18
Name Reactions
Name Reactions
Jie Jack Li
Name Reactions
A Collection of Detailed Mechanismsand Synthetic Applications
Sixth Edition
Jie Jack Li
Discovery Chemistry
ChemPartner
San Francisco, CA, USA
ISBN 978-3-030-50864-7 ISBN 978-3-030-50865-4 (eBook)
https://doi.org/10.1007/978-3-030-50865-4 © Springer Nature Switzerland AG 2021
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, 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. The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or
the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG.
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
, Ph.D
Dedicated to Prof. David R. Williams
Preface
Five years have elapsed since the fifth edition was published. Much has happened
since then. The author has migrated from academia back to industry. I have taken
out some name reactions from the fifth edition because the book was physically
getting too heavy and unwieldy. This change allows more space to expand and
update the more popular name reactions. All references have been updated to 2020
when available.
As in previous editions, each reaction is delineated by detailed, step-by-step,
electron-pushing mechanism, supplemented with the original and the latest refer-
ences, especially review articles. Now, with addition of many synthetic applica-
tions, it is not only an indispensable resource for senior undergraduate and gradu-
ate students to learn mechanisms and synthetic utility of name reactions and to
prepare for their exams, but also a good reference book for all organic chemists in
both industry and academia.
As always, I welcome your critique. Please send your comments to this email
address: [email protected].
Jie Jack Li March 1, 2020
San Mateo, California
ix
Table of Contents
Preface ................................................................................................................... vii
Abbreviations ....................................................................................................... xv
Alder ene reaction ................................................................................................... 1
Aldol condensation .................................................................................................. 4
Arndt–Eistert homologation .................................................................................... 7
Baeyer–Villiger oxidation ..................................................................................... 10
Baker–Venkataraman rearrangement .................................................................... 13
Bamford–Stevens reaction ..................................................................................... 16
Barbier reaction ..................................................................................................... 19
Barton–McCombie deoxygenation ........................................................................ 22
Beckmann rearrangement ...................................................................................... 25
Abnormal Beckmann rearrangement .............................................................
Benzilic acid rearrangement ..................................................................................
Benzoin condensation ............................................................................................
Bergman cyclization ..............................................................................................
Biginelli reaction ...................................................................................................
Birch reduction ......................................................................................................
Bischler–Napieralski reaction ...............................................................................
Brook rearrangement .............................................................................................
Brown hydroboration ............................................................................................
Bucherer–Bergs reaction .......................................................................................
Büchner ring expansion .........................................................................................
Buchwald–Hartwig amination ...............................................................................
Burgess reagent .....................................................................................................
Cadiot–Chodkiewicz coupling .............................................................................. 67
Cannizzaro reaction ............................................................................................... 70
Catellani reaction ................................................................................................... 73
Chan–Lam C–X coupling reaction ........................................................................ 77
Chapman rearrangement ........................................................................................ 81
28
29
32
35
38
41
44
47
50
53
56
59
64
xi
Chichibabin pyridine synthesis.............................................................................. 83
Chugaev reaction ................................................................................................... 86
Claisen condensation ............................................................................................. 89
Claisen rearrangement ........................................................................................... 91
para-Claisen rearrangement ........................................................................ 94
Abnormal Claisen rearrangement ................................................................. 97
Eschenmoser–Claisen amide acetal rearrangement .................................... 100
Ireland–Claisen (silyl ketene acetal) rearrangement ................................... 103
Johnson–Claisen (orthoester) rearrangement ............................................. 106
Clemmensen reduction ........................................................................................ 109
Cope elimination ................................................................................................. 112
Cope rearrangement ............................................................................................ 115
Anionic oxy-Cope rearrangement ............................................................... 118
Oxy-Cope rearrangement ............................................................................ 120
Siloxy-Cope rearrangement ......................................................................... 122
Corey–Bakshi–Shibata (CBS) reagent ................................................................ 124
CoreyChaykovsky reaction ............................................................................... 128
Corey–Fuchs reaction .......................................................................................... 131
Curtius rearrangement ......................................................................................... 134
Dakin oxidation ................................................................................................... 137
Dakin–West reaction ........................................................................................... 140
Darzens condensation .......................................................................................... 144
de Mayo reaction ................................................................................................. 147
Demjanov rearrangement .................................................................................... 151
Tiffeneau–Demjanov rearrangement ........................................................... 153
Dess–Martin oxidation ........................................................................................ 157
Dieckmann condensation .................................................................................... 162
Diels–Alder reaction ........................................................................................... 166
Hetero-Diels–Alder reaction ...................................................................... 170
Inverse electronic demand Diels–Alder reaction ......................................... 173
Dienone–phenol rearrangement........................................................................... 176
Dötz reaction ....................................................................................................... 179
Eschweiler–Clarke reductive amination .............................................................. 182
Favorskii rearrangement ...................................................................................... 186
quasi-Favorskii rearrangement .................................................................... 190
Ferrier carbocyclization ....................................................................................... 191
Ferrier glycal allylic rearrangement .................................................................... 194
Fischer indole synthesis....................................................................................... 197
Friedel–Crafts reaction ........................................................................................ 200
Friedel–Crafts acylation reaction ................................................................ 200
Friedel–Crafts alkylation reaction ............................................................... 204
Friedländer quinoline synthesis ........................................................................... 206
Fries rearrangement ............................................................................................. 209
Gabriel synthesis ................................................................................................. 212
Ing–Manske procedure ................................................................................ 216
Gewald aminothiophene synthesis ...................................................................... 218
xii Table of Contents
Glaser coupling.................................................................................................... 221
Eglinton coupling ........................................................................................ 224
Gould–Jacobs reaction......................................................................................... 228
Grignard reaction ................................................................................................. 231
Grob fragmentation ............................................................................................. 235
Hajos–Wiechert reaction ..................................................................................... 238
Hantzsch dihydropyridine synthesis .................................................................... 241
Heck reaction ....................................................................................................... 244
Henry nitroaldol reaction ..................................................................................... 248
Hiyama reaction .................................................................................................. 251
Hofmann elimination ........................................................................................... 254
Hofmann rearrangement ...................................................................................... 256
Hofmann–Löffler–Freytag reaction ..................................................................... 259
Horner–Wadsworth–Emmons reaction ............................................................... 262
Still–Gennari phosphonates ......................................................................... 265
Houben–Hoesch synthesis ................................................................................... 269
Hunsdiecker–Borodin reaction ............................................................................ 272
Jacobsen–Katsuki epoxidation ............................................................................ 275
Jones oxidation .................................................................................................... 279
Collins oxidation ......................................................................................... 283
PCC oxidation ............................................................................................. 284
PDC oxidation ............................................................................................. 286
Julia–Kocienski olefination ................................................................................. 288
Julia–Lythgoe olefination .................................................................................... 291
Knoevenagel condensation .................................................................................. 294
Knorr pyrazole synthesis ..................................................................................... 298
Koenig–Knorr glycosidation ............................................................................... 301
Krapcho reaction ................................................................................................. 305
Kröhnke pyridine synthesis ................................................................................. 307
Kumada cross-coupling reaction ......................................................................... 310
Lawessonʹs reagent .............................................................................................. 314
Leuckart–Wallach reaction .................................................................................. 317
Lossen rearrangement .......................................................................................... 320
McMurry coupling .............................................................................................. 323
Mannich reaction ................................................................................................. 326
Markovnikovʹs rule .............................................................................................. 329
Anti-Markovnikov ....................................................................................... 332
Martin’s sulfurane dehydrating reagent ............................................................... 335
Meerwein–Ponndorf–Verley reduction ............................................................... 339
Meisenheimer complex ....................................................................................... 342
Meyer–Schuster rearrangement ........................................................................... 345
Michael addition .................................................................................................. 348
Michaelis–Arbuzov phosphonate synthesis ......................................................... 352
Minisci reaction ................................................................................................... 354
Mitsunobu reaction .............................................................................................. 358
Miyaura borylation .............................................................................................. 362
xiiiTable of Contents
Morita–Baylis–Hillman reaction ......................................................................... 366
Mukaiyama aldol reaction ................................................................................... 370
Mukaiyama Michael addition .............................................................................. 373
Mukaiyama reagent ............................................................................................. 376
Nazarov cyclization ............................................................................................. 380
Neber rearrangement ........................................................................................... 383
Nef reaction ......................................................................................................... 386
Negishi cross-coupling reaction .......................................................................... 389
NewmanKwart reaction .................................................................................... 393
Nicholas reaction ................................................................................................. 396
Noyori asymmetric hydrogenation ...................................................................... 399
Nozaki–Hiyama–Kishi reaction .......................................................................... 403
Olefin metathesis ................................................................................................. 407
Oppenauer oxidation ........................................................................................... 412
Overman rearrangement ...................................................................................... 415
Paal–Knorr pyrrole synthesis .............................................................................. 418
Parham cyclization .............................................................................................. 421
Passerini reaction ................................................................................................. 424
Paternò–Büchi reaction ....................................................................................... 427
Pauson–Khand reaction ....................................................................................... 430
Payne rearrangement ........................................................................................... 433
Petasis reaction .................................................................................................... 436
Peterson olefination ............................................................................................. 440
Pictet–Spengler tetrahydroisoquinoline synthesis ............................................... 443
Pinacol rearrangement ......................................................................................... 446
Pinner reaction..................................................................................................... 449
Polonovski reaction ............................................................................................. 452
Polonovski–Potier rearrangement ....................................................................... 455
Prins reaction ....................................................................................................... 458
Pummerer rearrangement .................................................................................... 462
Ramberg–Bäcklund reaction ............................................................................... 465
Reformatsky reaction .......................................................................................... 468
Ritter reaction ...................................................................................................... 471
Robinson annulation ............................................................................................ 474
Sandmeyer reaction ............................................................................................. 477
Schiemann reaction ............................................................................................. 480
Schmidt rearrangement........................................................................................ 483
Shapiro reaction ................................................................................................... 486
Sharpless asymmetric amino hydroxylation ........................................................ 489
Sharpless asymmetric dihydroxylation ................................................................ 493
Sharpless asymmetric epoxidation ..................................................................... 497
Simmons–Smith reaction ................................................................................... 501
Smiles rearrangement .......................................................................................... 504
TruceSmile rearrangement ........................................................................ 507
Sommelet–Hauser rearrangement ....................................................................... 510
Sonogashira reaction ........................................................................................... 513
Table of Contentsxiv
Stetter reaction ..................................................................................................... 516
Stevens rearrangement......................................................................................... 520
Stille coupling...................................................................................................... 523
Strecker amino acid synthesis ............................................................................. 527
Suzuki–Miyaura coupling ................................................................................... 530
Swern oxidation ................................................................................................... 533
Takai reaction ...................................................................................................... 536
Tebbe reagent ...................................................................................................... 540
Tsuji–Trost allylation .......................................................................................... 543
Ugi reaction ......................................................................................................... 547
Ullmann coupling ................................................................................................ 552
Vilsmeier–Haack reaction ................................................................................... 555
von Braun reaction .............................................................................................. 559
Wacker oxidation ................................................................................................ 561
Wagner–Meerwein rearrangement ...................................................................... 564
Williamson ether synthesis .................................................................................. 567
Wittig reaction ..................................................................................................... 570
[1,2]-Wittig rearrangement ..........................................................................
[2,3]-Wittig rearrangement ..........................................................................
Wolff rearrangement ........................................................................................... 580
Wolff–Kishner reduction ..................................................................................... 583
Subject Index ....................................................................................................... 586
574
577
Table of Contents xv
Abbreviations and Acronyms
Polymer support
1,10-phen 1,10-Phenanthroline
3CC Three-component condensation
3CR Three-component reaction
4CC Four-component condensation
9-BBN 9-Borabicyclo[3.3.1]nonane
A Adenosine
Ac Acetyl
acac Acetylacetonate
ACC Acetyl-CoA carboxylase
ADDP 1,1′-(Azodicarbonyl)dipiperidine
AIBN 2,2′-Azobisisobutyronitrile
Alpine-borane® B-Isopinocampheyl-9-borabicyclo[3.3.1]-nonane
AOM p-Anisyloxymethyl = p-MeOC6H4OCH2-
Ar Aryl
ARA Asymmetric reductive amination
ATH Asymmetric transfer hydrogenation
ATPH Tris(2,6-diphenyl)phenoxyaluminane
B: Generic base
BBEDA Bis-benzylidene ethylenediamine
bmim 1-Butyl-3-methylimidazolium
BINAP 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
BINOL 1,1ʹ-Bi-2-naphthaol
Bn Benzyl
Boc tert-Butyloxycarbonyl
BQ Benzoquinone
BPR Back pressure regulator
BT Benzothiazole
Bz Benzoyl
xvii
CAN Cerium ammonium nitrate
CBS Corey–Bakshi–Shibata reaction
Cbz Benzyloxycarbonyl
CCB Calcium channel blockers
CD4 Cluster of differentiation 4
CDK Cyclin-dependent kinase
CFC Continuous flow centrifugation
cod 1,5-Cyclooctadiene
COPC Carbonyl–olefin [2 + 2] photocycloaddition
Cp Cyclopentyl
CPME Cyclopentyl methyl ether
CSA Camphorsulfonic acid
CuTC Copper thiophene-2-carboxylate
Cy Cyclohexyl
DABCO 1,4-Diazabicyclo[2.2.2]octane
dba Dibenzylideneacetone
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
o-DCB ortho-Dichlorobenzene
DCC 1,3-Dicyclohexylcarbodiimide
DCE Dichloroethane
DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
de Diastereoselctive excess
DEAD Diethyl azodicarboxylate
DEL DNA-encoded library
DET Diethyl tartrate
Reaction heated under reflux
(DHQ)2-PHAL 1,4-Bis(9-O-dihydroquinine)-phthalazine
(DHQD)2-PHAL 1,4-Bis(9-O-dihydroquinidine)-phthalazine
DIAD Diisopropyl azodidicarboxylate
DIBAL Diisobutylaluminum hydride
DIC N,Nʹ-Diisopropylcarbodimide
DIPT Diisopropyl tartrate
DIPEA Diisopropylethylamine
DKR Dynamic kinetic resolution
DLP Dilauroyl peroxide
DMA N,N-dimethylacetamide
DMAP 4-N,N-Dimethylaminopyridine
DME 1,2-Dimethoxyethane
DMF N,N-Dimethylformamide
DMFDMA N,N-Dimethylformamide dimethyl acetal
DMP Dess–Martin periodinane
DMPU N,Nʹ-Dimethylpropyleneurea
DMS Dimethylsulfide
DMSO Dimethylsulfoxide
DMSY Dimethylsulfoxonium methylide
DMT Dimethoxytrityl
xviii Abbreviations and Acronyms
DPP-4 Dipeptidyl peptidase IV
DPPA Diphenylphosphoryl azide
dppb 1,4-Bis(diphenylphosphino)butane
dppe 1,2-Bis(diphenylphosphino)ethane
dppf 1,1′-Bis(diphenylphosphino)ferrocene
dppp 1,3-Bis(diphenylphosphino)propane
dr Diastereoselective ratio
DTBAD Di-tert-butylazodicarbonate
DTBMP 2,6-Di-tert-butyl-4-methylpyridine
DTBP Di-tert-butyl peroxide
E1 Unimolecular elimination
E1cB 2-Step, base-induced -elimination via carbanion
E2 Bimolecular elimination
EAN Ethylammonium nitrate
EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
EDDA Ethylenediamine diacetate
EDG Electron-donating group
EDTA Ethylenediaminetetraacetic acid
ee Enantiomeric excess
Ei Two groups leave at about the same time and bond to
each other as they are doing so.
EMC Meerwein–Eschenmoser–Claisen
ERK Extracellular signal-regulated kinase
Eq Equivalent
Equiv Equivalent
Et Ethyl
EtOAc Ethyl acetate
EWG Electron-withdrawing group
FEP Fluorinated ethylene propene
Fmoc Fluorenylmethyloxycarbonyl protecting group
fod 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-
octanedionate = Sieverʹs reagent
FVP Flash vacuum pyrolysis
HCV Hepatitis virus C
HFIP Hexafluoroisopropanol
HKR Hydrolytic kinetic resolution
HMDS Hexamethyldisilazane
HMPA Hexamethylphosphoramide
HMTA Hexamethylenetetramine
HMTTA 1,1,4,7,10,10-Hexamethyltriethylenetetramine
HOMO Highest occupied molecular orbital
IBDA Iodosobenzene diacetate, also known as PIDA
IBX o-Iodoxybenzoic acid
IDH1 Isocitrate dehydrogenase 1
IEDDA Inverse-electron-demand Diels–Alder
Imd Imidazole
xixAbbreviations and Acronyms
IMDA Intramolecular Diels–Alder reaction
IPA Isopropyl alcohol (Indian pale ale)
IPB Insoluble polymer bound
IPr Diidopropyl-phenylimidazolium derivative
JAK Janus kinase
KHMDS Potassium hexamethyldisilazide
LAH Lithium aluminum hydride
LDA Lithium diisopropylamide
LED Light-emitting diode
LHMDS Lithium hexamethyldisilazide
LUMO Lowest unoccupied molecular orbital
LTMP Lithium 2,2,6,6-tetramethylpiperidide
M Metal
MBI Mechanism-based inhibitors
m-CPBA m-Chloroperoxybenzoic acid
MCRs Multicomponent reactions
Mes Mesityl
Mincle Macrophage-inducible C-type lectin
MLCT Metal to ligand charge transfer
MOM ether Methoxymethyl ether
MPL Medium pressure lamp
MPM Methyl phenylmethyl
MPS Morpholine-polysulfide
Ms Methanesulfonyl (mesyl)
MS Molecular sieves
MWI Microwave irradiation
MTBE Methyl tertiary butyl ether
MVK Methyl vinyl ketone
NaDA Sodium diisopropylamide
NBE Norbornene
NBS N-Bromosuccinimide
NCL Native chemical ligation
NCS N-Chlorosuccinimide
nbd 2,5-Norbornadiene
NBE Norbornene
Nf Nonafluorobutanesulfonyl
NFSI N-Fluorobenzenesulfonimide
NHC N-Heterocyclic carbene
NIS N-Iodosuccinimide
NMM N-Methyl morpholine
NMO N-Methylmorpholine N-oxide (NMMO)
NMP 1-Methyl-2-pyrrolidinone
Nos Nosylate = 4-nitrobenzenesulfonyl = Ns
NRI Noradrenaline reuptake inhibitor
N-PSP N-Phenylselenophthalimide
N-PSS N-Phenylselenosuccinimide
xx Abbreviations and Acronyms
Nu Nucleophile
Nuc Nucleophile
Ns Nosylate
PAR-1 Protease activated receptor-1
PARP Poly(ADP-ribosyl) polymerase
PCC Pyridinium chlorochromate
PDC Pyridinium dichromate
PDI Phosphinyl dipeptide isostere
PE Premature ejaculation
PEG Polyethylene glycol
PEPPSI Pyridine-enhanced pre-catalyst preparation,
stabilization, and initiation
phen 1,10-Phenanthroline
PIDA Phenyliodine diacetate (same as IBDA)
Pin Pinacol
Piv Pivaloyl
PNB p-Nitrobenzyl
PMB para-Methoxybenzyl
PPA Polyphosphoric acid
PPSE Trimethylsilyl polyphosphate
PPTS Pyridinium p-toluenesulfonate
PT Phenyltetrazolyl
PTADS Tetrakis[(R)-(+)-N-(p-dodecylphenylsulfonyl)prolinato]
PTSA p-Toluenesulfonic acid
PyPh2P Diphenyl 2-pyridylphosphine
Pyr Pyridine
rac Racemic
Red-Al Sodium bis(methoxy-ethoxy)aluminum hydride
(SMEAH)
rr regioisomeric ratio
Salen N,Nʹ-Disalicylidene-ethylenediamine
SET Single-electron transfer
SIBX Stabilized IBX
SM Starting material
SMC Sodium methyl carbonate
SMEAH Sodium bis(methoxy-ethoxy)aluminum hydride:
trade name Red-Al
SN1 Unimolecular nucleophilic substitution
SN2 Bimolecular nucleophilic substitution
SNAr Nucleophilic substitution on an aromatic ring
SSRI Selective serotonin reuptake inhibitor
T3P Propylphosphonic anhydride
TBABB Tetra-n-butylammonium bibenzoate
TBAF Tetra-n-butylammonium fluoride
TBAI Tetra-n-butylammonium iodide
TBAO 1,3,3-Trimethyl-6-azabicyclo[3.2.1]octane
xxiAbbreviations and Acronyms
TBDMS tert-Butyldimethylsilyl
TBDPS tert-Butyldiphenylsilyl
TBHP tert-Butyl hydroperoxide
TBS tert-Butyldimethylsilyl
t-Bu tert-Butyl
TDI Thiophosphinyl dipeptide isostere
TDS Thexyldimethylsilyl
TEA Triethylamine
TEMPO 2,2,6,6-Tetramethylpiperidinyloxy
TEOC Trimethysilylethoxycarbonyl
TES Triethylsilyl
Tf Trifluoromethanesulfonyl (triflate)
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
TFE Trifluoroethanol
TFEA Trifluoroethyl trifluoroacetate
THF Tetrahydrofuran
TFP Tri-2-furylphosphine
TFPAA Trifluoroperacetic acid
TIPS Triisopropylsilyl
TMEDA N,N,N′,N′-Tetramethylethylenediamine
TMG 1,1,3,3-Tetramethylguanidine
TMOF Trimethyl orthoformate
TMP Tetramethylpiperidine
TMS Trimethylsilyl
TMSCl Trimethylsilyl chloride
TMSCN Trimethylsilyl cyanide
TMSI Trimethylsilyl iodide
TMSOTf Trimethylsilyl triflate
TMU Tetramethylurea
Tol Toluene or tolyl
Tol-BINAP 2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl
TosMIC (p-Tolylsulfonyl)methyl isocyanide
TPPO Triphenylphosphine oxide
TrxR Thioredoxin reductase
Ts Tosyl
TsO Tosylate
TTBP 2,4,6-Tri-tert-butylpyrimidine
UHP Urea-hydrogen peroxide
VAPOL 2,2′-Diphenyl-(4-biphen-anthrol)
VMR Vinylogous Mannich reaction
WERSA Water extract of rice straw ash
xxii Abbreviations and Acronyms
