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
