E-elimination via carbanion ethylammonium nitrate ethylenediamine diacetate enantiomeric excess two groups leave at about the same time and bond to each other as they are doing so. equivalent ethyl ethyl acetate hexamethyldisilazane hexamethylphosphoramide 1,1,4,7,10,10-hexamethyltriethylenetetramine imidazole potassium hexamethyldisilazide lithium aluminum hydride lithium diisopropylamide lithium hexamethyldisilazide lithium 2,2,6,6-tetramethylpiperidide metal mesityl methanesulfonyl methyl vinyl ketone N-bromosuccinimide N-chlorosuccinimide N-iodosuccinimide 1-methyl-2-pyrrolidinone nosylate (4-nitrobenzenesulfonyl) nucleophile N-phenylselenophthalimide N-phenylselenosuccinimide pyridinium chlorochromate pyridinium dichromate pivaloyl para-methoxybenzyl polyphosphoric acid pyridinium p-toluenesulfonate diphenyl 2-pyridylphosphine pyridine sodium bis(methoxy-ethoxy)aluminum hydride (SMEAH) N,N´-disalicylidene-ethylenediamine single electron transfer starting material

XX

SMEAH SN1 SN2 SNAr TBABB TBAF TBDMS TBDPS TBS TEA TEOC Tf TFA TFAA TFP THF TIPS TMEDA TMG TMP TMS TMSCl TMSCN TMSI TMSOTf Tol Tol-BINAP TosMIC Ts TsO UHP

sodium bis(methoxy-ethoxy)aluminum hydride (Red-Al) unimolecular nucleophilic substitution bimolecular nucleophilic substitution nucleophilic substitution on an aromatic ring tetra-n-butylammonium bibenzoate tetra-n-butylammonium fluoride tert-butyldimethylsilyl tert-butyldiphenylsilyl tert-butyldimethylsilyl triethylamine trimethysilylethoxycarbonyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid trifluoroacetic anhydride tri-2-furylphosphine tetrahydrofuran triisopropylsilyl N,N,N’,N’-tetramethylethylenediamine tetramethylguanidine tetramethylpiperidine trimethylsilyl trimethylsilyl chloride trimethylsilyl cyanide trimethylsilyl iodide trimethylsilyl triflate toluene or tolyl 2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl (p-tolylsulfonyl)methyl isocyanide tosyl tosylate urea-hydrogen peroxide

1

Alder ene reaction Addition of an enophile to an alkene via allylic transposition. Also known as hydroallyl addition.

O

O '

O

O

O

O enophile

O O

O O

ene

H

O

reaction O

Example 113

H2N N

O

KOH, Pt/Clay, 35% O (Kishner reduction)

H

H

O H

O

O

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

O

O OH

Example 214 O O

H

Tol., reflux

N

O N

5 h, 95% O

H

2

References 1.

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

Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. 1943, 76, 27. Kurt Alder (Germany, 19021958) shared the Nobel Prize in Chemistry in 1950 with his teacher Otto Diels (Germany, 18761954) for development of the diene synthesis. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). Oppolzer, W. Angew. Chem. 1984, 96, 840. Mackewitz, T. W.; Regitz, M. Synthesis 1998, 125138. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325335. (Review). Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 15951615. Mikami, K.; Nakai, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., ed.; WileyVCH: New York, 2000, 543568. (Review). Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243. Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198. Shibata, T.; Takesue, Y.; Kadowaki, S.; Takagi, K. Synlett 2003, 268. Suzuki, K.; Inomata, K.; Endo, Y. Org. Lett. 2004, 6, 409. Brummond, K. M.; McCabe, J. M. The Rhodium(I)-catalyzed Alder-ene Reaction. In Modern Rhodium-Catalyzed Organic Reactions 2005, 151172. (Book chapter). Miles, W. H.; Dethoff, E. A.; Tuson, H. H.; Ulas, G. J. Org. Chem. 2005, 70, 2862. 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. 2

O R

R OH O

1. base

R3

R1

O

2.

R 3

2

R

R

O

O R

R1

R

deprotonation

R1

R

H

condensation

R1 R2

3

O

B:

R2 O O 1

R3

R2 OH O

acidic R

workup

R3

R1 R

R Example 13

o

O

LDA, THF, then MgBr2, 110 C, then OTMS OHC OH

BnO

O

O

OBn

O OTMS

85% yield

4

Example 212

LDA, THF, 78 to 40 oC, then aldehyde, 1 h, 83%, 3:2 de O

CO2H OTBS H O

HO

O

CO2H OTBS

References 1.

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

Wurtz, C. A. Bull. Soc. Chim. Fr. 1872, 17, 436. Charles Adolphe Wurtz (18171884) 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 organic synthesis. Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1438. (Review). Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980, 21, 1031, 1035. Mukayama, T. Org. React. 1982, 28, 203331. (Review). Mukayama, T.; Kobayashi, S. Org. React. 1994, 46, 1103. (Review on Tin(II) enolates). Saito, S.; Yamamoto, H. Chem. Eur. J. 1999, 5, 19591962. (Review). Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325335. (Review). Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432440. (Review). Nicolaou, K. C.; Ritzén, A.; Namoto, K. Chem. Commun. 2001, 1523. Palomo, C.; Oiarbide, M.; García, J. M. Chem. Eur. J. 2002, 8, 3644. (Review). Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 15951601. (Review). Wei, H.-X.; Hu, J.; Purkiss, D. W.; Paré, P. W. Tetrahedron Lett. 2003, 44, 949. Bravin, F. M.; Busnelli, G.; Colombo, M.; Gatti, F.; Manzoni, L.; Scolastico, C. Synthesis 2004, 353. Mahrwald, R. (ed.) Modern Aldol Reactions, WileyVCH: Weinheim, Germany, 2004. (Book).

5

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

R1

OH

Ar

R1

H2O2, NaOH

O

Ar OH

O

R2

O

R2

R1

O

Ar OH

R2 OH

O O

HO, H2O2

E-attack

D

O

O

E O

O O

O

OH O

OH O

flavonol

A side reaction:

O D O

E O

D-attack then dehydration

O

O aurone

6

Example 15

OH 1. PhCHO, NaOH, EtOH, rt

O

O

2. H2O2, 15 to 50 oC, 54%

Ph OH

O

Example 25

CHO , aq. NaOH, EtOH

1. O

OH

O

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

O

O OH O

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

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.

O

OH R1 R O

O R1

O

R

R1CO2Na, '

O

OH R1

OH

O

enolization R

R O

R1

O

H

acylation

O

O R1

O

1

R CO2 OH R1

OH R1 O OCOR1 R

enolization

 O2CR

O

O H

O: R1

O

1

R

H O2CR1 O

R1 OH

O R O

R OH

H O2CR1

O

R1 R

O

9

Example 16

OMe

O OH

HO

O O

OMe

MeO

OMe

OMe O

PhCO2Na, 170180 oC

OMe

OMe HO

O

8 h, 45%

OMe OMe O

References 1.

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

Allan, J.; Robinson, R. J. Chem. Soc. 1924, 125, 2192. Robert Robinson (United Kingdom, 18861975) won the Nobel Prize in Chemistry in 1947 for his studies on alkaloids. However, Robinson himself considered his greatest contribution to science was that he founded the qualitative theory of electronic mechanisms in organic chemistry. Robinson, along with Lapworth (a friend) and Ingold (a rival), pioneered the arrow pushing approach to organic reaction mechanism. Robinson was also an accomplished pianist. J. Allan, his student, also coauthored another important paper with Robinson on the relative directive powers of groups for aromatic substitution. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715. Wagner, H.; Maurer, I.; Farkas, L.; Strelisky, J. Tetrahedron 1977, 33, 1405. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. Indian J. Chem., Sect. B 1982, 21B, 1037. Patwardhan, S. A.; Gupta, A. S. J. Chem. Res., (S) 1984, 395. Horie, T.; Tsukayama, M.; Kawamura, Y.; Seno, M. J. Org. Chem. 1987, 52, 4702. Horie, T.; Tsukayama, M.; Kawamura, Y.; Yamamoto, S. Chem. Pharm. Bull. 1987, 35, 4465. 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.

OH R

X

CX4, PPh3 R

R1

R1

X X

X

Ph3P X, CX3

X

Ph3P: Appel’s salt

Ph3P X

Ph3P X, X3C H

O

R

O R

X3CH R1

R

PPh3 R1

O R1

X R

R1

Ph3P O

X Example 17

AcO

AcO BnO BnO

CBr4, PPh3

O BnO

OH

DMF, 24 h, 96%

BnO BnO

O BnO Br

11

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

CO2Me

CO2Me NH O

N

CCl4, PPh3, Et3N

NH CH2Cl2, reflux, 5 h, 63%

N N N

References 1.

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

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. Appel, R.; Kleinstück, R.; Ziehn, K.-D. Chem. Ber. 1971, 104, 1335. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (Review). Beres, J.; Bentrude, W. G.; Parkanji, L.; Kalman, A.; Sopchik, A. E. J. Org. Chem. 1995, 50, 1271. Lee, K. J.; Kim, S. Heon; K., Jong H. Synthesis 1997, 1461. Lee, K.-J.; Kwon, H.-T.; Kim, B.-G. J. Heterocycl. Chem. 1997, 34, 1795. Lim, J.-S.; Lee, K.-J. J. Heterocycl. Chem. 2002, 39, 975. Nishida, Y.; Shingu, Y.; Dohi, H.; Kobayashi, K. Org. Lett. 2003, 5, 2377. 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

O

SOCl2

O

R

OH

O

1. CH2N2 Cl

R

2. H2O, hv

OH

O O R

R

O R

Cl

Cl N

H 2C N N

O

 CH3N2

N

R

N H H

Cl N

H 2C N N

O

N

N

R

N

O



H C C O R H :OH2 D-ketocarbene intermediate ketene intermediate

:

H C R

O

OH R OH

OH

side reaction:

Cl H3C N N

CH3Cln

N2n

hv

H

H

R

N

N2n

13

Example 110

CO2H 1. ClCO2Et, Et3N, THF, 10 oC, 15 min

BnO BnO

HN

Boc

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

O N2

BnO BnO

HN

AgOBz, Et3N, MeOH/THF, dark

25 oC to rt, 3 h, 61%

Boc

BnO BnO

CO2Me HN

Boc

References Arndt, F.; Eistert, B. Ber. Dtsch. Chem. Ges. 1935, 68, 200. Fritz Arndt (18851969) was born in Hamburg, Germany. He discovered the ArndtEistert homologation at the University of Breslau where he extensively investigated the synthesis of diazomethane and its reactions with aldehydes, ketones, and acid chlorides. Fritz Arndt’s chain-smoking of cigars ensured that his presence in the laboratories was always well advertised. Bernd Eistert (19021978), born in Ohlau, Silesia, was Arndt’s Ph.D. student. 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 Enantioselective Synthesis of E-Amino Acids Juaristi, E. ed. Wiley-VCH, New York, N. Y. 1997, pp 105126. (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.; Wyvratt, 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. 1.

14

Baeyer–Villiger oxidation General scheme:

O O

H 2

1

R

O

R3

O

O R1

or H2O2

R

O R2

O

HO

R3

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

O

O

m-CPBA

O H

Cl

HO

 AcO

O O HOAc

O Cl

:

O

H

O

Cl O H O

alkyl O

O

HO

O O

migration

O

Cl

15

Example 210

OH

OH

O

m-CPBA,

O

Ph

Ph NH

CH2Cl2, rt

O OH

O

NH O O OH

O

m-CPBA, O

NH O

CH2Cl2, rt

NH O

References v. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625. Adolf von Baeyer (18351917) was one of the most illustrious organic chemists in history. He contributed 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 synthesis 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 (18681934), 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, 251798. (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. 1.

16

Baker–Venkataraman rearrangement Base-catalyzed acyl transfer reaction that converts D-acyloxyketones to Ediketones.

O OH O Ph

O

O

O

base Ph

Ph

O Ph

O

:B

O

O

Ph O

O

O

H

O

O

O

O

OH O

O

O

+

acyl Ph transfer

H workup

Ph

Example 17

NEt2

O

OH

O

NaH, THF NEt2 reflux, 2 h, 84% O

O

O

Example 28

O

NEt2 O

2.5 eq. NaH, PhMe, reflux, 2 h then 6 eq. TFA, reflux, 1 h, 93%

MeO O

17

O

O

MeO OH References Baker, W. J. Chem. Soc. 1933, 1381. Wilson Baker (19002002) was born in Runcorn, England. He studied chemistry at Manchester under Arthur Lapworth and at Oxford under Robinson. In 1943, Baker was the first one who confirmed that penicillin contained sulfur, of which Robinson commented: “This is a feather in your cap, Baker.” Baker began his independent academic career at University of Bristol. He retired in 1965 as the head of the School of Chemistry. Baker was a well-known chemist centenarian, spending 47 years in retirement! 2. Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934, 1767. K. Venkataraman studied under Robert Robinson Manchester. He returned to India and later arose to be the director of the National Chemical Laboratory at Poona. 3. Kraus, G. A.; Fulton, B. S.; Wood, S. H. J. Org. Chem. 1984, 49, 3212. 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. Tetrahedron 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. 1.

18

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

H N

NH2

H2SO4

OH

H2O H N

OH

H

HO H H N H O H

+

H2O:

NH2 NH2

H H O

HSO4

H

H HO

HSO4

NH2 HO Example 15

NH2 NHOH

o

HClO4, 40 C 96% OH

References 1.

2. 3.

Bamberger, E. Ber. Dtsch. Chem. Ges. 1894, 27, 1548. Eugen Bamberger (18571932) was born in Berlin. He taught in Munich and at ETH in Zurich. He introduced sodium and amyl alcohol as a reducing agent. Bamberger also engaged in a long (18941900) and acrimonious controversy with Arthur Hantzsch on the structure of diazo-compounds. Shine, H. J. in Aromatic Rearrangement Elsevier: New York, 1967, pp 182190. (Review). Buckingham, J. Tetrahedron Lett. 1970, 11, 2341.

19

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. 4.

20

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

2

N R

H N

R1 NaOMe

3

H R

MeO

3

R1

1

R

H N

N

R1

2

R H

Ts

3

N

3

2

N

R H

Ts

:

R2 H

R

Ts

2

R

N 3

R

R

In protic solvent: 1

R1

S H R R2 N H 3 N R

2

R H

S

R3

N2 N

R1

R1

R1 R2 H

H N

H

3

R

R2

R2

R3

R3

H

H

In aprotic solvent: R1

R1 R2 H

N R3

N

R2 H

N2

N R3

N

SH

N

21

R1

R1

H2O

R2

:

R2 H

R2

3

3

R3 H

R

R

R

R1

R1

H R2

3

Example 1, thermal Bamford–Stevens5

N Me3Si

N

Ph

Ph

Tol., 145 oC

Me3Si

Ph

E : Z = 90 : 10

sealed tube, 65%

Example 29

N NHTs O

t-BuOK, t-BuOH reflux, 83%

Ot-Bu O

References Bamford, W. R.; Stevens, T. S. M. J. Chem. Soc. 1952, 4735. Thomas Stevens (19002000), a chemist centenarian, was born in Renfrew, Scotland. He and his student W. R. Bamford published this paper at the University of Sheffield, UK. Stevens also contributed to another name reaction, the McFadyenStevens reaction (page 354). 2. Shapiro, R. H. Org. React. 1976, 23, 405507. (Review). 3. Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 5559. (Review on the Shapiro reaction). 4. Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 183. (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. 1.

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. Grignard reaction.

O R1

OH

R3X, M

R M

R1

R2

R

R2

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

R3 X

SET-1

M

R X

MX SET-2

R

R

R M

M

Ionic mechanism,

R2 G G O R1 R MgX G G

R1 R2 R

R 1 R2

H

R

OMgX

Single electron transfer mechanism, R2 R1

R2 R1

O R MgX

R1 R2 R

OMgX

O MgX R

H

R1 R2 R

OH

OH

23

Example 18

OH

O Sm, THF, rt

O

O

Br 20 min. 70%

Example 211

O Ph

Zn, THF, aq. NH4Cl Br

NHCO2Et

0 oC, 82%, 95% de

OH Ph NHCO2Et

References Barbier, P. C. R. Hebd. Séances Acad. Sci. 1899, 128, 110. Phillippe Barbier (18481922) 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. 1.

24

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

NH2

NaOH, CHCl3

H N

CH2Cl2, BnEt3NCl

X

O

XH

X = O, NR O

O HO

O

deprotonation

H CCl3

CCl2 Cl

CCl3

O

H N

:

Cl Cl

NH2

HX

Cl

Cl

O

XH H N HX

Cl

H N O

X

O

Example 12 NH2

O NaOH, CHCl3

NH CH2Cl2, BnNEt3Cl

H N N

67%

H N O

N

15%

O

H

25

Example 26

H2N HO

H N

1. NaOH, CHCl3, acetone 2. CSA, toluene, 66%

O

O

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

Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329. Lai, J. T. J. Org. Chem. 1980, 45, 754. Lai, J. T. Synthesis 1981, 754. Lai, J. T. Synthesis 1984, 122. Lai, J. T. Synthesis 1984, 124. Rychnovsky, S. D.; Beauchamp, T.; Vaidyanathan, R.; Kwan, T. J. Org. Chem. 1998, 63, 6363. 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 711, 2003 (2003), ORGN-078.

26

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

MgBr

1. NO2

2. H2O

R

+

N H

R

BrMg

R

N O

O

O N OMgBr

R

BrMg N

OMgBr

[3,3]-sigmatropic O

O

N MgBr

R

R nitroso intermediate

rearrangement

BrMg O

H

H+

H

R

OMgBr

N MgBr

N

workup

R H OH2+ R

N H

R

N H

Example 13

1.

MgBr (3 eq) o

40 C, THF NO2

2. aq. NH4Cl, 67%

N H

27

Example 28

Me

Me MgCl NO2

Br

THF, 40 oC 67%

Br

N H

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

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. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, P. E. J. Chem. Soc., Chem. Commun. 1988, 807. Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129. Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J. Chem. Soc., Perkin Trans. 2 1991, 657. Mechanistic studies. Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc., Perkin Trans. 1 1991, 2757. Dobson, D. R.; Gilmore, J.; Long, D. A. Synlett 1992, 79. Dobbs, A. P.; Voyle, M.; Whittall, N. Synlett 1999, 1594. Dobbs, A. J. Org. Chem. 2001, 66, 638. Pirrung, M. C.; Wedel, M.; Zhao, Y. Synlett 2002, 143. Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179. Knepper, K.; Braese, S. Org. Lett. 2003, 5, 2829. Li, J.; Cook, J. M. Bartoli indole synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 100103. (Review). Dalpozzo, R.; Bartoli, G. Current Org. Chem. 2005, 9, 163178. (Review).

28

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

O R

HO Cl

O

N

R

O

n-Bu3SnH

N

R

AIBN, '

S Barton ester

' NC

N N

N2n

CN

homolytic cleavage 2,2’-azobisisobutyronitrile (AIBN)

CN

n-Bu3Sn

CN

n-Bu3Sn H

2

H

O R

O

O

N

N R

S Bu3Sn

SnBu3

CO2n

H SnBu3

R

O

S

R

H

Bu3Sn

Example 13

OAc OAc H

H 1. (COCl)2 2.

CO2H

S NaO

N

O O

N S

CN

H

29

OAc OAc H

1. m-CPBA, 78 oC

' 98% S

H

2. 100 oC, 78%

N

Example 211 S

Ph HO2C

2

N

OTBDPS

Ph

O

Bu3P, THF, PhH

Me3SiH, AIBN

N O

OTBDPS O

o

PhH, 80 C, 75%

Ph

OTBDPS

S References 1.

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

Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939. Derek Barton (United Kingdom, 19181998) studied under Ian Heilbron at Imperial College in his youth. He taught in England, France and the US. Barton won the Nobel Prize in Chemistry in 1969 for development of the concept of conformation. He passed away in his office at the University of Texas at Austin. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1986, 58, 675. Barton, D. H. R.; Bridon, D.; Zard, S. Z.; Fernandaz-Picot, I. Tetrahedron 1987, 43, 2733. Cochane, E. J.; Lazer, S. W.; Pinhey, J. T.; Whitby, J. D. Tetrahedron Lett. 1989, 30, 7111. Barton, D. H. R. Aldrichimica Acta 1990, 23, 3. (Review). Gawronska, K.; Gawronski, J.; Walborsky, H. M. J. Org. Chem. 1991, 56, 2193. Eaton, P. E.; Nordari, N.; Tsanaktsidis, J.; Upadhyaya, S. P. Synthesis 1995, 501. Crich, D.; Hwang, J.-T.; Yuan, H. J. Org. Chem. 1996, 61, 6189. Attardi, M. E.; Taddei, M. Tetrahedron Lett. 2001, 42, 3519. Materson, D. S.; Porter, N. A. Org. Lett. 2002, 4, 4253. Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org. Chem. 2003, 68, 9255. Zard, S. Z. Radical Reactions in Organic Synthesis Oxford University Press: Oxford, UK, 2003. (Book). 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. R1 R2

O

R1

n-Bu3SnH, AIBN

S

PhH, reflux

S

H

' NC

N N

O C Sn

n-Bu3SnSMe

R2

2

N2n

CN

CN

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn

CN

n-Bu3Sn H n-Bu3Sn R1 R2

R1

S O

R2

S

E-scission

n-Bu3Sn

n-Bu3Sn

R1

hydrogen atom

R2

abstraction

S

O

S O

S R1 R2

S

R1 R2

n-Bu3Sn H

n-Bu3SnSMe

O C Sn

S

Example 15

O O

O

O O

O Ph S

CN

SnBu3

S

O

n-Bu3Sn H

H

AIBN, ', 74% (CH2)4Bu2SnH

31

O O

O

O O Example 29

O

O

OH

O

OBn O

O

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

O

OBn O

O

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

Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574. Stuart McCombie, a Barton student, now works at ScheringPlough. Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672. Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949. Hansen, H. I.; Kehler, J. Synthesis 1999, 1925. Boussaguet, P.; Delmond, B.; Dumartin, G.; Pereyre, M. Tetrahedron Lett. 2000, 41, 3377. Cai, Y.; Roberts, B. P. Tetrahedron Lett. 2001, 42, 763. Clive, D. L. J.; Wang, J. J. Org. Chem. 2002, 67, 1192. Rhee, J. U.; Bliss, B. I.; RajanBabu, T. V. J. Am. Chem. Soc. 2003, 125, 1492. 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 J-oximino alcohol.

NO O

O NOCl

HO

OAc

OAc

OAc

O

hQ

O

O

O

O N Cl

OAc

OAc

NO O

O

HO

O

HO OH H N

O

HCl

O

O

OAc

hQ homolytic

O

O

1,5-hydrogen

H

cleavage ON•

abstraction O OAc

OAc O N

HO

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

O

O H OH N

O

nitroso intermediate

O

33

OAc HO H OH N

tautomerization

O

O

Example11

HO

HO HO N 1. NOCl, CH2Cl2, 20 C, 100% o

O H OAc

2. Irradiation at 350 nM 5 h, PhH, 0 oC, 50%

O H OAc

References 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 satisfying 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, 102/1102/16. (Review). 1.

34

Barton–Zard reaction Base-induced reaction of nitroalkenes with alkyl D-isocyanoacetates to afford pyrroles.

R2 NO2

Base C=NCH2CO2R3

R1

R1 CO2R3

N H

R2 R1 = H, alkyl, aryl R2 = H, alkyl R3 = Me, Et, t-Bu Base = KOt-Bu, DBU, guanidine bases

Example 1

Base

C=NCH2CO2R3

NO2

B

N O H

C=N O

C

C=N CO2R

N

N

CO2R

Michael addition

O2 N N

CO2R

 HNO2

CO2R

O

H B

O

O2N N

CO2R

N H

H CO2R

H B

[1,5] N

CO2R

N H

CO2R

35

Example 25

CNCH2CO2Et DBU, THF rt, 8 h, 75%

O2N

N H

CO2Et

Example 37

NO2 N SO2Ph

CNCH2CO2Et DBU THF, rt, 20 h 85%

N PhO2S

N H

CO2Et

References 1.

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

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. van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337. Barton, D. H. R.; Kervagoret, J.; Zard, S. Z. Tetrahedron 1990, 46, 7587. Sessler, J. L.; Mozaffari, A.; Johnson, M. R. Org. Synth. 1991, 70, 68. Ono, N.; Hironaga, H.; Ono, K.; Kaneko, S.; Murashima, T.; Ueda, T.; Tsukamura, C.; Ogawa, T. J. Chem. Soc., Perkin Trans. 1 1996, 417. Murashima, T.; Fujita, K.; Ono, K.; Ogawa, T.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 1996, 1403. Pelkey, E. T.; Chang, L.; Gribble, G. W. Chem. Commun. 1996, 1909. Uno, H.; Ito, S.; Wada, M.; Watanabe, H.; Nagai, M.; Hayashi, A.; Murashima, T.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 4347. Murashima, T.; Tamai, R.; Nishi, K.; Nomura, K.; Fujita, K.; Uno, H.; Ono, N. J. Chem. Soc., Perkin Trans. 1 2000, 995. Fumoto, Y.; Uno, H.; Tanaka, K.; Tanaka, M.; Murashima, T.; Ono, N. Synthesis 2001, 399. Lash, T. D.; Werner, T. M.; Thompson, M. L.; Manley, J. M. J. Org. Chem. 2001, 66, 3152. 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). Murashima, T.; Nishi, K.; Nakamoto, K.; Kato, A.; Tamai, R.; Uno, H.; Ono, N. Heterocycles 2002, 58, 301. Gribble, G. W. BartonZard Reaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 7078. (Review).

36

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

R1 R2

R NO2

OR3 N C OR3 H

R1 N R2 R

DMF, '

1. Pd/C, H2

NO2

R N H

2. 5% HCl Example 1

NMe2

DMFDMA NO2

NO2

DMF, '

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

Pd/C, H2 N H

MeO

MeO N MeO

+ N

OMe

37

OMe H CH2

MeO

CH2 N O

N O O MeO

O

MeOH

NMe2

+ N

NMe2

H

NO2

NO2

:

NMe2

[H] reduction

NMe2

NH2 H N H

NH

 NHMe2

N H

NMe2

Example 25 CO2H

1. MeI, NaHCO3

CO2Me NMe2

NO2

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

NO2 CO2Me

Pd/C, H2, PhH, 82% N H

38

Example 314 Me2NCH(OMe)2

OBn

OBn

OBn

pyrrolidine NO2

o

DMF, 110 C

NMe2 NO2

NO2

15 : 1

3 h, 95%

OBn

OBn NMe2 NO2

Ni, NH2NH2

THF, MeOH 96%

N H

References 1.

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

20.

Leimgruber, W.; Batcho, A. D. Third International Congress of Heterocyclic Chemistry: Japan, 1971. Andrew D. Batcho and Willy Leimgruber were both chemists at HoffmannLa Roche in Nutley, NJ, USA. Leimgruber, W.; Batcho, A. D. US 3732245 1973. Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York & London, 1970. (Review). Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45, 3550. Maehr, H.; Smallheer, J. M. J. Org. Chem. 1981, 46, 1752. Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. Gupton, J. T.; Lizzi, M. J.; Polk, D. Synth. Commun. 1982, 12, 939. Repke, D. B.; Ferguson, W. J. J. Heterocycl. Chem. 1982, 19, 845. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195. (Review). Clark, R. D.; Repke, D. B. J. Heterocycl. Chem. 1985, 22, 121. Feldman, P. L.; Rapoport, H. Synthesis 1986, 735. Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am. Chem. Soc. 1982, 104, 7622. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106. Toste, F. D.; Still, I. W. J. Org. Prep. Proced. Int. 1995, 27, 576. Coe, J. W.; Vetelino, M. G.; Bradlee, M. J. Tetrahedron Lett. 1996, 37, 6045. Grivas, S. Current Org. Chem. 2000, 4, 707. Siu, J.; Baxendale, I. R.; Ley, S. V. Org. Biomolecular Chem. 2004, 2, 160. Li, J.; Cook, J. M. Batcho–Leimgruber Indole Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 104109. (Review). 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 carboncarbon 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, D-alkoxycarbonyl ketones, aldimines, and Michael acceptors. General scheme:

X

R1

catalytic

EWG

XH EWG

2

1

R

2

R

R

tertiary amine

X = O, NR2, EWG = CO2R, COR, CHO, CN, SO2R, SO3R, PO(OEt)2, CONR2, CH2=CHCO2Me Example 1:

Ph

N

O

O

OH

N

O

Ph

H O

O

H O

Ph

aldol

conjugate addition

N:

N

N

N O Ph

OH

O H

Ph N

N N

N

O

40

OH

O N

Ph

N

E2 (bimolecular elimination) mechanism is also operative here:

OH O Ph

OH O

E2

H

2

Ph

N

N:

N

N N

N Example 210

O

O H

OMe

Cl

N

OH O

N MeOH, rt, 8 h, 79%

OMe Cl

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: N R

1

OH

O H

R

1

N R1

OH

H

R2

R2

N H

R2

N

OH2

R1 R2 the substituent trans to the leaving group migrates

R1 N

R1 N

N R2

:

2

2

R

R

H+

N R2

R1

R1 O H

:OH2 tautomerization

H

HN

OH

R2

R1 O

With PCl5: N R1

Cl

R1

O R2

O

PCl5

R

1

R2

N H

R2

PCl4

HCl

: N

OH

H

N R1

OPCl4 2

R

the substituent trans to the leaving group migrates

42

R1 N

R1 N

N R2

:

2

2

R

R

H+

N R2

R1

:OH2 tautomerization

OH

R1 O H

H

HN R2

R1 O

Example 112

N

OH PPA

H N

HO O

N

O PPA

NH

21%

72%

PPA = polyphosphoric acid References 1.

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

Beckmann, E. Chem. Ber. 1886, 89, 988. Ernst Otto Beckmann (18531923) was born in Solingen, Germany. He studied chemistry and pharmacy at Leipzig. In addition to the Beckmann rearrangement of oximes to amides, his name is associated with the Beckmann thermometer, used to measure freezing and boiling point depressions. Mazur, R. H. J. Org. Chem. 1961, 26, 1289. Chatterjea, J. N.; Singh, K. R. R. P. J. Indian Chem. Soc. 1982, 59, 527. Gawley, R. E. Org. React. 1988, 35, 1420. (Review). Catsoulacos, P.; Catsoulacos, D. J. Heterocycl. Chem. 1993, 30, 1. Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000, 41, 7235. Khodaei, M. M.; Meybodi, F. A.; Rezai, N.; Salehi, P. Synth. Commun. 2001, 31, 2047. Torisawa, Y.; Nishi, T.; Minamikawa, J.-i. Bioorg. Med. Chem. Lett. 2002, 12, 387. Sharghi, H.; Hosseini, M. Synthesis 2002, 1057. Chandrasekhar, S.; Copalaiah, K. Tetrahedron Lett. 2003, 44, 755. Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J. Tetrahedron Lett. 2004, 45, 3369. Hilmey, D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067. Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671. 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.

O

O N O N

Et3N

Ph

EtOH

CO2Et

O

O N O N

O Et3N:

H O

Ph

N O

CO2Et

Ph

Ph

O

O N O N O

O

O

O

CO2Et

O N

CO2Et

O

O N

Ph

Ph O

N

:

CO2Et

CO2Et OH

:NEt3 O O H N

O N

O

N O

CO2Et

Ph

Ph

N CO Et OH 2 O

Example 13 O N O N

O H3C

morpholine,

O OEt

o

0 C, 10 h, 82%

O N

O

N O

CH3

OEt

44

Example 27

O N O N

O Ph

O

silica gel N H

O N

O

N O

Ph

N H

Ph

MeOH, 90%

Ph

References 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, 504509. (Review). 1.

45

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

O

KOH

Ar Ar

Ar O

Ar

O Ar

Ar

Ar

OH O

O

O

OH

O Ar Ar

OH OH

O Ar Ar

OH O

acidic O +

OH

H

workup

O Ar Ar

OH OH

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

H3C H3C

O O

H H

KOH, MeOH/H2O 130140 oC, 3 h, 32%

H

O H3C CO2H OH H

H 3C H

H

O

References 1.

Liebig, J. Ann. 1838, 27. Justus von Liebig (18031873) pursued his Ph.D. in organic chemistry in Paris under the tutelage of Joseph Louis Gay-Lussac (17781850). 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.

OH Ar

H

cat. CN

Ar

Ar

O

O CN H

Ar

CN H

Ar

O

O

Ar

proton

Ar

transfer

proton transfer

CN

O

H

Ar

OH

Ar NC Ar

NC Ar

H O

OH

OH

H OH

Ar

O

Ar

CN

O

Example 111 N

CHO

HO CH3 O

CH3 O

Br S

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

Example 211

O O

N HO

CH3 Br

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

CH3 OH

48

O

O OH

O2 (air)

O

References Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. Arthur Lapworth (18721941) 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, 269304. (Review). 3. Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407496. (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, 13261328. (Review). 1.

49

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

' or hydrogen donor

hv

electrocyclization

H H

reversible

enediyne

1,4-benzenediyl diradical

Example 114

S

S

Ph

S

S

Ph

S

S

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

S

S

Ph

Example 215

H3C N N

hv THF, 45%

H3C N N

References 1. 2. 3. 4.

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

50

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

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. Rawat, D. S.; Zaleski, J. M. Chem. Commun. 2000, 2493. Clark, A. E.; Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123, 2650. Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453. Eshdat, L.; Berger, H.; Hopf, H.; Rabinovitz, M. J. Am. Chem. Soc. 2002, 124, 3822. Yus, M.; Foubelo, F. Rec. Res. Dev. Org. Chem. 2002, 6, 205. (Review). Feng, L.; Kumar, D.; Kerwin, S. M. J. Org. Chem. 2003, 68, 2234. Basak A.; Mandal S.; Bag S. S. Chem. Rev. 2003, 103, 4077. (Review). Bhattacharyya, S.; Pink, M.; Baik, M.-H.; Zaleski, J. M. Angew. Chem., Int. Ed. Engl. 2005, 44, 592. 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). O O

O

O

R

'

R CHO

HN

NH2 HCl, EtOH

H 2N

O

O

NH O

H H

O

O

O

O O

enolization R

O H

H

H O

H

O

O

R

OH

O

O H H H

O

O R

H

O

O

+

O

OH

R

OH2

OH O

O

O

conjugate

O

addition

:

R

addition

O

H2N

NH2

HN O

R NH2

O O

H

O

O

O H

HO

H+ H2N O

O

:

H

aldol

N H

R

HN

R

NH O

52

O

O H

H2O

H+

HN

O R

O R

H2O

NH

HN

O

NH O

Example9

OMe O

O

O +

MeO

+ O

H2N

NH2

H OMe

CeCl3.7H2O

MeOOC

NH

EtOH, ', 2.5 h 95% References

N H

O

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, 1116. (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, 509520. (Review). 1.

53

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

Benzene ring bearing an electron-donating substituent:

O

O

Na, liq. NH3 ROH

O

O

O

single electron

H

transfer (SET)

O

H radical anion O

H H

e

H OR

H H

O

H

H

H OR

Benzene ring with an electron-withdrawing substituent:

CO2H

CO2H Na, liq. NH3

CO2

CO2H

e

CO2

e

H radical anion

54

CO2

CO2

CO2H

H

H Example 1

H NH2

H H

8

OMe

OMe 1. Na, NH3, THF78 oC N

O O

Example 214

2. MeI, 98%, 30:1 dr

N

O O

OMe

OMe

Na, NH3, THF N

78 oC, quant.

N

References 1.

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

Birch, A. J. J. Chem. Soc. 1944, 430. Arthur Birch (19151995), an Australian, developed the “Birch reduction” at Oxford University during WWII in Robert Robinson’s laboratory. The Birch reduction was instrumental to the discovery of the birth control pill and many other drugs. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1334. (Review). Birch, A. J. Pure Appl. Chem. 1996, 68, 553. (Review). Schultz, A. G. Chem. Commun. 1999, 1263. Ohta, Y.; Doe, M.; Morimoto, Y.; Kinoshita, T. J. Heterocycl. Chem. 2000, 37, 751. Labadie, G. R.; Cravero, R. M.; Gonzalez-Sierra, M. Synth. Commun. 2000, 30, 4065. Guo, Z.; Schultz, A. G. J. Org. Chem. 2001, 66, 2154. Donohoe, T. J.; Guillermin, J.-B.; Calabrese, A. A.; Walter, D. S. Tetrahedron Lett. 2001, 42, 5841. Yamaguchi, S.; Hamade, E.; Yokoyama, H.; Hirai, Y.; Shiotani, S. J. Heterocycl. Chem. 2002, 39, 335. Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2002, 34, 611642. (Review). Jiang, J.; Lai, Y.-H. Tetrahedron Lett. 2003, 44, 1271. Subba Rao, G. S. R. Pure Appl. Chem. 2003, 75, 14431451. (Review). Zvilichovsky, G.; Gbara-Haj-Yahia, I. J. Org. Chem. 2004, 69, 5490. Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054.

55

Bischler–Möhlau indole synthesis 3-Arylindoles from the cyclization of Ȧ-arylamino-ketones and anilines.

Br O

H2 N

' O

H 2N

N H

N H

:

:

SN2 O

Br

N H

H

O

H

H dehydration

HO H

N H

N H

N H

56

Example 15

O

NaHCO3, EtOH

O

Br

reflux, 4 h

NH2

o

230250 C

O N H

O N H

silicone oil, 1015 min 3580%

O

Example 29 OTBS

N

F

OMe

H2 N

O

N

NH2

N OMe DME, H2SO4 reflux, 53%

F H2N

N

N H

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

Möhlau, R. Ber. Dtsch. Chem. Ges. 1881, 14, 171. Bischler, A.; Fireman, P. Ber. Dtsch. Chem. Ges. 1893, 26, 1346. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970, p 164. (Book). Buu-Hoï, N. P.; Saint-Ruf, G.; Deschamps, D.; Bigot, P. J. Chem. Soc. (C) 1971, 2606. The Chemistry of Heterocyclic Compounds, Indoles (Part 1), Houlihan, W. J., ed.; Wiley & Sons: New York, 1972. (Review). Bigot, P.; Saint-Ruf, G.; Buu-Hoi, N. P. J. Chem. Soc., J. Chem. Soc., Perkin 1 1972, 2573. Bancroft, K. C. C.; Ward, T. J. J. Chem. Soc., Perkin 1 1974, 1852. Coic, J. P.; Saint-Ruf, G. J. Heterocycl. Chem. 1978, 15, 1367. Henry, J. R.; Dodd, J. H. Tetrahedron Lett. 1998, 39, 8763.

57

Bischler–Napieralski reaction Dihydroisoquinolines from E-phenethylamides using phosphorus oxychloride.

HN

O

POCl3

N R

R

Cl HN

O

O P Cl Cl

Cl

HN

POCl2

R

R

N H

NH R

H OPOCl2

HCl +

O

Cl

R OPOCl2

N H O R O P Cl Cl

N R

O + HCl + O P Cl

Example 16

MeO

Bn N CO2Me

MeO POCl3 P2O5, 96%

N O

Bn

58

Example 210

O

O O

HN

O

N

O POCl3 toluene, 95%

MeO

OMe OMe

MeO

OMe OMe

References Bischler, A.; Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903. Augustus Bischler (18651957) 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.; Yamazaki, 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.; Yamashita, 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 Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 376385. (Review). 1.

59

Blaise reaction E-Ketoesters from nitriles and D-haloesters using Zn. CO2R2

Br R CN

1

R

2. H3O+

CO2R2

CO2R2

R 1

R

R Br

O

1. Zn, THF, reflux

N

Zn(0)

nucleophilic

OR2

R1

O

ZnBr

addition

1

R H2O H N

H

ZnBr

workup 2

H CO2R2

R

CO2R

R

N

R1

H2O:

R1 H 2O H

O H 2N O H CO2R2 R R1

CO2R2

R R1

Example 1, preparation of the statin side chain10

Cl

OTMS CN

Br

1. cat. Zn, THF, reflux +

2. H3O , 85%

OH Cl

CO2t-Bu O CO2t-Bu

60

Example 211

F

CN Br

Cl

N

HN F Cl

CO2Et

THF, reflux, 2.5 h

Cl Br Zn

Zn, MeSO3H

O

O

HCl, 72%

F

OEt

OEt N

Cl

Cl

O

N

Cl

References Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132, 478, 978. Blaise was at Institut 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. 1.

61

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

ZnCl2

Cl

HCl O

H 2O

O

1,3,5-trioxane O O O

H+

H

H H

O

H

H+

HO

H

HO

+

Cl SN2

Cl

H 2O

OH2

Example 112

NH3Cl

NH3Cl CH3 O

20 oC, 2 h, 71% O

CH3 O

(OCH2)n, HCl, PhCl O Cl

References 1.

Blanc, G. Bull. Soc. Chim. Fr. 1923, 33, 313. Gustave Louis Blanc (18721927), born in Paris, France, studied under Charles Friedel in Paris. He developed the chloromethylation of aromatic hydrocarbons while he was a director at the Intendance militaire aux Invalides.

62

Fuson, R. C.; McKeever, C. H. Org. React. 1942, 1, 63. (Review). Olah, G.; Tolgyesi, W. S. In FriedelCrafts and Related Reactions vol. II, Part 2, Olah, G., Ed.; Interscience: New York, 1963, pp 659784. (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. 2. 3.

63

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

N3

O

NaN3

R1

R

2

R

R2

Staudinger

OH

R2

1

SN2

R

R2

2

R

R1

N3

O 1

H N

PPh3

1

R

OH

N3

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

R1

R1

HO

HO 2

N N N

:PPh3

R

N N N PPh3

R2

1

R

N PR3

HO R2

N N N PR3

N

N

X

PR3 N R1

N2

PR3 N HO

R2 OH

proton transfer

R3P NH :O R2

R1

R2 1

R 1

R

O

NH R2

PPh3

H N R1

R2

64

Example 13

O

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

OTr

HN

2. Ph3P, CH3CN, reflux, 30 min, 6075%

Example 25

NaN3, NH4Cl, MeOH

O OTBS

reflux, 4 h, 50% OH

N3

OTBS

OTBS N3

OH Ph3P, CH3CN reflux, 99%

NH OTBS

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

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. Tanner, D.; Somfai, P. Tetrahedron Lett. 1987, 28, 1211. Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36, 3639. Fürmeier, S.; Metzger, J. O. Eur. J. Org. Chem. 2003, 649. Oh, K.; Parson, P. J.; Cheshire, D. Synlett 2004, 2771. 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.

TFAA N O

OH

N

TFAA, trifluoroacetic anhydride

O2CCF3 N O F3C

acyl O

O

transfer

CF3

H

N O

N O

O

O CF3

CF3

O hydrolysis O

N

CF3

OH

N

O Example 16

Ac2O, CH2Cl2 N

N

reflux, 1 h, 90%

N

N OAc

O Example 29

OtBu

OtBu 1. TFAA, CH2Cl2

N O

2. Na2CO3, 3 h 89%

N OH

66

References Boekelheide, V.; Linn, W. J. J. Am. Chem. Soc. 1954, 76, 1286. Virgil Boekelheide (19192003) 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, 10111049. (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, 340349. (Review). 1.

67

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

N

N H

N N

N

O

H O

:

N

H2O

OH

HN

N N

N N

Hetero-Diels-Alder

N

N

N

reaction

N

:B Retro-Diels-Alder N

reaction, N2

H N

N

Example 14

EtO2C EtO2C

CO2Et

N N

N

N

+

CHCl3, 60 oC

EtO2C

26 h, 92%

EtO2C

N

O

CO2Et

68

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

Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179. Dale Boger is a professor at the Scripps Research Institute. Boger, D. L.; Panek, J. S.; Meier, M. M. J. Org. Chem. 1982, 47, 895. Boger, D. L. Tetrahedron 1983, 39, 28692939. (Review). Boger, D. L. Chem. Rev. 1986, 86, 781793. (Review). Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1987, 66, 142. Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451512. (Review). Golka, A.; Keyte, P. J.; Paddon-Row, M. N. Tetrahedron 1992, 48, 7663. Behforouz, M.; Ahmadian, M.Tetrahedron 2000, 56, 52595288. (Review). Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahedron 2001, 57, 60996138. (Review). Jayakumar, S.; Ishar, M. P. S.; Mahajan, M. P. Tetrahedron 2002, 58, 379471. (Review). Rykowski, A.; Olender, E.; Branowska, D.; Van der Plas, H. C. Org. Prep. Proced. Int. 2001, 33, 501. Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron Lett. 2003, 44, 693. Galatsis, P. Boger Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 323339. (Review).

69

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

O R1

R3

R2

H N

R4 R3

O R1

R1

H

H N

R2 R4

OH R2

R3

H N

R1 R3

R1 R N: 2 R4 R3 R4

R2 N

H

R1 R3

R4

H N

R2 R4

Example 14

O CH3 NH2

1. TiCl4, Et3N, CH2Cl2, rt, 48 h 2. NaCNBH3, MeOH, rt, 15 min. 94%

HN CH3

70

Example 25

NH2

O

O

5 N HCl, NaCNBH3

N

MeOH, rt, 72 h, 75%

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

Borch, R. F. J. Am. Chem. Soc. 1969, 91, 3996. Richard F. Borch was born in Cleveland, Ohio. He was a professor at the University of Minnesota. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897. Borch, R. F.; J. Chem. Soc., Perkin I 1984, 717. Barney, C. L.; Huber, E. W.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 5547. Mehta, G.; Prabhakar, C. J. Org. Chem. 1995, 60, 4638. Lewin, G.; Schaeffer, C. Heterocycles 1998, 48, 171. 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.

HCl N H

N

N H

H

[3,3]-sigmatropic N H

N

N H

H+

NH

H

H+ NH

rearrangement

NH

NH

NH2

H N H

NH2 H

N H

+

Example 18

CH3 H3CO

HCl, NaNO2, AcONa

HO NH2

O

H2O, MeOH, 54%

72

CH3

CH3 HOAc, HCl, reflux H3CO H3CO

O N H

N

10 min., 44%

N H

O

References Drechsel, E. J. Prakt. Chem. 1858, 38, 69. 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 suffered 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. 1. 2.

73

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

X

Y Z H

H

B D

A

X Y

N Z

Example 17

N: H

N

o

150 C N O

+

H

H

N

N O

N

Ph

Ph

O

N N

N H

Ph

Example 211

Ph

O

F3C

O

NH2NH2, DMF

Ph

N

rt, 1 h

N

F3C

N N

F3C

O

HO NH

Ph

N

N N H 5%

N Ph

N

O F3C

N NH2

N H

N

92%

74

O N F7C3 F7C3

Ph

O

NH2NH2, DMF rt, 1 h

N

HO NH

Ph

N H

N

24%

Ph

N

O N

N

F7C3

N H

N

70%

References 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 Advances 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. 1.

75

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

1. M 2. DMF R X

R CHO +

3. H O Me2N R X

M

H

O M Me2N

R M

H+

R CHO

R

A modification by Comins:7

O

Li

N

N

LiO

H

N N H

N O

n-BuLi

N

1. RX, X = Br, I H

ortho-lithiation

O Li

2. H3O+

R

Example 16

Br

Li, DMF, THF, 10 oC ultrasound 5 min, 85%

CHO

76

References Bouveault, L. Bull. Soc. Chim. Fr. 1904, 31, 1306, 1322. Louis Bouveault (18641909) 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. 1.

77

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

O

Na, EtOH

R

O R

R

OEt

single-electron

OH

O

H OEt

OEt transfer (SET)

e

R

OEt

ketyl (radical anion)

R

OEt

OH



OH

O

e

R

OEt

OEt R

H OEt O R

H

e H

O R

OEt

H OEt H

OH OH R

H

e

R

H

R

OH

H OEt

Example 18 O

Na, Al2O3 t-BuOH, Tol.

OH

OEt reflux, 6 h, 66%

References 1. 2. 3. 4.

Bouveault, L.; Blanc, G. Compt. Rend. 1903, 136, 1676. Bouveault, L.; Blanc, G. Bull. Soc. Chim. 1904, 31, 666. Ruehlmann, K.; Seefluth, H.; Kiriakidis, T.; Michael, G.; Jancke, H.; Kriegsmann, H. J. Organomet. Chem. 1971, 27, 327. Castells, J.; Grandes, D.; Moreno-Manas, M.; Virgili, A. An. Quim. 1976, 72, 74.

78

5. 6. 7. 8. 9.

Sharda, R.; Krishnamurthy, H. G. Indian J. Chem., Sect. B 1980, 19B, 405. Banerji, J.; Bose, P.; Chakrabarti, R.; Das, B. Indian J. Chem., Sect. B 1993, 32B, 709. Seo, B. I.; Wall, L. K.; Lee, H.; Buttrum, J. W.; Lewis, D. E. Synth. Commun. 1993, 23, 15. Singh, S.; Dev, S. Tetrahedron 1993, 49, 10959. Schopohl, Matthias C.; Bergander, Klaus; Kataeva, Olga; Froehlich, Roland; Waldvogel, Siegfried R. Synthesis 2003, 2689.

79

Boyland–Sims oxidation Oxidation of anilines to phenols using alkaline persulfate.

NR2

NR2

K2S2O8

NR2

+ OSO3 K

H+

OH

aq. KOH

O O O S O O S O ipso-attack O O NR2

O

R2N

SO4

O R2N:

O

:

O

O S

O S

R2N

O O

O

O S

O

O H

O

O S

R2N

O

NR2

O

+ OSO3 K

H OH Another pathway is also operative:

O

O S

R2N

O

O

O S O R2N O O

NR2 E2

H OH

+ OSO3 K

80

Example 13

NH2

NH2

NH2 K2S2O8

+

OSO3 K

aq. KOH 50-55%

+ OSO3 K

+ OSO3 K

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

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. Boyland, E.; Sims, P. J. Chem. Soc. 1954, 980. Behrman, E. J. J. Am. Chem. Soc. 1967, 89, 2424. Krishnamurthi, T. K.; Venkatasubramanian, N. Indian J. Chem., Sect. A 1978, 16A, 28. Behrman, E. J.; Behrman, D. M. J. Org. Chem. 1978, 43, 4551. Srinivasan, C.; Perumal, S.; Arumugam, N. J. Chem. Soc., Perkin Trans. 2 1985, 1855. Behrman, E. J. Org. React. 1988, 35, 421511. (Review). Behrman, E. J. J. Org. Chem. 1992, 57, 2266.

81

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

HBr R CH3CO2H

R anthracene

O

H+

R

R O

H

O

H+ RO H

H

R OH

H H+ R

OH2

R

Example5

O

HBr, CH3CO2H Br

150 oC, 7 h, 21%

Br

References 1. 2.

Bradsher, C. K. J. Am. Chem. Soc. 1940, 62, 486. Charles K. Bradsher was a professor at Duke University. Bradsher, C. K.; Smith, E. S. J. Am. Chem. Soc. 1943, 65, 451.

82

3. 4. 5. 6. 7. 8. 9. 10.

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

83

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

OH R1 R2

O

RLi

R1

SiR3

R2

SiR3 Li

R O R1 R2

O

O

H R1

R2

SiR3

R1

SiR3 R2

SiR3

pentacoordinate silicon intermediate

O Ph Ph

SiPh3

O

workup Ph Ph

H OH

SiPh3 H

Example 111

O

t-BuMe2Si

o

CN Ph

1. 4 eq. NaHMDS, 78 to 15 C o

2. PhCH2Br, 10 C, 75% CN

t-BuMe2SiO Ph Ph

84

Example 214

t-BuLi, Et2O Br

Ph

Li

Ph

o

78 C O Me3Si o

O

Ph

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

Ph

Ph SiMe3

References 1.

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

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

1. R'2BH R

OH

R 2. H2O2, NaOH

R' B R'

H R

H R

R' B R'

H

syn-

R' B

R

addition

R'

O OH H

BaeyerVilliger-

R' R' OH B O

R

O

R

O

R

like reaction OR' B OR'

OH

B R'

OH

R

R'

O OH

B(OH)3

Example 12

1. BH3•SMe3, THF

H H

2. NaOOH

H

H

OH H H

H

HO

H

H H 35%

H

H 40%

86

Example 213

OMe

MeO

OMe

NO2

BH3•SMe3, NaOOH

MeO

OMe

Me

NO2 OMe

Me

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

OBn

HO

HO

HO

Example 314

OH

1. Pyridine•BH3, I2, CH2Cl2, 2 h Ph 2. H2O2, NaOH, MeOH, 92%

Ph

Ph OH 15:1

References 1.

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

Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1958, 80, 1552. Herbert C. Brown (USA, 19122004) 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, 18971987) for their development of organic boron and phosphorous compounds. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1120. Nussium, M.; Mazur, Y.; Sondheimer, F. J. Org. Chem. 1964, 29, 1131. Streitwieser, A., Jr.; Verbit, L.; Bittman, R. J. Org. Chem. 1967, 32, 1530. Herz, J. E.; Marquez, L. A. J. Chem. Soc. (C) 1971, 3504. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents Academic Press: New York, 1972. (Review). Brewster, J. H.; Negishi, E. Science 1980, 207, 44. (Review). Brown, H. C.; vara Prasad, J. V. N. Heterocycles 1987, 25, 641. Fu, G. C.; Evans, D. A.; Muci, A. R. Advances in Catalytic Processes 1995, 1, 95121. (Review). Hayashi, T. Comprehensive Asymmetric Catalysis IIII 1995, 1, 351364. (Review). Morrill, T. C.; D’Souza, C. A.; Yang, L.; Sampognaro, A. J. J. Org. Chem. 2002, 67, 2481. Hupe, E.; Calaza, M. I.; Knochel, P. Tetrahedron Lett. 2001, 42, 8829. Carter K. D; Panek J. S. Org. Lett. 2004, 6, 55. 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

NaHSO3 NH

NHNH2

H+

H H

H+

H H

O

OH

OH

OSO2H

OSO2H H+

H H O

:NH2NHPh OSO2H H H

H+

NHNHPh

OH NHNHPh

:B

H OSO2H

OSO2H

NH NH

H+ [3,3]-sigmatropic rearrangement

88

H

NH2 NH

H

NH2 H+ NH

NH

Example 13

OH CO2H

NHNH2

NaHSO3, NaOH, ', 130 oC several days, 46%

N H

Example 24

OH 1) aq. NaHSO3, ' H2NHN

2) H

N H

References 1.

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

Bucherer, H. T. J. Prakt. Chem. 1904, 69, 49. Hans Th. Bucherer (18691949) was born in Ehrenfeld, Germany. He shuttled between industry and academia all through his career. Bucherer, H. T.; Seyde, F. J. Prakt. Chem. 1908, 77, 403. Bucherer, H. T.; Schmidt, M. J. Prakt. Chem. 1909, 79, 369. Bucherer, H. T.; Sonnenburg, E. F. J. Prakt. Chem. 1909, 81, 1. Friedländer, P. Chem. Ztg. 1916, 40, 918. Fuchs, W.; Niszel, F. Chem. Ber. 1927, 60, 209. Drake, N. L. Org. React. 1942, 1, 105. (Review). Buu-Hoï, N. P.; Hoán, N.; Khôi, N. H. J. Org. Chem. 1949, 14, 492. Buu-Hoï, N. P.; Royer, R.; Eckert, B.; Jacquignon, P. J. Chem. Soc. 1952, 4867. Zander, M.; Franke, W. Chem. Ber. 1963, 96, 699. Seeboth, H.; Bärwolff, D.; Becker, B. Justus Liebigs Ann. Chem. 1965, 683, 85. Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. 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 E-naphthols to E-naphthylamines using ammonium sulfite.

OH

(NH4)2SO3•NH3

NH2

H2O, 150 oC H+

H H

H+

O O

O

H OSO2NH4

:NH3

OH2 NH2

H+

OSO2NH4

OSO2NH4

OSO2NH4

OSO2NH4 H

H

OH NH2

O

tautomerization

H H

NH2

NH2

H OSO2NH4

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

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

References 1. 2. 3. 4.

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

NH2

91

5. 6. 7. 8. 9.

Gilbert, E. E. Sulfonation and Related Reactions Wiley: New York, 1965, p166. (Review). Seeboth, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 307. Gruszecka, E.; Shine, H. J. J. Labelled. Compd. Radiopharm. 1983, 20, 1257. Belica, P. S.; Manchand, P. S. Synthesis 1990, 539. 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 ammonium carbonate. It belongs to the category of multiple component reaction (MCR).

R1

H N

R1

KCN O

2

R2

(NH4)2CO3

R

O NH

O

(NH4)CO2 ļ 2 NH3 + CO2 + H2O 1

R1

O R2

NH2 1

N

R

:

NC

O C O

OH CN R2

:

R

2

H3N cyanohydrin :

H N

R1

OH R1

O

R2

R HN

H+

O N

2

R

NH2

O isocyanate intermediate

O O

H N

R1

C :

R2

H N

2

N

R1

R

O NH

O

Example 110

CH3O CH3O

N

KCN, (NH4)2CO3 48 h, 60 oC, 83%

O

93

CH3O

CH3O N

CH3O

CH3O

H

O

O

HN

N H NH HN

NH O

O

Example 211

O H O O

H

KCN, (NH4)2CO3 CO2Et H

EtOH/H2O, 70 oC, 50% O

HN NH H

O O O

H

CO2Et H

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

Bergs, H. Ger. Pat. 566, 094, 1929. Hermann Bergs worked at I. G. Farben in Germany. Bucherer, H. T., Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 69. Bucherer, H. T., Steiner, W. J. Prakt. Chem. 1934, 140, 291. (Mechanism). E. Ware, Chem. Rev. 1950, 46, 403. (Review). Wieland, H. et al., in HoubenWeyl's Methoden der organischen Chemie, Vol. XI/2, 1958, p 371. Chubb, F. L.; Edward, J. T.; Wong, S. C. J. Org. Chem. 1980, 45, 2315. Rousset, A.; Laspéras, M.; Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2649. Bowness, W. G.; Howe, R.; Rao, B. S. J. Chem. Soc., Perkin Trans. 1 1983, 2649. Haroutounian, S. A.; Georgiadis, M. P.; Polissiou, M. G. J. Heterocycl. Chem. 1989, 26, 1283. Menéndez, J. C.; Díaz, M. P.; Bellver, C.; Söllhuber, M. M. Eur. J. Med. Chem. 1992, 27, 61. Domínguez, C.; Ezquerra, A.; Prieto, L.; Espada, M.; Pedregal, C. Tetrahedron: Asymmetry 1997, 8, 511. Micǂvá, J.; Steiner, B.; Kóoš, M.; Langer, V.; Gyepesova, D. Synlett 2002, 1715. Li, J. J. Bucherer–Bergs Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds.; Wiley & Sons: Hoboken, NJ, 2005, 266274. (Review).

94

Büchner–Curtius–Schlotterbeck reaction Reaction of carbonyl compounds with aliphatic diazo compounds to deliver homologated ketones.

R

O

H

R1 R

O

2

R1

R

N2

R2 R1

R2

R2

N2

N N

nucleophilic

O

H

N

N

R2

N

N

O R O

H R2

addition

R

H

H

rearrangement

1

R

N2n

R 2

R

R1

Example 13

O

O CH2N2

Cl O

O

N2CH2

Et2O

H3C

O

O HCl

Cl H3C

O

O

Example 26

NC

CN

Ph

H

CH2N2, Et2O

NC

CN

rt, 100%

Ph

CH3

O

95

33% aq. NaOH o

45 C, 99%

O Ph

CH3

References 1.

2. 3. 4. 5. 6.

Büchner, E.; Curtius, T. Ber. Dtsch. Chem. Ges. 1885, 18, 2371. Eduard Büchner (Germany, 18601917) won the Nobel Prize in Chemistry in 1907 for biochemical studies and discovery of fermentation without cells. Schlotterbeck, F. Ber. Dtsch. Chem. Ges. 1907, 40, 479. Fried, J.; Elderfield, R. C. J. Org. Chem. 1941, 6, 577. Gutsche, C. D. Org. React. 1954, 8, 364. (Review). Bastús, J. B. Tetrahedron Lett. 1963, 955. Kirmse, W.; Horn, K. Tetrahedron Lett. 1967, 1827.

96

Büchner method of ring expansion Reaction of benzene with diazoacetic esters to give cyclohepta-2,4,6trienecarboxylic acid esters. Cf. PfauPlatter azulene synthesis. CO2CH3

N2

CO2CH3 [Rh]

[Rh] N2

CO2CH3

N2n

CO2CH3 [Rh]

CO2CH3 [Rh] Rhodium carbenoid CO2CH3

[2 + 2]

[Rh]

cycloaddition

electrocyclic CO2CH3

ring opening Example 17

O N2

Rh2(OAc)4 H O

CH2Cl2, 98% Example 28

I

Br

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

Ac2O, CH2Cl2, 73%

N2 References 1. 2. 3.

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

OAc

97

4. 5. 6. 7. 8.

Marchard, A. P.; Brockway, N. M. Chem. Rev. 1974, 74, 431. (Review). Anciaux, A. J.; Demonceon, A.; Noels, A. F.; Hubert, A. J.; Warin, R.; Teyssié, P. J. Org. Chem. 1981, 46, 873. Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933. Manitto, P.; Monti, D.; Speranza, G. J. Org. Chem. 1995, 60, 484. 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 N H

Br

N

Pd(OAc)2, dppf NaOt-Bu, Tol., '

Pd(II) Br

Pd(0) oxidative addition

Pd(II) N

N H ligand exchange HBr

reductive

N

elimination Pd(0) The C–O bond formation reaction follows a similar mechanistic pathway.79 Example 111

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

Cl

HN

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

O

N

O

ligand =

P N

N N N

i-Bu

99

Example 212

CO2Me I

NH2

OCF3 MeO2C

Pd(OAc)2, Cs2CO3 DPE-Phos, Tol., 95 oC 95% PPh2

PPh2

H N

O DPE-Phos = OCF3

References 1.

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

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 independently discovered this chemistry. Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901. Steve Buchwald is a professor at MIT. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333. Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413. Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (Review). Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (Review). Frost, C. G.; Mendonça, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615. (Review). Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125. (Review). Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G. Tetrahedron 2003, 59, 975. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135. Csuk, R.; Barthel, A.; Raschke, C. Tetrahedron 2004, 60, 5737. Li, C. S.; Dixon, D. D. Tetrahedron Lett. 2004, 45, 4257. 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

O CH3O2C N S NEt3 R1 CH3 O OH R2 Burgess reagent R2 O N S Cl O

O

CH3O2C

H N

S

O

HNEt3

O O

O CH3O2C N S Cl :NEt3 O

H3C OH

O CH3O2C N S NEt3 O Reaction,

O CH3O2C N S NEt3 O CH3 R1 OH R2

Ei

H

SN2 HNEt3

R1

R1 R2

O

N SO2

H N

O S O O

2

CH3O2C

OH

O CH3O2C N S NEt3 O

R Example 14

tol., 95 oC, 2 h, 80%

CO2CH3

HNEt3

101

O

N SO2

CO2CH3 [SO3]

NHCO2Me

Example 25

H N

N

O

N

O CH3O2C N S NEt3 O

N

o

OH

H N

N

O

DMF, 80 C, 18 h, 87%

Example 310

N Si

OH

1.5 eq. Burgess, THF reflux, 1 h, 97%

O

N Si

O

References Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. Edward M. Burgess 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. 1.

102

Cadiot–Chodkiewicz coupling Bis-acetylene synthesis from alkynyl halides and alkynyl copper reagents. Cf. CastroStephens reaction.

R1 R1

X

Cu

R1

R2

Cu

X

R2 X Cu

oxidative

R2

R1

R2

addition Cu(III) intermediate

reductive

R1

CuX

R2

elimination Example 16

Br OH cat. CuCl, NH2OH•HCl OH

EtNH2, MeOH, 040 oC, 7080% Example 211

TBS

Br

OH

cat. CuCl, NH2OH•HCl TBS

OH

30% n-BuNH2, H2O, 92% References 1. 2. 3. 4. 5.

Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci. 1955, 241, 1055. Paul Cadiot (1923) and Wladyslav Chodkiewicz (1921) are both French chemists. Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., ed.; Dekker: New York, 1969, 597647. (Review). Eastmond, R.; Walton, D. R. M. Tetrahedron 1972, 28, 4591. Ghose, B. N.; Walton, D. R. M. Synthesis 1974, 890. Hopf, H.; Krause, N. Tetrahedron Lett. 1985, 26, 3323.

103

6. 7. 8. 9. 10. 11. 12. 13.

Gotteland, J.-P.; Brunel, I.; Gendre, F.; Désiré, J.; Delhon, A.; Junquéro, A.; Oms, P.; Halazy, S. J. Med. Chem. 1995, 38, 3207. Bartik, B.; Dembinski, R.; Bartik, T.; Arif, A. M.; Gladysz, J. A. New J. Chem. 1997, 21, 739. Montierth, J. M.; DeMario, D. R.; Kurth, M. J.; Schore, N. E. Tetrahedron 1998, 54, 11741. Negishi, E.-i.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687. Steffen, W.; Laskoski, M.; Collins, G.; Bunz, U. H. F. J. Organomet. Chem. 2001, 630, 132. Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841. Utesch, N. F.; Diederich, F. Org. Biomol. Chem. 2003, 1, 237. 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)-substitutedquinolin-2-ol (3), or a mixture.

OH

O

R1

1

R

NaOR

NH

ROH R2

O

2

1

R1

O R1 NH

R2

NaOR ROH

N

2

OH

R

O 1

3

O 1

O

OR

R

R1

H

R2

NH

N H

R2

O

R2

N

O

1

OH

O 1

R N H OH

R1

H R2

N 2

R2

105

O

R1

R1 O

R2

NH R2

O

N H

H 1

O

OR R1

R1 HO

R2 N H

R2

H N

O

OH

3

Example 11,2

O

OH NaOH, H2O

NH

104 °C

N

O

OH

N 20%

69%

Example 28

O

OH N

O Me

Me

Me H2O, 90%

HN

N

NaOH N

Me

References 1. 2. 3. 4.

Camps, R. Chem. Ber. 1899, 32, 3228. Rudolf Camps worked under Professor Engler from 1899 to 1902 at the Technische Hochschule in Karlsruhe, Germany. Camps, R. Arch. Pharm. 1899, 237, 659. Clemence, F.; LeMartret, O.; Collard, J. J. Heterocycl. Chem. 1984, 21, 1345. 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. 6.

7. 8.

Hino, K.; Kawashima, K.; Oka, M.; Nagai, Y.; Uno, H.; Matsumoto, J. Chem. Pharm. Bull. 1989, 37, 110. Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951, 73, 2641. Barret, R.; Ortillon, S.; Mulamba, M.; Laronze, J. Y.; Trentesaux, C.; Lévy, J. J. Heterocycl. Chem. 2000, 37, 241. Pflum, D. A. Camps Quinolinol Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 386389. (Review).

107

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

O

OH

2 H

R

O H

R

OH

OH

HO O R

R

OH

O O

H

R

H

OH Pathway A: O R

hydride

H H O R

transfer

O R

H

O

R

O

OH O R

OH

R

O

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

O

hydride

H H O R

R

transfer

R

O

O O

acidic workup

R

OH

R

OH

O

108

Example 111 CHO

CO2H

KOH powder

OH

100 oC, 5 min solvent-free Example 213 H CHO

N

O

H N

OH

Na THF, 0 oC, 5 h, 76% References 1.

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

Cannizzaro, S. Justus Liebigs Ann. Chem. 1853, 88, 129. Stanislao Cannizzaro (18261910) was born in Palermo, Sicily, Italy. In 1847, he had to escape to Paris for participating in the Sicilian Rebellion. Upon his return to Italy, he discovered benzyl alcohol synthesis by the action of potassium hydroxide on benzaldehyde. Political interests brought Cannizzaro to the Italian Senate and he later became its vice president. Geissman, T. A. Org. React. 1944, I, 94. (Review). Hazlet, S. E.; Stauffer, D. A. J. Org. Chem. 1962, 27, 2021. Hazlet, S. E.; Bosmajian, G., Jr.; Estes, J. H.; Tallyn, E. F. J. Org. Chem. 1964, 29, 2034. Sen Gupta, A. K. Tetrahedron Lett. 1968, 5205. Swain, C. G.; Powell, A. L.; Sheppard, W. A.; Morgan, C. R. J. Am. Chem. Soc. 1979, 101, 3576. Mehta, G.; Padma, S. J. Org. Chem. 1991, 56, 1298. Sheldon, J. C.; et al. J. Org. Chem. 1997, 62, 3931. Thakuria, J. A.; Baruah, M.; Sandhu, J. S. Chem. Lett. 1999, 995. Russell, A. E.; Miller, S. P.; Morken, J. P. J. Org. Chem. 2000, 65, 8381. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. Reddy, B. V. S; Srinvas, R.; Yadav, J. S.; Ramalingam, T. Synth. Commun. 2002, 32, 219. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.; Rosati, O. Org. Lett. 2005, 7, 1331.

109

Carroll rearrangement Thermal rearrangement of E-ketoesters followed by decarboxylation to yield J-unsaturated ketones via anion-assisted Claisen rearrangement. It is a variant of the Claisen rearrangement (page 131). O

R1 R1

R

1

O

1

R1 R1

CO2n

O

O R2O

ester

O

O

O H

exchange

OR2

:B

O

O

O

anion-assisted

O

O

R1

Claisen rearrangement R

O

R1 R1 O

O

O

O

R2OH

R1 R1

base

OH

R1 R1

base

R2O

OH R

O

1

R

1

R

1

O R

CO2n R1

1

R1

acidic workup

R

1

O

110

Example 19

O

O

2 eq. NaH, xylene

O TESO

reflux, 96%

H

O O TESO

Carroll

O

rearrangement

H

CO2H CO2

O

O TESO

H

TESO

H

Example 210 O O

O LDA, THF, 78 oC to rt

MeO OMe HO2C

O

MeO

Me

Me

OMe

O

CCl4, reflux, 86% MeO

OMe

111

References Carroll, M. F. J. Chem. Soc. 1940, 704. Michael F. Carroll worked at A. Boake, Roberts 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. 1.

112

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

X

Cu

R

Ar

R

L ArX Cu L

R

reflux

Ar

X

L3Cu

R

X Ar

Cu CuX

Ar

R

R

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

X Ar Cu

oxidative Cu

Ar X

R

R

addition Cu(III) intermediate

reductive CuX

Ar

R

elimination Example7 O

O cat. CuI, Ph3P, K2CO3 O I

DMF, 120 oC, 37%

O

113

References 1.

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

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. Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 3313. Staab, H. A.; Neunhoeffer, K. Synthesis 1974, 424. Kabbara, J.; Hoffmann, C.; Schinzer, D. Synthesis 1995, 299. von der Ohe, F.; Brückner, R. New J. Chem. 2000, 24, 659. White, J. D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407. Coleman, R. S.; Garg, R. Org. Lett. 2001, 3, 3487. 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 LiAlH4. OH

OH

NaAlH2(OCH2CH2OCH3)2 in PhH

R1

R

Et2O, heat, 20 h, 83%

R

R1

R

OH

R

H Al

AlH2R2

O

H2n

R1

R1

R

R R H R

R Al

OH

workup

O

R

R1

R1

Example 13 OH

LiAlH4

OH

77% Example 24 OH

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

Ph CO2Me

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

I CO2Me

115

References 1.

2. 3. 4. 5.

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 HoffmannLa Roche, Inc., Nutley, NJ, USA. Blunt, J. W.; Hartshorn, M. P.; Munro, M. H. G.; Soong, L. T.; Thompson, R. S.; Vaughan, J. J. Chem. Soc., Chem. Commun. 1980, 820. Midland, M. M.; Gabriel, J. J. Org. Chem. 1985, 50, 1143. Meta, C. T.; Koide, K. Org. Lett. 2004, 6, 1785. 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 temperature. The reaction works even for poorly nucleophilic substrates such as arylamide. R B(OH)2, Cu(OAc)2 R X H

X CH2Cl2, rt, Et3N or pyridine X = NR'2, OR"

Example 11 H3C

B(OH)2

NH

N

CH3

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

Mechanism: L Cu(OAc)2, pyridine

N

NH coordination and deprotonation

CuII

L OAc pyridium acetate

Ph

L H3C

B(OH)2

CuII

L

N AcOB(OH)2

transmetallation

CH3 Ph

reductive N elimination

CH3

117

Example 23 Cl CO2Me

S Cl CO2Me

S N H

O

B(OH)2

N

O

Cu(OAc)2, Et3N, MS 4 Å CH2Cl2, rt, 48 h, 29%

References 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. Tetrahedron 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. 1.

118

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

Ar1

'

N

Ar Ar

Ar1

OPh

Ar

O

Ar1

S NAr

N:

Ar1 N Ph

N

Ar

O Ar oxazete intermediate

O

Example 12 Cl MeO2C

MeO

NaOEt, EtOH/Et2O

Cl N

NaO

0 oC to rt, 48 h

Ph

Cl 210215 oC, 70 min

MeO2C MeO

O N

MeO

28% for 2 steps Ph

MeO2C

Cl MeO

N O

Ph

HO2C

N H

Cl

Ar1 N Ph

119

Example 24 Ph Ph Ph

O N

Ph

O

o

300 C Ph

Ph

N

30 min., 87%

References 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, 151. (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. 1.

120

Chichibabin pyridine synthesis Condensation of aldehydes with ammonia to afford pyridines. R 3 R

NH3

CHO

R

R

N

H3N: O

R

H

H

H3N:

R

NH2

R

OH

NH

R

H

H

NH2

enamine H

:NH3 R

H O

R

imine

R

H

H

O

Aldol

R

condensation

H

H O OH H

R

O H R

 H2 O

O

R

R

Michael R

O

R

addition

H R

:

N

HN H3 N H

H OH

O R

H

R

R H N

R

R

N H

N H

H OH R

R

:

R

R

R

H

R H

R autoxidation N

[O]

R R

R N

121

Example 14 O NH4OH, NH4OAc

CHO N

250 oC, autoclave, 32%

N N

N

N

N Example 25 O

NH4OAc, HOAc

CHO

reflux, 1 h, 68%

N

References 1.

2. 3. 4. 5. 6.

Chichibabin, A. E. J. Russ. Phys. Chem. Soc. 1906, 37, 1229. Alexei E. Chichibabin (18711945) 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.” Sprung, M. M. Chem. Rev. 1940, 40, 297338. (Review). Frank, R. L.; Seven, R. P. J. Am. Chem. Soc. 1949, 71, 2629. Frank, R. L.; Riener, E. F. J. Am. Chem. Soc. 1950, 72, 4182. Weiss, M. J. Am. Chem. Soc. 1952, 74, 200. Herzenberg, J.; Boccato, G. Chem. Ind. 1950, 80, 248.

122

Levitt, L. S.; Levitt, B. W. Chem. Ind. 1963, 1621. Kessar, S. V.; Nadir, U. K.; Singh, M. Indian J. Chem. 1973, 11, 825. 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, 308309. (Review). 7. 8. 9.

123

Chugaev elimination Thermal elimination of xanthates to olefins. OH

R

1. CS2, NaOH

O

R

S S

2. CH3I

xanthate

'

OCS

R

CH3SH

R O

R

S

'

S

H S

O S

O S H

R

O C Sn

CH3SHn

S

Example 16

O

O H

H

H

H O

O H

CS2, MeI, NaH

H

THF, rt, 2 h, 51% S HO

O O

S

O

O O

124

O H

H O

o

dodecane, reflux (216 C)

H

48 h, 74% O O

Example 2, Chugaev syn-elimination is followed by an intramolecular ene reaction7

S OH O O

CS2, MeI, NaH

O

N Cbz

S

O

THF, 92%

O

N Cbz

NaHCO3, diphenyl ether reflux, 45 min. 72%

O N Cbz

O

References 1.

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

Chugaev, L. Ber. Dtsch. Chem. Ges. 1899, 32, 3332. Lev A. Chugaev (18731922) was born in Moscow, Russia. He was a Professor of Chemistry at Petrograd, a position once held by Dimitri Mendeleyev and Paul Walden. In addition to terpenoids, Chugaev also investigated nickel and platinum chemistry. He completely devoted his life to science. The light in Chugaev’s study would invariably burn until 4 to 5 a.m. Chande, M. S.; Pranjpe, S. D. Indian J. Chem. 1973, 11, 1206. Kawata, T.; Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1973, 21, 604. Harano, K.; Taguchi, T. Chem. Pharm. Bull. 1975, 23, 467. Ho, T.-L.; Liu, S.-H. J. Chem. Soc., Perkin Trans. 1 1984, 615. Meulemans, T. M.; Stork, G. A.; Macaev, F. Z.; Jansen, B. J. M.; de Groot, A. J. Org. Chem. 1999, 64, 9178. Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. 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.

Cl

CHCl3 N H Cl3C H

NaOH

H2O OH

N 

Cl

CCl2 Cl

:CCl2 carbene

Cl Cl CCl2

Cl

N H

N H

N

HO

Example 18

2 eq. PhHgCCl3 N H

PhH, '54%

Cl N

126

Example 210

Cla Clb N H

NaO2CCl3

H N

26%

Cla

N N

N

HN

NH

b

Cl

Cla

Clb

N Clb

Cla

References Ciamician, G. L.; Dennsted, M. Ber. Dtsch. Chem. Ges. 1881, 14, 1153. Giacomo Luigi Ciamician (18571922) was born in Trieste, Italy. After his Ph.D. training at Giessen, Germany, Ciamician carried out most of his work at the University of Bologna, 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, 350354. (Review). 1.

127

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

R2

OR1

OR1 R

O R

O

O OR3

R2

base

O deprotonation

1

OR

R R2

H

condensation

1

OR OR3

B:

O R2 O 3

O

O R2

1

R O

O

OR

OR1 R

R Example 19

O Ph

O

t-BuOK, solvent-free

O

Ph O

Ph

O

o

90 C, 20 min., 84%

Ph

Example 212

Cbz

H N

O

CO2Me

O

Ph 3.5 eq. LDA, THF 45 to 50 oC Cbz then H+, 97%

H N Ph

O

t-Bu

O O

t-Bu

Ph

128

References 1

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

Claisen, R. L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651. Rainer Ludwig Claisen (18511930), born in Cologne, Germany, probably had the best pedigree in the history of organic chemistry. He apprenticed under Kekulé, Wöhler, von Baeyer, and Fischer before embarking on his own independent research. Hauser, C. R.; Hudson, B. E. Org. React. 1942, 1, 266302. (Review). Thaker, K. A.; Pathak, U. S. Indian J. Chem. 1965, 3, 416. Schäfer, J. P.; Bloomfield, J. J. Org. React. 1967, 15, 1203. (Review). Tanabe, Y. Bull. Chem. Soc. Jpn. 1989, 62, 1917. Leijonmarck, H. K. E. Chem. Commun. Stockhol. 1992, 33, 1. (Review). Kashima, C.; Takahashi, K.; Fukusaka, K. J. Heterocycl. Chem. 1995, 32, 1775. Tanabe, Y.; Hamasaki, R.; Funakoshi, S. Chem. Commun. 2001, 1674. Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42, 7983. Mogilaiah, K.; Kankaiah, G. Indian J. Chem., Sect. B 2002, 41B, 2194. Heath, R. J.; Rock, C. O. Nat. Prod. Rep. 2002, 19, 581. (Review). Honda, Y.; Katayama, S.; Kojima, M.; Suzuki, T.; Izawa, K. Org. Lett. 2002, 4, 447. Mogilaiah, K.; Reddy, N. V. Synth. Commun. 2003, 33, 73. Linderberg, M. T.; Moge, M.; Sivadasan, S. Org. Pro. Res. Dev. 2004, 8, 838.

129

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

O

O R

O

R1

O

O

R1

O

R1

 H2O

R2 O

R2

NH2OH

R

N H

R2

R2

O

O OR

R1

OH N

O

O

OH R1 R2

N H

OH

:NH2OH R2

R2

O

R1 O

HO

NH

R1

R2

O

 H2O

NH

O

OH

N O 3-isoxazolol

R1

A side reaction:

O

O O

R1

R

NH2OH

H HON OH O

H O: N

O

R1 R2

R2

N O

O R

R

R2

:NH2OH

 H2O

O

R1

R2

O H OR

R1 R2

O

R1

O

N

5-isoxazolone

130

Example20

O

O OMe

NH2OH-HCl, NaOH, MeOH

OH

o

50 C, 2 h then 85 oC, 1 h, 65%

O

N

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21.

Claisen, L; Lowman, O. E. Ber. Dtsch. Chem. Ges. 1888, 21, 784. Claisen, L.; Zedel, W. Ber. 1891, 24, 140. Hantzsch Ber. 1891, 24, 495. Barnes, R.A. In Heterocyclic Compounds; Elderfield, R. C., Ed.; Wiley: New York, 1957; Vol. 5, p 474 ff. (Review). Loudon, J. D. In Chemistry of Carbon Compounds; Rodd, E. H., Ed.; Elsevier: Amsterdam, 1957; Vol. 4a, p. 345ff. (Review). Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 41. Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12, 51. Katritzky, A.R.; Oksne, S.; Boulton, A. J. Tetrahedron 1962, 18, 777. Katritzky, A. R.; Oksne, S. Proc. Chem. Soc. 1961, 387. Jacquier, R.; Petrus, C.; Petrus, F.; Verducci, J. Bull. Soc. Chem. Fr. 1970, 2685. Cocivera, M.; Effio, A.; Chen, H. E.; Vaish, S. J. Am. Chem. Soc. 1976, 98, 7362. Jacobsen, N.; Kolind-Andersen, H.; Christensen, J. Can. J. Chem. 1984, 62, 1940. Katritzky, A. R.; Barczynski, P.; Ostercamp, D. L.; Yousaf, T. I. J. Org. Chem. 1986, 51, 4037. Krogsgaard-Larsen, K.; Sorensen, U. S. Org. Prep. Proc. Int. 2001, 33, 515. Sorensen, U. S.; Falch, E.; Krogsgaard-Larsen, K. J. Org. Chem. 2000, 65, 1003. Chen, B.-C. Heterocycles, 1991, 32, 529. McNab, H. Chem. Soc. Rev. 1978, 7, 345. (Review). Frølund, B.; Kristiansen, U.; Brehm, L.; Hansen, A.B.; Krogsgaard-Larsen, K.; Falch, E. J. Med. Chem. 1995, 38, 3287. Frølund, B.; Tagmose, L.; Liljefors, T.; Stensbøl, T. B.; Engblom, C.; Kristiansen, U.; Krogsgaard-Larsen, K. J. Med. Chem. 2000, 43, 4930. Madsen, U.; Bräuner-Osborne, H.; Frydenvang, K.; Hvene, L.; Johansen, T.N.; Nielsen, B.; Sánchez, C.; Stensbøl, T.B.; Bischoff, F.; Krogsgaard-Larsen, K. J. Med. Chem. 2001, 44, 1051. Brooks, D. A. Claisen Isoxazole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 220224. (Review).

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.

R

1

2

O 1

3

', [3,3]-sigmatropic

3

rearrangement

2 R1 3

O

O 1

2

R

3 2

Example 17

OBn OBn

BnO BnO

BnO BnO

O O

BnO

O

O

180 oC, 70% O

O

n-decane/toluene 5:1 BnO

O

O O

Example 28

Et2AlCl, hexanes

O

78 oC, 81%

O

O OH References 1. 2.

Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1252. (Review).

O

132

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

Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 827873. (Review). Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 4350. (Review). Castro, A. M. M. Chem. Rev. 2004, 104, 29393002. (Review). Jürs, S.; Thiem, J. Tetrahedron: Asymmetry 2005, 16, 1631. 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 E-carbon becoming attached to the ring.

OH

O

'

D

D E

O

G

HD O

E G

[3,3]-sigmatropic rearrangement

O

G

ene

E G

reaction

tautomerization

H

"normal Claisen"

H O

E

[1,5]-H-atom D

MeO

CHO

O MeO OMe

CHO PhNEt2 MeO 180 C 40%

D E

shift

Example 14

o

OH

O

OMe

MeO kodsurenin M

G

134

Example 25

(R)-(+)-BINOL-Me•FeCl3

O

CH2Cl2, 78 oC, 76% OH

Example 36

O

O o

Tol. 180 C

O O

O O

24 h, 65% References 1. 2. 3. 4. 5. 6. 7.

Hansen, H.-J. In Mechanisms of Molecular Migrations; vol. 3, Thyagarajan, B. S., ed.; Wiley-Interscience: New York, 1971, pp 177236. (Review). Shah, R. R.; Trivedi, K. N. Curr. Sci. 1975, 44, 226. Kilenyi, S. N.; Mahaux, J.-M.; van Durme, E. J. Org. Chem. 1991, 56, 2591. Yi, W. M.; Xin, W. A.; Fu, P. X. J. Chem. Soc., (S), 1998, 168. Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131. Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.; Nieuwenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561. 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 JG-unsaturated amides. Since Eschenmoser was inspired by Meerwein’s observations on the interchange of amide, the Eschenmoser–Claisen rearrangement is sometimes known as the Meerwein–Eschenmoser–Claisen rearrangement.

OMe

MeO OMe NMe2 OMe H

H Me2N: OMe H O

NMe2 O: R1

R

OMe

NMe2

R

O

NMe2 H

NMe2

CONMe2

[3,3]-sigmatropic

O

rearrangement

R1

R

R1

R

R1

R

R1

Example 17

CH3C(OMe)2NMe2

F3C

O OH

Ph PhH, 100 oC, 2 h, 60% CF3 O

Ph

O

NMe2

Example 29

O 5 eq. CH3C(OMe)2NMe2

NMe2

xylene, reflux, 48 h, 50% HO

CO2Me

OMe

CO2Me

136

References 1. 2.

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

Meerwein, H.; Florian, W.; Schön, N.; Stopp, G. Justus Liebigs Ann. Chem. 1961, 641, 1. 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. Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta 1969, 52, 1030. Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 827873. (Review). Coates, B.; Montgomery, D.; Stevenson, P. J. Tetrahedron Lett. 1991, 32, 4199. Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. Konno, T.; Nakano, H.; Kitazume, T. J. Fluorine Chem. 1997, 86, 81. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 4350. (Review). Loh, T.-P.; Hu, Q.-Y. Org. Lett. 2001, 3, 279. Gradl, S. N.; Kennedy-Smith, J. J.; Kim, J.; Trauner, D. Synlett 2002, 411. 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. Castro, A. M. M. Chem. Rev. 2004, 104, 29393002. (Review). 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 JG-unsaturated carboxylic acids. The Ireland–Claisen rearrangement seems to be advantageous to the other variants of the Claisen rearrangement in terms of E/Z geometry control and mild conditions.

OSiMe3

O LDA, then

O

O Me3SiCl

', [3,3]-sigmatropic

OSiMe3

CO2H

H+

O rearrangement Example 13

O

O

N Bn

TIPSOTf, Et3N N Bn

PhH, rt, 62%

CO2TIPS

Example 2, a modified Ireland–Claisen rearrangement10

F F

O O

F O

BBr3, Et3N, PhMe chiral ligand

F

HO

F

78 to rt, 79%, > 99% ee

F

138

Example 314

OPMP KHMDS, TMSCl, THF O

O

78 to 25 oC, 1 h, 81%

PMPO CO2Me O

O References 1.

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

11. 12. 13. 14.

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. Cha, J. K.; Lewis, S. C. Tetrahedron Lett. 1984, 25, 5263. Corey, E. J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026. (Enantioselective variant of the Ireland–Claisen rearrangement). Pereira, S.; Srebnik, M. Aldrichimica Acta 1993, 26, 1729. (Review). Ganem, B. Angew. Chem., Int. Ed. Engl. 1996, 35, 936. Mohamed, M.; Brook, M. A. Tetrahedron Lett. 2001, 42, 191. Hong, S.-p.; Lindsay, H. A.; Yaramasu, T.; Zhang, X.; McIntosh, M. C. J. Org. Chem. 2002, 67, 2042. Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron 2002, 58, 29052928. (Review). 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. 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. Höck, S.; Koch, F.; Borschberg, H.-J. Tetrahedron: Asymmetry 2004, 15, 1801. Hutchison, J. M.; Hong, S.-p.; McIntosh, M. C. J. Org. Chem. 2004, 69, 4185. Gilbert, J. C.; Yin, J.; Fakhreddine, F. H.; Karpinski, M. L. Tetrahedron 2004, 60, 51. 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 rearrangement to give a JG-unsaturated ester.

2

CH(OR )3

OH R1

R

+

H R O: OR2 H O

OR2

2

H

R

O

R1

R

R1

:B

H

OR2

CO2R2

[3,3]-sigmatropic O R1

R

rearrangement

R1

R

Example 12

OH Cl

CH3C(OCH3)3, TsOH

Cl OTBS

170 oC, 55%

Cl Cl

O OMe

OTBS

Example 27

OMe OMe N

CH3C(OCH3)3 cat. CH3CH2CO2H reflux, 77%

N O OMe

OH 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 (19131995) 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

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

sin for 20 years before moving to Stanford University, where he was credited with building the modern-day Stanford Chemistry Department. Schlama, T.; Baati, R.; Gouverneur, V.; Valleix, A.; Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2085. Giardiná, A.; Marcantoni, E.; Mecozzi, T.; Petrini, M. Eur. J. Org. Chem. 2001, 713. Funabiki, K.; Hara, N.; Nagamori, M.; Shibata, K.; Matsui, M. J. Fluorine Chem. 2003, 122, 237. Montero, A.; Mann, E.; Herradón, B. Eur. J. Org. Chem. 2004, 3063. Scaglione, J. B.; Rath, N. P.; Covey, D. F. J. Org. Chem. 2005, 70, 1089. Zartman, A. E.; Duong, L. T.; Fernandez-Metzler, C.; Hartman, G. D.; Leu, C.-T.; Prueksaritanont, T.; Rodan, G. A.; Rodan, S. B.; Duggan, M. E.; Meissner, R. S. Bioorg. Med. Chem. Lett. 2005, 15, 1647.

141

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

Zn(Hg)

O 1

R

R

H H R

HCl

R1

The zinc-carbenoid mechanism:6 O

Zn(Hg), HCl

Ph

CH3

Ph CH3 radical anion

SET

Zn

OZnCl Ph

Zn

ZnCl

O

Ph

CH3

CH3

Zinc-carbenoid H

H+ Ph

H

CH3

The radical anion mechanism:

Zn(Hg)

O Ph O Ph

CH3

O

Ph Cl

OZnCl

e; H+

Ph CH3 radical anion

H

OZnCl

+

H

ZnCl

CH3

Ph

SET

H

Ph

HCl

Zn(Hg), HCl CH3

H H

H

CH3

H

SN2 Ph

Cl

CH3

CH3

142

H

e Ph

e; H+

H H

CH3

Ph

CH3

Example 18

Zn(Hg), HCl OH O OH

O

MeOH, reflux, 1 h

OH

OH

18%

67%

Example 210

O

H

H Zn(Hg), HCl

H O

N Ph

Et2O, 5 oC, 57%

H O

N Ph

References Clemmensen, E. Ber. Dtsch. Chem. Ges. 1913, 46, 1837. Erik C. Clemmensen (18761941) 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 carbonyl compounds with amalgamated zinc. Clemmensen later founded a few chemical companies and was the president of one of them, the Clemmensen Chemical Corporation in Newark, New York. 2. Martin, E. L. Org. React. 1942, 1, 155209. (Review). 3. Brewster, J. H. J. Am. Chem. Soc. 1954, 76, 6361. 4. Vedejs, E. Org. React. 1975, 22, 401422. (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. 1.

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. Synthesis 2002, 355. 14. Alessandrini, L.; Ciuffreda, P.; Santaniello, E.; Terraneo, G. Steroids 2004, 69, 789.

144

Combes quinoline synthesis Acid-catalyzed condensation of anilines and E-diketones to assemble quinolines. Cf. Conrad-Limpach reaction. R2 O R1

NH2

H2SO4

O R2

'

R1

N O

NH2

:

R

O R

R

2

1

2

transfer

N 1 OH H2 R

O H O

proton

O R

2

O R2

R2

: N 1 OH2 H R

N H

R

1

N

imine

H R2 O

R2 O

H+

:

N R1 H enamine H O 2 H R N R1 H+

N H H

O

N H

R2

R1

H+ R1

R

1

145

H

H

O

R2

2

R2

R

:

R1

N H

R1

N H

N

R1

An electrocyclization mechanism is also possible: 2

R

H

R2

H

O

6S-electrocyclization

O :

N H

R1

N

R2

HO

R1

R2

OH2 H R2

proton N H

R1

transfer N

N

R1

Example 110

NH2

N PPA, 110 °C

MeO

O N H

O

MeO N H

35%

Example 211

O CO2Et NH2

N H

O Ph

cat. p-TsOH, 220 °C neat, 38%

CO2Et

Ph N

N H

R1

146

References Combes, A. Bull. Soc. Chim. Fr. 1888, 49, 89. Alphonse-Edmond Combes (18581896) was born in St. Hippolyte-du-Fort, France. He apprenticed with Wurtz at Paris. He also collaborated with Charles Friedel of the FriedelCrafts 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 Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 390397. (Review). 1.

147

Conrad–Limpach reaction Thermal or acid-catalyzed condensation of anilines with E-ketoesters leads to quinolin-4-ones. Cf. Combes quinoline synthesis. O Ph2O O O

NH2

OEt

O

260 oC

N H CO2Et

proton

H2O

:

:

NH2 transfer

OH

N H

EtO2C

OEt CO2Et

HO

6S electron

tautomerize

N Schiff base

electrocyclization

N

H O H OEt

H

O

HOEt N

N

H OEt OH

O

proton

Example 13 NH2

N

transfer

N H

O

N

CHCl3, HCl (cat.)

O OEt

60%

148

HN CO2Et

OH

60%

N

Example 2

N

Ph2O, reflux N

12

NH2 +

2

HO

MeO2C

MeO2C

CO2Me HCl, MeOH O2N

N H

64%

O

NO2 O Dowtherm A 250 °C, 55% References 1.

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

O2N N H

H N

NHPhNO2 CO2Me

NO2

CO2Me

Conrad, M.; Limpach, L. Ber. Dtsch. Chem. Ges. 1887, 20, 944. Max Conrad (18481920), born in Munich, Germany, was a professor of the University of Würzburg, where he collaborated with Leonhard Limpach (18521933) on the synthesis of quinoline derivatives. Manske, R. F., Chem Rev. 1942, 30, 113–114. (Review). Misani, F.; Bogert, M. T. J. Org. Chem. 1945, 10, 347. Reitsema, R. H. Chem. Rev. 1948, 43, 43–68. (Review). Elderfield, R. C. In Chemistry of Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New York, 1952, vol. 4, 31–36. (Review). Heindel, N. D.; Bechara, I. S.; Kennewell, P. D.; et al. J. Med. Chem. 1968, 11, 1218. Perche, J. C.; Saint-Ruf, G. J. Heterocycl. Chem. 1974, 11, 93. Jones, G. In Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, New York, 1977, Quinolines, Vol 32, 137–151. (Review). Barker, J. M.; Huddleston, P. R.; Jones, A. W.; Edwards, M. J. Chem. Res., (S) 1980, 4. Guay, V.; Brassard, P. J. Heterocycl. Chem. 1987, 24, 1649. Deady, L. W.; Werden, D. M. J. Org. Chem. 1987, 52, 3930. Kemp, D. S.; Bowen, B. R. Tetrahedron Lett. 1988, 29, 5077. Hormi, O. E. O.; Peltonen, C.; Heikkila, L. J. Org. Chem. 1990, 55, 2513. Billah, M.; Buckley, G. M.; Cooper, N; et al. Bioorg. Med. Chem. 2002, 12, 1617. Curran, T. T. Conrad–Limpach Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 398406. (Review).

149

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

O H R

N R1 R2

'

R3

O H R

N 1

R R

2 R3

R

R3

R1

R2

'

R

Ei

R

1

OH N

R3 R

OH N

2

Example 17

O O

m-CPBA, CHCl3

N

rt, 67% OH O O

HO H

O O N

N

O OH OH

150

Example 211

N O

N

m-CPBA, CH2Cl2 rt, 100%

CN

CN

O O NC

N OH

H

O

References Cope, A. C.; Foster, T. T.; Towle, P. H. J. Am. Chem. Soc. 1949, 71, 3929. Arthur Clay Cope (19091966) 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, 317493. (Review). 3. DePuy, C. H.; King, R. W. Chem. Rev. 1960, 60, 431457. (Review). 4. Gallagher, B. M.; Pearson, W. H. Chemtracts: Org. Chem. 1996, 9, 126130. (Review). 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. 1.

151

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

R

', [3,3]-sigmatropic

R

R

rearrangement Example 15

CO2Me

CO2Me

o

100 C, 12 h

O

O TMS

TMS

84%

Example 28

CO2Me

dioxane, Et3N, 60 oC

O

CO2Me O

CO2Me

22 h, 1 bar, 92%

CO2Me

References Cope, A. C.; Hardy, E. M. J. Am. Chem. Soc. 1940, 62, 441. Frey, H. M.; Walsh, R. Chem. Rev. 1969, 69, 103124. (Review). Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 1252. (Review). Hill, R. K. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds., Pergamon, 1991, Vol. 5, 785826. (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, 52035223. (Review). 7. Miyashi, T.; Ikeda, H.; Takahashi, Y. Acc. Chem. Res. 1999, 32, 815824. (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 Organic Synthesis 2002, 2, 29192934. (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. 1. 2. 3. 4.

152

Oxy-Cope rearrangement OH R

OH R

', [3,3]-sigmatropic

rearrangement

OH R

O tautomerize R

Example 12

PhMe2SiO

O

t-Bu

1. 170 oC

PhMe2Si O PhMe2SiO OHC

2. p-TsOH-H2O 6575%

O O

O

t-Bu

O

Example 24

OH

xylene, Ace® tube

O

225 oC, 24 h, 49% References 1. 2. 3. 4.

Paquette, L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609626. (Review). Schneider, C.; Rehfeuter, M. Chem. Eur. J. 1999, 5, 2850. Schneider, C. Synlett 2001, 10791091. (Review on siloxy-Cope rearrangement). DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.; Spencer, N. S.; Tolley, M. Org. Biomol. Chem. 2003, 1, 4423.

153

Anionic oxy-Cope rearrangement OH R

OK R

KH

', [3,3]-sigmatropic

THF

rearrangement

OK R

OK R

OH R

H2O

O

tautomerize

R

Example 11

OH

KH, THF, rt

O

then H2O, 88% Example 26

O OH

NaH, THF, reflux 22 h, 88%

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

Wender, P. A.; Sieburth, S. M.; Petraitis, J. J.; Singh, S. K. Tetrahedron 1981, 37, 3967. Wender, P. A.; Ternansky, R. J.; Sieburth, S. M. Tetrahedron Lett. 1985, 26, 4319. Paquette, L. A. Tetrahedron 1997, 53, 1397114020. (Review). Voigt, B.; Wartchow, R.; Butenschon, H. Eur. J. Org. Chem. 2001, 2519. Hashimoto, H.; Jin, T.; Karikomi, M.; Seki, K.; Haga, K.; Uyehara, T. Tetrahedron Lett. 2002, 43, 3633. 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.

H PhPh O N B H

cat.

O

OH

BH3, THF, rt, 97% ee

BH3

O N B H

H

O

H Ph Ph

H PhPh

RS

RL

O

N B H3B H H

Ph

N H2B H RS

RL

H

H PhPh O

N B H3B H

O

O BH

RS RL

Ph

O B

H

RS

H O

RL

BH3

H

B

H2B

Ph

O

N

Ph

2

The catalytic cycle is shown on the next page.

H2O

H

OBH2

RS RL

H

OH

RS RL

155

The catalytic cycle: H Ph Ph O N B H RS H2B HO

O

H Ph Ph O

N

RL

RS

RL

H Ph Ph

BH3

O N B H3B H

B H

H Ph Ph O N B H2B H O RS

OBH2 RL

RS

RL

BH3

Example 19

O SO2C6H4CH3-p

0.1 eq. (S)-CBS 1.0 eq. i-Pr(Et)NPh•BH3 THF, rt, syringe pump 1.5 h, 98%, 97% ee

O

H Ph Ph

OH SO2C6H4CH3-p

(S)-CBS =

O

O N B CH3

Example 214

O

O O O

BH3•SMe2, cat. (R)-CBS CH2Cl2, 30 oC, 84%, > 99% ee

HO

O O O

156

References 1.

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

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 University of Illinois in 1950 and moved to Harvard University in 1959. Corey won the Nobel 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. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925. Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1992, 3, 1583. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. 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. Itsuno, S. Org. React. 1998, 52, 395576. (Review). Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 19862012. (Review). Cho, B. T.; Kim, D. J. Tetrahedron: Asymmetry 2001, 12, 2043. de Koning, C. B.; Giles, R. G. F.; Green, I. R.; Jahed, N. M. Tetrahedron Lett. 2002, 43, 4199. Price, M. D.; Sui, J. K.; Kurth, M. J.; Schore, N. E. J. Org. Chem. 2002, 67, 8086. Fu, X.; McAllister, T. L.; Thiruvengadam, T. K.; Tann, C.-H.; Su, D. Tetrahedron Lett. 2003, 44, 801. Degni, S.; Wilen, C.-E.; Rosling, A. Tetrahedron: Asymmetry 2004, 15, 1495. Watanabe, H.; Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652.

157

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

CH2 S O H3C CH3

CH2 S H3C CH3

1

2

X

X

1 or 2

R1

R

R1

R

4

3

X = O, CH2, NR2, S, CHCOR3, CHCO2R3, CHCONR2, CHCN O R

1

R

O S H3C CH2 CH3

H3C

O S

R CH3

R1

O

O R O S H 3C CH2 CH3

O R R1 S H 3C CH3 O

R1

H3C

O S

R CH3

O

R1

Example 112

BF4 Ph2S R20

CHO

KOH, DMSO, rt, 62%

R20 O

158

Example 214 O 

N

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

60 oC, 3.5 h, 79%

F Cl

O N O F Cl

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867. Michael Chaykovsky last published from Prospect Pharma, USA Corey, E. J.; Chaykovsky, M. Tetrahedron Lett. 1963, 4, 169. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1964, 86, 1640. Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides Academic Press: New York, 1975. (Review). Block, E. Reactions of Organosulfur Compounds Academic Press: New York, 1978. (Review). Johnson, C. R. Aldrichimica Acta 1985, 18, 310. (Review). Gololobov, Y. G.; Nesmeyanov, A. N., Iysenko, V. P.; Boldeskul, I. E. Tetrahedron 1987, 43, 26092651. (Review). Aubé, J. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Ed.; Pergamon: Oxford, 1991, Vol. 1, pp 820825. (Review). Okazaki, R.; Tokitoh, N. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, pp 213941. (Review). Ng, J. S.; Liu, C. In Encyclopedia of Reagents in Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995, 215965. (Review). Corey, E. J.; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997, 119, 1277. Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 23412372. (Review). Vacher, B.; Bonnaud, B.; Funes, P.; et al. J. Med. Chem. 1999, 42, 1648. Shea, K. J. Chem. Eur. J. 2000, 6, 11131119. (Review). Saito, T.; Sakairi, M.; Akiba, D. Tetrahedron Lett. 2001, 42, 5451. 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. CoreyChaykovsky Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 114. (Review).

160

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

CBr4, PPh3

R

Zn

H

R CHO

Br3C

Br

n-BuLi

Br

R Br SN2

:PPh3

 

Br

PPh3 

H

SN2

CBr3

Br

PPh3

Br SN2

Br

CBr3

Br

PPh3 Br

O Br Br2

R

PPh3

R

H

Br O PPh3

H Br Br Wittig reaction (see page 621 for the mechanism)

Br2

ZnBr2

Zn R

Br

H

Br



R

Br

Bu

Bu acidic R

R workup Example 13

OMe O O OHC OTBS

CBr4, Ph3P, CH2Cl2 rt, 35 min., 90%

H

161

OMe O

Br

O

2.0 eq. THF•BH3, THF, 15 oC, 26 h

Br OTBS

then CH3OH, 3 N NaOH, 30% H2O2 rt, 2 h, 85%

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

O OTBS

o

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

OH

Example 28

CHO OTBS

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. Tetrahedron: 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.

OH 1

NCS, DMS

O

2

then NEt3 R2 R1 NCS = N-Chlorosuccinimide; DMS = Dimethylsulfide. R

R

O

O

N Cl O

O

S Cl

N

:S

O Cl

O

Cl

NH

H

N S

S O

:O

O

R1

1

R

O

R2

H :NEt3

H R2

S

Et3N·HCl

O

O R1

(CH3)2Sn

R1

2H

R

Example 1, fluorous CoreyKim reaction5

NO2

C6F13 OH

S

NO2 CHO o

NCS, toluene, 25 C, 2 h then Et3N, 86%

R2

163

Example 2, odorless CoreyKim reaction8

S

N O OH D

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

S

N O 45%

O

D

86%

References 1

2 3 4 5 6 7 8

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). Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178. Shapiro, G.; Lavi, Y. Heterocycles 1990, 31, 2099. Pulkkinen, J. T.; Vepsäläinen, J. J. J. Org. Chem. 1996, 61, 8604. Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865. Nishide, K.; Ohsugi, S.-I.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177. Ohsugi, S.-I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron 2003, 59, 8393. Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142.

164

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

O

Also

N S

OH

S

O

N

n

OH

O

n

Ph3P H

N S

S

HS

N

N

N S

PPh3

Ph3P: N N

H S

PPh3

S

O

O O

H

O

n

n

OH

N S

O

PPh3

OH

PPh3 N H

O PPh3

O n

S O O

n

OH O N H

S O

O

n n

O

N H

S

2-pyridinethione

165

Example 13

Ph Ph Ph

Ph

O

O O

OH (2-pyr-S)2, PPh3

H

O

HO2C

CHCl3, ', 75%

N

O H

O

N Example 26

OH OMOM

O

O OH

O

(2-pyr-S)2, PPh3 AgClO4, ', 33%

O Dowex, MeOH 58%

O HO

OH OH

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

Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614. Nicolaou, K. C. Tetrahedron 1977, 33, 683–710. (Review). Devlin, J. A.; Robins, D. J.; Sakdarat, S. J. Chem. Soc., Perkin Trans. 1 1982, 1117. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1985, 2475. Barbour, R. H.; Robins, D. J. J. Chem. Soc., Perkin Trans. 1 1988, 1169. Andrus, M. B.; Shih, T.-L. J. Org. Chem. 1996, 61, 8780. Lu, S.-F.; O'yang, Q. Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J. Org. Chem. 1997, 62, 8400. 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 example of umpolung.

SH

CH2(OMe)2

S

SH

Et2O•BF3

S

S

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

HgCl2, 50 oC

OHC

S

H H

S

I

Cl

Bu S

Cl

50%

Cl

S S S S Cl

Example 16

CHO

n-BuLi, THF

S S Ph

HO S Ph

S Ph

o

0 C, 30 min. 99%

PhI(O2CCCl3)2

HO

O

CH3CN, H2O, rt, 5 min. 95%

Ph

Ph

167

Example 28

O

CHO

Ph

S

S

n-BuLi, THF, 78 to 0 oC OH O

S S

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

Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. 1965, 4, 1075, 1077. Dieter Seebach is a professor at ETH in Zürich, Switzerland. Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. Seebach, D.; Jones, N. R.; Corey, E. J. J. Org. Chem. 1968, 33, 300. Seebach, D.; Corey, E. J. Org. Synth. 1968, 50, 72. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231. Stowell, M. H. B.; Rock, R. S.; Rees, D. C.; Chan, S. I. Tetrahedron Lett. 1996, 37, 307. Hassan, H. H. A. M.; Tamm, C. Helv. Chim. Acta 1996, 79, 518. Lee, H. B.; Balasubramanian, S. J. Org. Chem. 1999, 64, 3454. 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

OH

R1

OH

S N

R

O

R1

O

N

S N

N

P(OMe)3

R

H

R1

H

S N

R

:

R

OH

R1

OH

O

R1 R

OH

O

1

Imd

OH

R

O

R1

O

:P(OMe)3

S

O

R1

S

R

O

1

O

R1

:P(OMe)3

O

S P(OMe)3

O

R

S P(OMe)3

H

O

H

O

P(OMe)3 1

R

S Imd

S P(OMe)3

O

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

N S H

N

N

N

R

N

N

N

R

O

R1

O

P(OMe)3

O C On

P(OMe)3

169

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

R

O

:P(OMe)3

S R1

R

R

O

R1

O

S P(OMe)3

O

S P(OMe)3

R

R1

O

:P(OMe)3

O

O

R

H

1

H

P(OMe)3 R1

O

R

O :P(OMe)3

P(OMe)3

O C On

O Example 17

O

O N

HO HO

N

OMe Imd2CS, toluene reflux, 79%

OMOM CF3

O S O

OMOM CF3

N

OMe

O P(OMe)3 92%

F3C OMOM One olefin isomer

Example 211

OMe TBSO

H OAc

HO HO

CSCl2, DMAP CH2Cl2, rt, 96%

H

OMe

170

OMe TBSO

H OAc

O S O

H OMe TBSO

(EtO)3P

H OAc

reflux, 76% H References 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. 1.

171

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

1

R2

O

Pb(OAc)4

R3

R1

R4

O R2

AcO Pb(OAc)3 HO OH R

1

R R4

R2

HOAc

OAc Pb

O R

O

O

O

1

R R2

2 HOAc

OAc (AcO)2Pb O OH 1 R R3 2 R4 R

3

AcO

HOAc

Pb(OAc)2

R4

R3

R1

3

R2

R3

Pb(OAc)2

R4

R4

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

O H

O:

Pb(OAc)3 O

O HOAc

O OH

H

O

AcO O PbII(OAc)2 O

HOAc

O Pb(OAc)2

172

Example 17

CO2Et

OH

CO2Et

N

Ph

N

Pb(OAc)4, K2CO3 H

O

O

o

PhH, 0 C, 80%

OH

O

Example 29

H HO PhO2S

OH

Pb(OAc)4, CH2Cl2, K2CO3 15 oC to rt, 1 h, then Ph3P=CHCO2Me, CH3CN, 80%

H

H

CO2Me

E:Z = 10:1 PhO2S

H

References Criegee, R. Ber. Dtsch. Chem. Ges. 1931, 64, 260. Rudolf Criegee (19021975) 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. 1

173

Criegee mechanism of ozonolysis O O

O3

O O

1,3-dipolar

O

:

O

O

O

O

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

O

O

O O

1,3-dipolar O

O

cycloaddition

zwitterionic peroxide (Criegee zwitterion) also known as “carbonyl oxide”

secondary ozonide (1,2,4-trioxolane)

Example 114

H

o

HO

O3, EtOAc, 78 C, then

O OAc

O HO

O

Ac2O, Et3N, DMAP, 78 oC to rt, 75%

H

Example 215

O O

O3, CH2Cl2 O

CHOMe

70 oC

MeOH

CO2Me

quant.

CO2Me

O

References 1. 2. 3. 4. 5.

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

174

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Schreiber, S. L.; Liew, W.-F. Tetrahedron Lett. 1983, 24, 2363. Wojciechowski, B. J.; Pearson, W. H.; Kuczkowski, R. L. J. Org. Chem. 1989, 54, 115. Bunnelle, W. H. Chem. Rev. 1991, 91, 335362. (Review). Kuczkowski, R. L. Chem. Soc. Rev. 1992, 21, 7983. (Review). Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675. Ponec, R.; Yuzhakov, G.; Haas, Y.; Samuni, U. J. Org. Chem. 1997, 62, 2757. Anglada, J. M.; Crehuet, R.; Maria Bofill, J. Chem. Eur. J. 1999, 5, 1809. Dussault, P. H.; Raible, J. M. Org. Lett. 2000, 2, 3377. Jiang, L.; Martinelli, J. R.; Burke, S. D. J. Org. Chem. 2003, 68, 1150. 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 isocyanate intermediates. While the thermal rearrangement is a concerted process, the photochemical rearrangement goes through a nitrene intermediate. The thermal rearrangement:

O R

N2n

Cl

R

R N C O

O R

O

NaN3

N3

H 2O

R

O

Cl

R

O

' N N N

O N3

N3

R

CO2n

R NH2

O N3 Cl

'

N2n

N N N

R

H+ R N C O

:OH2 isocyanate intermediate

R

H N

O

R NH2

H

O

CO2n

:B

The photochemical rearrangement: O R

hQ N N N

O

N2n

R N: nitrene

O R

N

R N C O

R NH2

CO2n

176

Example 19

O HO2C O

CO2Me DPPA, Et N, t-BuOH BocHN 3

O

80 oC, 16 h, 64%

O

O

CO2Me O

Example 211

CO2H O O

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

NHCO2Et O O

References Curtius, T. Ber. Dtsch. Chem. Ges. 1890, 23, 3023. Theodor Curtius (18571928) was born in Duisburg, Germany. He studied music before switching to chemistry under Bunsen, Kolbe, and von Baeyer before succeeding Victor Meyer as a Professor of Chemistry at Heidelberg. He discovered diazoacetic ester, hydrazine, pyrazoline derivatives, and many nitrogen-heterocycles. Curtius also sang in concerts and composed music. 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. 1.

177

Dakin oxidation Oxidation of aryl aldehydes or aryl ketones to phenols using basic hydrogen peroxide conditions. Cf. Baeyer–Villiger oxidation.

H2O2, NaOH HO

CHO

HO

OH

o

HCO2H

4550 C O

O HO

aryl

H

HO

O

H O

O

migration

HO

H

OH HO

hydrolysis

O

HO

O

H H

O

HO

O

HO2CH

HO

OH

O OH

CHO2

Example 16

OBn CHO 2.5 eq. 30% H2O2 4% (PhSe)2, CH2Cl2, 18 h

CO2H NHCO2t-Bu OBn

OBn O

CHO

CO2H NHCO2t-Bu

OH NH3, MeOH, 1 h 78%

CO2H NHCO2t-Bu

178

Example 27

CHO urea-hydrogen peroxide (UHP) HO

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

OH HO

References: 1.

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

Dakin, H. D. J. Am. Chem. Soc. 1909, 42, 477. Henry D. Dakin (18801952) was born in London, England. During WWI, he invented his hypochlorite solution (Dakin’s solution), which became a popular antiseptic for the treatment of wounds. After the Great War, he emmigrated to New York, where he investigated the B vitamins. Hocking, M. B.; Bhandari, K.; Shell, B.; Smyth, T. A. J. Org. Chem. 1982, 47, 4208. Matsumoto, M.; Kobayashi, H.; Hotta, Y. J. Org. Chem. 1984, 49, 4740. Zhu, J.; Beugelmans, R.; Bigot, A.; Singh, G. P.; Bois-Choussy, M. Tetrahedron Lett. 1993, 34, 7401. Guzmán, J. A.; Mendoza, V.; García, E.; Garibay, C. F.; Olivares, L. Z.; Maldonado, L. A. Synth. Commun. 1995, 25, 2121. Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. Varma, R. S.; Naicker, K. P. Org. Lett. 1999, 1, 189. Roy, A.; Reddy, K. R.; Mohanta, P. K.; Ila, H.; Junjappa, H. Synth. Commun. 1999, 29, 3781. Lawrence, N. J.; Rennison, D.; Woo, M.; McGown, A. T.; Hadfield, J. A. Bioorg. Med. Chem. Lett. 2001, 11, 51.

179

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

O R

CO2H

Ac2O

R

CO2n

NH2 R

NHAc O

CO2H

R

NH2

OH

:

HN

O O

H+ O R

O H O O

H

O

N

OH O

AcO H

AcO H O R

O

OH

H

N

O

N

O

O

R

OH

R

O

N

O

O OH

H

oxazolone (azalactone) intermediate

O R HN

H

O

O

O H

CO2

O

O

R

tautomerization N

R

OH

NHAc

Example 112

Me

CO2H NH2

Ac2O, AcOH, Et3N o

DMAP, 50 C, 14 h, > 90%

O

Me

Me NHAc

180

Example 214

HO O N H

O

Ac2O, pyr.

O OBn

90 oC, 2 h, 58%

O

O N H

Me O OBn

References: 1.

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

Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Dakin and Rudolf West, a clinician, reported on the reaction of D-amino acids with acetic anhydride to give D-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and D-phenylananine gave “abnormal” products when acetylated under these conditions.2,3 Unfortunately, they were slow to identify the products and lost an opportunity to be immortalized by a name reaction. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1927, 74, 689. Levene, P. A.; Steiger, R. E. J. Biol. Chem. 1928, 79, 95. Cornforth, J. W.; Elliott, D. F. Science 1950, 112, 534. Allinger, N. L.; Wang, G. L.; Dewhurst, B. B. J. Org. Chem. 1974, 39, 1730. Buchanan, G. L. Chem. Soc. Rev. 1988, 17, 91. (Review). Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1997, 62, 1553. Kawase, M.; Hirabayashi, M.; Koiwai, H.; Yamamoto, K.; Miyamae, H. Chem. Commun. 1998, 641. Kawase, M.; Okada, Y.; Miyamae, H. Heterocycles 1998, 48, 285. Kawase, M.; Hirabayashi, M.; Kumakura, H.; Saito, S.; Yamamoto, K. Chem. Pharm. Bull. 2000, 48, 114. Kawase, M.; Hirabayashi, M.; Saito, S. Recent Res. Dev. Org. Chem. 2001, 4, . (Review). Fischer, R. W.; Misun, M. Org. Proc. Res. Dev. 2001, 5, 581. Orain, D.; Canova, R.; Dattilo, M.; Klöppner, E.; Denay, R.; Koch, G.; Giger, R. Synlett 2002, 1443. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623. Khodaei, M. M.; Khosropour, A. R.; Fattahpour, P. Tetrahedron Lett. 2005, 46, 2105.

181

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

O SiMe3 TiCl4, CH2Cl2

SiMe3

o

75 C, 82%

Cl Cl3Ti

Cl3Ti

Cl

O

O SiMe3

SiMe3

Cl3Ti

O

1,2-shift of SiMe3

silyl group

Transition State Cl Cl3Ti

O O SiMe3 SiMe3

182

Example 17

O TiCl4, CH2Cl2

SiMe3

OMe

78 oC

O O

O

O

OMe O

OMe OH

OMe O

Me3Si

15%

6%

48%

Example 28 O SiMe3

TiCl4, CH2Cl2

75 oC, 91%

O

O

H

H

(1:1) Me3Si

Me3Si

H

H

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

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

183

Darzens glycidic ester condensation DE-Epoxy esters (glycidic esters) from base-catalyzed condensation of D-haloesters with carbonyl compounds. X R

O R1

CO2Et

O

OEt

R1

R CO2Et

R2

R2 O

OEt

X

H

R

X

OEt

O

O R CO2Et

X

R2 OEt

R

O

R1 R2

R1

intramolecular

O 1

R

R2

SN2

R CO2Et

Example 14

O +

Cl

CO2Et

O

t-BuOK, t-BuOH

CO2Et

10°C, 85–95% Example 29

O H3C

t-BuMe2Si

Br

LDA, THF, –78 °C then PhCHO, –90 °C

O H3C

t-BuMe2Si

O

H Ph

H

66%, 90% de

References 1

2

Darzens, G. A. Compt. Rend. Acad. Sci. 1904, 139, 1214. George Auguste Darzens (18671954) born in Moscow, Russia, studied at École Polytechnique in Paris and stayed there as a professor. Newman, M. S.; Magerlein, B. J. Org. React. 1949, 5, 413–441. (Review).

184

3 4 5 6

7 8 9 10 11 12 13 14 15

Ballester, M. Chem. Rev. 1955, 55, 283–300. (Review). Hunt, R. H.; Chinn, L. J.; Johnson, W. S. Org. Syn. Coll. 1963, 4, 459. Bauman, J. G.; Hawley, R. C.; Rapoport, H. J. Org. Chem. 1984, 49, 3791. Rosen, T. Darzens Glycidic Ester Condensation In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, vol. 2, pp 409–439. (Review). Takahashi, T.; Muraoka, M.; Capo, M.; Koga, K. Chem. Pharm. Bull. 1995, 43, 1821. Ohkata, K.; Kimura, J.; Shinohara, Y.; Takagi, R.; Hiraga, Y. Chem. Commun. 1996, 2411. Enders, D.; Hett, R. Synlett 1998, 961. Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem. Soc., Perkin Trans. 1 1998, 689. Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825. Shinohara, Y.; Ohba, Y.; Takagi, R.; Kojima, S.; Ohkata, K. Heterocycles 2001, 55, 9. Arai, A.; Suzuki, Y.; Tokumaru, K.; Shioiri, T. Tetrahedron Lett. 2002, 43, 833. Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. 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, 1521. (Review).

185

Davis chiral oxaziridine reagents Chiral N-sulfonyloxaziridines employed for asymmetric hydroxylation, etc.

RSO2

O N

Ar

e.g.

S O O O

R1

R

Cl Cl N

RSO2

O N

Ar

O M

O

R1

R

M N

Ar

O SO2R

RSO2

O Ar

R1

R

N O R1

R

O

O

M O M R1

R

Ar

N

SO2R

O

Example 12

1. NaHMDS, THF, 78 oC O

O Ph

N

o

2. THF, 78 C O

PhSO2

O N

Ph

O

O Ph

N

O

OH

3. camphor sulfonic acid, THF 85%, 90% de

186

Example 25 o

O Ph

NaHMDS, THF, 78 C

O

61%, 95% ee

Ph Cl Cl N

OH

S O O O

References 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 University, 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, 919934. (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, 1356. (Review). 1

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 D-halo-ketones.

N Ar

X

N N

X

N N

N N

HX

Ar

Ar

N

NH3 X

hexamethylenetetramine

[ArCH2-C6H12N4]+X = ArCH2NH2•HX

+

Ar

SN2 X

+

3NH4Cl

N

H N

N N

N N

Ar X

H2O:

O CH2

6CH2O

+ 6H2O

N

N:

N N

3HCl

:

N N N

+

Ar

N N

N

O H Ar

H N N N

N

Ar

Ar

NH3 X

Example 14

O Br

1. (CH2)6N4, NaHCO3 15 h, EtOH, H2O OH 2. HCl, EtOH, reflux, 15 h, 85%

O H2N

OH

188

Example 28

Br

hexamethylenetetramine

N

N

Br

CH2Cl2, refux, 5 h, then

30 oC

Br

N

N +

N4C6H12 Br



conc. HCl, EtOH reflux, 1 d 78%, 2 steps

Br

N

N NH2

References 1.

2. 3. 4. 5. 6.

Delépine, M. Bull. Soc. Chim. Paris 1895, 13, 355; 1897, 17, 290. Stephe Marcel Delépine (18711965) was born in St. Martin le Gaillard, France. He was a professor at the Collège de France after working for M. Bertholet at that institute. Delépine’s long and fruitful career in science encompassed organic chemistry, inorganic chemistry, and pharmacy. Delépine, M. Compt. Rend. Acad. Sci. 1895, 120, 501. 1897, 124, 292. Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585. Wendler, N. L. J. Am. Chem. Soc. 1949, 71, 375. Quessy, S. N.; Williams, L. R.; Baddeley, V. G. J. Chem. Soc., Perkin Trans. 1 1979, 512. Blažzeviü, N.; Kolnah, D.; Belin, B.; Šunjiü, V.; Kafjež, F. Synthesis 1979, 161. (Re-

view). 7. 8.

Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D. W.; Nissan, R. A. J. Org. Chem. 1990, 55, 1796. 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 retroaldol reaction to give 1,5-diketones. O

O

O

CO2Me

CO2Me hQ OH

OH

O

CO2Me

O

O

hQ, [2 + 2] CO2Me OH head-to-tail alignment

OH

CO2Me

cycloaddition

O H

O

O

retro-aldol cyclobutane cleavage O

CO2Me

O

H

O

CO2Me

CO2Me

Minor regioisomer: O

O

CO2Me

CO2Me

hQ, [2 + 2] cycloaddition

OH

OH head-to-head alignment

O H

O CO2Me

retro-aldol

H

CO2Me

CO2Me

cyclobutane cleavage O

O

O

O

190

Example 15 O

Ph

O 1. hQ, cyclohexane, 83%

O

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

O

O Example 29 O

hQ, MeOH > 90% OH O

O

H

H

HO H

H O

References 1.

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

13. 14.

de Mayo, P.; Takeshita, H.; Sattar, A. B. M. A. Proc. Chem. Soc., London 1962, 119. Paul de Mayo received his doctorate from Sir Derek Barton at Birkbeck College, University of London. He later became a professor at the University of Western Ontario in London, Ontario, Canada, where he discovered the de Mayo reaction. Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570. Challand, B. D.; Hikino, H.; Kornis, G.; Lange, G.; de Mayo, P. J. Org. Chem. 1969, 34, 794. de Mayo, P. Acc. Chem. Res. 1971, 4, 49. (Review). Oppolzer, W.; Godel, T. J. Am. Chem. Soc. 1978, 100, 2583. Oppolzer, W. Pure Appl. Chem. 1981, 53, 1181. (Review). Pearlman, B. A. J. Am. Chem. Soc. 1979, 101, 6398. Kaczmarek, R.; Blechert, S. Tetrahedron Lett. 1986, 27, 2845. Disanayaka, B. W.; Weedon, A. C. J. Org. Chem. 1987, 52, 2905. Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297588. (Review). Quevillon, T. M.; Weedon, A. C. Tetrahedron Lett. 1996, 37, 3939. 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. Minter, D. E.; Winslow, C. D. J. Org. Chem. 2004, 69, 1603. 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 CC bond migration.

HNO2

OH

NH2

OH H

2 HO

N

H+

O

O

N

O

H2O

O

N

O

N

O

H2O N

O

O

O

N

HNO2

:

N H

NH2 H+

N O

H2O N N

N N OH2

:

N N OH

H O

:

N2 N N

:

H O or N N

H

H

H+

OH

N2 H+

OH

Example 17

H

NH2

O

N

NaNO2, AcOH/H2O 100110 oC, 2 h, 61%

H

OH

192

Example 29

O NaNO2, 04 oC

NH2

0.25 M H2SO4/H2O

O

O

OH

HO

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

Demjanov, N. J.; Lushnikov, M. J. Russ. Phys. Chem. Soc. 1903, 35, 26. Nikolai J. Demjanov (18611938) was a Russian chemist. Smith, P. A. S.; Baer, D. R. Org. React. 1960, 11, 157188. (Review). Kotani, R. J. Org. Chem. 1965, 30, 350. Diamond, J.; Bruce, W. F.; Tyson, F. T. J. Org. Chem. 1965, 30, 1840. Alam, S. N.; MacLean, D. B. Can. J. Chem. 1965, 43, 3433. 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. Nakazaki, M.; Naemura, K.; Hashimoto, M. J. Org. Chem. 1983, 48, 2289. Uyehara, T.; Kabasawa, Y.; Furuta, T.; Kato, T. Bull. Chem. Soc. Jpn. 1986, 59, 539. Fattori, D.; Henry, S.; Vogel, P. Tetrahedron 1993, 49, 1649.

193

Tiffeneau–Demjanov rearrangement Carbocation rearrangement of E-aminoalcohols via diazotization to afford carbonyl compounds through CC bond migration.

OH

O

NaNO2

NH2

H+

Step 1, Generation of N2O3

H HO

H+

N

O

O

N

O

H2O

N

H2O

O

+

H

O

N

O

N

O

Step 2, Transformation of amine to diazonium salt

O

N

OH

O

N

OH

O HONO

:

N N O H

NH2 OH

OH

H+

H2O

OH N N

N N OH2+

:

N N OH Step 3, Ring-expansion via rearrangement

N

N

O H

O

:

OH

N2

H+

Example 110

NaNO2, AcOH/H2O, 0 oC, 1 h OH NH2

then reflux 1 h, 98%

O

194

Example 212

O HO

NH2 SiMe3

O

NaNO2 SiMe3

AcOH 72% SiMe3

28%

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

195

DessMartin periodinane oxidation Oxidation of alcohols to the corresponding carbonyl compounds using triacetoxyperiodinane. AcO OAc I OAc O OH R

1

AcO OAc I OAc O

R

O

O

2

R1

2

AcO OAc I O H O 1 2 R R

H :O R2 R

R

1

O

OAc

O OAc I O

H

O

O O

R2

R1

O

Example 19 AcO OAc I OAc O OH

O

O

O

O O O

CH2Cl2, 2 h, 67%

O

O O

Example 215 AcO OAc I OAc O

O

CHO O

N

NaN3, CH2Cl2 o

0 C, 3 h, 86%

O

N3 N

196

References 1.

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

Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. James Cullen (J. C.) Martin (19281999) had a distinguished career spanning 36 years both at the University of Illinois at Urbana-Champaign and Vanderbilt University. J. C.’s formal training in physical organic chemistry with Don Pearson at Vanderbilt and P. D. Bartlett at Harvard prepared him well for his early studies on carbocations and radicals. However, it was his interest in understanding the limits of chemical bonding that led to his landmark investigations into hypervalent compounds of the main group elements. Over a 20-year period the Martin laboratories successfully prepared unprecedented chemical structures from sulfur, phosphorus, silicon and bromine while the ultimate “Holy Grail” of stable pentacoordinate carbon remained elusive. Although most of these studies were driven by J. C.’s fascination with unusual bonding schemes, they were not without practical value. Two hypervalent compounds, Martin’s sulfurane (for dehydration, page 365) and the Dess-Martin periodinane have found widespread application in synthetic organic chemistry. J. C. Martin and his student Daniel Dess developed this methodology at the University of Illinois at Urbana. (Martin’s biography is kindly supplied by Prof. Scott E. Denmark). Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899. Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996, 338, 588590. (Review). Chaudhari, S. S.; Akamanchi, K. G. Synthesis 1999, 760. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. Angew. Chem., Int. Ed. 2000, 39, 622. Jenkins, N. E.; Ware, R. W., Jr.; Atkinson, R. N.; King, S. B. Synth. Commun. 2000, 30, 947. Promarak, V.; Burn, P. L. J. Chem. Soc., Perkin 1 2001, 14. Bach, T.; Kirsch, S. Synlett 2001, 1974. Wavrin, L.; Viala, J. Synthesis 2002, 326. Wellner, E.; Sandin, H.; Pääkkönen, L. Synthesis 2003, 223. Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575. Bose, D. S.; Reddy, A. V. N. Tetrahedron Lett. 2003, 44, 3543. Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111124. (Review). Deng, G.; Xu, B.; Liu, C. Tetrahedron 2005, 61, 5818.

197

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

CO2Et OEt O

H

O

NaOEt

CO2Et CO2Et

CO2Et

O enolate

5-exo-trig

OEt OEt

formation

ring closure

O OEt O OEt

O

CO2Et

CO2Et

Example 17

H MeO2C

H

OBn NaHMDS, THF

O

OTBS

N

N

OBn OTBS

o

78 C, 58%

MeO2C

MeO2C

Example 29

EtO2C O

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

N

O

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

N

O

198

References 1.

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

Dieckmann, W. Ber. Dtsch. Chem. Ges. 1894, 27, 102. Walter Dieckmann (18691925), born in Hamburg, Germany, studied with E. Bamberger at Munich. After serving as an assistant to von Baeyer in his private laboratory, he became a professor at Munich. At age 56, he died while working in his chemical laboratory at the Barvarian Academy of Science. Davis, B. R.; Garratt, P. J. Comp. Org. Synth. 1991, 2, 795863. (Review). Toda, F.; Suzuki, T.; Higa, S. J. Chem. Soc., Perkin Trans. 1 1998, 3521. Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc. 1999, 121, 6507. Balo, C.; Fernández, F.; García-Mera, X.; López, C. Org. Prep. Proced. Int. 2000, 32, 563. Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403. Rabiczko, J.; UrbaĔczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron 2002, 58, 1433. Ho, J. Z.; Mohareb, R. M.; Ahn, J. H.; Sim, T. B.; Rapoport, H. J. Org. Chem. 2003, 68, 109. 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 illustrative. Normal Diels–Alder reaction EDG

EDG EWG

diene

'

EWG

dienophile

adduct

EDG = electron-donating group; EWG = electron-withdrawing group Example 113

OMe

OMe

CO2Et Me3SiO

hydroquinone

Me3SiO

180 oC, 1.5 h, 62%

AcO

CO2Et H

OAc

Alder’s endo rule

Danishefsky diene OMe

OMe CO2Et

Me3SiO

CO2Et

EtO2C

AcO

AcO

OSiMe3

4:1 D-OMe : E-OMe Example 217

O F

F O

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

O O

H

200

Inverse electronic demand Diels–Alder reaction EWG

EWG EDG

diene

'

EDG

dienophile

adduct

Example 12 N

CO2Me

N

'

CO2Me

Hetero-Diels–Alder reaction Heterodiene addition to dienophile

EtO2C

SO2Ph N

EtO2C OEt

N

EtO2C

OEt H

Ph

Ph

SO2Ph

Ph

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

CO2Me OMe

N N

MeO OMe MeO

CHCl3, reflux

N N

5 days, 65%

CO2Me MeO2C MeO MeO

N N CO2Me CO2Me

MeO2C N N

SO2Ph N OEt

201

Heterodienophile addition to diene2

MeO

toluene

CO2Et O

CO2Et

MeO O

110 oC, 60%

Example 2, using the Rawal diene9

NMe2 O Me

CO2Me

OTBS

CHCl3, 40 oC 71%

O Me MeO2C

O

References 1.

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

Diels, O.; Alder, K. Justus Liebigs Ann. Chem. 1928, 460, 98. Otto Diels (Germany, 18761954) and his student, Kurt Alder (Germany, 19021958), shared the Nobel Prize in Chemistry in 1950 for development of the diene synthesis. In this article they claimed their territory in applying the Diels–Alder reaction in total synthesis: “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.” Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987, 109, 4390. Boger, D. L.; Panek, J. S.; Yasuda, M. Org. Synth. 1988, 66, 142. Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 315399. (Review). Boger, D. L. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 451512. (Review). Weinreb, S. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 5, 401449. (Review). Wasserman, H. H.; DeSimone, R. W.; Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 8457. Boger, D. L.; Baldino, C. M. J. Am. Chem. Soc. 1993, 115, 11418. Huang, Y.; Rawal, V. H. Org. Lett. 2000, 2, 3321. Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278. (Review). Yli-Kauhaluoma, J. Tetrahedron 2001, 57, 7053. (Review). Ghosh, A. K.; Shirai, M. Tetrahedron Lett. 2001, 42, 6231. Wang, J.; Morral, J.; Hendrix, C.; Herdewijn, P. J. Org. Chem. 2001, 66, 8478. JØrgensen, K. A. Eur. J. Org. Chem. 2004, 2093. (Review). Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (Review). Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668. (Review). 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 3,4disubstituted phenols. O

OH H+ R

R R H+

H

R

OH

O

:

O

OH

1,2-alkyl H

H+ H

shift

R

R R

R R

R

R R

Example 14

O

O O

O

50% aq. H2SO4 reflux, 80% HO

O Example 25

OH

O HO

conc. H2SO4

HO

Et2O, 95% References 1. 2.

Shine, H. J. In Aromatic Rearrangements; Elsevier: New York, 1967, pp 55ҟ68. (Review). Schultz, A. G.; Hardinger, S. A. J. Org. Chem. 1991, 56, 1105.

203

3. 4.

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1992, 114, 1824. 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-S-methane rearrangement Conversion of 1,4-dienes to vinylcyclopropanes under photolysis. Also known as the Zimmerman rearrangement. R R1 R 4

R R 1,4-diene

2

R

hQ

R

2

R4

3

R1 R3

vinylcyclopropane

R R1

R R1 R

4

R R

2

R2

hQ

3

4

R R diradical

R R1 R2 4

R R diradical

R2

3

3

R

R1

R4

R3

Example 19

CN

CN

hQ, acetone CN 90% CN Example 2, aza-S-methane rearrangement2

hQ, acetophenone Ph

N OAc Ph

benzene, 86%

Ph Ph

N

OAc

205

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

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. Armesto, D.; Horspool, W. M.; Langa, F.; Ramos, A. J. Chem. Soc. Perkin Trans. I 1991, 223. Zimmerman, H. E.; Armesto, D. Chem. Rev. 1996, 96, 3065. (Review). Janz, K. M.; Scheffer, J. R. Tetrahedron Lett. 1999, 40, 8725. Zimmerman, H. E.; Církva, V. Org. Lett. 2000, 2, 2365. Tu, Y. Q.; Fan, C. A.; Ren, S. K.; Chan, A. S. C. J. Chem. Soc., Perkin 1 2000, 3791. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Chem. Commun. 2000, 2341. Ihmels, H.; Mohrschladt, C. J.; Grimme, J. W.; Quast, H. Synthesis 2001, 1175. Ünaldi, N. S.; Balci, M. Tetrahedron Lett. 2001, 42, 8365. Altundas, R.; Dastan, A.; Ünaldi, N. S.; Güven, K.; Uzun, O.; Balci, M. Eur. J. Org. Chem. 2002, 526. Zimmerman, H. E.; Chen, W. Org. Lett. 2002, 4, 1155. Tanifuji, N.; Huang, H.; Shinagawa, Y.; Kobayashi, K. Tetrahedron Lett. 2003, 44, 751. Singh, V.; Vedantham, P.; Sahu, P. K. Tetrahedron 2003, 60, 8161. 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.

CO2H O N

CO2H

NH2 OHC

O H

OH2

H2O

:

:

NH2

H

N H H

O

H+ O

CO2H

CO2H

N H

N H B:

HO CO2H H

H2O CO2H H

H+ N

N H

H

CO2H

CO2H

air oxidation

H2O N H

2 H

N

207

Example 12

H

O

MeO NH2

NO2

O

CO2H

CO2H MeO EtOH, ', 95%

NO2

N Example 26

H

O NH2

O

CO2H

CO2H EtOH, reflux 3 h, 20%

N

References 1.

2. 3. 4.

5. 6. 7. 8.

Doebner, O. G. Justus Liebigs Ann. Chem. 1887, 242, 265. Oscar Gustav Doebner (18501907) was born in Meiningen, Germany. After studying under Liebig, he actively took part in the Franco-Prussian War. He apprenticed with Otto and Hofmann for a few years after the war, then began his independent researches at the University at Halle. Mathur, F. C.; Robinson, R. J. Chem. Soc. 1934, 1520. Allen, C. F. H.; Spangler, F. W.; Webster, E. R. J. Org. Chem. 1951, 16, 17. 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. 2529. (Review). Jones, G. in Chemistry of Heterocyclic Compounds, Jones, G., ed.; John Wiley & Sons, Inc.: New York, 1977, Vol. 32; Quinolines, pp. 125131. (Review). Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396. Herbert, R. B.; Kattah, A. E.; Knagg, E. Tetrahedron 1990, 46, 7119. Pflum, D. A. Doebner Quinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 407410. (Review).

208

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

OH OR (OC)5Cr

RL 1

RS

'

2

R

2

R

RL

R1

RS

R

OR OR

OR

CO

(OC)5Cr R1

alkyne

(OC)4Cr R1

R2

R2

RS OR

(OC)4Cr R1

R

alkyne insertion

OR

R3

RL

R2

2

R1 OR electrocyclic

O C

RS

ring closure

RL OC

Cr CO CO OH

O 2

2

R

RL

R1

RS OR

RS

Cr CO OC OC CO

R CO insertion

coordination

R1

2

RL

Cr(CO)3

Cr(CO)3

RL

R tautomerization

R1

RS OR

Cr(CO)3

209

Example 17

OMe

NO2

(OC)5Cr

Se

O 1. THF, reflux

Se NO2

2. CAN, 22% O Example 211

BnO Cr(CO)5

MOMO BnO

MeO

OMOM OH

OMe

THF, 50 oC, 61% MeO OMe

References Dötz, K. H. Angew. Chem., Int. Ed. 1975, 14, 644. Karl H. Dötz (1943) was a professor 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 carbenemediated benzannulation reaction. In Computational Modeling of Homogeneous Catalysis Maseras, F.; Lledós, A. eds.; Kluwer Academic: Boston; 2002, 269287. (Review). 10. Pulley, S. R.; Czakó, B. Tetrahedron Lett. 2004, 45, 5511. 11. White, J. D; Smits, H. Org. Lett. 2005, 7, 235. 1.

210

DowdBeckwith ring expansion Radical-mediated ring expansion of 2-halomethyl cycloalkanones.

O

Br CO2CH3

PhH, reflux

CO2CH3

' NC

O

Bu3SnH, AIBN

N N

CN

homolytic cleavage

N2n

2

CN

2,2’-azobisisobutyronitrile (AIBN)

n-Bu3Sn H

n-Bu3Sn

CN SnBu3

O

O Bu3SnBr

Br

H

CO2CH3

CO2CH3

O

O

H SnBu3

CO2CH3

CO2CH3

O Bu3Sn CO2CH3

CN

211

Example 19

H 1.2 eq. Bu3SnH, cat. AIBN O

H CO2Et

Tol., reflux, 23 h

I H

H O H CO2Et 86%

O

H CO2Et H

13%

References 1. 2.

3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3493. Paul Dowd (19361996) was a professor at the University of Pittsburgh. 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 Adelaide, Adelaide, Australia. Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem. Soc. 1988, 110, 2565. Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77. Dowd, P.; Choi, S.-C. Tetrahedron Lett. 1989, 30, 6129. Dowd, P.; Choi, S.-C. Tetrahedron 1991, 47, 4847. Bowman, W. R.; Westlake, P. J. Tetrahedron 1992, 48, 4027. Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091. (Review). Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525. Wang, C.; Gu, X.; Yu, M. S.; Curran, D. P. Tetrahedron 1998, 54, 8355. Hasegawa, E.; Kitazume, T.; Suzuki, K.; Tosaka, E. Tetrahedron Lett. 1998, 39, 4059. Hasegawa, E.; Yoneoka, A.; Suzuki, K.; Kato, T.; Kitazume, T.; Yanagi, K. Tetrahedron 1999, 55, 12957. Studer, A.; Amrein, S. Angew. Chem., Int. Ed. 2000, 39, 3080. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317. (Review). Sugi, M.; Togo, H. Tetrahedron 2002, 58, 3171. Ardura, D.; Sordo, T. L. Tetrahedron Lett. 2004, 45, 8691.

212

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

Ac2O

HN R1

N

CO2H O

R1

O

O

AcO O HN R1

N

O

O O O

H

O R1

H

O O O

O

mixed anhydride N R1

2 AcOH

O

O

Example14

O HN Ph

CO2H

H

O

O O

NaOAc, Ac2O

O N

110 oC, 6973%

Ph

O

O

O

References 1. 2.

3. 4.

Plöchl, J. Ber. Dtsch. Chem. Ges. 1884, 17, 1616. Erlenmeyer, E., Jr. Ann. 1893, 275, 1. Emil Erlenmeyer, Jr. (18641921) was born in Heidelberg, Germany to Emil Erlenmeyer (18251909), a famous chemistry professor at the University of Heidelberg. He investigated the ErlenmeyerPlöchl azlactone synthesis while he was a Professor of Chemistry at Strasburg. Carter, H. E. Org. React. 1946, 3, 198239. (Review). Baltazzi, E. Quart. Rev. Chem. Soc. 1955, 9, 150. (Review).

213

5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Filler, R.; Rao, Y. S. New Development in the Chemistry of Oxazolines, In Adv. Heterocyclic Chem; Katritzky, A. R. and Boulton, A. J., Eds; Academic Press, Inc: New York, 1977, Vol. 21, pp. 175206. (Review). Kumar, P.; Mishra, H. D.; Mukerjee, A. K. Synthesis 1980, 10, 836. Mukerjee, A. K.; Kumar, P. Heterocycles 1981, 16, 1995. (Review). Mukerjee, A. K. Heterocycles 1987, 26, 1077. (Review). Cornforth, J.; Ming-hui, D. J. Chem. Soc. Perkin Trans. I 1991, 2183. Ivanova, G. G. Tetrahedron 1992, 48, 177. Combs, A. P.; Armstrong, R. W. Tetrahedron Lett. 1992, 33, 6419. Monk, K. A.; Sarapa, D.; Mohan, R. S. Synth. Commun. 2000, 30, 3167. Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L. J. Fluorine Chem. 2002, 115, 27. Buck, J. S.; Ide, W.S. Org. Synth. Coll. 1943, 2, 55. Brooks, D. A. ErlenmeyerPlöchl Azlactone Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 229233. (Review).

214

EschenmoserTanabe fragmentation Fragmentation of DE-epoxyketones via the intermediacy of DE-epoxy sulfonylhydrazones.

O 1. H2O2, OH +

2. H2NNHSO2Ar, H 3. OH

O 

O OH O

OH O O



O

O

H2NNHSO2Ar, H+ N



O

O

O



OH N

N SO2Ar H

N SO2Ar

O 

SO2Ar

N

N2n

N SO2Ar

Example 14

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

rt, 5 h, 73%

215

O

AcO Example 27

Me

Me 1. TsNHNH2, rt O

O

Me

2. 55 oC, 2 h, 50%

O

Me

References Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708. 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. 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.

1. 2.

216

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

HCO2H

CH2O

R NH2

formic acid is the hydrogen source as a reducing agent H

O

OH

H

R N

:

H

OH2

H+ R N

H

R NH2

H

H

H O C On

H

H

R NH

:

H+

O

:

R N H O

O

OH2

R N

O C On

H O

R N H O

R N H

H+

R N

Example 17

O N H

Pd/C/Na2SO4, H2 40 bar N

O EtOAc, 100 oC, 98%

O

217

Example 211

O H3C

NH CH3

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

O H3C

CD3 N CH3

d3-tamoxifen References Eschweiler, W. Chem. Ber. 1905, 38, 880. Wilhelm Eschweiler (18601936) 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 (18871927) 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. 1

218

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

O

O N

1. Bu2BOTf, R3N

O

O

O

Ph

N

O

2. PhCHO, 78 oC

Bu Bu B O O

Bu2B OTf O

O N

PhCHO

Z-(O)-boron enolate O

N

O

formation

H R3N:

Bu O O

O N

H Bu

aldol

B

condensation

H O

H

Bu B

Ph Bu

O

O N

O Ph

OH

workup

Ph

O

O N

O

Example 17

MeO

O

O N

N OMe CO2Me

O

O

219

O

O

TiCl4, DIPEA o

CH2Cl278 C, 1.5 h

N MeO2C

N

O

then rt, overnight, 52% OMe Example 213

S O

O

O

N OBn

OTES

Bn S

1 eq. Bu2BOTf, 1.1 eq. Et3N O

O

OTES

N

PhMe, 0.15 M, 50 to 30 oC 2 h, 72%

OH

OBn Bn

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

Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127. David Evans is a professor at Harvard University. Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981, 103, 2876. Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996, 37, 8023. Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3. (Review). Braddock, D. C.; Brown, J. M. Tetrahedron: Asymmetry 2000, 11, 3591. Lu, Y.; Schiller, P. W. Synthesis 2001, 1639. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411. Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem 2001, 66, 8463. Matsushima, Y.; Itoh, H.; Nakayama, T.; Horiuchi, S.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin 1 2002, 949. Guerlavais, V.; Carroll, P. J.; Joullié, M. M. Tetrahedron: Asymmetry 2002, 13, 675. Hein, J. E.; Hultin, P. G. Synlett 2003, 635. Li, G.; Xu, X.; Chen, D.; Timmons, C.; Carducci, M. D.; Headley, A. D. Org. Lett. 2003, 5, 329. 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 D-haloketones to esters, carboxylic acids, or amides via alkoxide-, hydroxide-, or amine-catalyzed rearrangements, respectively.

O

O Cl



OR

OR

enolizable D-haloketone

O

O H 

Cl

Cl HOR

OR O



OR

O

OR

Cl

cyclopropanone intermediate

O

OR H OR

O

OR

HOR



OR

Example 1, homo-Favorskii rearrangement3

TsO

O

1.96 eq. NaOH

O

O H

dioxane/H2O 90 oC, 3 h, 86%

51:40:9

O

221

Quasi-Favorskii rearrangement

O

OH

OH

O

Br non-enolizable ketone

CO2H

Br

Example 111

Li Br O

THF, 78 to 30 oC, 90%

O

References Favorskii, A. E. J. Prakt. Chem. 1895, 51, 533. Aleksei E. Favorskii (18601945), born in Selo Pavlova, Russia, studied at St. Petersburg State University, where he became 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, 286291. (Review). 5. Barreta, A.; Waegell, B. In Reactive Intermediates; Abramovitch, R. A., ed.; Plenum Press: New York, 1982, 2, pp 527585. (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 rearrangement). 1.

222

Feist–Bénary furan synthesis D-Haloketones react with E-ketoesters in the presence of base to fashion furans. O

O Cl

OEt

Et3N:

O

Et3N, 0 °C, 52 h

O

CO2Et

5457%

Et3N H CO2Et

H

O

O

rate-determining

CO2Et

Cl

step

O

OH CO2Et H

Cl O

HO

:NEt3

CO2Et

Et3N H

H2O

O

:

O

CO2Et H

CO2Et

O

O

Et3N: Example 14,5

O O

O + OEt Cl

KOH, MeOH

OCH3

O H3CO2C

O OCH3

57% O Example 26

CO2Et

223

O

O H

O Cl +

O

pyridine, rt to 50 °C, 4 h OEt then rt, overnight, 86%

CO2Et

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

8. 9.

10.

11. 12. 13.

Feist, F. Ber. Dtsch. Chem. Ges. 1902, 35, 1537. Bénary, E. Ber. Dtsch. Chem. Ges. 1911, 44, 489. Bisagni, É.; Marquet, J.-P.; André-Louisfert, J.; Cheutin, A.; Feinte, F. Bull. Soc. Chim. Fr. 1967, 2796. Gopalan, A.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 1756. Gopalan, A.; Magnus, P. J. Org. Chem. 1984, 49, 2317. Padwa, A.; Gasdaska, J. R. Tetrahedron 1988, 44, 4147. 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, 167238. (Review). Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth. Commun. 1990, 20, 1923. 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, 351393. (Review). König, B. Product Class 9: Furans. In Science of Synthesis: HoubenWeyl Methods of Molecular Transformations; Maas, G., Ed.; Georg Thieme Verlag: New York, 2001; Cat. 2, Vol. 9, 183278. (Review). Calter, M.; Zhu, C. Org. Lett. 2002, 4, 205. Calter, M.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209. Shea, K. M. Feist–Bénary Furan Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 160167. (Review).

224

Ferrier carbocyclization This process (also known as the “Ferrier II Reaction”) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry.1,2 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 cyclopentanes 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 refluxing aqueous acetone afforded the unstable hemiacetal 2 from which aldehydoketone 3 and hence the hydroxyketone 4 were formed spontaneously, the latter crystallizing 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 reported 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: HgCl

HgCl O

BzO BzO

HgCl2, Me2CO, H2O reflux, 4.5 h

TsO OMe

O+

BzO BzO

TsO OMe

1

HgCl

O

HO O OMe Ts 2

O BzO BzO

BzO BzO

BzO BzO

O

BzO BzO

O O Ts O 3

OBz

OBz

BzO BzO

BzO BzO BzO 4 OH 93%

OBz O OMe

O BzO BzO

4

O OBz 83%6 OH

TsO OH

BzO

83%3

O

BzO BzO OMe O OH BzO OBz

80%6

225

More complex products

O

BzO

AcO OMe AcO

O

O

BzO AcO

O

AcO OMe

OMe

O

OC6H4OMe(p) O

O

BzO

BzO AcO

OH OAc

O

OAc

83%7

O AcO OH 75%7

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

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

O O

H NH

O OH O

Paniculide A9

OH

O BnO OMe

a,b

H c BnO BnO

O BnO OMe

d

HO HO

OH

NH

HO 11

10

Pancratistatin

Modified hex-5-enopyranosides and reactions OAc

BnO BnO

HO

H

Calystegine B2

HO OAc BnO BnO BnO OH 85%

14

BnO BnO

HO O Bn OMe 79%13 O

BnO BnO

BnO OMe 13 98% a, Hg(OCOCF3)2, Me2CO, H2O, 0 oC; b, NaBH(OAc)3, AcOH, MeCN, rt; c, iBu3Al, PhMe, 40 °C; d, Ti(Oi-Pr)Cl3, CH2Cl2, –78 °C, 15 min. (Note: The aglycon is retained in the Al- and Ti-induced reactions).

226

References 1. 2. 3.

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

Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 27792831. (Review). Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277291 (Review). 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 Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand. Blattner, R.; Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. 1, 1985, 2413. Chida, N.; Ohtsuka, M.; Ogura, K.; Ogawa, S. Bull. Chem. Soc. Jpn. 1991, 64, 2118. Machado, A. S.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1985, 135, 231. Sato, K.-i.; Sakuma, S.; Nakamura, Y.; Yoshimura, J.; Hashimoto, H. Chem. Lett. 1991, 17. Ermolenko, M. S.; Olesker, A.; Lukacs, G. Tetrahedron Lett. 1994, 35, 711. Amano, S.; Takemura, N.; Ohtsuka, M.; Ogawa, S.; Chida, N. Tetrahedron 1999, 55, 3855. Park, T. K.; Danishefsky, S. J. Tetrahedron Lett. 1995, 36, 195. Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50, 10443. Das, S. K.; Mallet, J.-M.; Sinaÿ, P. Angew. Chem. Int. Ed. Engl. 1997, 36, 493. Sollogoub, M.; Mallet, J.-M.; Sinaÿ, P. Tetrahedron Lett. 1998, 39, 3471. Bender, S. L.; Budhu, R. J. J. Am. Chem. Soc. 1991, 113, 9883. 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 2,3unsaturated glycosyl products.1,2 This allylic transformation has been termed the “Ferrier Reaction” or, to avoid complications, the “Ferrier I Reaction” or the “Ferrier Rearrangement”. However, the reaction was first noted by Emil Fischer when he heated tri-O-acetyl-D-glucal in water.3 When carbon nucleophiles are involved, the term “Carbon Ferrier Reaction” has been used,4 although the only contribution the Ferrier group made in this area was to find that tri-O-acetyl-D-glucal dimerizes under acid catalysis to give a C-glycosidic product.5 The general reaction is illustrated by the separate conversions of tri-O-acetyl-D-glucal with O-, S- and Cnucleophiles to the corresponding 2,3-unsaturated glycosyl derivatives. Normally, Lewis acids are used as catalysts, boron trifluoride etherate being the most common. Allyloxycarbenium ions are involved as intermediates, high yields of products are obtained, and glycosidic compounds with quasi-axial bonds (as illustrated) predominate (commonly in the Į,ȕ-ratio of about 7:1). The examples illustrated4,6,7 are typical of a very large number of literature reports.1

i) HOCH2CCH6 AcO AcO AcO

ii) HSPh7 + Lewis acid

O

+

AcO

O

4

OAc

iii)

R = i) OCH2CCH6

OAc O

ii) SPh7 iii)

AcO

4

R

General examples4

OAc AcO AcO

SnBr4, C6H14, EtOAc

O rt, 5 min, 94% OAc AcO

O

H

228

More complex products made directly from the corresponding glycols: O

OH

O OH

OMe O

AcO

OH O AcO

O O

NHC(O)CCl3

By spontaneous sigmatropic

In PhCOCH2CO2Et,

rearrangement of the glycal

In benzene, BF3.OEt2, BF3.OEt2, rt, 15 min, 5 oC, 10 min, (67%,

3-trichloroacetimidate made with NaH, Cl3CCN,

(81% D-anomer).9

D-anomer).8

O

Ph

EtO

O

O O

OAc O

(78% Danomer).10

Products formed without acid catalysts

HO

OO

OO

OMe AcO

Promoter: DEAD, Ph3P D-anomer)11

DDQ (88%, mainly D)12

C-3 leaving group of glycal: acetoxy hydroxy

O O

O O

O O

O

O O

N-iodonium dicollidine perchlorate (65%, mainly D)13 pent-4-enoyloxy

229

Modified glycals and their reactions: OH OBn O OBn + Ph

O

I O

OBn O BnO

O o

BF3•OEt2, CH2Cl2, 0 C

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

N Cl

O

(70%, mainly D 14 References

N

N

N

Ph

O

2. 3. 4.

N H

O OAc

N +

BnO

1.

Me

O

N H

N

AgNO3, Na2CO3, reflux MeNO2, 15 6 h (58%, DE 

Ferrier, R. J.; Zubkov, O. A. Transformation of glycals into 2,3-unsaturated glycosyl derivatives, In Org. React. 2003, 62, 569736. (Review). It was almost 50 years after Fischer’s seminal finding that water took part in the reaction3 that Ann Ryan, working in George Overend’s Department in Birkbeck College, University of London, found, by chance, that p-nitrophenol likewise participates.16 Robin Ferrier, her immediate supervisor, who suggested her experiment, then found that simple alcohols at high temperatures also take part,17 and with other students, notably Nagendra Prasad and George Sankey, he explored the reaction extensively. They did not apply it to make the very important C-glycosides. Ferrier, R. J. Top. Curr. Chem. 2001, 215, 175. (Review). Fischer, E. Chem. Ber. 1914, 47, 196. Herscovici, J.; Muleka, K.; Boumaïza, L.; Antonakis, K. J. Chem. Soc., Perkin Trans. 1 1990, 1995. Ferrier, R. J.; Prasad, N. J. Chem. Soc. (C) 1969, 581. Moufid, N.; Chapleur, Y.; Mayon, P. J. Chem. Soc., Perkin Trans. 1 1992, 999. Whittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D. J. Org. Chem. 1990, 55, 1979. Klaffke, W.; Pudlo, P.; Springer, D.; Thiem, J. Liebigs Ann. Chem. 1991, 509. Yougai, S.; Miwa, T. J. Chem. Soc., Chem. Commun. 1983, 68. Armstrong, P. L.; Coull, I. C.; Hewson, A. T.; Slater, M. J. Tetrahedron Lett. 1995, 36. 4311. Sobti, A.; Sulikowski, G. A. Tetrahedron Lett. 1994, 35. 3661. Toshima, K.; Ishizuka, T.; Matsuo, G.; Nakata, M.; Kinoshita, M. J. Chem. Soc., Chem. Commun. 1993, 704. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 3851. Booma, C.; Balasubramanian, K. K. Tetraherdron Lett. 1993, 34, 6757. Tam, S. Y.-K.; Fraser-Reid, B. Can. J. Chem. 1977, 55, 3996. Ferrier, R. J.; Overend, W. G.; Ryan, A. E. J. Chem. Soc. (C) 1962, 3667. Ferrier, R. J. J. Chem. Soc.1964, 5443.

230

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

O MeO2C

HS

CO2Me

OMe CO2Me

NaOMe

OH

S MeO2C O

O

MeO2C

O

OCH3

+

S

O S

HS

OMe

OMe

H3CO O

OMe O

MeO2C

OMe

MeO2C

S S

S MeO2C

O S

O

MeO2C

OMe CO2Me

OMe

OMe O H

O HS

MeO OMe MeO2C

O

S S

OMe CO2Me

NaOMe

231

OCH3 O

CO2Me O O

S

S S

OMe

OMe

MeO2C S CO2Me

CO2Me

MeO2C

H

CO2Me HOMe

O

S

OMe

H

MeO2C S

CO2Me MeO

H

CO2Me

CO2Me

OH

S

O

S

MeO2C

MeO2C Example 16

O N

HS

Cl

N OEt

NaH, DMSO, 89%

CN

S CO2Et NH2

Example 28

HSCH2CO2Me CN

NaOMe, 68%

S

CO2Me NH2

References 1.

2.

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. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., Ed.; Wiley & Sons: New York, 1985, 88125. (Review).

232

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.; Conroy, 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, 184192. (Review). 3.

233

Fischer indole synthesis Cyclization of arylhydrazones to indoles.

R1

1

R

2

N H

H

R

NH2

N

N H phenylhydrazone

O

phenylhydrazine

2

2

R

R

N H protonation

H

NH2 N H ene-hydrazine

N +

H

R1

N H

NH3

[3,3]-sigmatropic rearrangement

R1 2

R N H

R2

tautomerization

NH2

N H2

H+ double imine R1 H N H H

2

R

R1

R1

H

R1

R2

NH2

R1

R1 H R2

R2

NH2

NH3

N H

NH3

R2 N H

Example 18,12

O O N N H

Ph + N

N H

NH2

234

N HN

1) neat, 160 oC, 24 h 2) NH2NH2, 120 oC, 12 h

N

71% N H

Example 213

O AcOH, '5 h NH

NH2

CN CO2Et

N H

57%

CN CO2Et

References Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241. H. Emil Fischer (18521919) 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, 373401. (Review). 5. Robinson, B. Chem. Rev. 1969, 69, 227250. (Review). 6. Ishii, H. Acc. Chem. Res. 1981, 14, 275283. (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 Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 100103. (Review). 1.

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.

OH R1

R2

ether R2CHO

CN

O N

HCl

H2O

R1

H OH

H+

R1

R1

Cl

Cl

R1

HCl

H O

R2

R2

O

SN2

N

H2O

R2 N

HO

NH

R1

Cl

R2

H O

:

O OH

N

HCl

H

N

R1

Cl

Cl R2

H

isomerization

R1

O

N

R2

elimination

O

HCl

Cl

N

R1

Example 16

OH

TsOH, Tol. NH2

H3C

CHO

O

reflux

POCl3, 8085 oC

O

O

CH3

HN

15 min., 40% O

N

CH3

236

Example 210

OH

Cl dry HCl gas

NH

CN SOCl2, ether

HO

Cl

HO

N

N

O

CHO dry HCl gas, 16.5%

N

OH

halfordinal References Fischer, E. Ber. 1896, 29, 205. Ingham, B. H. J. Chem. Soc. 1927, 692. 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, 401442. (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, 309312. (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, 234236. (Review). 1. 2. 3.

237

FlemingKumada oxidation Stereoselective oxidation of alkyl-silanes into the corresponding alkyl-alcohols using peracids.

1. HX 2. ArCO3H, base

SiMe2Ph R1

R

R R1 retention of configuration

3. hydrolysis

H

ipso

H :O 1

R

:

R

Ar

Ar O

HX

Si

O

O

O

ArCO2

H

O O

O R1

R H O

Si

X

R R1 the E-carbocation is stabilized by the silicon group

R

Si

R

substitution

1

R

X

Si

H+

O

Ar

Si

O 1

R

R

O

O

Ar O

R

O

ArCO2

:

Si

OH

O Si R O

O Si O R

O

Ar O

O

O 1

O

1

O O

Si

O

R

R

R1

Ar

R1

O O

Ar

238

O

HO O hydrolysis

O Ar O Si O O OH

O Ar O Si O O

R1

R

R1

R O HO

Ar

OH

O R

R1

R

1

R

Example 17

C8H18

O

O

OH O

m- CPBA, KHF2, DMF

NBoc

0 to 25 oC, 5570%

(EtO)2 PhSi OTBS

C8H18

O

O

OH O NBoc

HO OTBS Example 212

MeO2C

CO2Me

SiMe2(OMe)

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

MeO2C

OH

CO2Me

239

TamaoKumada oxidation15 Oxidation of alkyl fluorosilanes to the corresponding alcohols. A variant of the FlemingKumada oxidation.

F F Si R R

F F

F

R

R

: O

F

H

2 ROH

KHCO3, DMF F

F

R Si F R F

Si

KF, H2O2

H

R

R Si F R O F HO H

F R

F

HO H

O

F

F O Si R

O

Si

F

F R

O Si R

F

F O

2 ROH

R

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem. Commun. 1984, 29. Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229. Fleming, I.; Dunoguès, J.; Smithers, R. Org. React. 1989, 37, 57576. (Review). Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599. Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 1112. Knölker, H.-J.; Jones, P. G.; Wanzl, G. Synlett 1997, 613. 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. Lee, T. W.; Corey, E. J. Org. Lett. 2001, 3, 3337. Rubin, M.; Schwier, T.; Gevorgyan, V. J. Org. Chem. 2002, 67, 1936. Boulineau, F. P.; Wei, A. Org. Lett. 2002, 4, 2281. Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68, 2572. Clive, D. L. J.; Cheng, H.; Gangopadhyay, P.; Huang, X.; Prabhudas, B. Tetrahedron 2004, 60, 4205. Sanganee, M. J.; Steel, P. G.; Whelligan, D. K. Org. Biomol. Chem. 2004, 2, 2393. Ko, C. H.; Jung, D. Y.; Kim, M. K.; Kim, Y. H. Synlett 2005, 304. 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.

O R

O Cl

R

HCl

AlCl3 O AlCl3 R

O:

complexation R

Cl:

Cl

O

O

electrophilic

R

AlCl4

AlCl3

substitution

R acylium ion

Cl Cl Al Cl Cl

O

aromatization H

O

R

HCl

AlCl3

R

Example 116

F O

F

O

F

Cl N

CHO

AlCl3, CH2Cl2 88%

F

N

CHO

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.

R

AlCl3

R

Cl: Cl Cl Al Cl Cl H

Cl

AlCl3

AlCl4

R

R aromatization R

HCl

alkyl cation Example 27

O O

O Br

O O SnCl4, CH2Cl2 0 oC, 1 h, 84%

O

O

O

References 1.

Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392. Charles Friedel (18321899) 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 (18391917) was born in Boston, Massachusetts. He studied under Bunsen and Wurtz in his youth and became a professor at Cornell and MIT. From 1874 to 1891, Crafts collaborated with Friedel at École de Mines in Paris, where they discovered the Friedel–Crafts reaction. He returned to MIT

242

2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

12. 13. 14. 15. 16.

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 acidcatalyzed alkylations and acylations and published more than 50 papers and patents on the Friedel–Crafts reaction, which has become one of the most useful organic reactions. Pearson, D. E.; Buehler, C. A. Synthesis 1972, 533. Gore, P. H. Chem. Ind. 1974, 727. Chevrier, B.; Weiss, R. Angew. Chem., Int. Ed. Engl. 1974, 13, 1. Schriesheim, A.; Kirshenbaum, I. Chemtech 1978, 8, 310314. (Review). Hermecz, I.; Mészáros, Z. Adv. Heterocyclic Chem. 1983, 33, 241. Patil, M. L.; Borate, H. B.; Ponde, D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahedron Lett. 1999, 40, 4437. Ottoni, O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005. Fleming, I. Chemtracts: Org. Chem. 2001, 14, 405. (Review). Metivier, P. Friedel-Crafts Acylation In Friedel-Crafts Reaction Sheldon, R. A.; Bekkum, H. eds., Wiley-VCH: New York. 2001, pp161172. (Review). Meima, G. R.; Lee, G. S.; Garces, J. M. Friedel-Crafts Alkylation In FriedelCrafts Reaction Sheldon, R. A.; Bekkum, H. eds. Wiley-VCH: New York. 2001, pp550556. (Review). Le Roux, C.; Dubac, J. Synlett 2002, 181. Sefkow, M.; Buchs, J. Org. Lett. 2003, 5, 193. Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. Engl. 2004, 43, 550556. (Review). Fakhraian, H.; Zarinehzad, M.; Ghadiri, H. Org. Prep. Proced. Int. 2005, 37, 377. 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 D-amino aldehyde or ketone with another aldehyde or ketone with at least one methylene D adjacent to the carbonyl to furnish a substituted quinoline. The reaction can be promoted by acid, base, or heat.

CHO

O R

R1

NH2

N

R1

O

O R

R

OH

R O

R1 H

R1

Aldol condensation

H HO

NH2 OH

R OH

R1 NH2O

:

R H COR1 NH2

R R N H

OH R1

N

R1

HO Example 15

CHO NH2

NBn O

NaOMe, EtOH reflux, 3 h, 90%

NBn N

244

Example 215

H

O

N

O

AcOH, 100 °C

N

N

O

O 88% NHBoc

OBn

OBn

References 1.

2.

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

Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572. Paul Friedländer (18571923), born in Königsberg, Prussia, apprenticed under Carl Graebe and Adolf von Baeyer. He was interested in music and was an accomplished pianist. 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). Jones, G. in Heterocyclic Compounds, Quinolines, vol. 32, 1977; Wiley & Sons: New York, 181–191. (Review). Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37. (Review). Shiozawa, A.; Ichikawa, Y.-I.; Komuro, C.; Kurashige, S.; Miyazaki, H.; Yamanaka, H.; Sakamoto, T. Chem. Pharm. Bull. 1984, 32, 2522. Thummel, R. P. Synlett 1992, 1. Riesgo, E. C.; Jin, X.; Thummel, R. P. J. Org. Chem. 1996, 61, 3017. Mori, T.; Imafuku, K.; Piao, M.-Z.; Fujimori, K. J. Heterocycl. Chem. 1996, 33, 841. Ubeda, J. I.; Villacampa, M.; Avendaño, C. Synthesis 1998, 1176. Bu, X.; Deady, L. W. Synth. Commun. 1999, 29, 4223. Strekowski, L.; Czarny, A.; Lee, H. J. Fluorine Chem. 2000, 104, 281. 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. Gladiali, S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M.-A.; Thummel, R. P. J. Org. Chem. 2001, 66, 400. Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101; and 2002, 4, 1243. Henegar, K. E.; Baughman, T. A. J. Heterocycl. Chem. 2003, 40, 601. 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. Pflum, D. A. Friedländer Quinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 411415. (Review).

245

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

OH

O O

OH O R

AlCl3

R

and/or O

R

AlCl3 Cl3Al

O: O

R

complexation

O

O

CO bond

R

AlCl3

O

O

fragmentation

R

aluminum phenolate, acylium ion

O

H+

AlCl3

O O

H

OH O

O

R

R

R

O

O

AlCl3

R

H+

OH

O

H R

O

O

R

246

Example 111

Br OH O

OH

ZrCl4, PhCl

OMe O Br

O

160 oC, 3 h, 63%

Br

Br

Example 212

O O

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

OAc

OAc

References 1.

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

Fries, K.; Finck, G. Ber. Dtsch. Chem. Ges. 1908, 41, 4271. Karl Theophil Fries (18751962) was born in Kiedrich near Wiesbaden on the Rhine. He earned his doctorate under Theodor Zincke. Although G. Finck co-discovered the rearrangement of phenolic esters, somehow his name has been forgotten by history. In all fairness, the Fries rearrangement should really be the FriesFinck rearrangement. Martin, R. Bull. Soc. Chim. Fr. 1974, 983988. (Review). Martin, R. Org. Prep. Proced. Int. 1992, 24, 369-435. (Review). Trehan, I. R.; Brar, J. S.; Arora, A. K.; Kad, G. L. J. Chem. Educ. 1997, 74, 324. Boyer, J. L.; Krum, J. E.; Myers, M. C.; Fazal, A. N.; Wigal, C. T. J. Org. Chem. 2000, 65, 4712. Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 1979. Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G. Eur. J. Org. Chem. 2001, 2221. Kozhevnikova, E. F.; Derouane, E. G.; Kozhevnikov, I. V. Chem. Commun. 2002, 1178. Clark, J. H.; Dekamin, M. G.; Moghaddam, F. M. Green Chem. 2002, 4, 366. Sriraghavan, K.; Ramakrishnan, V. T. Tetrahedron 2003, 59, 1791. Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem. 2004, 69, 8982. Ollevier, T.; Desyroy, V.; Asim, M.; Brochu, M.-C. Synlett 2004, 2794. 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-dinitrobenzenesulfonyl chloride and an alcohol. Also known as FukuyamaMitsunobu procedure.

SO2Cl NO2

1. R1NH2, pyr.

S

2

2. R OH, PPh3, DEAD 1

R

R2

SO2

3. HSCH2CO2H

NO2

:

R1NH2

H N

CO2H NO2

NO2 Cl SO2 NO2

SO2NHR1 2 NO2 R OH, PPh3

H+

SO2NR1R2 NO2

DEAD NO2

NO2

NO2 See page 390 for mechanism of the Mitsunobu reaction.

H

S

:

CO2H 1 2

SO2NR R NO2

SNAr

HO2C

NR1R2 S SO2 NO2 +

H

NO2 Meisenheimer complex

NO2

S 1

R

H N

CO2H NO2 SO2

R2 NO2

248

Example 19

H2N OH

SO2 NO2

PyPh2P, DTBAD CH2Cl2, 84%

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

HN

K2CO3, PhSH

SO2 NO2

CH3CN, 80%

NH2

References Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. Tohru Fukuyama 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. 1.

249

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

Et3SiH, Pd/C

O R

SEt

O R

THF, rt

H

Path A:

O R

O

Pd(0) SEt

O R

R

oxidative addition

Pd

Et3Si

SEt

O

reductive Pd

Et3SiH

SEt

Pd(0)

H

R

elimination

H

Path B:

O R

Et3SiPdH

Pd(0)

Et3SiH

OSiEt3

Et3SiPdH R

SEt

Pd

SEt H

OSiEt3 R

SEt

Pd(0) O

Et3Si

SEt

R

H

Example 11

CO2Me

CO2Me O

O Et3SiH, 10% Pd/C O

O

COSEt

acetone, rt, 92%

O

O

CHO

250

Example 23

HO2C

EtSH, DCC, DMAP EtS CO2Me O NHBoc CH3CN, rt, 1 h, > 70% Et3SiH, 10% Pd/C acetone, rt, 30 min., >74%

H O

CO2Me NHBoc

CO2Me NHBoc

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

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

O N

1. RX K

CO2H

2. OH

O O N

CO2H H2N R

+

SN2

K+

OH

O

R X

hydrolysis

N R

O

O

O

OH

O

O H N

N R O

CO2 H N O OH

O

OH

H

R OH CO2

R

H2N R CO2

252

Example 110

O

O

Br

NK

CO2Et

CO2Et N

o

DMF, 90 C, 3 h, 77% O

O O

O N O

O



O

O 6 M HCl, reflux 14 h, 93%

O HCl•H2N

OH

References Gabriel, S. Ber. Dtsch. Chem. Ges. 1887, 20, 2224. Siegmund Gabriel (18511924), 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. 1.

253

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

O

O 1. RX

K+

N

NH NH

H2N R 2. NH2NH2

O

O O

O

R X

N

SN2

K+

:NH2NH2

N R

O

O O

O

NHNH2

:

NHNH2

N R O

O O

NH R O

NH NH

NH NH

H2N R

O NH R

O

Example6

NH2

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

NH2

254

References 1.

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

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. Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228. Khan, M. N. J. Org. Chem. 1995, 60, 4536. Hearn, M. J.; Lucas, L. E. J. Heterocycl. Chem. 1984, 21, 615. Khan, M. N. J. Org. Chem. 1996, 61, 8063. Tanyeli, C.; Özçubukçu, S. Tetrahedron: Asymmetry 2003, 14, 1167. 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.

O

O R

OH O

NaOR

Ar

N G G = CO, SO2 O

R

Ar

ROH

O OMe

OMe

N

N R

O

R

O

O

O O

O OMe O N

R O O

O

OMe H N

O

O O

NH

G

O OH

O

R

R

R

N

NH

NH

OH

O

O Example11

O

OH

O Oi-Pr

O

4 equiv i-PrONa

Oi-Pr

N S O O

i-PrOH, reflux 5 min., 85%

O

S O

NH O

256

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 980. Gabriel, S.; Colman, J. Chem. Ber. 1900, 33, 2630. Gabriel, S.; Colman, J. Chem. Ber. 1902, 35, 1358. Allen, C. F. H. Chem. Rev. 1950, 47, 275305. (Review). Hauser, C.R. and Kantor, S. W. J. Am. Chem. Soc. 1951, 73, 1437. Gensler, W. J. Heterocyclic Compounds, Vol. 4, R. C. Elderfield, Ed., Wiley & Sons., New York, N.Y., 1952, 378. (Review). Albert, A. and Hampton, A. J. Chem. Soc. 1952, 4985. Koelsch, C. F.; Lindquist, R. M. J. Org. Chem. 1956, 21, 657. Hill, J. H. M.; J. Org. Chem. 1965, 30, 620. (Mechanism). Lombardino, J. G.; Wiseman, E. H.; McLamore, W. M. J. Med. Chem. 1971, 14, 1171. Schapira, C. B.; Perillo, I. A.; Lamdan, S. J. Heterocycl. Chem. 1980, 17, 1281. Schapira, C. B.; Abasolo, M. I.; Perillo, I. A. J. Heterocycl. Chem. 1985, 22, 577. Groutas, W. C.; Chong, L. S.; Venkataraman, R.; Epp, J. B.; Kuang, R.; HouserArchield, N.; Hoidal, J. R. Bioorg. Med. Chem. 1995, 3, 187. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; et al. J. Med. Chem. 1997, 40, 980. Pflum, D. A. GabrielColman Rearrangement In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 416422. (Review).

257

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

S

t-BuOCl

R

S NH Cl

NH2

Et3N

R

O

N H

Et3N

:

R

S

: O

NH Cl

Et3N: R

S

H

H

[2,3]-sigmatropic rearrangement (Sommelet-Hauser) Et3N:

S

: N H

R

S N H sulfonium ion

O

N H

O

SN2

S O

NEt3

H

R NH

H S

R OH

S R

R

N H

N H

Example 11 S

1) t-BuOCl NH2

CH3

2) S O

3) Et3N, 69%

N H

Me

258

Example 21 SCH3 1) t-BuOCl O

NH2

2)

N

SCH3

3) Et3N LiAlH4, Et2O 0 oC, 48% overall

N H

References 1.

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

Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, B. W., Jr. J. Am. Chem. Soc. 1974, 96, 5495. Paul G. Gassman (19351993) was a professor at the University of Minnesota (19741993). Gassman, P. G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5508. Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am. Chem. Soc. 1974, 96, 5512. Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621. Ishikawa, H.; Uno, T.; Miyamoto, H.; Ueda, H.; Tamaoka, H.; Tominaga, M.; Nakagawa, K. Chem. Pharm. Bull. 1990, 38, 2459. Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990, 112, 8197. Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen, E. G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438. Savall, B. M.; McWhorter, W. W.; Walker, E. A. J. Org. Chem. 1996, 61, 8696. 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, 128131. (Review).

259

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

CHO

AlCl3 HCl

CO

Cu2Cl2

:

: :

:C O

:C O:

:C O AlCl3

AlCl3

O Cl

C O AlCl3

:

HCl

:C O AlCl3

H+

O

: O:

AlCl3 Cl3Al

Cl

:

Cl

Cl

H

H

AlCl4 H acylium ion Cl

CHO

O

H

CHO

AlCl4

H

AlCl3

CHO HCl

AlCl3

Example, a more practical variant4

OH

OH Zn(CN)2, AlCl3 NH2 HCl (g), 0 oC;

HO orcinol

HO

Cl

260

OH

H2O, 0 to 100 oC 95%

CHO HO

References Gattermann, L.; Koch, J. A. Ber.1897, 30, 1622. Ludwig Gattermann (18601920) 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, 290300. (Review). 3. Truce, W. E. Org. React. 1957, 9, 3772. (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. 1.

261

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

R

CO2R2

O

S8 1

1

R

CN

R

OR2

O R

R1

OR

H

condensation

OR2

O

R O

HO NC

CN

1

CN

Knoevenagel

OR2

R

BH

H

R1

NH2

S

O

O

B:

CO2R2

R

Base

R

BH

2

HO

R1

OR2

NC

:B

R

O

CN H :B

O R

OR2

OR2

O

H B CN S S S S

S S

N :

R1

R R1

S S S 6

S S R2O2C R

NH S S S S R1 H S S S S

CO2R2

R R1

S7 S

NH2

B

262

Example 18

H3C

N

CH3

CO2Et CO2Et +

S8 S

CN

morpholine

NH2

N

82%

N Example 213 O

CO2Et S8, EtOH, morpholine

O

Me

CO2Et

+ O

CN

60 oC, 5 h, 74%

t-BuO2C

S

NH2

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Gewald, K. Z. Chem. 1962, 2, 305. Gewald, K.; Schinke, E.; Böttcher, H. Chem. Ber. 1966, 99, 94. Gewald, K.; Neumann, G.; Böttcher, H. Z. Chem. 1966, 6, 261. Gewald, K.; Schinke, E. Chem. Ber. 1966, 99, 2712. Mayer, R.; Gewald, K. Angew. Chem., Int. Ed. Engl. 1967, 6, 294306. (Review). Gewald, K. Chimia 1980, 34, 101110. (Review). Peet, N. P.; Sunder, S.; Barbuch, R. J.; Vinogradoff, A. P. J. Heterocycl. Chem. 1986, 23, 129. Bacon, E. R.; Daum, S. J. J. Heterocycl. Chem. 1991, 28, 1953. Sabnis, R. W. Sulfur Reports 1994, 16, 1. (Review). Guetschow, M.; Schroeter, H.; Kuhnle, G.; Eger, K. Monatsh. Chem. 1996, 127, 297. Zhang, M.; Harper, R. W. Bioorg. Med. Chem. Lett. 1997, 7, 1629. Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. J. Heterocycl. Chem. 1999, 36, 333. (Review). Gütschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.; Löser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999, 42, 5437. 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. Pinto, I. L.; Jarvest, R. L.; Serafinowska, H. T. Tetrahedron Lett. 2000, 41, 1597. Buchstaller, H.-P.; Siebert, C. D.; Lyssy, R. H.; Frank, I.; Duran, A.; Gottschlich, R.; Noe, C. R. Monatsh. Chem. 2001, 132, 279. Hoener, A. P. F.; Henkel, B.; Gauvin, J.-C. Synlett 2003, 63. Tinsley, J. M. Gewald Aminothiophene Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 193198. (Review).

263

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

CuCl, O2 H NH4OH, EtOH H

CuCl

O2

Base Cu(I)

Cu(I)

Cu(II)

dimerization

Example 11

O2 2

Cu

NH4OH, EtOH 90%

Example 2, homo-coupling2

Cu, NH4Cl HO

O2, 90%

HO

OH

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

Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. Bowden, K.; Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1947, 1583. Hoeger, S.; Meckenstock, A.-D.; Pellen, H. J. Org. Chem. 1997, 62, 4556. Li, J.; Jiang, H. Chem. Commun. 1999, 2369. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632. (Review). Setzer, W. N.; Gu, X.; Wells, E. B.; Setzer, M. C.; Moriarity, D. M. Chem. Pharm. Bull. 2001, 48, 1776.

264

Kabalka, G. W.; Wang, L.; Pagni, R. M. Synlett 2001, 108. 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. Tetrahedron 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. 7. 8.

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.

Cu(OAc)2 R

R

H

R

pyridine/MeOH AcO Cu OAc pyridine R

H

R

N H R

R

Cu OAc

dimerization

R

R

R Example 1, homo-coupling6

Cl NC

N

NC Cu(OAc)2, pyridine

N N

MeOH, 1.5 h, 68% Cl Cl Example 2, cross-coupling4

SPh

Cu(OAc)2 pyridine/MeOH (1:1) rt, 72%

Ph

CO2Me

CN

266

SPh

CO2Me Ph References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

12. 13.

Eglinton, G.; Galbraith, A. R. Chem. Ind. 1956, 737. Geoffrey Eglinton (1927) was born in Cardiff, Wales. Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem. Soc. 1960, 3614. Eglinton, G.; McRae, W. Adv. Org. Chem. 1963, 4, 225. (Review). Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5558. Altmann, M.; Friedrich, J.; Beer, F.; Reuter, R.; Enkelmann, V.; Bunz, U. H. F. J. Am. Chem. Soc. 1997, 119, 1472. Srinivasan, R.; Devan, B.; Shanmugam, P.; Rajagopalan, K. Indian J. Chem., Sect. B 1997, 36B, 123. Nakanishi, H.; Sumi, N.; Aso, Y.; Otsubo, T. J. Org. Chem. 1998, 63, 8632. Müller, T.; Hulliger, J.; Seichter, W.; Weber, E.; Weber, T.; Wübbenhorst, M. Chem. Eur. J. 2000, 6, 54. Märkl, G.; Zollitsch, T.; Kreimeier, P.; Prinzhorn, M.; Reithinger, S.; Eibler, E. Chem. Eur. J. 2000, 6, 3806. Kaigtti-Fabian, K. H. H.; Lindner, H.-J.; Nimmerfroh, N.; Hafner, K. Angew. Chem., Int. Ed. 2001, 40, 3402. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed. 2000, 39, 2632. (Review). Inouchi, K.; Kabashi, S.; Takimiya, K.; Aso, Y.; Otsubo, T. Org. Lett. 2002, 4, 2533. 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. O

N2

OH O

N N

Ph N N

:

N N

Ph

OH

OH

N N O

N N Ph

Ph N2 n

N N O

O

Ph N N O Ph N N H

OH

O O

Example 14

O O

N2 BF4

O

KOAc, 18-C-6 rt, 55%

O O

O

268

Example 25

NH2 N

N MeO

ONO N

PhH, TFAA, reflux 2 d, 33%

N

N

N MeO

N

N

References 1.

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

Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339. Moses Gomberg (18661947) 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 (19011951), Gomberg’s Ph.D. student, was born in Detroit, Michigan. After his postdoctoral trainings in Europe Bachmann returned to the University of Michigan as the Moses Gomberg Professor of Chemistry. DeTar, D. F.; Kazimi, A. A. J. Am. Chem. Soc. 1955, 77, 3842. Eliel, E. L.; Saha, J. G.; Meyerson, S. J. Org. Chem. 1965, 30, 2451. Beadle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; Garcia-Slanga, B. J.; Gokel, G. W. J. Org. Chem. 1984, 49, 1594. McKenzie, T. C.; Rolfes, S. M. J. Heterocycl. Chem. 1987, 24, 859. Gurczynski, M.; Tomasik, P. Org. Prep. Proced. Int. 1991, 23, 438. Hales, N. J.; Heaney, H.; Hollinshead, J. H.; Sharma, R. P. Tetrahedron 1995, 51, 7403. 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. condensation of an aniline 1 with either alkoxy methylenemalonic ester or acyl malonic ester 2 providing the anilidomethylenemalonic ester 3; b. cyclization of 3 to the 4hydroxy-3-carboalkoxyquinoline 4; c. saponification to form acid 5, and d. decarboxylation to give the 4-hydroxyquinoline 6. RO2C + NH2

R'

1

RO2C

heat

CO2R

R''OH

OR'' 2

3

N H

CO2R

'

R'

R = alkyl R' = alkyl, aryl, or H R'' = alkyl or H CO2R N

OH

OH

OH

CO2H

HO N

R'

4

' N

R'

5

6

O EtO2C

O OEt

NH2

EtO2C

heat

N H2

O

EtO CO2Et

 EtOH

N

O H CO2Et N H

CO2Et electrocylization

 EtOH

OEt

'

N H O

H OEt

OEt

EtO

R'

6S

H

O CO2Et N

270

OH CO2Et

tautomerization N

Example 113 EtO2C

O

CO2Et

Ph2O, reflux 75%, 10:1

N H OH

OH CO2Et

O N

O

CO2Et N

References 1.

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

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. Baker, R. H., Lappin, G. R., Albisetti, C. J., Riegel, B. J. Am. Chem. Soc. 1946, 68, 1267. Jones, G. In Heterocyclic Compounds, Quinolines Vol. 32, chapter 2, pp 146150, 158, 159. (Review). Reitsema, R. H. Chem. Rev. 1948, 53, 43. (Review). Elderfield, R. C. In Heterocyclic Compounds, Elderfield, R. C., Wiley & Sons, New York, 1952, vol. 4, pps. 3841. (Review). Price, C. C., Snyder, H. R., Bullitt, O. H., Kovacic, P. J. Am. Chem. Soc. 1947, 69, 374. Briehl, H., Lukosch, A., Wentrup, C. J. Org. Chem. 1984, 49, 2772. Ouali, M. S., Vaultier, M., Carrie, R. Tetrahedron 1980, 36, 1821. Horvath, G., Hermecz, I., Gorvath, A., Pongor-Csakvari, M., Pusztay, L. J. Heterocycl. Chem. 1985, 22, 481. Agui, H., Komatsu, T., Nakagome, T. J. Heterocycl. Chem. 1975, 12, 557. Sabnis, R. W., Rangnekar, D. W. J. Heterocycl. Chem. 1991, 28, 1105. Suzuki, N., Tanaka, Y., Dohmori, R. Chem. Pharm. Bull. 1979, 27, 1. Cruickshank, P. A., Lee, F. T., Lupichuk, A. J. Med. Chem. 1970, 13, 1110. Hayakawa, I., Suzuki, N., Suzuki, K., Tanaka, Y. Chem. Pharm. Bull. 1984, 32, 4914. Wang, C. G., Langer, T., Kiamath, P. G., Gu, Z. Q., Skolnick, P., Fryer, R. I. J. Med. Chem. 1995, 38, 950. Leyva, E., Monreal, E., Hernandez, A. J. Fluorine Chem. 1999, 94, 7. Dave, C. G.; Joshipura, H. M. Indian J. Chem., Sect. B 2002, 41B, 650. Curran, T. T. Gould–Jacobs REaction in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 423436. (Review).

271

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

R X

R1

R MgX

R1 R2

R2

R

OH

Formation of the Grignard reagent: Mg Mg

Mg Mg R X

R

X

Mg Mg

single electron

R MgX

transfer

MgBr

R

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

R2 R1

R1 R2

O R MgX

R

Radical mechanism, R2 R1

R

O R2 R1

R MgX

R1 R2 R

OMgX

H

O MgX R1 R2 R

OH

OMgX

272

Example 16

O O O

O O

O

Ph

65%

OMe O MeO

O O

Mg

Br +

N

O

MeO

Ph

N

OMe

MeO

MeO

OMe

MeO OMe Example 24

EtMgBr NOH

NH

reflux, tol./ether, 76% H

This reaction is known as the Hoch–Campbell aziridine synthesis, which entails treatment of ketoximes with excess Grignard reagents and subsequent hydrolysis of the organometallic complex to produce aziridines. References Grignard, V. C. R. Acad. Sci. 1900, 130, 1322. Victor Grignard (France, 18711935) 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. (Review). 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 126. (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, 20812091. (Review). 11. Graden, H.; Kann, N. Cur. Org. Chem. 2005, 9, 733763. (Review). 1.

273

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

X

:

Y

Y

X

X = OH2+, OTs, I, Br, Cl; Y = O, NR2 Example 1

OMOM

OMOM MsO

MsO

NaH 15-crown-5

O

OH OMOM

O Example 2, aza-Grob fragmentation7

N

O S

OH

15 eq. NaBH4, THF o

70 C, 31 h, 53%

N H

SH

274

Example 312

OTs o

NaH, DMSO, 40 C, 1 h; OH MeO

o

then tosylate, 40 C, 1 h 52%

O MeO References Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594. Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1. French, L. G.; Charlton, T. P. Heterocycles 1993, 35, 305. Harmata, M.; Elahmad, S. Tetrahedron Lett. 1993, 34, 789. 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. 1. 2. 3. 4. 5.

275

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

R

R

CN

R

R1O

O

H3N: R1O

H3N H

R

R1O

CN

H

R1OH

O H

O

O

N H

H3N:

H2N

O

H2N

O

R OH R

R

O

CN

CN

CN

NH3

O

CN R

O H2N

O

O

H3N:

R

:NH3

R

R

CN

H

CN

HO

CN H O NH2

CN

H2O R

O

H3N H

R

O : NH2

N O H H

O

R

Example7

CN

NH3

CO2Et

75%

+ O

NC

CN

N O H Guareschi imide O

N H

O

276

References 1. 2.

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

Guareschi, I. Mem. Reale Accad. Sci. Torino 1896, II, 7, 11, 25. 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 College. Vogel, A. I. J. Chem. Soc. 1934, 1758. McElvain, S. M.; Lyle, R. E. Jr. J. Am. Chem. Soc. 1950, 72, 384. Brunskill, J. S. A. J. Chem. Soc. (C) 1968, 960. Brunskill, J. S. A. J. Chem. Soc., Perkin Trans. 1 1972, 2946. Holder, R. W.; Daub, J. P.; Baker, W. E.; Gilbert, R. H. III; Graf, N. A. J. Org. Chem. 1982, 47, 1445. Collins, D. J.; Jones, A. M. Aust. J. Chem. 1989, 42, 215. Krstic, V.; Misic-Vukovic, M.; Radojkovic-Velickovic, M. J. Chem. Res. (S) 1991, 82. Narsaiah, B.; Sivaprasad, A.; Venkataratnam, R. V. Org. Prep. Proced. Int. 1993, 25, 116. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1995, 34B, 348. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 1998, 37B, 988. Al-Omran, F.; El-Khair, A. A. Mijin, D. Z.; Misic-Vukovic, M. M. Indian J. Chem., Sect. B 2001, 40B, 608. Galatsis, P. GuareschiThorpe Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 307308. (Review).

277

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

O

O

HO2C H cat. CH3CN

O

O

O

N H O

H O Michael addition

O

O

O

HO2C H

N H

enamine formation

O

O O

N H

:

catalytic asymmetric

N

O H

enamine aldol

O

CO2 N

CO2

H CO2

O hydrolysis N

of iminium salt

OH

:

H2O:

O HO N

CO2

OH CO2

O

O O E1cB

O H B:

OH

O

OH

O

278

Example 11

O

O 3 mol% (S)-proline

O

CH3CN, 100%, 93.4% ee

O

O

Example 29

O

O

L-phenylalanine, PPTS O

O OBz

DMSO, 50 oC, 24 h sonication, 97%, 93% ee

O OBz

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

Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615. Hajos and Parrish were chemists at Hoffmann-La Roche. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496. Brown, K. L.; Dann, L.; Duntz, J. D.; Eschenmoser, A.; Hobi, R.; Kratky, C. Helv. Chim. Acta 1978, 61, 3108. Agami, C. Bull. Soc. Chim. Fr. 1988, 499. Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. 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 derivative and a neutral fragment in which the carbonyl group is replaced by a hydrogen.

O

O

NaNH2

5

R R1

R 4 PhH, reflux 2 3R R R non-enolizable ketone

R R1

O R R1

R5 R4 R3

R2

R R1

H NH2 2

R

R5 R4 R3

O NH2 R5 R4 R2 R3

NH2

O R R1

R5 R4 R3

NH2 2

R

H

R5 4 3R R

Example 14

CO2H

t-BuOK, t-BuOH O

43%

Example 212

HN C6H13 10 mol% LDA, THF

O

O

LiHNC6H13 Ph

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

280

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

Haller, A.; Bauer, E. Compt. Rend. 1908, 147, 824. Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989, 54, 1399. Paquette, L. A.; Gilday, J. P.; Maynard, G. D. J. Org. Chem. 1989, 54, 5044. Paquette, L. A.; Gilday, J. P. Org. Prep. Proc. Int. 1990, 22, 167. Muir, D. J.; Stothers, J. B. Can. J. Chem. 1993, 71, 1290. Mehta, G.; Praveen, M. J. Org. Chem. 1995, 60, 279. Mehta, G.; Reddy, K. S.; Kunwar, A. C. Tetrahedron Lett. 1996, 37, 2289. Mehta, G.; Reddy, K. S. Synlett 1996, 229. Mittra, A.; Bhowmik, D. R.; Venkateswaran, R. V. J. Org. Chem. 1998, 63, 9555. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 13991422. (Review). Arjona, O.; Medel, R.; Plumet, J. Tetrahedron Lett. 2001, 42, 1287. Ishihara, K.; Yano, T. Org. Lett. 2004, 6, 1983.

281

Hantzsch dihydropyridine synthesis Dihydropyridine from the condensation of aldehyde, E-ketoester and ammonia.

CO2Et

O R

H

R NH3

R1

O

CO2Et

EtO2C R1

R1

N H O

H3N:

H

CO2Et

O

R1

OH

aldol R condensation

R

formation

H

H3N:

:NH3 H CO2Et

O

O

enolate

R

R1

formation

CO2Et

CO2Et

R

R1

O

enamine

CO2Et R1

O

OH

R1

CO2Et :NH3

H

R1

O

CO2Et

H2O

HO R1 H2N: R

H3N:

H

CO2Et

H2N H EtO2C R1

R

R1

CO2Et O

:

R1

H2N

EtO2C H2N

addition

R1

:NH3 H

O N H

CO2Et R1

Michael

R tautomerization

EtO2C

H2N H

O R1

CO2Et R1 NH2

282

H3N: EtO2C

H

R

R EtO2C

CO2Et

HO N R1 H

R1

R1

CO2Et N H

1

R

Example 16

O

CO2Et H

NO2

O

NH3

EtO2C

NO2 CO2Et N H nifedipine

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 183. Bottorff, E. M.; Jones, R. G.; Kornfeld, E. C.; Mann, M. J. J. Am. Chem. Soc. 1951, 73, 4380. Berson, J. A.; Brown, E. J. Am. Chem. Soc. 1955, 77, 444 Marsi, K. L.; Torre, K. J. Org. Chem. 1964, 29, 3102. Meyers, A. I.; Sircar, J. C.; Singh, S. J. Heterocycl. Chem. 1967, 4, 461 Bossert, F.; Vater, W. Naturwissinschaften 1971, 58, 578 Balogh, M.; Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1986, 42, 5729. Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. Sainai, J. B.; Shah, A. C.; Arya, V. P. Indian J. Chem. B. 1995, 34B(1), 17. Menconi, I.; Angeles, E.; Martinez, L.; Posada, M. E.; Toscano, R. A.; Martinez, R. J. Heterocycl. Chem. 1995, 32, 831. Goerlitzer, K.; Heinrici, C.; Ernst, L. Pharmazie 1999, 54, 35. Raboin, J.-C.; Kirsch, G.; Beley, M. J. Heterocycl. Chem. 2000, 37, 1077. Sambongi, Y.; Nitta, H.; Ichihashi, K.; Futai, M.; Ueda, I. J. Org. Chem. 2002, 67, 3499. Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 304307. (Review).

283

Hantzsch pyrrole synthesis Reaction of D-chloromethyl ketones with E-ketoesters and ammonia to assemble pyrroles.

CO2Et

CO2Et

O

NH3 N H

O

Cl

CO2Et :NH3

formation

O

H2O

H

H3N:

CO2Et

enamine HO H2N :

CO2Et

CO2Et

H2N

H2N

H3N H

OH

O Cl

CO2Et

H2N

H2O

CO2Et H

Cl

:

HN

:NH3

CO2Et Cl

CO2Et

CO2Et :

H3N:

HN

H

N H

N H

Example 15

F3C

DME, 87140 oC

O Br

H2N

CO2Me

2.5 h, 60%

F3C

N H

CO2Me

284

Example 28

CO2Et NH , EtOH 3

O Cl

O

CO2Et

48 h, 48% N H

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

Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. Hort, E. V.; Anderson, L. R. Kirk-Othmer Encycl. Chem. Technol.; 3rd Ed.; 1982, 19, 499. (Review). Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron 1987, 43, 5171. Kirschke, K.; Costisella, B.; Ramm, M.; Schulz, B. J. Prakt. Chem. 1990, 332, 143. Kameswaran, V.; Jiang, B. Synthesis 1997, 530. Trautwein, A. W.; Süȕmuth, R. D.; Jung, G. Bioorg. Med. Chem. Lett. 1998, 8, 2381. 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, 411454. (Review). 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.

Pd(0) R X

R

Z

Z X = I, Br, OTf, Cl, etc. Z = H, R, Ar, CN, CO2R, OR, OAc, NHAc, etc.

R X Pd(0) R

oxidative addition

H Pd X

Z

cis-Eelimination

R Pd(II) X

R H H

Pd X Z Z coordination R Pd(II) X

insertion (cis)

Z Example 17

O Cl MeO

O O

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

O

286

Example 26 OTBS

N I N

H

O

N

0.3 eq. Pd(OAc)2 Bu4NCl, DMF, K2CO3 70 oC, 3 h, 74%

N O

H

H OTBS

References 1.

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

Heck, R. F.; Nolley, J. P., Jr. J. Am. Chem. Soc. 1968, 90, 5518. Richard Heck discovered the Heck reaction when he was an assistant professor at the University of Delaware. Despite having discovered a novel methodology that would see ubiquitous utility in organic chemistry and having published a popular book,4 Heck had difficulties in securing funding for his research, he left chemistry and moved to Asia. Now he is retired in Florida. Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (Review). Heck, R. F. Org. React. 1982, 27, 345. (Review). Heck, R. F. Palladium Reagents in Organic Synthesis, Academic Press, London, 1985. (Book). Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 103113. (Book). Rawal V. H.; Iwasa, H. J. Org. Chem. 1994, 59, 2685. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10. Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 30093066. (Review). Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314. (Review). Link, J. T. Org. React. 2002, 60, 157534. (Review). Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 29452963. (Review). Beller, M.; Zapf, A.; Riermeier, T. H. Transition Metals for Organic Synthesis (2nd edn.) 2004, 1, 271305. (Review). Oestreich, M. Eur. J. Org. Chem. 2005, 783792. (Review).

287

Heteroaryl Heck reaction Intermolecular or intramolecular Heck reaction that occurs onto a heteroaryl recipient.

Pd(Ph3P)4, Ph3P, CuI

N

S

I

N

Cs2CO3, DMF, 140 oC

S

N Pd(0)

I

S

Pd(II)I

insertion

oxidative addition S N

H

S

Cs2CO3

N

Pd(II) I

B:

Pd(0)

CsI

CsHCO3

Example 13

O N N

N

O

N N

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

Cl

N

Example 22

N

N

Br

N

Pd(OAc)2, NaHCO3 N

N Bu

n-Bu4NCl, DMA O

150 oC, 24 h, 83%

N Bu

O

288

References 1. 2. 3.

4. 5. 6.

Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaka, R.; Miyafuji, A.; Nakata, T.; Tani, N. Aoyagi, Y. Heterocycles 1990, 31, 1951. Kuroda, T.; Suzuki, F. Tetrahedron Lett. 1991, 32, 6915 Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J. Honma, R. Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257. Proudfoot, J. R. et al. J. Med. Chem. 1995, 38, 1406. Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. 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 indoles. Cf. Wacker oxidation. PdCl2(CH3CN)2, THF MeO2C

then, Et3N, 84%

NH2

CH3 N H

MeO2C

PdCl2(CH3CN)2 MeO2C

palladation

NH2

NH2

MeO2C

Pd

Cl

Cl precipitate

Cl Cl Et3N Pd

Et3N

: NH2

MeO2C Et3N Cl H Pd Cl MeO2C

N H2

– HCl – "PdH"

"PdH" MeO2C

N H

H PdLn MeO2C

N H

CH3

E-elimination

CH3 MeO2C

N H

Example 11

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

10 eq. Et3N, THF, reflux, 85%

CH3 N H

290

Example 24

Br

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

10 eq. LiCl, THF, reflux, 79%

Br

N Ts

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

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. Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800. Hegedus, L. S.; Winton, P. M.; Varaprath, S. J. Org. Chem. 1981, 46, 2215. Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657. Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (Review). Brenner, M.; Mayer, G.; Terpin, A.; Steglich, W. Chem. Eur. J. 1997, 3, 70. Osanai, Y. Y.; Kondo, K.; Murakami, Y. Chem. Pharm. Bull. 1999, 47, 1587. A ruthenium variant: Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186. Johnston, J. N. Hegedus Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 135139. (Review).

291

Hell–Volhard–Zelinsky reaction D-Bromination of carboxylic acids using Br2/PBr3.

O R

OH

R

O

O

R

O

H2O

R

Br

Br P

O R

Br

Br

H

OH

Br D-bromoacid

Br

O

P Br Br

R

Br2

Br

O

O

PBr3

O

Br P

Br

Br O R

O P Br

H Br

enolization

O

R

Br

H Br

Br

Br H+ O R

B:

O O

R

Br Br

H

hydrolysis

:OH2

Br

OH

R Br

Example 17

CO2H

Cl2, cat. PCl3 97 oC, 6 h, 77%

OH Br

Cl

CO2H

292

Example 28

Br

PBr3 CO2H

Br2, 57%

Br CO2H

CO2H

H

References 1.

2.

3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Hell, C. Ber. Dtsch. Chem. Ges. 1881, 14, 891. Carl M. von Hell (18491926) 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. Volhard, J. Justus Liebigs Ann. Chem. 1887, 242, 141. Jacob Volhard (18491909) was born in Darmstadt, Germany. He apprenticed under Liebig, Will, Bunsen, Hofmann, Kolbe, and von Baeyer. He improved Hell’s original procedure in preparing Dbromo-acid during his research in thiophenes. Zelinsky, N. A. Ber. Dtsch. Chem. Ges. 1887, 20, 2026. Nikolai D. Zelinsky (18611953) 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 professor at the University of Moscow. On his ninetieth birthday in 1951, he was awarded the Order of Lenin. Watson, H. B. Chem. Rev. 1930, 7, 173201. (Review). Sonntag, N. O. V. Chem. Rev. 1953, 52, 237246. (Review). Harwood, H. J. Chem. Rev. 1962, 62, 99154. (Review). Jason, E. F.; Fields, E. K. US Patent 3,148,209 (1964). Chow, A. W.; Jakas, D. R.; Hoover, J. R. E. Tetrahedron Lett. 1966, 5427. Little, J. C.; Sexton, A. R.; Tong, Y.-L. C.; Zurawic, T. E. J. Am. Chem. Soc. 1969, 91, 7098. Chatterjee, N. R. Indian J. Chem., Sect. B 1978, 16B, 730. Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263. Kolasa, T.; Miller, M. J. J. Org. Chem. 1990, 55, 4246. Liu, H.-J.; Luo, W. Synth. Commun. 1991, 21, 2097. Krasnov, V. P.; Bukrina, I. M.; Zhdanova, E. A.; Kodess, M. I.; Korolyova, M. A. Synthesis 1994, 961. Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier, W. R., Jr. Tetrahedron Lett. 1998, 39, 9621. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1999, 64, 8059. 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.

O R2 R

OH

N H

NO2

NO2

R R1

R1

H N: H

deprotonation R N O

N

O

H R2

R2

R1

O R2

N O

O

nitronate

OH

nucleophilic

NO2

R addition

R1

N H

R2

Example 16

CHO HO NO2

Amberlyst A-21 (basic) rt, 62%

NO2

H

294

Example 2, aza-Henry reaction14

O P Ph N Ph Ph

o

5 mol% TMG, 100 C Ph

NO2

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

O P Ph HN Ph Ph

Ph NO2

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Henry, L. Compt. Rend. 1895, 120, 1265. Matsumoto, K. Angew. Chem. 1984, 96, 599. Sakanaka, O.; Ohmori, T.; Kozaki, S.; Suami, T.; Ishii, T.; Ohba, S.; Saito, Y. Bull. Chem. Soc. Jpn. 1986, 59, 1753. Barrett, A. G. M.; Robyr, C.; Spilling, C. D. J. Org. Chem. 1989, 54, 1233. Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, 2, 321340. (Review). Chen, Y.-J.; Lin, W.-Y. Tetrahedron Lett. 1992, 33, 1749. Bandgar, B. P.; Uppalla, L. S. Synth. Commun. 2000, 30, 2071. Luzzio, F. A. Tetrahedron 2001, 57, 915. (Review). Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861. Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401. Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (Review on aza-Henry reaction). Risgaard, T.; Gothelf, K. V.; Jøgensen, K. A. Org. Biomol. Chem. 2003, 1, 153. Ballini, R.; Bosica, G.; Livi, D.; Palmieri, A.; Maggi, R.; Sartori, G. Tetrahedron Lett. 2003, 44, 2271. Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168. Chung, W. K.; Chiu, P. Synlett 2005, 55. 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 D-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 1.

O

EtO

S

O OEt

S

HO

NaOEt, EtOH 2. H3O+

O

O

O

O OH

Ph Ph

O

Ph

Ph CO2Et

EtO

O Ph O

O

S

S

Ph CO2Et

CO2Et

O

O S

O Ph O

Ph H

Ph

CO2Et

O2C

Ph S

CO2Et

EtO Ph

Ph HO2C

S

CO2Et

H+, H2O reflux

Ph

Ph HO2C

S

CO2H

296

Example 111

O

O (CHO)3, NaOMe

S

S MeOH, 59%

O

O Example 215

H3C

CH3

NaOH, MeOH NC

O

O

S

CN 94%

H3C NC

CH3 NH2 S O

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Hinsberg, O. Ber. Dtsch. Chem. Ges. 1910, 43, 901. Gronowitz, S. In Thiophene and Its Derivatives, Part 1, Gronowitz, S., ed.; WileyInterscience: New York, 1985, 3441. (Review). Wynberg, H.; Zwanenburg, D. J. J. Org. Chem. 1964, 29, 1919. Wynberg, H.; Kooreman, H. J. J. Am. Chem. Soc. 1965, 87, 1739. Chadwick, D. J.; Chambers, J.; Meakins, G. D.; Snowden, R. L. J. Chem. Soc., Perkin I, 1972, 2079. Kumar, A.; Tilak, B. D. Indian J. Chem.1986, 25B, 880. Miyahara, Y.; Inazu, T.; Yoshino, T. Chem. Lett. 1980, 397. Miyahara, Y.; Inazu, T.; Yoshino, T. Bull. Chem. Soc. Jpn. 1980, 53, 1187. Huybrechts, L.; Buffel, D.; Freyne, E.; Hoornaert, G. Tetrahedron 1984, 40, 2479. Miyahara, Y.; Inazu, T.; Yoshino, T. Tetrahedron Lett. 1984, 25, 415. Miyahara, Y.; Inazu, T.; Yoshino, T. J. Org. Chem. 1984, 49, 1177. Vogel, E. Pure Appl. Chem. 1990, 62, 557. Christl, M.; Krimm, S.; Kraft, A. Angew. Chem. Int. Ed. Engl. 1990, 29, 675. Rangnekar, D. W.; Mavlankar, S. V. J. Heterocycl. Chem. 1991, 28, 1455. Beye, N.; Cava, M. P. J. Org. Chem. 1994, 59, 2223. Vogel, E.; Pohl, M.; Herrmann, A.; Wiss, T.; König, C.; Lex, J.; Gross, M.; Gisselbrecht, J. P. Angew. Chem. Int. Ed. Engl. 1996, 35, 1520. Mullins, R. J.; Williams, D. R. Hinsberg Synthesis of Thiophene Derivatives In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 199206. (Review).

297

Hiyama cross-coupling reaction Palladium-catalyzed cross-coupling reaction of organosilicons with organic halides, triflates, etc. in the presence of an activating agent such as fluoride or hydroxide (transmetalation is reluctant to occur without the effect of an activating agent). For the catalytic cycle, see the Kumada coupling on page 345.

O MeO2C

O

F3Si

Br

Pd(Ph3P)4, TBAF

MeO2C

O

O

O

THF

O O

F3Si Bu4N

nucleophilic

O

attack

F

O O F4Si

O

F4Si

Bu4N

O Bu4N

oxidative MeO2C

O

Pd(Ph3P)4

Br

MeO2C

addition

O

Pd Br

O F4Si

CO2Me

O

MeO2C

O

trans"metal"lation reductive elimination

MeO2C

O

O O

Pd

Pd(Ph3P)4

298

Example 11

I MeO2C S

Si(Et)F2

S

S

3

(K -C3H5PdCl)2 DMF, KF, 100 oC 82%

MeO2C

S

Example 25

Br N C5H11

Si(OMe)3

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

C5H11 N References Hatanaka, Y.; Fukushima, S.; Hiyama, T. Heterocycles 1990, 30, 303. Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471. 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. Organometallics 2005, 24, 3957. 1. 2. 3.

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 coupling. This variant has obvious advantages of avoiding incompatibility with fluoride (silicon protective groups and large-scale reactors). Mechanistic study5

n-C5H11

Me Me Si OH

Me Me ArylPdL2X Si - + O M

MH

n-C5H11

MX

n-C5H11

n-C5H11

Me Me L Si O Pd Aryl L

transmetalation Me

Me C7H13Me2Si

L Pd Aryl L

n-C5H11

O

Si

OK Aryl

Many organosilanol substrates and different bases have been demonstrated. 1. Alkenylsilanol (KOSiMe3)6

CH2OTBS

n-C5H11

OH I Si + Me Me

KOSiMe3 (2.0 eq.) Pd(dba)2 (5 mol %) DME, 9 h, r.t.

CH2OTBS

n-C5H11

80% (E: Z = 99.5/0.5)

300

2. Arylsilanol (Cs2CO3)7

Me Me Si OH

CO2Et + Br

MeO

CO2Et

Cs2CO3 + 3 H2O (2 equiv) [(allyl)PdCl]2 (5 mol %) MeO

dppb (10 mol %) toluene, 90 oC 24 h, 90% 3. Arylsilanol (Ag2O)8 Me

Me Si OH + Aryl-I

MeO

Ag2O (1 equiv) Pd(PPh3)4 (5 mol %) THF, 60 oC, 36 h

Me

MeO

69%

4. Alkynylsilanol (KOSiMe3)9

SiMe2OH I

C5H11

CH2OH

TMSOK (2 equiv), PdCl2(PPh3)2 (2.5 mol %) DME, rt, 3 h, 84%

CH2OH C5H11

5. 2-Indolylsilanol (KOt-Bu)10 Me Me + I Si OH N Boc

CO2t-Bu

301

NaOt-Bu (2.0 equiv) CO2t-Bu

Pd2(dba)3•CHCl3 (5 mol%) CuI (1.0 equiv) toluene, rt, 84%

N Boc

6. 4-Isoxazolylsilanol (NaOt-Bu)11 N

Et Me HO

O

Si

Et

Pd2dba3•CHCl3(5 mol %) NaOtB-u (2.5 equiv)

I

N

O Ph

+ NO2

Ph Me

Cu(OAc)2 (1.0 equiv) toluene, 40 ºC, 78%

O2 N

7. 1,4-Bis-silyl-1,3-butadienes (KOSiMe3)12

SiMe2Bn MeO

n-Bu4N+ F- (2.0 equiv) Pd(dba)2 (2.5 mol%) THF, rt, 1 h

+ I

CO2Et

CO2Et

MeO

90% References Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. Scott Denmark is a professor 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. deMeijere, 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. 1.

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 Hofmann degradation reaction.

Br2

O

H2O

R N C O

R

NH2

O

O R

CO2n

R NH2

NaOH

NH H

O R

Br

R

Br

NH

N H

Br

O R

N

OH

OH

R N C O R OH isocyanate intermediate

H N

O

H

CO2n

R NH2

O OH

Example 14

H N

O NBS, DBU, MeOH NH2 O2N

Br

reflux, 25 min., 70%

O2N

O O

303

Example 29

OCOCF3

O

I

OH

CH3CN/H2O, 4.5 h, 100%

Ph O I N O CF3 H OH :

OCOCF3

NH2

O

H N

C

O

H N O

:

O

OH References Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1881, 14, 2725. Grillot, G. F. Mech. Mol. Migr. 1971, 237. (Review). Jew, S. S.; Park, H. G.; Park, H. J.; Park, M. S.; Cho, Y. S. Ind. Chem. Library 1991, 3, 14753. (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, 28932903. (Review). 1. 2. 3.

304

Hofmann–Löffler–Freytag reaction Formation of pyrrolidines or piperidines by thermal or photochemical decomposition of protonated N-haloamines.

Cl N

1

R

Cl N

R1

1. H+, '

N 2 R

2. OH

R

H+

'

Cl H N 2 R

R1

R2

R1



2

homolytic cleavage

chloroammonium salt

H Cl

1,5-hydrogen

H N R2

1

R

R1

H

N H R2

atom transfer

nitrogen radical cation

NH2

R1

R 

R2 Cl H N 2 R

1

Cl

1

R

H R2

R

1

: NH R2

R1



N H R2

R1

OH

Example 16

NCS, ether, Et3N then hv, (Hg0 lamp) NH

Cl

NH2 R2

SN2

OH

N

R1

N

N o

0 C, 3.5 h in N2 100%

N

N R2

305

Example 23

NH 1. NaOCl, 95% H H

2. TFA, hv, 87% 3. NaOH, MeOH, 76%

H

O N H H

H

O References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Hofmann, A. W. Ber. Dtsch. Chem. Ges. 1879, 12, 984. Löffler, K.; Freytag, C. Ber. Dtsch. Chem. Ges. 1909, 42, 3727. 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. Wolff, M. E. Chem. Rev. 1963, 63, 55. (Review). Furstoss, R.; Teissier, P.; Waegell, B. Tetrahedron Lett. 1970, 11, 1263. Kimura, M.; Ban, Y. Synthesis 1976, 201. Deshpande, R. P.; Nayak, U. R. Indian J. Chem., Sect. B 1979, 17B, 310. Hammerum, S. Tetrahedron Lett. 1981, 22, 157. Uskokovic, M. R.; Henderson, T.; Reese, C.; Lee, H. L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc. 1978, 100, 571. Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337422. (Review). Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (Review). Madsen, J.; Viuf, C.; Bols, M. Chem. Eur. J. 2000, 6, 1140. Togo, H.; Katohgi, M. Synlett 2001, 565. (Review). Pellissier, H.; Santelli, M. Org. Prep. Proced. Int. 2001, 33, 455. (Review). Li, J. J. Hofmann–Löffler–Freytag Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 8097. (Review).

306

Horner–Wadsworth–Emmons reaction Olefin formation from aldehydes and phosphonates. Workup is more advantageous than the corresponding Wittig reaction because the phosphate by-product can be washed away with water.

O EtO P EtO

O OEt

RCHO

O EtO P EtO

O EtO P EtO ONa

CO2Et

NaH, then R

O

O EtO P EtO

OEt H

O OEt

H

O

R

H O EtO P EtO

O

O

R

OEt

erythro (kinetic) or threo (thermodynamic)

O H R

O H R

O OEt O OEt O P OEt P OEt H H H CO2Et CO2Et R erythro, kinetic adduct O OEt P OEt CO2Et H

R

CO2Et

O OEt CO2Et O P OEt CO2Et H R H R threo, thermodynamic adduct

307

Example 15

O CHO

O EtO P EtO

O

O

CO2Et

OEt

NaH, THF, 91% OMe

OMe Example 28

CHO BnO

O EtO P EtO

O CO2Et

OEt

KOH, THF, 95%

BnO

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

Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733. Wadsworth, D. H.; Schupp, O. E.; Seus, E. J.; Ford, J. A., Jr. J. Org. Chem. 1965, 30, 680. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863927. (Review). Shair, M. D.; Yoon, T. Y.; Mosny, K. K.; Chou, T. C.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 9509. Ando, K. J. Org. Chem. 1997, 62, 1934. Ando, K. J. Org. Chem. 1999, 64, 6815. 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. Reiser, U.; Jauch, J. Synlett 2001, 90. Comins, D. L.; Ollinger, C. G. Tetrahedron Lett. 2001, 42, 4115. Harusawa, S.; Koyabu, S.; Inoue, Y.; Sakamoto, Y.; Araki, L.; Kurihara, T. Synthesis 2002, 1072. Lattanzi, A.; Orelli, L. R.; Barone, P.; Massa, A.; Iannece, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 1333. Blasdel, L. K.; Myers, A. G. Org. Lett. 2005, 7, 4281.

308

HoubenHoesch reaction Acid-catalyzed acylation of phenols as well as phenolic ethers using nitriles.

OH

OH

OH RCN OH

OH

HCl, AlCl3 R

OH

NH•HCl

R

O

:OH electrophilic

AlCl3 complexation N:

R

OH R

substitution

N AlCl3

H+

OH

O OH

H2O: Cl

H R

OH

R

NH•HCl

NH OH OH

hydrolysis R

OH + NH2 H O H

OH R

O

Cl Example 1, intramolecular HoubenHoesch reaction5

O

OMe

O

OMe

1. ZnCl2, HCl(g), Et2O CN OMe

2. H2O, reflux, 89%

O

OMe

309

Example 28

OH

F PivO

CO2Me

CN OMe

MeO

OH OPiv

MeO

F OMe

SbCl5, 2-chloropropane CH2Cl2, rt, 2 h, 95%

N H

O

OH CO2Me

References 1.

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

Hoesch, K. Ber. Dtsch. Chem. Ges. 1915, 48, 1122. Kurt Hoesch (18821932) was born in Krezau, Germany. He studied at Berlin under Emil Fischer. During WWI, Hoesch was Professor of Chemistry at the University of Istanbul, Turkey. After the war he gave up his scientific activities to devote himself to the management of a family business. Houben, J. Ber. Dtsch. Chem. Ges. 1926, 59, 2878. Amer, M. I.; Booth, B. L.; Noori, G. F. M.; Proenca, M. F. J. R. P. J. Chem. Soc., Perkin Trans. 1 1983, 1075. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691. Rao, A. V. R.; Gaitonde, A. S.; Prakash, K. R. C.; Rao, S. P. Tetrahedron Lett. 1994, 35, 6347. Sato, Y.; Yato, M.; Ohwada, T.; Saito, S.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 3037. Kawecki, R.; Mazurek, A. P.; Kozerski, L.; Maurin, J. K. Synthesis 1999, 751. Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc. 2002, 124, 5294. Sanchez-Viesca, F.; Gomez, M. R.; Berros, M. Org. Prep. Proc. Int. 2004, 36, 135.

310

HunsdieckerBorodin reaction Conversion of silver carboxylate to halide by treatment with halogen.

O R

X2 O

X X

O

O R

AgX O

R

Ag

AgX

CO2n

R X

Ag

homolytic O

X cleavage

O O X

R

CO2n

O

R

R

O

X

O R X

R

O

Example 16

Br

CO2H

+

NBS, n-Bu4N

CF3CO2

ClCH2CH2Cl, 96% MeO

MeO Example 210

Cl CO2H

N N F

HO

Br

2 BF4 "Select fluor"

KBr, CH3CN, 82%

HO

References 1.

Borodin, A. Justus Liebigs Ann. Chem. 1861, 119, 121. Aleksandr Porfireviþ Borodin (18331887) 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 HunsdieckerBorodin 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 Hunsdiecker 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.; Pergamon, 1991, Vol. 7, 723734. (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. N N

O SOCl2

R1

HN N

R1 = OR, NH2

R3

S

R1 R2

2

R

HN N

Tos

SOCl2 R3

1

R = OR, NH2

R2

O X S Cl Cl N HN S O

X NH

N

N S N

R1

R1 R2

R3

R2 X N + N S O R1

S O HCl

R2

R2 X = Tos, COR1 ClSO2 HCl

X N N S+

N N 1

R

R1

2

R

2

R Example17

N

O H 2N

N S

SOCl2, CH2Cl2

HN N

rt, 6 h, 56% CN

CN

S

313

References 1. 2. 3.

4.

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

Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359. Meier, H.; Hanold, N. In Methoden der Organischen Chemie: HoubenWeyl, Georg Thieme: Stuttgart – New York, 1994; Vol. E8d, p.60. (Review). 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). 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). Stanetty, P.; Turner, M.; Mihovilovic, M. D. In Targets in Heterocyclic Systems 1999, 3, 265–299. (Review). Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.; Williams, D. J. J. Med. Chem. 1985, 28, 442. Lewis, G. S.; Nelson, P. H. J. Med. Chem. 1979, 22, 1214. Fujita, M.; Nimura, K.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1995, 41, 2413. Peet, N. P.; Sunder, S. J. Heterocycl. Chem. 1975, 12, 1191. Zimmer, O.; Meier, H. Chem. Ber. 1981, 114, 2938. Britton, T. C.; Lobl, T. J.; Chidester, C. G. J. Org. Chem. 1984, 49, 4773. Fujita, M.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles 1993, 36, 33. D'Hooge, B.; Smeets, S.; Toppet, S.; Dehaen, W. Chem. Commun. 1997, 1753. 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. Hu, Y.; Baudart, S.; Porco, J. A., Jr. J. Org. Chem. 1999, 64, 1049. Abramov, M. A.; Dehaen, W. Synthesis 2000, 1529. Morzherin, Y. Y.; Glukhareva, T. V.; Mokrushin, V. S.; Tkachev, A. V.; Bakulev, V. A. Heterocyclic Commun. 2001, 7, 173. Hameurlaine, A.; Abramov, M. A.; Dehaen, W. Tetrahedron Lett. 2002, 43, 1015. Sakya, S. M. Hurd–Mori 1,2,3-Thiadiazole Synthesis In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 199206. (Review).

314

Jacobsen–Katsuki epoxidation Manganese-catalyzed asymmetric epoxidation of (Z)-olefins.

H N

Mn O Cl O

t-Bu Ph

H N

t-Bu

CO2Me

t-Bu

O

t-Bu

Ph

CO2Me

NaOCl, aq. buffer, CH2Cl2

1. Concerted oxygen transfer (cis-epoxide): R R

O Mn(V)

R1

R1

R1 O Mn(V)

O Mn(V)

R1

R O

Oxygen transfer via radical intermediate (trans-epoxide):

2.

R R

3.

R

R1

O Mn(V)

R1 O Mn(V)

R

R1

R

O Mn(V)

R1 O

Oxygen transfer via manganaoxetane intermediate (cis-epoxide): R

R1

R1

O Mn(V)

R [2 + 2] cycloaddition

R1 R

O Mn(V)

O Mn(V) R

R1 O

315

Example5

cat, 4-phenylpyridine-N-oxide CO2Et

CO2Et NaOCl, CH2Cl2, 4 oC, 12 h

O

56%, 9597% ee

H

H N

cat. =

t-Bu

N Mn O O Cl t-Bu t-Bu

t-Bu

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

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

Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N. J. Am. Chem. Soc. 1990, 112, 2801. Irie, R.; Noda, K.; Ito, Y.; Matsumoto, N.; Katsuki, T. Tetrahedron Lett. 1990, 31, 7345. Irie, R.; Noda, K.; Ito, Y.; Katsuki, T. Tetrahedron Lett. 1991, 32, 1055. Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296. Schurig, V.; Betschinger, F. Chem. Rev. 1992, 92, 873. (Review). Deng, Li; Jacobsen, E. N. J. Org. Chem. 1992, 57, 4320. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, New York, 1993, Ch. 4.2. (Review). Katsuki, T. Coord. Chem. Rev. 1995, 140, 189214. (Review). E. N. Jacobsen, in Comprehensive Organometallic Chemistry II, Eds. G. W. Wilkinson, G. W.; Stone, F. G. A.; Abel, E. W.; Hegedus, L. S., Pergamon, New York, 1995, vol 12, Chapter 11.1. (Review). Palucki, M.; McCormick, G. J.; Jacobsen, E. N. Tetrahedron Lett. 1995, 36, 5457. Senananyake, C. H. Aldrichimica Acta 1998, 31, 3. (Review). 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). Katsuki, T. In Catalytic Asymmetric Synthesis; 2nd edn.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, 287. (Review). Katsuki, T. Synlett 2003, 281. (Review). Palucki, M. Jacobsen–Katsuki epoxidation In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 2943. (Review).

316

Japp–Klingemann hydrazone synthesis Hydrazones from D-ketoesters and diazonium salts with the acid of base.

CO2R

Cl

ArN2

KOH Ar

O E-keto-ester

Diazonium salt

H N

O N

CO2R

OH

hydrazone

OH

N N Ar coupling

deprotonation

H CO2R

CO2R O

O

Ar N N CO2R

Ar N N CO2R

HO

O OH

O H

O OH

Ar

N

N

Ar

CO2R

H N

N

CO2R

Example 16

CO2Et

CO2Et Me

N

S O O

NaNO2 conc. HCl, H2O NH2 0 oC

Me

N

S O O

Cl N

N

317

O

CO2Et

Me

NMe2 CO2Et

Me

NaOAc (pH 34) 0 to 50 oC 72% Example 29

S O O

0.5 N KOH, THF, rt, 1 h NH

HO2C

then

O

N2+Cl OBn

NMe2

N

N H

N CO2Et

H N

NH

N

OBn

O

62% yield

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

Japp, F. R.; Klingemann, F. Justus Liebigs Ann. Chem. 1888, 247, 190. Laduree, D.; Florentin, D.; Robba, M. J. Heterocycl. Chem. 1980, 17, 1189. Strandtmann, M. v.; Cohen, Marvin P.; Shavel, J. Jr. J. Med. Chem. 1963, 6, 719. Loubinoux, B.; Sinnes, J.-L.; O'Sullivan, A. C.; Winkler, T. J. Org. Chem. 1995, 60, 953. Saha, C., Miss; Chakraborty, A.; Chowdhury, B. K. Indian J. Chem. 1996, 35B, 677. Pete, B.; Bitter, I.; Harsanyi, K.; Toke, L. Heterocycles 2000, 53, 665. Atlan, V.; Kaim, L. E.; Supiot, C. Chem. Commun. 2000, 1385. Shawali, A. S.; Abdallah, M. A.; Mosselhi, M. A. N.; Farghaly, T. A. Heteroatom Chem. 2002, 13, 136. 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 Corey´s PCC (pyridinium chlorochromate) and PDC (pyridinium dichromate) oxidations 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

Cr2O7

CrO3Cl

CrO3

N H

N H

2

PDC

PCC

Collins/Sarett

2

Jones oxidation

R1

R2 O Cr

O H : O R1

O

CrO3

OH

R2

R1

H2SO4, acetone O

O H Cr O OH

O H R1

R2 O R1

R2

H R2

:OH2

OH Cr O OH

The intramolecular mechanism is also operative:

O

OH Cr O O R1

H R2

O R1

R2

OH Cr O OH

319

Example 114

OH O O

O O

O O

H

1. Jones reagent acetone, 20 min. 2. HCO2H, rt, 1 h 96% 2 steps

CO2t-Bu O O O

O O

O O

CO2H

H

()-CP-263114

Example 215

O

O

CO2Me

CO2Me CrO3, H2SO4 acetone/H2O

HO H

O H

rt, 74% H

H Collins/Sarett oxidation5

O

O Ph

OH O

O

O

8 eq CrO3•2Pyr

Ph

CHO O

O

CH2Cl2, 15 min. 86%

O

PCC oxidation6

EtO2C

OH 1.5 eq PCC, CH2Cl2 N

rt, 3 h, 75%

EtO2C

O N

320

PDC oxidation7

S O S

OH

PDC, CH2Cl2 S O

24 h, 68% S

CHO

References 1.

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

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. Poos, G. I.; Arth, G. E.; Beyler, R. E.; Sarett, L. H. J. Am. Chem. Soc. 1953, 75, 422. Ratcliffe, R. W. Org. Syn. 1973, 53, 1852. Andrieux, J.; Bodo, B.; Cunha, H.; Deschamps-Vallet, C.; Meyer-Dayan, M.; Molho, D. Bull. Soc. Chim. Fr. 1976, 1975. Vanmaele, L.; De Clerq, P.; Vandewalle, M. Tetrahedron Lett. 1982, 23, 995. Krow, G. R.; Shaw, D. A.; Szczepanski, S.; Ramjit, H. Synth. Commun. 1984, 14, 429. Terpstra, J. W.; Van Leusen, A. M. J. Org. Chem. 1986, 51, 230. Gomez-Garibay, F.; Quijano, L.; Pardo, J. S. C.; Aguirre, G.; Rios, T. Chem. Ind. 1986, 827. Glinski, J. A.; Joshi, B. S.; Jiang, Q. P.; Pelletier, S. W. Heterocycles 1988, 27, 185. Turjak-Zebic, V.; Makarevic, J.; Skaric, V. J. Chem. Soc. (S) 1991, 132. Luzzio, F. A. Org. React. 1998, 53, 1222. (Review). Zhao, M.; Li, J.; Song, Z.; Desmond, R. J.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323. (Catalytic CrO3 oxidation). Caamano, O.; Fernandez, F.; Garcia-Mera, X.; Rodriguez-Borges, J. E. Tetrahedron Lett. 2000, 41, 4123. Waizumi, N.; Itoh, T.; Fukuyama, T. J. Am. Chem. Soc. 2000, 122, 7825. Hagiwara, H.; Kobayashi, K.; Miya, S.; Hoshi, T.; Suzuki, T.; Ando, M. Org. Lett. 2001, 3, 251. Arumugam, N.; Srinivasan, P. C. Synth. Commun. 2003, 33, 2313. Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2005, 44, 1275. 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 heteroarylsulfones and aldehydes. A sulfone reduction step is not required.

N N R1 1. KHMDS SO 2 N N 2. R2CHO Ph

R2

R1

N N OH N N Ph

SO2

O

N(TMS)2 R2

H N N R1 SO2 N N Ph

O

H

N N R1 SO2 N N Ph

N N R1 SO 2 N N Ph

N N O N N Ph R1

K R2 O N N N R1 N S O 2 Ph

R2

R1

R2

N N OH N N Ph

R2 S O

O

SO2

The use of larger counterion (such as K+) and polar solvents (such as DME) favors an open transition state (PT = phenyltetrazolyl):

O R1 H

H R2 SO2PT

R1

SO2PT R2 OK

322

Example 1, (BT = benzotriazole)4

SO2BT

OHC

OTIPS

NaHMDS, DMF

78 oC to rt, 90% Example 2

OTIPS

E:Z (78:22)

6

OTBS OPiv O

O

N O

S S O O

OMe o

KHMDS, THF, 78 C, 85% OPiv

OTBS

O O

OMe

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336. Baudin, J. B.; Hareau, G.; Julia, S. A.; Loene, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856. Charette, A. B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morely, A. Synlett 1998, 26. Blakemore, P. R.; Kocienski, P. J.; Morley, A.; Muir, K. J. Chem. Soc., Perkin Trans. 1 1999, 955. Williams, D. R.; Brooks, D. A.; Berliner, M. P. J. Am. Chem. Soc. 1999, 121, 4924. Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365. Smith, A. B., III; Wan, Z. J. Org. Chem. 2000, 65, 3738. Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772. Compostella, F.; Franchin, L.; Panza, L.; Prosperi, D.; Ronchetti, F. Tetrahedron 2002, 58, 4425. Meyers, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 694. Furuichi, N.; Hara, H.; Osaki, T.; Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949. Bedel, O.; Haudrechy, A.; Langlois, Y. Eur. J. Org. Chem. 2004, 3813. Alonso, D. A.; Najera, C.; Varea, M. Tetrahedron Lett. 2004, 45, 573. 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

1. n-BuLi 2. R1CHO

Ar

S O O

R

3. Ac2O

Na(Hg)

R

SO2Ar H

D-deprotonation

O O

Ar S O O

acetylation

SO2Ar R1

coupling

R1

R

R1

R

CH3OH

OAc

n-Bu

R

SO2Ar R1

H

O O

R

SO2Ar R1 O

R

O O

SO2Ar R1 OAc

O

Na(Hg) single electron transfer (SET)

4 possible diastereomers

SO2Ar

R

Na(Hg)

R1

single electron transfer (SET)

OAc

R

R1 OAc OAc

R

O

R1

324

Example 13

SO2Ph

1. n-BuLi, THF, 78 oC

3. Ac2O

2.

4. Na(Hg)

E:Z (99:1) OHC

Example 24

O OTBS O N TEOC

SO2Ph Li

H CHO

N TEOC

OTBS

H

1. THF, 78 oC 2. Ac2O 3. 5% Na(Hg), 77%

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Julia, M.; Paris, J. M. Tetrahedron. Lett. 1973, 4833. Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1978, 834. Kocienski, P. J.; Lythgoe, B. J. Chem. Soc., Perkin Trans. 1 1980, 1045. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194. Marko, I. E.; Murphy, F.; Dolan, S. Tetrahedron Lett. 1996, 37, 2089. Satoh, T.; Hanaki, N.; Yamada, N.; Asano, T. Tetrahedron 2000, 56, 6223. Charette, A. B.; Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42, 5149. Marko, I. E.; Murphy, F.; Kumps, L.; Ates, A.; Touillaux, R.; Craig, D.; Carballares, S.; Dolan, S. Tetrahedron 2001, 57, 2609. Breit, B. Angew. Chem., Int. Ed. 1998, 37, 453. Zanoni, G.; Porta, A.; Vidari, G. J. Org. Chem. 2002, 67, 4346. Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci, F. C. J. Am. Chem. Soc. 2002, 124, 1664. D’herde, J. N. P.; De Clercq, P. J. Tetrahedron Lett. 2003, 44, 6657. Bernard, A. M.; Frongia, A.; Piras, P. P.; Secci, F. Synlett 2004, 1064. 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 glycosyl acceptor. The sulfoxide activation is achieved using Tf2O.

OPiv

PivO

O PivO

O Ph O HO

O S Ph

PivO

O N3

SPh

CH3 OPiv

PivO

t-Bu

t-Bu

N

O PivO

Tf2O, CH2Cl2,78 to 30 oC F F OPiv

PivO

F

O PivO

O:

PivO

PivO

F F

OTf S Ph

SN1

Ph

OPiv O

PivO

F

OPiv

TfO PivO

O O S O S O O

PivO

oxonium ion

O Ph O HO

O N3

SPh

O

O N3

O S Ph

PivO

PivO

PivO

Ph O O

S

OTf

SPh

326

PivO

OPiv Ph O O

O PivO Example 1

PivO

O

O N3

SPh

2

O BzO

OMOM OMOM OMe OH

OBn OBn

O Tf2O, DTBMP, CH2Cl2

S(O)Ph OBn

O

BzO

OMOM OMOM OMe O O

70 to 50 oC, 38%

OBn OBn

OBn

Example 26

O

O Ph

O

O SPh

O MeO

OTBS OPMB

o

78 to 0 C, 67%

OTBS OH

Ph Tf2O, DTBMP, CH2Cl2

OTIPS

O O

PMBO

MeO O O OTBS

O OTIPS OTBS

References Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am. Chem. Soc. 1989, 111, 6881. 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, 115251. (Review). 1. 2.

327

Keck macrolactonization Macrolactonization of Ȧ-hydroxyl acids using a combination of DCC, DMAP and DMAPxHCl.

O

O

DCC, DMAP

HO

n

OH

H Cy N C N H+ Cy N C N O H O 1,3-dicyclohexylcarbodiimide (DCC)

N Cy

HN Cy O O

+

H

:

n

n

OH

n

OH

HN Cy N

n

Cy N

O

DMAP•HCl, CHCl3

O

O H N

OH N

N dimethylaminopyridine (DMAP)

H+ O

O N H

1,3-dicyclohexylurea

N N

n

OH

:

N H

328

N

O N

O

O H O

DMAP

n

n

Example 17

H

HO2C

N

N-(3-methylaminopropyl)N'-ethylcarbodiimide hydrochloride H

OH

DMAP, DMAP•HCl, CHCl3, THF reflux, 10 h, > 32%

Cl OH

H O

N O H

Cl

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

Boden, E. P.; Keck, G. E. J. Org. Chem. 1985, 50, 2394. Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming, J. G.; Smith, J. D. J. Am. Chem. Soc. 1994, 116, 9391. Keck, G. E.; Sanchez, C.; Wager, C. A. Tetrahedron Lett. 2000, 41, 8673. Tsai, C.-Y.; Huang, X.; Wong, C.-H. Tetrahedron Lett. 2000, 41, 9499. Hanessian, S.; Ma, J.; Wang, W. J. Am. Chem. Soc. 2001, 123, 10200. Lewis, A.; Stefanuti, I.; Swain, S. A.; Smith, S. A.; Taylor, R. J. K. Org. Biomol. Chem. 2003, 1, 104. 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(CO2R )2

CO2R1

R

OH

CO2H

R

1

CO2R

deprotonation

NH

(CO2R1)2CH

H :

H

iminium ion

OH R :N

NH R

O

formation

H R

NH

R

R

H 1 CO2R 1 CO2R

H N

O

O

N

OH

O

: NH2

CH(CO2R1)2

NH2

:

H CH(CO2R1)2

N H

1

O R1

R1 hydrolysis

OH

HO O R O HO

O

O R1

O R1

R

OH H+ R workup

O O

O

O

O

O H

H+ decarboxylation

CO2n

R

x

O OH

H

R

CO2H

330

Example 17

O

O O

N H Boc

NCbz

NCbz

N H Boc

O

Meldrum's acid

O

O

o

CHO

EDDA, PhH, 60 C 12 h, 84%

O

O

Example 2, using ionic liquid ethylammonium nitrate (EAN) as solvent13

CHO

CN CO2Et

ethylammonium nitrate rt, 10 h, 87% CN CO2Et

References 1.

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

Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1898, 31, 2596. Emil Knoevenagel (18651921) 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. Jones, G. Org. React. 1967, 15, 204. (Review). Van der Baan, J. L.; Bickelhaupt, F. Tetrahedron 1974, 30, 2447. Green, B.; Khaidem, I. S.; Crane, R. I.; Newaz, S. S. Tetrahedron 1976, 31, 2997. Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. J. Chem. Soc., Perkin Trans. 1 1989, 105. Paquette, L. A.; Kern, B. E.; Mendez-Andino, J. Tetrahedron Lett. 1999, 40, 4129. Tietze, L. F.; Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045. Balalaie, S.; Nemati, N. Synth. Commun. 2000, 30, 869. Pearson, A. J.; Mesaros, E. F. Org. Lett. 2002, 4, 2001. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Tsadjout, A. Synth. Commun. 2002, 32, 355. Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem. 2002, 67, 4615. Wada, S.; Suzuki, H. Tetrahedron Lett. 2003, 44, 399. 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).

R3

R O

NH NH2

N

O R2

R1

R N

R2

R1

R3

R N N

R2 R3

R1

R = H, Alkyl, Aryl, Het-aryl, Acyl, etc.

R3

R NH NH2

O R1

O

N

OR2

R1

R O

NH2NH2

O R

R N

OH R3

R N NH

N NH R

R1

R OH NH NH OH R

R

R

OH

Alternatively,

R

R O

N NH2 O

NH2NH2

O R

R R

R

N NH

N NH R

OH

R

N

R N

O R3

332

Example 15

OMe O MeO

MeNHNH2

HCl, H2O N

Me

Me N

84% Me

Example 213

O

O Me

EtO2CCF3, NaOMe, MeOH reflux, 24 h, 94%

Me

O CF3

Me Me

O H2N S O

N NH2xHCl H EtOH, reflux, 46%

N N

CF3

O S H2N

O

Celebrex

References 1

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

Knorr, L. Ber Dtsch. Chem. Ges. 1883, 16, 2597. Ludwig Knorr (18591921) was born near Munich, Germany. After studying under Volhard, Emil Fischer, and Bunsen, he was appointed professor of chemistry at Jena. Knorr made tremendous contributions in the synthesis of heterocycles in addition to discovering the important pyrazolone drug, pyrine. Knorr, L. Ber Dtsch. Chem. Ges. 1884, 17, 546, 2032. Knorr, L. Ber Dtsch. Chem. Ges. 1885, 18, 311. Knorr, L., Justus Liebigs Ann. Chem. 1887, 238, 137. Burness, D. M. J. Org. Chem. 1956, 21, 97. Jacobs, T. L., in Heterocyclic Compounds, Elderfield, R. C., Ed.; Wiley: New York, 1957, 5, 45. (Review). Houben-Weyl, 1967, 10/2, 539, 587, 589, 590. (Review). Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996, 37, 1003. Elguero, J., In Comprehensive Heterocyclic Chemistry II, Katrizky, A. R.; Rees, C. W.: Scriven, E. F. V., Eds; Elsevier: Oxford, 1996, 3, 1. (Review). Penning, T. D.; Talley, J. J.; et al. J. Med. Chem. 1997, 40, 1347. Shen, D-M.; Shu, M.; Chapman, K. T. Org. Lett. 2000, 2, 2789. Stanovnik, E.; Svete, J. in Science Of Synthesis, 2002, 12, 15; Ed. by Neier, R.; Thieme. (Review). Carpino, P. A.; Lefker, B. A.; Toler, S. M.; et al. Bioorg. Med. Chem. 2003,11, 581. Sakya, S. M. Knorr Pyrazole Synthesis In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 292300. (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).

O

R2 NH2

R1

R

R

O H2N R2

:

O

O 1

R

R

R

H OH

HO

:

HO

N R1 R2

R

:

HO R

N 2 R

R H

H R

1

R

R1 OH

HN R2

O

slow

R1

N R2

H N R2

R1

H R

1

N 2 R

R

N R2

R1

Example 15 EtO

OEt

OEt F

O

O CONHPh

H2N

OEt

1 eq. pivalic acid THF, reflux, 43%

F

N CONHPh

334

2+

Ca HO

CO2

HO F

N H N O Lipitor

Example 2

2

7

Cl

O

N

NH4OAc O

F N

HOAc 110 °C 90% F

N H

Cl

References Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. Corwin, A. H. Heterocyclic Compounds Vol. 1, Wiley, NY, 1950; Chapter 6. (Review). 3. Jones, R. A.; Bean, G. P. The Chemistry of Pyrroles, Academic Press, London, 1977, pp 5157, 7479. (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 PaalKnorr Pyrrole Syntheses In Name Reactions in Heterocyclic Chemistry, Eds, Li, J. J.; Corey, E. J. Wiley & Sons: Hoboken, NJ, 2005, 7988. (Review). 1. 2.

335

Koch–Haaf carbonylation Strong acid-catalyzed tertiary carboxylic acid formation from alcohols or olefins and CO.

R

OH

R

CO, H2O

CO2H

H+

R

H

H O:

R

protonation

O H

H+

R

:C O:

R

alkyl

R

migration the tertiary carbocation is thermodynamically favored O

O

R

R

OH2

:OH2

acylium ion

O

H+

R

OH

Example 15

OH

CO2H HCO2H, H2SO4 rt, 66%

O

336

Example 27

OH

HCO2H, H2SO4 CCl4, 5 oC, 95%

CO2H

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Koch, H.; Haaf, W. Justus Liebigs Ann. Chem. 1958, 618, 251. Kell, D. R.; McQuillin, F. J. J. Chem. Soc., Perkin Trans. 1 1972, 2096. Norell, J. R. J. Org. Chem. 1972, 37, 1971. Booth, B. L.; El-Fekky, T. A. J. Chem. Soc., Perkin Trans. 1 1979, 2441. Langhals, H.; Mergelsberg, I.; Rüchardt, C. Tetrahedron Lett. 1981, 22, 2365. Farooq, O.; Marcelli, M.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem. Soc. 1988, 110, 864. Takahashi, Y. Synth. Commun. 1989, 19, 1945. Stepanov, A. G.; Luzgin, M. V.; Romannikov, V. N.; Zamaraev, K. I. J. Am. Chem. Soc. 1995, 117, 3615. Olah, G. A.; Prakash, G. K. S.; Mathew, T.; Marinez, E. R. Angew. Chem., Int. Ed. 2000, 39, 2547. Xu, Q.; Inoue, S.; Tsumori, N.; Mori, H.; Kameda, M.; Tanaka, M.; Fujiwara, M.; Souma, Y. J. Mol. Catal. A: Chem. 2001, 170, 147. Tsumori, N.; Xu, Q.; Souma, Y.; Mori, H. J. Mol. Catalysis A: Chem. 2002, 179, 271. Mori, H.; Mori, A.; Xu, Q.; Souma, Y. Tetrahedron Lett. 2002, 43, 7871. Li, T.; Tsumori, N.; Souma, Y.; Xu, Q. Chem. Commun. 2003, 2070. Haubein, N. C.; Broadbelt, L. J.; Schlosberg, R. H. Ind. Eng. Chem. Res. 2004, 43, 18.

337

Koenig–Knorr glycosidation Formation of the E-glycoside from D-halocarbohydrate under the influence of silver salt.

AcO

AcO

O

AcO AcO

H

O Br Ac

H H

AcO AcO AcO

H H

O H H

O

H2O

CO2n

O

H AcO AcO

O Br Ac Ag+

H O R

O

OR

O H Ac

H H

AcO

O:

:

AcO AcO

AcO AcO

Ag2CO3

AgBr AcO

O

ROH

H O H oxonium ion AcO

E-anomer is

AcO AcO

favored

O:

O O H Ac

H H E-anomer

Example 113

MeO2C

O

Br

NO2 HO

N

OPiv

PivO

N

OPiv Ag2O, 10 eq. HMTTA CH3CN, rt, 6 h, 41%

CF3

OR

338

NO2 MeO2C

O

O

N N

OPiv

PivO

CF3

OPiv Example 215

OMe

AcO AcO AcO

O H H

H O Br Ac

OH OMe

Cd2CO3, Tol. reflux, 6 h, 84%

AcO AcO AcO

O H H

O

O Ac

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Koenig, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957. Igarashi, K. Adv. Carbohydr. Chem. Biochem. 1977, 34, 24383. (Review). Schmidt, R. R. Angew. Chem. 1986, 98, 213. Greiner, J.; Milius, A.; Riess, J. G. Tetrahedron Lett. 1988, 29, 2193. Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. J. Am. Chem. Soc. 1991, 113, 2092. Li, H.; Li, Q.; Cai, M.-S.; Li, Z.-J. Carbohydr. Res. 2000, 328, 611. Fürstner, A.; Radkowski, K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000, 65, 8758. Josien-Lefebvre, D.; Desmares, G.; Le Drian, C. Helv. Chim. Acta 2001, 84, 890. Seebacher, W.; Haslinger, E.; Weis, R. Monatsh. Chem. 2001, 132, 8397. Yashunsky, D. V.; Tsvetkov, Y. E.; Ferguson, M. A. J.; Nikolaev, A. V. J. Chem. Soc., Perkin Trans. 1 2002, 242. Kroger, L.; Thiem, J. J. Carbohydrate Chem. 2003, 22, 9. Somsak, L.; Kovacs, L.; Gyollai, V.; Osz, E. Chem. Commun. 1999, 591. Stazi, F.; Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J. Org. Chem. 2004, 69, 1097. Claffey, D. J.; Casey, M. F.; Finan, P. A. Carbohydrate Res. 2004, 339, 2433. 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 Na

OH

OH

CO2

CO2 Na

H

CO2H

pressure

O Na

O

CO2 complexation

Na

O

nucleophilic

O

addition

H

OH

aromatization

Na O O O

OH CO2 Na

H workup

CO2H

Example 13

OH

OH

CO2, KHCO3 NH2

HO2C

8590 oC, 60%

NH2

Example 2, the Marasse modification of the Kolbe–Schmitt reaction uses excess of anhydrous potassium carbonate in place of carbon dioxide4

OH

K2CO3, 175 oC 1200200 psi CO2

OH CO2 K

340

Example 3, the Jones modification of the Kolbe–Schmitt reaction employs sodium ethyl carbonate5

OH

OH NaOCO2C2H5

CO2 Na

C2H5OH

Salicylic acid is the precursor to the synthesis of aspirin:

O

OH

HO

O (CH3CO2)2O 90%

salicylic acid

O

OH CH3CO2H

O aspirin

References Kolbe, H. Justus Liebigs Ann. Chem. 1860, 113, 1125. Hermann Kolbe (18181884) 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 under high pressure at 180200 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. Organomet. Chem. 2000, 14, 841. 10. Rahim, M. A.; Matsui, Y.; Kosugi, Y. Bull. Chem. Soc. Jpn. 2002, 75, 619. 1.

341

Kostanecki reaction Also known as KostaneckiRobinson reaction. Transformation 1o2 represents an AllanRobinson reaction (see page 8), whereas 1o3 is a Kostanecki (acylation) reaction:

O

OH

O

R

O

R

O

O

R

O R

O

O 1

2

R

R

: O

H O

O O O

H O

O

3

O

acyl

O transfer

R R

O H O

O O R

6-exo-trig

O

enolization

R

O

ring closure

O

O

O R H

OH

O

O

O

O

H2O R

:B

R

OH

Example 15

O

O

OH H

O

O

OEt

OEt HCO2Na, rt, 15 h, 76% O

O

O

O

342

Example 213

O

O NaOAc, Ac2O, reflux HO

O O

O

62 %

O

O

O

O

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

10. 11.

12. 13. 14. 15.

von Kostanecki, S.; Rozycki, A. Ber. Dtsch. Chem. Ges. 1901, 34, 102. Hauser, C. R.; Swamer, F. W.; Adams, J. T. Org. React. 1954, 8, 59. (Review). Cook, D.; McIntyre, J. S. J. Org. Chem. 1968, 33, 1746. Széll, T.; Dózsai, L.; Zarándy, M.; Menyhárth, K. Tetrahedron 1969, 25, 715. Pardanani, N. H.; Trivedi, K. N. J. Indian Chem. Soc. 1972, 49, 599. Okumura, K.; Kondo, K.; Oine, T.; Inoue, I. Chem. Pharm. Bull. 1974, 22, 331. Wagner, H.; Farkas, L. In The Flavanoids; Harborne, J. B.; Mabry, T. J.; Mabry H., eds.; Academic Press: New York, 1975; p 127. (Review). Ahluwalia, V. K. Indian J. Chem., Sect. B 1976, 14B, 682. Ellis, G. P., Chromenes, Chromanones, and Chromones from The Chemistry of Heterocyclic Compounds, Weissberger, A. and Taylor, E. C., eds.; Wiley & Sons: New York, 1977, vol. 31, p.495. (Review). Looker, J. H.; McMechan, J. H.; Mader, J. W. J. Org. Chem. 1978, 43, 2344. Stanton, J. In Comprehensive Organic Chemistry-The Synthesis and Reactions of Organic Compounds; Sammes, P. G., ed.; Pergamon Press: New York, 1979, vol.4; p. 659. (Review). Iyer, P. R.; Iyer, C. S. R.; Prasad, K. J. R. Indian J. Chem., Sect. B 1983, 22B, 1055. Flavin, M. T.; Rizzo, J. D.; Khilevich, A.; et al. J. Med. Chem. 1996, 39, 1303. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Ya. A. Chemistry of Heterocyclic Compounds 2003, 39, 96. Limberakis, C. KostaneckiRobinson Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 521535. (Review).

343

Kröhnke pyridine synthesis Pyridines from D-pyridinium methyl ketone salts and DE-unsaturated ketones.

O O

R1

N

R

R2

NH4OAc, HOAc

Br H+ O

H

R

Michael

N

R R1

R2

Br

Br

R

R N

N

O

R1 H

1

R

H O

O +

H

2

R

2

R R

R

R

O

O 1

O

addition

O

O

R

Br

H Br AcO

2

N

O

enolization

N

R

R1

R

O 1

R

R1

HN

OAc

:

HO H2N

:NH3 2 R R2 The ketone is more reactive than the enone

H

2

R

R1 R1 R2 AcO

N H

R OH +

H

R2

N

R

344

Example 12

N + Ph

O

Ph

NH4OAc AcOH

Ph

90% O

Ph

Ph

N

Ph

Example 210

N N

N

N N N N O

O

NH4OAc AcOH

N

81%

N N

N

N

O References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Zecher, W.; Kröhnke, F. Ber. 1961, 94, 690. Kröhnke, F.; Zecher, W. Angew. Chem. Intl. Ed. 1962, 1, 626. Kröhnke, F. Synthesis 1976, 124. (Review). Chatterjea, J. N.; Shaw, S. C.; Singh, J. N.; Singh, S. N. Indian J. Chem., Sect. B 1977, 15B, 430. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584, 3585. Newkome, G. R.; Hager, D. C.; Kiefer, G. E. J. Org. Chem. 1986, 51, 850. Constable, E. C.; Ward, M. D.; Tocher, D. A. J. Chem. Soc., Dalton Trans. 1991, 1675. Constable, E. C.; Chotalia, R. J. Chem. Soc., Chem. Commun. 1992, 65. Markovac, A.; Ash, A. B.; Stevens, C. L.; Hackley, B. E., Jr.; Steinberg, G. M. J. Heterocycl. Chem. 1977, 14, 19. Kelly, T. R.; Lee, Y.-J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774. Bark, T.; Von Zelewsky, A. Chimia 2000, 54, 589. Malkov, A. V.; Bella, M.; Stara, I. G.; Kocovsky, P. Tetrahedron Lett. 2001, 42, 3045. Cave, G. W. V.; Raston, C. L. J. Chem. Soc. Perkin Trans. 1 2001, 3258. Galatsis, P. Kröhnke Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 311313. (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 reaction of a Grignard reagent with an organic halide, triflate, etc.

Pd(0)

R1 MgX

R X

oxidative R X

R

L2Pd(0) addition L

MgX2

L Pd 1 R R

R R1 L Pd X L

MgX2 R1 MgX

transmetallation isomerization

reductive R R1

L2Pd(0)

elimination

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 reactions, for which an additional activation step is required for the transmetalation to occur. The catalytic cycle:

LnPd(II)

R1M

transmetallation

reductive R elimination

1

R1

R1 LnPd(II)

LnPd(0)

R1

346

R X L2Pd(0) R R1 oxidative addition

R

L Pd X L

R1M

reductive elimination transmetallation and isomerization L

L Pd 1 R R MX

Example 12

Pd(dppf)Cl2, Et2O O

Br

S

MgBr

O o

S

–30 C to rt, 5 h, 98%

Example 24

Br

N

MgBr N

N

Br

S

PdCl2•(dppb) THF, rt, 87%

N

Br

MgBr

PdCl2•(dppb) THF, reflux, 98%

N N S

347

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodma, S.-i.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958. Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919. Kalinin, V. N. Synthesis 1992, 413. Meth-Cohn, O.; Jiang, H. J. Chem. Soc., Perkin Trans. 1 1998, 3737. Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). Park, M.; Buck, J. R.; Rizzo, C. J. Tetrahedron 1998, 54, 12707. Huang, J.; Nolan, S. P. J. Am. Chem. Soc. 1999, 121, 9889. Uenishi, J.; Matsui, K. Tetrahedron Lett. 2001, 42, 4353. Li, G. Y. J. Organomet. Chem. 2002, 653, 63. Anctil, E. J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150. Banno, T.; Hayakawa, Y.; Umeno, M. J. Organomet. Chem. 2002, 653, 288. Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68, 1190. Phan, N. T. S.; Brown, D. H.; Styring, P. Green Chem. 2004, 6, 526. Mans, D. M.; Pearson, W. H. J. Org. Chem. 2004, 69, 6419. Shao, L.-X.; Shi, M. Org. Biomol. Chem. 2005, 3, 1828. 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, transforms the carbonyl groups of ketones, amides and esters into the corresponding thiocarbonyl compounds. Cf. Knorr thiophene synthesis.

S P S S P S

O

O

N H

O S

N H

Lawesson's reagent

S

S P S S P S

O

2 O

NH

S P S O

H N N H

NH

S

O P S

O

Example 14

H

H

O O

O

Lawesson's reagent (Me2N)2C=S

H xylene, 160 oC, 47% OMe

S

:

O

P O

O

S S P O

O

O S

S

H OMe

349

Example 24

S

O MeO2C

N

H Lawesson's

MeO2C

N

H

reagent, 95% References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Lawesson, S. O.; Perregaad, J.; Scheibye, S.; Meyer, H. J.; Thomsen, I. Bull. Soc. Chim. Belg. 1977, 86, 679. Navech, J.; Majoral, J. P.; Kraemer, R. Tetrahedron Lett. 1983, 24, 5885. Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061. (Review). Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. Angew. Chem., Int. Ed. Engl. 1989, 27, 1362. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Luheshi, A. B. N.; Smalley, R. K.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 123. Luo, Y.; He, L.; Ding, M.; Yang, G.; Luo, A.; Liu, X.; Wu, T. Heterocycl. Commun. 2001, 7, 37. He, L.; Luo, Y.; Li, K.; Ding, M.; Luo, A.; Liu, X.; Wu, T.; Cai, F. Synth. Commun. 2002, 32, 1415. 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 presence 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.

R3

R1 HN

O

R4

R2

R3 N R4

R2

CO2n

H2O

H

R1

HO H 1 R N R3 2 4 R R

O 2

R

H

1

3

R

:N

H2O

R N R4

R2

HO N R3 R2 R4 D-aminoalcohol

R1

R1 HCO2H

R2

:

R4 H R3

R1

HCO2H

R3 N R4 H O

H O

iminium ion intermediate

CO2

R1 R2 H

R3 N R4 H

reduction

H+

R1 R2

R3 N R4

Example 15

CHO

H N

HCO2H

O

60 oC, 57%

O N

Example 27

HCO2H, H2O

O

o

OHC

N

190 C, autoclave 16 h, 75%

N

351

References Leuckart, R. Ber. Dtsch. Chem. Ges. 1885, 18, 2341. Carl L. R. A. Leuckart (18541889) was born in Giessen, Germany. After studying under Bunsen, Kolbe, and von Baeyer, he became an assistant professor at Göttingen. Unfortunately, chemistry lost a brilliant contributor by his sudden death at age 35 as a result of a fall in his parent’s house. 2. Wallach, O. Justus Liebigs Ann. Chem. 1892, 272, 99. Otto Wallach (18471931), 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. 1.

352

Lossen rearrangement Treatment of O-acylated hydroxamic acids with base provides isocyanates. O R1

N H

O

R2

OH

O

R2

R1 N C O

H 2O

R1 NH2

CO2n

O O

R

1

N H

O R1

O

N

R2

O O

OH HO H R1 N C O

2

R CO2

:OH2 isocyanate intermediate

1

R

H N

O O

decarboxylation

H

R1 NH2

CO2n

:B

Example 16

O Cl Br

EtO2C

H N

O

CO2Et

Et3N, H2O

Br NH2

EtOH, H2O 50%

N

Br

C

O

353

Example 28

N

N AcO

H N

DBU, THF, H2O

N O

O MeO

reflux, 1 h

O

C

N

OMe

N O MeO

OMe

N H2N

N O MeO

OMe

References 1.

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

Lossen, W. Ann. 1872, 161, 347. Wilhelm C. Lossen (18381906) 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. Bauer, L.; Exner, O. Angew. Chem. 1974, 86, 419. Lipczynska-Kochany, E. Wiad. Chem. 1982, 36, 735. Casteel, D. A.; Gephart, R. S.; Morgan, T. Heterocycles 1993, 36, 485. Zalipsky, S. Chem. Commun. 1998, 69. Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett. 2000, 41, 5291. Needs, P. W.; Rigby, N. M.; Ring, S. G.; MacDougall, A. J. Carbohydr. Res. 2001, 333, 47. 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.

O R

N H

O R

N H

H N

H N

O

Base SO2Ar

R

H

O SO2Ar

R

N

N

H

B:

O

homolytic N2n

cleavage

O H

R

R

H

Example 19 O O2N

NH HN SO2

O K2CO3, MeOH

O2 N

reflux, 1 h, 75%

Example 211

O N N H

NaCO3, glass powder ethylene glycol

O NHNHTs

microwave (450 W) 90% O

N N H

O H

H

355

References 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 Glasgow, he worked for ICI for 15 years before returning to Canada where he worked for the Canadian Industries, Ltd., Montreal. 2. Newman, M. S.; Caflisch, E. G., Jr. J. Am. Chem. Soc. 1958, 80, 862. 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. 1.

356

McMurry coupling Olefination of carbonyls with low-valent titanium such as Ti(0) derived from TiCl3/LiAlH4. Single-electron process.

R1 O 2

R

1. TiCl3, LiAlH4

R1

R1

2. H2O

R2

R2

Ti(III)Cl3

R1

Ti(0)

LiAlH4

Ti Ti O O

single electron O

R2

:Ti(0)

R 2 2 R R radical anion intermediate R

Ti Ti O O R1

R 2

R R

homocoupling 1

1

transfer

TiO

Ti Ti O O

1

R1

2

R1 R2 R2

R1

R1

R2

R2

Ti Ti O O oxide-coated titanium surface

Example 112

OH MeO2S Zn, TiCl4, reflux O O

4.5 h, 75%, >99% Z

357

MeO2S

OH

Example 213

S

CHO

Zn, TiCl4, THF,110 oC microwave (10 W), 10 min. 87%

S S

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

McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc. 1974, 96, 4708. McMurry, J. E. Chem. Rev. 1989, 89, 15131524. (Review). Ephritikhine, M. Chem. Commun. 1998, 2549. Hirao, T. Synlett 1999, 175. Yamato, T.; Fujita, K.; Tsuzuki, H. J. Chem. Soc., Perkin Trans. 1 2001, 2089. Sabelle, S.; Hydrio, J.; Leclerc, E.; Mioskowski, C.; Renard, P.-Y. Tetrahedron Lett. 2002, 43, 3645. Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem. Soc. 2003, 125, 1843. Kowalski, K.; Vessieres, A.; Top, S.; Jaouen, G.; Zakrzewski, J. Tetrahedron Lett. 2003, 44, 2749. Honda, T.; Namiki, H.; Nagase, H.; Mizutani, H. Tetrahedron Lett. 2003, 44, 3035. Ephritikhine, M.; Villiers, C. in Modern Carbonyl Olefination Takeda, T. ed., WileyVCH: Weinheim, Germany, 2004, 223285. (Review). Rajakumar, P.; Gayatri Swaroop, M. Tetrahedron Lett. 2004, 45, 6165. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Synlett 2004, 1513. Stuhr-Hansen, N. Tetrahedron Lett. 2005, 46, 5491.

358

MacMillan catalyst Highly enantioselective and general asymmetric organocatalytic Diels-Alder reaction using D-amino acid-derived imidazolidinones (of type 1) as catalysts. The first generation of MacMillan catalyst (1) has been employed in a variety of organocatalytic enantioselective reactions. Typical examples are: Diels-Alder reaction;1 nitrone cycloaddition,2 pyrrole FriedelCrafts reaction,3 indole addition,4 vinylogous Michael addition;5 D-chlorination;6 hydride addition;7 cyclopropanation;8 D-fluorination.9 The second generation of MacMillan catalyst (2) was used to catalyze 1,4-addition of C-nucleophiles employing various indoles.

O

Me N

Ph

N H

HX

Me Me

imidazolidinone 1 5 mol% (1)

O

+

23 oC

O

Me N

Ph CHO HX

CHO 82%, 94% ee (endo/exo 14:1)

N H

O

Me

dienophile

Me

O

Me N

H

Me Me + N N Me Ph

+ N Ph

O diene

Me Me

359

O N N H

R2 R3

R4

imidazolidinone 2

O

20 mol% 2, CH2Cl2-i-PrOH 87 to 50 oC

N R1 R2 R3

R4

H O

7094% yield 8997% ee

N R1 Example 111 O

O 20 mol% 2 Bn

O N Bn

O

90%, 90% ee

Bn

N Bn

Example 210

BocHN Br 1. 20 mol% 2 N

O

2. NaBH4, MeOH

360

OH

Br

N

H

N Boc

78% yield 90% ee

Br

N

H

N Me

()-flustramine B

References Ahrendt, K.; Borths, C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. Jen, W.; Wiener, J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874. Paras, N.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 1172. 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. 1. 2. 3. 4. 5.

361

Mannich reaction Three-component aminomethylation from amine, formaldehyde and a compound with an acidic methylene moiety. O

R

O

R NH

H

H

O R1

H

O

R

OH H

N R

R

2

R2

N R

R1

OH2

H+

R

H

R

:

HH N: R R

R

H

+

N R

H

N R

When R = H, the +Me2N=CH2 salt is known as Eschenmoser’s salt

O R1

R1

H+

O 2

enolization

R

R

H O R2

R

N R

R2

N R

R1

The Mannich reaction can also operate under basic conditions:

O

O R1

1

R

enolate

2

R H

R

formation

B:

R2

O R

N R

N R

R2 1

R

Mannich Base Example 1, asymmetric Mannich reaction4

NH2 O

OHC NO2

O

362

O 35 mol% (L)-proline

O HN

DMSO, rt, 50%, 94% ee NO2 Example 2, asymmetric aza-Mannich reaction13

N

o-Ts

O N OH

O

o-Ts

NH O

In(Oi-Pr)3, ligand MS 5 Å, THF, rt, 80%

N O

OH

References 1.

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

Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647. Carl U. F. Mannich (18771947) 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. Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1045. Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235. List, B. J. Am. Chem. Soc. 2000, 122, 9336. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221. (Review). Vicario, J. L.; Badía, D.; Carrillo, L. Org. Lett. 2001, 3, 773. Martin, S. F. Acc. Chem. Res. 2002, 35, 895904. (Review). Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580591. (Review). Córdova, A. Acc. Chem. Res. 2004, 37, 102112. (Review). 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 BH3xSMe2 NaOMe

OMs OMs BH3xSMe2 H 2B

H 

OMe

OMs H 2B H 

OMe

Example 15 OMs o

1. BH3xSMe2, THF, 0 C to rt, 3 h

OH

2. NaOMe, MeOH, rt, overnight 68%

OH

364

Example 26 OMs 1. BH3xSMe2, THF, 0 oC to rt, 3 h OAc

2. NaOMe, MeOH, rt, overnight 11%

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

Marshall, J. A.; Huffman, W. F. J. Am. Chem. Soc. 1970, 92, 6358. Marshall, J. A. Synthesis 1971, 229. (Review). Wharton, P. S.; Sundin, C. E.; Johnson, D. W.; Kluender, H. C. J. Org. Chem. 1972, 37, 34. Minnaard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. Tetrahedron 1994, 50, 4755. Zhabinskii, V. N.; Minnard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. J. Org. Chem. 1996, 61, 4022. 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. OH

Ph2S[OC(CF3)2Ph]2

Ph2S O

HOC(CF3)2Ph

Ph2S

H OtBu OC(CF3)2Ph

HOC(CF3)2Ph

Ph2S

OC(CF3)2Ph

O

:OC(CF3)2Ph The alcohol is acidic

H OC(CF3)2Ph : Ph2S O

OC(CF3)2Ph

protonation OC(CF3)2Ph

H OC(CF3)2Ph Ph2S O

Ph2S

OC(CF3)2Ph

O H

E-elimination

Ph2S O

HOC(CF3)2Ph

E1cB Example 19

OMe

OBn O

BzO OBn

OH

O

O

O OMe

O O

OPMB

Martin's sulfurane Et3N, CHCl3, 50 oC 85%

366

OMe

OBn O

BzO

O

O

O OMe

O O

OPMB

OBn Example 210 CO2Me

HO CO2Me 1.5 eq. Martin's sulfurane TBS O

O O MeO

TBSO OMe

CH2Cl2, rt, 24 h, 84%

O O MeO

OMe

References 1.

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

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 sulfurane dehydrating reagent. Martin also developed the DessMartin periodinane oxidation (page 195) with his student Daniele Dess. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327. Martin, J. C.; Arhart, R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977, 57, 22. Bartlett, P. D.; Aida, T.; Chu, H.-K.; Fang, T.-S. J. Am. Chem. Soc. 1980, 102, 3515. Gallagher, T. F.; Adams, J. L. J. Org. Chem. 1992, 57, 3347. Tse, B.; Kishi, Y. J. Org. Chem. 1994, 59, 7807. Winkler, J. D.; Stelmach, J. E.; Axten, J. Tetrahedron Lett. 1996, 37, 4317. Rao, P. N.; Wang, Z. Steroids 1997, 62, 487. Nicolaou, K. C.; Rodríguez, R. M.; Fylaktakidou, K. C.; Suzuki, H.; Mitchell, H. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 3340. Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P. M.; Whitehead, R. C. Synlett 2002, 358. Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679. 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. 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 O (EtO)2P

CHO

AcO

O

OEt D-keto or D-alkoxycarbonyl phosphonate required N N

CO2Et

AcO LiCl, CH3CN 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)

O (EtO)2P

O OEt deprotonation

H

O (EtO)2P

LiCl

O

:

OEt chelation

N N

O (EtO)2P

Li

O OEt

EtO2C

H AcO

O

EtO2C AcO

O P(OEt)2 O

AcO

O P OEt OEt O

AcO

CO2Et

368

Example 16

O

H MOMO

O

O

OMe

7

OO (EtO)2(O)P

MeO

O

O

LiCl, Hunig base

7

OMe

MOMO

OO

MeCN, rt, 14 h, 58%

MeO Example 27

Ph

Ph CHO

BocN

N

(EtO)2(O)P O

O

O O

Li, DBU, CH3CN, rt, 67% Ph

Ph N

BocN O

O

O O

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

Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183. Marshall, J. A.; DuBay, W. J. J. Org. Chem. 1994, 59, 1703. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 1035. Tius, M. A.; Fauq, A. H. J. Am. Chem. Soc. 1986, 108, 6389. Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058. Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123. Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.; Gilbert, J.; Kahn, I.; Redshaw, 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.

O R1

R2

HOi-Pr

1

R2

R

Al(Oi-Pr)3 : R1

R1

coordination

O

O

OH

Al(Oi-Pr)3

R R2

Oi-Pr O Al Oi-Pr O

2

H

cyclic transition state i-PrO Oi-Pr Al O O R1

O

R2

O R1

hydride transfer

H

Al(Oi-Pr)2

H+

OH R1

R2

R2

Example 12

O H O

H MeO2C

Al(Oi-Pr)3 HOi-Pr, 90%

H

OH H

H OH O

H

370

Example 212

O Br3C

OH H

Ph

O Al O

O O Br3C

CH2Cl2, rt, 2.5 h, 58%

Ph

References 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. 1.

371

Meisenheimer complex Also known as MeisenheimerJackson salt, the stable intermediate for certain SNAr reactions.

R

F NO2

NO2

RNH2

NO2 Sanger’s reagent

SNAr

NO2

R NH2

R HN

:

F

SNAr, slow,

NO2

NH

F NO2

rate-determining step NO2

NO2 ipso attack

ipso substitution

R NH F

R NO2

NH NO2

fast F

NO2

NO2

Meisenheimer complex (MeisenheimerJackson salt) Example 110

O NO2 CO2Et Ph

CN

N

O CO2Et

t-BuOK, DMF/THF 70 oC, argon

H NC

Ph

372

Example 213

OH CH2Cl2

NO2

O2N

2

N C N

argon, rt, 3 h

NO2 H O N N i-Pr i-Pr N N O2 N NO2

O N O2 N

N H NO2 15.8%

O

N

15.5%

NO2

O

The reaction using Sanger’s reagent is faster than using the corresponding chloro-, bromo-, and 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. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Meisenheimer, J. Justus Liebigs Ann. Chem. 1902, 323, 205. Strauss, M. J. Acc. Chem. Res. 1974, 7, 181. (Review). Bernasconi, C. F. Acc. Chem. Res. 1978, 11, 147. (Review). Terrier, F. Chem. Rev. 1982, 82, 77. (Review). Buncel, E.; Dust, J. M.; Manderville, R. A. J. Am. Chem. Soc. 1996, 118, 6072. Sepulcri, P.; Goumont, R.; Hallé, J.-C.; Buncel, E.; Terrier, F. Chem. Commun. 1997, 789. Manderville, R. A.; Buncel, E. J. Org. Chem. 1997, 62, 7614. Weiss, R.; Schwab, O.; Hampel, F. Chem. Eur. J. 1999, 5, 968. Hoshino, K.; Ozawa, N.; Kokado, H.; Seki, H.; Tokunaga, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 4572. Adam, W.; Makosza, M.; Zhao, C.-G.; Surowiec, M. J. Org. Chem. 2000, 65, 1099. Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548. Kim, H.-Y.; Song, H.-G. Appl. Microbiol. Biotech. 2003, 61, 150. 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: R R1 N R2 O

Example 15 O

' R2

N

then PtO2, rt, 4.5 h

O N

O

Example 26 O

O

THF, reflux, 1 h

O

O

O

O

m-CPBA O

N

Cl

POCl3

O N

CH2Cl2, 50%

N

N

O

64%, 2 steps

O N

R

O

35% H2O2, CHCl3/MeOH, rt, 15 h

O

N

R1 N

O

N O

N

O N

O

o

100 C, 66%

N

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

Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. [1,2]-Sigmatropic rearrangement, Castagnoli, N., Jr.; Craig, J. C.; Melikian, A. P.; Roy, S. K. Tetrahedron 1970, 26, 4319. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). Molina, J. M.; El-Bergmi, R.; Dobado, J. A.; Portal, D. J. Org. Chem. 2000, 65, 8574. Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.; Kurihara, T. Tetrahedron 1996, 52, 14563. 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: 3

3

2 1

2

'

O N 2 R R1

1

R

O N

2 1

R

Example 17

PhSO2

O N

Ph

Et2O, rt, 48 h 48%, 61% de

N

N

O

Example 28

Bn HO O N O

Bn N O

O

m-CPBA OH CH2Cl2, 100%

Bn O O N O

Al2O3 (alumina)

OH

MeOH Bn CDCl3, rt 67%, 65% de

O N O

O OH

OH

375

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

Meisenheimer, J. Ber. Dtsch. Chem. Ges. 1919, 52, 1667. [2,3]-Sigmatropic rearrangement, Yamamoto, Y.; Oda, J.; Inouye, Y. J. Org. Chem. 1976, 41, 303. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249. (Review). Kurihara, T.; Sakamoto, Y.; Matsumoto, H.; Kawabata, N.; Harusawa, S.; Yoneda, R. Chem. Pharm. Bull. 1994, 42, 475. Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2000, 41, 8279. Enders, D.; Kempen, H. Synlett 1994, 969. Buston, J. E. H.; Coldham, I.; Mulholland, K. R. Synlett 1997, 322. Guarna, A.; Occhiato, E. G.; Pizzetti, M.; Scarpi, D.; Sisi, S.; van Sterkenburg, M. Tetrahedron: Asymmetry 2000, 11, 4227. 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.

R2

R2

DMF, POCl3

1

1

R

N H

O

O Cl P Cl Cl O

:

N

R

'

N

SN2

Cl

O O PCl2

N



H

Cl

H

:

N

Cl

O O PCl2 H

N

H

O O PCl2

Cl

Vilsmeier–Haack reagent

R2 R1 N H

R2

R2 R1

O

Cl

R1 N H

POCl3

H

Cl

Cl

N

(Me)2N

Me N Me

R2 1

R

N

OPOCl2

Cl R2

2

R =H

Cl

R1 N

Cl

377

Example 15

Me N H

O

CHO

DMF, POCl3 75 oC, 16.5 h, 68%

N

Cl

Example 25

Me S

N H

O

DMF (1 equiv.), POCl3 (3 equiv.), (CH2Cl)2 ', 4 h, 79%

S

N

Cl

References Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 2045; Meth-Cohn, O.; Narine, B.; Tarnowski, B. Tetrahedron Lett. 1979, 3111. Meth-Cohn, O.; Tarnowski, B. Tetrahedron Lett. 1980, 21, 3721. 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. Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 443450. (Review). 1. 2. 3. 4.

378

Meyers oxazoline method Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds.

Ph

O

OMe

N

2) R-X

Ph H Ph

O

OMe

N

R

N(i-Pr)2

H

Ph

O

1) LDA

O N Li

H3C OMe

N

O

Me Ph

Ph H3C

H3C

O

H R X

N Li

H O

O N R O

Me

Me

Example 18

O

1) LDA

Ph

2) TMSO

Br

N OMe

3) LDA 4) Me2SO4

TMSO O H

Ph

N OMe

O H3O+

O

66% yield 70% ee

379

Example 212

OMe Ph O

O N

1)

O I

Ph

OMe

O

Li

2)

O

N O 99% yield

References 1.

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

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 pharmaceutical firm Parke-Davis (Drs. George Moersch and Harry Crooks) donated several kilograms of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol (Meyers referred to it as the Parke-Davis diol), from which his chemistry with chiral oxazolines began. Meyers is currently Professor Emeritus at Colorado State University. Meyers, A. I.; Knaus, G. J. Am. Chem. Soc. 1974, 96, 6508. Meyers, A. I.; Knaus, G. Tetrahedron Lett. 1974, 1333. Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975, 97, 6266. Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 1186. Meyers, A. I.; Mihelich, E. D. Angew. Chem. Int. Ed. 1976, 15, 270. (Review). Meyers, A, I. Acc. Chem. Res. 1978, 11, 375–381. (Review). Meyers, A. I.; Yamamoto, Y.; Mihelich, E. D.; Bell, R. A. J. Org. Chem. 1980, 45, 2792. Meyers, A. I., Lutomski, K. A. in Asymmetric Synthesis, Morrison, J. D. ed. Vol III, part B, Chapter 3, Academic Press, 1983. (Review). Reuman, M.; Meyers, A. I. Tetrahedron 1985, 41, 837–860. (Review). Meyers, A. I.; Barner, B. A. J. Org. Chem. 1986, 51, 120. Robichaud, A. J.; Meyers, A. I. J. Org. Chem. 1991, 56, 2607. Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297–2360. (Review). Meyers, A. I. J. Heterocycl. Chem. 1998, 35, 991–1002. (Review). Wolfe, J. P. Meyers Oxazoline Method In Name Reactions in Heterocycl. Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 237248. (Review).

380

Meyer–Schuster rearrangement The isomerization of secondary and tertiary D-acetylenic alcohols to DEunsaturated carbonyl compounds via 1,3-shift. When the acetylenic group is terminal, the products are aldehydes, whereas the internal acetylenes give ketones. Cf. Rupe rearrangement. R R

OH

R

+

H , H 2O R

R1

R R

OH

O

R R

H+

R1

OH2

E1 R1

R1 R

R R

R

•

R1

:OH2

R1

R R

H+ •

R1

R

tautomerization

O

R

R1

OH Example 18

O P

OH PhS

O

O O O O O P P O O P OTMS TMSO OTMS o

ClCH2CH2Cl, 83 C, 30 min.

PhS 54% PhS 6%

381

Example 210

O

O

O

O O

O

O

O

O

CO2Et

HO 21% CO2Et

10% H2SO4 THF, rt, 1.5 h HO

OEt

70%

References Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. 1922, 55, 819. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). 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. 1. 2. 3.

382

Michael addition Conjugate addition of a carbon-nucleophile to an DE-unsaturated system. Example 1

ONa O CO2Et

NaCH(CO2Et)2

CO2Et O acidic CO2Et

workup

CO2Et Example 2 O

O R2CuX

R

O

conjugate R Cu

O

H+

O workup

addition

R

R

R

Example 34

O

O O N

H2S, NaOMe MeOH, 75%

HS

O N

383

Example 43 O

O

O

O

N

Si(Me)2Ph

PhMgBr, CuBr•DMS

Ph

N

Si(Me)2Ph

o

O

CPh3

ether, THF, 55 C 92%, 92% de

O

CPh3

References Michael, A. J. Prakt. Chem. 1887, 35, 349. Arthur Michael (18531942) 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 organic chemists in this period. Since he failed miserably as an administrator, Michael and his wife set up their own private laboratory at Newton Center, Massachusetts, where the Michael addition was discovered. 2. 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, 135631. (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.; Leȕmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry 2003, 14, 189. 1.

384

MichaelisArbuzov phosphonate synthesis Phosphonate synthesis from the reaction of alkyl halides with phosphites. General scheme: O P OR1 OR1

'

1

R2

R2 X

(R O)3P

R1 X

R1 = alkyl, etc.; R2 = alkyl, acyl, etc.; X = Cl, Br, I For instance: O (CH3O)3P

Br

' O

CH3Brn

O

Br

O Br

O

O CH3O P CH3O

O

CH3

CH3

SN2

O CH3O P CH3O

(CH3O)3P: SN2

O CH3O P CH3O

O

O O

CH3Brn

Example 13

Br

(EtO)3P, Tol. o

Br

145 C, 4 h, 70%

P(OEt)2 O

O

CH3

385

Example 213

O BnO P BnO

140 oC Cl

O BnO P BnO

(BnO)3P 8 h, 92%

O OBn P OBn

Example 314

F

O

F

F

Br

(EtO)3P, NiCl2

F

O

100 oC, 72 h, 10%

F

F

O P OEt OEt

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

12. 13. 14. 15.

Michaelis, A.; Kaehne, R. Ber. 31, 1048 (1898). Arbuzov, A. E. J. Russ. Phys. Chem. Soc. 1906, 38, 687. Surmatis, J. D.; Thommen, R. J. Org. Chem. 1969, 34, 559. Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. Engl. 1973, 12, 91. (Review). Saady, M.; Lebeau, L.; Mioskowski, C. Tetrahedron Lett. 1995, 36, 5183. Kato, T.; Tejima, M.; Ebiike, H.; Achiwa, K. Chem. Pharm. Bull. 1996, 44, 1132. WaschbĦsch, R.; Carran, J.; Marinetti, A.; Savignac, P. Synthesis 1997, 727. Griffith, J. A.; McCauley, D. J.; Barrans, R. E., Jr.; Herlinger, A. W. Synth. Commun. 1998, 28, 4317. Kiddle, J. J.; Gurley, A. F. Phosphorus, Sulfur Silicon Relat. Elem. 2000, 160, 195. Bhattacharya, A. K.; Stolz, F.; Schmidt, R. R. Tetrahedron Lett. 2001, 42, 5393. 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. Battaggia, S.; Vyle, J. S. Tetrahedron Lett. 2003, 44, 861. Erker, T.; Handler, N. Synthesis 2004, 668. Souzy, R.; Ameduri, B.; Boutevin, B.; Virieux, D. J. Fluorine Chem. 2004, 125, 1317. 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.

O

OH

Alpine-borane

1

R1

R

neat

R H B

R

THF

B

reflux (1R)-(+)-D-pinene

9-BBN

(R)-Alpine-borane

9-BBN = 9-borabicyclo[3.3.1]nonane

O

H R

B O R1

B

1

R R

hydride

O

B

workup

1

R

transfer

OH

H2O2, NaOH

R1 R

R Example 16

O

(R)-Alpine-borane, THF

BnO H

o

10 C to rt, 95%, 88% ee

387

OH BnO H Example 27

O

(R)-Alpine-borane OPMB

TBSO

22 oC, 6 kbar, 82% 80% de OH OPMB TBSO

References 1.

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

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, Riverside. Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867. Brown, H. C.; Pai, G. G.; Jadhav, P. K. J. Am. Chem. Soc. 1984, 106, 1531. Brown, H. C.; Pai, G. G. J. Org. Chem. 1982, 47, 1606. Singh, V. K. Synthesis 1992, 605. (Review). Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001, 3, 2721. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891.

388

Mislow–Evans rearrangement [2,3]-Sigmatropic rearrangement of allylic sulfoxide to allylic alcohol. O S

R

Ar

'

S

Ar

HO

P(OCH3)3

O

R

R 2

R

O S

3 2 1

2

[2,3]-sigmatropic

1

Ar

S

Ar

S

O

1

3

R

rearrangement

Ar

:P(OCH3)3 HO

H+

O

SN2

2

1

P(OCH3)3

R

R

Example 16

O

O NaIO4 dioxane/H2O 50%

TBSO

TBSO CHO

OMe

PhS Example 211

OMe MeO

OMe

O O

OTBS

MeO (EtO)3P, EtOH

O O

OTBS

reflux, 16 h, 98% O S Ph

OH

References 1. 2. 3.

Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100. Evans, D. A.; Andrews, G. C.; Sims, C. L. J. Am. Chem. Soc. 1971, 93, 4956. Evans, D. A.; Andrews, G. C. J. Am. Chem. Soc. 1972, 94, 3672.

389

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

Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147. (Review). Masaki, Y.; Sakuma, K.; Kaji, K. Chem. Pharm. Bull. 1985, 33, 2531. Sato, T.; Shima, H.; Otera, J. J. Org. Chem. 1995, 60, 3936. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Am. Chem. Soc. 1995, 117, 9077. Jones-Hertzog, D. K.; Jorgensen, W. L. J. Org. Chem. 1995, 60, 6682. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23. Zhou, Z. S.; Flohr, A.; Hilvert, D. J. Org. Chem. 1999, 64, 8334. Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341. 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

Nu

NuH

OH R2

R1

DEAD, PPh3

R2

H Nu N N

EtO2C

CO2Et

:PPh3

adduct

CO2Et N N

formation

EtO2C

Ph3P

Diethyl azodicarboxylate (DEAD)

CO2Et

H N N Ph3P EtO2C

activation

:OH R1

alcohol

O PPh3 R1

EtO2C

H N N H CO2Et

+

R2

R2 O PPh3 1

R

SN2

2

R

reaction

Nu R1

R2

+

O PPh3

Nu Example 14

OH

O O

DEAD, PPh3, Tol.

O2N

4-O2NPhCOO

CO2H

O O

30 to 0 oC, 1 h, 90%

391

Example 23 CH2OAc O

CH2OAc O

PhCO2H DIAD, PPh3, THF OH

OAc

50 oC to rt, 2 h, 80%

OAc OAc

O2CPh

OAc OAc OAc

2:1ED

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

Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380. Mitsunobu, O. Synthesis 1981, 1. (Review). Smith, A. B., III; Hale, K. J.; Rivero, R. A. Tetrahedron Lett. 1986, 27, 5813. KocieĔski, P. J.; Yeates, C.; Street, D. A.; Campbell, S. F. J. Chem. Soc., Perkin Trans. 1, 1987, 2183. Hughes, D. L. Org. React. 1992, 42, 335656. (Review). Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127. (Review). Barrett, A. G. M.; Roberts, R. S.; Schroeder, J. Org. Lett. 2000, 2, 2999. 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. Langlois, N.; Calvez, O. Tetrahedron Lett. 2000, 41, 8285. Charette, A. B.; Janes, M. K.; Boezio, A. A. J. Org. Chem. 2001, 66, 2178. Ahn, C.; Correia, R.; DeShong, P. J. Org. Chem. 2002, 67, 1751. Dandapani, S.; Curran, D. P. Tetrahedron 2002, 58, 3855. Bitter, I.; Csokai, V. Tetrahedron Lett. 2003, 44, 2261.

392

Miyaura borylation Palladium-catalyzed reaction of aryl halides with diboron reagent to produce arylboronates. Also known as HosomiMiyaura borylation.

O

O Ar

I

O

Pd(0)

B B

Ar O

O

base

O

I

L Pd I L

Ar

oxidative Ar

L2Pd(0) addition

transmetallation

base O

O

base

B B O

B

O

O

Ar

B B

O

O L Pd B O Ar O

O

L Pd I L

L O I B O

O

reductive Ar elimination

L2Pd(0)

B O

Example 111

OAc O

O

O

O B B

Ph O

O

Ph CuCl, LiCl, KOAc, DMF, 92%

B O O

Example 212

O

O B B O N OTf Cbz

O

3% (Ph3P)2PdCl2, 6% Ph3P 1.5 eq. K2CO3, dioxane, 90 oC 85%

N B O Cbz O

393

References Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. (Review). Suzuki, A. J. Organomet. Chem. 1995, 576, 147. (Review). Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2000, 2, 3477. Willis, D. M.; Strongin, R. M. Tetrahedron Lett. 2000, 41, 8683. Takahashi, K.; Takagi, J.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 126. Todd, M. H.; Abell, C. J. Comb. Chem. 2001, 3, 319. Giroux, A. Tetrahedron Lett. 2003, 44, 233. Arterburn, J. B.; Bryant, B. K.; Chen, D. Chem. Commun. 2003, 1890. Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 7885. 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.

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

394

Moffatt oxidation Oxidation of alcohols using DCC and DMSO, also known as “PfitznerMoffatt oxidation”. OH R1

O

DCC 1

R2

R R DMSO, HX DCC, 1,3-dicyclohexylcarbodiimide

2

H

H+

N C N

N C N

O

S

H HN C N O S

O N H

H :O

R

1

N H

R2

1,3-dicyclohexylurea

H H H

S O 1

R

X

S O

R2

R1

H R2

O R1

R2

(CH3)2S

Example 13

OH DCC, DMSO, PhNH+CF3CO2

O

OH

O

PhH, rt, 70%

395

Example 210

A

A

OH

O

O

CHO

DCC, DMSO, Cl2CHCO2H O

O

rt, 90 min., 90%

O

O

A = adenosine References Pfitzner, K. E.; Moffatt, J. G. J. Am. Chem. Soc. 1963, 85, 3027. Harmon, R. E.; Zenarosa, C. V.; Gupta, S. K. J. Org. Chem. 1970, 35, 1936. Schobert, R. Synthesis 1987, 741. Liu, H. J.; Nyangulu, J. M. Tetrahedron Lett. 1988, 29, 3167. Tidwell, T. T. Org. React. 1990, 39, 297. (Review). 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.

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

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.15

R3

O

MR4

+ R1

R1

R2

H

R4

OH

R3

Ni(COD)2, L

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 elimination sequence. If R4 possesses a E-hydrogen, then E-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

R3

Ln Ni

O R1

H

Ln Ni

R3

O

R2

R1

MR4

R2

4

R LnNi

3

MO

R

R4

OM

R4 lacks E-H R1

R1 H2C

R2

R2 4

R =H

R4 = Et

CH2

R3

H OM

LnNi MO R1

H

3

R R2

R3

R1 2

R

397

Example 16 CH3

CH3 H3C

H3C

O

O

Et3SiH

H H3C

O

N

Ni(COD)2 PBu3

H

N

CH3

CH3

O

H H3C

O OBn

OSiEt3 OBn

93 % (single diast.)

Example 27

H N

H

C6H13 Ni(COD)2

O

N

+ ZrCp2Cl

OH

ZnCl2

CH3

H3C 69 %

C6H13

Example 38

Me

O

O

O

H Me Ph

O

Ph Me

Me

Me

Ph Me HO

O

Ni(COD)2, PBu3 Et3B

Me Ph

Me

O

O 44 % (>10:1 dr)

398

Example 49

O

R1

H

Ni(COD)2, ligand reducing agent

O O

OR2

R1 R2O

R1

or

O

O

O

O ligand

reducing agent

yield (ratio)

Et3B

89 % (4.5:1)

Et3SiH

93 % (1:5)

PMe3 Ar N

N Ar :

Ar = 2,6 di-isopropylphenyl

A number of related processes involving alternate S-systems including enones, dienes, and allenes have been reported.10 References Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098. Huang, W.-S.; Chan, J.; Jamison, T. F. Org. Lett. 2000, 2, 4221. Mahandru, G. M.; Liu, G.; Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698. Miller, K. M.; Huang, W.-S.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 3442. Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6950. Ni, Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743. Colby, E. A.; O'Brien, K. C.; Jamison, T. F. J. Am. Chem. Soc. 2004, 126, 998. 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). 1. 2. 3. 4. 5. 6. 7. 8. 9.

399

Morgan–Walls reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls with phosphorus oxychloride in boiling nitrobenzene.

R O

R

NH

N

POCl3

R1

R1

Cl

POCl2 O NH R

:

O P Cl Cl O R

NH 1

R

1

R

OPOCl2 NH :

R H

R N

HOPOCl2 R1

R1 Example 110 O2N

NO2 HN

O2N

NO2 N

nitrobenzene, POCl3 O SnCl4, 98% CN CN

400

Pictet–Hubert reaction Phenanthridine cyclization by dehydrative ring closure of acyl-o-aminobiphenyls on heating with zinc chloride at 250300 °C.

R

R O

NH

R1

N

ZnCl2 250300 oC

R1

Example 27

ZnCl2, 250300 oC H

N

N 80% O

References Pictet, A.; Hubert, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1182. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1931, 2447. Morgan, C. T.; Walls, L. P. J. Chem. Soc. 1932, 2225. Gilman, H.; Eisch, J. J. Am. Chem. Soc. 1957, 79, 4423. Hollingsworth, B. L.; Petrow, V. J. Chem. Soc. 1961, 3664. Nagarajan, K.; Shah, R. K. Indian J. Chem. 1972, 10, 450. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 1279. 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. Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 465468. (Review). 1. 2. 3. 4. 5. 6. 7. 8.

401

MoriBan indole synthesis Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole.

CO2Me

CO2Me

Br

Pd(OAc)2, Ph3P

N Ac

NaHCO3, DMF, 130 oC,

N Ac

Reduction of Pd(OAc)2 to Pd(0) using Ph3P:

AcO Pd OAc Ph3P Pd OAc

AcO :PPh3 O Pd(0)

O PPh3

AcO

O O PPh3

O O

MoriBan indole synthesis:

CO2Me Br

Pd(0) oxidative addition

N Ac

Br PdLn

CO2Me insertion

N Ac

MeO2C H N Ac

PdBrLn

CO2Me

E-hydride H PdBrLn elimination

N Ac

402

addition of PdH

N Ac

CO2Me E-hydride PdBrLn elimination H

CO2Me N Ac

Regeneration of Pd(0):

H PdBrLn

NaHCO3

Pd(0)

NaBr

H2O

CO2n

Example 11 I

Me

Pd(OAc)2

N H

Et3N, MeCN sealed tube 110 °C, 87%

N H

Example 212 SO2NHMe Br N Br

COCF3 Cbz N

Pd(OAc)2, Bu4NCl Et3N, DMF heat, DME, 76%

Cbz N SO2NHMe

Br

N H

References 1. 2.

3. 4. 5. 6. 7.

MoriBan 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. 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. Macor, J. E.; Ogilvie, R. J.; Wythes, M. J. Tetrahedron Lett. 1996, 37, 4289. Li, J. J. J. Org. Chem. 1999, 64, 8425. 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. Sparks, S. M.; Shea, K. J. Tetrahedron Lett. 2000, 41, 6721. 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.

R2 R1

R CHO

O

R1

R2

acid

R

1

OH O

X

X SiMe3

R2

R O

O

R

OSiMe3

LA H R2

R

OH

Lewis

R1

SiMe3

Example 114

O O OHC OTBDMS

N Boc

N Bn O OH O

BF3•OEt2, DTBMP CH2Cl2, 78 to 50 oC, 93%

N O Bn

N Boc

Example 215

CHO O

OH O

1. PhCO2H, rt

O

O

2. TFA, 60%

OSiMe3 CN

O

NC

404

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. Langer, P.; Koehler, V. Org. Lett. 2000, 2, 1597. Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett. 2000, 41, 103. Delas, C.; Blacque, O.; Moise, C. Tetrahedron Lett. 2000, 41, 8269. Ishihara, K.; Kondo, S.; Yamamoto, H. J. Org. Chem. 2000, 65, 9125. Kumareswaran, R.; Reddy, B. G.; Vankar, Y. D. Tetrahedron Lett. 2001, 42, 7493. Armstrong, A.; Critchley, T. J.; Gourdel-Martin, M.-E.; Kelsey, R. D.; Mortlock, A. A. J. Chem. Soc., Perkin Trans. 1 2002, 1344. Clézio, I. L.; Escudier, J.-M.; Vigroux, A. Org. Lett. 2003, 5, 161. Muñoz-Muñiz, O.; Quintanar-Audelo, M.; Juaristi, E. J. Org. Chem. 2003, 68, 1622. Ishihara, K.; Yamamoto, H. Boron and Silicon Lewis Acids for Mukaiyama Aldol Reactions. In Modern Aldol Reactions Mahrwald, R. (ed.), 2004, 2568. (Review). Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 55905614. (Review). 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. Adhikari, S.; Caille, S.; Hanbauer, M.; Ngo, V. X.; Overman, L. E. Org. Lett. 2005, 7, 2795. 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 DE-unsaturated system. O R2 Lewis O R1 R1 R2 O OSiMe3 R acid R Example 14

OSiMe3

O

OMe

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

O O

OSiMe3

1. neat DBU, rt, 24 h

OMe

O 2. 1 N HCl, THF, 68% O

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

Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. Mukaiyama, T.; Narasaka, K.; Banno, K. J. Am. Chem. Soc. 1974, 96, 7503. Mukaiyama, T. Angew. Chem., Int. Ed. 2004, 43, 55905614. (Review). Gnaneshwar, R.; Wadgaonkar, P. P.; Sivaram, S. Tetrahedron Lett. 2003, 44, 6047. Wang, X.; Adachi, S.; Iwai, H.; Takatsuki, H.; Fujita, K.; Kubo, M.; Oku, A.; Harada, T. J. Org. Chem. 2003, 68, 10046. Jaber, N.; Assie, M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075. Shen, Z.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2005, 46, 507. 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:

N Y base R3

X R1CO2H

R2OH

O R1

O

R2

O

N R3

X = F, Cl, Br Example 13

F4B

Br

HO

CO2H

O

N

O

O

Bu3N, CH2Cl2

O

O

SNAr N BF 4

Br O H

:

O O

O Br

O +

H

N

NBu3 O Br



O

O

O N



O

BF4

:

HO Bn

O

:

OBn

O

O H+

N

O O Bn

HO

N

N





BF4

BF4

407

Amide formation using the Mukaiyama reagent follows a similar mechanistic pathway.4 Example 2, polymer-supported Mukaiyama reagent8

TfO

OH O

N N

Cl

O

Cl

Tf2O, CH2Cl2, 16 h, rt 1.25 mmol/g O NHBoc

NHBoc O CO2H N H

NH

NH2 polymer-supported Mukaiyama reagent Et3N, CH2Cl2, rt 16 h, 88%

N H

O O O

References Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. Chem. Lett. 1975, 1045. Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T. Chem. Lett. 1977, 635. Mukaiyama, T. Angew. Chem., Int. Ed. 1979, 18, 707. 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. 1. 2. 3. 4.

408

MyersSaito cyclization Cf. Bergman cyclization and Schmittel cyclization.

' or

•

hydrogen atom donor

hv

reversible

H

•

allenyl enyne

diradical

H

Example 16

PhH, reflux

Ph Ph

96 h, 40% Ph Ph

H

409

Example 2, aza-MyersSaito reaction16 N

OMe

MeOH 0 oC, 14 h Ph

Ph

N

CDCl3

N

CHO

10 oC, 12 h Ph

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

Myers, A. G.; Proteau, P. J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. Saito, K.; Watanabe, T.; Takahashi, K. Chem. Lett. 1989, 2099. Saito, I.; Nagata, R.; Yamanaka, H.; Murahashi, E. Tetrahedron Lett. 1990, 31 2907. Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem. Soc. 1992, 114, 9369. Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995, 36, 4975. Schmittel, M.; Steffen, J.-P.; Auer, D.; Maywald, M. Tetrahedron Lett. 1997, 38, 6177. Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew. Chem., Int. Ed. 1998, 37, 1960. Ferri, F.; Bruckner, R.; Herges, R. New J. Chem. 1998, 22, 531. Cramer, C. J.; Squires, R. R. Org. Lett. 1999, 1, 215. Bruckner, R; Suffert, J. Synlett 1999, 657679. (Review). Kim, C.-S.; Diez, C.; Russell, K. C. Chem. Eur. J. 2000, 6, 1555. Cramer, C. J.; Kormos, B. L.; Seierstad, M.; Sherer, E. C.; Winget, P. Org. Lett. 2001, 3, 1881. Stahl, F.; Moran, D.; Schleyer, P. von R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2002, 67, 1453. Musch, P. W; Remenyi, C.; Helten, H.; Engels, B. J. Am. Chem. Soc. 2002, 124, 1823. Bui, B. H.; Schreiner, P. R. Org. Lett. 2003, 5, 4871. Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M. Org. Lett. 2004, 6, 2059. 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.

O

H+ O

O +

H

H

HO O

protonation H O

OH tautomerization

Example 12

O

H O ZrCl4, (CH2Cl)2

N CO2Me

SiMe3 60 oC, 36 h, 76%

N H CO2Me

Example 2, cyclization of in situ generated di-vinyl ketone12

H3PO4, 6065 oC

O

6 h, 65% References 1. 2. 3.

Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N. Bull. Acad. Sci. (USSR) 1942, 200. I. N. Nazarov (19001957) discovered this reaction in 1942 in Russia. Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim. Acta 1988, 71, 2821. Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994, 45, 1158. (Review).

411

Kuroda, C.; Koshio, H.; Koito, A.; Sumiya, H.; Murase, A.; Hitono, Y. Tetrahedron 2000, 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. 4.

412

Neber rearrangement D-Aminoketone from tosyl ketoxime and base.

OTs

N 1

R

R

2. H2O

ketoxime

H EtO

R2

R1

2

N

NH2

1. KOEt

TsOH

O D-aminoketone

OTs N

deprotonation R2

OTs

cyclization

R2

1

R

R1 H+ N

TsOH

:OH2

hydrolysis

R2 R1 azirine intermediate

R1

H N O H R2

NH2 R2

R1 O

Example 15

TsO

EtO OEt

N 1. EtOH, HCl (g)

Br

2. Na2CO3, 92%

NH2 Br

413

Example 215 Ts N

TsON N MeO

N

Br

o

KOH, H2O, EtOH, 0 C, 3 h o

2. 6 N HCl, 60 C, 10 h, 96% 3. K2CO3, THF, H2O, 10 min.

OMe

N

O

1.

SEM

Ts N

O N

H2N MeO

N O

Br OMe

HN

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Neber, P. W.; v. Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449, 109. O’Brien, C. Chem. Rev. 1964, 64, 81. (Review). Kakehi, A.; Ito, S.; Manabe, T.; Maeda, T.; Imai, K. J. Org. Chem. 1977, 42, 2514. Friis, P.; Larsen, P. O.; Olsen, C. E. J. Chem. Soc., Perkin Trans. 1 1977, 661. LaMattina, J. L.; Suleske, R. T. Synthesis 1980, 329. Corkins, H. G.; Storace, L.; Osgood, E. J. Org. Chem. 1980, 45, 3156. Hyatt, J. A. J. Org. Chem. 1981, 46, 3953. Parcell, R. F.; Sanchez, J. P. J. Org. Chem. 1981, 46, 5229. Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am. Chem. Soc. 1996, 118, 8491. Oldfield, M. F.; Botting, N. P. J. Labelled Compounds Radio. 1998, 41, 29. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144146, 351. Banert, K.; Hagedorn, M.; Liedtke, C.; Melzer, A.; Schoffler, C. Eur. J. Org. Chem. 2000, 257. Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett. 2002, 41, 5363. Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640. 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.

1. NaOH

NO2 1

R2

R

O 1

O R1

N H

O

O

H2O

R2

R1

1/2H2O

1/2N2O

R2

R

2. H2SO4

N

O

H+

R2

nitronate HO HO

N

R1

OH

H+ HO

R2

N

O

H

O

H2O

1

R1

:OH2

R

R2 OH

N

+ H+

R2 OH

nitronic acid HO

O

N

R1 R2 O H

1

R

R

2

HNO

1/2N2O

1/2H2O

O R1

Example 17

O

1. NaOH, EtOH, 0 oC, 30 min. NO2

2. 3 M HCl, 20 oC, 12 h, 68%

O O

R2

415

Example 211

HO

H

NO2 1. 2 M NaOH, MeOH 2. ice-cooled KMnO4 45%

HO

O

H

References Nef, J. U. Justus Liebigs Ann. Chem. 1894, 280, 263. John Ulrich Nef (18621915) 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 University, and the University of Chicago. The Nef reaction was discovered at Clark University in Worcester, Massachusetts. Nef was temperamental and impulsive, suffering from a couple of mental breakdowns. He was also highly individualistic, and had never published with a coworker save for three early articles. 2. Pinnick, H. W. Org. React. 1990, 38, 655. (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. Commun. 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. 1.

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 ketones, esters, amines, and nitriles. For the catalytic cycle, see the Kumada coupling on page 345.

Pd(0)

R1 ZnX

R X

oxidative

R

L2Pd(0)

R X

addition L ZnX2

L Pd 1 R R

R R1 1

ZnX

R

L Pd X L

reductive

ZnX2

transmetallation isomerization R R1

L2Pd(0)

elimination

Example 15 CH2CO2Et

I N

N

BrZnCH2CO2Et, Pd(Ph3P)4

HO O O O O

Ph

HO O O O O

HMPA/(CH2OCH3)2 (1:1) 3.5 h, 40%

Ph

Ph Ph

Example 26

O

O

activated I

BnO NHTrt

Zn/Cu couple

ZnI

BnO NHTrt

417

Boc

NHBoc

N I

N

Boc

CO2t-Bu

N

BnO PdCl2(Ph3P)2, DMA 40 oC, 79%

NHBoc

N

O

CO2t-Bu

NHTrt

References Negishi, E.-I.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596. Negishi, E.-I. et al. J. Org. Chem. 1977, 42, 1821. Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (Review). Erdik, E. Tetrahedron 1992, 48, 9577. (Review). De Vos, E.; Esmans, E. L.; Alderweireldt, F. C.; Balzarini, J.; De Clercq, E. J. Heterocycl. 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.; Gilligan, 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. 1. 2. 3. 4. 5.

418

Nenitzescu indole synthesis 5-Hydroxylindole from condensation of p-benzoquinone and E-aminocrotonate. H O

CO2R3

HO

'

R1

HN R2

O

O

conjugate

HO

addition

R1

O

O HN R2 CO2R3

R2

CO2R3

HO

R1

N H+

H

HO

N R2 CO2R3 H

3

:

R1

R1

CO2R

H

CO2R3

N OH R2 H+

R1

N R2

Example 17 O

O O HN

Bn

HO O 1. aetone, rt, 48 h 2. 20% TFA, CH2Cl2 86%

N H

NH2

N Bn

Example 28 H O

HN O

CO2CH3

HO

CO2CH3

CH3NO2, rt N 95%

419

References Nenitzescu, C. D. Bull. Soc. Chim. Romania 1929, 11, 37. Allen, Jr. G. R. Org. React. 1973, 20, 337. (Review). Patrick, J. B.; Saunders, E. K. Tetrahedron Lett. . 1979, 4009. Bernier, J. L.; Henichart, J. P. J. Org. Chem. 1981, 46, 4197. 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. Tetrahedron 2005, 61, 9129.

1. 2. 3. 4. 5.

420

Nicholas reaction Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives propargylated product.

R

OR2 3 R 4 R

1

1. Co2(CO)8 2. H+ or Lewis acid

CO (CO)4Co Co(CO)3 R

1

 CO

OR2 R R3 4

+ H+

(CO)3Co Co(CO)3

NuH

(CO)3Co Co(CO)3 R1

R1

SN1

H O 2 4 3 R R R

R1

OR2 4 3 R R

(CO)3Co Co(CO)3

2. [O]

R1

(CO)3Co Co(CO)3 R

Nu 3 R 4 R

R1

CO  CO (CO) Co Co(CO) 3 3

OR2 3 R 4 R

1

1. NuH

[O]

Nu

demetallation R4 R3 R4 R3 propargyl cation intermediate (stabilized by the hexacarbonyldicobalt complex). (CO)3Co Co(CO)2 O C On

R

1

Nu R3 4 R

R1

Nu R4 R3

Example 1, chromium variant of the Nicholas reaction5 OH

o

1. HBF4·Et2O, CH2Cl2, 60 C 2. 5 eq. X, CH2Cl2,60 oC, 86% Cl

Cr(CO)3

X = HN

N O CO2n-Bu

421

Cl

Cl

N

2HCl

N

N

O

N O

CO2n-Bu

CO2H

Zyrtec

Cr(CO)3

Example 2, intramolecular Nicholas reaction using chromium11 Cr(CO)3 OAc

BF3•OEt2, CH2Cl2 0 oC, 3.5 h, 49%

Cr(CO)3

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

Nicholas, K. M. J. Organomet. Chem. 1972, C21, 44. Lockwood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 4163. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207. (Review). Roth, K. D. Synlett 1992, 435. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837. Diaz, D.; Martin, V. S. Tetrahedron Lett. 2000, 41, 743. Guo, R.; Green, J. R. Synlett 2000, 746. Green, J. R. Curr. Org. Chem. 2001, 5, 809826. (Review). Teobald, B. J. Tetrahedron 2002, 58, 41334170. (Review). Takase, M.; Morikawa, T.; Abe, H.; Inouye, M. Org. Lett. 2003, 5, 625. Ding, Y.; Green, J. R. Synlett 2005, 271. Crisostomo, F. R. P.; Carrillo, R.; Martin, T.; Martin, V. S. Tetrahedron Lett. 2005, 46, 2829.

422

Nicolaou dehydrogenation D,E-Unsaturation of aldehydes and ketones mediated by stoichiometric amounts of IBX (o-iodoxybenzoic acid), alternative to Saegusa oxidation (page 515).1 O I

HO O R2

O R1

O R3

R2

O

1 IBX = o-iodoxybenzoic acid R

R3

A SET mechanism has also been proposed.2 Additionally, silyl enol ethers are also viable substrates.3

R2

O R1

HO

tautomerization

R

R1

R3

O HO I O

2

R3

O

O

O I O HO R1

R2

O

OH R2 H

R1

R3

R3

Example 11

IBX fluorobenzene DMSO

H H O

H

H

65 °C, 24 h O 80%

H H H

H

423

Example 24 H

O H

O

IBX

TBSO

O

MeO2C

DMSO–Tol. H 80 °C, 3 h, 52% CO2Me

TBSO

O

MeO2C

H CO2Me

e. g.310 H

N Me

MeO

H

H

IBX

O

N

Tol., DMSO 70 °C

H O

H

MeO

N Me

H O

N H

H O

References Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. Nicolaou, K. C.; Montagnon, T.; Baran, P. S. Angew. Chem., Int. Ed. 2002, 41, 993. 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. 1. 2. 3.

424

Nicolaou hydroxy-dithioketal cyclization Two step synthesis of medium-ring ethers through the intermediacy of thionium ions followed by sulfide reduction. EtS EtS OH

H H O

1. NCS, AgNO3, SiO2, 2,6-lut. 2. Ph3SnH, AIBN

The mechanism is analogous to the hydroxy-ketone cyclization except that the mixed ketal is isolable. It can be reductively cleaved using Ph3SnH/AIBN: O NO3 Ag Cl

N

Cl EtS EtS

O

EtS EtS OH

HO

SnPh3 thionium formation

EtS H O

EtS OH

H homolytic reduction

H O

H H O

425

e. g. 11 1. AgNO3, NCS, SiO2 2,6-lut., 3 Å MS 5 min, 95% O H 2. Ph SnH, AIBN, 3 toluene, 110 °C, 95%

EtS H OH EtS O

H HO

O H

O

Example 2, carbocyclization is also possible3: EtS EtS H

N

EtS

AgNO3, 3 Å MS SiO2, 2,6-lut., NCS

N

H

H N H

CH3CN, 44%

H OAc

H

N

H H H OAc

Example 3, the cyclizations tolerate ordinary acetals5: H H O Ph

O

1. AgClO4, NaHCO3 SiO2, 3 Å MS CH3NO2, 25 °C 4 h, 74%

O

EtS EtS OH H

OPiv

2. Ph3SnH, AIBN toluene, 110 °C 3 h, 95%

H H O Ph

O

OH H

O OPiv

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

Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K. J. Am. Chem. Soc. 1986, 108, 2468. Inoue, M.; Sasaki, M.; Tachibana, K. J. Org. Chem. 1999, 64, 9416. Shin, K.; Moriya, M.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 3765. Trost, B. M.; Nübling, C. Carbohydrate Res. 1990, 202, 1. 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. 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.

Et3SiH, TMSOTf O OH

CH2Cl2, 0 °C 15 min., 90%

Ph

H

O

H

Ph

The mechanism involves hemiketal formation followed by reduction of the oxocarbonium group:

O OH

silylation; hemiketal

Ph

TMS OTf

H

H

formation

O

Ph

H

Ph OTMS

O

O

H

Ph

TES H Example 11 H BnO BnO

H

H

O

H

O

H

O

O O HO

H H

BnO BnO

H

O

Me

H

O

TMSOTf, MePh2SiH CH2Cl2, 0 °C, 2 h, 62%

H

H

H

O

H O O H H Me

427

e. g. 22 H OMTM

O O O

TfOH, EtMe2SiH

OBn CH2Cl2, CH3CN, 50 to 20 °C, 1 h, 81%

OBz

H O

OBz

O H

O

H

OBn

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

Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989, 111, 4136. Smith, A. B.; Cui, H. Helv. Chim. Acta 2003, 86, 3908. Watanabe, K.; Suzuki, M.; Murata, M.; Oishi, T. Tetrahedron Lett. 2005, 46, 3991. Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011. González, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099. 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 employing N-phenylselenophthalimide or N-phenylselenosuccinimide as an electrophilic source of the phenylseleno group. O

O

N Se

N Se

O

O

N-PSP = N-phenylselenophthalimide N-PSS = N-phenylselenosuccinimide Se

N-PSP CH2Cl2, H2O, 89%

OH

The reagent may require acid activation depending on the type of transformation being attempted. The mechanism parallels that of halohydrin formation using an electrophilic source of halide in an aqueous medium:

O Ph

Se N

selenonium formation

O

Se Markovnikov Nu M

O

addition

N O O Se + Nu

N M O

429

Example 13

BnO BnO MeO

O

N-PSP, CSA O OH

MeO

O

O

CH2Cl2, rt 2 h, 60%

O

PhSe

H

Example 2, in addition to oxyselenide formation, carbo- and heteroseleno cyclization, 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

O

O O

O

N-PSP, n-Bu3P OH OTBDPS

CH2Cl2, 25 to 20 °C 3 h, 73%

SePh OTBDPS

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

Nicolaou, K. C.; Claremon, D. A.; Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979, 101, 3704. Chrétien, F.; Chapleur, Y. J. Org. Chem. 1988, 53, 3615. Kühnert, S. M.; Maier, M. E. Org. Lett. 2002, 4, 643. Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125, 7822. Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. Grieco, P. A.; Jaw, J. Y.; Claremon, D. A.; Nicolaou, K. C. J. Org. Chem. 1981, 46, 1215. 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.

O

O

R

OH O

H2 1

OR

OR1

R

(R)-BINAP-Ru

(R)-BINAP-Ru =

PPh2 RuCl2L2 PPh2

[RuCl2(binap)(solv)2]

H2

[RuHCl(binap)(solv)2]

HCl The catalytic cycle: OR1 O solv

H+

(binap)ClHRu O R

O R

O OR1 OR1 O

[RuHCl(binap)(solv)2]

(binap)ClRu O H

H+, solv

H R solv

H2

OH O

[RuCl(binap)(solv)2]+ R

OR1

431

Example 12

Ru((S)-BINAP(CF3CO2)2 OH

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.

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

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. Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.; Inoue, S.; Kasahara, I.; Noyori, R.; nnn J. Am. Chem. Soc. 1987, 109, 1596. 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. Noyori, R.; Ohkuma, T.; Kitamura, H.; Takaya, H.; Sayo, H.; Kumobayashi, S.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856. Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J. R. Synlett 1991, 781. King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57, 6689. Noyori, R. In Asymmetric Catalysis in Organic Synthesis; Ojima, I., ed.; Wiley: New York, 1994, chapter 2. (Review). Chung, J. Y. L.; Zhao, D.; Hughes, D. L.; Mcnamara, J. M.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7379. Bayston, D. J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron: Asymmetry 1998, 9, 2015. Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (Review, Nobel Prize Address). Berkessel, A.; Schubert, T. J. S.; Mueller, T. N. J. Am. Chem. Soc. 2002, 124, 8693. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003, 5, 733.

432

Nozaki–Hiyama–Kishi reaction CrNi bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes.

OH

CrCl2, NiBr2 1

Br

R

CHO

R

SMe2

NiBr2

Br

R Ni(0)

reduction

oxidative addition

R Ni(II)

Ni(II) Br

R

CrCl3

CrCl2

R1

R

DMSOSMe2

R1 CHO

Cr(III)Cl2

nucleophilic addition

Ni(0)

Transmetalation and then reduction by Me2S

OCrCl2

OH

hydrolysis

1

R

R

R

CrCl2X

1

R

The catalytic cycle:7

X

2 CrX2

CrX2

RCHO

OCrX2

2 CrX3

R

MnX2

Mn OSiMe3 R

Me3SiX

433

Example 18

OTHP AcO

I

OTBDPS

CHO

10 eq CrCl2, cat. NiCl2 o

DMSO, 25 C, 12 h, 80%

OTHP AcO

OTBDPS OH

Example 212

O OTf OHC

OH O O

O

4 eq CrCl2 0.008 eq NiCl2 DMF, rt, 15 h 35%

O O

References 1. 2.

3.

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

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. 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 reaction and is a professor at Okayama University. Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. Yoshita Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. Wessjohann, L. A.; Scheid, G. Synthesis 1991, 1. (Review). Kress, M. H.; Ruel, R.; Miller, L. W. H.; Kishi, Y. Tetrahedron Lett. 1993, 34, 5999. The catalytic cycle: Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 12349. Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565. Boeckman, R. K., Jr.; Hudack, R. A., Jr. J. Org. Chem. 1998, 63, 3524. Fürstner, A. Chem. Rev. 1999, 99, 9911046. (Review). Kuroboshi, M.; Tanaka, M.; Kishimoto, S. Goto, K.; Mochizuki, M.; Tanaka, H. Tetrahedron Lett. 2000, 41, 81. Blaauw, R. H.; Benningshof, J. C. J.; van Ginkel, A. E.; van Maarseveen, J. H.; Hiemstra, H. J. Chem. Soc., Perkin Trans. 1 2001, 2250. Berkessel, A.; Menche, D.; Sklorz, C. A.; Schroder, M.; Paterson, I. Angew. Chem. Int. Ed. 2003, 42, 1032. Takai, K. Org. React. 2004, 64, 253612. (Review).

434

Oppenauer oxidation Alkoxide-catalyzed oxidation of secondary alcohols.

Al(Oi-Pr)3

OH R1

R2

R1

O

Oi-Pr Al(Oi-Pr)2

OH

O R2

O OH

Al(Oi-Pr)2

O

: OH R1

coordination

R2

R1

R2 i-PrO

Oi-Pr R1 O Al Oi-Pr H O R2

O

Oi-Pr Al

H

O

R1

R2

cyclic transition state

hydride transfer

O R1

OH R2

Example 1, magnesium Oppenauer oxidation3

OH

1. EtMgBr, i-Pr2O

O

2. PhCHO, 60% Example 212

OH

OH

(i-PrO)2AlO2CCF3 p-O2N-Ph-CHO PhH, rt, 24 h, 70%

O

OH

435

References 1.

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

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 HoffmanLa Roche, Oppenauer worked for the Ministry of Public Health in Buenos Aires, Argentina. Djerassi, C. Org. React. 1951, 6, 207. (Review). Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769. de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007. Almeida, M. L. S.; Kocovsky, P.; Bäckvall, J.-E. J. Org. Chem. 1996, 61, 6587. Akamanchi, K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997, 38, 6925. Raja, T.; Jyothi, T. M.; Sreekumar, K.; Talawar, M. B.; Santhanalakshmi, J.; Rao, B. S. Bull. Chem. Soc. Jpn. 1999, 72, 2117. Nait Ajjou, A. Tetrahedron Lett. 2001, 42, 13. Schrekker, H. S.; de Bolster, M. W. G.; Orru, R. V. A.; Wessjohann, L. A. J. Org. Chem. 2002, 67, 1975. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669. Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68, 1601. Auge, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819. 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

CCl3

CCl3

OH

cat. NaH

R

HN

1

Cl3CCN

R

'

O

HN

or Hg(II) or Pd(II) R1 trichloroacetimidate

N H

O

H

R

R1

R

CCl3 O

H2n

1

O

R

1

R

R

CCl3 O R CCl3 HN

H 1

R

N

O 1

R

R

CCl3

', [3,3]-sigmatropic HN

O R1

R

rearrangement

O R1

R

Example 113

O O

H

O

O

O O O

HO

H

Cl3CCN, DBU o

CH2Cl2, 78 C

O

O O

HN O Cl3C

437

O

H

O

K2CO3, p-xylene reflux, 90%, 2 steps

Cl3C

HN

O

O O

O Example 214

TBDMSO

TBDMSO Cl3C

O NH

O

O

K2CO3, p-xylene O

O reflux, 77%

Cl3C

NH O

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Overman, L. E. Acc. Chem. Res. 1971, 4, 49. (Review). Overman, L. E. J. Am. Chem. Soc. 1974, 96, 597. Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. Isobe, M.; Fukuda, Y.; Nishikawa, T.; Chabert, P.; Kawai, T.; Goto, T. Tetrahedron Lett. 1990, 31, 3327. Eguchi, T.; Koudate, T.; Kakinuma, K. Tetrahedron 1993, 49, 4527. Toshio, N.; Masanori, A.; Norio, O.; Minoru, I. J. Org. Chem. 1998, 63, 188. Cho, C.-G.; Lim, Y.-K.; Lee, K.-S.; Jung, I.-H.; Yoon, M.-Y. Synth. Commun. 2000, 30, 1643. Martin, C.; Prunck, W.; Bortolussi, M.; Bloch, R. Tetrahedron: Asymmetry 2000, 11, 1585. Demay, S.; Kotschy, A.; Knochel, P. Synthesis 2001, 863. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Org. Lett. 2002, 4, 151. Reilly, M.; Anthony, D. R.; Gallagher, C. Tetrahedron Lett. 2003, 44, 2927. O’Brien, P.; Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523. Tsujimoto, T.; Nishikawa, T.; Urabe, D.; Isobe, M. Synlett 2004, 433. Montero, A.; Mann, E.; Herradon, B. Tetrahedron Lett. 2005, 46, 401. 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.

O O H3C

CH3

P2S5, tetralin, reflux

H3C

S CH3

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

S CH3

H3C

P2S5

CH3

H3C

O

X = O or S

X

SH

tautomerization

CH3

H3C X H3C

S XH

H2X

H3C

S CH3

CH3 H Example 14

O N

Ph O

Lawesson's reagent 110 ºC, 10 min, 82%

Ph

S

N

439

Example 28

O O

Ph O

Ph O

Ph Ph

Lawesson's reagent chlorobenzene, reflux, 36 h 69%

Ph

Ph

S Ph

S Ph

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

10. 11. 12. 13.

Paal, C. Chem. Ber. 1885, 18, 251. Paal, C. Chem. Ber. 1885, 18, 367. Campaigne, E.; Foye, W. O. J. Org. Chem. 1952, 17, 1405. Thomsen, I.; Pedersen, U.; Rasmussen, P. B.; Yde, B.; Andersen, T. P.; Lawesson, S.O. Chem. Lett. 1983, 809. Freeman, F.; Kim, D. S. H. L. J. Org. Chem. 1992, 57, 1722. Johnson, M. R.; Miller, D. C.; Bush, K.; Becker, J. J.; Ibers, J. A. J. Org. Chem. 1992, 57, 4414. Freeman, F.; Lee, M. Y.; Lu, H.; Rodriguez, E.; Wang, X. J. Org. Chem. 1994, 59, 3695. Parakka, J. P.; Sadannandan, E. V.; Cava, M. P. J. Org. Chem. 1994, 59, 4208. 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. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J. J. Org. Chem. 2001, 66, 7283. Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66, 7925. Mullins, R. J.; Williams, D. R. Paal Thiophene Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J. Eds., Wiley & Sons: Hoboken, NJ, 2005, 207217. (Review).

440

Paal–Knorr furan synthesis Acid-catalyzed cyclization of 1,4-ketones to form furans.

R2

O

R3

R R1

R1

2

R

R3

H R

R HO

O

R1

R3

O

O

R3

+

H

:

R

R2

R2 :

R 1

R

or P2O5

O

H+ O

R1

cat. H+

R1

R2

R2 H3O+

R3

O

R

R3

O

Example 110

F

Cl

O

Cl O

TsOH O

F

toluene, reflux

N

N

Example 214 O

n-Bu

OMe

OMe

MeO O

p-TsOH O

MeO

OMe

toluene

n-Bu

98% MeO

441

References 1. 2. 3. 4. 5.

6. 7. 8.

9. 10. 11. 12. 13. 14. 15.

16.

Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. Knorr, L. Ber. Dtsch. Chem. Ges. 1885, 18, 299 Paal, C. Ber. Dtsch. Chem. Ges. 1885, 18, 367. Haley, J. F., Jr.; Keehn, P. M. Tetrahedron Lett. 1973, 4017. 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, 167238. (Review). Amarnath, V.; Amarnath, K. J. Org. Chem. 1995, 60, 301. Truel, I.; Mohamed-Hachi, A.; About-Jaudet, E.; Collignon, N. Synth. Commun. 1997, 27, 1165. Friedrichsen, W. Furans and Their Benzo Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New York, 1996; Vol. 2, 351393. (Review). Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Longman: Singapore, 1997; 211. (Review). de Laszlo, S. E.; Visco, D.; Agarwal, L.; et al. Bioorg. Med. Chem. Lett. 1998, 8, 2689. Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry, Springer: New York, 1999; Vol. 2, 8384. (Review). Stauffer, F.; Neier, R. Org. Lett. 2000, 2, 3535. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Science: Cambridge, 2000; 308-309. (Review). Mortensen, D. S.; Rodriguez, A. L.; Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2001, 44, 3838. 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, 183278. (Review). Shea, K. M. Paal–Knorr Furan Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 168181. (Review).

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 exchange and subsequent nucleophilic cyclization to form 4- to 7-membered rings. CH3O

O

I 2.2 eq. t-BuLi N

CH3O

NEt2 THF, 78 oCort

O

CH3O

I

halogen-metal N

CH3O

I

NEt2

O

N

CH3O

CH3O

CH3O CH3O

Et2N Li

O

Et2N O cyclization

N

CH3O

CH3O

exchange O

CH3O

N

CH3O

N

The fate of the second equivalent of t-BuLi:

I

H I Example 19 I

O 2 eq. n-BuLi

N O

MeO OMe

o

THF, 78 C 2.5 h, 83%

MeO MeO

N

O

443

Example 216

O

Br

O

t-BuLi, THF, 100 oC

N OMe PMB

Ar, 30 min., 55% O

O N PMB References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12.

13. 14. 15. 16.

Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1975, 40, 2394. William E. Parham was a professor at Duke University. Parham, W. E.; Jones, L. D.; Sayed, Y. J. Org. Chem. 1976, 41, 1184. Bradsher, C. K.; Hunt, D. A. Org. Prep. Proced. Int. 1978, 10, 267. Bradsher, C. K.; Hunt, D. A. J. Org. Chem. 1981, 46, 4608. Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. (Review). Quallich, G. J.; Fox, D. E.; Friedmann, R. C.; Murtiashaw, C. W. J. Org. Chem. 1992, 57, 761. Couture, A.; Deniau, E.; Grandclaudon, P. J. Chem. Soc., Chem. Commun. 1994, 1329. 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). Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org. Chem. 1997, 62, 2080. Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2000, 41, 5211. Osante, I.; Collado, M. I.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2001, 1267. 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 Chemistry: Rome, 2001; p 393. (Review). Mealy, M. M.; Bailey, W. F. J. Organomet. Chem. 2002, 646, 59. (Review). Sotomayor, N.; Lete, E. Current Org. Chem. 2003, 7, 275. (Review). González-Temprano, I.; Osante, I.; Lete, E.; Sotomayor, N. J. Org. Chem. 2004, 69, 3875. 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 D-acyloxycarboxamides. Cf. Ugi reaction.

O R1 N C

R4 CO2H

3

2

R

R

R1

2 3 H R R O N O R4 O

isocyanide

O 4

O 2

4

R

R3

R

R

H O

CO2H

O R2

R3

H O O 4

R

O

C N R1

R2 R3

N R1

H O acyl

R2 R3

O

4

R

transfer

R1

O N R1

2 3 H R R O N O R4 O

H+

Example 15

HOAc, THF CHO

HN

rt, 93% CN

O

AcO Et

445

Example 23

Ts OMe MeO

CN

TFA, PhH

OMe

rt, 2 h, 93% OMe

MeO OMe

MeO MeO

OMe H N O

Ts OMe OMe

References 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, 1140. (Review). 1.

446

Paternó–Büchi reaction Photoinduced electrocyclization of a carbonyl with an alkene to form polysubstituted oxetane ring systems

O

O

hv R

1

R

R

O

hv

R1 oxetane

O

1

R

R

1

R R n, S* triplet O

O R

R1 triplet diradical

O

R

R1 singlet diradical

R

R1

Example 14

O

O O Ph

Me Me

H

O

Ph

hQ, C6H6, 99%

O

O

O *ROOC

O Ph

H

Example 26

+ Ph

Ph

i-Pr

hQ, C6H6

i-Pr

O

O Ph

SMe (E/Z = 6/1)

73%

Ph

SMe

447

References 1. 2.

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

Paternó, E.; Chieffi, G. Gazz. Chim. Ital. 1909, 39, 341. Emaubuele Paternó (18471935) was born in Palermo, Sicily, Italy. Büchi, G.; Inman, C. G.; Lipinsky, E. S. J. Am. Chem. Soc. 1954, 76, 4327. George H. Büchi (19211998) 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. Jones, G. In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1981, pp 1. (Review). Koch, H.; Runsink, J.; Scharf, H.-D. Tetrahedron Lett. 1983, 24, 3217. Carless, H. A. J. In Synthetic Organic Photochemistry; Horspool, W. M., Ed.; Plenum Press: New York, 1984, pp 425. (Review). Morris, T. H.; Smith, E. H.; Walsh, R. J. Chem. Soc., Chem. Commun. 1987, 964. Porco, J. A., Jr.; Schreiber, S. L. In Comprehensive Organic Synthesis Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, 151192. (Review). Griesbeck, A. G.; Mauder, H.; Stadtmüller, S. Acc. Chem. Res. 1994, 27, 70. (Review). Fleming, S. A.; Gao, J. J. Tetrahedron Lett. 1997, 38, 5407. Hubig, S. M.; Sun, D.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2 1999, 781. D'Auria, M.; Racioppi, R.; Romaniello, G. Eur. J. Org. Chem. 2000, 3265. Bach, T.; Brummerhop, H.; Harms, K. Chem. Eur. J. 2000, 6, 3838. Bach, T. Synlett 2000, 1699. Abe, M.; Tachibana, K.; Fujimoto, K.; Nojima, M. Synthesis 2001, 1243. D'Auria, M.; Emanuele, L.; Poggi, G.; Racioppi, R.; Romaniello, G. Tetrahedron 2002, 58, 5045. Griesbeck, A. G. Synlett 2003, 451. Liu, C. M. Paternó–Büchi Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 4449. (Review).

448

PausonKhand cyclopentenone synthesis Formal [2 + 2 +1] cycloaddition of an alkene, alkyne, and carbon monoxide mediated by octacarbonyl dicobalt. O O

H

Co2(CO)8

Co(CO)3 Co(CO)3

CO (CO)4Co Co(CO)3

o

toluene, 6080 C 46 d, 60%

H  CO

Co(CO)3 Co(CO)3

O

H

 CO

Co(CO)3 Co(CO)3

OC H

hexacarbonyldicobalt complex

H O

Co(CO)3 Co(CO)2 O

CO

exo complex

CO

(CO)3Co

H

CO

O

insertion (CO)3Co H towards CH H sterically-favored isomer (CO)3Co (CO)3Co

O

insertion (CO)3Co

O

O

O

reductive elimination  Co2(CO)6

H

(CO)3Co

O

H

O

449

Example 16

O Co2(CO)8 O

O

O o

benzene, 65 C 16 h, 23%

O

Example 2, a catalytic version9

Ts N

5 mol% Co2(CO)8 20 mol% P(OPh)3 Ts N

O

3 atm CO, DME 120 oC, 48 h, 94% References 1.

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

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. Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.; Foreman, M. I. J. Chem. Soc., Perkin Trans. 1 1973, 977. Bladon, P.; Khand, I. U.; Pauson, P. L. J. Chem. Res. (M), 1977, 153. Pauson, P. L. Tetrahedron 1985, 41, 5855. (Review). Schore, N. E. Chem. Rev. 1988, 88, 1081. (Review). Billington, D. C.; Kerr, W. J.; Pauson, P. L.; Farnocchi, C. F. J. Organometal. Chem. 1988, 356, 213. Schore, N. E. In Comprehensive Organic Synthesis; Paquette, L. A.; Fleming, I.; Trost, B. M., Eds.; Pergamon: Oxford, 1991, Vol. 5, p.1037. (Review). Schore, N. E. Org. React. 1991, Vol. 40, pp 190. (Review). Jeong, N.; Hwang, S. H.; Lee, Y.; Chung, J. J. Am. Chem. Soc. 1994, 116, 3159. Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263. (Review). Son, S. U.; Lee, S. I.; Chung, Y. K. Angew. Chem., Int. Ed. 2000, 39, 4158. Kraft, M. E.; Fu, Z.; Boñaga, L. V. R. Tetrahedron Lett. 2001, 42, 1427. Muto, R.; Ogasawara, K. Tetrahedron Lett. 2001, 42, 4143. Areces, P.; Durán, M. Á.; Plumet, J.; Hursthouse, M. B.; Light, M. E. J. Org. Chem. 2002, 67, 3506. Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68, 1376. 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 migration.

R

OH

aq. NaOH

O

R

OH R

R

OH

O O

R

O

H

O

OH

H+

O

SN2

O

O

R

workup

O

Example 12

O

NaOMe, MeOH

TrO HO HO

OTr

O TrO

reflux, 1 h, 84%

HO

OH OTr

Example 23

OBz

OH K2CO3, MeOH

OTs BzO

CO2Me

rt, 2 h, 98%

O

CO2Me

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

Payne, G. B. J. Org. Chem. 1962, 27, 3819. George B. Payne was a chemist at Shell Development Co. in Emeryville, CA. Buchanan, J. G.; Edgar, A. R. Carbohydr. Res. 1970, 10, 295. Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammerstrom, S. J. Am. Chem. Soc. 1980, 102, 1436, 3663. Page, P. C. B.; Rayner, C. M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1, 1990, 1375. Konosu, T.; Miyaoka, T.; Tajima, Y.; Oida, S. Chem. Pharm. Bull. 1992, 40, 562. Dols, P. P. M. A.; Arnouts, E. G.; Rohaan, J.; Klunder, A. J. H.; Zwanenburg, B. Tetrahedron 1994, 50, 3473.

451

7. 8. 9. 10. 11. 12. 13.

Ibuka, T. Chem. Soc. Rev. 1998, 27, 145. (Review). Bickley, J. F.; Gillmore, A. T.; Roberts, S. M.; Skidmore, J.; Steiner, A. J. Chem. Soc., Perkin Trans. 1 2001, 1109. Tamamura, H.; Hori, T.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2002, 577. Hanson, R. M. Org. React. 2002, 60, 1156. (Review). Tamamura, H.; Kato, T.; Otaka, A.; Fujii, N. Org. Biomol. Chem. 2003, 1, 2468. Yamazaki, T.; Ichige, T.; Kitazume, T. Org. Lett. 2004, 6, 4073. 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 E-ketoester to produce coumarin.

OH

O

O

O

AlCl3

R

O

OEt R

O AlCl 3 O

H EtO O:

O

O

R

R

:

O

O

O

H+ R

R

H

O

O

Michael

O

H

O

OEt O

O

O

H

addition OH H

O

R OH H+

R OH

O

R

Example 111

O

O OEt

HO

OH

[bimim]Cl•2AlCl3 130 oC, 35 min., 90%

HO

O

O

[bimim]Cl•2AlCl3 = 1-Butyl-3-methylimidazolium chloroaluminuminate (a Lewis acid ionic liquid)

453

Example 214

O

O

OH

O

O

OH

OEt o

OH

BiCl3, 75 C, 2 h, 66%

O

O

References 1.

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

v. Pechmann, H.; Duisberg, C. Ber. Dtsch. Chem. Ges. 1883, 16, 2119. Hans von Pechmann (18501902) 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. Hirata, T.; Suga, T. Bull. Chem. Soc. Jpn. 1974, 47, 244. Chaudhari, D. D. Chem. Ind. 1983, 568. Holden, M. S.; Crouch, R. D. J. Chem. Educ. 1998, 75, 1631. Corrie, J. E. T. J. Chem. Soc., Perkin Trans. 1 1990, 2151. Hua, D. H.; Saha, S.; Roche, D.; Maeng, J. C.; Iguchi, S.; Baldwin, C. J. Org. Chem. 1992, 57, 399. Biswas, G. K.; Basu, K.; Barua, A. K.; Bhattacharyya, P. Indian J. Chem., Sect. B 1992, 31B, 628. Li, T.-S.; Zhang, Z.-H.; Yang, F.; Fu, C.-G. J. Chem. Res., (S) 1998, 38. Sugino, T.; Tanaka, K. Chem. Lett. 2001, 110. Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285. Khandekar, A. C.; Khandilkar, B. M. Synlett. 2002, 152. Shockravi, A.; Heravi, M. M.; Valizadeh, H. Phosphorus, Sulfur Silicon Relat. Elem. 2003, 178, 143. Smitha, G.; Sanjeeva Reddy, C. Synth. Commun. 2004, 34, 3997. De, S. K.; Gibbs, R. A. Synthesis 2005, 1231.

454

Perkin reaction Cinnamic acid synthesis from aryl aldehyde and acetic anhydride.

Ar

CHO

OAc O

AcONa

Ac2O

Ar

O O

enolate

O H

O

OH cinnamic acid

O aldol

O

OAc

Ar

H2 O

O O

O

OH

H

formation

Ar

condensation

O

O

O

intramolecular O

O

O

O

acyl transfer Ar

Ar

O

O O

O

O

O O

O

O

Ar

O

O

acyl

O

Ar transfer

O

O H

H

OH O

E2 Ar

O

Ac2O

O

elimination OAc

O

O HO O Ar

O

Ar

O

HOAc O

Ar

OH

455

Example 19

MeO CHO

MeO CO2H

MeO MeO H Ac2O, Et3N, 90 oC

CO2H MeO

5 h, 66% MeO Example 210

Ac2O, '

ClF2C

ClF2C

O Ph

AcONa, 46%

Ph

CO2H

References Perkin, W. H. J. Chem. Soc. 1868, 21, 53. William Henry Perkin (18381907), 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. 1.

456

Petasis reaction Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction.

R1

R3

O

R2 NH

H

R3

R2

R4

(HO)2B

N R1

R4

R3

O H

R2

R3

R2 NH R1

N OH R1 (HO)2B

R4

R3 R2

R3

O H B(OH)2

N R1

R2

N R1

R4

R4

Example 15

Ph

OH B OH

C5H11

O

Ph

EtOH, rt 84%, 99% de

Ph

OH

Ph

N C5H11 OH

N H

457

Example 27

Me HO

(HO)2B CHO

HO

HO MeNHBn, EtOH, rt 24 h, 72%, 99% de OMe

N Bn

HO

OMe

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

9.

Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, 16463. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. Koolmeister, T.; Södergren, M.; Scobie, M. Tetrahedron Lett. 2002, 43, 5969. Orru, R. V. A.; deGreef, M. Synthesis 2003, 1471. (Review). Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004, 15, 3149. Chang, Y. M.; Lee, S. H.; Nam, M. H.; Cho, M. Y.; Park, Y. S.; Yoon, C. M. Tetrahedron 2005, 46, 3053. Follmann, M.; Graul, F.; Schaefer, T.; Kopec, S.; Hamley, P. Synlett 2005, 1009.

458

Peterson olefination Alkenes from D-silyl carbanion and carbonyl compounds. Also known as silaWittig reaction. H

O R1

R2

M

+

HO 2 R 1 R

SiR3

R

3

SiR3 H 3 R

acid or

R1

H

base

R

2

R

Basic conditions: O R1

R2

O R

H +

R2

SiR3

M

1

SiR3 H R3

R3

E-silylalkoxide intermediate O SiR3 1 R H R2 R3

syn-

R1

H

elimination

R2

R3

Acidic conditions:

HO R1 R2

SiR3 H R3

H2O R1 R2

3

rotation

R3 H SiR3

HO R R1 H SiR3 R2 E-hydroxysilane

H+

E2 anti-

R

1

R

elimination

R2

H

:OH2

3

Example 110

PhO2S

F

1. n-BuLi, Et2O, 78 oC

F TBS

Ph

PhO2S 2. benzophenone, 63%

Ph

3

459

Example 212

1. KHMDS, THF, 78 oC (t-BuO)Ph2Si

CN 2. N

CHO

CN N 88% yield 92:8 Z:E

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

14.

Peterson, D. J. J. Org. Chem. 1968, 33, 780. Ager, D. J. Synthesis 1984, 38498. (Review). Ager, D. J. Org. React. 1990, 38, 1. (Review). Barrett, A. G. M.; Hill, J. M.; Wallace, E. M.; Flygare, J. A. Synlett 1991, 764770. (Review). Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron Lett. 2001, 42, 6125. van Staden, L. F.; Gravestock, D.; Ager, D. J. Chem. Soc. Rev. 2002, 31, 195. (Review). Ager, D. J. Science of Synthesis 2002, 4, 789809. (Review). Adam, W.; Ortega-Schulte, C. M. Synlett 2003, 414. Murai, T.; Fujishima, A.; Iwamoto, C.; Kato, S. J. Org. Chem. 2003, 68, 7979. Asakura, N.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2003, 124, 81. Suzuki, H.; Ohta, S.; Kuroda, C. Synth. Commun. 2004, 34, 1383. Kojima, S.; Fukuzaki, T.; Yamakawa, A.; Murai, Y. Org. Lett. 2004, 6, 3917. Kano, N.; Kawashima, T. The Peterson and Related Reactions in Modern Carbonyl Olefination Takeda, T. (ed.), Wiley-VCH: Weinheim, Germany, 2004, 18103. (Review). 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 E-hydroxy-E-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. 4

OH 4

H N 1 R

3

3

P2O5, decalin 1

reflux

O

N

R P2O5 actually exists as P4O10, an adamantane-like structure.

OH

OH

O

HN:

O

O P O P O O

O

HN

R

R O

OH

H

O P O P O: O O

:NH N

H R OPO2 R OPO2 H

N

N R

R

P O

O

461

Example 110

OH P2O5 H

N

N

O Cl

Cl

o-dichlorobenzene 80%

Example 27

POCl3, P4O10, decalin HO O

NH

N

180 oC, 6 h, 14% N

OH

H N

H N O

OH N

O

Reference Pictet, A.; Gams, A. Ber. Dtsch. Chem. Ges. 1909, 42, 1973, 2943. Amé Pictet (18571937), 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 Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 457465. (Review). 1.

462

Pictet–Spengler tetrahydroisoquinoline synthesis Tetrahydroisoquinolines from condensation of E-arylethylamines and carbonyl compounds followed by cyclization.

R1O

R1O

O 2

NH2

R1O

R

HCl R2

R1O NH2 H

1

:

R O

R1O

H O

1

R O

2

R

R O

H

N:

OH2

N

R1O

R2 R1O NH H 12

H

R2 R1O

R1O

R1O

OH

N

R1O

H2O 1

H

+ H+

R2

R1O

Example 1

NH

R1O

H

R1O

R2

NH H

NH

1

R O R2

R2

N NHMe

MeO

(CH2O)n

i-PrO

MeO

i-PrO aq. HCl, EtOH

i-PrO

75%

i-PrO

Me

463

Example 29

O O HO

AcO NH2

MeO

+ Me

S O N

O O HO

silica gel

NH

MeO

O AcO

dry EtOH

S O

Me

80% N O O

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

Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030. Hudlicky, T.; Kutchan, T. M.; Shen, G.; Sutliff, V. E.; Coscia, C. J. J. Org. Chem. 1981, 46, 1738. Miller, R. B.; Tsang, T. Tetrahedron Lett. 1988, 29, 6715. Rozwadowska, M. D. Heterocycles 1994, 39, 903. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (Review). Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 9202. Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611. Kang, I.-J.; Wang, H.-M.; Su, C.-H.; Chen, L.-C. Heterocycles 2002, 57, 1. Zhou, B.; Guo, J.; Danishefsky, S. J. Org. Lett. 2002, 4, 43. Yu, J.; Wearing, X. Z.; Cook, J. M. Tetrahedron Lett. 2003, 44, 543. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177. Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron: Asymmetry 2003, 14, 1309. Tinsley, J. M. Pictet–Spengler Isoquinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 469479. (Review).

464

Pinacol rearrangement Acid-catalyzed rearrangement of vicinyl diols (pinacols) to carbonyl compounds.

HO R R1

OH R2 3 R

O

+

H

R

R2 R3 R1

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

HO R R1 HO R R1

OH R2 3 R

HO R R1

H+

H alkyl

2

R 3 R

migration

OH2 R2 3 R

H2O

O

O 2

R

R R3 R1

2

H+

R

R R3 R1

Example 112

Ph

O

1. MsCl, Et3N, CH2Cl2 0 oC, 10 min.

OH OH N SO2Ph

Ph

2. Et3Al, CH2Cl2, 78 oC 10 min., 90%

N SO2Ph

Example 214

Ph Ph

OH OH

O cat. TsOH

Ph

O Ph Ph

CDCl3 3:1

Ph

465

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Fittig, R. Justus Liebigs Ann. Chem. 1860, 114, 54. Toda, F.; Shigemasa, T. J. Chem. Soc., Perkin Trans. 1 1989, 209. Nakamura, K.; Osamura, Y. J. Am. Chem. Soc. 1993, 115, 9112. Paquette, L. A.; Lord, M. D.; Negri, J. T. Tetrahedron Lett. 1993, 34, 5693. Jabur, F. A.; Penchev, V. J.; Bezoukhanova, C. P. J. Chem. Soc., Chem. Commun. 1994, 1591. Patra, D.; Ghosh, S. J. Org. Chem. 1995, 60, 2526. Magnus, P.; Diorazio, L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tetrahedron 1996, 52, 14147. Bach, T.; Eilers, F. J. Org. Chem. 1999, 64, 8041. Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693. Chen, X.; Esser, L.; Harran, P. G. Angew. Chem., Int. Ed. 2000, 39, 937. Rashidi-Ranjbar, P.; Kianmehr, E. Molecules 2001, 6, 442. Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937. Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 71437157. (Review). Mladenova, G.; Singh, G.; Acton, A.; Chen, L.; Rinco, O.; Johnston, L. J.; Lee-Ruff, E. J. Org. Chem. 2004, 69, 2017. 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. O +

H , H2O 1

R CN

R

HCl (g)

OH

NH2

OR1

R

NH3, EtOH

R

H+ protonation R

N:

R

R

NH nucleophilic

O:

1

OR1

R

NH2 Cl

NH2•HCl

NH2 Cl

addition

OR1

R

H

common intermediate

NH2 Cl

hydrolysis

1

R

H+

O

H2N O H

OR

R

H2O:

OR

H+

NH2 Cl R

OR1

R

1

nucleophilic

HCl•H2N OR1

addition

R

OR1

H3N:

NH2 R

NH2 H

Example 13

O Ph

Ph N H

Ph

EtSH, HCl, CH2Cl2 N

o

0 C, 10 min., 95% NH2

Ph

NH pyr., H2S

N

N

O Ph

4 h, 0 oC, 42%

O Ph

NH2•HCl

467

Example 23

O Ph

EtSH, HCl, CH2Cl2 N H

O Ph

N H

SEt NH

N

0 oC, 1 h, 85%

pyr., H2S 2 h, 0 oC, 40%

O

Ph N H

SEt S

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

Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10, 1889. Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1878, 11, 1825. Poupaert, J.; Bruylants, A.; Crooy, P. Synthesis 1972, 622. Wagner, G.; Horn, H. Pharmazie 1975, 30, 353. Lee, Y. B.; Goo, Y. M.; Lee, Y. Y.; Lee, J. K. Tetrahedron Lett. 1990, 31, 1169. Cheng, C. C. Org. Prep. Proced. Int. 1990, 22, 643. Neugebauer, W.; Pinet, E.; Kim, M.; Carey, P. R. Can. J. Chem. 1996, 74, 341. Siskos, A. P.; Hill, A. M. Tetrahedron Lett. 2003, 44, 789. Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331. Cushion, M. T.; Walzer, P. D.; Collins, M. S.; Rebholz, S.; Vanden Eynde, J. J.; Mayence, A.; Huang, T. L. Antimicrob. Agents Chemoth. 2004, 48, 4209.

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.

R1 N O R

R2

(CH3CO)2O R pyr., CH2Cl2

O R1 N O R

2

R

R1 N

O R2

O

O

2

R acylation

O

H

H

R1 O N O R

CH3CO2 O

O

1

2

R

HOAc

R N

R

R2

CH3CO2

R1 N: R O O

O

iminium ion

R1 O N R

2

R O

R

O

R1 N

O R2

H

O

OAc The intramolecular pathway is also possible:

R1 N

R2

: O

2

R R O

R1 N R O O

R

R1 N

O R2 O

H

469

Example 11

(CH3CO)2O N

N O

o

100 C

O

Example 22

O

O N

(CH3CO)2O

N

< 30 oC, 98% References Polonovski, M.; Polonovski, M. Bull. Soc. Chim. Fr. 1927, 41, 1190. Michelot, R. Bull. Soc. Chim. Fr. 1969, 4377. Volz, H.; Ruchti, L. Ann. 1972, 763, 184. Hayashi, Y.; Nagano, Y.; Hongyo, S.; Teramura, K. Tetrahedron Lett. 1974, 15, 1299. M’Pati, J.; Mangeney, P.; Langlois, Y. Tetrahedron Lett. 1981, 22, 4405. Lounasmaa, M.; Koskinen, A. Tetrahedron Lett. 1982, 23, 349. Lounasmaa, M.; Karvinen, E.; Koskinen, A.; Jokela, R. Tetrahedron 1987, 43, 2135. Tamminen, T.; Jokela, R.; Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45, 2683. Grierson, D. Org. React. 1990, 39, 85. (Review). Lounasmaa, M.; Jokela, R.; Halonen, M.; Miettinen, J. Heterocycles 1993, 36, 2523. Morita, H.; Kobayashi, J. J. Org. Chem. 2002, 67, 5378. 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. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

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 (CF3CO)2O

N O

pyr., CH2Cl2

O

CF3

tertiary N-oxide

O F3C

O O

N O CF3

acylation

CF3

H O

N O CF3CO2 N

N:

H

F3C

O O enamine

CF3CO2 iminium ion

N

N CF3CO2

H O

CF3

O

CF3

O

CF3

471

Example 12

O (CF3CO2)2O, CH2Cl2, 0 oC

N

N H

N

N H H

then, HCl, heat, 30% HO

HO

Example 25

O O HHN

N

O OH

O H

(CF3CO2)2O, pyr.

HHN

N

O OH

o

CH2Cl2, 0 C, 65% F3C

H O

References 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. 1.

472

Pomeranz–Fritsch reaction Isoquinoline synthesis via acid-mediated cyclization of the appropriate aminoacetal intermediate. OEt OEt OEt

H2 N

OEt

CHO

H

+

N

N

OEt :

H2N

OEt

OEt

OEt

condensation :N

H

H

OH2

O H+

H : OEt

imine

OEt :

OEt

formation

OEt

N

N

OEt

OEt

HOEt N

N

H OEt +

H

H

N

N

473

Example 15

EtO

OEt

MeO

BF3, (CF3CO)2O

MeO

6082 %

MeO

N

MeO

N

Example 212

MeO OMe

H

OMe

TiCl4, CH2Cl2

78 oC, 69 %

N O

N O

Me

Me

Schlittler–Müller modification OEt NH2

OHC

OEt

R OEt H+

OEt

N

N R

R Example 37

OEt O

i) EtO H H2N

NH2

ii) oleum 30 %

N

N

474

References 1.

2.

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

Pomeranz, C. Monatsh. 1893, 14, 116. Cesar Pomeranz (18601926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419. Paul Fritsch (18591913) 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. Schlittler, E.; Müller, J. Helv. Chim. Acta 1948, 31, 914, 1119. Gensler, W. J. Org. React. 1951, 6, 191. (Review). Bevis, M. J.; Forbes, E. J.; Naik, N. N.; Uff, B. C. Tetrahedron 1971, 27, 1253. Birch, A. J.; Jackson, A. H.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1 1974, 2185, 2190. Gill, E. W.; Bracher, A. W. J. Heterocycl. Chem. 1983, 20, 1107. Ishii, H.; Ishida, T. Chem. Pharm. Bull. 1984, 32, 3248. Bobbitt, J. M.; Bourque, A. J. Heterocycles 1987, 25, 601. (Review). Katritzky, A. R.; Yang, Z.; Cundy, D. J. Heteroat. Chem. 1994, 5, 103. Schlosser, M.; Simig, G.; Geneste, H. Tetrahedron 1998, 54, 9023. Poli, G.; Baffoni, S. C.; Giambastiani, G.; Reginato, G. Tetrahedron 1998, 54, 10403. GluszyĔska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2000, 11, 2359. Capilla, A. S.; Romero, M.; Pujol, M. D.; Caignard, D. H.; Renard, P. Tetrahedron 2001, 57, 8297. Hudson, A. Pomeranz–Fritsch Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 480486. (Review).

475

Prévost trans-dihydroxylation Cf. Woodward cis-dihydroxylation.

O2CPh

I2 AgO2CPh

I

OH

hydrolysis

OH

O2CPh

I

I

SN2

O2CPh cyclic iodonium ion intermediate O2CPh

I SN2 O

SN2 O

O

O

Ph Ph neighboring group assistance O2CPh

OH

hydrolysis

OH

O2CPh Example 18

O

AgOCOPh, I2 Ph F

PhH, rt, 2 h, reflux, 10 h, 46%

O O

O Ph

F

476

Example 212

O2C-C6H4-p-OMe

AgOCOPh, I2 CCl4, 74%

O

OAc

OH O2C-C6H4-p-OMe

I O

1. KOH, H2O

AcO

2. Ac2O, pyr.

O

OAc

Woodward cis-dihydroxylation13 Cf. Prévost trans-dihydroxylation.

1. I2, AgOAc HO OH

2. H2O, H+ I

I

I

SN2

OAc cyclic iodonium ion intermediate I : O

SN2

O

O

H+

O

O

O

H O

H2O: neighboring group assistance

:OH2

protonation

HO O O

HO O O

H

477

hydrolysis

HO O HO O

HO OH H

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

Prévost, C. Compt. Rend. 1933, 196 1129. Campbell, M. M.; Sainsbury, M.; Yavarzadeh, R. Tetrahedron 1984, 40, 5063. 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. Prasad, K. J. R.; Subramaniam, M. Indian J. Chem., Sect. B 1994, 33B, 696. Ciganek, E.; Calabrese, J. C. J. Org. Chem. 1995, 60, 4439. Deota, P. T.; Singh, V. J. Chem. Res. (S), 1996, 258. Brimble, M. A.; Nairn, M. R. J. Org. Chem. 1996, 61, 4801. Zajc, B. J. Org. Chem. 1999, 64, 1902. Hamm, S.; Hennig, L.; Findeisen, M.; Muller, D.; Welzel, P. Tetrahedron 2000, 56, 1345. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B. C.; Lin, J.-M.; Amin, S. J. Org. Chem. 2000, 65, 8134. Sabat, M.; Johnson, C. R. Tetrahedron Lett. 2001, 42, 1209. Hodgson, R.; Nelson, A. Org. Biomol. Chem. 2004, 2, 373. Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80, 209. Robert Burns Woodward (USA, 19171979) won the Nobel Prize in Chemistry in 1953 for his synthesis of natural products.

478

Prins reaction Addition of alkene to formaldehyde.

H+

O R

H

OH

H2O

H

R

OH

O or

R

OH

O

or R

OH O H

H+

H

OH

H2 O

H

R

H

OH

R

OH

R

the common intermediate

R

 H+

OH

R

H

OH

:B

H H+

O O H

H

R

OH

H

R

O

O R

H

Example 18

SnBr4, CH2Cl2

OAc O

78 oC, 84%

TsO

OBn Br

O TsO

OBn

O

479

Example 210

O

O

(CH2O)n, Bi(OTf)3 AcO

CH3CN, rt, 10 h, 77% AcO

References Prins, H. J. Chem. Weekblad 1919, 16, 64, 1072. Hendrik J. Prins (18891958), born in Zaandam, The Netherlands, was not even an organic chemist per se. After obtaining a doctorate in chemical engineering, Prins worked for an essential oil company and then a company dealing with the rendering of condemned meats and carcasses. But he had a small laboratory near his house where he carried out his experiments in his spare time, which obviously was not a big distraction—for he rose to be the presidentdirector of the firm he worked for. 2. Adam, D. R.; Bhatnagar, S. P. Synthesis 1977, 661672. (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. 1.

480

Pschorr cyclization The intramolecular version of the GombergBachmann reaction.

CO2H

CO2H

NaNO2, HCl Cu

NH2 H HO

N

H+ O

O

N

O

H2O

H2O N

O

O

CO2H

N

O

H+

NH2

NH N O

:

N

O

N

O

CO2H

N N

H

O

CO2H

NO2

O

N

CO2H H+

H2O N: N

O H

+

OH2

CO2H

CO2H Cu(0)

N2n

Cu(I)

N2

H CO2H 6-exo-trig radical cyclization

H

481

CO2H Cu(I) Cu(0)

H+ Example 110

O

O

O

1. NaNO2, HCl-H2O-HOAc 0 to 5 oC, 2 h NH2 S

O

O

2. CuSO4, HOAc, reflux 2 h, 86%

O

O

S 6:1

O

O

S

Example 211

O

O N N

NH2

NaNO2, HCl 5 to 20 oC, 64%

N N

482

References Pschorr, R. Ber. Dtsch. Chem. Ges. 1896, 29, 496. Robert Pschorr (18681930), 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, 13591469. (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.; TapolcĞanyi, P.; Monsieurs, K.; Éliás, O.; Dommisse, R. A.; Krajsovszky, G. Synlett 2004, 1123-1139. (Review). 1.

483

Pummerer rearrangement The transformation of sulfoxides into D-acyloxythioethers using acetic anhydride.

R1

O S

R2

Ac2O

R2

S

R1

OAc O

O

O

O

O

R1

O S

O O

acyl transfer

R2

R1

R1

AcO

O S

O S

R2 H

R2 AcO

HOAc

1

R

1

R

R2

S

R2

S

R1

S

OAc AcO

Example 12

OH Ph2HCO

o

1. m-CPBA, CH2Cl2, 78 C SPh 2. Ac2O, NaOAc, ', 93%

OH

OH OAc Ph2HCO

SPh OH

Example 213

Bn

Bn N

R2

O

Ph

O S

Ac2O, pyr., DMAP CH2Cl2, rt, 91%

Bn

Bn N Ph

O S OAc

484

References 1.

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

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. Masamune, S.; Sharpless, K. B. et al. J. Org. Chem. 1982, 47, 1373. De Lucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40, 157406. (Review). Padwa, A.; Gunn, D. E., Jr.; Osterhout, M. H. Synthesis 1997, 13531378. (Review). Kita, Y. Phosphorus, Sulfur Silicon Relat. Elem. 1997, 120 & 121, 145164. (Review). Padwa, A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175203. (Review). Marchand, P.; Gulea, M.; Masson, S.; Averbuch-Pouchot, M.-T. Synthesis 2001, 1623. Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851862. (Review). Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003, 68, 929. Matsuda, H.; Fujita, J.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashimoto, K. Tetrahedron Lett. 2003, 44, 4089. Fujita, J.; Matsuda, H.; Yamamoto, K.; Morii, Y.; Hashimoto, M.; Okuno, T.; Hashimoto, K. Tetrahedron 2004, 60, 6829. Ruano, J. L.; Alemán, J.; Aranda, M. T.; Arévalo, M. J.; Padwa, A. Org. Lett. 2005, 7, 19. Suzuki, T.; Honda, Y.; Izawa, K.; Williams, R. M. J. Org. Chem. 2005, 70, 7317.

485

Ramberg–Bäcklund reaction Olefin synthesis via D-halosulfone extrusion.

X R

R1

Base

O S On

R1

S O O

R

:B

X R

R

backside

H X

R1

S O O

1

S O O

R

R1

R

R1

SO2 S

extrusion

displacement

O S On R

O O episulfone intermediate Example 14

H KOt-Bu, THF S H O 2

Br

o

15 C to rt, 71%

Example 25

H

Br

KOt-Bu, THF/HOt-Bu

SO2CH2Br

0 oC to rt, 0.5 h, 65%

H

486

References Ramberg, L.; Bäcklund, B. Arkiv. Kemi, Mineral Geol. 1940, 13A, 50. Paquette, L. A. Acc. Chem. Res. 1968, 1, 209216. (Review). Paquette, L. A. Org. React. 1977, 25, 171. (Review). Becker, K. B.; Labhart, M. P. Helv. Chim. Acta 1983, 66, 1090. Block, E.; Aslam, M.; Eswarakishnan, V. et al. J. Am. Chem. Soc. 1986, 108, 4568. Braverman, S.; Zafrani, Y. Tetrahedron 1998, 54, 1901. Taylor, R. J. K. Chem. Commun. 1999, 217227. (Review). MaGee, D. I.; Beck, E. J. Can. J. Chem. 2000, 78, 1060. McAllister, G. D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197. Murphy, P. V.; McDonnell, C.; Hämig, L.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron: 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, 357475. (Review). 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

487

Reformatsky reaction Nucleophilic addition of organozinc reagents generated from D-haloesters to carbonyls.

OR2

O Br

R1

R

HO R

Zn

O

2

OR R1

O

O OR2

Br

oxidative addition or electron transfer

O

BrZnO R

nucleophilic addition

H2O, hydrolysis

OR2 O

R1

O

OR2 R1

O

5

OTBDMS

OTBDMS Ph S

ZnBr

OR2

HO R

during workup Example 1

R1

R

Zn(0)

N Boc

BrCH2CO2Me

Ph

MeO2C N Boc

Zn, THF, reflux, 71%

Example 211

O

O

Zn, THF O

o

60 C

Br

MeO

O O

HO O MeO

HCl THF, rt, 10 h 92%

O MeO

488

References 1.

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

Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. Sergei Reformatsky (18601934) was born in Russia. He studied at the University of Kazan in Russia, the cradle of Russian chemistry professors, where he found competent guidance of a distinguished chemist, Alexander M. ZaƱtsev. Reformatsky then studied at Göttingen, Heidelberg, and Leipzig in Germany. After returning to Russia Reformatsky became the Chair of Organic Chemistry at the University of Kiev. Gaudemar, M. Organometal. Chem. Rev., A 1972, 8, 183. (Review). Rathke, M. W. Org. React. 1975, 22, 423460. (Review). Fürstner, A. Synthesis 1989, 571590. (Review). Lee, H. K.; Kim, J.; Pak, C. S. Tetrahedron Lett. 1999, 40, 2173. Fürstner, A. In Organozinc Reagents Knochel, P.; Jones, P. eds.; Oxford University Press: New York, 1999, pp 287305. (Review). Hirashita, T.; Kinoshita, K.; Yamamura, H.; Kawai, M.; Araki, S. J. Chem. Soc., Perkin Trans. 1 2000, 825. Kurosawa, T.; Fujiwara, M.; Nakano, H.; Sato, M.; Yoshimura, T.; Murai, T. Steroids 2001, 66, 499. Ocampo, R.; Dolbier, W. R., Jr.; Abboud, K. A.; Zuluga, F. J. Org. Chem. 2002, 67, 72. Obringer, M.; Colobert, F.; Neugnot, B.; Solladié, G. Org. Lett. 2003, 5, 629. Zhang, M.; Zhu, L. Tetrahedron: Asymmetry 2003, 14, 3447. Ocampo, R.; Dolbier, W. R., Jr. Tetrahedron 2004, 60, 93259374. (Review). Scherkenbeck, T.; Siegel, K. Org. Proc. Res. Dev. 2005, 9, 216. Orsini, F.; Sello, G.; Manzo, A. M.; Lucci, E. M. Tetrahedron: Asymmetry 2005, 16, 1913. 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.

OR1

R O

N2

TsN3, Et3N MeCN

O

OR1

R O

H

enolate OR1

O

O O N N N S O

:NEt3

R

OR1

R

formation

O

O

O

N

R

N SO2Tol N H OR1 O

N N:

proton transfer

1

OR O

O

SO2Tol OR1

O

N N

H N

R

O

R

Ts NH2

O

O H2N S O tosyl amide is the by-product

When only one carbonyl is present, ethylformate can be used as an activating auxiliary:69

O NaH, HCO2Et

O

MsN3 OH

Et2O

Et2O

O N2

490

O N N N S Me O

:NEt3

O O

O

H

O

O

N N

N

SO2Me

O

H O

N N N SO Me 2 H O

O

O HN S Me O O H

N

O

N

N2

Alternatively, the triazole intermediate may be assembled via a 1,3-dipolar cycloaddition of the enol and mesyl azide: O O N N N S Me O

O

1,3-dipolar cycloaddition

OH

N N N SO Me 2 H OH

O HN S Me O O H

O N2

Example 110

H N

O Ot-Bu O

O

O

SO2N3

491

O

Et3N, CH3CN

N2 Ot-Bu

o

0 C, 5 h, 45%

O

O

Example 26

O

O

O

O

N

N H

OTIPS

CH3CN, 84%

N

O

O

O N

N2

CH3SO2N3

O N H

OTIPS

N

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Regitz, M. Angew. Chem., Int. Ed. Engl. 1967, 6, 733. Regitz, M.; Anschütz, W.; Bartz, W.; Liedhegener, A. Tetrahedron Lett. 1968, 3171. Regitz, M. Synthesis 1972, 351–373. (Review). Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986, 51, 4077. Taber, D. F.; Schuchardt, J. L. Tetrahedron 1987, 43, 5677. Pudleiner, H.; Laatsch, H. Justus Liebigs Ann. Chem. 1990, 423. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem. Soc. 1990, 112, 4011. Ihara, M.; Suzuki, T.; Katogi, M.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Chem. Commun. 1991, 646. Charette, A. B.; Wurz, R. P.; Ollevier, T. J. Org. Chem. 2000, 65, 9252. Hodgson, D. M.; Labande, A. H.; Pierard, F. Y. T. M.; Expésito Castro, M. A. J. Org. Chem. 2003, 68, 6153. Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 13624. Mejía-Oneto, J. M.; Padwa, A. Org. Lett. 2004, 6, 3241. Muroni, D.; Saba, A.; Culeddu, N. Tetrahedron: Asymmetry 2004, 15, 2609. Rowlands, G. J.; Barnes, W. K. Tetrahedron Lett. 2004, 45, 5347. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967. 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

OH CHCl3

a.

CHO

3 KOH

3 KCl

2 H2O

Carbene generation:

fast

Cl3C H OH b.

CCl2 Cl

H2O

Clslow

:CCl2

D-elimination

Addition of dichlorocarbene and hydrolysis:

OH

O

O KOH H2O

O

H CCl2

CCl2

O

Cl CHCl

OH

Cl

O

H

O

H

OH

O

CHO H

Example 1, photo Reimer–Tiemann reaction without base8

OH

O

CHCl2

hv (Hg lamp) CHCl3, 5 h, 48% CN

CN

Cl

OH H

493

Example 29

OH

OH CHO CHCl3, 6 eq. NaOH CO2H

NHBoc

2 eq. H2O, reflux 4 h, 64%

CO2H NHBoc

References 1.

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

Reimer, K.; Tiemann, F. Ber. Dtsch. Chem. Ges. 1876, 9, 824. Karl L. Reimer (18451883) 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 shortlived career in organic chemistry. Johann K. F. Tiemann (18481899) 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. Wynberg, H.; Meijer, E. W. Org. React. 1982, 28, 1–36. (Review). Smith, K. M.; Bobe, F. W.; Minnetian, O. M.; Hope, H.; Yanuck, M. D. J. Org. Chem. 1985, 50, 790. Bird, C. W.; Brown, A. L.; Chan, C. C. Tetrahedron 1985, 41, 4685. Neumann, R.; Sasson, Y. Synthesis 1986, 569. Cochran, J. C.; Melville, M. G. Synth. Commun. 1990, 20, 609. Langlois, B. R. Tetrahedron Lett. 1991, 32, 3691. Jiménez, M. C.; Miranda, M. A.; Tormos, R. Tetrahedron 1995, 51, 5825. 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.

O R

N Cl

H CN

N

KCN O

H2SO4

O R

NH3

H

:

N

Cl

R

O

O

CO2H

N 

N

R

CN H CN

N

H O

R

R

Reissert compound

H

H

N

O N

R

NH

N: O H

R H

NH

N

R H

H+

N R H

O

OH NH2

NH

N

O

R

H

O :

H

H+

O

O H N R H

O

NH2

H+

495

O R

O

N

H

H3O+

O

N

H

NH2 H2O:

NH2 H O

NH3

N HO NH 2

N

CO2H

Example 14

O MeO

NaCN, H2O, CH2Cl2

Cl

MeO

N

OMe

4.5 h, 95%

O N MeO

CN O

30% H2SO4

MeO

H

reflux, 1 h, 95% MeO

MeO

OMe OMe

Example 210

chiral Al catalyst TMSCN, CH2=CHOCOCl

N Br

o

CH2Cl2, 40 C, 72 h, 53%

N

O

CN O Br 73% ee

496

References 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. 1.

497

Reissert indole synthesis The Reissert indole synthesis involves base-catalyzed condensation of an onitrotoluene derivative with an ethyl oxalate, which is followed by reductive cyclization to an indole-2-carboxylic acid derivative.

+

R

NO2

CO2Et CO2Et

H+

B

CO2Et R

O NO2

R N H

H

CO2H

H CH3

O

CH2 EtO

B

NO2

NO2 OH OEt CO2Et NO2

OEt

O

O

hydrolysis

CO2Et NO2 O

H

CO2H NO2

O

H

CO2H NH2

H CO2H N H

OH

CO2H N H

498

Example 13

MeO N O

NO2

KOEt

CO2Et CO2Et

CO2Et

93%

MeO H2, Pd/C

MeO N

N

EtOH, 85% NO2

N H

CO2Et

Example 25

+ NO2 CO2Et OK NO2

CO2Et CO2Et

KOEt, EtOH Et2O, 76%

H2 (30 psi), PtO2 HOAc, 42%

N H

CO2Et

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

Reissert, A. Ber. 1897, 30, 1030. Julian, P. C.; Meyer, E. W.; Printy, S. C. Heterocyclic Compounds; : New York, 1962; p 18. (Review). Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem. Soc. 1965, 87, 3530. Brown, R. K. In Indoles, Part 1; Houlihan, W. J. Ed.; Wiley & Sons: New York, 1972; pp 397413. (Review). Noland, W. E.; Baude, F. J. Org. Synth.; Ed, Baumgarten, H. E.; Wiley & Sons: New York, 1973; p. 567. Leadbetter, G.; Fost, D. L.; Ekwuribe, N. N.; Remers, W. A. J. Org. Chem. 1974, 39, 3580. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G. D. Tetrahedron Lett. 2001, 42, 2031. Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.; Sato, Y.; Yamada, H.; Murakami, Y. Synlett 2000, 1196. Li, J.; Cook, J. M. Reissert Indole Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 154158. (Review).

499

Ring-closing metathesis (RCM)

(Cy)3P Cl Ru Cl P(cy)3

Ph

(Cy)3P

Cl Cl Ph Mes N

Ph

Ru

F3C F3C

N Mes

N Mo O O

Ph

F3C F3C Schrock’s reagent

Grubbs’ reagents Mes = mesityl All three catalysts are illustrated as “LnM=CHR” in the mechanism below. Generation of the catalyst from the precatalysts:

LnM

LnM CHR

the real catalyst

LnM CHR

[2 + 2]

LnM CHR

cycloaddition cycloreversion

MLn

CHR

[2 + 2] cycloaddition

MLn

cycloreversion LnM

Catalytic cycle:

LnM

LnM

[2 + 2] cycloaddition

LnM

cycloreversion

500

[2 + 2]

MLn

cycloaddition MLn

cycloreversion LnM

Example 14

10 mol% (PCy3)2Cl2Ru=CHPh O

O

C11H23

0.3 eq. Ti(Oi-Pr)4 CH2Cl2, 40 oC, 93%

O

O

C11H23

Example 29

(Cy)3P

E E

Ph Cl Ru Cl Mes N N Mes

E

E

o

References

45 C, 60 min. 100% E = CO2Et

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. 1.

501

Ritter reaction Amides from nitriles and alcohols in strong acids. General scheme:

1

R

1

R

CN

R

OH

O

H+

2

N H

R2

e.g.:

O

H2SO4

OH

H3C CN

N H

H2O Similarly:

O

H2SO4 H3C CN

N H

H2O

OH

H3O+

E1 OH2

:N H2O

:OH2

N N nitrilium ion

OH2 N

H+

O

OH N

N H

502

Example 14

CH3 CH3

t-BuOH, conc. H2SO4

O

N N

CN

7075 oC, 75 min., 97%

HN

Example 28

fuming H2SO4, CH3CN, rt, 30 min., O

then H2O, 100 oC, 2 h, 77%

OH NH2

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

Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045. Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70, 4048. Krimen, L. I.; Cota, D. J. Org. React. 1969, 17, 213–329. (Review). Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T. A. J. Org. Chem. 1989, 54, 2242. Djaidi, D.; Leung, I. S. H.; Bishop, R.; Craig, D. C.; Scudder, M. L. J. Chem. Soc., Perkin 1 2000, 2037. Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R. Synthesis 2000, 1709. Le Goanric, D.; Lallemand, M.-C.; Tillequin, F.; Martens, T. Tetrahedron Lett. 2001, 42, 5175. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906. Nair, V.; Rajan, R.; Rath, N. P. Org. Lett. 2002, 4, 1575. Reddy, K. L. Tetrahedron Lett. 2003, 44, 1453. Janin, Y. L.; Decaudin, D.; Monneret, C.; Poupon, M.-F. Tetrahedron 2004, 60, 5481. Concellén, J. M.; Riego, E.; Suárez, J. R.; García-Granda, S.; Díaz, M. R. Org. Lett. 2004, 6, 4499. 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 intramolecular aldol condensation to afford six-membered DE-unsaturated ketones.

O

O

O

base

R

R methyl vinyl ketone (MVK)

O

O

enolate H

R

Michael

O

formation

addition

R

B: O

H B aldol

isomerization R

O O

O

addition

R :B

HO

H

O

 H2O O dehydration

R

R Example11

O

O

3 TfOH, P4O10 O CH2Cl2, microwave 40 oC, 8 h, 57%

504

References 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 cholesterol. Robinson, incensed and shouting ‘Why do you always steal my research topic?’, hit Woodward with his umbrella.”—An excerpt from Barton, Derek, H. R. Some Recollections of Gap Jumping, American Chemical Society, Washington, 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. 1.

505

Robinson–Gabriel synthesis Cyclodehydration of 2-acylamidoketones to give 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles.

R2

R2

H2O

HN

N

R3

R1

R1

OO

O

R3

R1, R2, R3 = alkyl, aryl, heteroaryl H R2 N R3

R2

H N

R3

R1

R1

OO

O

OH

R2

H2O

N R1

O

R3

Example 19

OTIPS O O MeO

O

H N

H

N O

HO OH 1. Dess-Martin, CH2Cl2 2. Ph3P, BrCCl2CCl2Br 3. DBU, CH3CN 4. TBAF, THF 42%

O

OMe O OMe H

N O

(+)-hennoxazole A

N

R

506

Example 28

H H N

O

O O

Ph3P, I2, Et3N

H N

H CbzHN

O

O

55%

CbzHN

O

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Robinson, R. J. Chem. Soc. 1909, 95, 2167. Gabriel, S. Chem. Ber. 1910, 43, 134, 1283. Wiley, R. H.; Borum, O. H. J. Am. Chem. Soc. 1948, 70, 2005. Atkins, G. M., Jr.; Burgess, E. M. J. Am. Chem. Soc. 1968, 90, 4744. Wasserman, H. H.; Vinick, F. J. J. Org. Chem. 1973, 38, 2407. Meguro, K.; Tawada, H.; Sugiyama, Y.; Fujita, T.; Kawamatsu, Y. Chem. Pharm. Bull. 1986, 34, 2840. Turchi, I. J. In The Chemistry of Heterocyclic Compounds, 45; Wiley: New York, 1986; pp 1342. (Review). Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604. Wipf, P. Lim, S. J. Am. Chem. Soc. 1995, 117, 558. Brain, C. T.; Paul, J. M. Synlett 1999, 10, 1642. Yokokawa, F.; Asano, T.; Shioiri, T. Org Lett 2000, 2, 4169. Morwick, T.; Hrapchak, M.; DeTuri, M.; Campbell, S. Org Lett 2002, 4, 2665. 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. Godfrey, A. G.; Brooks, D. A.; Hay, L. A.; Peters, M.; McCarthy, J. R.; Mitchell, D. J. Org. Chem. 2003, 68, 2623. Brooks, D. A. Robinson–Gabriel Synthesis in Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 249253. (Review).

507

RobinsonSchöpf reaction Tropinone synthesis.

CO2H

N

CHO NH2

O

CHO

CO2H

O H

NH2:

HN:

H

2 H2O

2 CO2n

 H2O

imine

O

HO2C

CO2H

OH

O

formation

N CHO

CHO

CHO

O HO2C

O CO2H

HO2C

:N H H

CO2H :N

OH

O

hemiaminal

O  H2O

HO2C

H CO2H

N

N

HO2C

O

H O

O

N decarboxylation

CO2n HO2C

O H

508

N

N

N CO2n

O H

O

O

O H

O

Example7

CHO CHO

CO2H O

NH2

CO2H

OH O N THF, rt, 72 h, 51%

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

Robinson, R. J. Chem. Soc. 1917, 111, 762. Büchi, G.; Fliri, H.; Shapiro, R. J. Org. Chem. 1978, 43, 4765. Guerrier, L.; Royer, J.; Grierson, D. S.; Husson, H. P. J. Am. Chem. Soc. 1983, 105, 7754. Royer, J.; Husson, H. P. Tetrahedron Lett. 1987, 28, 6175. Bermudez, J.; Gregory, J. A.; King, F. D.; Starr, S.; Summersell, R. J. Bioorg. Med. Chem. Lett. 1992, 2, 519. Langlois, M.; Yang, D.; Soulier, J. L.; Florac, C. Synth. Commun. 1992, 22, 3115. Jarevång, T.; Anke, H.; Anke, T.; Erkel, G.; Sterner, O. Acta Chem. Scand. 1998, 52, 1350. Amedjkouh, M.; Westerlund, K. Tetrahedron Lett. 2004, 45, 5175.

509

Rosenmund reduction Hydrogenation reduction of acid chloride to aldehyde using BaSO4-poisoned palladium catalyst. Without poison, the resulting aldehyde may be further reduced to alcohol.

O R

H2 Cl

O R

PdBaSO4

Pd Pd

H

Pd Pd H H

H H

Pd Pd H H O R

H Pd H O

Pd(0) Cl

O R

R

oxidative addition

H Pd H Pd

Cl

ligand exchange

reductive Pd

O Pd(0)

H

R

elimination

H

Example 16

Me2N

N(Boc)2

N(Boc)2 HO

CO2t-Bu

Cl

Cl

CO2t-Bu O

O H2, 5% Pd/C 2,6-lutidine THF, 2 h, 78%

N(Boc)2 H

CO2t-Bu O

510

Example 29

O

1. SOCl2, cat. DMF, reflux, 4 h OH 2. H , 5% Pd/C, EtOAc, 53% 2 O H

References 1.

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

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 Institute in Kiel in 1925. Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362–377. (Review). Tsuji, J.; Ono, K.; Kajimoto, T. Tetrahedron Lett. 1965, 4565. Burgstahler, A. W.; Weigel, L. O.; Schäfer, C. G. Synthesis 1976, 767. McEwen, A. B.; Guttieri, M. J.; Maier, W. F.; Laine, R. M.; Shvo, Y. J. Org. Chem. 1983, 48, 4436. Bold, V. G.; Steiner, H.; Moesch, L.; Walliser, B. Helv. Chim. Acta 1990, 73, 405. Yadav, V. G.; Chandalia, S. B. Org. Proc. Res. Dev. 1997, 1, 226. Chandnani, K. H.; Chandalia, S. B. Org. Proc. Res. Dev. 1999, 3, 416. Chimichi, S.; Boccalini, M.; Cosimelli, B. Tetrahedron 2002, 58, 4851.

511

Rubottom oxidation D-Hydroxylation of enolsilanes. O

OSiR3

1. m-CPBA

OH

2. K2CO3, H2O Ar O O H R3SiO O

Ar

Prilezhaev

R3Si

O R3SiO

O

epoxidation

O

O

O

H

The “butterfly” transition state

R3Si

O

+

H

H

O

O

SiR3 OH

O K2CO3, H2O

OH

hydrolysis Example 15

N

OSiMe3 CO2Me

2.5 eq m-CPBA ClCH2CH2Cl o

0 C to rt, 1 h, 80%

O N

OH CO2Me

512

Example 210

TMSCl, NaI O

Et3N, rt, 91%

1. m-CPBA, NaHCO3, pentane, 0 oC

OTMS OH

2. aq. K2CO3, 0 oC, 20 h, 80% O References 1.

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

Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett. 1974, 4319. George Rubottom discovered the Rubottom oxidation when he was an assistant professor at the University of Puerto Rico. He is now a grant officer at the National Science Foundation. Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77, C19. Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40, 3427. Rubottom, G. M.; Gruber, J. M.; Boeckman, R. K., Jr.; Ramaiah, M.; Medwid, J. B. Tetrahedron Lett. 1978, 4603. Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. Tetrahedron Lett. 1985, 26, 3563. Paquette, L. A.; Lin, H.-S.; Coghlan, M. J. Tetrahedron Lett. 1987, 28, 5017. Hirota, H.; Yokoyama, A.; Miyaji, K.; Nakamura, T.; Takahashi, T. Tetrahedron Lett. 1987, 28, 435. Gleiter, R.; Krämer, R.; Irngartinger, H.; Bissinger, C. J. Org. Chem. 1992, 57, 252. Johnson, C. R.; Golebiowski, A.; Steensma, D. H. J. Am. Chem. Soc. 1992, 114, 9414. Jauch, J. Tetrahedron 1994, 50, 12903. Gleiter, R.; Staib, M.; Ackermann, U. Liebigs Ann. 1995, 1655. Xu, Y.; Johnson, C. R. Tetrahedron Lett. 1997, 38, 1117. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.; Vilotijevic, I.; Yang, J. J. Org. Chem. 2004, 69, 2454. Christoffers, J.; Baro, A.; Werner, T. Adv. Synth. Cat. 2004, 346, 143151. (Review).

513

Rupe rearrangement Acid-catalyzed rearrangement of tertiary D-acetylenic (terminal) alcohols, leading to the formation of DE-unsaturated ketones rather than the corresponding DEunsaturated aldehydes. Cf. MeyerSchuster rearrangement.

OH

OH

O

H+, H2O

OH2

H+

H2O dehydration

H

H2O: +

H+

H

protonation H H

: OH

O

H

tautomerization

H H+

Example 16

O

conc. H2SO4 OH

CHCl3, HOAc, reflux, 1 h

Example 210 H3C OH H H O

H

O +

H3 C

A-252C H resin EtOAc, reflux

H H

4 h, 78% O

514

References Rupe, H.; Kambli, E. Helv. Chim. Acta 1926, 9, 672. Hennion, G. F.; Davis, R. B.; Maloney, D. E. J. Am. Chem. Soc. 1949, 71, 2813. Schmidt, C.; Thazhuthaveetil, J. Tetrahedron Lett. 1970, 2653. Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429. (Review). Hasbrouck, R. W.; Kiessling, A. D. J. Org. Chem. 1973, 38, 2103. Apparu, M.; Glenat, R. Tetrahedron 1988, 41, 2181. Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389. 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. 1. 2. 3. 4. 5. 6. 7. 8.

515

Saegusa oxidation Palladium-catalyzed conversion of enol silanes to enones, also known as the Saegusa enone synthesis.

Me3Si

O

O

0.5 Pd(OAc)2

Me

0.5 p-benzoquinone benzene, rt, 3 h, 91%

Me

The mechanism is similar to that of the Wacker oxidation (page 610). AcO Me3Si

AcO Pd(II) OAc

Me3Si

O:

O Pd(II) OAc

Me

Me

O E-hydride

Pd(II) OAc

O OSiMe3

H Me

O

elimination

O

H Pd OAc Me

Pd(0)

HOAc

Me

Regenerating the Pd(II) oxidant:

O Pd(0)

OH Pd(OAc)2

2 HOAc O

OH

516

Larock reported regeneration of the Pd(II) oxidant using oxygen:4

O2

Pd(0)

Pd

O O

HOAc

HOOPdOAc

O OSiMe3

Pd(II)(OAc)2

HOOSiMe3

Example 13 OMe

OMe O

O

O Me3SiCl, Et3N

O H H

O

O

O

TMSO H

CH3OCH2CH2OCH3 rt, 3 h, 74%

O

H

OMe Pd(OAc)2, p-benzoquinone

O

O

O H

CH3CN, rt, 60 oC, 53%

O

H Example 28

O

O

LDA, TBSCl

O

O

HMPA-THF O

78 to 0 oC, 93% Pd(OAc)2, O2 DMSO, 80 oC 48 h, 77%

OTBS O O O

O

O

517

References 1. 2. 3. 4. 5.

6. 7. 8. 9.

Ito, Y.; Hirao, T.; Saegusa, T.; J. Org. Chem. 1978, 43, 1011. Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5350. Kim, M.; Applegate, L. A.; Park, O.-S.; Vasudevan, S.; Watt, D. S. Synth. Commun. 1990, 20, 989. Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423. 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. Williams, D. R.; Turske, R. A. Org. Lett. 2000, 2, 3217. Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2000, 122, 7596. Kadota, K.; Kurusu, T.; Taniguchi, T.; Ogasawara, K. Adv. Synth. Catal. 2001, 343, 618. 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 compound directly if it is not part of an DE-unsaturated system (Example 2), giving rise to an alcohol.

O O SiMe3

TiCl4

TiCl4 :

complexation

O

O

Cl TiCl3

SiMe3

O

TiCl3

Michael

silicon

addition

cleavage SiMe3

Cl The E-carbocation is stabilized by the silicon atom

O

TiCl3

O H2O

Me3Si

Cl workup

Example 12

EtAlCl2, Tol. TMS O

0 oC, 50%

O

519

Example 214

O

CHO

Br

SiMe3 OTIPS OH

TiCl4, CH2Cl2

O Br

rt, 10 min., 67% OTIPS

9:1 dr

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295. Majetich, G.; Behnke, M.; Hull, K. J. Org. Chem. 1985, 50, 3615. Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117, 4570. Markó, I. E.; Mekhalfia, A.; Murphy, F.; Bayston, D. J.; Bailey, M.; Janousek, Z.; Dolan, S. Pure Appl. Chem. 1997, 69, 565. Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A.; Varchi, G. Tetrahedron: Asymmetry 1998, 9, 2979. Wang, D.-K.; Zhou, Y.-G.; Tang, Y.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 1999, 64, 4233. Sugita, Y.; Kimura, Y.; Yokoe, I. Tetrahedron Lett. 1999, 40, 5877. Wang, M. W.; Chen, Y. J.; Wang, D. Synlett 2000, 385. Organ, M. G.; Dragan, V.; Miller, M.; Froese, R. D. J.; Goddard, J. D. J. Org. Chem. 2000, 65, 3666. Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima, K. Tetrahedron: Asymmetry 2001, 12, 301. Leroy, B.; Markó, I. E. J. Org. Chem. 2002, 67, 8744. Itsuno, S.; Kumagai, T. Helv. Chim. Acta 2002, 85, 3185. Nosse, B.; Chhor, R. B.; Jeong, W. B.; Böhm, C.; Reiser, O. Org. Lett. 2003, 5, 941. Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003, 125, 13155. Knepper, K.; Ziegert, R. E.; Bräse, S. Tetrahedron 2004, 60, 8591. 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

CuX

Y

Ar X

X = Cl, Br, CN

e.g.: ArN2

ArN2

Cl

CuCl

CuCl

Cl

N2n

Ar

Ar

CuCl2

Cl

Ar Cl

CuCl

Example 15

Cl 1. FeCl3

N2 Cl

2. CuCl2 Cl Cl

Cl DMSO, rt N2 Cl

Cl

CuCl4

97% Cl

2

Example 211

CF3

CF3

CF3 CuCN, NaCN

1. H2SO4 N

NH2 2. NaNO2 Cl

Cl

N

Na2CO3, 50%

CN Cl

References 1.

2.

Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. Traugott Sandmeyer (18541922) 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. Galli, C. J. Chem. Soc., Perkin Trans. 2 1984, 897.

521

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. 3.

522

Schiemann reaction Fluoroarene formation from arylamines. Also known as the BalzSchiemann reaction. Ar

HNO2

NH2

HBF4

HO

N

H 2O

N

N

O

O

H N

N 2n

F

O:

O

N

Ar

N

O

O

N

O

Ar

N

N

OH

: Ar

N

N

'

BF4

ArN2

N

N

O

Ar

H+

H2O

:

O NH2

N O

:

Ar

HBF4 O

HO

'

BF4

ArN2

OH2

N2n

Ar

H2O

Ar

N N

Ar

F BF3

BF3

F

Example 14

F

NH2 N

N F

N R

N

NaNO2, HBF4, H2O

N

N

10 to 0 oC, 25%

F

N

N R

Example 210

F HN

NHBoc N

1. HBF4 2. NaNO2 3. hv

F

F

F

HN

N

36%

HN

N 8%

BF3

523

References 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, 193228. (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. Heterocycles 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. 1.

524

Schmidt reaction Conversion of ketones to amides using HN3 (hydrazoic acid).

HN3

O R1

R2

O R2

+

H

R1

N H

N2n

N O R

1

H R

+

O

2

R

1

H R

R

H2O

R

1

R

R

R

R2 R1 azido-alcohol

N N N

R1 N

2

HO N 2

R1 R2

2

1

N2n

2

HO N3

:

N N H2O N

H+

HN3

N

HO +

H

R1 migration

R1 N

:

R2 H2O nitrilium ion intermediate (Cf. Ritter intermediate) O tautomerization

R2

N H

R1

Example 1, a classic example11

H N

O CO2Et

NaN3 MeSO3H 35%

O

CO2Et

525

Example 2, a variant15

OH

O N3

OH

TfOH, CH2Cl2 0 oC, 79%

N O

References 1.

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

Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. Karl Friedrich Schmidt (18871971) collaborated with Curtius at the University of Heidelberg, where Schmidt became a Professor of Chemistry after 1923. Schmidt, K. F. Ber. Dtsch. Chem. Ges. 1924, 57, 704. Wolff, H. Org. React. 1946, 3, 307. (Review). Richard, J. P.; Amyes, T. L.; Lee, Y.-G.; Jagannadham, V. J. Am. Chem. Soc. 1994, 116, 10833. Kaye, P. T.; Mphahlele, M. J. Synth. Commun. 1995, 25, 1495. Krow, G. R.; Szczepanski, S W.; Kim, J. Y.; Liu, N.; Sheikh, A.; Xiao, Y.; Yuan, J. J. Org. Chem. 1999, 64, 1254. Mphahlele, M. J. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144-146, 351. Mphahlele, M. J. J. Chem. Soc., Perkin Trans. 1 1999, 3477. Iyengar, R.; Schildknegt, K.; Aubé, J. Org. Lett. 2000, 2, 1625. Pearson, W. H.; Hutta, D. A.; Fang, W.-k. J. Org. Chem. 2000, 65, 8326. Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667. Pearson, W. H.; Walavalkar, R. Tetrahedron 2001, 57, 5081. Golden, J. E.; Aubé, J. Angew. Chem., Int. Ed. 2002, 41, 4316. Cristau, H.-J.; Marat, X.; Vors, J.-P.; Pirat, J.-L. Tetrahedron Lett. 2003, 44, 3179. Wrobleski, A.; Sahasrabudhe, K.; Aubé, J. J. Am. Chem. Soc. 2004, 126, 5475. 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 phenols.

HN O

OH

O

cat. NaH OAc

AcO

Cl3CCN

OCH3

BF3xOEt2

O

OAc OCH3 trichloroacetimidate

AcO

Ar O

O

HO Ar

CCl3

OAc

AcO

OCH3 N O AcO

O

H H

deprotonation

OAc OCH3

AcO H3CO

O

O

H2n AcO

OAc OCH3

O

OAc

HN

O H

O N

O AcO

CCl3 O

CCl3 O

OAc OCH3

AcO

OAc OCH3

CCl3

527

BF3xOEt2 HN

CCl3

BF3xOEt2 O

O AcO CH3O

O

neighboring group assistance

O

:

H O Ar O Cl3C

O

O

AcO CH3O

O

NH2

O AcO

Example 15 HN O

O AcO

CCl3

I

OAc OCH3

CO2Me

HO

OMe OMe

I BF3xOEt2, 4 Å MS

O

OMe

O

OMe

o

CH2Cl2, 50 C, 95%

CO2Me

AcO

OAc OCH3

Ar O

OAc OCH3

528

Example 27

BnO BnO BnO

OH

O AcO

O

NH CCl3

BF3•OEt2 CH2Cl2/hexane o

20 C, 68%

BnO BnO BnO

O O AcO

References Grundler, G.; Schmidt, R. R. Carbohydr. Res. 1985, 135, 203. Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (Review). 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, 15031531. (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. 1. 2. 3.

529

Shapiro reaction The Shapiro reaction is a variant of the BamfordStevens reaction. The former uses bases such as alkyl lithium and Grignard reagents whereas the latter employs bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. Consequently, the Shapiro reaction generally affords the less-substituted olefins as the kinetic products, while the BamfordStevens reaction delivers the more-substituted olefins as the thermodynamic products.

R1 R2

N

H N

R1 2

E

R

2 n-BuLi Ts

R

R1 N

H N

R H Ts

R

N R

N

Ts

3

Bu

3

R1

R1 2

N R

E 3

2

2

R

R

R1

Bu

R

2

R3

3

R H

R1

+

N

N2

3

R

2

E R

+

R1 R2

E

3

R

3

Example 13

NNHTs

MeLi, Et2O-PhH 7580%

Example 22

NNHTs

MeLi, Et2O 98%

2%

530

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

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. Shapiro, R. H.; Heath, M. J. J. Am. Chem. Soc. 1967, 89, 5734. Dauben, W. G.; Lorber, M. E.; Vietmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.; Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762. Casanova, J.; Waegell, B. Bull. Soc. Chim. Fr. 1975, 922. Shapiro, R. H. Org. React. 1976, 23, 405507. (Review). Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983, 16, 55. (Review). Chamberlin, A. R.; Bloom, S. H. Org. React. 1990, 39, 183. (Review). Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8915. Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J. Synlett 2000, 547. Kurek-Tyrlik, A.; Marczak, S.; Michalak, K.; Wicha, J.; Zarecki, A. J. Org. Chem. 2001, 65, 6994. Tormakangas, O. P.; Toivola, R. J.; Karvinen, E. K.; Koskinen, A. M. P. Tetrahedron 2002, 58, 2175. Alvarez, R.; Dominguez, M.; Pazos, Y.; Sussman, F.; de Lera, A. R. Chem. Eur. J. 2003, 9, 5821. Harrowven, D. C.; Pascoe, D. D.; Demurtas, D.; Bourne, H. O. Angew. Chem., Int. Ed. Engl. 2005, 44, 1221. 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. Regioselectivity may be controlled by ligand. Nitrogen sources (XNClNa) include: R O

O S NClNa

O

O

O BnO EtO

NClNa

NClNa

O NBrLi

TMS

NClNa

R = p-Tol; Me

chiral ligand K2OsO2(OH)4

R1

ClNaNX t-BuOH, H2O

R

R HO

R1 NHX

The catalytic cycle: OsO4

ClNX

R1

R HO

O O Os N X O

NHX

L*

H2O

O O Os N X O L*

R O O Os N ON X X

R1

R1 R

L* R ClNX

O O Os N O L* X

1

R

R O O Os N O L* X

R1

532

Example 14 5 mol% (DHQD)2PHAL 4 mol% K2OsO2(OH)4

O BnO

NClNa

O NH

OH

BnO

n-PrOH/H2O (1:1), 63% ee

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine (page 536). Example 29

CO2Et BnO

BnOCONH2 NaOH, t-BuOCl (DHQD)2AQN

K2OsO2(OH)4 BnO n-PrOH/H2O (1:1) rt, 12 h, 45%, 87% ee

OH CO2Et NHCbz

References 1.

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

14.

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. Mangatal, L.; Adeline, M. T.; Guenard, D.; Gueritte-Voegelein, F.; Potier, P. Tetrahedron 1989, 45, 4177. Engelhardt, L. M.; Skelton, B. W.; Stick, R. V.; Tilbrook, D. M. G.; White, A. H. Aust. J. Chem. 1990, 43, 1657. Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. Rubin, A. E.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2637. Kolb, H. C.; Sharpless, K. B. Transition Met. Org. Synth. 1998, 2, 243. (Review). Thomas, A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8279. Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783. 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. Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 2, 2221. Bolm, C.; Hildebrand, J. P.; Muñiz, K. In Catalytic Asymmetric Synthesis; 2nd edn., Ojima, I., ed.; WileyVCH: New York, 2000, 399. (Review). Bodkin, J. A.; McLeod, M. D. J. Chem. Soc., Perkin 1 2002, 27332746. (Review). Nilov, D.; Reiser, O. Recent Advances on The Sharpless Asymmetric Aminohydroxylation. In Organic Synthesis Highlights Schmalz, H.-G.; Wirth, T., eds., Wiley-VCH: Weinheim, Germany 2003, 118124. (Review). 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 OH

R2 R1

L-(+)-diethyl tartrate

R

R2

1

t-BuOOH, Ti(Oi-Pr)4

R

1

R

R O R2

t-BuOOH, Ti(Oi-Pr)4 OH

R O R2

D-()-diethyl tartrate

The putative active catalyst, E = CO2Et:2

EtO O OEt O

O Ti

Oi-Pr Ti

E

i-PrO

O

O

O

i-PrO

EtO2C Oi-Pr The transition state:

EtO2C

O

O

O Ti

O

t-Bu

CO2Et

O

OH

OH

534

The catalytic cycle: OiPr LnTi OiPr

OH

O

tBuOOH O

OH LnTi

O O

tBu

* LnTi O O tBu

O

O LnTi O tBu

* O L*n*Ti O O* tBu

O * Ln*Ti *O O tBu

Example 15

Ti(O-iPr)4, 4 Å MS, (+)-DET Me

OH

O Me

t-BuOOH, CH2Cl2 20 °C

crude: 88% yield, 92.3 % ee recrystallization: 73% yield, > 98% ee OH

535

Example 25

()-DIPT, Ti(Oi-Pr)4 OH

O

OH

TBHP, 3 Å MS 5060%, 8892% ee References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. Williams, I. D.; Pedersen, S. F.; Sharpless, K. B.; Lippard, S. J. J. Am. Chem. Soc. 1984, 106, 6430. Rossiter, B. E. Chem. Ind. 1985, 22(Catal. Org. React.), 295. (Review). Pfenninger, A. Synthesis 1986, 89. (Review). Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. Corey, E. J. J. Org. Chem. 1990, 55, 16931694. (Review). Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis; Trost, B. M., Ed,; Pergamon Press: New York, 1991; Vol. 7, Chapter 3.2. (Review). Woodard, S. S.; Finn, M. G.; Sharpless, K. B. J. Am. Chem. Soc. 1991, 113, 106. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., ed,; VCH: New York, 1993; Chapter 4.1, pp 103158. (Review). Schinzer, D. Org. Synth. Highlights II 1995, 3. (Review). Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1299. (Review). Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; 2nd ed., Ojima, I., ed.; Wiley-VCH: New York, 2000, 231285. (Review). Black, P. J.; Jenkins, K.; Williams, J. M. J. Tetrahedron: Asymmetry 2002, 13, 317. Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry 2003, 14, 629. Palucki, M. SharplessKatsuki Epoxidation In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 5062. (Review).

536

Sharpless asymmetric dihydroxylation Enantioselective cis-dihydroxylation of olefins using osmium catalyst in the presence of cinchona alkaloid ligands. AD-mix-E

HO (DHQD)2-PHAL

RS RL

K2OsO2(OH)4

RM H

K2CO3, K3Fe(CN)6

RS RL

(DHQ)2-PHAL AD-mix-D

N

N N O

O

H O

O N

N

(DHQ)2-PHAL = 1,4-bis(9-O-dihydroquinine)phthalazine:

N

N

N N O

O O

O N

N

The concerted [3 + 2] cycloaddition mechanism:

O

O Os O O

L

O O Os O O L

RL H

O O Os O O L

RM

RS RM H

HO

(DHQD)2-PHAL = 1,4-bis(9-O-dihydroquinidine)phthalazine:

N

OH

OH

537

O O Os O O L

[3 + 2]-like cycloaddition

hydrolysis

HO HO

The catalytic cycle is shown on page 539 (the secondary cycle is shut off by maintaining a low concentration of olefin): Example 13

O

OH

K2OsO2(OH)4 (DHQD)2PHAL

EtO2C N3

OH

O

OH

EtO2C

K2CO3, MeSO2NH2 t-BuOH/H2O (1:1) rt, 12 h, 90% de

OH

N3

Example 29

1. AD-mix-E, MeSO2NH2 CO2Et t-BuOH/H2O (1:1), rt, 12 h BnO

2. NosCl, Et3N, CH2Cl2 0 oC, 54%, 92% ee OH CO2Et BnO

ONos

Nos = nosylate = 4-nitrobenzenesulfonyl References 1. 2. 3. 4. 5. 6.

Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. 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. Kim, N.-S.; Choi, J.-R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096. Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 24832547. (Review). Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319. (Mechanism). 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. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Rouhi, A. M. A Reaction under Scrutiny, in Chem. Eng. News 1997, November 3, 23. (Review, Mechanism). Bolm, C.; Gerlach, A. Eur. J. Org. Chem. 1998, 21. 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. Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 863. Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem. 2000, 65, 3143. Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; Beller, M. Tetrahedron Lett. 2000, 41, 8083. Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (Review, Nobel Prize Address). Moitessier, N.; Henry, C.; Len, C.; Postel, D.; Chapleur, Y. J. Carbohydrate Chem. 2003, 22, 25. Choudary, B. M.; Chowdari, N. S.; Madhi, S.; Kantam, M. L. J. Org. Chem. 2003, 68, 1736. Junttila, M. H.; Hormi, O. E. O. J. Org. Chem. 2004, 69, 4816. McNamara, C. A.; King, F.; Bradley, M. Tetrahedron Lett. 2004, 45, 8527. Zhang, Y.; O'Doherty, G. A. Tetrahedron 2005, 61, 6337. Hoevelmann, C. H.; Muniz, K. Chem. Eur. J. 2005, 11, 3951.

539

R R O O O Os O O R R

L

H2O

Secondary cycle low ee R R

R

OH

R

OH

low ee R R O O O Os O O

R

L R

NMM

NMO

O O Os L O O

H2O

R

OH

R

OH

Primary cycle high ee

R L

high ee O

O Os O O The catalytic cycle of the Sharpless dihydroxylation

R

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.

NO2 SeCN O

R

R

OH

R

Se NO2

Bu3P, THF, rt

R

O

H

:

Bu3P: NO2

NO2

SN2

Se CN

Se PBu 3

CN

NO2 Se

R R

R

O

O PBu3

Se

PBu3

NO2

O Se

R H

NO2

Se O

NO2

NO2

syn-elimination

R

Se OH

541

Example 19

OH H 1. Bu3P, o-O2NPhSeCN, THF, rt 2. CSA, PhH, rt to 70 oC

H OH

3. m-CPBA, 2,4,6-collidine CH2Cl2, 0 oC, 42%

N MeO H

H O

N H Example 213

MeO O

O

O

OH OH

1. Bu3P, o-O2NPhSeCN THF, rt, 6 h, 97% 2. m-CPBA, Et3N, o CH2Cl2, 78 C 86%

OH MeO O

O

O OH OH

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

Sharpless, K. B.; Young, M. Y.; Lauer, R. F. Tetrahedron Lett. 1973, 1979. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120. Grieco, P. A.; Miyashita, M. Tetrahedron Lett. 1974, 1869. Sharpless, K. B.; Young, M. Y. J. Org. Chem. 1975, 40, 947. Grieco, P. A.; Masaki, Y.; Boxler, D. J. Am. Chem. Soc. 1977, 97, 1597. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.

542

Grieco, P. A.; Yokoyama, Y. J. Am. Chem. Soc. 1977, 99, 5210. Meade, E. A.; Krawczyk, S. H.; Townsend, L. B. Tetrahedron Lett. 1988, 29, 4073. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron 1989, 45, 2431. Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1296. (Review). Krief, A.; Laval, A.-M. Bull. Soc. Chim. Fr. 1997, 134, 869874. (Review). Hsu, D.-S.; Liao, C.-C. Org. Lett. 2003, 5, 4741. Meilert, K.; Pettit, G. R.; Vogel, P. Helv. Chim. Acta 2004, 87, 1493. 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 trisubsituted olefin, possibly by the o-nitrophenylselenic acid via an intramolecular process.

7. 8. 9. 10. 11. 12. 13. 14.

543

Simmons–Smith reaction Cyclopropanation of olefins using CH2I2 and Zn(Cu).

CH2I2

Zn(Cu)

ICH2ZnI

Zn, Oxidative I CH2 I

ICH2ZnI addition SimmonsSmith reagent

2 ICH2ZnI I

ZnI

C H2

ZnI2

(ICH2)2Zn I ZnI

ZnI2

Example 12

O

O Zn/Cu [from Zn and Cu(SO4)2] CH2I2, Et2O, reflux, 36 h, 90% Example 2, asymmetric version13

CONEt2 OH OH

(1 eq)

CONEt2

OH

6 eq Zn/Cu, 3 eq CH2I2

MeO

CH2Cl2, 0 oC, 15 h 78%, 94% ee OH MeO

544

References 1.

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

Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323. Howard E. Simmons (19291997) was born in Norfolk, Virginia. He carried out his graduate studies at MIT under John D. Roberts and Arthur Cope. After obtaining his Ph.D. in 1954, he joined the Chemical Department of the Dupont Company, where he discovered the Simmons–Smith reaction with his colleague, R. D. Smith. Simmons rose to be the vice president of the Central Research at Dupont in 1979. His views on physical exercise were the same as those of Alexander Woollcot’s: “If I think about exercise, I know if I wait long enough, the thought will go away.” Limasset, J.-C.; Amice, P.; Conia, J.-M. Bull. Soc. Chim. Fr. 1969, 3981. Kaltenberg, O. P. Wiad. Chem. 1972, 26, 285. Takai, K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994, 59, 2671. Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tetrahedron 1995, 51, 12013. Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844. Kaye, P. T.; Molema, W. E. Chem. Commun. 1998, 2479. Kaye, P. T.; Molema, W. E. Synth. Commun. 1999, 29, 1889. Loeppky, R. N.; Elomart, S. J. Org. Chem. 2000, 65, 96. Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.; Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81. Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1415. (Review). Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 2341. Mahata, P. K.; Syam Kumar, U. K.; Sriram, V.; Ila, H.; Junjappa, H. Tetrahedron 2003, 59, 2631. Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632. 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).

HO

H2SO4

OH OH

NH2

PhNO2

N

H HO

OH

H+

HO

dehydration

OH

OH

HO

OH2

OH

glycerol

CHO

HO

H+

CHO

H2O

dehydration

OHC

H acrolein H+ O

conjugate H

O

addition

O

H intramolecular

H

O H+ N H

N H

:

NH2

H+

H

OH

:

addition

OH H+

N H

N H

N H

OH2 oxidation by

H dehydration N H

N H

PhNO2H2

N

For an alternative mechanism, see that of the Doebnervon Miller reaction (page 547).

546

Example 19

H2SO4, FeSO4 H3BO3, 80 %

F OH

F + HO F

OH

F F

SO3H

NH2

F

N

NO2 Example 210

O OH + HO N

O

NH2 O

H2SO4, H3BO3 FeSO4•7H2O 75 %

OH

N

O

N

References 1.

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

Skraup, Z. H. Monatsh. Chem. 1880, 1, 316. Zdenko Hans Skraup (18501910) was born in Prague, Czechoslovakia. He apprenticed under Lieben at the University of Vienna. Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086. Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 80. (Review). Bergstrom, F. W. Chem. Rev. 1944, 35, 152153. (Review). Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. Takeuchi, I.; Hamada, Y.; Hirota, M. Chem. Pharm. Bull. 1993, 41, 747. Fujiwara, H.; Okabayashi, I. Chem. Pharm. Bull. 1994, 42, 1322. Fujiwara, H. Heterocycles 1997, 45, 119. Oleynik, I. I.; Shteingarts, V. D. J. Fluorine Chem. 1998, 91, 25. Fujiwara, H.; Kitagawa, K. Heterocycles 2000, 53, 409. Theoclitou, M.-E.; Robinson, L. A. Tetrahedron Lett. 2002, 43, 3907. Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U.; Tetrahedron 2003, 59, 813. 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, 488494. (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:

HCl or OHC ZnCl2

NH2

N

O H N H

:

NH2

H

N

: N H

:

[2 + 2]

OH2

N

cycloaddition

N

:

N Ph H

N H

B: +

H

H N

N

N H

N

HN H

:

N H

N H

N H

548

N H HN:

HN N H

Ph Ph air oxidation

2 H Example 1

7

N CO2Me

NH2

O MeO2C

TsOH, CH2Cl2 CO2Me

Example 28 F F

reflux, 24 h

N

CO2Me

F H 6 N HCl, Tol.

F

O NHAc

100 °C, 2 h, 70%

N

Me

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

9. 10. 11. 12. 13.

Doebner, O.; von Miller, W. Ber. Dtsch. Chem. Ges. 1883, 16, 2464. Schindler, O.; Michaelis, W. Helv. Chim. Acta 1970, 53, 776. Corey, E. J.; Tramontano, A. J. Am. Chem. Soc. 1981, 103, 5599. Eisch, J. J.; Dluzniewski, T. J. Org. Chem. 1989, 54, 1269. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 1996, 377. Zhang, Z. P.; Tillekeratne, L. M. V.; Hudson, R. A. Tetrahedron Lett. 1998, 39, 5133. Carrigan, C. N.; Esslinger, C. S.; Bartlett, R. D.; Bridges, R. J. Bioorg. Med. Chem. Lett. 1999, 9, 2607. 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. Matsugi, M.; Tabusa, F.; Minamikawa, J.-i. Tetrahedron Lett. 2000, 41, 8523. Fürstner, A.; Thiel, O. R.; Blanda, G. Org. Lett. 2000, 2, 3731. Kavitha, J.; Vanisree, M.; Subbaraju, G. V. Indian J. Chem., Sect. B 2001, 40B, 522. Li, X.-G.; Cheng, X.; Zhou, Q.-L. Synth. Commun. 2002, 32, 2477. 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, 488494. (Review).

549

Smiles rearrangement Intramolecular nucleophilic aromatic rearrangement. General scheme:

Z X

strong

X

Z

base

YH

Y

X = S, SO, SO2, O, CO2 YH = OH, NHR, SH, CH2R, CONHR Z = NO2, SO2R e.g.: O2 S



NO2 

O 2S

O

OH O2 S

NO2

OH

NO2 

OH

O2 S

NO2 SNAr

O

OH O2 NO2 S O

spirocyclic anion intermediate (Meisenheimer complex)



O2S

NO2

O

550

Example8

O O

Br

O NH2 H2N

O

NaOH, DMA

HO

O

O NaOH, H2O HO o

50 C

O

N H

O H2O, reflux 59%, 3 steps

H2N

References 1.

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

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. Truce, W. E.; Kreider, E. M.; Brand, W. W. Org. React. 1970, 18, 99215. (Review). Gerasimova, T. N.; Kolchina, E. F. J. Fluorine Chem. 1994, 66, 6974. (Review). Boschi, D.; Sorba, G.; Bertinaria, M.; Fruttero, R.; Calvino, R.; Gasco, A. J. Chem. Soc., Perkin Trans. 1 2001, 1751. Hirota, T.; Tomita, K.-I.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocycles 2001, 55, 741. Selvakumar, N.; Srinivas, D.; Azhagan, A. M. Synthesis 2002, 2421. Kumar, G.; Gupta, V.; Gautam, D. C.; Gupta, R. R. Heterocyclic Commun. 2002, 8, 447. Mizuno, M.; Yamano, M. Org. Lett. 2005, 7, 3629. Bacque, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817.

551

NewmanKwart reaction Transformation of phenol to the corresponding thiophenol, a variant of the Smile reaction (page 549).

S S

OH

O Cl

NMe2

NMe2

'

O S

NMe2

hydrolysis

SH

Mechanism:

O

NMe2 O

S

S

O Me2N

NMe2

S

Example 18

S OH OH

Cl

S NMe2

O OH

NaH, DMF 85 oC, 1 h, 45%

O o

275 C, 0.8 mmHg 55%

S OH

NMe2

NMe2

552

Example 29

O

1. Br2, CH2Cl2, 5 to 20 oC, 90 min. CH2Cl2, 20 oC, 16 h, 37.4%

S

2.

OH

Cl

NMe2

O

O Br

Me2N

O

dimethylaniline

Br Me2N

218 oC, 7 h, 65.7%

S

S O

O 1. KOH, MeOH, reflux, 2 h 2. MeI, K2CO3, 90%

Br S

References Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410. Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980. Newman, M. S.; Hetzel, F. W. J. Org. Chem. 1969, 34, 3604. Cossu, S.; De Lucchi, O.; Fabbri, D.; Valle, G.; Painter, G. F.; Smith, R. A. J. Tetrahedron 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. Tetrahedron 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). 1. 2. 3. 4.

553

TruceSmile rearrangement Smiles rearrangement where Y is carbon:

Z X

Z Y

base

L

L YH

XH

Example 16

CF3

CF3 N

N KH or NaH

O

O

CO2Me

MO

OMe

CF3 N O OMe OM

CF3

CF3 N

N

OH

O O

O

554

Example 28

N NaOH, H2O

O2S

EtOH, reflux

NO2 O

NO2

N

O2 S

O2S NO2

41%

H N

46%

Example 39

O O2N

K2CO3, DMF HO

F

O2N

O

O

reflux, 73%

O2 N

O

OH

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

Truce, W. E.; Ray, W. J. Jr.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc. 1958, 80, 3625. Truce, W. E.; Hampton, D. C. J. Org. Chem. 1963, 28, 2276. Bayne, D. W; Nicol, A. J.; Tennant, G. J. Chem. Soc., Chem. Comm. 1975, 19, 782. Fukazawa, Y.; Kato, N.; Ito, S.; Tetrahedron Lett.1982, 23, 437. Hoffman, R. V.; Jankowski, B. C.; Carr, C. S. J. Org. Chem. 1986, 51, 130. Erickson, W. R.; McKennon, M. J.; Tetrahedron Lett. 2000, 41, 4541. Hirota, T.; Tomita, K.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S.; Heterocycles 2001, 55, 741. Kimbaris, A.; Cobb, J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807. 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. N Ar

X

N N

' N

X

N

CHCl3

N N

' Ar

N

Ar

CHO

H 2O

hexamethylenetetramine N N N

X S N2

N: Ar

N N

X

N CH 2 H N N N Ar

hydride

:

H

+

N

transfer

N CH 3 Ar N N N O H hemiaminal

N

Ar

N CH 3 Ar N N N :OH2

Ar

CHO

N CH 3 N NH N

The hydride transfer and the ring-opening of hexamethylenetetramine may occur in a synchronized fashion: X N N N

N

H Ar

N CH 3 Ar N N N

556

Example9

F

F

HOAc, H2O

N

Cl F

N N

N

', 62%

CHO

F

References Sommelet, M. Compt. Rend. 1913, 157, 852. Marcel Sommelet (18771952) 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. 1.

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

NH2

NH3

N

N

N

NH3

H 

[2,3]-sigmatropic rearrangement

NH2

ammonium ylide

H NH2 aromatization N N H Example 15

DMF, reflux Ph

N

SiMe3

I N

I

18 h, 94%

CsF, HMPA SiMe3

rt, 23 h, 86%

N

558

Example 26

Br N

CsF, HMPA

SiMe3 10 oC, 0.5 h, 32%

AcO N AcO

46:54

AcO

N

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

Sommelet, M. Compt. Rend. 1937, 205, 56. Pine, S. H. Tetrahedron Lett. 1967, 3393. Wittig, G. Bull. Soc. Chim. Fr. 1971, 1921. Robert, A.; Lucas-Thomas, M. T. J. Chem. Soc., Chem. Commun. 1980, 629. Shirai, N.; Sato, Y. J. Org. Chem. Soc. 1988, 53, 194. Shirai, N.; Watanabe, Y.; Sato, Y. J. Org. Chem. 1990, 55, 2767. Tanaka, T.; Shirai, N.; Sugimori, J.; Sato, Y. J. Org. Chem. 1992, 57, 5034. Klunder, J. M. J. Heterocycl. Chem. 1995, 32, 1687. Maeda, Y.; Sato, Y. J. Org. Chem. 1996, 61, 5188. 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 CastroStephens reaction. The Castro– Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper.

PdCl2x(PPh3)2 R

X

R'

R

R'

CuI, Et3N, rt Ph3P

II

Pd

Ph3P

Cl Cl CuC

CR'

Ph3P

II

Pd

C C

CR'

R'C

X R

CH

ii

i

Ph3P

0

Pd (PPh3)2

CR'

Ph3P CC

HX-amine

R'C

CuX

CH

Cycle A

iii

R'C

CCu

Cycle B

RX R'C

CuX

Ph3P

II

Pd

Ph3P

Cycle B'

ii

Ph3P

HX-amine

II

Pd

C

CR'

R

CR' iii

RC

CR'

i. oxidative addition ii. transmetalation iii. reductive elimination

Note that Et3N may reduce Pd(II) to Pd(0) as well, where Et3N is oxidized to iminium ion at the same time:

PdCl2

H

NEt3

NEt2

NEt2

H PdCl2

H Pd Cl Cl

reductive

NEt2 Cl Cl

Pd

H

HCl elimination

Pd(0)

560

Example 13

I N H

CO2Et

PdCl2•(Ph3P)2 CuI, Et3N 60 oC, 89%

N H

CO2Et

Example 25

Br

Br

SiMe3 N

Br

PdCl2•(Ph3P)2, CuI Et3N, rt, 65–74%

N SiMe3

References 1.

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

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. McCrindle, R.; Ferguson, G.; Arsenaut, G. J.; McAlees, A. J.; Stephenson, D. K. J. Chem. Res. (S) 1984, 360. Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 2248. Rossi, R. Carpita, A.; Belina, F. Org. Prep. Proc. Int. 1995, 27, 129. Ernst, A.; Gobbi, L.; Vasella, A. Tetrahedron Lett. 1996, 37, 7959. Campbell, I. B. In Organocopper Reagents; Taylor, R. J. K. Ed.; IRL Press: Oxford, UK, 1994, 217. (Review). Hundermark, T.; Littke, A.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. Dai, W.-M.; Wu, A. Tetrahedron Lett. 2001, 42, 81. Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114. Bates, R. W.; Boonsombat, J. J. Chem. Soc., Perkin Trans. 1 2001, 654. Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411. Balova, I. A.; Morozkina, S. N.; Knight, D. W.; Vasilevsky, S. F. Tetrahedron Lett. 2003, 44, 107. Garcia, D.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2004, 6, 4175. Li, P.; Wang, L.; Li, H. Tetrahedron 2005, 61, 8633. Lemhadri, M.; Doucet, H.; Santelli, M. Tetrahedron 2005, 61, 9839.

561

Staudinger ketene cycloaddition [2 + 2] Cycloaddition of ketene and imine to form E-lactam. Other coupling partners for ketene also include: olefin to give cyclobutanone and carbonyl to give Elactone.

O

O

R1

X R3

R2

X

X = NR; O; CHR R3

R4

R4

R2 R1

puckered transition state:

O

O X R1

X

R3 R4 R2

R3

R4

R2 R1

Example 18

PhO

Cl

Ot-Bu

p-Tol

N

N

O

O

O

PhO

Et3N, CH2Cl2 10 oC to rt, 24 h 88%

N O

Example 29

O AcO N

Cl

Et3N, CH2Cl2 78 oC to rt, 88%

O N AcO

Ot-Bu

N p-Tol

562

References 1.

2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

12. 13.

Staudinger, H. Ber. Dtsch. Chem. Ges. 1907, 40, 1145. Hermann Staudinger (Germany, 18811965) won the Nobel Prize in Chemistry in 1953 for his discoveries in the area of macromolecular chemistry. Cooper, R. D. G.; Daugherty, B. W.; Boyd, D. B. Pure Appl. Chem. 1987, 59, 485492. (Review). Snider, B. B. Chem. Rev. 1988, 88, 793811. (Review). Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159646. (Review). Venturini, A.; Gonzalez, Jr. J. Org. Chem. 2002, 67, 9089. Orr, R. K.; Calter, M. A. Tetrahedron 2003, 59, 35453565. (Review). 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. Bianchi, L.; Dell’Erba, C.; Maccagno, M.; Mugnoli, A.; Novi, M.; Petrillo, G.; Sancassan, F.; Tavani, C. Tetrahedron 2003, 59, 10195. Becker, F. F.; Banik, I.; Banik, B. K. J. Med. Chem. 2003, 46, 505. Cremonesi, G.; Dalla Croce, P.; La Rosa, C. Tetrahedron 2004, 60, 93. 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. Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org. Chem. 2005, 70, 334. 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. X N3

X N N N

PR3

X N N N PR3 phosphazide

N2

X N N N PR3

X N N N PR3

:PR3

X N PR3

phosphazide

N PR3 N N X

N PR3 N N X

N PR3 N N X

4-membered ring transition state N2

X N PR3

H2 O

X NH2

O PR3

Example 17

OMe

OMe O

Ph3P, THF

N3 OTBDMS

N

N OTBDMS

', 81% N

564

Example 212

N3 BnO BnO

O

1.1 eq. PMe3, 2.4 eq. Boc-ON

N3 N3 O AcO

o

N3

Tol., 78 to 10 C

OAc N3 BnO BnO

N3 O

37%

N3 N3 O AcO

BnO BnO NHBoc

OAc

O

42%

N3 NHBoc O N3 AcO OAc

References Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635. Leffler, J. E.; Temple, R. D. J. Am. Chem. Soc. 1967, 89, 5235. Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437. Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353. Velasco, M. D.; Molina, P.; Fresneda, P. M.; Sanz, M. A. Tetrahedron 2000, 56, 4079. 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. 1. 2. 3. 4. 5. 6.

565

Sternbach benzodiazepine synthesis Treatment of quinazoline 3-oxide with amines gives the rearrangement product, 1,4-benzodiazepine. H N

N N

Cl CH3NH2

N

Cl

N

Cl

O

O

chlordiazepoxide (Librium)

quinazoline 3-oxide

H2N : N

Cl

Cl

O

H N

concerted Cl

G Cl

H N

slow step

N

CH3NH2

N

O

H N

N Cl

N

Cl N

N O

O

chlordiazepoxide (Librium)

566

A step-wise mechanism is also possible:

H N

H2N : N

Cl

Cl

Cl

:

N G

Cl

N O

OH

H N

N Cl

N

N O

chlordiazepoxide (Librium) References 1. 2. 3. 4. 5. 6.

Sternbach, L. H.; Kaiser, S.; Reeder, E. J. Am. Chem. Soc. 1960, 82, 475. Sternbach, L. H.; Archer, G.; Reeder, E. J. Org. Chem. 1963, 28, 3013. Stempel, A.; Reeder, E.; Sternbach, L. H. J. Org. Chem. 1965, 30, 4267. (Mechanism). Sternbach, L. H. Angew. Chem., Int. Ed. 1971, 10, 34. (Review). Sternbach, L. H. In The Benzodiazepines, Garattini, S.; Mussini, E.; Randall, L. O. eds., Raven Press: New York, 1973, pp126. (Review). Sternbach, L. H. In The Benzodiazepines: From Molecular Biology to Clinical Practice, Costa, Erminio, ed.; Raven Press: New York, 1983, pp 120. (Review).

567

Stetter reaction 1,4-Dicarbonyl derivatives from aldehydes and DE-unsaturated ketones. The thiazolium catalyst serves as a safe surrogate for CN. Also known as the MichaelStetter reaction. Cf. Benzoin condensation. Ph N

HO

O S

R CHO

R

NH3

O

O Bn

Ph N

HO

deprotonation H

S

N H

R1

1

R = HOCH2CH2CH2-

S R

:NH3

Bn

Bn

N R1

N

OH H

S

OH

R1

S

R

R B

O

Bn N

Michael

tautomerization

OH

1

R

addition

S

O

R Bn N

R1

O

O R

S

Ph N

HO S

O

O

R

NH4+

Ph N

HO S

O

568

Example 14

OHC HO

S

O

O

O

I

N

CHO

O

(cat.)

O O

o

Et3N, EtOH, 80 C, 56%

O

Example 211

O N

CO2Me H

N HO

S

O

Cl

N

(cat.)

N

Ph

Et3N, DMF, 100 ºC, 75%

CO2Me

O

N

O

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Stetter, H. Angew. Chem. 1973, 85, 89. Hermann Stetter (19171993), born in Bonn, Germany, was a chemist at Technische Hochschule Aachen in West Germany. Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639. Castells, J.; Dunach, E.; Geijo, F.; Lopez-Calahorra, F.; Prats, M.; Sanahuja, O.; Villanova, L. Tetrahedron Lett. 1980, 21, 2291. El-Haji, T.; Martin, J. C.; Descotes, G. J. Heterocycl. Chem. 1983, 20, 233. Ho, T. L.; Liu, S. H. Synth. Commun. 1983, 13, 1125. Phillips, R. B.; Herbert, S. A.; Robichaud, A. J. Synth. Commun. 1986, 16, 411. Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26. Ciganek, E. Synthesis 1995, 1311. Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899. Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649. Kikuchi, K.; Hibi, S.; Yoshimura, H.; Tokuhara, N.; Tai, K.; Hida, T.; Yamauchi, T.; Nagai, M. J. Med. Chem. 2000, 43, 409. Kobayashi, N.; Kaku, Y.; Higurashi, K.; Yamauchi, T.; Ishibashi, A.; Okamoto, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1747. Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 6284. Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61, 6368.

569

Still–Gennari phosphonate reaction A variant of the HornerEmmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins.

O (CF3CH2O)2P

KN(SiMe3)2, 18-Crown-6 CO2CH3

O CF3CH2O P CF3CH2O

CO2CH3

Ph

then PhCH2CHO

O

O CF3CH2O P CF3CH2O

OMe H SiMe3

O OMe

H

Ph

O

N SiMe3

O

O OCH2CF3 P OCH CF 2 3 H CO2CH3

H Ph erythro isomer, kinetic adduct Ph

O OCH CF 2 3 O P OCH CF 2 3 H H CO2CH3 Ph

CO2CH3

Example 13

O (CF3CH2O)2P

KN(SiMe3)2, 18-Crown-6 78 oC, THF, 30 min. CO2CH3 then PhCH2CHO, 87%

Ph

CO2CH3

570

Example 212

MeO O

O O O TBS TBS

P(OCH2CF3)2 O

NaH, THF

CHO

OTBS

O OPMB TBS

73%, Z:E 5:1

MeO O

O O O TBS TBS

OTBS

O OPMB TBS

References 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. 1.

571

Stille coupling Palladium-catalyzed cross-coupling reaction of organostannanes with organic halides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 345.

Pd(0)

R1 Sn(R2)3

R X

oxidative

R

L2Pd(0)

R X

addition L

X Sn(R2)3

L Pd 1 R R

R R1

X Sn(R2)3 R1 Sn(R2)3

L Pd X L

transmetalation isomerization

reductive R R1

L2Pd(0)

elimination

Example 16 PhO2S

SnBu3 N SO2Ph

Cl

N

Br

Cl

N

NH2

PdCl2•(Ph3P)2, CuI THF, reflux, 92%

Cl

N

Cl

N

N

NH2

Example 27

(MeCN)2PdCl2

Cl TBDPSO

Br

Me3Sn

Cl TBDPSO

Cl

AsPh3, NMP o 80 C, 1.5 h, 55% Cl

HCl Cl

HN

Cl

Zoloft

572

References 1.

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

13.

Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636. John Kenneth Stille (19301989) 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. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997, 50, 1–652. (Review). 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). Li, J. J.; Yue, W. S. Tetrahedron Lett. 1999, 40, 4507. Lautens, M.; Rovis, T. Tetrahedron, 1999, 55, 8967. Nakamura, H.; Bao, M.; Yamamoto, Y. Angew. Chem., Int. Ed. 2001, 40, 3208. Heller, M.; Schubert, U. S. J. Org. Chem. 2002, 67, 8269. Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968. Samuelsson, L.; Langstrom, B. J. Labelled Comd. Radiopharm. 2003, 46, 263. 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, 125161. Wiley-VCH: Weinheim, Germany. (Review). Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 22452267. (Review).

573

StilleKelly reaction Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides using ditin reagents.

Br Me3Sn SnMe3 Br

Pd(Ph3P)4

OH

OH

OH

OH

BrPd Br

Br

Pd(0) Br OH OH

oxidative addition

Me3Sn SnMe3 OH

transmetalation

OH

Me3Sn Pd

Me3Sn

Br

Br

reductive Pd(0) OH

elimination

OH

OH

OH Me3Sn PdBr

Pd(0) oxidative addition

transmetalation OH OH

Pd

reductive Pd(0) OH OH

elimination

OH OH

574

Example8

I I N

HO

I Cl

O

NaH, DMF, reflux, 89%

Me3Sn SnMe3 PdCl2•(Ph3P)2 xylene, reflux, 92%

I

N

N O

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

Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161. Grigg, R.; Teasdale, A.; Sridharan, V. Tetrahedron Lett. 1991, 32, 3859. Sakamoto, T.; Yasuhara, A.; Kondo, Y.; Yamanaka, H. Heterocycles 1993, 36, 2597. Iyoda, M.; Miura, M.i; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.; Yoshida, M. Heterocycles 1997, 38, 4581. Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M. Tetrahedron Lett. 1999, 40, 105. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 1505. Fukuyama, Y.; Yaso, H.; Mori, T.; Takahashi, H.; Minami, H.; Kodama, M. Heterocycles 2001, 54, 259. Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201. 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.

O R1

R

t-BuO

O OEt CO2Et

1

R

KOt-Bu

CO2Et

HOt-Bu

CO2Et CO2H

R R1

R1

enolate

H

R

CO2Et

O

formation

O R

CO2Et

1

R

aldol

OEt CO2Et

R

addition

CO2Et

lactonization O

O

EtO

R1

R

EtO O

O

CO2Et

ring

H O

CO2Et CO2

R

Ot-Bu opening

R

1

+

H

CO2Et CO2H

R R1

O

Example 112

O CHO O

CO2Me

1. t-BuOK, t-BuOH, reflux

CO2Me

2. Ac2O, NaOAc, reflux 84%

O O

CO2Me O O

OAc

576

Example 213 O

O O

CHO O

O

O

aq. NaOH, EtOH

O

10 oC, 5 h, 88%

O

OH O

References 1.

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

Stobbe, H. Ber. Dtsch. Chem. Ges. 1893, 26, 2312. Hans Stobbe (18601938) was born in Tiehenhof, Germany. He earned his Ph.D. in 1889 at the University of Leipzig where he became a professor in 1894. El-Rayyes, N. R.; Al-Salman, Mrs. N. A. J. Heterocycl. Chem. 1976, 13, 285. Baghos, V. B.; Nasr, F. H.; Gindy, M. Helv. Chim. Acta 1979, 62, 90. Welch, W. M.; Harbert, C. A.; Koe, K. B.; Kraska, A. R. US 4536518 (1985). Zerrer, R.; Simchen, G. Synthesis 1992, 922. Baghos, V. B.; Doss, S. H.; Eskander, E. F. Org. Prep. Proced. Int. 1993, 25, 301. Moldvai, I.; Temesvari-Major, E.; Balazs, M.; Gacs-Baitz, E.; Egyed, O.; Szantay, C. J. Chem. Res., (S) 1999, 3018. Moldvai, I.; Temesvari-Major, E.; Gacs-Baitz, E.; Egyed, O.; Gomory, A.; Nyulaszi, L.; Szantay, C. Heterocycles 2001, 53, 759. Yvon, B. L.; Datta, P. K.; Le, T. N.; Charlton, J. L. Synthesis 2001, 1556. Liu, J.; Brooks, N. R. Org. Lett. 2002, 4, 3521. Moldvai, I.; Temesvari-Major, E.; Incze, M.; Platthy, T.; Gacs-Baitz, E.; Szantay, C. Heterocycles 2003, 60, 309. Giles, R. G. F.; Green, I. R.; van Eeden, N. Eur. J. Org. Chem. 2004, 4416. 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

O

O

N H

N

methyl vinyl ketone (MVK)

conjugate

O

N:

N

O

isomerization

addition

B: H

N

O

O

N O

Example 17

O

Br

N H F

PhH, 4 Å MS reflux

O

N H

PhH, reflux, 12 h Br

F

578

O H2O, reflux

N

O 1 h, 55%

O

Br

F

Br

F

Example 28

Ph N H

CH3O

N H

N

2. MVK, cat. hydroquinone PhH, reflux 3. NaOAc, HOAc, H2O

O

Ph CH3O

N H

, PhH, reflux

1.

Ph N

CH3O

H

N H

N H

O 17%

O

22%

O

References 1.

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

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 became an assistant professor at Harvard. Since he was not awarded tenure in 1953, Stork moved to Columbia University where he has taught ever since. Singerman, G.; Danishefsky, S. Tetrahedron Lett. 1964, 5, 2249. Enamines: Synthesis, Structure, and Reactions; Cook, A. G., Ed.; Dekker: New York, 1969, 514. (Review). Autrey, R. L.; Tahk, F. C. Tetrahedron 1968, 24, 3337. Hickmott, P. W. Tetrahedron 1982, 38, 1975. (Review). Hammadi, M.; Villemin, D. Synth. Commun. 1996, 26, 2901. Bridge, C. F.; O'Hagan, D. J. Fluorine Chem. 1997, 82, 21. Li, J. J.; Trivedi, B. K.; Rubin, J. R.; Roth, B. D. Tetrahedron Lett. 1998, 39, 6111. 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 D-amino nitrile, which may be hydrolyzed to D-amino acid.

O 1

R

R

H2N

H

H

O

O

R1

:

N H

R R2

R2

H+

HN R1

CN

H :

1

H H2N

HN

AcOH

H+ R1

NaCN

2

R2 CO2H

R1 NH R2

2

R

H

NC

iminium ion

HN

R2

R1

HN N

R1

+

H R2

:OH2

acidic amide

NH2

1

R

tautomerization NH

OH

H2O: HN

R2

hydrolysis

O

HN HO

R2 NH3

R1 HO

O H

HN R1

H+ NH2

R1

H+ HN

R2

OH

R2 CO2H

580

Example 16

NH

CHO S

Cl

acetone cyanohydrin MgSO4, 45 oC, toluene, 31%

CN

O

Cl

O

Cl

N

N S

S

Plavix Example 213

O Ph

NaCN, NH4Cl

i-PrOH, NH4OH

CN Ph

NH2 Ph CN H 34%

35%

NH2 H

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

11. 12. 13.

Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27. Chakraborty, T. K.; Hussain, K. A; Reddy, G. V. Tetrahedron 1995, 51, 9179. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. Amino Acids 1996, 11, 259. Mori, A.; Inoue, S. Compr. Asymmetric Catal. I-III 1999, 2, 983. (Review). Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled. Compd. Radiopharm. 2000, 43, 891. Ishitani, H.; Komiyama, S.; Hasegawa, Y.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 762. Ding, K.; Ma, D. Tetrahedron 2001, 57, 6361. Matsumoto, K.; Kim, J. C.; Hayashi, N.; Jenner, G. Tetrahedron Lett. 2002, 43, 9167. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Organic Synthesis Highlights V, Schmalz, H.-G.; Wirth, T. eds., Wiley-VCH: Weinheim, Germany, 2003, pp 187193. (Review). Meyer, U.; Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004, 15, 2029. Huang, J.; Corey, E. J. Org. Lett. 2004, 6, 5027. Cativiela, C.; Lasa, M.; Lopez, P. Tetrahedron: Asymmetry 2005, 16, 2613.

581

Suzuki coupling Palladium-catalyzed cross-coupling reaction of organoboranes with organic halides, 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 coupling on page 345.

L2Pd(0)

2 R1 B(R )2

R X

R R

3

1

NaOR

L Pd X L

R

oxidative L2Pd(0)

R X

addition

NaOR3 1

OR3 R B(R2)2

2

R B(R )2

1

addition of base R

L Pd X L

R3O B(R2)2

OR3 B(R2)2

R1

transmetalation isomerization

L

L Pd 1 R R

reductive

R R1

L2Pd(0)

elimination

Example 11

I CO2Me N CO2Et

CO2Me

O

+

B O

Pd(OAc)2 CO2Me Ph3P, K2CO3 THF, MeOH 70 °C, 15 h, 80%

N CO2Et

CO2Me

582

Example 24

B(OH)2 I N I

I N SEM

I

N TBS I Pd(Ph3P)4, Na2CO3, 45%

N N SEM

N TBS

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

13.

Tidwell, J. H.; Peat, A. J.; Buchwald, S. L. J. Org. Chem. 1994, 59, 7164. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 24572483. (Review). Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.; Stang, P. J., Eds.; WileyVCH: Weinhein, Germany, 1998, 49–97. (Review). Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S. Heterocycles 1998, 48, 748 Stanforth, S. P. Tetrahedron 1998, 54, 263. (Review). Li, J. J. Alkaloids: Chem. Biol. Perspect. 1999, 14, 437. (Review). Groger, H. J. Prakt. Chem. 2000, 342, 334. Franzen, R. Can. J. Chem. 2000, 78, 957. LeBlond, C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett. 2001, 3, 1555. Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802. Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. Zapf, A. Coupling of Aryl and Alkyl Halides With Organoboron Reagents (Suzuki Reaction). In Transition Metals for Organic Synthesis (2nd edn), Beller, M.; Bolm, C. eds., 2004, 1, 211229. Wiley-VCH: Weinheim, Germany. (Review). 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.

(COCl)2, DMSO R1

O

O

1

R2

R

R2

then Et3N

O

S

O O

Cl

Cl

Cl

O

CH2Cl2,78 oC

OH

S

O

Cl

Cl O

S 

O

Cl

O Cl S CO2n



H

COn

:O 1

R2

R

Cl S O H R2 R1

S 1

R

H

:NEt3

O

O

Et3NxHClp

H

R1

R2

(CH3)2Sn

R2 sulfur ylide

Example 15

O

OH C11H23

C6H13 OSiMe2t-Bu

(COCl)2, DMSO then Et3N, 89%

C11H23

C6H13 OSiMe2t-Bu

584

Example 211

OMe HO

OMe

OTBDPS N

O

(COCl)2, DMSO

N3

N3 OTBDPS

then Et3N, 85% N

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329. Huang, S. L.; Omura, K.; Swern, D. Synthesis 1978, 4, 297. Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. Tidwell, T. T. Org. React. 1990, 39, 297. (Review). Chadka, N. K.; Batcho, A. D.; Tang P. C.; Courtney, L. F.; Cook C. M.; Wovliulich, P. M.; Uskoviü, M. R. J. Org. Chem. 1991, 56, 4714 Nakajima, N.; Ubukata, M. Tetrahedron Lett. 1997, 38, 2099. Harris, J. M.; Liu, Y.; Chai, S.; Andrews, M. D.; Vederas, J. C. J. Org. Chem. 1998, 63, 2407. (odorless protocol). Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson, D. P. J.; Veal, K. T. Tetrahedron Lett. 1999, 40, 4593. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1999, 40, 5161. 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. 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. Nishide, K.; Ohsugi, S.-i.; Fudesaka, M.; Kodama, S.; Node, M. Tetrahedron Lett. 2002, 43, 5177. (New odorless protocols). Firouzabadi, H.; Hassani, H.; Hazarkhani, H. Phosphorus, Sulfur Silicon Related Elements 2003, 178, 149. Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. Green Chem. 2004, 6, 142. 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 using CHI3 and CrCl2.

O R

H

I H

CHI3, CrCl2 THF I

CrCl2

I

I

R

CrCl2

I CrIIICl2

H

I R O

R

H H

III

CrIIICl2 I CrIIICl2

Cl2Cr

Cr Cl2

III

I I

R A radical mechanism is recently proposed10

I

I

I

H

I

I H

CrIIII

CrII

CrII OCrIII O I

R

H

H

R

I CrIII

I

I H

CrII

OCrIII R CrII

I H

OCrIII R

I CrIII

R

I

586

Example 12

CHI3, CrCl2 Ph

CHO

THF, 70%

OTBS

Ph

I

20: 1 E:Z

OTBS Example 25

CHI3, CrCl2, 0 oC

OTES OHC

CO2Me

THF, 50%

OTES I

CO2Me

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

Takai, K.; Nitta, Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408. Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem. Soc. 1997, 119, 12159. Arnold, D. P.; Hartnell, R. D. Tetrahedron 2001, 57, 1335. Solsona, J. G.; Romea, P.; Urpi, F. Org. Lett. 2003, 5, 4681. Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2004, 45, 8717. Dineen, T. A.; Roush, W. R. Org. Lett. 2004, 6, 2043. Lipomi, D. J.; Langille, N. F.; Panek, J. S. Org. Lett. 2004, 6, 3533. Paterson, I.; Mackay, A. C. Synlett 2004, 1359. Mulzer, J.; Berger, M. J. Org. Chem. 2004, 69, 891. 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.

O Cp2Ti

Al(CH 3)2

R

Cl

R1

Tebbe’s reagent

R

Cp2TiCl2

Cp2Ti O

R1

ClAl(CH3)2

transmetalation

2 Al(CH3)3

H

D-hydride

Cp2Ti CH3

abstraction

titanocene dichloride

Cp2Ti

CH4n

Cl Al(CH3)2

CH2

Cp2Ti

coordination titanocene methylidene

Cp2Ti

Cp2Ti

cycloaddition

Cp2Ti Cl Al(CH3)2

Cl

[2 + 2]

Tebbe’s reagent

dissociation

Al(CH3)2

Al(CH3)2 Cl

O

CH2 R1

R oxatitanacyclobutane

O

retro-[2 + 2] cycloaddition

R

R1

CH2 R1 R

Cp2Ti O

formation of the strong Ti=O is the driving force.

Petasis alkenylation The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefination 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 oxide ring intermediate.9

588

Example 13

O

Tebbe's reagent, Tol. CO2Et

CO2Et then 1, THF, 0 C to rt, 30 min., 67%

1

o

Example 24

O MeO MeO

Br

2

1. Cp2TiCl2, AlMe3, Tol, 3 d 2. 2, THF, 40 oC, 30 min. then 0 oC, 1.5 h; rt, 1 h, 93%

MeO

Br

MeO References Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100, 3611. Chou, T. S.; Huang, S. B. Tetrahedron Lett. 1983, 24, 2169. 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, 198. (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, 27632793. (Review). 12. Jung, M. E.; Pontillo, J. Tetrahedron 2003, 59, 2729. 1. 2. 3.

589

TEMPO-mediated oxidation O

NaOCl, cat. TEMPO R

OH KBr, NaHCO3, CH2Cl2

R

OH

TEMPO = tetramethyl pentahydropyridine oxide:

NHAc

N O NHAc

NHAc 1/2 NaOCl

N O

N O NHAc

NHAc NHAc

:

:

N O

N O

N O

: O Cl

NHAc

N O

NHAc

NHAc

N OH

N O

590

NHAc NHAc N O N O

O

H R

H

:

HO

AcHN

R

N O

O R

:B

O

H R

H O

O Cl

Cl

OH

O R

R

O

O

Example 17 OH HO HO

NaOCl, cat. TEMPO

O OH

OMe

KBr, NaHCO3, CH2Cl2 55%

HO2C HO HO

O OH

OMe

Example 210

O cat. TEMPO, 2 eq. 2,6-lutidine electrolysis in CH3CN/H2O (95:5) 95%

591

Example 312

OH

OH

Ormosil-TEMPO, NaOCl OH

CO2H CH3CN, NaHCO3, 5%

Cl

0 oC, 80%

Cl

“Ormosil-TEMPO” is a sol-gel hydrophobized nanostructured silica matrix doped with TEMPO References Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11, 4905. Yamaguchi, M.; Miyazawa, T.; Takata, T.; Endo, T. Pure Appl. Chem. 1990, 62, 217. 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. 1. 2. 3.

592

ThorpeZiegler reaction The intramolecular version of the Thorpe reaction, which is base-catalyzed selfcondensation of nitriles to yield imines that tautomerize to enamine.

CN CN CN

EtO

OEt NH2

HOEt

H

N H

N H OEt

N H OEt

N

CN

H CN

EtO

OEt

NH2

NH H OEt Example 1, a radical ThorpeZiegler reaction5

Bu3SnH, AIBN

CN

H2N

CN

syringe pump

NC Br

o

PhH, 80 C, 56%

Example 210

CN

N CN Ph

LDA, THF 78 oC to rt 2 h, 80%

NH2 CN N Ph

593

References 1. 2.

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

Baron, H.; Remfry, F. G. P.; Thorpe, Y. F. J. Chem. Soc. 1904, 85, 1726. Ziegler, K. et al. Justus Liebigs Ann. Chem. 1933, 504, 94. Karl Ziegler (18981973), born in Helsa, Germany, received his Ph.D. in 1920 from von Auwers at the University of Marburg. He became the director of the Max-Planck-Institut für Kohlenforschung at Mülheim/Ruhr in 1943. He shared the Nobel Prize in Chemistry in 1963 with Giulio Natta (19031979) for their work in polymer chemistry. The ZieglerNatta catalyst is widely used in polymerization. Rodriguez-Hahn, L.; Parra M., M.; Martinez, M. Synth. Commun. 1984, 14, 967. Yakovlev, M. Yu.; Kadushkin, A. V.; Solov’eva, N. P.; Granik, V. G. Heterocyclic Commun. 1998, 4, 245. Curran, D. P.; Liu, W. Synlett 1999, 117. Dansou, B.; Pichon, C.; Dhal, R.; Brown, E.; Mille, S. Eur. J. Org. Chem. 2000, 1527. Kovacs, L. Molecules 2000, 5, 127. Gutschow, M.; Powers, J. C. J. Heterocycl. Chem. 2001, 38, 419. Keller, L.; Dumas, F.; Pizzonero, M.; d’Angelo, J.; Morgant, G.; Nguyen-Huy, D. Tetrahedron Lett. 2002, 43, 3225. Malassene, R.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Synlett 2002, 895. Malassene, R.; Vanquelef, E.; Toupet, L.; Hurvois, J.-P.; Moinet, C. Org. Biomol. Chem. 2003, 1, 547. Satoh, T.; Wakasugi, D. Tetrahedron Lett. 2003, 44, 7517. Wakasugi, D.; Satoh, T. Tetrahedron 2005, 61, 1245.

594

TsujiTrost reaction Palladium-catalyzed allylation using nucleophiles with allylic halides, acetates, carbonates, etc. via intermediate allylpalladium complexes, and typically with overall retention of stereochemistry. N BnO O BnO

OPh

Pd2(dba)3, dppb

N H

THF, 60–70 oC

72%

BnO O BnO

N N

Pd(0)Ln

BnO

Pd(0)Ln

O BnO

BnO

OPh

O

coordination

BnO

OPh

BnO BnO

O O

Pd(II)Ln

Pd(II)Ln

H N

BnO

BnO

N S-allyl complex

BnO O BnO

Pd(0)Ln

N N

Example 1

4

NH2 N

AcO

OAc

N H

N

NaH, Pd(Ph3P)4, DMF 60 oC, 18 h, 79%

NH2

N

N AcO

N

N N

595

Example 27

N O

N H

N HO

N

Pd(Ph3P)4, THF rt, 64 h, 35% References Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (Review). 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. 1. 2. 3.

596

Ugi reaction Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction.

R1 NH2

R CO2H

2

R2

O R

O

R3 N C isocyanide

CHO

R

N R1

H N

R3

O

N R1

HO H N 1 R R2 H

R2

R

:

H

2

:

R1 NH2

H imine

H N R1

O R CO2H

3

O

2

R

O R

R

C N R3 + 3 R H N

O O

2

R

N R1

R

R2

O R

O

N R1

H N R2

H N O

R

:

H

N

R3

R1

597

Example 110

OMe

OMOM

C N

BnO O I BocHN

NH2

O O

OTBDPS

H O

CO2H OMOM

NHPMP O

MeOH, '

N

NHBoc

O

1 h, 90%

OMe O TBDPSO

O I

OBn

Example 213

O HN

CO2H

NH2

O2 N O2 S

N OMe

OTBS

CHO

O2N

O2S N

O

MeOH, ' OO

61%

N

NHt-Bu

HN

OMe

OTBS

N C

598

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

Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8. Skorna, G.; Ugi, I. Chem. Ber. 1979, 112, 776. Hoyng, C. F.; Patel, A. D. Tetrahedron Lett. 1980, 21, 4795. Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 2, 1083. (Review). Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (Review). Ugi, I. Pure Appl. Chem. 2001, 73, 187. (Review). Zimmer, R.; Ziemer, A.; Grunner, M.; Brüdgam, I.; Hartl, H.; Reissig, H.-U. Synthesis 2001, 1649. Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167. Baldoli, C.; Maiorana, S.; Licandro, E.; Zinzalla, G.; Perdicchia, D. Org. Lett. 2002, 4, 4341. Portlock, D. E.; Ostaszewski, R.; Naskar, D.; West, L. Tetrahedron Lett. 2003, 44, 603. Beck, B.; Larbig, G.; Mejat, B.; Magnin-Lachaux, M.; Picard, A.; Herdtweck, E.; Doemling, A. Org. Lett. 2003, 5, 1047. Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596. 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.

2

I

Cu

CuI2

Cu, single

Cu(II)I

I

Cu(I)I electron transfer

SET I

Cu(II)I

CuI2

The overall transformation of PhI to PhCuI is an oxidative addition process. Example 15

NO2 NO2

Cu powder, DMF

N

N N

100105 oC, 4 h, 63%

Cl

O2N

Example 26

O S

N I

I

O Cu

N

NMP, rt, 88%

References 1.

2. 3. 4. 5.

Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174. Fritz Ullmann (18751939), born in Fürth, Bavaria, studied under Graebe at Geneva. He taught at the Technische Hochschule in Berlin and the University of Geneva. Ullmann, F. Justus Liebigs Ann. Chem. 1904, 332, 38. Fanta, P. E. Chem. Rev. 1946, 38, 139. (Review). Fanta, P. E. Synthesis 1974, 9. (Review). Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J.-P. Tetrahedron 1994, 50, 1153.

600

6. 7. 8. 9. 10. 11. 12. 13. 14.

Zhang, S.; Zhang, D.; Liebskind, L. S. J. Org. Chem. 1997, 62, 2312. Stark, L. M.; Lin, X.-F.; Flippin, L. A. J. Org. Chem. 2000, 65, 3227. Belfield, K. D.; Schafer, K. J.; Mourad, W.; Reinhardt, B. A. J. Org. Chem. 2000, 65, 4475. Venkatraman, S.; Li, C.-J. Tetrahedron Lett. 2000, 41, 4831. Farrar, J. M.; Sienkowska, M.; Kaszynski, P. Synth. Commun. 2000, 30, 4039. Ma, D.; Xia, C. Org. Lett. 2001, 3, 2583. Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623. Hameurlaine, A.; Dehaen, W. Tetrahedron Lett. 2003, 44, 957. Nelson, T. D.; Crouch, R. D. Org. React. 2004, 63, 265556. (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.

O O S

N

O

NC

K2CO3 H

O

MeOH, reflux

p-tolylsulfonylmethyl isocyanide (TosMIC)

O O S

N

O O S

C

N

C

H R

O

B O O S

N

R

O

N

Tos

C

+ H+

O

H Tos

N

R

H

O

N

H

 TosH

O

R H

R B

Example 17

O O S

O

H H

NC

HN

Pr N Pr

H

602

N O H

NaOMe MeOH, reflux 81%

Pr N Pr

HN

Example 210

O

O EtO

O S

O

NC K2CO3

H O

DMF, 80%

N

EtO O

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

van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 13, 2369. Possel, O.; van Leusen, A. M. Heterocycles 1977, 7, 77. Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A. M. Chem. Pharm. Bull. 1979, 27, 793. van Nispen, S. P. J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723. van Leusen, A. M.; van Leusen, D. In Encyclopedia of Reagents of Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7, 49734979. (Review). Sisko, J.; Mellinger, M.; Sheldrake, P. W.; Baine, N. Tetrahedron Lett. 1996, 37, 8113; 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. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5633. Kulkarni, B. A.; Ganesan, A. Tetrahedron Lett. 1999, 40, 5637. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org. Chem. 2000, 65, 1516. Barrett, A. G. M.; Cramp, S. M.; Hennessy, A. J.; Procopiou, P. A.; Roberts, R. S. Organic Lett. 2001, 3, 271. Herr, R. J.; Fairfax, D. J., Meckler, H.; Wilson, J. D. Org. Process Rec. Dev. 2002, 6, 677. 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, 254259. (Review).

603

VilsmeierHaack reaction The Vilsmeier–Haack reagent, a chloroiminium salt, is a weak electrophile. Therefore, the Vilsmeier–Haack reaction works better with electron-rich carbocycles and heterocycles.

O O

O

DMF, POCl3

CHO

100 oC, 24 h CHO 34%

Cl O

:

N

O P Cl Cl

SN2

4%

O O PCl2

N



H

Cl

H

:

N

Cl

O O PCl2 H

N

H

O O PCl2

Cl

Vilsmeier–Haack reagent O

O:

N

H H

Cl

H

O

N

Cl

B

H N:

Cl

O

O

O

aqueous workup

:

H

N

:

H O H

HO

H N

CHO

604

Example 13

DMF, POCl3

N

100 oC, 83%

N

N CHO N

Example 22

OMe MeO

DMF, POCl3 100 oC, 14 h, 98%

OH OHC

OMe MeO References Vilsmeier, A.; Haack, A. Ber. Dtsch. Chem. Ges. 1927, 60, 119. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. Jpn. 1985, 33, 3122. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Book). 5. Seybold, G. J. Prakt. Chem. 1996, 338, 392396 (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). 1. 2. 3. 4.

605

Vilsmeier mechanism for acid chloride formation Transformation of a carboxylic acid to the corresponding acid chloride using oxalyl chloride and catalytic amount of dimethyl formamide (DMF). It is a lot faster than without DMF, which generally needs reflux.

(COCl)2, cat. DMF

O R

O R

CH2Cl2, rt

OH

Cl

O O Cl

O

:

N

N

O

Cl

Cl H

O

O

H

Cl DMF

oxalyl chloride

O :

N Cl

O H

N

COn

CO2n

Cl

H Cl

O

Cl

Vilsmeier–Haack reagent

N

H N

R

:

Cl O O

Cl

H

O H

R O

Cl N

O H

R

N

CHO

O

R Cl O DMF recovered, therefore only catalytic amount is required

606

Vinylcyclopropanecyclopentene rearrangement Transformation of vinylcyclopropane to cyclopentene via a diradical intermediate.

R2

R2

'

R1

R1

R2

R2 R1

R1

R2 R2 R1

R1

Example 15

O 340 oC, 2 h CO2Me

O

CO2Me

50%

Example 26

1. n-BuLi, THF-HMPT 78 to 30 oC; 2. PhCH2Br SO2Ph 3. desulfonylation, 77%

Ph

References 1. 2. 3. 4. 5.

Neureiter, N. P. J. Org. Chem. 1959, 24, 2044. Vogel, E. Angew. Chem. 1960, 72, 4. Overberger, C. G.; Borchert, A. E. J. Am. Chem. Soc. 1960, 82, 1007, 4896. Flowers, M. C.; Frey, H. M. J. Chem. Soc. 1961, 3547. Brule, D.; Chalchat, J. C.; Garry, R. P.; Lacroix, B.; Michet, A.; Vessier, R. Bull. Soc. Chim. Fr. 1981, 57.

607

6. 7. 8. 9. 10. 11. 12. 13.

Danheiser, R. L.; Bronson, J. J.; Okano, K. J. Am. Chem. Soc. 1985, 107, 4579. Hudlický, T.; Kutchan, T. M.; Naqvi, S. M. Org. React. 1985, 33, 247335. (Review). Goldschmidt, Z.; Crammer, B. Chem. Soc. Rev. 1988, 17, 229267. (Review). Sonawane, H. R.; Bellur, N. S.; Kulkarni, D. G.; Ahuja, J. R. Synlett 1993, 875884. (Review). Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994, 35, 153. Chuang, S.-C.; Islam, A.; Huang, C.-W.; Shih, H.-T.; Cheng, C.-H. J. Org. Chem. 2003, 68, 3811. Baldwin, J. E. Chem. Rev. 2003, 103, 11971212. (Review). 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 cyanamide and alkyl halides.

R1

R N

Br

CN R1

R2

CN N R2

Br

R

Cyanogen bromide (BrCN) is a counterattack reagent.

Br

NC Br 1

R

R N:

R1

R2

R CN N R2

SN2 R1

CN N R2

Br

R

Example 16

CF3

CF3 Br-CN

O

O N

Tol.

N

CN

CF3 KOH, glycol

O

Prozac N H

water

Example 27

CO2Me

CO2Me CO2Me N

Br-CN, THF, H2O 79%

CO2Me Br N CN

609

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

von Braun, J. Ber. Dtsch. Chem. Ges. 1907, 40, 3914. Julius von Braun (18751940) was born in Warsaw, Poland. He was a Professor of Chemistry at Frankfurt. Hageman, H. A. Org. React. 1953, 7, 198. (Review). Fodor, G.; Abidi, S.-Y.; Carpenter, T. C. J. Org. Chem. 1974, 39, 1507. Nakahara, Y.; Niwaguchi, T.; Ishii, H. Tetrahedron 1977, 33, 1591. Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 12791300. (Review). Perni, R. B.; Gribble, G. W. Org. Prep. Proced. Int. 1980, 15, 297. Verboom, W.; Visser, G. W.; Reinhoudt, D. N. Tetrahedron 1982, 38, 1831. McLean, S.; Reynolds, W. F.; Zhu, X. Can. J. Chem. 1987, 65, 200. Cooley, J. H.; Evain, E. J. Synthesis 1989, 1. Aguirre, J. M.; Alesso, E. N.; Ibanez, A. F.; Tombari, D. G.; Moltrasio Iglesias, G. Y. J. Heterocycl. Chem. 1989, 26, 25. Laabs, S.; Scherrmann, A.; Sudau, A.; Diederich, M.; Kierig, C.; Nubbemeyer, U. Synlett 1999, 25. Chambert, S.; Thomasson, F.; Décout, J.-L. J. Org. Chem. 2002, 67, 1898. Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908.

610

Wacker oxidation Palladium-catalyzed oxidation of olefins to ketones.

O

cat. PdCl2, H2O R

CuCl2, O2

R

R oxidation

olefin complexation

PdCl2

Pd(0) HCl reductive elimination H Pd Cl

Cl Pd Cl

E-hydride elimination

R :

H O H

OH OH

R

R

PdCl H HCl

nucleophilic attack

tautomerization O R Regeneration of Pd(II):

Pd(0)

2 CuCl2

PdCl2

2 CuCl

Regeneration of Cu(II):

CuCl

O2

CuCl2

H2O

611

Example 16

O CO2H

O

O2, 5% Pd(OAc)2 NaOAc, DMSO, 80%

Example 210

O2, 20 mol% Cu(OAc)2 10 mol% PdCl2 O

O

DMA/H2O (7:1) 84%

O

O

O

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

11. 12. 13. 14. 15.

16.

Smidt, J.; Sieber, R. Angew. Chem., Int. Ed. 1962, 1, 80. Tsuji, J. Synthesis 1984, 369. (Review). Miller, D. G.; Wayner, D. D. M. J. Org. Chem. 1990, 55, 2924. Hegedus, L. S. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 4, 552. (Review). Tsuji, J. In Comp. Org. Syn. Trost, B. M.; Fleming, I., Eds.; Pergamon, 1991, Vol. 7, 449. (Review). Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298. Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books: Mill Valley, CA, pp 199208. (Review). Kang, S.-K.; Jung, K.-Y.; Chung, J.-U.; Namkoong, E.-Y.; Kim, T.-H. J. Org. Chem. 1995, 60, 4678. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M.; Bolm, C., eds., Wiley-VCH: Weinheim, Germany. 1998, 2, 307315. (Review). Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima, M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J.-W. J. Am. Chem. Soc. 1999, 121, 10468. Gaunt, M. J.; Yu, J.; Spencer, J. B. Chem. Commun. 2001, 1844. Barker, D.; Brimble, M. A.; McLeod, M.; Savage, G. P.; Wong, D. J. J. Chem. Soc., Perkin Trans. 1, 2002, 924. Thadani, A. N.; Rawal, V. H. Org. Lett. 2002, 4, 4321. Ho, T.-L.; Chang, M. H.; Chen, C. Tetrahedron Lett. 2003, 44, 6955. Hintermann, L. Wacker-type Oxidations. In Transition Met. Org. Synth. (2nd edn.) Beller, M.; Bolm, C., eds., Wiley-VCH: Weinheim, Germany. 2004, 2, 379388. (Review). 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. 1

R R2

R1 R2

R

R H OH R3 R1 R2

H+

H OH R3

H+

R1 H R R3

R2

R H OH2 R3 H+

R1

R

R2

R3

R1 R2

 H2O

R H R3

R1

R

R2

R3

Example 113

O

O

O OEt

HO

O OEt

TFA, CH2Cl2 72 h, 76%

Example 214

Br HBr, THF OH

0 oC, 10 min., 85%

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

Wagner, G. J. Russ. Phys. Chem. Soc. 1899, 31, 690. Hogeveen, H.; Van Kruchten, E. M. G. A. Top. Curr. Chem. 1979, 80, 89. (Review). Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Fernandez, A. H.; De La Moya Cerero, S.; Jimenez, F. M. Tetrahedron 1998, 54, 4607. Birladeanu, L. J. Chem. Educ. 2000, 77, 858. Kobayashi, T.; Uchiyama, Y. J. Chem. Soc., J. Chem. Soc., Perkin 1 2000, 2731. Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162.

613

7. 8. 9. 10. 11. 12. 13. 14.

Cerda-Garcia-Rojas, C. M.; Flores-Sandoval, C. A.; Roman, L. U.; Hernandez, J. D.; Joseph-Nathan, P. Tetrahedron 2002, 58, 1061. Colombo, M. I.; Bohn, M. L.; Ruveda, E. A. J. Chem. Educ. 2002, 79, 484. Román, L. U.; Cerda-Garcia-Rojas, C. M.; Guzmán, R.; Armenta, C.; Hernández, J. D.; Joseph-Nathan, P. J. Nat. Products 2002, 65, 1540. Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; Martinez-Ruiz, P. Tetrahedron 2003, 59, 1565. Guizzardi, B.; Mella, M.; Fagnoni, M.; Albini, A. J. Org. Chem. 2003, 68, 1067. 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. Bose, G.; Ullah, E.; Langer, P. Chem. Eur. J. 2004, 10, 6015. 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

R

aq. buffer

O O

EtO2C O EtO2C EtO2C O H EtO2C

R

R

O

O H EtO2C

R1

O

EtO2C

H

OH

O

O R1

R

R

R O

O H EtO2C

OH R1

1

R

O

CO2Et

O H EtO2C

CO2Et

EtO2C

1

EtO2C

CO2Et

EtO2C

R CO2Et

O

EtO2C

R

EtO2C

R CO2Et

HO

HO

EtO2C

OH

O EtO2C

EtO2C

R1 CO Et 2

H R

1

EtO2C

H

EtO2C

EtO2C

O R

O

R

EtO2C

OH

O

1

EtO2C

CO2Et

R

O R1 CO Et 2

HO EtO2C

H

1

R

R

H CO2Et

CO2Et

CO2Et OH

R1 CO Et 2

615

Example 12

CO2CH3

1. pH = 8.3 2. HOAc/HCl, '

O O

CO2CH3

O

90%

CHO

O H

Example 23

CO2CH3

O

1. pH = 6.8 2. HOAc/HCl

O

O

O

O

80% CO2CH3

Example 36 O MeO2C O

O

O

pH 5.6

MeO2C MeO2C

O

CO2Me CO2Me

86% MeO2C

References Weiss, U.; Edwards, J. M. Tetrahedron Lett. 1968, 9, 4885. Kubiak, G.; Fu, X.; Gupta, A. K.; Cook, J. M. Tetrahedron Lett. 1990, 31, 4285. 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. 1. 2. 3.

616

Wharton oxygen transposition reaction Reduction of DE-epoxy ketones by hydrazine to allylic alcohols.

NH2NH2 O

O

'

OH

O

O

O

H2O

N

O

OH NH NH2 :

:NH2NH2 H N

H2O

N2n

tautomerization H

O

H N

:OH2 N

+ H3O+

Nn O

OH

Example 15

OH

O O N TEOC

NH2NH2•H2O, MeOH H

H

HOAc, rt, 52%

N TEOC

H

617

Example 27

O O TESO

O O

NH2NH2•H2O, MeOH HOAc, rt, 59%

TESO

O

OH

O

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

Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615. Wharton, P. S. J. Org. Chem. 1961, 26, 4781. Caine, D. Org. Prep. Proced. Int. 1988, 20, 1. (Review). Dupuy, C.; Luche, J. L. Tetrahedron 1989, 45, 34373444. (Review). Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Di Filippo, M.; Fezza, F.; Izzo, I.; De Riccardis, F.; Sodano, G. Eur. J. Org. Chem. 2000, 3247. Takagi, R.; Tojo, K.; Iwata, M.; Ohkata, K. Org. Biomol. Chem. 2005, 3, 2031.

618

Willgerodt–Kindler reaction Conversion of ketones to the corresponding thioamide and/or ammonium salt.

O

HN

S

O

N O

TsOH, S8, ' 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: SH S S S S S O N S S S S S S S S S S O NH O NH sulfenamide

O N: SH S S S HS S

O N S

O

N S

O

N S

N O

O O O

N S

N S

N N

H O thiirene

619

O

O

N S

N S N HN O

O O

O S

N S :N

:N

N O O

N

N

O

O S

S8

N O

Example 1, the Willgerodt–Kindler reaction was a key operation in the initial synthesis of racemic Naproxen:6

O

HN

O

O N

O

S8 O

O

620

1. H+ 2. CH3OH, H2SO4

OH O

O

3. NaH, CH3I 4. NaOH

naproxen

Example 211

O

HN

O

S N

S8, microwave 4 min., 40%

O

References 1.

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

Willgerodt, C. Ber. Dtsch. Chem. Ges. 1887, 20, 2467. Conrad Willgerodt (18411930), born in Harlingerode, Germany, was a son of a farmer. He worked to accumulate enough money to support his study toward his doctorate, which he received from Claus. He became a professor at Freiburg, where he taught for 37 years. Kindler, K. Arch. Pharm. 1927, 265, 389. Carmack, M. Org. React. 1946, 3, 83. (Review). Schneller, S. W. Int. J. Sulfur Chem. B 1972, 7, 155. Schneller, S. W. Int. J. Sulfur Chem. 1973, 8, 485. Harrison, I. T.; Lewis, B.; Nelson, P.; Rooks, W.; Roskowski, A.; Tomolonis, A.; Fried, J. H. J. Med. Chem. 1970, 13, 203. Schneller, S. W. Int. J. Sulfur Chem. 1976, 8, 579. Carmack, M. J. Heterocycl. Chem. 1989, 26, 1319. You, Q.; Zhou, H.; Wang, Q.; Lei, X. Org. Prep. Proced. Int. 1991, 23, 435. Chatterjea, J. N.; Singh, R. P.; Ojha, N.; Prasad, R. J. Inst. Chem. (India) 1998, 70, 108. Nooshabadi, M.; Aghapoor, K.; Darabi, H. R.; Mojtahedi, M. M. Tetrahedron Lett. 1999, 40, 7549. Moghaddam, F. M.; Ghaffarzadeh, M.; Dakamin, M. G. J. Chem. Res., (S) 2000, 228. Poupaert, J. H.; Bouinidane, K.; Renard, M.; Lambert, D. M.; Isa, M. Org. Prep. Proced. Int. 2001, 33, 335. Alam, M. M.; Adapa, S. R. Synth. Commun. 2003, 33, 59. Reza Darabi, H.; Aghapoor, K.; Tajbakhsh, M. Tetrahedron Lett. 2004, 45, 4167. Purrello, G. “Some aspects of the WillgerodtKindler reaction and connected reactions.” Heterocycles 2005, 65, 411449. (Review).

621

Wittig reaction Olefination of carbonyls using phosphorus ylides.

X

R1 Ph3P

R

R1 H R

Ph3P

X

base

R3 1

R

R2

Ph3P

R3

O Ph3P O

R

R1

R2 R

X

R1

Ph3P: R

SN2

Ph3P

X

2

R1

Ph3P

R1 H R

:B

O

R

R1

[2 + 2]

Ph3P

cycloaddition

R

R3 R “puckered” transition state, irreversible and concerted R3

Ph3P O R

3

R 1 2 R R oxaphosphetane intermediate

Ph3P O

R1

R2 R

Example 13

NaH, Et2O; then add CHO NHTs

CH2=CHPPh3+Br DMF, reflux, 48 h, 50%

N Ts

622

Example 24

2.0 N KOH, i-PrOH PPh3

Cl HO

O 30 oC, 1.5 h, 91.5%

O

CO2H CO2H Accutane

2-cis-4-cis-vitamin A acid

Schlosser modification of the Wittig reaction1117 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.

Br

PhLi

PhLi

t-BuOH t-BuOK

H

Ph3P R

R

R1

R1

O

Br Ph3P

H H R

Ph3P

H

Ph3P

R

R

Ph

R1

phosphorus ylide

Br

Br

Ph3P OLi

Ph3P OLi 1

RH

R

R Li

t-BuOH

R1

Ph LiBr complex of E-oxo ylide

O

623

PPh3 Br LiO R

t-BuOH H

t-BuOK

R Ph3P O

LiBr

R1

H R1 LiBr complex of threo-betaine References 1.

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

Wittig, G.; Schöllkopf, U. Ber. Dtsch. Chem. Ges. 1954, 87, 1318. Georg Wittig (Germany, 18971987), 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, 19122004) for their development of organic boron and phosphorous compounds. Maercker, A. Org. React. 1965, 14, 270490. (Review). Schweizer, E. E.; Smucker, L. D. J. Org. Chem. 1966, 31, 3146. Garbers, C. F.; Schneider, D. F.; van der Merwe, J. P. J. Chem. Soc. (C) 1968, 1982 Murphy, P. J.; Brennan, J. Chem. Soc. Rev. 1988, 17, 130. (Review). Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1988, 89, 863927. (Review). Vedejs, E.; Peterson, M. J. Top. Stereochem. 1994, 21, 1. (Review). Heron, B. M. Heterocycles 1995, 41, 2357. Murphy, P. J.; Lee, S. E. J. Chem. Soc., Perkin Trans. 1 1999, 3049. Blackburn, L.; Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2003, 44, 115. Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1966, 5, 126. Schlosser, M.; Christmann, K. F. Justus Liebigs Ann. Chem. 1967, 708, 35. Schlosser, M.; Christmann, K. F.; Piskala, A.; Coffinet, D. Synthesis 1971, 29. Deagostino, A.; Prandi, C.; Tonachini, G.; Venturello, P. Trends Org. Chem. 1995, 5, 103. (Review). Celatka, C. A.; Liu, P.; Panek, J. S. Tetrahedron Lett. 1997, 38, 5449. 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

O 1

2

R1

R2Li

R1

R

2

OH 1

R2 deprotonation H

R

O

R1

1

R

O

R

R1

[1,2]-sigmatropic rearrangement

R

R1

workup R

O

OH

The radical mechanism is also possible as radical intermediates have been identified. Example 14

NOMe

NOMe

2 eq. LDA, THF O 78 oC, 82%

O

O

Example 25

TBSO

OTBS O

n-BuLi, THF Ph o

20 to 0 C, 32%

TBSO TBSO

OH Ph

OH

625

References Wittig, G.; Löhmann, L. Justus Liebigs Ann. Chem. 1942, 550, 260. Tomooka, K.; Yamamoto, H.; Nakai, T. Justus Liebigs Ann. Chem. 1997, 1275. Maleczka, R. E., Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551. Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915. 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. 1. 2. 3. 4. 5.

626

[2,3]-Wittig rearrangement Transformation of allyl ethers into homoallylic alcohols by treatment with base. Also known as StillWittig rearrangement. Cf. SommeletHauser rearrangement 2

3

1 1

X

[2,3]-sigmatropic

2

1

3

rearrangement

Y

X

2

Y2

1

R1

O

R

R

R2Li

R1 OH

R1 = alkynyl, alkenyl, Ph, COR, CN.

R R

1

O

R

deprotonation

O

H

R1 2

R

R

[2,3]-sigmatropic rearrangement

O

R

workup

R1

HO

Example 13

LDA, THF O

CO2H

78 oC, 80%

74% E HO

CO2H

Example 22

KOt-Bu, HOt-Bu, THF O O

0 oC, 26 h, 22%

HO O

R1

627

References Cast, J.; Stevens, T. S.; Holmes, J. J. Chem. Soc. 1960, 3521. Thomas, A. F.; Dubini, R. Helv. Chim. Acta 1974, 57, 2084. Nakai, T.; Mikami, K.; Taya, S.; Kimura, Y.; Mimura, T. Tetrahedron Lett. 1981, 22, 69. 4. Nakai, T.; Mikami, K. Org. React. 1994, 46, 105209. (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. Tetrahedron: 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. 1. 2. 3.

628

Wohl–Ziegler reaction Radical-initiated allylic bromination using NBS, and catalytic AIBN as initiator or NBS under photolysis.

NBS, AIBN Br CCl4, reflux Initiation:

'

NC

N N

CN

homolytic cleavage 2,2’-azobisisobutyronitrile (AIBN)

N2n

2

CN

O

O N Br

Br

N

CN

CN

O

O Propagation:

O

O

N

H abstraction H

O

NH O

O N Br

O Br

N

O O The succinimidyl radical is now available for the next cycle of the radical chain reaction.

629

Example 13

OAc

OAc

OAc

O

NBS, CCl4 reflux, 30 min., 48% AcO

AcO Example 213

CO2Me

1.2 eq. NBS, 0.1 eq. AIBN

CO2Me

solvent free, 60 to 65 oC 89%

Br

References 1.

2.

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

Wohl, A. Ber. Dtsch. Chem. Ges. 1919, 52, 51. Alfred Wohl (18631939), born in Graudenz, Germany, received his Ph.D. from A. W. Hofmann. In 1904, he was appointed Professor of Chemistry at the Technische Hochschule in Danzig. Ziegler, K. et al. Justus Liebigs Ann. Chem. 1942, 551, 30. Karl Ziegler (18981973), 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 (19031979) for their work in polymer chemistry. The ZieglerNatta catalyst is widely used in polymerization. Djerassi, C.; Scholz, C. R. J. Org. Chem. 1949, 14, 660. Wolfe, S.; Awang, D. V. C. Can. J. Chem. 1971, 49, 1384. Ito, I.; Ueda, T. Chem. Pharm. Bull. 1975, 23, 1646. Pennanen, S. I. Heterocycles 1978, 9, 1047. Rose, U. J. Heterocycl. Chem. 1991, 28, 2005. Greenwood, J. R.; Vaccarella, G.; Capper, H. R.; Mewett, K. N.; Allan, R. D.; Johnston, G. A. R. THEOCHEM 1996, 368, 235. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351. Jeong, I. H.; Park, Y. S.; Chung, M. W.; Kim, B. T. Synth. Commun. 2001, 31, 2261. Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002, 43, 4609. Stevens, C. V.; Van Heecke, G.; Barbero, C.; Patora, K.; De Kimpe, N.; Verhe, R. Synlett 2002, 1089. Togo, H.; Hirai, T. Synlett 2003, 702.

630

Wolff rearrangement One-carbon homologation via the intermediacy of D-diazoketone and ketene.

H C C O R1

O N2n

N2

1

R

D-diazoketone

O N2

R

H N

1

R

R2

O

ketene intermediate

O 1

R2 NH2

N

1

R



1

R

N

1

R

O N2n

O

N

N

alkyl CH:

migration

D-ketocarbene H+

H H H N 2 N 1 1 2 C C O H+ R R R R R1 O O :NH2 R2 H Treatment of the ketene with water would give the corresponding homologated carboxylic acid. Example 12

O

O

O

O

' or hv O

H EtOH, dioxane (1:1) > 90%

N2 Example 24

O

CO2Me

N2

hv, MeOH

O

90%

O N

N

631

References 1.

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

Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 25. Johann Ludwig Wolff (18571919) 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. Zeller, K.-P.; Meier, , H.; Müller, E. Tetrahedron 1972, 28, 5831. Meier, H.; Zeller, K. P. Angew. Chem., Int. ed. Engl. 1975, 14, 32. Kappe, C.; Fäber, G.; Wentrup, C.; Kappe, T. Chem. Ber. 1993, 126, 2357. Podlech, J.; Linder, M. R. J. Org. Chem. 1997, 62, 5873. Wang, J.; Hou, Y. J. Chem. Soc., Perkin Trans. 1 1998, 1919. Müller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837. Lee, Y. R.; Suk, J. Y.; Kim, B. S. Tetrahedron Lett. 1999, 40, 8219. Tilekar, J. N.; Patil, N. T.; Dhavale, D. D. Synthesis 2000, 395. Yang, H.; Foster, K.; Stephenson, C. R. J.; Brown, W.; Roberts, E. Org. Lett. 2000, 2, 2177. Xu, J.; Zhang, Q.; Chen, L.; Chen, H. J. Chem. Soc., Perkin Trans. 1 2001, 2266. Kirmse, W. “100 years of the Wolff Rearrangement” Eur. J. Org. Chem. 2002, 2193. (Review). Bogdanova, A.; Popik, V. V. J. Am. Chem. Soc. 2003, 125, 1456. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125, 4478. Zeller, K.-P.; Blocher, A.; Haiss, P. “Oxirene participation in the Photochemical Wolff Rearrangement” Mini-Reviews in Organic Chemistry 2004, 1, 291308. (Review).

632

Wolff–Kishner reduction Carbonyl reduction to methylene using basic hydrazine.

O

NH2NH2 R1

R

R1

R

NaOH, reflux

HO O

NH2 HO NH

:

R1

R

N

R1

:

R

R

NH2NH2

N

R1

N

N2

H

O

H

H

R1

R R

R

O

H

R1 H

HO H

H N

R1

Example 111 H2N

O 80% NH2NH2•H2O MeO2C

toluene, microwave 20 min., 75%

N

MeO2C

KOH, microwave 30 min., 40%

MeO2C

Example 212

OH O 85% NH2NH2•H2O, KOH OH H2O, 0.5 h, 165 oC, 87% HO

633

OH OH O H 1,5-hydride shift

HO

OH OH H H H

HO References Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582. Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 86. Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487. (the Huang-Minlon modification). Todd, D. Org. React. 1948, 4, 378. (Review). Cram, D. J.; Sahyun, M. R. V.; Knox, G. R. J. Am. Chem. Soc. 1962, 84, 1734. Szmant, H. H. Angew. Chem., Int. Ed. Engl. 1968, 7, 120. Murray, R. K., Jr.; Babiak, K. A. J. Org. Chem. 1973, 38, 2556. Akhila, A.; Banthorpe, D. V. Indian J. Chem. 1980, 19B, 998. Bosch, J.; Moral, M.; Rubiralta, M. Heterocycles 1983, 20, 509. Taber, D. F.; Stachel, S. J. Tetrahedron Lett. 1992, 33, 903. Gadhwal, S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573. 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. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

634

Yamaguchi esterification Esterification using 2,4,6-trichlorobenzoyl chloride (the Yamaguchi reagent).

Cl O Cl

O

O R

O

Cl

Cl R

Cl OH

O

Et3N, CH2Cl2

Cl

Cl

O

HO R1 DMAP, Tol., reflux

R

O

R1

Cl O

O

O Cl Cl

Cl Cl

R

O R

O

R

Cl O O

Cl

H

Cl

R O O

O N

:

Cl

O

:NEt3

Cl

N

Cl

Cl

O Cl

Cl

N

N DMAP (Dimethylaminopyridine)

O

O

Cl R

O Cl

Steric hindrance of the chloro substituents blocks attack of the other carbonyl.

Cl

R1 O: H

N N

635

R O R1

O

O

N R

N

O

R1

Example 19

OMe I

CO2H OTES 2,4,6-trichlorobenzoyl chloride DMAP, Tol., Et3N

OH

n-Bu3Sn

ODMT rt, 24 h, 89%

OMe OMe I

O OTES

O

n-Bu3Sn

ODMT OMe

636

Example 211

O O

O

O

HO CO2H

2,4,6-trichlorobenzoyl chloride Et3N, THF then DMAP, toluene, 62%

O O

O

O

O O

References 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. 1.

637

Zincke reaction The Zincke reaction is an overall amine exchange process that converts N-(2,4dinitrophenyl)pyridinium salts, known as Zincke salts, to N-aryl or N-alkyl pyridiniums upon treatment with the appropriate aniline or alkyl amine.

NH2 N

Cl

O2 N

R NH2

O2N

N R

Cl NO2

NO2 Zincke salt

:

H2N R

Cl N

N

O2 N

O2N

NO2

N

R

opening

O2N

N H

N

O2 N

R H

NO2 NH2

R H2N R

O2N R NO2

NO2

H

NH

ring-

NO2

NH

R

NO2

N H

O2N

N H2

H N

H N

R

638

H R

H N

N

ringclosure

H

R

N H

R

N R

N R

inversion

:

N R

cis-trans

N H2

N H

R

R

N R

Cl

Example 113

Et Cl NO2

Et N

Acetone, '

N

Cl

NO2

overnight (79%) NO2 NO2 Et

Cl

Et NH2

N NO2

Ph

OH

n-BuOH, ' 20 h (86%)

Cl Ph

N OH

NO2 Example 216

NH2

Cl NO2 N

N

OH OH NO2

H2O, ', 16 h

N

N Cl

OH OH

639

EtO

OEt

H CaCO3, H2O/THF (4:1) 20 oC, 3 days 25%, 2 steps

N

N

O

HO

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

Zincke, T. Justus Liebigs Ann. Chem. 1903, 330, 361. Zincke, Th.; Heuser, G.; Möller, W. Justus Liebigs Ann. Chem. 1904, 333, 296. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 338, 107. Zincke, Th.; Würker, W. Justus Liebigs Ann. Chem. 1905, 341, 365. Zincke, Th.; Weisspfenning, G. Justus Liebigs Ann. Chem. 1913, 396, 103. Marvell, E. N.; Caple, G.; Shahidi, I. Tetrahedron Lett. 1967, 8, 277. Marvell, E. N.; Caple, G.; Shahidi, I. J. Am. Chem. Soc. 1970, 92, 5641. Epszju, J.; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26, 1665. (Review). de Gee, A. J.; Sep, W. J.; Verhoeven, J. W.; de Boer, T. J. J. Chem. Soc., Perkin Trans. 1 1974, 676. Becher, J. Synthesis 1980, 589. (Review). Kost, A. N.; Gromov, S. P.; Sagitullin, R. S. Tetrahedron 1981, 37, 3423. (Review). Barbier, D.; Marazano, C.; Das, B. C.; Potier, P. J. Org. Chem. 1996, 61, 9596. Wong, Y.-S.; Marazano, C.; Gnecco, D.; Génisson, Y.; Chiaroni, A.; Das, B. C. J. Org. Chem. 1997, 62, 729. Barbier, D.; Marazano, C.; Riche, C.; Das, B. C.; Potier, P. J. Org. Chem. 1998, 63, 1767. Magnier, E.; Langlois, Y. Tetrahedron Lett. 1998, 39, 837. Urban, D.; Duval, E.; Langlois, Y. Tetrahedron Lett. 2000, 41, 9251. Eda, M.; Kurth, M. J. J. Chem. Soc., Chem. Commun. 2001, 723. Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34, 585. (Review). Rojas, C. M. Zincke Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J.; Corey, E. J., Eds.; Wiley & Sons: Hoboken, NJ, 2005, 355375. (Review).

641

Subject index A Abnormal Claisen rearrangement, 133 Accutane, 622 Acetone cyanohydrin, 580 D-Acetylamino-alkyl methyl ketone, 179 O-Acylated hydroxamic acids, 352 Acetylation, 323, 468, 470 Į,ȕ-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 D-Acyloxycarboxamides, 444 D-Acyloxyketones, 16 D-Acyloxythioethers, 483 Acyl transfer, 65, 341, 444, 483, 511 Intramolecular acyl transfer, 454 AD-mix-D, 536 AD-mix-E, 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 S-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, 137 Alpine-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, 472 Amino acid, 179, 579 D-Aminoalcohols, 350 E-Aminoalcohols, 193 o-Aminobenzaldehyde, 243 E-Aminocrotonate, 418 Amino hydroxylation, 531 D-Aminoketone, 412 2-Amino-2-methyl-1-propanol, 24 D-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 E-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, 112 Arylamides, 116 N-Arylation,116 Aryl diazonium salt, 267 E-Arylethylamines, 462 Aryl hydrazines, 87 Arylhydrazones, 233 O-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-MyersSaito reaction, 409 Aza-S-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 B Baeyer–Villiger oxidation, 14, 85 Baker–Venkataraman rearrangement, 16 BalzSchiemann 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, 102 Bischler–Möhlau indole synthesis, 55 2,4-Bis-(4-methoxyphenyl)[1,3,2,4]dithiadiphosphetane 2,4disulfide, 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 D-Bromination, 291 D-Bromoacid, 291 Brook rearrangement, 83 Brown hydroboration, 85 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, 365 “Butterfly” transition state, 511 C Cadiot–Chodkiewicz coupling, 102 Camps quinolinol synthesis, 104 Cannizzaro disproportionation, 107 Carbazole, 87 Carbene, 12, 169, 492, 630 E-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, 406 3-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, 154 CoreyChaykovsky reaction, 157 Corey–Fuchs reaction, 160 Corey–Kim oxidation, 162 Corey–Nicolaou macrolactonization, 164 Corey–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 CrNi 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 MyersSaito, 408 Nazarov, 410 Nicolaou 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 D Dakin 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 D-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-DielsAlder, 67 retro-DielsAlder, 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-S-methane rearrangement, 204 2,4-Dinitrobenzenesulfonyl chloride, 153 Diol, 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 E E1, 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 E-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 D-haloketone, 220 Enolization, 8, 197, 281, 291, 341, 343, 361, 454, 489, 503 Enolsilanes, 511, 515 Enones, 189, 515 Enophile, 1 Episulfone, 485 Epoxidation CoreyChaykovsky, 157 Jacobsen–Katsuki, 314 Sharpless, 533 Epoxide, 157 Epoxide migration, 450 2,3-Epoxy alcohols, 450 DE-Epoxy esters, 183 DE-Epoxy ketones, 214, 616 DE-Epoxy sulfonylhydrazones ErlenmeyerPlöchl azalactone synthesis, 212 erythro, 306, 567 Eschenmoser–Claisen amide acetal rearrangement, 135 Eschenmoser’s salt, 361 Eschenmoser–Tanabe fragmentation, 214 Eschweiler–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, 197 6-Exo-trig-ring closure, 341, 480 F Favorskii rearrangement and quasiFavorskii 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 CoreyKim 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 G Gabriel–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 H Hajos–Wiechert reaction, 277 Halfordinal, 236 Halichlorine, 328 Haller–Bauer reaction, 279 N-Haloamines, 304 D-Haloesters, 59, 183, 222, 489 Halogen-metal exchange, 442 Halohydrin, 428 D-Haloketones, 222 D-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-DielsAlder, 67 Heterodiene, 201 Heterodienophile, 201 Hexacarbonyldicobalt, 420, 448 Hexamethylenetetramine, 187, 555 Hinsberg synthesis of thiophene derivatives, 295 Hiyama cross-coupling reaction, 297 Hiyama–Denmark cross-coupling reaction, 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 HosomiMiyaura borylation, 392 Hosomi–Sakurai reaction, 518 Houben–Hoesch synthesis, 308 Intramolecular HoubenHoesch, 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 E-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 D-Hydroxylation, 511 5-Hydroxylindole, 418 2’-hydroxychalcones, 5 2-Hydroxymethylpyridine, 65 4-Hydroxyquinoline, 269 D-Hydroxysilane, 83 E-Hydroxysilane, 458 Hypohalite, 257, 302 I IBX, 422-423 Imidazolidinones, 358 Imine, 69, 120, 144, 472, 507, 547, 592, 596 Iminium 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 HoubenHoesch reaction, 308 Intramolecular Nicholas reaction, 421 Iodoalkene, 585 Iodonium ion, 475, 476 o-Iodoxybenzoic acid, 420-423 Ipso, 79, 237, 371 Ireland–Claisen (silyl ketene acetal) rearrangement, 137 Isocyanide, 444, 596 Isocyanate, 92, 175, 302, 352 D-Isocyanoacetates, 34

Isoflavones, 8 Isoquinoline, 206, 460, 462, 472 Isoquinoline 1,4-diol, 255 3-Isoxazolols, 129 5-Isoxazolone, 129 4-Isoxazolylsilanol, 301 J Jacobsen–Katsuki epoxidation, 314 Japp–Klingemann hydrazone synthesis, 316 Johnson–Claisen (orthoester) rearrangement, 139 Jones modification of the Kolbe– Schmitt reaction, 340 Jones oxidation, 318 Julia–Kocienski olefination, 321 Julia–Lythgoe olefination, 323 K Kahne–Crich glycosidation, 325 Keck macrolactonization, 327 Ketene, 12, 208, 561, 630 Ketene acetal, 139, 630 Ketocarbene, 12, 630 D-Ketoesters, 316 E-Ketoesters, 59, 109, 127, 129, 281, 283, 452 1,4-Ketones, 438, 440 J-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 E-Lactam, 561 E-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 M McFadyen–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 reaction, 456 Markownikoff addition, 428 Marasse modification of the Kolbe– Schmitt reaction, 339 Marshall boronate fragmentation, 363 Martin’s sulfurane dehydrating reagent, 365 Masamune–Roush conditions, 367 MCRs, 51, 92 Meerwein–Ponndorf–Verley reduction, 369 Meisenheimer complex, 247, 371, 549 MeisenheimerJackson 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 MichaelStetter reaction, 567 Michaelis–Arbuzov phosphonate synthesis, 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 MyersSaito cyclization, 408 N Naphthol, 87, 90 E-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 NewmanKwart reaction, 551 Nicholas reaction, 420 Nickel-catalyzed coupling, 396 Nicolaou dehydrogenation, 422 Nicolaou hydroxy-dithioketal cyclization, 424 Nicolaou hydroxy-ketone reductive cyclic 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 O Octacarbonyl dicobalt, 448 Odorless CoreyKim 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 DessMartin, 109 Fleming-Tamao, 237 Jones, 318 Moffatt, 394 Oppenauer, 434 PCC, 319 PDC, 320 Prilezhaev, 511 Rubottom, 511

Sarett, 319 Swern, 583 TamaoKumada, 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, 265 N-Oxide, 149 Oximes, 41 J-Oximino alcohol, 32 Oxirane, 61 Oxonium ion, 325, 337 Oxy-Cope rearrangement, 152 Oxygen transfer, 314 Oxygen transposition, 616 Oxyselenation, 428 Oxyselenide, 429 P Paal–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 synthesis, 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 PfitznerMoffatt oxidation, 394 Phenanthridine, 399, 400 E-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, 460 Phosphorous 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)-(+)-D-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 D-Pyridinium methyl ketone salts, 343 2-Pyridone, 275 2-Pyridinethione, 164 Pyrimidone, 51 Pyrroles, 34, 283, 331, 333 Pyrrolidines, 37, 304 Q Quasi-Favorskii rearrangement, 221 Quinoline, 144, 243, 376, 494, 545, 547 Quinoline-4-carboxylic acid, 206 Quinoxaline-1,4-dioxide, 43 Quinazoline 3-oxide, 565 Quinolinol, 104 Quinolin-4-ones, 147 R Radical 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 ThorpeZiegler 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-S-methane, 204 Eschenmoser–Claisen, 135 Favorskii, 220 Ferrier, 227 Fries, 245 Hofmann, 302 Ireland–Claisen, 137 Johnson–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-DielsAlder, 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 S Saegusa 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 glycosidation reaction, 526 Schrock’s reagent, 499 E-Scission, 30 Secondary ozonide, 173 Selenides, 429 Selenol esters, 429

651

Selenonium, 428 Shapiro reaction, 529 Sharpless asymmetric amino hydroxylation, 531 Sharpless asymmetric epoxidation , 533 Sharpless asymmetric dihydroxylation, 536 Sharpless 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 E-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 StillWittig 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, 489 N-Sulfonyloxaziridines, 185 Sulfoxide, 325 Sulfur, 261, 438, 618 Sulfur ylide, 157, 583 Suzuki coupling, 581 Swern oxidation, 583 T Takai iodoalkene synthesis, 585 TamaoKumada 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, 589 TFAA, 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 ThorpeZiegler reaction, 592 Three-component coupling, 206, 444, 456 threo, 306 Tiffeneau–Demjanov rearrangement, 193 Titanium 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, S* Triplet, 446 Triplet diradical, 446 Tropinone, 507 TruceSmile rearrangement, 553 Tsuji–Trost allylation, 594 U Ugi reaction, 596 UHP, 178 Ullmann reaction, 599 DE-Unsaturated aldehydes, 513 DE-Unsaturated ketone, 181, 343, 513 Urea, 51 Urea-hydrogen peroxide, 178 V van 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 Vinylcyclopropanecyclopentene rearrangement, 606 Vinyl halides, 432 E-Vinyl iodide, 585 Vinyl ketones, 39 Vinyl sulfones, 39 von Braun reaction, 608 W Wacker oxidation, 515, 610 Wagner–Meerwein rearrangement, 612 Weiss–Cook reaction, 614 Wharton oxygen transposition reaction, 616 Willgerodt–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 X Xanthate, 123 Y Yamaguchi esterification, 634 Yamaguchi reagent, 634 Z Zimmerman rearrangement, 204 Zinc-carbenoid, 141 Zincke reaction, 637 Zincke salt, 637 Zoloft, 571 Zwitterionic peroxide, 173

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