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 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