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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: [email protected]fizer.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
R1 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.
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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.
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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
References
N
N
N
Ph
O
2.
3.
4.
N
H
O
OAc
N
+
BnO
1.
Me
O
14
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
O
O
O
6 M HCl, reflux
N
14 h, 93%
O
OH
HCl•H2N
O
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.
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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).
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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).
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Little, J. C.; Sexton, A. R.; Tong, Y.-L. C.; Zurawic, T. E. J. Am. Chem. Soc. 1969, 91,
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Chatterjee, N. R. Indian J. Chem., Sect. B 1978, 16B, 730.
Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263.
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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.
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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.
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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%
Al2O3 (alumina)
Bn
O
O
N O
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.
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O’Brien, P.; Pilgram, C. D. Org. Biomol. Chem. 2003, 1, 523.
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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
H
O
R
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.
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4475.
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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.
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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).
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(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.
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J. Heterocycl. Chem. 1989, 26, 25.
Laabs, S.; Scherrmann, A.; Sudau, A.; Diederich, M.; Kierig, C.; Nubbemeyer, U.
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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.
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449. (Review).
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Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima,
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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.
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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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