PracticalSyntheticOrganicChemistry
Reactions,Principles,andTechniques
Editedby StéphaneCaron
PfizerWorldwideR&D
Groton,CT,USA
SecondEdition
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LibraryofCongressCataloging-in-PublicationData
Names:Caron,Stéphane,editor.
Title:Practicalsyntheticorganicchemistry:reactions,principles,and techniques/editedbyStéphaneCaron.
Description:Secondedition.|Hoboken,NJ:Wiley,[2020]|Includes bibliographicalreferencesandindex.
Identifiers:LCCN2019024991(print)|LCCN2019024992(ebook)|ISBN 9781119448853(paperback)|ISBN9781119448884(adobepdf)|ISBN 9781119448907(epub)
Subjects:LCSH:Organiccompounds–Synthesis.
Classification:LCCQD262.P6882020(print)|LCCQD262(ebook)|DDC 547/.2–dc23
LCrecordavailableathttps://lccn.loc.gov/2019024991
LCebookrecordavailableathttps://lccn.loc.gov/2019024992
CoverDesign:Wiley
CoverImage:©SebastianKaulitzki/Shutterstock
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PrintedinUnitedStatesofAmerica
10987654321
Dedicatedtothememoryof
FrankR.BuschandMarkE.Webster Twooutstandingscientistsandfriendswholeftustoosoon andtoJean-YvesCaronanexceptionalfatherandrolemodel
Contents
ListofContributors xxxi
Preface xxxiii
1AliphaticNucleophilicSubstitution 1
JadeD.Nelson
1.1Introduction 1
1.2OxygenNucleophiles 1
1.2.1ReactionswithWater 1
1.2.1.1HydrolysisofAlkylHalides 1
1.2.1.2Hydrolysisof gem-Dihalides 2
1.2.1.3Hydrolysisof1,1,1-Trihalides 2
1.2.1.4HydrolysisofAlkylEstersofInorganicAcids 3
1.2.1.5HydrolysisofDiazoKetones 3
1.2.1.6HydrolysisofAcetals,EnolEthers,andRelatedCompounds 3
1.2.1.7HydrolysisofSilylEnolEthers 5
1.2.1.8HydrolysisofSilylEthers 5
1.2.1.9HydrolysisofEpoxides 6
1.2.2ReactionswithAlcohols 6
1.2.2.1PreparationofEthersfromAlkylHalides 6
1.2.2.2PreparationofMethylEthers 7
1.2.2.3PreparationofEthersfromAlkylSulfonates 9
1.2.2.4Iodoetherification 9
1.2.2.5PreparationofSilylEthers 9
1.2.2.6CleavageofSilylEtherswithAlcohols 10
1.2.2.7Transetherification 10
1.2.2.8PreparationofEpoxides 11
1.2.2.9ReactionofAlcoholswithEpoxides 12
1.2.2.10TheReactionofAlcoholswithDiazoCompounds 12
1.2.2.11PreparationofEthersviaDehydrationofAlcohols 13
1.2.2.12AdditionofAlcoholstoBoron,Phosphorous,andTitanium 13
1.2.3ReactionswithCarboxylates 14
1.2.3.1AlkylationofCarboxylicAcidSalts 14
1.2.3.2Iodolactonization 14
1.2.3.3PreparationofSilylEsters 15
1.2.3.4PreparationofMixedOrganic–InorganicAnhydrides 15
1.2.3.5CleavageofEtherswithAceticAnhydride 16
1.2.3.6AlkylationofCarboxylicAcidsandEnolswithDiazoCompounds 16
1.2.4ReactionswithOtherOxygenNucleophiles 17
1.2.4.1FormationofSilylEnolEthersandSilylKeteneAcetals 17
1.2.4.2FormationofEnolTriflates 18
1.2.4.3FormationofOxoniumSalts 19
1.2.4.4ReactionsofCarbonylCompoundswithOxoniumSalts 19
1.2.4.5PreparationofHydroperoxidesandPeroxyethers 19
1.2.4.6AlkylationofOximes 20
1.3PhosphorusNucleophiles 21
1.3.1PreparationofReagentsforWittigReactions 21
1.4SulfurNucleophiles 21
1.4.1ReactionswithThiols 21
1.4.1.1PreparationofThioethers 21
1.4.1.2CleavageofArylmethylEthers 22
1.4.2AlkylationofSulfides 22
1.4.3ReactionswithOtherSulfurNucleophiles 22
1.4.3.1PreparationofThiols 22
1.4.3.2FormationofBunteSalts 24
1.4.3.3AlkylationofSulfinicAcidSalts 24
1.4.3.4AttackbySulfiteIon 25
1.4.3.5PreparationofAlkylThiocyanates 25
1.5NitrogenNucleophiles 26
1.5.1AmineAlkylation 26
1.5.1.1AmineAlkylationwithAlkylHalidesandOniumSalts 26
1.5.1.2AmineAlkylationwithInorganicEsters 27
1.5.1.3AmineAlkylationwithAlcohols 29
1.5.1.4AmineAlkylationwithDiazoCompounds 30
1.5.1.5Transamination 30
1.5.1.6AmineAlkylationwithEpoxides 30
1.5.1.7AmineAlkylationwithCyclicCarbonates 31
1.5.1.8Preparationof1∘ AminesviaHexamethyldisilazane 32
1.5.1.9PreparationofIsocyanides(“Isonitriles”) 32
1.5.1.10MethylationofAmines,theEschweiler–Clarkereaction 33
1.5.1.11PreparationSulfenamides 33
1.5.2N-AlkylationofAmides,Lactams,Imides,andCarbamates 34
1.5.2.1AlkylationwithAlkylHalides 34
1.5.2.2AlkylationwithAlkylSulfonatesandDerivatives 35
1.5.3OtherNitrogenNucleophiles 36
1.5.3.1NitriteNucleophiles:PreparationofNitroCompounds 36
1.5.3.2AzideNucleophiles 36
1.5.3.3IsocyanatesandIsothiocyanatesasNucleophiles 37
1.6HalogenNucleophiles 38
1.6.1AttackbyHalidesatAlkylCarbonorSilicon 38
1.6.1.1HalideExchange 38
1.6.1.2PreparationofHalidesfromSulfonicAcidEsters 38
1.6.1.3PreparationofAlkylHalidesfromAlcohols 39
1.6.1.4PreparationofAlkylHalidesfromEthers 40
1.6.1.5PreparationofAlkylHalidesfromEpoxides 41
1.6.1.6CleavageofAlkylEtherswithHalideIon 42
1.6.1.7CleavageofSilylEthersandSilylEnolEtherswithHalideIon 44
1.6.1.8CleavageofCarboxylicAcidandSulfonicAcidEsterswithHalideIon 45
1.6.1.9PreparationofHalidesfrom α-DiazoCarbonylCompounds 46
1.6.1.10PreparationofCyanamides 46
1.7CarbonNucleophiles 47
1.7.1AttackbyCarbonatAlkylCarbon 47
1.7.1.1DirectCouplingofAlkylHalides 47
1.7.1.2ReactionsofOrganometallicReagentswithAlkylHalides 47
1.7.1.3CouplingsofAllylicandPropargylicHalides 48
1.7.1.4CouplingsofOrganometallicReagentswithSulfonateEsters 49
1.7.1.5CouplingsInvolvingAlcohols 49
1.7.1.6ReactionsofOrganometallicReagentswithAllylicEstersandCarbonates 50
1.7.1.7ReactionsofOrganometallicReagentswithEpoxides 50
1.7.1.8AlkylationofMalonateandAcetoacetateDerivatives 51
1.7.1.9AlkylationofAldehydes,Ketones,Nitriles,andCarboxylicEsters 51
1.7.1.10AlkylationofCarboxylicAcidSalts 54
1.7.1.11Alkylation α toaHeteroatom 54
1.7.1.12Alkylation α toaMaskedCarboxylicAcid 56
1.7.1.13AlkylationatAlkynylCarbon 57
1.7.1.14AlkylationofCyanideIon–PreparationofNitriles 58
1.8NucleophilicSubstitutionataSulfonylSulfurAtom 60
1.8.1AttackbyOxygen 60
1.8.1.1HydrolysisofSulfonicAcidDerivatives 60
1.8.1.2FormationofSulfonateEsters 61
1.8.2AttackbyNitrogen 61
1.8.2.1FormationofSulfonamides 61
1.8.3AttackbyHalogen 61
1.8.3.1FormationofSulfonylHalides 61
1.8.4AttackbyCarbon 63
1.8.4.1PreparationofSulfones 63
2AdditiontoCarbon-HeteroatomMultipleBonds 65 PrantikMaityandRajappaVaidyanathan
2.1Introduction 66
2.2AdditionofWatertoAldehydesandKetones:FormationofHydrates 66
2.3AdditionofBisulfitetoAldehydesandKetones 67
2.4TheAdditionofAlcoholstoAldehydesandKetones:AcetalFormation 69
2.5TheAdditionofThiolstoAldehydesandKetones:S,S-AcetalFormation 71
2.6ReductiveEtherification 72
2.7AdditionofNH3 ,RNH2 ,andR2 NH 74
2.7.1TheAdditionofAminestoAldehydesandKetones:ImineandOximeFormation 74
2.7.2RedoxNeutralAmination 77
2.8FormationofHydrazones 79
2.9FormationofOximes 80
2.10TheFormationofgem-DihalidesfromAldehydesandKetones 80
2.11TheAldolReaction 82
2.11.1KeteneandSilylEnolEtherAdditiontoAldehydes 87
2.11.2SilylEnolEtherAdditiontoAldehydes:TheMukaiyamaAldol 87
2.11.3KeteneSilylAcetalandThioacetalAdditiontoAldehydes 90
2.12Allylorganometallics:Stannane,Borane,andSilane 92
2.12.1AllylsilaneAdditions 92
2.12.2AllylboraneAdditions 94
2.12.3AllylstannaneAdditions 96
2.13TheNozaki–Hiyama–KishiReaction 97
2.14AdditionofTransitionMetalAlkynylidestoCarbonylCompounds 99
2.15AdditionofOrganometallicReagentstoCarbonyls 100
2.15.1UsingOrganolithiumReagents 100
2.15.2UsingOrganomagnesiumReagents 102
2.16AdditionofConjugatedAlkenestoAldehydes:theBaylis–HillmanReaction 103
2.17TheReformatskyReaction 104
2.18TheWittigReaction 106
2.19Horner–Wadsworth–EmmonsReaction 108
2.20PetersonOlefination 109
2.21Julia–LythgoeOlefination 110
2.22TebbeMethylenation 112
2.23TheMannichReaction 113
2.24TheStreckerReaction 115
2.25HydrolysisofCarbon–NitrogenDoubleBonds 117
2.26ConversionofCarboxylicAcidstoAcylChlorides 118
2.26.1ProceduresUsingOxalylChlorideintheAbsenceofDMF 119
2.26.2ProceduresUsingThionylChlorideintheAbsenceofDMF 119
2.26.3ProceduresUsingaHalogenatingAgentandDMF 120
2.26.4ProceduresUsingVilsmeierReagent 122
2.27SynthesisofAcylFluoridesfromCarboxylicAcids 122
2.28FormationofAmidesfromCarboxylicAcids 123
2.28.1DirectCouplingofCarboxylicAcidsandAmines 123
2.28.2ViaAcidChlorides 126
2.28.3ViaAcylImidazoles(Imidazolides) 126
2.28.4ViaAcylImidazoliumIons 127
2.28.5ViaAnhydrides 128
2.29FormationofAmidesfromEsters 130
2.30HydrolysisofAcylHalides 132
2.31ConversionofCarboxylicAcidstoEsters 132
2.31.1FisherEsterification 132
2.31.2Widmer’sMethodfortheSynthesisoft-ButylEsters 133
2.31.3ViaAcidChlorides 133
2.31.4ViaAcylImidazoles(Imidazolides) 133
2.31.5UsingCarbodiimides 134
2.31.6ViaAnhydrides 134
2.31.7MiscellaneousMethods 136
2.32HydrolysisofAmides 136
2.32.1UnderAcidicConditions 136
2.32.2UnderBasicConditions 137
2.32.3UnderOxidativeConditions 137
2.32.4MiscellaneousMethods 138
2.33ConversionofN-AcyloxazolidinonestoOtherCarboxylDerivatives 139
2.34AlcoholysisofAmides 140
2.35HydrolysisofEsters 141
2.35.1UnderBasicConditions 141
2.35.2UnderAcidicConditions 142
2.35.3MiscellaneousMethods 143
2.36Transesterification 143
2.37AlkylThiolAdditiontoEsters 144
2.38AdditionofOrganometallicReagentstoCarboxylicAcidDerivatives 145
2.39TheKulinkovichCyclopropanation 149
2.40SynthesisofAcylCyanides 150
2.40.1UsingTrimethylsilylCyanide 150
2.40.2UsingCopper(I)Cyanide 150
2.40.3MiscellaneousMethods 151
2.41TheRitterReaction 151
2.42ThorpeReaction 154
2.43AdditionofOrganometallicReagentstoNitriles 155
2.44ConversionofNitrilestoAmides,Esters,andCarboxylicAcids 155
2.44.1HydrolysisofNitrilesUnderAcidicConditions 155
2.44.2HydrolysisofNitrilesUnderBasicConditions 157
2.44.3HydrolysisofNitrilesUnderOxidativeConditions 157
2.44.4EnzymaticHydrolysisofNitriles 157
2.44.5Miscellaneous 158
2.45ConversionofNitrilestoThioamides 158
2.45.1ConversionofNitrilestoAldehydes 159
2.46TheAdditionofAmmoniaorAminestoNitriles 160
2.47TheAdditionofAlcoholtoNitriles 161
2.48AlkylThiolAdditiontoNitriles 162
2.49TheBlaiseReaction 162
2.50TheAdditionofAlcoholstoIsocyanates 163
2.51TheAdditionofAminesandAmidestoIsocyanates 164
2.52TheFormationofXanthates 165
2.53TheAdditionofAminestoCarbonDioxide 166
2.54TheAdditionofAminestoCarbonDisulfide 167
2.55AdditionofOrganometallicReagentstoCarbonDioxide 167
3AdditiontoCarbon–CarbonMultipleBonds 169
JohnA.Ragan
3.1Introduction 169
3.2Hydrogen–HalogenAddition(Hydrohalogenation) 169
3.2.1HydrohalogenationofOlefins 169
3.2.2HydrohalogenationofAlkynes 172
3.3Hydrogen–OxygenAddition 173
3.3.1AdditionofH–OH(Hydration) 173
3.3.1.1HydrationofOlefins 173
3.3.1.2HydrationofAcetylenes 175
3.3.2AdditionofH–OR(Hydroalkoxylation) 176
3.3.2.1AdditionofH–ORtoOlefins 176
3.3.2.2AdditionofH–ORtoAcetylenes 177
3.4Hydrogen–NitrogenAddition(Hydroamination) 178
3.4.1HydroaminationofOlefins 178
3.4.2HydroaminationofAcetylenesandAllenes 179
3.5Hydrogen–CarbonAddition(Hydroalkylation) 180
3.5.1DirectHydrogen-AlkylAddition 180
3.5.2Hydrogen–AllylAddition(AlderEneReaction) 181
3.5.3Hydrogen–Malonate/EnolateAddition(MichaelReaction) 182
3.5.4Hydrogen–AlkylAddition,StorkEnamineReaction 184
3.5.5Hydrogen–AlkylAddition,Metal-Catalyzed 185
3.5.6Hydroformylation/Hydroacylation 188
3.5.7NazarovCyclization 190
3.5.8Radical-MediatedC—HAddition 191
3.6Halogen–HalogenAddition 191
3.7Hydroxy–HalogenAddition 192
3.8Amino–HalogenAddition 194
3.9Carbon–HalogenAddition 194
3.9.1Alkyl–HalogenAddition 194
3.9.2Acyl–HalogenAddition 195
3.10Oxygen–OxygenAddition 196
3.10.1DihydroxylationofOlefins 196
3.10.2Keto-HydroxylationofOlefins 197
3.10.3DihydroxylationofAcetylenes 198
3.10.4Epoxidation 198
3.10.5SingletOxygenAdditiontoDienes 202
3.11Oxygen–NitrogenAddition 202
3.12Nitrogen–NitrogenAddition 204
3.12.1Aziridination 204
3.12.2N—NAdditiontoOlefins 204
3.12.3TriazinesfromAzide–OlefinCycloaddition 205
3.12.4N—NAdditiontoDienes(1,4) 205
3.13Carbon–OxygenAddition 206
3.13.1Carbon–OxygenAdditiontoOlefins(1,2) 206
3.13.1.1[2+2]CycloadditionsofOlefinsandCarbonylCompounds 206
3.13.1.2Nitrone–Olefin[3+2]Cycloadditions 207
3.13.1.3NoncycloadditionCarbon–OxygenAdditions 209
3.13.2Carbon–OxygenAdditiontoDienes(1,4) 210
3.13.2.1HeteroDiels–AlderCycloaddition 210
3.14Carbon–NitrogenAddition 211
3.14.1Carbon–NitrogenAdditiontoOlefins 211
3.14.2Carbon–NitrogenAdditiontoAlkynes 212
3.14.3Carbon–NitrogenAdditiontoDienes 212
3.15Carbon–CarbonAddition 212
3.15.1[4+2]Cycloaddition:Diels–AlderReaction 212
3.15.1.1Intermolecular,Nonsubstituted 212
3.15.1.2Intermolecular,Heteroatom-substitutedDienophile 213
3.15.1.3Intermolecular,HeteroatomsubstitutedDiene 213
3.15.1.4Intermolecular,AqueousMedia 214
3.15.1.5Intermolecular,AromaticProduct 214
3.15.1.6Intermolecular,LewisAcid–Catalyzed 215
3.15.1.7Intermolecular,Inverse-electronDemand 216
3.15.1.8Intermolecular,BenzyneasDienophile 217
3.15.1.9IntramolecularExamples 217
3.15.1.10AsymmetricExamples 218
3.15.2[2+2]Cycloaddition 219
3.15.3[3+2]Cycloaddition 221
3.15.4CarbeneAddition(Cyclopropanation) 225
3.15.5[4+3]Cycloadditions 227
3.15.6ConjugateAddition-Alkylation 228
3.15.7Bis-Alkoxycarbonylation 229
3.15.8CascadeCyclizations 229
4NucleophilicAromaticSubstitution 231
StéphaneCaronandEmmaMcInturff
4.1Introduction 231
4.2OxygenNucleophiles 232
4.2.1PreparationofPhenols 232
4.2.2PreparationofArylEthers 232
4.2.3PreparationofDiarylEthers 234
4.3SulfurNucleophiles 234
4.3.1PreparationofArylThioethers 234
4.3.2PreparationofDiarylThioethers 235
4.3.3OtherSulfurNucleophiles 236
4.4NitrogenNucleophiles 236
4.4.1PreparationofAnilines 236
4.4.2PreparationofArylAmines 237
4.4.3PreparationofDiarylAmines 238
4.4.4OtherNitrogenNucleophiles 240
4.5HalogenNucleophiles 241
4.5.1ReactionofDiazoniumSalts 241
4.5.2Preparationof2-HalopyridinesandDerivatives 242
4.6CarbonNucleophiles 243
4.6.1CyanideasaNucleophile 243
4.6.2MalonatesasNucleophiles 243
4.6.3OtherCarbonNucleophiles 244
4.7ortho-Arynes 245
5ElectrophilicAromaticSubstitution 247
StéphaneCaronandEmmaMcInturff
5.1Introduction 247
5.2NitrogenElectrophiles 247
5.2.1Nitration 247
5.2.2Nitrosation 249
5.2.3DiazoniumCoupling 250
5.3SulfurElectrophiles 250
5.3.1Sulfonation 250
5.3.2Halosulfonation 251
5.3.3Sulfurization 251
5.3.4Sulfinylation 252
5.3.5Sulfonylation 252
5.3.6Thiocyanation 252
5.4Halogenation 253
5.4.1Fluorination 253
5.4.2Chlorination 253
5.4.3Bromination 254
5.4.4Iodination 255
5.5CarbonElectrophiles 257
5.5.1Friedel–CraftsAlkylation 257
5.5.2Friedel–CraftsArylation 259
5.5.3ClaisenRearrangement 259
5.5.4Formylation 260
5.5.5Hydroxyalkylation 261
5.5.6Haloalkylation 262
5.5.7Aminoalkylation 262
5.5.8Thioalkylation 263
5.5.9Friedel–CraftsAcylation 263
5.5.10FriesRearrangement 265
5.5.11Carboxylation 265
5.5.12Amidation 266
5.5.13ThioamidationandThioesterification 266
5.5.14Cyanation 267
6SelectedCatalyticReactions 269
SebastienMonfette,AdamR.Brown,PascalDubé,NathanD.Ide,ChadA.Lewis,JaredL.Piper, ShashankShekhar,andShuYu
6.1Introduction 269
6.2OrganoboronReagents:TheSuzuki–MiyauraCoupling 270
6.2.1PreparationofBiaryls 271
6.2.2PreparationofAlkynyl-SubstitutedArenes 278
6.2.3PreparationofVinyl-SubstitutedArenes 279
6.2.4PreparationofDienes 280
6.2.5PreparationofAlkyl-SubstitutedArenes 280
6.2.6PreparationofAlkyl-SubstitutedAlkenes 281
6.2.7PreparationofAlkanes 282
6.3OrganomagnesiumReagents:Kumada–CorriuCoupling 282
6.3.1PreparationofBiaryls 283
6.3.2PreparationofVinyl-SubstitutedArenes 283
6.3.3PreparationofAryl—AlkylBonds 285
6.3.4PreparationofVinyl—AlkylBonds 286
6.4OrganozincReagents:NegishiCoupling 287
6.4.1PreparationofBiaryls 287
6.4.2PreparationofAryl—AlkylBonds 289
6.4.3PreparationofAlkanes 290
6.4.4Preparationof1,3-Dienes 290
6.4.5PreparationofKetones 291
6.5Cross-ElectrophileCoupling 291
6.6OrganotinReagents:TheStilleCoupling(Migita-StilleReaction) 292
6.6.1PreparationofBiaryls 292
6.6.2PreparationofVinyl-SubstitutedArenes 293
6.6.3Preparationof1,3-Dienes 294
6.6.4PreparationofAlkyl-SubstitutedAlkenes 295
6.7Cross-CouplingReactionswithOrganosiliconCompounds 295
6.8Metal-catalyzedCouplingofAlkynes(SonogashiraCoupling) 296
6.8.1ReactionwithArylHalides 296
6.8.2PreparationofEnynes 298
6.9Metal-CatalyzedCouplingofAlkenes(HeckCoupling) 298
6.9.1FormationofArylAlkenes 299
6.9.2FormationofDienes 301
6.9.3ReductiveHeck 302
6.9.4OxidativeHeck 303
6.10EnolateArylations 303
6.10.1 α-ArylationofKetones 304
6.10.2 α-ArylationofEsters 304
6.10.3 α-ArylationofAmides 305
6.10.4
α-ArylationofNitrile 305
6.11Pd-andCu-CatalyzedArylC—NBondFormation 306
6.11.1AlkylAmineasNucleophile 307
6.11.2ArylAmineasNucleophile 311
6.11.3AmidesasNucleophile 312
6.11.4OtherAmineasNucleophile 314
6.11.5CouplingwithAmmoniaSurrogate 316
6.11.6OxidativeCoupling 318
6.12Pd-andCu-CatalyzedArylC—OBondFormation 320
6.13Pd-andCu-CatalyzedArylC—SBondFormation 322
6.14ArylC—BBondFormation 324
6.14.1ArylBromidesandIodides 324
6.14.2VinylBromide 326
6.14.3ArylChloridesandTriflates 327
6.15Pd-CatalyzedArylC—CNBondFormation 327
6.16Metal-CatalyzedAllylicSubstitution 329
6.16.1CarbonNucleophiles 331
6.16.2NitrogenNucleophiles 334
6.16.3OxygenNucleophiles 335
6.17CatalyticMetal-MediatedMethodsforFluorination 337
6.17.1ArylFluorination 337
6.17.2VinylFluorides 339
6.17.3 α-FluorinationofCarbonylCompounds 340
6.17.4Difluoromethylation(—CF2 R) 342
6.17.5Trifluoromethylation(—CF3 ) 344
6.17.6EmergingMethodsforMetal-CatalyzedFluorination 346
6.17.7SummaryandOutlookforMetal-CatalyzedFluorination 347
6.18SelectedMetal-MediatedC—HFunctionalization 347
6.18.1Introduction 347
6.18.2Metal-Catalyzed,DirectedC—HFunctionalization 348
6.18.2.1Ru-CatalyzedMethods 348
6.18.2.2Palladium-CatalyzedMethods 351
6.18.2.3Rhodium-CatalyzedMethods 353
6.18.3Metal-CatalyzedUndirectedC—HFunctionalization 353
6.18.3.1FormationofC—BBonds 353
6.18.3.2FormationofC—SiBonds 354
6.18.3.3FormationofC—CBonds 355
6.19C—XBondFormingReactionsviaBorrowedHydrogenMethodologies 357
6.19.1Introduction 357
6.19.2C—CBondformation 357
6.19.2.1Allylation/Crotylation 357
6.19.2.2AlkylationofAromatics 358
6.19.3RedoxNeutralHomologationofAlcohols 359
6.19.4KetoneFunctionalization 359
6.19.5C—NBondFormation 360
6.19.5.1PrimaryAmines 360
6.19.5.2SecondaryAmines 360
6.19.5.3TertiaryAmines 361
6.20AlkeneandAlkyneMetathesisReactions 362
6.20.1Introduction 362
6.20.2Ring-closingMetathesis 363
6.20.2.1AlkeneRing-ClosingMetathesis 363
6.20.2.2AlkyneRing-ClosingMetathesis 364
6.20.2.3EnyneRing-closingMetathesis 366
6.20.2.4 Z -SelectiveOlefinMetathesis 366
6.20.3Cross-Metathesis 367
6.20.3.1AlkeneCross-Metathesis 367
6.20.3.2AlkaneCross-Metathesis 368
6.20.3.3AlkyneCross-Metathesis 368
6.20.4MetathesisPolymerization 369
6.21Organocatalysis 369
6.21.1Introduction 369
6.21.2PhaseTransferCatalysis 369
6.21.2.1CarbonAlkylation 369
6.21.2.2HeteroatomAlkylation 370
6.21.2.3ConjugateAdditionsofCarbonNucleophiles 371
6.21.2.4AdditionofHeteroatomNucleophiles 372
6.21.3AminoOrganocatalysisviaIminiumandEnamineIntermediates 372
6.21.3.1IminiumCatalysis:ConjugateAddition 372
6.21.3.2IminiumCatalysis:Cycloadditions 373
6.21.3.3EnamineCatalysis:Aldol/Mannich 373
6.21.4NucleophilicCatalysis 373
6.21.4.1AcylTransferReactions 374
6.21.4.2ReactionsProceedingviaAcylAnionEquivalents 374
6.21.4.3Morita–Baylis–HillmanReactions 375
7Rearrangements 377
DavidH.BrownRipinandChadA.Lewis
7.1Introduction 377
7.2[1,2]-Rearrangements 377
7.2.1Carbon-to-CarbonMigrationsofCarbonandHydrogen 377
7.2.1.1Wagner–MeerweinandRelatedReactions 377
7.2.1.2PinacolRearrangement:VicinalDiolstoKetonesorAldehydes 378
7.2.1.3ExpansionandContractionofRings 380
7.2.1.4RearrangementsofKetonesandAldehydes 381
7.2.1.5DienonetoPhenolRearrangement 381
7.2.1.6BenziltoBenzilicAcidRearrangement 382
7.2.1.7FavorskiiRearrangement:AnionicRearrangementof α-Haloketones 382
7.2.1.8Arndt–EistertSynthesis:HomologationofCarboxylicAcidsviaWolffRearrangementof α-Diazoketones 384
7.2.1.9HomologationofAldehydesandKetones 384
7.2.1.10Fritsch–Buttenberg–WiechellRearrangement:Acetylenesfrom1,1-DisubstitutedOlefins 385
7.2.1.11OtherCarbon-to-CarbonMigrationsofCarbon 386
7.2.1.12OtherCarbon-to-CarbonMigrationsofHydrogen 387
7.2.2Carbon-to-CarbonMigrationsofOtherGroups 387
7.2.2.1MigrationofHalogen,Hydroxy,Amino,andOtherGroups 387
7.2.2.2NeberRearrangement:Carbon-to-CarbonMigrationofNitrogenofActivatedOximes 388
7.2.2.3PayneRearrangement:Rearrangementof α-Hydroxyepoxides 389
7.2.3Carbon-to-NitrogenMigrationsofCarbon 390
7.2.3.1HofmannRearrangement:PrimaryAmidestoAminesorCarbamates 390
7.2.3.2CurtiusRearrangement:AcylAzidestoAminesorCarbamates 391
7.2.3.3LossenRearrangement:HydroxamicImidestoAminesorCarbamates 392
7.2.3.4SchmidtRearrangement:KetonestoAmides 395
7.2.3.5BeckmannRearrangement:OximestoAmides 395
7.2.3.6StieglitzRearrangementsandRelatedReactions:CationicCtoNMigrationofCarbon 396
7.2.4CarbontoOxygenMigrationsofCarbon 397
7.2.4.1Baeyer–VilligerOxidation:KetonesorAldehydestoEsters 397
7.2.5HeteroatomtoCarbonMigrations 398
7.2.5.1StevensRearrangement–[1,2]-RearrangementofN,O,orSYlideswithMigrationofCarbon 398
7.2.5.2[1,2]-MeisenheimerRearrangement–RearrangementofR3 NOtoR2 NOR 400
7.2.5.3OtherHeteroatomtoCarbonRearrangements 400
7.2.6CarbontoHeteroatomRearrangements 402
7.2.6.1BrookRearrangement,Carbon-to-OxygenMigrationofSilicon 402
7.3OtherRearrangements 402
7.3.1ElectrocyclicRearrangements 402
7.3.1.1RearrangementsofCyclobutenesand1,3-Cyclohexadienes 402
7.3.1.2StilbenestoPhenanthrenes 403
7.3.2SigmatropicRearrangements 403
7.3.2.1CyclopropylimineRearrangement 403
7.3.2.2CyclopropanestoAllenes:TheSkattebølandRelatedRearrangements 404
7.3.2.3CopeRearrangement 405
7.3.2.4ClaisenRearrangement 406
7.3.2.5FischerIndoleSynthesis 411
7.3.2.6BoekelheideRearrangement:2-Alkylpyridine N -OxideRearrangements 412
7.3.2.7[2,3]-WittigRearrangement:O-to-CShiftofCarbon 412
7.3.2.8[2,3]-MeisenheimerRearrangement:N-to-OMigrationofCarboninTertiary N -Oxides 413
7.3.2.9[2,3]-Sulfoxide,Selenoxide,andSulfilimineRearrangements 414
7.3.2.10Sommelet–HauserRearrangementandRelatedReactions–[2,3]-SigmatropicRearrangementsof Ylides 415
7.3.2.11BenzidineRearrangement 415
7.3.2.12OvermanRearrangement 416
7.3.2.13PropargylO-to-NMigration 416
7.3.3OtherCyclicRearrangements 417
7.3.3.1Di-π-MethaneandRelatedRearrangements 417
7.3.4AcyclicRearrangements 417
7.3.4.1MigrationofDoubleBonds 417
7.3.4.2HydrideShifts 418
7.3.4.3Newman–KwartRearrangement– O-phenylthiocarbanateto S -phenylcarbamate 419
7.3.4.4NitrosamideDecomposition 419
7.3.4.5TheAchmatowitzReaction:OxidativeFuranRearrangement 420
7.4MiscellaneousMigrations 420
7.4.1Hunsdiecker 420
7.4.2Jocic 420
7.4.3Smiles/Truce–Smiles 421
7.4.4Dakin–West–Dimroth 422
7.4.5Meinwald 423
8Eliminations 425 SallyGutRuggeri
8.1Introduction 425
8.2FormationofAlkenes 425
8.2.1EliminationofAlcohols 426
8.2.2EliminationofEthers 426
8.2.3EliminationofEsters 427
8.2.4EliminationofXanthates 428
8.2.5EliminationofAmmoniumorSulfoniumSalts 428
8.2.6Eliminationof N -Oxides 429
8.2.7EliminationofDiazoniumSalts 429
8.2.8EliminationofHydrazones 429
8.2.9EliminationofSulfoxidesandSelenoxides 430
8.2.10EliminationofHalides 431
8.2.11EliminationofNitriles 431
8.2.12Elimination β toanElectron-withdrawingGroup 432
8.2.13EliminationofDiolDerivatives 432
8.2.14EliminationofEpoxidesandEpisulfides 434
8.2.15Eliminationof α-HaloSulfones 435
8.2.16EliminationofAziridines 435
8.2.17EliminationofDihalides 436
8.2.18EliminationofHaloethers 436
8.2.19EliminationofHydroxy-orHaloacids 437
8.2.20EliminationofHydroxysulfones 437
8.2.21Eliminationof β-SilylAlcohols 438
8.2.22Eliminationof β-SilylEsters,Sulfides,andSulfones 438
8.3FormationofDienes 438
8.3.1FromAllylicSystems 439
8.3.2From1,4-Dihalo-2-butenes 440
8.3.3FromDiols 440
8.3.4From δ-Elimination 440
8.3.5FromSulfolenes 441
8.3.6ViaRetroDiels–AlderReactions 441
8.3.7FromExtrusionofCO 442
8.4FormationofAlkynes 442
8.4.1FromKetones 442
8.4.2FromBis(hydrazones) 443
8.4.3FromDihalides 443
8.4.4FromVinylHalides 443
8.4.5FromEliminationofSulfones 444
8.5FormationofC=Nbonds 444
8.5.1CarbodiimidesfromUreas 445
8.6FormationofNitriles 445
8.6.1NitrilesfromAmides 445
8.6.2NitrilesfromCleavageofN—OBonds 446
8.6.3IsonitrilesfromFormamides 447
8.7FormationofKetenesandRelatedCompounds 447
8.7.1Ketenes 447
8.7.2IsocyanatesandIsothiocyanates 448
8.7.3Ketimines 448
8.8Fragmentations 449
8.8.1GrobFragmentations 449
8.8.2EschenmoserFragmentations 450
8.8.3FormationofArenes 450
8.8.4ExtrusionofN2 450
8.8.5ExtrusionofS 451
8.8.6MulticomponentExtrusions 451
8.9DehydratingReagents 451
9Reductions 455
SallyGutRuggeri,StéphaneCaron,PascalDubé,NathanD.Ide,KristinE.PriceWiglesworth,JohnA.Ragan,andShuYu
9.1Introduction 455
9.2ReductionofC—CBonds 455
9.2.1ReductionofAlkynes 455
9.2.1.1ReductionofAlkynestoAlkenes 455
9.2.1.2ReductionofAlkynestoAlkanes 456
9.2.2ReductionofAlkenes 457
9.2.2.1ReductionofAlkenestoAlkanesWithoutFacialSelectivity 457
9.2.2.2ReductionofAlkenestoAlkaneswithFacialSelectivity 458
9.2.3ReductionofAromaticRingsandHeterocycles 461
9.2.3.1ReductionofBenzeneandNaphthaleneRings 461
9.2.3.2ReductionofPyridinesandQuinolines 462
9.2.3.3ReductionofPyrrolesandIndoles 464
9.2.3.4ReductionofFurans 464
9.2.4ConjugateReductions 465
9.2.4.1ReductionofConjugatedAlkynes 465
9.2.4.2Reductionof α,β-UnsaturatedAcidsandDerivatives 466
9.2.4.3ReductionofEnones 469
9.3ReductionofC—NBonds 471
9.3.1ReductionofNitrilestoIminesorAldehydes 471
9.3.2ReductionofNitrilestoPrimaryAmines 471
9.3.3ReductionofIminesorImineDerivatives 472
9.3.3.1AchiralReductions 472
9.3.3.2SubstrateControlinStereoselectiveReductions 473
9.3.3.3EnantioselectiveReductions 474
9.3.4ReductionofHydrazonestoAlkanes 477
9.3.5ReductionofCarbon–NitrogenSingleBonds 477
9.3.5.1ReductionofBenzylicAmines 477
9.3.5.2ReductionofAromaticCarbon–NitrogenSingleBonds 478
9.3.5.3ReductionofAliphaticNitroGroups 479
9.4ReductionofC—OBonds 479
9.4.1ReductionofCarboxylicAcidDerivatives 479
9.4.1.1ReductionofEsterstoAldehydes 479
9.4.1.2ReductionofEsterstoPrimaryAlcohols 480
9.4.1.3ReductionofCarboxylicAcidstoPrimaryAlcohols 481
9.4.1.4ReductionofAnhydridesandMixedAnhydridestoAldehydes 481
9.4.1.5ReductionofAnhydridesandMixedAnhydridestoPrimaryAlcohols 481
9.4.1.6ReductionofAmidesandImidestoAldehydes 482
9.4.1.7ReductionofAmidestoAlkylamines 484
9.4.1.8ReductionofCarbamatesto N -Methylamines 484
9.4.2ReductionofAldehydesandKetonestoAlcohols 485
9.4.2.1ReductionwithHydrideDonors 485
9.4.2.2Meerwein–Ponndorf–VerleyReaction 488
9.4.2.3ReductionviaCatalyticHydrogenation 489
9.4.2.4BiocatalyticRoutestoReductionofAldehydesandKetones 490
9.4.2.5Aldol–TishchenkoReaction 490
9.4.2.6ReductionofAcetalsandKetals 491
9.4.3ReductionofKetonestoAlkanes 492
9.4.3.1Wolff–KishnerReduction 492
9.4.3.2ClemmensenReduction 492
9.4.3.3Silane-MediatedReduction 492
9.4.4ReductionofAlcoholstoAlkanes 492
9.4.4.1ReductionofAliphaticAlcohols 492
9.4.4.2ReductionofBenzylicAlcohols 493
9.4.4.3ReductionofBenzylicEthers 493
9.5ReductionofC—SBonds 494
9.5.1ReductionofAlkylSulfides,Sulfoxides,andSulfones 494
9.5.2ReductionofVinylSulfides,Sulfoxides,andSulfones 496
9.5.3ReductionofArylSulfides,Sulfoxides,andSulfones 497
9.5.4ReductionofThioketones 498
9.5.5ReductionofThioestersandThioamides 498
9.5.6ReductionofMiscellaneousThiocarbonyls 499
9.6ReductionofC—XBonds 500
9.6.1AlkylHalideReductions 500
9.6.2AcidHalidestoAldehydes 502
9.6.3VinylHalideReductions 503
9.6.4ArylHalideReductions 503
9.7ReductionofHeteroatom–HeteroatomBonds 504
9.7.1ReductionofNitrogen–NitrogenBonds 504
9.7.1.1ReductionofAzides 505
9.7.2ReductionofNitrogen–OxygenBonds 505
9.7.2.1ReductionofNitroGroupstoAmines 506
9.7.2.2PartialReductionofAromaticNitroCompounds 507
9.7.2.3PartialReductionofAliphaticNitroCompounds 507
9.7.3ReductionofOxygen–OxygenBonds 508
9.7.3.1ReductionofPeroxides 508
9.7.3.2ReductionofOzonides 508
9.7.4ReductionofOxygen–SulfurBonds 509
9.7.4.1ReductionofSulfonestoSulfides 509
9.7.4.2ReductionofSulfoxidestoSulfides 510
9.7.5ReductionofDisulfidestoThiols 510
9.7.6ReductionofPhosphineOxidestoPhosphines 511
10Oxidations 513
EricC.Hansen,RobertPerkins,andDavidH.BrownRipin
10.1Introduction 513
10.2OxidationofC—CSingleandDoubleBonds 514
10.2.1OxidativeCleavageofGlycols β-Aminoalcohols, α-HydroxyaldehydesandKetones,andRelated Compounds 514
10.2.2Ozonolysis 515
10.2.2.1OzonolysisFollowedbyReductiontotheAlcohol 515
10.2.2.2OzonolysistotheKetoneorAldehydeOxidationState 515
10.2.2.3OzonolysisResultinginCarboxylicAcidsorEsters 516
10.2.2.4OzonolysisFollowedbyCriegeeRearrangement 517
10.2.3OxidativeCleavageofDoubleBondsandAromaticRings 517
10.2.4OxidativeCleavageofAlkylGroupsfromRings 518
10.2.5OxidativeDecarboxylation 518
10.2.6OxidativeDecyanation 519
10.2.7OxidationofOlefinstoAldehydesandKetones 520
10.3OxidationofC—HBonds 520
10.3.1AromatizationofSix-MemberedRings 520
10.3.2DehydrogenationsYieldingCarbon–CarbonBonds 521
10.3.3Halogenation α toaKetoneorAldehyde,orCarboxylicAcid 522
10.3.3.1Chlorination 522
10.3.3.2Bromination 523
10.3.3.3Iodination 525
10.3.3.4Fluorination 525
10.3.3.5HaloformReaction 526
10.3.3.6CleavageofKetoneswithMNH2 527
10.3.4Oxygenation α toaKetone,Aldehyde,orCarboxylicAcid 527
10.3.5IntroductionofNitrogen α toaKetone,Aldehyde,orCarboxylicAcid 528
10.3.5.1AliphaticDiazoniumCoupling 528
10.3.5.2NitrosationofActivatedCarbon–HydrogenBonds 529
10.3.5.3FormationofDiazoCompounds 529
10.3.5.4Amination α toaCarbonyl 530
10.3.6SulfenationandSelenylationofKetones,Aldehydes,andEsters 531
10.3.7SulfonylationofAldehydes,Ketones,andAcids 531
10.3.8AllylicandBenzylicHalogenation 532
10.3.8.1Oxygenations 533
10.3.8.2AllylicAmination 534
10.3.9NitreneInsertionintoCarbon–HydrogenBonds 535
10.4OxidationofCarbon–OxygenBondsandatCarbonBearinganOxygenSubstituent 536
10.4.1OxidationofAlcoholstoAldehydesandKetones 536
10.4.1.1TEMPO-MediatedProcesses 537
10.4.1.2MoffattandModified-MoffattProcesses 537
10.4.1.3Metal-MediatedProcesses 539
10.4.1.4AlternativeMethods 541
10.4.1.5OxidationofBenzylicandAllylicAlcohols 541
10.4.1.6OxidationofDiolstoLactones,SelectiveOxidationofPrimaryorSecondaryAlcohols 542
10.4.2OxidationofPrimaryAlcoholstoCarboxylicAcids 542
10.4.2.1TEMPO/SodiumChloriteOxidationofAlcoholstoCarboxylicAcidsandDerivatives 542
10.4.2.2Metal-MediatedOxidationofAlcoholstoCarboxylicAcidsandDerivatives 543
10.5OxidationofAldehydestoCarboxylicAcidsandDerivatives 543
10.5.1SodiumChloriteOxidationofAldehydestoCarboxylicAcidsandDerivatives 543
10.5.1.1HydrogenPeroxideOxidationofAldehydestoCarboxylicAcidsandDerivatives 543
10.5.1.2Metal-MediatedOxidationsofAldehydestoCarboxylicAcidsandDerivatives 543
10.5.1.3OxidationofBisulfiteAdducts 544
10.5.2OxidationofCarboxylicAcidstoPeroxyacids 544
10.5.3OxidationofPhenolsandAnilinestoQuinones 544
10.5.4Oxidation α toOxygenandNitrogen 545
10.6OxidationofCarbon–NitrogenBondsandatCarbonBearingaNitrogenSubstituent 546
10.6.1DehydrogenationofAminestoIminesandNitriles 546
10.6.1.1Oxidation α toNitrogen 546
10.6.1.2OxidationofAldoximesandHydrazonesofAldehydes 548
10.7OxidationofNitrogenFunctionalities 548
10.7.1DiazotizationofAmines 548
10.7.2OxidationsofHydrazinesandHydrazones 549
10.7.3AminationofNitrogen 550
10.7.4OxidationofAminestoAzoorAzoxyCompounds 551
10.7.5OxidationofPrimaryAminestoHydroxylamines 551
10.7.6OxidationofNitrogentoNitrosoCompounds 551
10.7.6.1NitroneFormation 552
10.7.6.2OxidationofHydroxylaminetoNitrosoCompounds 552
10.7.7NitrosationofSecondaryAminesandAmides 553
10.7.8OxidationofPrimaryAmines,Oximes,orNitrosoCompoundstoNitroCompounds 553
10.7.9OxidationofTertiaryAminestoAmineOxidesandEliminationtoFormImines 553
10.7.10OxidationofPyridinestoPyridine N-Oxides 554
10.7.11HalogenationorSulfinationofAminesandAmides 554
10.8OxidationofSulfurandatCarbonAdjacenttoSulfur 555
10.8.1PummererRerrangement 555
10.8.2Formationof α-Halosulfides 556
10.8.3HalogenationofSulfoxides,Sulfones,andPhosphineOxides 556
10.8.4OxidationofMercaptansandOtherSulfurCompoundstoSulfonicAcidsorSulfonylChlorides 557
10.8.4.1Peroxide-BasedOxidations 557
10.8.4.2ChlorineOxidations 557
10.8.5OxidationofSulfidestoSulfoxidesandSulfones 557
10.8.5.1OxidationofaSulfidetoaSulfoxide 557
10.8.5.2OxidationofaSulfidetoaSulfone 559
10.8.5.3OxidationofSelenides 560
10.8.6OxidationofMercaptanstoDisulfides 561
10.9OxidationofOtherFunctionality 561
10.9.1OxidationofPrimaryHalides 561
10.9.2OxidationofC—SiBonds:TheTamaoOxidation 562
11SelectedFreeRadicalReactions 563
ChristopheAllais,EricC.Hansen,NathanD.Ide,RobertJ.Perkins,andElizabethC.Swift
11.1Introduction 563
11.1.1RadicalReactionsDiscussedinOtherChapters 563
11.2RadicalReactionsviaChemicalInitiation 563
11.2.1RadicalCyclizations 563
11.2.2AtomTransferRadicalCyclizations 564
11.2.3RadicalAllylation 564
11.2.3.1KeckRadicalAllylation 564
11.2.3.2Tin-FreeRadicalAllylations 565
11.2.4RemoteFunctionalizationReactions 566
11.2.5BartonNitriteEsterReaction 566
11.2.5.1Hofmann–Löffler–FreytagReaction 567
11.2.6HypohaliteReaction 568
11.2.7TheHunsdieckerReaction 568
11.2.7.1BartonModificationoftheHunsdieckerReaction 569
11.2.7.2SuárezModificationoftheHunsdieckerReaction 569
11.2.7.3CatalyticHunsdieckerReactionwith α,β-UnsaturatedCarboxylicAcids 570
11.2.7.4Nitro-HunsdieckerReaction 571
11.2.8TheMinisciReaction 571
11.2.9RadicalConjugateAdditions 572
11.2.9.1IntramolecularRadicalConjugateAdditions 573
11.2.9.2IntermolecularRadicalConjugateAdditions 573
11.2.10 β-ScissionReactions 574
11.2.11FreeRadicalPolymerization 575
11.3PhotoredoxCatalysis 575
11.3.1DualCatalyticCross-couplingReactions 576
11.3.2PhotoredoxMinisciReactions 578
11.3.3PhotoredoxConjugateAddition 580
11.3.4PhotoredoxRearrangements 580
11.3.5PhotoredoxCycloadditions 581
11.3.6PhotoredoxNetOxidationsandReductions 582
11.3.6.1Oxidations 582
11.3.6.2Reductions 583
11.4ElectrochemicalMethods 583
11.4.1AnodicDecarboxylations:KolbeandNon-KolbeReactions 583
11.4.2TheShonoOxidation 585
11.4.3ElectrochemicalReductionofAlkylHalides 585
11.4.4IndirectElectrolysisReactions 586
11.4.5OxidationandReductionatSulfur 588
12Synthesisof“Nucleophilic”OrganometallicReagents 591 DavidH.BrownRipinandAdamR.Brown
12.1Introduction 591
12.2Synthesisof“Nucleophilic”OrganometallicReagents 592
12.2.1Lithium 592
12.2.1.1Deprotonation 592
12.2.1.2Metal–HalogenExchange 593
12.2.1.3Metal–MetalExchange 594
12.2.2Boron 594
12.2.2.1Hydroboration 594
12.2.2.2Metal–MetalExchange 595
12.2.2.3Cross-couplingwithR2 B–BR2 596
12.2.2.4C–HBorylation 597
12.2.2.5Other 597
12.2.3Magnesium 598
12.2.3.1Metal–HalogenExchange 598
12.2.3.2Metal–MetalExchange 599
12.2.3.3Hydromagnesiation 600
12.2.3.4Carbomagnesiation 600
12.2.4Aluminum 600
12.2.4.1Metal–HalogenExchange 600
12.2.4.2Carboalumination 601
12.2.4.3Hydroalumination 601
12.2.4.4Metal–MetalExchange 602
12.2.5Silicon 602
12.2.5.1Metal–MetalExchange 602
12.2.5.2Hydrosilylation 603
12.2.5.3Metal–HalogenExchange 603
12.2.5.4C–HSilylation 603
12.2.5.5UseofNucleophilicSiliconReagents 604
12.2.6Titanium 604
12.2.6.1Metal–MetalExchange 604
12.2.6.2Other 605
12.2.7Chromium 605
12.2.7.1Metal–HalogenandMetal–MetalExchange 605
12.2.8Manganese 606
12.2.8.1Metal–MetalExchange 606
12.2.9Iron 606
12.2.9.1Metal–HalogenExchange 606
12.2.10Copper 607
12.2.10.1Metal–MetalExchange 607
12.2.11Zinc 608
12.2.11.1Metal–HalogenExchange 609
12.2.11.2Metal–MetalExchange 609
12.2.11.3Other 610
12.2.12Zirconium 610
12.2.12.1Hydrozirconation 610
12.2.13Indium 611
12.2.14Tin 612
12.2.14.1Metal–MetalExchange 612
12.2.14.2NucleophilicSn 612
12.2.14.3Cross-couplingwithR3 Sn–SnR3 613
12.2.14.4Hydrostannation 613
12.2.14.5ElectrophilicTin 614
12.2.15Cerium 614
12.2.16Bismuth 615
12.3StrategiesforMetalatingHeterocycles 615
12.3.1StrategiesforMetalatingFive-MemberedHeterocycles 615
12.3.2StrategiesforMetalatingSix-MemberedHeterocycles 617
12.4Reactionsof“Nucleophilic”OrganometallicReagents 618
12.4.1UncatalyzedC–MtoC–O 618
12.4.2UncatalyzedC–MtoC–SorC–Se 619
12.4.3UncatalyzedC–MtoC–X 619
12.4.4UncatalyzedC–MtoC–N 620
13SynthesisofCommonAromaticHeterocycles 621
StéphaneCaron
13.1Introduction 621
13.2Pyrroles 623
13.2.1Condensationof1,4-DicarbonylswithaPrimaryAmine 623
13.2.2Condensationof1,3-Dicarbonylswithan α-AminocarbonylCompound 624
13.2.3DipolarCycloaddition 624
13.3Indoles 624
13.3.1FisherIndoleSynthesis 625
13.3.2IntramolecularCondensationofAnilineswithPhenacylDerivatives 625
13.3.3CycloeliminationofEnamines 625
13.3.4AldolandMichaelAdditions 625
13.3.5AlkylationofanAniline 626
13.3.6AdditionofVinylGrignardReagentstoNitrobenzeneDerivatives 626
13.42-Indolinones(Oxindoles) 626
13.4.1Lactamization 627
13.4.2Friedel–CraftsAlkylation 627
13.4.3C–HInsertion 627
13.5Isatins(2,3-Indolindiones) 628
13.5.1CyclizationofIsonitrosoacetanilides 628
13.5.2Friedel–CraftsAcylation 628
13.6Carbazoles 628
13.6.1OxidationofanIndole 628
13.6.2ReductiveCyclizationofaNitro-BiphenylDerivative 628
13.7Pyrazoles 629
13.7.1CondensationofaHydrazinewitha1,3-DicarbonylDerivative 629
13.7.2CondensationofaHydrazinewithaMichaelAcceptor 630
13.8Indazoles 630
13.8.1NucleophilicAromaticSubstitutionofArylhydrazones 630
13.8.2DiazotizationofaToluidine 631
13.8.3Metal-MediatedCyclization 631
13.9ImidazolesandBenzimidazoles 631
13.9.1Condensationofa1,2-DiaminewithaCarboxylicAcid 632
13.9.2CondensationofanAmidinewithaHalocarbonylDerivative 632
13.9.3Condensationof1,4-DicarbonylswithanAmine 633
13.9.4Condensationof1,2-DicarbonylswithanAldehydeandAmmonia 633
13.101,2,3-TriazolesandBenzotriazole 633
13.10.1DipolarCycloadditionofAzideswithanAlkynes 634
13.10.2DipolarCycloadditionofAzideswithEnolates 634
13.10.3Diazaotizationof o-Dianilines 634
13.111,2,4-Triazoles 635
13.11.1Cyclodehydration 635
13.12Tetrazoles 635
13.12.1CycloadditionofanAzideandaNitrile 636
13.12.2ActivationofanAmideandAdditionofanAzide 636
13.13Dihydropyridines 637
13.13.1ReactionofKetoestersandAldehydesinthePresenceofAmmonia 637
13.13.2ReactionofAminocrotonateswithAldehydesandß-Ketoesters 637 13.14Pyridines 637
13.14.1Condensationofa1,3-DicarbonylDerivativewithaCyanoacetamide 637
13.14.2CondensationofEnolateswithEnaminoesters 638
13.14.3Condensationofa1,5-DicarbonylCompoundwithAmmonia 638 13.15Quinolines 639
13.15.1FriedländerQuinolineSynthesis 639
13.15.2AdditiontoIsatins 640
13.15.3ElectrophilicAromaticSubstitution 640
13.15.4IntramolecularCyclizationofanIminiumIon 640
13.16Quinolinonesand2-Hydroxyquinolines 641
13.16.1ElectrophilicCyclization 641
13.16.2IntramolecularAldolRingClosure 641
13.16.3IntramolecularCondensation 641
13.16.4OxidationofaQuinoline 642
13.17Isoquinolines 642
13.17.1IntramolecularCyclizationofImidoylChlorides 642
13.17.2IntramolecularCyclizationofanOxoniumIon 643
13.17.3CondensationofPhenacylDerivativeswithAmmonia 643
13.18Isoquinolinones 643
13.18.1BenzamideImineCondensation 643
13.18.2AmideCyclization 643
13.19Quinolones(4-Hydroxyquinolines) 644
13.19.1ElectrophilicCyclization 644
13.19.2NucleophilicAromaticSubstitution 644
13.19.3IntramolecularClaisenRingClosure 645
13.20PyrimidinesandPyrimidones 645
13.20.1CondensationofAmidineswith1,3-DicarbonylDerivatives 645
13.20.2CondensationofAmidineswithMichaelAcceptors 646
13.20.3CyclizationofCyanoAmides 646
13.21QuinazolinesandQuinazolinones 647
13.21.1DerivatizationofAnthranilicAcids 647
13.21.2ReactionofBenzonitriles 647
13.21.3IntramolecularCondensations 648
13.21.4ElectrophilicAromaticSubstitution 648
13.22PyrazinesandQuinoxalines 648
13.22.1CondensationofDianilines 649
13.22.2CondensationofDicarbonylDerivativeswithAmmonia 649
13.23Pyridazines,Phtalazines,andCinnolines 650
13.23.1AdditionofHydrazinetoDicarbonylDerivatives 650
13.23.2AdditiontoaDiazoDerivative 650
13.23.3ElectrophilicAromaticSubstitution 651
13.241,2,4-Triazines 651
13.24.1ReactionofAmidrazoneswithGlyoxalDerivatives 651
13.24.2ReactionofNitroanilineswithCyanamide 651
13.24.3ReactionofAminopyrroles 651
13.25FuransandBenzofurans 652
13.25.1Condensationof1,3-Dicarbonylswithan α-Halocarbonyl 652
13.25.2Cyclodehydrationofa1,4-DicarbonylCompound 653
13.25.3Dehydration 653
13.25.4Metal-MediatedCyclization 653
13.26Benzopyran-4-One(Chromen-4-One,Flavone)andXanthone 653
13.26.1Condensationofortho-Phenoxy-1,3-dicarbonylDerivatives 654
13.26.2Condensationofortho-AcylcarbonylDerivatives 654
13.26.3ElectrophilicCyclization 654
13.26.4NucleophilicAromaticSubstitution 654
13.27Coumarins 655
13.27.1Condensationofortho-AcylcarbonylDerivatives 655
13.27.2ArylationofBromobenzoicAcidDerivatives 655
13.28ThiophenesandBenzothiophenes 656
13.28.1AldolCondensation 656
13.28.2KnoevenagelCondensation 656
13.28.3Cyclodehydrationof1,4-DicarbonylDerivatives 657
13.28.4NucleophilicAdditiontoSulfurFollowedbyCyclocondensation 657
13.29IsoxazolesandBenzisoxazoles 657
13.29.1HydroxylamineAdditionto1,3-DicarbonylDerivatives/Enaminoketones 658
13.29.2AlkylationofDihalides 658
13.29.3DipolarCycloaddition 658
13.29.4NucleophilicAromaticSubstitution 659
13.30OxazolesandBenzoxazoles 659
13.30.1CyclizationonanActivatedCarbonylDerivative 659
13.30.2DipolarCycloaddition 660
13.31IsothiazolesandBenzisothiazoles 660
13.31.1IntramolecularCyclization 660
13.31.2Additiontoortho-Thiobenzonitriles 661
13.32ThiazolesandBenzothiazoles 661
13.32.1CondensationofThioamideswithHaloketones 661
13.32.2CondensationofCarboxylicAcidDerivativeswith2-Aminothiols 662
13.32.3NucleophilicAromaticSubstitution 662
13.331,2,4-Oxadiazoles 662
13.33.1CondensationofHydroxyureawithCarboxylicAcids 662
13.33.2CondensationofHydroxyureawithCarboxylicAcidDerivatives 663
13.341,3,4-Oxadiazoles 663
13.34.1CyclodehydrationofHydrazide 663
13.34.2NitrogenExtrusion 664
14AccesstoChirality 665
AngelaL.A.Puchlopek-DermenciandRobertW.Dugger
14.1Introduction 665
14.2UsingtheChiralPool 665
14.3ClassicalResolutions 668
14.3.1TheFamilyApproach(theDutchResolution) 670
