Multicomponent Reactions towards Heterocycles: Concepts and Applications

Description

Presents a wide-ranging overview of essential topics and recent advances in MCR chemistry Heterocycles are a central component in natural product chemistry, pharmaceuticals, agrochemicals, and material science. New synthetic methodologies integrating the sequencing of multicomponent reactions (MCRs) are today being used for the rapid synthesis of diversified heterocycles in just one step. Multicomponent Reactions towards Heterocycles presents an up-to-date summary MCR chemistry with a focus on the conjugation between modern synthetic methodologies and MCRs. Featuring contributions by leaders in the field, this comprehensive resource highlights applications of MCRs in natural products and intermediate synthesis, discusses current trends and future prospects in MCR chemistry, outlines novel multicomponent procedures, and more. The authors provide the practical information required for designing new reaction strategies and mechanisms, covering topics including MCR-based green synthetic methods, cyclization and cycloaddition reactions, heterocycle multicomponent syntheses in a continuous flow, catalytic alkynoyl generation, MCR synthesis of saturated heterocycles, and C–H functionalization and multicomponent reactions. Provides a thorough overview of heterocycles as input in multicomponent reactions Discusses recent advances in the field of MCR chemistry and progress in the synthesis and functionalization of heterocycles Demonstrates the use of MCRs to simplify synthetic design and achieve complexity and diversity in novel bioactive molecules Highlights examples of multicomponent polymerizations, target-oriented synthesis, and applications of MCR in medicinal chemistry Explains the methodology of using on-resin MCRs to produce heterocycle compounds Illustrating the key role of MCRs towards heterocycles in natural product synthesis, drug discovery, organic synthesis, and other applications, Multicomponent Reactions towards Heterocycles is required reading for synthetic chemists in academia and industry alike. Cover Half Title Multicomponent Reactions towards Heterocycles: Concept and Applications Copyright Contents Preface 1. Heterocycles as Inputs in MCRs: An Update 1.1 Introduction 1.2 Concerted MCRs 1.3 Radical MCRs 1.4 Metal‐catalyzed MCRs 1.5 Carbonyl/Imine Polar MCRs 1.6 Isocyanide‐based MCRs 1.7 Miscellany Processes 1.8 Conclusion Acknowledgment References 2. Heterocycles and Multicomponent Polymerizations 2.1 Introduction 2.2 Ugi‐type Multicomponent Polymerizations 2.3 Mannich‐type Multicomponent Polymerizations 2.4 Biginelli‐type Multicomponent Polymerizations 2.5 Hantzsch‐type Multicomponent Polymerizations 2.6 Debus–Radziszewski‐type Multicomponent Polymerizations 2.7 Other Multicomponent Polymerizations 2.7.1 The Cu(I)‐catalyzed MCP of Diynes, Azides, and Carbodiimides/Nitriles 2.7.2 The Pd‐catalyzed MCP of Imines, Acyl Chlorides, and N‐Sulfonyl Imines 2.7.3 The Mercaptoacetic Acid Locking Imine Reaction 2.8 Conclusions and Outlook References 3. Multicomponent Reactions in Medicinal Chemistry 3.1 Introduction 3.1.1 Example: Protein–Protein Interaction p53‐MDM2 3.2 Scaffolds and the Chemical Space of MCR 3.2.1 Marketed and Clinical Stage Drugs 3.3 Some Biopharmaceutical Application of MCR 3.3.1 Computational Methods of MCR Chemical Space Screening 3.4 Conclusion References 4. Solid‐Phase Heterocycle Synthesis Using Multicomponent Reactions 4.1 Introduction 4.2 Synthesis of Five‐Membered Ring Heterocycles 4.3 Synthesis of Six‐Membered Ring Heterocycles 4.4 Synthesis of Fused Heterocyclic Ring Systems 4.5 Synthesis of Heterocycles on Solid‐Supported Amino Acids 4.6 Solid‐Phase Multicomponent Construction of DNA‐Encoded Heterocycle Libraries 4.7 Miscellaneous Supports for Multicomponent Synthesis of Heterocycles 4.8 Conclusions References 5. Green Synthesis of Heterocycles Via MCRs 5.1 Introduction 5.2 High‐Order MCRs 5.3 Consecutive MCRs 5.4 MCRs Followed by Cyclization Reactions 5.5 MCRs Followed by Cycloaddition or Annulation Reactions 5.6 Conclusion and Outlook References 6. The Use of Flow Chemistry in the Multicomponent Synthesis of Heterocycles 6.1 Introduction 6.2 Multicomponent Reactions Under Standard Flow Conditions 6.3 Multicomponent Reactions with Hazardous Reagents 6.4 Multicomponent Reactions Under Special Conditions 6.4.1 Reactions with Microwave or Inductive Heating 6.4.2 Reactions with Active Packed‐Bed Columns 6.4.3 Reactions Under Other Conditions 6.5 Telescoped Reactions 6.6 Conclusions References 7. C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles 7.1 Introduction 7.2 Transition‐metal‐involved C–H Functionalization 7.2.1 Multicomponent Synthesis of Heterocycles Through C–H Functionalization 7.3 Transition‐metal‐involved C–H Functionalization 7.3.1 Multicomponent C–H Functionalization of Heterocycles 7.3.1.1 C(sp2)‐H Functionalization 7.3.1.2 C(sp3)‐H Functionalization 7.4 Transition‐metal‐free C–H Functionalization 7.4.1 Multicomponent Synthesis of Heterocycles Through C–H‐functionalization 7.4.2 Multicomponent C–H Functionalization of Heterocycles References 8. Multicomponent‐Switched Reactions in Synthesis of Heterocycles References 9. Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery 9.1 Introduction 9.2 Multicomponent Reactions 9.3 The Ugi Reaction 9.3.1 The Ugi Reaction Used in Natural Product Synthesis 9.3.2 The Ugi Reaction in FDA‐approved Drugs and Drug Candidates 9.3.2.1 Synthesis of Lipitor Using Ugi 4CR 9.3.2.2 Synthesis of Ivosidenib Utilizing Ugi 4CR 9.3.3 Rapid Lead Optimization with Ugi 4CR 9.4 The Passerini Reaction 9.4.1 The Passerini Reaction in Natural Products 9.5 Groebke–Blackburn–Bienaymé (GBB‐3CR) MCR 9.6 Gewald (G‐3CR) Reaction 9.7 The Hantzsch Dihydropyridine (DHP) Synthesis 9.7.1 FDA‐approved Hantzsch Dihydropyridines 9.7.2 Anti‐bacterial Hantzsch DHPs 9.8 The Biginelli Reaction 9.8.1 Biginelli Reactions and Natural Products 9.8.2 Biginelli DHPMs as CNS Agents 9.8.3 Biginelli Products Antitumor Capabilities 9.9 van Leusen Reaction 9.9.1 Tosmic‐mediated Cyclization Toward Nitrogen‐containing Heterocycles 9.9.2 Applications of the van Leusen Reaction 9.9.2.1 Sequential One‐pot Three‐step 3C‐van Leusen Reaction/Deprotection/Cyclization 9.9.2.2 Sequential van Leusen Reaction/Staudinger/aza‐Wittig/Cyclization 9.9.2.3 DNA‐conjugated van Leusen Reaction 9.9.3 Applications of the van Leusen Reaction in Drug Discovery 9.9.3.1 Purinergic P2X7 Receptor Antagonists 9.9.3.2 Indoleamine 2,3‐Dioxygenase (IDO1) Inhibitors 9.9.3.3 Disruptors of P53/MDM2 Protein–Protein Interactions 9.9.3.4 Disruptors of PCSK9/LDLR Protein–Protein Interactions 9.9.3.5 Inhibitors of TGFβR1 as Immuno‐oncology Therapeutics References 10. Multicomponent Syntheses of Heterocycles by Catalytic Generation of Alkynoyl Intermediates 10.1 Introduction 10.2 Catalytic Generation of Alkynones 10.3 Multicomponent Syntheses of Five‐membered Heterocycles 10.3.1 Pyrazolines 10.3.2 Pyrazoles 10.3.3 Isoxazoles 10.3.4 Triazoles 10.3.5 Thiophenes 10.3.6 Indolones 10.4 Multicomponent Syntheses of Six‐membered Heterocycles 10.4.1 Pyranones 10.4.2 Pyridines 10.4.3 Pyrimidines 10.4.4 Oxazaborinines 10.4.5 Coumarines 10.4.6 Quinolines 10.4.7 Quinoxalines 10.5 Conclusion and Outlook References 11. Synthesis of Saturated Heterocycles via Multicomponent Reactions 11.1 Introduction 11.2 Three‐membered Ring Heterocycles 11.3 Four‐membered Ring Heterocycles 11.4 Five‐membered Ring Heterocycles 11.5 Six‐membered Ring Heterocycles 11.6 Seven‐membered Ring Heterocycles 11.7 Macrocycles 11.8 Fused Heterocycles 11.9 Spiro Heterocycles References 12. Multicomponent Reactions and Asymmetric Catalysis 12.1 Introduction 12.2 Imine‐based MCRs 12.2.1 Strecker Reaction 12.2.2 Mannich Reaction 12.2.2.1 Aza‐Henry Reaction 12.2.2.2 Petasis Reaction 12.2.2.3 Aza‐Diels–Alder Via Mannich Reaction Pathway 12.2.2.4 [2 + 2 + 2]‐Cycloaddition 12.2.3 Hantzsch Reaction 12.2.4 Biginelli Reaction 12.3 Michael Addition‐based MCRs 12.3.1 Oxa‐Michael/Michael/Michael/Aldol Condensation Cascade Reactions 12.3.2 Knoevenagel–Michael Cascade Reaction 12.3.3 Michael–Henry Cascade Reaction 12.4 Isocyanide‐Based MCRs 12.4.1 Passerini Reactions 12.4.1.1 Passerini‐type Two‐component Reactions 12.4.1.2 Passerini Three‐component Reaction 12.4.2 Isocyanide‐Based [3 + 2]‐Cycloaddition 12.4.3 Ugi‐type Reactions 12.5 Conclusion References 13. Recent Trends in Metal‐catalyzed MCRs Toward Heterocycles 13.1 Introduction 13.2 Five‐membered Heterocycles with One Heteroatom 13.3 Five‐membered Systems with Two Heteroatoms 13.4 Five‐membered Systems with Three Heteroatoms 13.5 Six‐membered Heterocycles with One Heteroatom and Their Benzo‐fused Derivatives 13.6 Six‐membered O‐heterocycles and their Benzofused Derivatives 13.7 Four‐membered N‐heterocycles and Seven‐membered Benzofused N‐heterocycles 13.8 Conclusion References Index