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

About the Author

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.