Molecular Rearrangements in Organic Synthesis

Christian M. Rojas, PhD, is Professor of Chemistry at Barnard College. He obtained his Ph.D. at Indiana University in 1995 and did postdoctoral studies at the Massachusetts Institute of Technology and then at The Scripps Research Institute. Professor Rojas began his independent career at Barnard College in 1997. His research explores the use of acyl nitrenes for the synthesis of amino sugars.

LIST OF CONTRIBUTORS xvii

PREFACE xxi

PART 1 1,2-MIGRATIONS 1

1 Pinacol and Semipinacol Rearrangements in Total Synthesis 3

1.1 Introduction 3

1.2 Pinacol Reaction 4

1.3 Semipinacol Rearrangement 15

1.4 Conclusion 30

References 32

2 Baeyer–Villiger (BV) Oxidation/Rearrangement in Organic Synthesis 35

2.1 Introduction 35

2.2 Mechanism 35

2.3 Synthetic Applications 37

2.4 Summary and Outlook 55

References 55

3 The Wolff Rearrangement: Tactics, Strategies and Recent Applications in Organic Synthesis 59

3.1 Introduction 59

3.2 Tactics and Strategies via the Wolff Rearrangement 60

3.3 Mechanistic Features and Selectivity Issues of the Wolff Rearrangement 63

3.4 Preparation of α-Diazocarbonyl Compounds 64

3.5 Recent Synthetic Applications of the Wolff Rearrangement 67

3.6 Conclusion and Outlook 80

References 81

4 Alkyl and Acyl Azide Rearrangements 85

4.1 Introduction 85

4.2 Alkyl Azide Rearrangements 86

4.3 Acyl Azide Rearrangements 98

4.4 Hofmann Rearrangement 102

4.5 Lossen Rearrangement 104

4.6 Conclusion 107

References 108

5 Beckmann Rearrangements and Fragmentations in Organic Synthesis 111

5.1 Introduction 111

5.2 Strategic Planning: A Historical Perspective 118

5.3 Recent Applications Toward the Synthesis of Natural Products 121

5.4 Access to Diverse Scaffolds via the Beckmann Reaction 129

5.4.1 Diterpene Hydrocarbons 129

5.5 Formation of Heterocyclic Scaffolds 136

5.6 Synthesis of Functional Groups 140

5.7 Summary and Outlook 144

References 145

6 Brook Rearrangement 151

6.1 Introduction 151

6.2 Mechanism 152

6.3 Methods for Generation of α-Silyl Alkoxides 153

6.4 Synthetic Reactions Using Brook Rearrangements in the Reactions of Acylsilanes with Nucleophiles 154

6.5 Synthetic Reactions Using Brook Rearrangements Triggered by Deprotonation of α-Silyl Alcohols 166

6.6 Synthetic Reactions Using Brook Rearrangements Triggered by Addition of Silylmetallic Reagents 169

6.7 Synthetic Reactions Using Brook Rearrangements in β-Silyl Alkoxides Generated via Regioselective β-Ring-Opening of α, β-Epoxysilanes by a Nucleophile 172

6.8 Synthetic Reactions Using Brook Rearrangements in α-Silyl Alkoxides Generated by a Base-Induced Ring-Opening of alpha;, β-Epoxysilanes 173

6.9 Conclusion 176

References 178

PART II 1,2-MIGRATIONS VIA THREE-MEMBERED RINGS 183

7 The Quasi-Favorskii Rearrangement 185

7.1 Introduction 185

7.2 Retrons of the Quasi-Favorskii Rearrangement 191

7.3 Mechanistic Considerations in the Quasi-Favorskii Rearrangement 192

7.4 The Preparation of Substrates for the Quasi-Favorskii Rearrangement 193

7.5 Applications of the Quasi-Favorskii Rearrangement in Synthesis 199

7.6 Conclusions and Prospects 220

Acknowledgments 222

References 222

8 The Ramberg–Bäcklund Reaction 227

8.1 Introduction 227

8.2 Methods to Synthesize Sulfones as RBR Precursors 229

8.3 Variations of the RBR 231

8.4 Mechanistic Evaluation of the RBR 233

8.5 Strategic Considerations Relevant to the Use of the RBR in Synthesis 234

8.6 Utility, Scope, and Limitations of the RBR 236

8.7 Recent Applications of the RBR in the Synthesis of Complex Target Structures 246

8.7.1 Fawcettidine 246

8.8 Concluding Remarks 254

Acknowledgments 256

References 256

9 Applications of Di-л-Methane and Related Rearrangement Reactions in Chemical Synthesis 261

9.1 Introduction: The Basic Process and its Variants 261

9.2 Mechanistic Features and Competing Reactions 265

9.3 Structural Requirements of Substrates and Matters of Regio- and Stereochemistry 271

9.4 Synthetic Routes to Substrates and Applications in Synthesis 277

9.5 Outlook 284

References 285

PARTIII 1,3-TRANSPOSITIONS 289

10 Payne Rearrangement 291

10.1 Background on the Payne Rearrangement 291

10.2 Synthetic Applications of 2,3-Epoxy Alcohols 295

10.3 Utilization of the Payne Rearrangement for the Preparation of Fluorine-Containing Compounds 307

10.4 Conclusion 317

References 318

11 Vinylcyclopropane–Cyclopentene Rearrangement 323

11.1 Introduction 323

11.2 Thermal VCP–CP Rearrangement 324

11.3 Acid-Mediated VCP–CP Rearrangement 328

11.4 Mechanisms 330

11.5 Heteroatom-Containing Analogues of the VCP–CP Rearrangement 334

11.6 Applications in Synthesis 336

11.7 Photochemical VCP–CP Rearrangement 340

11.8 Metal-Catalyzed VCP–CP Rearrangement 346

11.9 Heteroatom Variants of the Metal-Catalyzed VCP–CP Rearrangement 354

11.10 Summary and Outlook 359

References 360

12 Ferrier Carbocyclization Reaction 363

12.1 Introduction 363

12.2 General Discussion and Mechanistic Features 365

12.3 Synthetic Strategies Based on the Ferrier Carbocyclization Reaction 373

12.4 Methodologies for Assembling the Ferrier Carbocyclization Reaction Substrates 377

12.5 Applications of the Ferrier Carbocyclization Reaction in Natural Product Synthesis 380

12.6 Conclusion 397

References 398

PARTIV [3,3]- AND [2,3]-SIGMATROPIC REARRANGEMENTS 401

13 The Claisen Rearrangement 403

13.1 Introduction 403

13.2 Strategic Planning for the Claisen Rearrangement Reaction 407

13.3 Mechanistic Features of the Claisen Rearrangement Reaction 409

13.4 Methodologies for Synthesis of Claisen Rearrangement Substrates 417

13.5 Applications of the Claisen Rearrangement Reaction in Target-Oriented Synthesis 421

13.6 Conclusions 426

References 427

14 [3,3]-Sigmatropic Rearrangements with Heteroatom–Heteroatom Bonds 431

14.1 Introduction 431

14.2 [3,3]-Sigmatropic Rearrangements of N–O Bonds 434

14.3 [3,3]-Sigmatropic Rearrangements of N–N Bonds 445

14.4 [3,3]-Rearrangements of N–N Bond Fragments that Eliminate N2 451

14.5 Summary 454

References 455

15 [2,3]-Rearrangements of Ammonium Zwitterions 459

15.1 Introduction 459

15.2 [2,3]-Meisenheimer Rearrangement of Amine N-Oxides 460

15.3 [2,3]-Stevens Rearrangement of Ammonium Ylides 479

15.4 Conclusion and Outlook 492

References 493

16 Oxonium Ylide Rearrangements in Synthesis 497

16.1 Introduction 497

16.2 Applications in Synthesis: Oxonium Ylide [2,3]-Sigmatropic Rearrangements 507

16.3 Applications in Synthesis: Oxonium Ylide [1,2]-Stevens Rearrangements 528

16.4 Concluding Remarks 535

References 536

17 The [2,3]-Wittig Rearrangement 539

17.1 Introduction 539

17.2 [2,3]-Wittig Rearrangement of Allyl Propargyl Ethers 541

17.3 Factors Determining [2,3]-Wittig Versus [1,2]-Wittig Rearrangement 544

17.4 Acyclic [2,3]-Wittig Rearrangement of Propargyl-Allyl Ethers 547

17.5 [2,3]-Wittig–Still Rearrangement 552

17.6 Asymmetric [2,3]-Wittig Rearrangement 554

17.7 Aza-[2,3]-Wittig Rearrangement 555

17.8 Other Wittig Rearrangements and Miscellaneous 560

17.9 Conclusion 565

References 565

18 The Mislow–Evans Rearrangement 569

18.1 Introduction 569

Part 1 Mechanistic Aspects and the [2,3] Nature of the Rearrangement 571

18.2 Configurational Lability of Allylic Sulfoxides 571

18.3 Deuterium Labeling to Track [2,3] Pathway 573

18.4 Transition State Features 573

18.5 Equilibrium Between Sulfoxide and Sulfenate 576

18.6 Chirality Transfer 579

Part 2 Synthetic Considerations and Applications 580

18.7 Alkene Stereoselectivity 580

18.8 Diastereoface Selectivity in the Rearrangement 583

18.9 Epimerizations via Mislow–Evans Rearrangement Sequences 591

18.10 Vinyl Anion Synthons Accessible via Mislow–Evans Rearrangement 593

18.11 Sequential Processes Incorporating the Mislow–Evans Rearrangement 598

18.12 Heteroatom [2,3]-Rearrangement Variants 614

18.13 [2,3]-Rearrangements of Propargyl and Allenyl Sulfenates and Sulfoxides 620

18.14 Conclusion 622

References 622

PART V IPSO REARRANGEMENTS 627

19 Smiles Rearrangements 629

19.1 Introduction 629

19.2 Scope and Mechanistic Features 632

19.3 Application of Smiles Rearrangements 635

19.4 Conclusion 657

References 658

20 Pummerer-Type Reactions as Powerful Tools in Organic Synthesis 661

20.1 Introduction 661

20.2 Classical Pummerer Reaction 662

20.3 Vinylogous Pummerer Reaction 674

20.4 Interrupted and Additive Pummerer Reactions 680

20.5 Connective Pummerer Reaction 687

20.6 Pummerer Rearrangement in Multiple-Reaction Processes 693

20.7 Other Pummerer Rearrangements 696

20.8 Summary and Outlook 700

References 700

INDEX 703