Multicomponent Reactions in Organic Synthesis
Coordonnateurs : Zhu Jieping, Wang Qian, Wang Meixiang
Edited by the leading experts and with a list of authors reading like a "who's who" in multicomponent reaction chemistry, this is definitely a must-have for every synthetic organic chemist as well as medicinal chemists working in academia and pharmaceutical companies.
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
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
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