Multicomponent Reactions

Raquel P. Herrera, PhD, is Tenured Scientist of the Spanish National Research Council (CSIC) at the ISQCH-University of Zaragoza. Her research interests are focused on asymmetric organocatalysis and its applications. Eugenia Marqués-López, PhD, is an assistant professor at the University of Zaragoza. She performs her research on new catalytic methods, mainly based on asymmetric organocatalysis at the Institute of Chemical Synthesis and Homogeneous Catalysis (ISQCH-CSIC).

• List of Contributors xiiPreface xiiiList of Abbreviations xv1 Introduction: Multicomponent Strategies 1General Introduction 11.1 Basic Concepts 31.1.1 Clarifying Terminology: One‐Pot, Domino/Cascade, Tandem, and MCRs 31.1.2 Using Rational Design to Discover New MCRs 31.1.3 Discovering New MCRs with Automated Combinatorial Reaction Finding 51.1.4 Computational and Analytical Tools to Study MCRs 71.1.5 Diversity‐Oriented Synthesis and Biology‐Oriented Synthesis 71.1.6 Optimization of MCRs 71.2 Catalysis in MCRs and Various Synthetic Approaches 81.2.1 Organocatalysis in MCRs 81.2.2 Organometallic Catalysis in MCRs 81.2.3 Biocatalysis in MCRs 81.2.4 Combining Different Types of Catalysis 81.2.5 Other Methods 91.3 Green Chemistry 101.3.1 Atom Economy 101.3.2 Using Green Solvents 111.3.3 Solventless MCRs 111.3.4 Heterogeneous Catalysis in MCRs 111.4 Importance and Evolution 12References 122 Organocatalytic Asymmetric Multicomponent Reactions 162.1 Introduction 162.2 Three‐Component Mannich Reaction 172.3 Cycloaddition Reaction 262.4 Organocatalytic Multicomponent Domino Asymmetric Reactions 292.4.1 Michael‐Type Multicomponent Process: Cyclic Carbon Frameworks 302.4.2 Miscellaneous Domino Reactions 492.5 Development of Drug Intermediates 582.6 Miscellaneous Reaction 652.7 Conclusions 66References 663 Metal‐Catalyzed Multicomponent Reactions 723.1 Introduction 723.2 Palladium‐Catalyzed Mcrs 723.2.1 Palladium‐Catalyzed Carbonylation Reactions 723.2.2 Palladium‐Catalyzed Mcrs Involving Isocyanides 743.2.3 Carbopalladation of Unsaturated C─C π‐Components 763.2.4 Amines as Building Blocks 803.3 Nickel‐Catalyzed Mcrs 833.3.1 Nickel‐Catalyzed Cross‐Trimerization of Alkynes 833.3.2 Nickel‐Catalyzed π‐Systems Couplings 863.3.3 Ni‐Catalyzed Reductive Conjugate Addition 883.4 Group 11 Metal‐Catalyzed Mcrs 913.4.1 Copper‐Catalyzed Azide–Alkyne Cycloaddition 913.4.2 A 3 ‐Coupling 943.4.3 Miscellaneous 1013.5 Rhodium‐Catalyzed Mcrs 1013.5.1 Rhodium‐Catalyzed Mcrs via Onium Ylide Intermediates 1013.5.2 Rhodium‐Catalyzed Three‐Component Cross‐Addition Reactions 1083.6 Group 8 Metal‐Catalyzed Mcrs 1113.6.1 Iron‐Catalyzed Mcrs 1113.6.2 Ruthenium‐Catalyzed Mcrs 1133.7 Conclusions 117References 1174 Multicomponent Reactions with Organoboron Compounds 1274.1 Introduction 1274.2 Catalytic Mcrs with Organoboron Compounds 1274.2.1 Cobalt‐Catalyzed Mcrs Containing Organoboron Compounds 1274.2.2 Palladium‐Catalyzed Mcrs Containing Organoboron Compounds 1284.3 Multicomponent Assembly of Organoboron Compounds: Efficient Approach to Supramolecular Chemistry 1284.4 Multicomponent Petasis‐Borono–Mannich Reaction 1324.4.1 Organocatalytic Enantioselective Petasis‐Type Reaction 1334.4.2 Metal‐Catalyzed Four‐Component PBM Reaction 1344.4.3 Synthetic Applications of PBM 1354.5 Allenylborates in Mcrs 1404.6 Multicomponent Hetero‐Diels–Alder/Allylboration 1414.6.1 Chiral Catalyzed One‐Pot [4 + 2] Cycloaddition/Allylboration 1414.6.2 Polymer‐Supported Mcrs 1414.7 Palladium‐Catalyzed Asymmetric Allene Diboration/α‐Aminoallylation 1434.8 Synthetic Applications of Boron‐Based Mcrs 1434.9 Conclusion 146References 1465 Carbene‐Promoted Multicomponent Reactions 1495.1 Introduction 1495.2 Mcrs Involving Carbenes as Key Components 1495.2.1 Mcrs of Dimethoxycarbenes 1495.2.2 Mcrs of NHCs 1505.2.3 FCCs as Reagents: Approach to Highly Substituted Carbo‐ and Heterocycles 1585.3 Mcrs Involving Carbenes as Catalysts 1625.3.1 Nhcs as Organocatalysts in Mcrs 1625.3.2 Metal‐Catalyzed Mcrs Involving Nhcs as Ligands 1745.4 Synthetic Utility 1905.4.1 Carbenes as Components 1905.4.2 Nhcs as Catalysts/Ligand 1905.5 Conclusion 193References 1936 Multicomponent Reactions in the Synthesis of Target Molecules 1986.1 Introduction 1986.2 Mcrs in Drug Discovery and for the Synthesis of Biologically Important Molecules 1986.3 Synthesis of Natural Products in an Efficient Manner 2006.4 Heterocycles as Key Substrates in Mcrs 2056.4.1 Synthesis of Indoles 2066.4.2 Synthesis of Fused Polyheterocycles 2116.4.3 Synthesis of Spiro‐Type Polyheterocyclic Compounds 2176.4.4 Synthesis of DHPMs and Thiazines 2246.4.5 Synthesis of Pyrroles 2296.5 Amino Acid Derivatives by Mcrs 2336.6 Industrial Applications 2366.7 Conclusion 239References 2397 Recent Advances in the Ugi Multicomponent Reactions 2477.1 Introduction 2477.2 Ugi Three‐Component Reactions 2477.3 Ugi Four‐Component Reactions 2547.4 Five‐, Six‐, Seven‐, and Eight‐Component Reactions Based on the Ugi Reaction 2587.5 Ugi Postmodification Processes 2657.6 Ugi–Smiles Approach 2707.7 Ugi–Smiles Postmodification Processes 2747.8 Conclusion 278References 2788 Passerini Multicomponent Reactions 2838.1 Introduction 2838.2 O‐Alkylative and Silylative Passerini Three‐Component Reactions 2838.2.1 O‐Arylative Passerini Three‐Component Reactions 2838.2.2 Metal‐Catalyzed O‐Alkylative Passerini Three‐Component Reactions 2848.2.3 O‐Silylative Passerini Three‐Component Reactions 2858.3 Passerini 3CR Under Oxidative Conditions 2868.3.1 Metal‐Catalyzed Oxidation Passerini 3CR 2868.4 Synthesis of Macrocycles by a Passerini Reaction 2878.5 Enantioselective Metal‐Catalyzed Passerini Reaction 2908.6 Synthesis of Pharmacologically Important Peptidomimetics 2928.7 Multicomponent Passerini Approach to Important Targets 2938.8 α‐Hydroxycarboxamide, an Important Intermediate for Chemical Synthesis 2978.9 Passerini 3CR under Eco‐Friendly Reaction Conditions 2998.9.1 Aqueous Media 2998.9.2 Ionic Liquids and Peg 2998.9.3 Solvent‐Free Conditions 3008.9.4 MW‐Assisted Passerini Reaction 3008.10 Conclusions 301References 3029 Biginelli Multicomponent Reactions 3069.1 Introduction 3069.2 Mechanism 3069.3 Chiral Lewis‐ and Brønsted Acid‐Catalyzed Biginelli Reactions 3089.4 Brønsted Base‐Catalyzed One‐Pot Three‐Component Biginelli‐Type Reactions 3109.5 Organocatalytic Enantioselective Biginelli Reactions 3119.5.1 Chiral Brønsted Acid‐Organocatalyzed Biginelli Reactions 3119.5.2 Aminocatalyzed Biginelli Reactions 3139.6 Variations of the Traditional Biginelli Condensation 3189.7 Heterocycles beyond the DHPMs 3189.8 Important Targets 3199.9 Conclusion 325References 32510 Bucherer–Bergs And Strecker Multicomponent Reactions 33110.1 Bucherer–Bergs Reaction 33110.1.1 Introduction 33110.1.2 Comparative Stereochemical Course 33110.1.3 Synthesis of Five‐Membered Heterocycles 33110.1.4 Metal‐Catalyzed Synthesis of Hydantoin Derivatives 33410.1.5 Modified Bucherer–Bergs Reaction 33610.1.6 Synthesis of α‐Amino Acids via Hydantoin Intermediate 33810.1.7 Synthesis of Diaminodicarboxylic Acids 33910.2 Mc Strecker Reaction 34010.2.1 Introduction 34010.2.2 MC Strecker Reaction Using Aldehyde 34110.2.3 Strecker‐Type Reaction Using Ketones 34410.2.4 Catalyst‐Free Strecker Reactions in Water 34410.2.5 Catalyst‐Free Strecker Reactions under Solvent‐Free Conditions 34710.2.6 Metal‐Catalyzed Strecker‐Type Reaction 34810.2.7 Organocatalytic Mc Strecker Reaction 34810.2.8 Efficient Heterogeneous Catalysis for the Synthesis of α‐Aminonitriles 35110.2.9 Synthetic Utility 35110.3 Conclusions 352References 35211 Unusual Approach for Multicomponent Reactions 35811.1 Zeolite‐Catalyzed Mcrs 35811.1.1 Heterogeneous Hybrid Catalyst 35811.2 Mw‐Assisted Three‐Component Reactions 35911.2.1 Synthesis of Natural Products 36111.3 Ionic Liquid‐Promoted Mcrs 36311.4 Mcrs under Solvent‐Free Conditions 36411.5 Mcrs in Aqueous Media 37011.6 High‐Pressure Promoted Mcrs 37311.7 Three‐Component Reactions Using Supported Reagents 37511.8 Conclusion 376References 37712 Essential Multicomponent Reactions I 38212.1 Radziszewski Reactions (Imidazole Synthesis) 38212.1.1 Introduction 38212.1.2 Modified Radziszewski Reactions: Efficient Tool for the Synthesis of Substituted Imidazoles 38212.2 Sakurai Mcrs 38812.2.1 Introduction 38812.2.2 Synthesis of Homoallylic Ethers 38812.2.3 Synthesis of Homoallylic Amines: Aza‐Sakurai 39112.3 Gewald Mcrs 39412.3.1 Introduction 39412.3.2 Easy Protocol for Synthesizing 2‐Aminothiophene Derivatives 39512.4 Kabachnik–Fields Reactions 39612.4.1 Introduction 39612.4.2 Straightforward Synthesis of α‐Amino Phosphonates 39812.5 Conclusion 401References 40313 Essential Multicomponent Reactions Ii 41613.1 Knoevenagel Reactions in Multicomponent Syntheses 41613.1.1 Introduction 41613.1.2 Domino Knoevenagel/Hetero‐Diels–Alder Reaction and Pyran Syntheses 41913.1.3 Useful Syntheses of Heterocycles: 1,4‐Dihydropyridine and Diazine Syntheses 42713.1.4 Useful Syntheses of Heterocycles: Various Heterocyclic Scaffolds 43713.1.5 Other Knoevenagel Combinations 44213.2 Yonemitsu‐Type Trimolecular Condensations 44813.2.1 Introduction and Mechanistic Aspects 44813.2.2 Applications of the Original Yonemitsu Trimolecular Condensation 44913.2.3 Yonemitsu‐Type Reactions and Tetramolecular Condensations 45113.3 Mcrs Involving Meldrum’s Acid 45713.3.1 Introduction 45713.3.2 Applications and DOS 45813.3.3 Meldrum’s Acid as Synthetic Equivalent 46113.3.4 Meldrum’s Acid as Malonic Acid Equivalent 46413.4 Povarov Mcrs 46613.4.1 Introduction 46613.4.2 Mechanistic Aspects 46613.4.3 Efficient Synthesis of 1,2,3,4‐Tetrahydroquinolines 46813.4.4 Efficient Synthesis of Quinolines 47013.5 Hantzsch Multicomponent Synthesis of Heterocycles 47213.5.1 Introduction 47213.5.2 Catalysis and Mechanism 47413.5.3 Syntheses of 1,4‐Dihydropyridines and Their Oxidation to Pyridines 47513.5.4 Multicomponent Pyrrole Syntheses 48013.6 Conclusions 482References 482Index 496