Multicomponent Reactions towards Heterocycles: Concepts and Applications

616 Pages·2022·4.387 MB·English

by  Erik Van der Eycken (editor), Upendra K. Sharma (editor)

MulticomponentReactionstowardsHeterocycles
Multicomponent Reactions towards
Heterocycles
Concepts and Applications
Edited by
Erik V. Van der Eycken
Upendra K. Sharma
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10 9 8 7 6 5 4 3 2 1
v
Contents
Preface xi
1 HeterocyclesasInputsinMCRs:AnUpdate 1
OuldouzGhashghaei,MarinaPedrola,CarmenEscolano,
andRodolfoLavilla
1.1 Introduction 1
1.2 ConcertedMCRs 1
1.3 RadicalMCRs 11
1.4 Metal-catalyzedMCRs 16
1.5 Carbonyl/IminePolarMCRs 19
1.6 Isocyanide-basedMCRs 24
1.7 MiscellanyProcesses 33
1.8 Conclusion 36
Acknowledgment 40
References 40
2 HeterocyclesandMulticomponentPolymerizations 45
SusanSieben,JordyM.Saya,DeanJohnson,andRomanoV.A.Orru
2.1 Introduction 45
2.2 Ugi-typeMulticomponentPolymerizations 48
2.3 Mannich-typeMulticomponentPolymerizations 52
2.4 Biginelli-typeMulticomponentPolymerizations 64
2.5 Hantzsch-typeMulticomponentPolymerizations 71
2.6 Debus–Radziszewski-typeMulticomponentPolymerizations 73
2.7 OtherMulticomponentPolymerizations 76
2.7.1 TheCu(I)-catalyzedMCPofDiynes,Azides,and
Carbodiimides/Nitriles 78
2.7.2 ThePd-catalyzedMCPofImines,AcylChlorides,andN-Sulfonyl
Imines 78
2.7.3 TheMercaptoaceticAcidLockingImineReaction 80
2.8 ConclusionsandOutlook 83
References 84
vi Contents
3 MulticomponentReactionsinMedicinalChemistry 91
ZefengWangandAlexanderDomling
3.1 Introduction 91
3.1.1 Example:Protein–ProteinInteractionp53-MDM2 94
3.2 ScaffoldsandtheChemicalSpaceofMCR 108
3.2.1 MarketedandClinicalStageDrugs 110
3.3 SomeBiopharmaceuticalApplicationofMCR 121
3.3.1 ComputationalMethodsofMCRChemicalSpaceScreening 122
3.4 Conclusion 127
References 127
4 Solid-PhaseHeterocycleSynthesisUsingMulticomponent
Reactions 139
LeonardoG.Ceballos,DaylinF.Pacheco,BernhardWestermann,
andDanielG.Rivera
4.1 Introduction 139
4.2 SynthesisofFive-MemberedRingHeterocycles 140
4.3 SynthesisofSix-MemberedRingHeterocycles 144
4.4 SynthesisofFusedHeterocyclicRingSystems 147
4.5 SynthesisofHeterocyclesonSolid-SupportedAminoAcids 150
4.6 Solid-PhaseMulticomponentConstructionofDNA-Encoded
HeterocycleLibraries 153
4.7 MiscellaneousSupportsforMulticomponentSynthesisof
Heterocycles 154
4.8 Conclusions 157
References 157
5 GreenSynthesisofHeterocyclesViaMCRs 163
WeiZhang
5.1 Introduction 163
5.2 High-OrderMCRs 164
5.3 ConsecutiveMCRs 176
5.4 MCRsFollowedbyCyclizationReactions 187
5.5 MCRsFollowedbyCycloadditionorAnnulationReactions 200
5.6 ConclusionandOutlook 207
References 207
6 TheUseofFlowChemistryintheMulticomponentSynthesis
ofHeterocycles 211
ChiaraLambruschini,LisaMoni,andAndreaBasso
6.1 Introduction 211
6.2 MulticomponentReactionsUnderStandardFlowConditions 212
6.3 MulticomponentReactionswithHazardousReagents 217
6.4 MulticomponentReactionsUnderSpecialConditions 219
6.4.1 ReactionswithMicrowaveorInductiveHeating 220
Contents vii
6.4.2 ReactionswithActivePacked-BedColumns 223
6.4.3 ReactionsUnderOtherConditions 226
6.5 TelescopedReactions 229
6.6 Conclusions 233
References 235
7 C–HFunctionalizationasanImperativeToolToward
MulticomponentSynthesisandModificationof
Heterocycles 239
AlexeyA.FestaandLeonidG.Voskressensky
7.1 Introduction 239
7.2 Transition-metal-involvedC–HFunctionalization 240
7.2.1 MulticomponentSynthesisofHeterocyclesThroughC–H
Functionalization 240
7.3 Transition-metal-involvedC–HFunctionalization 259
7.3.1 MulticomponentC–HFunctionalizationofHeterocycles 259
7.3.1.1 C(sp2)-HFunctionalization 259
7.3.1.2 C(sp3)-HFunctionalization 267
7.4 Transition-metal-freeC–HFunctionalization 269
7.4.1 MulticomponentSynthesisofHeterocyclesThrough
C–H-functionalization 269
7.4.2 MulticomponentC–HFunctionalizationofHeterocycles 273
References 277
8 Multicomponent-SwitchedReactionsinSynthesisof
Heterocycles 287
ValentynA.Chebanov,SerhiyM.Desenko,VictoriaV.Lipson,
andNikolayYu.Gorobets
References 329
9 RecentApplicationsofMulticomponentReactionsToward
HeterocyclicDrugDiscovery 339
NathanBedard,AlessandraFistrovich,KevinSchofield,ArthurShaw,
andChristopherHulme
9.1 Introduction 339
9.2 MulticomponentReactions 339
9.3 TheUgiReaction 340
9.3.1 TheUgiReactionUsedinNaturalProductSynthesis 343
9.3.2 TheUgiReactioninFDA-approvedDrugsandDrugCandidates 343
9.3.2.1 SynthesisofLipitorUsingUgi4CR 349
9.3.2.2 SynthesisofIvosidenibUtilizingUgi4CR 349
9.3.3 RapidLeadOptimizationwithUgi4CR 349
9.4 ThePasseriniReaction 353
9.4.1 ThePasseriniReactioninNaturalProducts 353
9.5 Groebke–Blackburn–Bienaymé(GBB-3CR)MCR 353
viii Contents
9.6 Gewald(G-3CR)Reaction 361
9.7 TheHantzschDihydropyridine(DHP)Synthesis 364
9.7.1 FDA-approvedHantzschDihydropyridines 368
9.7.2 Anti-bacterialHantzschDHPs 368
9.8 TheBiginelliReaction 370
9.8.1 BiginelliReactionsandNaturalProducts 371
9.8.2 BiginelliDHPMsasCNSAgents 371
9.8.3 BiginelliProductsAntitumorCapabilities 371
9.9 vanLeusenReaction 379
9.9.1 Tosmic-mediatedCyclizationTowardNitrogen-containing
Heterocycles 379
9.9.2 ApplicationsofthevanLeusenReaction 383
9.9.2.1 SequentialOne-potThree-step3C-vanLeusen
Reaction/Deprotection/Cyclization 383
9.9.2.2 SequentialvanLeusenReaction/Staudinger/aza-Wittig/Cyclization 386
9.9.2.3 DNA-conjugatedvanLeusenReaction 386
9.9.3 ApplicationsofthevanLeusenReactioninDrugDiscovery 388
9.9.3.1 PurinergicP2X7ReceptorAntagonists 388
9.9.3.2 Indoleamine2,3-Dioxygenase(IDO1)Inhibitors 391
9.9.3.3 DisruptorsofP53/MDM2Protein–ProteinInteractions 392
9.9.3.4 DisruptorsofPCSK9/LDLRProtein–ProteinInteractions 392
9.9.3.5 InhibitorsofTGFβR1asImmuno-oncologyTherapeutics 397
References 397
10 MulticomponentSynthesesofHeterocyclesbyCatalytic
GenerationofAlkynoylIntermediates 411
JonasNiedballaandThomasJ.J.Müller
10.1 Introduction 411
10.2 CatalyticGenerationofAlkynones 412
10.3 MulticomponentSynthesesofFive-memberedHeterocycles 415
10.3.1 Pyrazolines 415
10.3.2 Pyrazoles 416
10.3.3 Isoxazoles 420
10.3.4 Triazoles 420
10.3.5 Thiophenes 422
10.3.6 Indolones 424
10.4 MulticomponentSynthesesofSix-memberedHeterocycles 427
10.4.1 Pyranones 427
10.4.2 Pyridines 427
10.4.3 Pyrimidines 429
10.4.4 Oxazaborinines 432
10.4.5 Coumarines 432
10.4.6 Quinolines 435
10.4.7 Quinoxalines 435
10.5 ConclusionandOutlook 442
References 442
Contents ix
11 SynthesisofSaturatedHeterocyclesviaMulticomponent
Reactions 447
CarlosK.Z.Andrade,CarlosE.M.Salvador,ThaissaP.F.Rosalba,
LucíliaZ.A.Correa,LuanA.Martinho,andYuriR.B.Sousa
11.1 Introduction 447
11.2 Three-memberedRingHeterocycles 447
11.3 Four-memberedRingHeterocycles 448
11.4 Five-memberedRingHeterocycles 449
11.5 Six-memberedRingHeterocycles 456
11.6 Seven-memberedRingHeterocycles 462
11.7 Macrocycles 463
11.8 FusedHeterocycles 464
11.9 SpiroHeterocycles 482
References 485
12 MulticomponentReactionsandAsymmetricCatalysis 493
MelodyE.BoëtiusandEelcoRuijter
12.1 Introduction 493
12.2 Imine-basedMCRs 494
12.2.1 StreckerReaction 494
12.2.2 MannichReaction 494
12.2.2.1 Aza-HenryReaction 498
12.2.2.2 PetasisReaction 498
12.2.2.3 Aza-Diels–AlderViaMannichReactionPathway 500
12.2.2.4 [2+2+2]-Cycloaddition 504
12.2.3 HantzschReaction 504
12.2.4 BiginelliReaction 506
12.3 MichaelAddition-basedMCRs 509
12.3.1 Oxa-Michael/Michael/Michael/AldolCondensationCascade
Reactions 509
12.3.2 Knoevenagel–MichaelCascadeReaction 511
12.3.3 Michael–HenryCascadeReaction 514
12.4 Isocyanide-BasedMCRs 514
12.4.1 PasseriniReactions 521
12.4.1.1 Passerini-typeTwo-componentReactions 521
12.4.1.2 PasseriniThree-componentReaction 522
12.4.2 Isocyanide-Based[3+2]-Cycloaddition 525
12.4.3 Ugi-typeReactions 525
12.5 Conclusion 529
References 536
13 RecentTrendsinMetal-catalyzedMCRsToward
Heterocycles 551
LiliaFuentes-MoralesandLuisD.Miranda
13.1 Introduction 551
13.2 Five-memberedHeterocycleswithOneHeteroatom 552
x Contents
13.3 Five-memberedSystemswithTwoHeteroatoms 558
13.4 Five-memberedSystemswithThreeHeteroatoms 561
13.5 Six-memberedHeterocycleswithOneHeteroatomandTheir
Benzo-fusedDerivatives 566
13.6 Six-memberedO-heterocyclesandtheirBenzofusedDerivatives 571
13.7 Four-memberedN-heterocyclesandSeven-memberedBenzofused
N-heterocycles 574
13.8 Conclusion 576
References 576
Index 583