Multicomponent Reactions towards Heterocycles

Erik V. Van der Eycken is Full Professor Organic Chemistry and head of the Division Molecular Design & Synthesis, as well as head of the Laboratory for Organic & Microwave-Assisted Chemistry at the University of Leuven (KU Leuven), Belgium. The main focus of his research is the investigation of the application of microwave irradiation in different domains of organic synthesis, i.e. synthesis of bioactive natural product analogues and heterocyclic molecules applying transition metal-catalyzed reactions (i.a. homogeneous and heterogeneous (nanoparticles) gold catalysis), C-H activation, multicomponent reactions (MCRs), post-MCR modifications, and solid phase organic synthesis. Also Flow Chemistry and Photoredox Chemistry have been recently addressed. He is presently author of >290 scientific manuscripts in peer reviewed journals and books and has an H-index of 44. Until now 32 PhD-students performed their research under his guidance.Dr. Upendra K. Sharma received his master degree from Guru Nanak Dev University in 2004 and his PhD degree (2011) in organic chemistry under the supervision of Dr. Arun K. Sinha at CSIR-Institute of Himalayan Bioresource Technology, Palampur, India. Thereafter, he worked as Assistant Professor at National Institute of Technology (NIT), Jalandhar, India. Later on, he joined the research group of Prof. Dr. Erik Van der Eycken, LOMAC, University of Leuven, Belgium as a postdoctoral fellow and until now has published more than 50 research articles in reputed international journals as well as co-edited a Springer series book on Flow Chemistry of Heterocycles. Recently, he has been permanently appointed as Research Expert in LOMAC, Department of Chemistry, KU Leuven. His research interests include the development of new synthetic methods for biologically relevant molecules employing modern methods of synthesis viz. flow chemistry, MCRs, photoredox catalysis and transition metal-catalyzed C-H functionalizations.

• Preface xi1 Heterocycles as Inputs in MCRs: An Update 1Ouldouz Ghashghaei, Marina Pedrola, Carmen Escolano, and Rodolfo Lavilla1.1 Introduction 11.2 Concerted MCRs 11.3 Radical MCRs 111.4 Metal-catalyzed MCRs 161.5 Carbonyl/Imine Polar MCRs 191.6 Isocyanide-based MCRs 241.7 Miscellany Processes 331.8 Conclusion 36Acknowledgment 40References 402 Heterocycles and Multicomponent Polymerizations 45Susan Sieben, Jordy M. Saya, Dean Johnson, and Romano V.A. Orru2.1 Introduction 452.2 Ugi-type Multicomponent Polymerizations 482.3 Mannich-type Multicomponent Polymerizations 522.4 Biginelli-type Multicomponent Polymerizations 642.5 Hantzsch-type Multicomponent Polymerizations 712.6 Debus–Radziszewski-type Multicomponent Polymerizations 732.7 Other Multicomponent Polymerizations 762.7.1 The Cu(I)-catalyzed MCP of Diynes, Azides, and Carbodiimides/Nitriles 782.7.2 The Pd-catalyzed MCP of Imines, Acyl Chlorides, and N-Sulfonyl Imines 782.7.3 The Mercaptoacetic Acid Locking Imine Reaction 802.8 Conclusions and Outlook 83References 843 Multicomponent Reactions in Medicinal Chemistry 91Zefeng Wang and Alexander Domling3.1 Introduction 913.1.1 Example: Protein–Protein Interaction p53-MDM2 943.2 Scaffolds and the Chemical Space of MCR 1083.2.1 Marketed and Clinical Stage Drugs 1103.3 Some Biopharmaceutical Application of MCR 1213.3.1 Computational Methods of MCR Chemical Space Screening 1223.4 Conclusion 127References 1274 Solid-Phase Heterocycle Synthesis Using Multicomponent Reactions 139Leonardo G. Ceballos, Daylin F. Pacheco, Bernhard Westermann, and Daniel G. Rivera4.1 Introduction 1394.2 Synthesis of Five-Membered Ring Heterocycles 1404.3 Synthesis of Six-Membered Ring Heterocycles 1444.4 Synthesis of Fused Heterocyclic Ring Systems 1474.5 Synthesis of Heterocycles on Solid-Supported Amino Acids 1504.6 Solid-Phase Multicomponent Construction of DNA-Encoded Heterocycle Libraries 1534.7 Miscellaneous Supports for Multicomponent Synthesis of Heterocycles 1544.8 Conclusions 157References 1575 Green Synthesis of Heterocycles Via MCRs 163Wei Zhang5.1 Introduction 1635.2 High-Order MCRs 1645.3 Consecutive MCRs 1765.4 MCRs Followed by Cyclization Reactions 1875.5 MCRs Followed by Cycloaddition or Annulation Reactions 2005.6 Conclusion and Outlook 207References 2076 The Use of Flow Chemistry in the Multicomponent Synthesis of Heterocycles 211Chiara Lambruschini, Lisa Moni, and Andrea Basso6.1 Introduction 2116.2 Multicomponent Reactions Under Standard Flow Conditions 2126.3 Multicomponent Reactions with Hazardous Reagents 2176.4 Multicomponent Reactions Under Special Conditions 2196.4.1 Reactions with Microwave or Inductive Heating 2206.4.2 Reactions with Active Packed-Bed Columns 2236.4.3 Reactions Under Other Conditions 2266.5 Telescoped Reactions 2296.6 Conclusions 233References 2357 C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles 239Alexey A. Festa and Leonid G. Voskressensky7.1 Introduction 2397.2 Transition-metal-involved C–H Functionalization 2407.2.1 Multicomponent Synthesis of Heterocycles Through C–H Functionalization 2407.3 Transition-metal-involved C–H Functionalization 2597.3.1 Multicomponent C–H Functionalization of Heterocycles 2597.3.1.1 C(sp2)-H Functionalization 2597.3.1.2 C(sp3)-H Functionalization 2677.4 Transition-metal-free C–H Functionalization 2697.4.1 Multicomponent Synthesis of Heterocycles Through C–H-functionalization 2697.4.2 Multicomponent C–H Functionalization of Heterocycles 273References 2778 Multicomponent-Switched Reactions in Synthesis of Heterocycles 287Valentyn A. Chebanov, Serhiy M. Desenko, Victoria V. Lipson, and Nikolay Yu. GorobetsReferences 3299 Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery 339Nathan Bedard, Alessandra Fistrovich, Kevin Schofield, Arthur Shaw, and Christopher Hulme9.1 Introduction 3399.2 Multicomponent Reactions 3399.3 The Ugi Reaction 3409.3.1 The Ugi Reaction Used in Natural Product Synthesis 3439.3.2 The Ugi Reaction in FDA-approved Drugs and Drug Candidates 3439.3.2.1 Synthesis of Lipitor Using Ugi 4CR 3499.3.2.2 Synthesis of Ivosidenib Utilizing Ugi 4CR 3499.3.3 Rapid Lead Optimization with Ugi 4CR 3499.4 The Passerini Reaction 3539.4.1 The Passerini Reaction in Natural Products 3539.5 Groebke–Blackburn–Bienaymé (GBB-3CR) MCR 3539.6 Gewald (G-3CR) Reaction 3619.7 The Hantzsch Dihydropyridine (DHP) Synthesis 3649.7.1 FDA-approved Hantzsch Dihydropyridines 3689.7.2 Anti-bacterial Hantzsch DHPs 3689.8 The Biginelli Reaction 3709.8.1 Biginelli Reactions and Natural Products 3719.8.2 Biginelli DHPMs as CNS Agents 3719.8.3 Biginelli Products Antitumor Capabilities 3719.9 van Leusen Reaction 3799.9.1 Tosmic-mediated Cyclization Toward Nitrogen-containing Heterocycles 3799.9.2 Applications of the van Leusen Reaction 3839.9.2.1 Sequential One-pot Three-step 3C-van Leusen Reaction/Deprotection/Cyclization 3839.9.2.2 Sequential van Leusen Reaction/Staudinger/aza-Wittig/Cyclization 3869.9.2.3 DNA-conjugated van Leusen Reaction 3869.9.3 Applications of the van Leusen Reaction in Drug Discovery 3889.9.3.1 Purinergic P2X7 Receptor Antagonists 3889.9.3.2 Indoleamine 2,3-Dioxygenase (IDO1) Inhibitors 3919.9.3.3 Disruptors of P53/MDM2 Protein–Protein Interactions 3929.9.3.4 Disruptors of PCSK9/LDLR Protein–Protein Interactions 3929.9.3.5 Inhibitors of TGFβR1 as Immuno-oncology Therapeutics 397References 39710 Multicomponent Syntheses of Heterocycles by Catalytic Generation of Alkynoyl Intermediates 411Jonas Niedballa and Thomas J.J. Müller10.1 Introduction 41110.2 Catalytic Generation of Alkynones 41210.3 Multicomponent Syntheses of Five-membered Heterocycles 41510.3.1 Pyrazolines 41510.3.2 Pyrazoles 41610.3.3 Isoxazoles 42010.3.4 Triazoles 42010.3.5 Thiophenes 42210.3.6 Indolones 42410.4 Multicomponent Syntheses of Six-membered Heterocycles 42710.4.1 Pyranones 42710.4.2 Pyridines 42710.4.3 Pyrimidines 42910.4.4 Oxazaborinines 43210.4.5 Coumarines 43210.4.6 Quinolines 43510.4.7 Quinoxalines 43510.5 Conclusion and Outlook 442References 44211 Synthesis of Saturated Heterocycles via Multicomponent Reactions 447Carlos K.Z. Andrade, Carlos E.M. Salvador, Thaissa P.F. Rosalba,Lucília Z.A. Correa, Luan A. Martinho, and Yuri R.B. Sousa11.1 Introduction 44711.2 Three-membered Ring Heterocycles 44711.3 Four-membered Ring Heterocycles 44811.4 Five-membered Ring Heterocycles 44911.5 Six-membered Ring Heterocycles 45611.6 Seven-membered Ring Heterocycles 46211.7 Macrocycles 46311.8 Fused Heterocycles 46411.9 Spiro Heterocycles 482References 48512 Multicomponent Reactions and Asymmetric Catalysis 493Melody E. Boëtius and Eelco Ruijter12.1 Introduction 49312.2 Imine-based MCRs 49412.2.1 Strecker Reaction 49412.2.2 Mannich Reaction 49412.2.2.1 Aza-Henry Reaction 49812.2.2.2 Petasis Reaction 49812.2.2.3 Aza-Diels–Alder Via Mannich Reaction Pathway 50012.2.2.4 [2+2+2]-Cycloaddition 50412.2.3 Hantzsch Reaction 50412.2.4 Biginelli Reaction 50612.3 Michael Addition-based MCRs 50912.3.1 Oxa-Michael/Michael/Michael/Aldol Condensation Cascade Reactions 50912.3.2 Knoevenagel–Michael Cascade Reaction 51112.3.3 Michael–Henry Cascade Reaction 51412.4 Isocyanide-Based MCRs 51412.4.1 Passerini Reactions 52112.4.1.1 Passerini-type Two-component Reactions 52112.4.1.2 Passerini Three-component Reaction 52212.4.2 Isocyanide-Based [3+2]-Cycloaddition 52512.4.3 Ugi-type Reactions 52512.5 Conclusion 529References 53613 Recent Trends in Metal-catalyzed MCRs Toward Heterocycles 551Lilia Fuentes-Morales and Luis D. Miranda13.1 Introduction 55113.2 Five-membered Heterocycles with One Heteroatom 55213.3 Five-membered Systems with Two Heteroatoms 55813.4 Five-membered Systems with Three Heteroatoms 56113.5 Six-membered Heterocycles with One Heteroatom and Their Benzo-fused Derivatives 56613.6 Six-membered O-heterocycles and their Benzofused Derivatives 57113.7 Four-membered N-heterocycles and Seven-membered Benzofused N-heterocycles 57413.8 Conclusion 576References 576Index 583