Multicomponent Reactions towards Heterocycles: Concepts and Applications

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.

Table of Contents:
Preface xi 1 Heterocycles as Inputs in MCRs: An Update 1 Ouldouz Ghashghaei, Marina Pedrola, Carmen Escolano, and Rodolfo Lavilla 1.1 Introduction 1 1.2 Concerted MCRs 1 1.3 Radical MCRs 11 1.4 Metal-catalyzed MCRs 16 1.5 Carbonyl/Imine Polar MCRs 19 1.6 Isocyanide-based MCRs 24 1.7 Miscellany Processes 33 1.8 Conclusion 36 Acknowledgment 40 References 40 2 Heterocycles and Multicomponent Polymerizations 45 Susan Sieben, Jordy M. Saya, Dean Johnson, and Romano V.A. Orru 2.1 Introduction 45 2.2 Ugi-type Multicomponent Polymerizations 48 2.3 Mannich-type Multicomponent Polymerizations 52 2.4 Biginelli-type Multicomponent Polymerizations 64 2.5 Hantzsch-type Multicomponent Polymerizations 71 2.6 Debus–Radziszewski-type Multicomponent Polymerizations 73 2.7 Other Multicomponent Polymerizations 76 2.7.1 The Cu(I)-catalyzed MCP of Diynes, Azides, and Carbodiimides/Nitriles 78 2.7.2 The Pd-catalyzed MCP of Imines, Acyl Chlorides, and N-Sulfonyl Imines 78 2.7.3 The Mercaptoacetic Acid Locking Imine Reaction 80 2.8 Conclusions and Outlook 83 References 84 3 Multicomponent Reactions in Medicinal Chemistry 91 Zefeng Wang and Alexander Domling 3.1 Introduction 91 3.1.1 Example: Protein–Protein Interaction p53-MDM2 94 3.2 Scaffolds and the Chemical Space of MCR 108 3.2.1 Marketed and Clinical Stage Drugs 110 3.3 Some Biopharmaceutical Application of MCR 121 3.3.1 Computational Methods of MCR Chemical Space Screening 122 3.4 Conclusion 127 References 127 4 Solid-Phase Heterocycle Synthesis Using Multicomponent Reactions 139 Leonardo G. Ceballos, Daylin F. Pacheco, Bernhard Westermann, and Daniel G. Rivera 4.1 Introduction 139 4.2 Synthesis of Five-Membered Ring Heterocycles 140 4.3 Synthesis of Six-Membered Ring Heterocycles 144 4.4 Synthesis of Fused Heterocyclic Ring Systems 147 4.5 Synthesis of Heterocycles on Solid-Supported Amino Acids 150 4.6 Solid-Phase Multicomponent Construction of DNA-Encoded Heterocycle Libraries 153 4.7 Miscellaneous Supports for Multicomponent Synthesis of Heterocycles 154 4.8 Conclusions 157 References 157 5 Green Synthesis of Heterocycles Via MCRs 163 Wei Zhang 5.1 Introduction 163 5.2 High-Order MCRs 164 5.3 Consecutive MCRs 176 5.4 MCRs Followed by Cyclization Reactions 187 5.5 MCRs Followed by Cycloaddition or Annulation Reactions 200 5.6 Conclusion and Outlook 207 References 207 6 The Use of Flow Chemistry in the Multicomponent Synthesis of Heterocycles 211 Chiara Lambruschini, Lisa Moni, and Andrea Basso 6.1 Introduction 211 6.2 Multicomponent Reactions Under Standard Flow Conditions 212 6.3 Multicomponent Reactions with Hazardous Reagents 217 6.4 Multicomponent Reactions Under Special Conditions 219 6.4.1 Reactions with Microwave or Inductive Heating 220 6.4.2 Reactions with Active Packed-Bed Columns 223 6.4.3 Reactions Under Other Conditions 226 6.5 Telescoped Reactions 229 6.6 Conclusions 233 References 235 7 C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles 239 Alexey A. Festa and Leonid G. Voskressensky 7.1 Introduction 239 7.2 Transition-metal-involved C–H Functionalization 240 7.2.1 Multicomponent Synthesis of Heterocycles Through C–H Functionalization 240 7.3 Transition-metal-involved C–H Functionalization 259 7.3.1 Multicomponent C–H Functionalization of Heterocycles 259 7.3.1.1 C(sp2)-H Functionalization 259 7.3.1.2 C(sp3)-H Functionalization 267 7.4 Transition-metal-free C–H Functionalization 269 7.4.1 Multicomponent Synthesis of Heterocycles Through C–H-functionalization 269 7.4.2 Multicomponent C–H Functionalization of Heterocycles 273 References 277 8 Multicomponent-Switched Reactions in Synthesis of Heterocycles 287 Valentyn A. Chebanov, Serhiy M. Desenko, Victoria V. Lipson, and Nikolay Yu. Gorobets References 329 9 Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery 339 Nathan Bedard, Alessandra Fistrovich, Kevin Schofield, Arthur Shaw, and Christopher Hulme 9.1 Introduction 339 9.2 Multicomponent Reactions 339 9.3 The Ugi Reaction 340 9.3.1 The Ugi Reaction Used in Natural Product Synthesis 343 9.3.2 The Ugi Reaction in FDA-approved Drugs and Drug Candidates 343 9.3.2.1 Synthesis of Lipitor Using Ugi 4CR 349 9.3.2.2 Synthesis of Ivosidenib Utilizing Ugi 4CR 349 9.3.3 Rapid Lead Optimization with Ugi 4CR 349 9.4 The Passerini Reaction 353 9.4.1 The Passerini Reaction in Natural Products 353 9.5 Groebke–Blackburn–Bienaymé (GBB-3CR) MCR 353 9.6 Gewald (G-3CR) Reaction 361 9.7 The Hantzsch Dihydropyridine (DHP) Synthesis 364 9.7.1 FDA-approved Hantzsch Dihydropyridines 368 9.7.2 Anti-bacterial Hantzsch DHPs 368 9.8 The Biginelli Reaction 370 9.8.1 Biginelli Reactions and Natural Products 371 9.8.2 Biginelli DHPMs as CNS Agents 371 9.8.3 Biginelli Products Antitumor Capabilities 371 9.9 van Leusen Reaction 379 9.9.1 Tosmic-mediated Cyclization Toward Nitrogen-containing Heterocycles 379 9.9.2 Applications of the van Leusen Reaction 383 9.9.2.1 Sequential One-pot Three-step 3C-van Leusen Reaction/Deprotection/Cyclization 383 9.9.2.2 Sequential van Leusen Reaction/Staudinger/aza-Wittig/Cyclization 386 9.9.2.3 DNA-conjugated van Leusen Reaction 386 9.9.3 Applications of the van Leusen Reaction in Drug Discovery 388 9.9.3.1 Purinergic P2X7 Receptor Antagonists 388 9.9.3.2 Indoleamine 2,3-Dioxygenase (IDO1) Inhibitors 391 9.9.3.3 Disruptors of P53/MDM2 Protein–Protein Interactions 392 9.9.3.4 Disruptors of PCSK9/LDLR Protein–Protein Interactions 392 9.9.3.5 Inhibitors of TGFβR1 as Immuno-oncology Therapeutics 397 References 397 10 Multicomponent Syntheses of Heterocycles by Catalytic Generation of Alkynoyl Intermediates 411 Jonas Niedballa and Thomas J.J. Müller 10.1 Introduction 411 10.2 Catalytic Generation of Alkynones 412 10.3 Multicomponent Syntheses of Five-membered Heterocycles 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 Multicomponent Syntheses of Six-membered Heterocycles 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 Conclusion and Outlook 442 References 442 11 Synthesis of Saturated Heterocycles via Multicomponent Reactions 447 Carlos K.Z. Andrade, Carlos E.M. Salvador, Thaissa P.F. Rosalba,Lucília Z.A. Correa, Luan A. Martinho, and Yuri R.B. Sousa 11.1 Introduction 447 11.2 Three-membered Ring Heterocycles 447 11.3 Four-membered Ring Heterocycles 448 11.4 Five-membered Ring Heterocycles 449 11.5 Six-membered Ring Heterocycles 456 11.6 Seven-membered Ring Heterocycles 462 11.7 Macrocycles 463 11.8 Fused Heterocycles 464 11.9 Spiro Heterocycles 482 References 485 12 Multicomponent Reactions and Asymmetric Catalysis 493 Melody E. Boëtius and Eelco Ruijter 12.1 Introduction 493 12.2 Imine-based MCRs 494 12.2.1 Strecker Reaction 494 12.2.2 Mannich Reaction 494 12.2.2.1 Aza-Henry Reaction 498 12.2.2.2 Petasis Reaction 498 12.2.2.3 Aza-Diels–Alder Via Mannich Reaction Pathway 500 12.2.2.4 [2+2+2]-Cycloaddition 504 12.2.3 Hantzsch Reaction 504 12.2.4 Biginelli Reaction 506 12.3 Michael Addition-based MCRs 509 12.3.1 Oxa-Michael/Michael/Michael/Aldol Condensation Cascade Reactions 509 12.3.2 Knoevenagel–Michael Cascade Reaction 511 12.3.3 Michael–Henry Cascade Reaction 514 12.4 Isocyanide-Based MCRs 514 12.4.1 Passerini Reactions 521 12.4.1.1 Passerini-type Two-component Reactions 521 12.4.1.2 Passerini Three-component Reaction 522 12.4.2 Isocyanide-Based [3+2]-Cycloaddition 525 12.4.3 Ugi-type Reactions 525 12.5 Conclusion 529 References 536 13 Recent Trends in Metal-catalyzed MCRs Toward Heterocycles 551 Lilia Fuentes-Morales and Luis D. Miranda 13.1 Introduction 551 13.2 Five-membered Heterocycles with One Heteroatom 552 13.3 Five-membered Systems with Two Heteroatoms 558 13.4 Five-membered Systems with Three Heteroatoms 561 13.5 Six-membered Heterocycles with One Heteroatom and Their Benzo-fused Derivatives 566 13.6 Six-membered O-heterocycles and their Benzofused Derivatives 571 13.7 Four-membered N-heterocycles and Seven-membered Benzofused N-heterocycles 574 13.8 Conclusion 576 References 576 Index 583