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Jieping Zhu received his BSc degree from Hanzhou Normal University (P.R. China) and his MSc degree from Lanzhou University (P.R. China) under the guidance of Prof. Y.-L. Li. He obtained his PhD from the Université Paris XI, France, under the supervision of Prof. H.-P. Husson and Prof. J. C. Quirion. After 18 months post-doctoral research with Prof. Sir D. H. R. Barton at Texas A&M University in USA, he joined the Institut de Chimie des Substances Naturelles (CNRS, France) as Chargé de Recherche and was promoted to Director of Research 2nd class in 2000 and then 1st class in 2006. He moved to Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland, in 2010 as a full professor. His main research interests center on the development of novel synthetic methods, their application in the synthesis of bioactive natural products, and the design of novel multicomponent reactions. He has published over 220 research articles and the well-received book "Multicomponenet Reactions" (Wiley-VCH, 2005).

Qian Wang received her BSc and MSc degree from Lanzhou University (P.R. China) under the guidance of Prof. Y. Li. She obtained her PhD degree from Chinese University of Hong Kong under the supervision of Prof. H.N.C. Wong. After several post-doctoral stays in Switzerland and in France, she joined the Institut de Chimie des Substances Naturelles (CNRS, France) as a research engineer. In 2010, she moved to Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland, as a research scientist.

Mei-Xiang Wang received a BSc degree in chemistry from Fudan University, Shanghai. After spending three years at the General Research Institute of Non-ferrous Metals (GRINM, Beijing) as a research associate, he joined the Institute of Chemistry, Chinese Academy of Sciences (ICCAS) at Beijing as a research student. He obtained his master degree and PhD in 1989 and 1992, respectively under the supervision of Prof. Z.-T. Huang. In the next 17 years, he worked at ICCAS ranking from assistant professor, associate professor to professor. During 2000 to 2004, he served as the Director of ICCAS and Center for Molecular Science, Chinese Academy of Sciences. Since May 2009, he has been a professor of chemistry at Tsinghua University in Beijing. He has published over 150 research articles and his research interests include enantioselective biotransformations using whole cell catalysts and selective organic reactions for the synthesis of natural products and bioactive compounds.

List of Contributors XIII

Preface XVII

1 General Introduction to MCRs: Past, Present, and Future 1
Alexander Dömling and AlAnod D. AlQahtani

1.1 Introduction 1

1.2 Advances in Chemistry 2

1.3 Total Syntheses 4

1.4 Applications in Pharmaceutical and Agrochemical Industry 4

1.5 Materials 10

1.6 Outlook 10

References 11

2 Discovery of MCRs 13
Eelco Ruijter and Romano V.A. Orru

2.1 General Introduction 13

2.2 The Concept 14

2.3 The Reaction Design Concept 15

2.3.1 Single Reactant Replacement 17

2.3.2 Modular Reaction Sequences 19

2.3.3 Condition-Based Divergence 21

2.3.4 Union of MCRs 23

2.4 Multicomponent Reactions and Biocatalysis 23

2.4.1 Multicomponent Reactions and (Dynamic) Enzymatic Kinetic Resolution 26

2.4.2 Multicomponent Reactions and Enzymatic Desymmetrization 29

2.5 Multicomponent Reactions in Green Pharmaceutical Production 31

2.6 Conclusions 36

Acknowledgments 36

References 36

3 Aryne-Based Multicomponent Reactions 39
Hiroto Yoshida

3.1 Introduction 39

3.2 Multicomponent Reactions of Arynes via Electrophilic Coupling 41

3.2.1 Multicomponent Reactions under Neutral Conditions 42

3.2.1.1 Isocyanide-Based Multicomponent Reactions 42

3.2.1.2 Imine-Based Multicomponent Reactions 46

3.2.1.3 Amine-Based Multicomponent Reactions 47

3.2.1.4 Carbonyl Compound-Based Multicomponent Reactions 49

3.2.1.5 Ether-Based Multicomponent Reactions 50

3.2.1.6 Miscellaneous 53

3.2.2 Multicomponent Reactions under Basic Conditions 53

3.3 Transition Metal-Catalyzed Multicomponent Reactions of Arynes 60

3.3.1 Annulations 60

3.3.2 Cross-Coupling-Type Reactions 65

3.3.3 Mizoroki–Heck-Type Reactions 65

3.3.4 Insertion into σ-Bond 65

3.4 Concluding Remarks 69

References 69

4 Ugi–Smiles and Passerini–Smiles Couplings 73
Laurent El Kaïm and Laurence Grimaud

4.1 Introduction 73

4.1.1 Carboxylic Acid Surrogates in Ugi Reactions 75

4.1.2 Smiles Rearrangements 76

4.2 Scope and Limitations 77

4.2.1 Phenols and Thiophenols 77

4.2.2 Six-Membered Ring Hydroxy Heteroaromatics and Related Mercaptans 84

4.2.3 Five-Membered Ring Hydroxy Heteroaromatic and Related Mercaptans 88

4.2.4 Related Couplings with Enol Derivatives 90

4.2.5 The Joullié–Smiles Coupling 90

4.2.6 The Passerini–Smiles Reaction 91

4.3 Ugi–Smiles Postcondensations 94

4.3.1 Postcondensations Involving Reduction of the Nitro Group 94

4.3.2 Transformations of Ugi–Smiles Thioamides 96

4.3.3 Postcondensations Involving Transition Metal-Catalyzed Processes 97

4.3.4 Reactivity of the Peptidyl Unit 101

4.3.5 Radical Reactions 103

4.3.6 Cycloaddition 103

4.4 Conclusions 105

References 105

5 1,3-Dicarbonyls in Multicomponent Reactions 109
Xavier Bugaut, Thierry Constantieux, Yoann Coquerel, and Jean Rodriguez

5.1 Introduction 109

5.2 Achiral and Racemic MCRs 111

5.2.1 Involving One Pronucleophilic Reactive Site 111

5.2.2 Involving Two Reactive Sites 115

5.2.2.1 Two Nucleophilic Sites 115

5.2.2.2 One Pronucleophilic Site and One Electrophilic Site 120

5.2.3 Involving Three Reactive Sites 134

5.2.4 Involving Four Reactive Sites 139

5.3 Enantioselective MCRs 142

5.3.1 Involving One Reactive Site 143

5.3.2 Involving Two Reactive Sites 146

5.3.3 Involving Three Reactive Sites 149

5.4 Conclusions and Outlook 150

References 151

6 Functionalization of Heterocycles by MCRs 159
Esther Vicente-García, Nicola Kielland, and Rodolfo Lavilla

6.1 Introduction 159

6.2 Mannich-Type Reactions and Related Processes 160

6.3 β-Dicarbonyl Chemistry 164

6.4 Hetero-Diels–Alder Cycloadditions and Related Processes 166

6.5 Metal-Mediated Processes 168

6.6 Isocyanide-Based Reactions 171

6.7 Dipole-Mediated Processes 175

6.8 Conclusions 176

Acknowledgments 178

References 178

7 Diazoacetate and Related Metal-Stabilized Carbene Species in MCRs 183
Dong Xing and Wenhao Hu

7.1 Introduction 183

7.2 MCRs via Carbonyl or Azomethine Ylide-Involved 1,3-Dipolar Cycloadditions 184

7.2.1 Azomethine Ylide 184

7.2.2 Carbonyl Ylide 185

7.3 MCRs via Electrophilic Trapping of Protic Onium Ylides 187

7.3.1 Initial Development 187

7.3.2 Asymmetric Examples 190

7.3.2.1 Chiral Reagent Induction 190

7.3.2.2 Chiral Dirhodium(II) Catalysis 190

7.3.2.3 Enantioselective Synergistic Catalysis 190

7.3.3 MCRs Followed by Tandem Cyclizations 196

7.4 MCRs via Electrophilic Trapping of Zwitterionic Intermediates 198

7.5 MCRs via Metal Carbene Migratory Insertion 199

7.6 Summary and Outlook 203

References 204

8 Metal-Catalyzed Multicomponent Synthesis of Heterocycles 207
Fabio Lorenzini, Jevgenijs Tjutrins, Jeffrey S. Quesnel, and Bruce A. Arndtsen

8.1 Introduction 207

8.2 Multicomponent Cross-Coupling and Carbonylation Reactions 208

8.2.1 Cyclization with Alkyne- or Alkene-Containing Nucleophiles 208

8.2.2 Cyclization via Palladium–Allyl Complexes 210

8.2.3 Fused-Ring Heterocycles for ortho-Substituted Arene Building Blocks 211

8.2.4 Multicomponent Cyclocarbonylations 214

8.2.5 Cyclization of Cross-Coupling Reaction Products 216

8.2.6 C-H Functionalization in Multicomponent Reactions 218

8.3 Metallacycles in Multicomponent Reactions 221

8.4 Multicomponent Reactions via 1,3-Dipolar Cycloaddition 223

8.5 Concluding Remarks 227

References 227

9 Macrocycles from Multicomponent Reactions 231
Ludger A. Wessjohann, Ricardo A.W. Neves Filho, Alfredo R. Puentes, and Micjel C. Morejon

9.1 Introduction 231

9.2 IMCR-Based Macrocyclizations of Single Bifunctional Building Blocks 237

9.3 Multiple MCR-Based Macrocyclizations of Bifunctional Building Blocks 245

9.4 IMCR-Based Macrocyclizations of Trifunctionalized Building Blocks (MiB-3D) 256

9.5 Sequential IMCR-Based Macrocyclizations of Multiple Bifunctional Building Blocks 259

9.6 Final Remarks and Future Perspectives 261

References 261

10 Multicomponent Reactions under Oxidative Conditions 265
Andrea Basso, Lisa Moni, and Renata Riva

10.1 Introduction 265

10.2 Multicomponent Reactions Involving In Situ Oxidation of One Substrate 266

10.2.1 Isocyanide-Based Multicomponent Reactions 266

10.2.1.1 Passerini Reactions 266

10.2.1.2 Ugi Reactions with In Situ Oxidation of Alcohols 271

10.2.1.3 Ugi Reaction with In Situ Oxidation of Secondary Amines 273

10.2.1.4 Ugi–Smiles Reaction with In Situ Oxidation of Secondary Amines 275

10.2.1.5 Ugi-Type Reactions by In Situ Oxidation of Tertiary Amines 277

10.2.1.6 Synthesis of Other Derivatives 279

10.2.2 Other Multicomponent Reactions 280

10.3 Multicomponent Reactions Involving Oxidation of a Reaction Intermediate 284

10.3.1 Reactions without Transition Metal-Mediated Oxidation 285

10.3.2 Reactions Mediated by Transition Metal Catalysis 292

10.4 Multicomponent Reactions Involving Oxidants as Lewis Acids 295

10.5 Conclusions 297

References 297

11 Allenes in Multicomponent Synthesis of Heterocycles 301
Hans-Ulrich Reissig and Reinhold Zimmer

11.1 Introduction 301

11.2 Reactions with 1,2-Propadiene and Unactivated Allenes 302

11.2.1 Palladium-Catalyzed Multicomponent Reactions 302

11.2.2 Copper-, Nickel-, and Rhodium-Promoted Multicomponent Reactions 310

11.2.3 Multicomponent Reactions without Transition Metals 314

11.3 Reactions with Acceptor-Substituted Allenes 316

11.3.1 Catalyzed Multicomponent Reactions 316

11.3.2 Uncatalyzed Multicomponent Reactions 318

11.4 Reactions with Donor-Substituted Allenes 323

11.5 Conclusions 329

List of Abbreviations 329

References 329

12 Alkynes in Multicomponent Synthesis of Heterocycles 333
Thomas J.J. Müller and Konstantin Deilhof

12.1 Introduction 333

12.2 σ-Nucleophilic Reactivity of Alkynes 335

12.2.1 Acetylide Additions to Electrophiles 335

12.2.1.1 Alkyne–Aldehyde–Amine Condensation – A3-Coupling 335

12.2.1.2 Alkyne–(Hetero)Aryl Halide (Sonogashira) Coupling as Key Reaction 337

12.2.2 Conversion of Terminal Alkynes into Electrophiles as Key Reactions 341

12.3 π-Nucleophilic Reactivity of Alkynes 345

12.4 Alkynes as Electrophilic Partners 351

12.5 Alkynes in Cycloadditions 356

12.5.1 Alkynes as Dipolarophiles 356

12.5.2 Alkynes in Cu(I)-Catalyzed 1,3-Dipolar Azide–Alkyne Cycloaddition 358

12.5.3 Alkynes as Dienophiles in MCRs 366

12.6 Alkynes as Reaction Partners in Organometallic MCRs 370

12.7 Conclusions 374

List of Abbreviations 374

Acknowledgment 375

References 375

13 Anhydride-Based Multicomponent Reactions 379
Kevin S. Martin, Jared T. Shaw, and Ashkaan Younai

13.1 Introduction 379

13.2 Quinolones and Related Heterocycles from Homophthalic and Isatoic Anhydrides 380

13.2.1 Introduction: Reactivity of Homophthalic and Isatoic Anhydrides 380

13.2.2 Imine–Anhydride Reactions of Homophthalic Anhydride 380

13.2.3 MCRs Employing Homophthalic Anhydride 382

13.2.4 Imine–Anhydride Reactions of Isatoic Anhydride 383

13.3 α,β-Unsaturated Cyclic Anhydrides: MCRs Involving Conjugate Addition and Cycloaddition Reactions 385

13.3.1 Maleic Anhydride MCRs 385

13.3.2 MCRs of Itaconic Anhydrides 388

13.3.3 Diels–Alder Reactions 390

13.4 MCRs of Cyclic Anhydrides in Annulation Reactions and Related Processes 392

13.4.1 MCR-Based Annulations: Succinic and Phthalic Anhydrides 393

13.5 MCRs of Acyclic Anhydrides 395

13.6 Conclusions 398

References 399

14 Free-Radical Multicomponent Processes 401
Virginie Liautard and Yannick Landais

14.1 Introduction 401

14.2 MCRs Involving Addition Across Olefin C.C Bonds 402

14.2.1 Addition of Aryl Radicals to Olefins 402

14.2.2 MCRs Using Sulfonyl Derivatives as Terminal Trap 404

14.2.3 Carboallylation of Electron-Poor Olefins 406

14.2.4 Carbohydroxylation, Sulfenylation, and Phosphorylation of Olefins 407

14.2.5 Radical Addition to Olefins Using Photoredox Catalysis 410

14.2.6 MCRs Based on Radical–Polar Crossover Processes 414

14.3 Free-Radical Carbonylation 419

14.3.1 Alkyl Halide Carbonylation 419

14.3.2 Metal-Mediated Atom-Transfer Radical Carbonylation 420

14.3.3 Alkane Carbonylation 421

14.3.4 Miscellaneous Carbonylation Reactions 423

14.4 Free-Radical Oxygenation 424

14.5 MCRs Involving Addition Across π-C.N Bonds 427

14.5.1 Free-Radical Strecker Process 427

14.5.2 Free-Radical Mannich-Type Processes 429

14.6 Miscellaneous Free-Radical Multicomponent Reactions 432

14.7 Conclusions 434

References 435

15 Chiral Phosphoric Acid-Catalyzed Asymmetric Multicomponent Reactions 439
Xiang Wu and Liu-Zhu Gong

15.1 Introduction 439

15.2 Mannich Reaction 439

15.3 Ugi-Type Reaction 442

15.4 Biginelli Reaction 444

15.5 Aza-Diels–Alder Reaction 446

15.6 1,3-Dipolar Cycloaddition 454

15.7 Hantzsch Dihydropyridine Synthesis 458

15.8 The Combination of Metal and Chiral Phosphoric Acid for Multicomponent Reaction 459

15.9 Other Phosphoric Acid-Catalyzed Multicomponent Reactions 465

15.10 Summary 467

References 467

Index 471