Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design

389 Pages·2004·3.762 MB·English

by  Dr. Florencio Zaragoza Dorwald(auth.)

FlorencioZaragozaD(cid:14)rwald
SideReactionsinOrganicSynthesis
SideReactionsinOrganicSynthesis.FlorencioZaragozaD(cid:15)rwald
Copyright(cid:23)2005WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31021-5
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Florencio Zaragoza D(cid:14)rwald
Side Reactions in Organic Synthesis
A Guide to Successful Synthesis Design
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(cid:23)2005WILEY-VCHVerlagGmbH&Co.KGaA,
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ISBN 3-527-31021-5
V
Contents
Preface IX
GlossaryandAbbreviations XI
1 OrganicSynthesis:GeneralRemarks 1
1.1 Introduction 1
1.2 SynthesisDesign 2
1.2.1 ConvergentvsLinearSyntheses 2
1.2.2 RetrosyntheticAnalysis 3
1.3 HardandSoftAcidsandBases 9
1.4 TheCurtin–HammettPrinciple 13
2 StereoelectronicEffectsandReactivity 17
2.1 HyperconjugationwithrBonds 17
2.2 HyperconjugationwithLoneElectronPairs 19
2.2.1 EffectsonConformation 19
2.2.2 TheAnomericEffect 20
2.2.3 EffectsonSpectraandStructure 21
2.3 HyperconjugationandReactivity 23
2.3.1 BasicityandNucleophilicity 23
2.3.2 RatesofOxidation 25
2.3.3 RatesofDeprotonation 26
2.3.4 OtherReactions 27
2.4 Conclusion 30
3 TheStabilityofOrganicCompounds 35
3.1 Introduction 35
3.2 StrainedBonds 35
3.3 IncompatibleFunctionalGroups 41
3.4 ConjugationandHyperconjugationofIncompatibleFunctional
Groups 42
3.5 StabilityTowardOxygen 45
3.5.1 HydrogenAbstraction 45
SideReactionsinOrganicSynthesis.FlorencioZaragozaD(cid:1)rwald
Copyright(cid:2)2005WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31021-5
VI Contents
3.5.2 OxidationbySET 48
3.5.3 AdditionofOxygentoC–CDoubleBonds 51
3.6 Detonations 52
4 AliphaticNucleophilicSubstitutions:ProblematicElectrophiles 59
4.1 MechanismsofNucleophilicSubstitution 59
4.2 StructureoftheLeavingGroup 62
4.2.1 GoodandPoorLeavingGroups 62
4.2.2 NucleophilicSubstitutionofFluoride 66
4.2.3 NucleophilicSubstitutionofSulfonates 70
4.3 StructureoftheElectrophile 72
4.3.1 StericEffects 72
4.3.2 Conjugation 75
4.3.3 Electrophileswitha-Heteroatoms 79
4.3.4 Electrophileswithb-Heteroatoms 84
4.3.5 Electrophileswitha-Electron-withdrawingGroups 86
4.3.6 Neighboring-groupParticipation 90
4.3.7 AllylicandPropargylicElectrophiles 93
4.3.8 Epoxides 97
5 TheAlkylationofCarbanions 143
5.1 Introduction 143
5.2 TheKineticsofDeprotonations 144
5.3 RegioselectivityofDeprotonationsandAlkylations 146
5.3.1 Introduction 146
5.3.2 Kinetic/ThermodynamicEnolateFormation 148
5.3.3 AllylicandPropargylicCarbanions 150
5.3.4 SuccinicAcidDerivativesandAmide-derivedCarbanions 155
5.3.5 BridgeheadCarbanions 157
5.3.6 Dianions 158
5.3.7 a-HeteroatomCarbanions 161
5.3.8 VinylicCarbanions 171
5.3.9 Acyl,Imidoyl,andRelatedCarbanions 173
5.3.10 AromaticCarbanions 175
5.3.11 AromaticvsBenzylicDeprotonation 180
5.4 TheStabilityofCarbanions 182
5.4.1 Introduction 182
5.4.2 a-Elimination 183
5.4.3 b-Elimination 184
5.4.4 Cyclization 190
5.4.5 Rearrangement 193
5.4.6 Oxidation 195
5.4.7 OtherFactorswhichInfluencetheStabilityofCarbanions 196
5.4.8 ConfigurationalStabilityofCarbanions 197
Contents VII
6 TheAlkylationofHeteroatoms 229
6.1 AlkylationofFluoride 229
6.2 AlkylationofAliphaticAmines 231
6.3 AlkylationofAnilines 234
6.4 AlkylationofAlcohols 239
6.5 AlkylationofPhenols 241
6.6 AlkylationofAmides 243
6.7 AlkylationofCarbamatesandUreas 248
6.8 AlkylationofAmidinesandGuanidines 250
6.9 AlkylationofCarboxylates 251
7 TheAcylationofHeteroatoms 261
7.1 ProblematicCarboxylicAcids 261
7.1.1 StericallyDemandingCarboxylicAcids 261
7.1.2 UnprotectedAminoandHydroxyCarboxylicAcids 262
7.1.3 CarboxylicAcidswithAdditionalElectrophilicGroups 265
7.2 ProblematicAmines 267
7.2.1 StericallyorElectronicallyDeactivatedAmines 267
7.2.2 AminoAcids 269
7.2.3 AmineswithAdditionalNucleophilicGroups 270
7.3 ProblematicAlcohols 271
7.3.1 StericallyDeactivatedandBase-labileAlcohols 271
7.3.2 AlcoholswithAdditionalNucleophilicGroups 273
8 Palladium-catalyzedC–CBondFormation 279
8.1 Introduction 279
8.2 ChemicalPropertiesofOrganopalladiumCompounds 279
8.3 MechanismsofPd-catalyzedC–CBondFormation 282
8.3.1 Cross-coupling 282
8.3.2 TheHeckReaction 285
8.4 HomocouplingandReductionoftheOrganylHalide 287
8.5 HomocouplingandOxidationoftheCarbonNucleophile 291
8.6 TransferofArylGroupsfromthePhosphineLigand 293
8.7 ipso-vscine-SubstitutionatVinylboronandVinyltinDerivatives 294
8.8 AllylicArylationandHydrogenationasSideReactionsoftheHeck
Reaction 295
8.9 ProtodemetalationoftheCarbonNucleophile 296
8.10 StericallyHinderedSubstrates 296
8.11 Cyclometalation 298
8.12 ChelateFormation 300
9 Cyclizations 309
9.1 Introduction 309
9.2 BaldwinsCyclizationRules 309
9.3 StructuralFeaturesoftheChain 315
VIII Contents
9.4 RingSize 319
9.4.1 FormationofCyclopropanes 321
9.4.2 FormationofCyclobutanes 325
9.5 Heterocycles 327
10 MonofunctionalizationofSymmetricDifunctionalSubstrates 333
10.1 Introduction 333
10.2 MonofunctionalizationofDicarboxylicAcids 334
10.3 MonofunctionalizationofDiols 336
10.4 MonofunctionalizationofDiamines 342
10.5 MonoalkylationofC,H-AcidicCompounds 346
10.6 MonoderivatizationofDihalides 348
Index 355
IX
Preface
Most non-chemists would probably be horrified if they were to learn how many
attemptedsynthesesfail,andhowinefficientresearchchemistsare.Theratioofsuc-
cessfultounsuccessfulchemicalexperimentsinanormalresearchlaboratoryisfar
below unity, and synthetic research chemists, in the same way as most scientists,
spendmostoftheirtimeworkingoutwhatwentwrong,andwhy.
Despite the many pitfalls lurking in organic synthesis, most organic chemistry
textbooks and research articles do give the impression that organic reactions just
proceed smoothly and that the total synthesis of complex natural products, for
instance,ismaybealabor-intensivebutotherwiseundemandingtask.Infact,most
synthesesofstructurallycomplexnaturalproductsaretheresultofseveralyearsof
hardworkbyateamofchemists,withalmosteverysteprequiringcarefuloptimiza-
tion. The final synthesis usually looks quite different from that originally planned,
because of unexpected difficulties encountered in the initially chosen synthetic
sequence.Onlytheseasonedpractitionerwhohasexperiencedforhimselfthemany
failuresandfrustrationswhichthedevelopment(sometimeseventherepetition)of
asynthesisusuallyimplieswillbeabletoappraisesuchwork.
Thisbookattemptstohighlightthecompetingprocessesandlimitationsofsome
ofthemostcommonandimportantreactionsusedinorganicsynthesis.Awareness
oftheselimitationsandproblemareasisimportantforthedesignofsyntheses,and
mightalsoaidelucidationofthestructureofunexpectedproducts.Twochaptersof
this book cover the structure–reactivity relationship of organic compounds, and
shouldalsoaidthedesignofbettersyntheses.
Chemists tend not to publish negative results, because these are, as opposed to
positive results, never definite (and far too copious). Nevertheless, I have ventured
todescribesomereactionsasdifficultorimpossible.Atalentedchemistmight,how-
ever, succeed in performing such reactions anyway, for what I congratulate him in
advance.Theaimofthisbookisnottostopthereaderfromdoingboldexperiments,
buttohelphimrecognizehisexperimentasbold,todrawhisattentiontopotential
problems,andtoinspire,challenge,andmotivate.
SideReactionsinOrganicSynthesis.FlorencioZaragozaD(cid:1)rwald
Copyright(cid:2)2005WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-31021-5
X Preface
I wish to express my thanks to Ullrich Sensfuss, Bernd Peschke, and Kilian W.
Conde-Frieboes for the many helpful discussions and for proofreading parts of the
manuscript,andtoJesperLau(myboss)forhissupport.
Smørum,Denmark FlorencioZaragozaD(cid:1)rwald
May2004