Multicomponent Reactions: Concepts and Applications for Design and Synthesis

Addressing a dynamic aspect of organic chemistry, this book describes synthetic strategies and applications for multicomponent reactions – including key routes for synthesizing complex molecules. •    Illustrates the crucial role and the important utility of multicomponent reactions (MCRs) to organic syntheses •    Compiles novel and efficient synthetic multicomponent procedures to give readers a complete picture of this class of organic reactions •    Helps readers to design efficient and practical transformations using multicomponent reaction strategies •    Describes reaction background, applications to synthesize complex molecules and drugs, and reaction mechanisms

Table of Contents:
List of Contributors xii Preface xiii List of Abbreviations xv 1 Introduction: Multicomponent Strategies 1 General Introduction 1 1.1 Basic Concepts 3 1.1.1 Clarifying Terminology: One]Pot, Domino/Cascade, Tandem, and MCRs 3 1.1.2 Using Rational Design to Discover New MCRs 3 1.1.3 Discovering New MCRs with Automated Combinatorial Reaction Finding 5 1.1.4 Computational and Analytical Tools to Study MCRs 7 1.1.5 Diversity]Oriented Synthesis and Biology]Oriented Synthesis 7 1.1.6 Optimization of MCRs 7 1.2 Catalysis in MCRs and Various Synthetic Approaches 8 1.2.1 Organocatalysis in MCRs 8 1.2.2 Organometallic Catalysis in MCRs 8 1.2.3 Biocatalysis in MCRs 8 1.2.4 Combining Different Types of Catalysis 8 1.2.5 Other Methods 9 1.3 Green Chemistry 10 1.3.1 Atom Economy 10 1.3.2 Using Green Solvents 11 1.3.3 Solventless MCRs 11 1.3.4 Heterogeneous Catalysis in MCRs 11 1.4 Importance and Evolution 12 References 12 2 Organocatalytic Asymmetric Multicomponent Reactions 16 2.1 Introduction 16 2.2 Three]Component Mannich Reaction 17 2.3 Cycloaddition Reaction 26 2.4 Organocatalytic Multicomponent Domino Asymmetric Reactions 29 2.4.1 Michael]Type Multicomponent Process: Cyclic Carbon Frameworks 30 2.4.2 Miscellaneous Domino Reactions 49 2.5 Development of Drug Intermediates 58 2.6 Miscellaneous Reaction 65 2.7 Conclusions 66 References 66 3 Metal]Catalyzed Multicomponent Reactions 72 3.1 Introduction 72 3.2 Palladium]Catalyzed Mcrs 72 3.2.1 Palladium]Catalyzed Carbonylation Reactions 72 3.2.2 Palladium]Catalyzed Mcrs Involving Isocyanides 74 3.2.3 Carbopalladation of Unsaturated C„ŸC π]Components 76 3.2.4 Amines as Building Blocks 80 3.3 Nickel]Catalyzed Mcrs 83 3.3.1 Nickel]Catalyzed Cross]Trimerization of Alkynes 83 3.3.2 Nickel]Catalyzed π]Systems Couplings 86 3.3.3 Ni]Catalyzed Reductive Conjugate Addition 88 3.4 Group 11 Metal]Catalyzed Mcrs 91 3.4.1 Copper]Catalyzed Azide–Alkyne Cycloaddition 91 3.4.2 A3]Coupling 94 3.4.3 Miscellaneous 101 3.5 Rhodium]Catalyzed Mcrs 101 3.5.1 Rhodium]Catalyzed Mcrs via Onium Ylide Intermediates 101 3.5.2 Rhodium]Catalyzed Three]Component Cross]Addition Reactions 108 3.6 Group 8 Metal]Catalyzed Mcrs 111 3.6.1 Iron]Catalyzed Mcrs 111 3.6.2 Ruthenium]Catalyzed Mcrs 113 3.7 Conclusions 117 References 117 4 Multicomponent Reactions with Organoboron Compounds 127 4.1 Introduction 127 4.2 Catalytic Mcrs with Organoboron Compounds 127 4.2.1 Cobalt]Catalyzed Mcrs Containing Organoboron Compounds 127 4.2.2 Palladium]Catalyzed Mcrs Containing Organoboron Compounds 128 4.3 Multicomponent Assembly of Organoboron Compounds: Efficient Approach to Supramolecular Chemistry 128 4.4 Multicomponent Petasis]Borono–Mannich Reaction 132 4.4.1 Organocatalytic Enantioselective Petasis]Type Reaction 133 4.4.2 Metal]Catalyzed Four]Component PBM Reaction 134 4.4.3 Synthetic Applications of PBM 135 4.5 Allenylborates in Mcrs 140 4.6 Multicomponent Hetero]Diels–Alder/Allylboration 141 4.6.1 Chiral Catalyzed One]Pot [4 + 2] Cycloaddition/Allylboration 141 4.6.2 Polymer]Supported Mcrs 141 4.7 Palladium]Catalyzed Asymmetric Allene Diboration/α]Aminoallylation 143 4.8 Synthetic Applications of Boron]Based Mcrs 143 4.9 Conclusion 146 References 146 5 Carbene]Promoted Multicomponent Reactions 149 5.1 Introduction 149 5.2 Mcrs Involving Carbenes as Key Components 149 5.2.1 Mcrs of Dimethoxycarbenes 149 5.2.2 Mcrs of NHCs 150 5.2.3 FCCs as Reagents: Approach to Highly Substituted Carbo] and Heterocycles 158 5.3 Mcrs Involving Carbenes as Catalysts 162 5.3.1 Nhcs as Organocatalysts in Mcrs 162 5.3.2 Metal]Catalyzed Mcrs Involving Nhcs as Ligands 174 5.4 Synthetic Utility 190 5.4.1 Carbenes as Components 190 5.4.2 Nhcs as Catalysts/Ligand 190 5.5 Conclusion 193 References 193 6 Multicomponent Reactions in the Synthesis of Target Molecules 198 6.1 Introduction 198 6.2 Mcrs in Drug Discovery and for the Synthesis of Biologically Important Molecules 198 6.3 Synthesis of Natural Products in an Efficient Manner 200 6.4 Heterocycles as Key Substrates in Mcrs 205 6.4.1 Synthesis of Indoles 206 6.4.2 Synthesis of Fused Polyheterocycles 211 6.4.3 Synthesis of Spiro]Type Polyheterocyclic Compounds 217 6.4.4 Synthesis of DHPMs and Thiazines 224 6.4.5 Synthesis of Pyrroles 229 6.5 Amino Acid Derivatives by Mcrs 233 6.6 Industrial Applications 236 6.7 Conclusion 239 References 239 7 Recent Advances in the Ugi Multicomponent Reactions 247 7.1 Introduction 247 7.2 Ugi Three]Component Reactions 247 7.3 Ugi Four]Component Reactions 254 7.4 Five], Six], Seven], and Eight]Component Reactions Based on the Ugi Reaction 258 7.5 Ugi Postmodification Processes 265 7.6 Ugi–Smiles Approach 270 7.7 Ugi–Smiles Postmodification Processes 274 7.8 Conclusion 278 References 278 8 Passerini Multicomponent Reactions 283 8.1 Introduction 283 8.2 O]Alkylative and Silylative Passerini Three]Component Reactions 283 8.2.1 O]Arylative Passerini Three]Component Reactions 283 8.2.2 Metal]Catalyzed O]Alkylative Passerini Three]Component Reactions 284 8.2.3 O]Silylative Passerini Three]Component Reactions 285 8.3 Passerini 3CR Under Oxidative Conditions 286 8.3.1 Metal]Catalyzed Oxidation Passerini 3CR 286 8.4 Synthesis of Macrocycles by a Passerini Reaction 287 8.5 Enantioselective Metal]Catalyzed Passerini Reaction 290 8.6 Synthesis of Pharmacologically Important Peptidomimetics 292 8.7 Multicomponent Passerini Approach to Important Targets 293 8.8 α]Hydroxycarboxamide, an Important Intermediate for Chemical Synthesis 297 8.9 Passerini 3CR under Eco]Friendly Reaction Conditions 299 8.9.1 Aqueous Media 299 8.9.2 Ionic Liquids and Peg 299 8.9.3 Solvent]Free Conditions 300 8.9.4 MW]Assisted Passerini Reaction 300 8.10 Conclusions 301 References 302 9 Biginelli Multicomponent Reactions 306 9.1 Introduction 306 9.2 Mechanism 306 9.3 Chiral Lewis] and Brønsted Acid]Catalyzed Biginelli Reactions 308 9.4 Brønsted Base]Catalyzed One]Pot Three]Component Biginelli]Type Reactions 310 9.5 Organocatalytic Enantioselective Biginelli Reactions 311 9.5.1 Chiral Brønsted Acid]Organocatalyzed Biginelli Reactions 311 9.5.2 Aminocatalyzed Biginelli Reactions 313 9.6 Variations of the Traditional Biginelli Condensation 318 9.7 Heterocycles beyond the DHPMs 318 9.8 Important Targets 319 9.9 Conclusion 325 References 325 10 Bucherer–Bergs And Strecker Multicomponent Reactions 331 10.1 Bucherer–Bergs Reaction 331 10.1.1 Introduction 331 10.1.2 Comparative Stereochemical Course 331 10.1.3 Synthesis of Five]Membered Heterocycles 331 10.1.4 Metal]Catalyzed Synthesis of Hydantoin Derivatives 334 10.1.5 Modified Bucherer–Bergs Reaction 336 10.1.6 Synthesis of α]Amino Acids via Hydantoin Intermediate 338 10.1.7 Synthesis of Diaminodicarboxylic Acids 339 10.2 Mc Strecker Reaction 340 10.2.1 Introduction 340 10.2.2 MC Strecker Reaction Using Aldehyde 341 10.2.3 Strecker]Type Reaction Using Ketones 344 10.2.4 Catalyst]Free Strecker Reactions in Water 344 10.2.5 Catalyst]Free Strecker Reactions under Solvent]Free Conditions 347 10.2.6 Metal]Catalyzed Strecker]Type Reaction 348 10.2.7 Organocatalytic Mc Strecker Reaction 348 10.2.8 Efficient Heterogeneous Catalysis for the Synthesis of α]Aminonitriles 351 10.2.9 Synthetic Utility 351 10.3 Conclusions 352 References 352 11 Unusual Approach for Multicomponent Reactions 358 11.1 Zeolite]Catalyzed Mcrs 358 11.1.1 Heterogeneous Hybrid Catalyst 358 11.2 Mw]Assisted Three]Component Reactions 359 11.2.1 Synthesis of Natural Products 361 11.3 Ionic Liquid]Promoted Mcrs 363 11.4 Mcrs under Solvent]Free Conditions 364 11.5 Mcrs in Aqueous Media 370 11.6 High]Pressure Promoted Mcrs 373 11.7 Three]Component Reactions Using Supported Reagents 375 11.8 Conclusion 376 References 377 12 E ssential Multicomponent Reactions I 382 12.1 Radziszewski Reactions (Imidazole Synthesis) 382 12.1.1 Introduction 382 12.1.2 Modified Radziszewski Reactions: Efficient Tool for the Synthesis of Substituted Imidazoles 382 12.2 Sakurai Mcrs 388 12.2.1 Introduction 388 12.2.2 Synthesis of Homoallylic Ethers 388 12.2.3 Synthesis of Homoallylic Amines: Aza]Sakurai 391 12.3 Gewald Mcrs 394 12.3.1 Introduction 394 12.3.2 Easy Protocol for Synthesizing 2]Aminothiophene Derivatives 395 12.4 Kabachnik–Fields Reactions 396 12.4.1 Introduction 396 12.4.2 Straightforward Synthesis of α]Amino Phosphonates 398 12.5 Conclusion 401 References 403 13 E ssential Multicomponent Reactions Ii 416 13.1 Knoevenagel Reactions in Multicomponent Syntheses 416 13.1.1 Introduction 416 13.1.2 Domino Knoevenagel/Hetero]Diels–Alder Reaction and Pyran Syntheses 419 13.1.3 Useful Syntheses of Heterocycles: 1,4]Dihydropyridine and Diazine Syntheses 427 13.1.4 Useful Syntheses of Heterocycles: Various Heterocyclic Scaffolds 437 13.1.5 Other Knoevenagel Combinations 442 13.2 Yonemitsu]Type Trimolecular Condensations 448 13.2.1 Introduction and Mechanistic Aspects 448 13.2.2 Applications of the Original Yonemitsu Trimolecular Condensation 449 13.2.3 Yonemitsu]Type Reactions and Tetramolecular Condensations 451 13.3 Mcrs Involving Meldrum’s Acid 457 13.3.1 Introduction 457 13.3.2 Applications and DOS 458 13.3.3 Meldrum’s Acid as Synthetic Equivalent 461 13.3.4 Meldrum’s Acid as Malonic Acid Equivalent 464 13.4 Povarov Mcrs 466 13.4.1 Introduction 466 13.4.2 Mechanistic Aspects 466 13.4.3 Efficient Synthesis of 1,2,3,4]Tetrahydroquinolines 468 13.4.4 Efficient Synthesis of Quinolines 470 13.5 Hantzsch Multicomponent Synthesis of Heterocycles 472 13.5.1 Introduction 472 13.5.2 Catalysis and Mechanism 474 13.5.3 Syntheses of 1,4]Dihydropyridines and Their Oxidation to Pyridines 475 13.5.4 Multicomponent Pyrrole Syntheses 480 13.6 Conclusions 482 References 482 INDEX 496