Cyclopropanes in Organic Synthesis

This is a practical guidebook about cyclopropanes that thoroughly surveys derivatives and transformations, synthetic methods, and experimental efficiency as a gateway for further research and development in the field.

• Provides comprehensive lists and synthetically-oriented synopses of cyclopropane chemistry review references along with publication data on applications in the syntheses of natural and related biologically active compounds
• Acts as a resource to help readers better understand cyclopropane applications for the efficient realization of synthetically important organic transformations and popular experimental procedures
• Includes new developments and up-to-date information that will lead to original methodologies for complex organic synthesis
• Stresses universality, flexibility, and experimental efficiency of a strategy based on preparing cyclopropane derivatives and performing ring cleavage reactions with inexpensive reagents
• Focuses on the synthetic potential of cyclopropane applications, for example the synthesis of natural compounds and other target-oriented syntheses via cyclopropane intermediaries, as well on their planning by retrosynthetic analysis

Preface ix

Part I Reactivity and availability 1

Introduction, 1

Reference, 2

1 Structure and Reactivity of the Cyclopropane Species 3

1.1 Geometry and Bonding, 3

1.2 Energy, 4

1.3 Spectra, 5

1.4 Cyclopropyl Cations, 5

1.5 Cyclopropyl Anions, 6

1.6 Cyclopropyl Radicals, 7

1.7 Cyclopropylidenes, 7

1.8 Cyclopropylcarbinyl Cations, 8

1.9 Cyclopropylcarbinyl Anions, 8

1.10 Cyclopropylcarbinyl Radicals, 10

1.11 Cyclopropylcarbenes, 10

1.12 Conclusion, 11

References, 13

2 Ring Cleavage Reactions 15

2.1 Cyclopropyl Activation, 16

2.1.1 Halogen, Oxy, and Sulfur Substituted Cyclopropanes, 16

2.1.2 Alkylidenecyclopropanes, 19

2.2 Cyclopropylcarbinyl Activation, 23

2.2.1 Halogeno, Oxy, Acyl and Metallomethyl Cyclopropanes, 23

2.2.2 Alkylidenecyclopropanes, 27

2.2.3 Vinyl and Ethynyl Cyclopropanes, 29

2.2.4 1,2]Divinylcyclopropanes, 33

2.2.5 Acceptor Cyclopropanes, 35

2.2.6 Donor Cyclopropanes, 38

2.2.7 Donor–Acceptor Cyclopropanes, 43

2.3 Conclusion, 48

References, 49

3 Synthesis of Cyclopropanes 57

3.1 1,3]Cyclization Reactions, 57

3.1.1 Cyclizations with Cleavage of Two Single Bonds, 58

3.1.2 Cyclizations with Cleavage of One Double Bond and One Single Bond, 59

3.1.3 Cyclizations with Cleavage of Two Double Bonds, 62

3.2 [2 + 1] Cyclization Reactions, 65

3.2.1 Cycloaddition of Carbene Equivalents to Olefins, 66

3.2.2 Coupling of 1,1]Carbodianion and 1,2]Carbodication Equivalents, 79

3.2.3 Coupling of 1,1]Carbodication and 1,2]Carbodianion Equivalents, 83

3.3 Addition Reactions to the Double Bond of Cyclopropenes, 88

3.4 Interconversion of Cyclopropanes, 90

3.5 Conclusion, 90

References, 90

Part Ii Synthetic Application 99

Introduction, 99

References, 100

4 Triangulation Retrosynthetic Analysis 103

4.1 Retrosynthetic Triangulation, 103

4.2 Conclusion, 108

References, 108

5 Acyclic Compounds 109

5.1 Formation of Carbon Substituents, 109

5.1.1 Nonactivated Cyclopropane Precursors, 109

5.1.2 Cyclopropylcarbinyl Activated Precursors, 112

5.1.3 Cooperatively Activated Precursors, 138

5.2 Formation of Olefin Groups, 139

5.2.1 Cyclopropylcarbinyl Activated Precursors, 139

5.2.2 Cyclopropyl Activated Precursors, 142

5.2.3 Fragmentation of the Cyclopropane Precursors, 146

5.2.4 Cooperatively Activated Cyclopropane Precursors, 147

5.3 Formation of Carbonyl Groups, 151

5.3.1 Cyclopropylcarbinyl Precursors, 151

5.3.2 Cooperatively Activated Precursors, 156

5.4 Retrosynthetic Account, 162

References, 163

6 Cyclobutane Derivatives 167

6.1 Grandisol Syntheses, 167

6.2 Cyclobutane Synthetic Intermediates, 169

6.3 Retrosynthetic Account, 183

References, 184

7 Cyclopentanes 187

7.1 Vinylcyclopropane–Cyclopentene Rearrangement, 187

7.1.1 Cyclopropylcarbinyl Activated Precursors, 187

7.1.2 Cooperatively Activated Precursors, 188

7.2 Cycloaddition Reactions, 221

7.2.1 Cyclopropylcarbinyl Activated Precursors, 221

7.2.2 Cooperatively Activated Precursors, 221

7.3 Modification of Substituents, 223

7.3.1 N onactivated Cyclopropane Precursors, 223

7.3.2 Cyclopropylcarbinyl Activated Precursors, 224

7.3.3 Cooperatively Activated Precursors, 231

7.3.4 Fragmentation Reactions, 245

7.4 Retrosynthetic Account, 246

References, 246

8 Cyclohexanes 251

8.1 Intramolecular Cyclization Reactions, 251

8.2 Cycloaddition Reactions, 255

8.3 Modification of Substituents, 269

8.3.1 Cyclopropylcarbinyl Activated Precursors, 269

8.3.2 Cyclopropyl Activated Precursors, 275

8.3.3 Cooperatively Activated Precursors, 277

8.4 Retrosynthetic Account, 282

References, 283

9 Cycloheptanes 285

9.1 Divinylcyclopropane–Cycloheptadiene Rearrangement, 285

9.2 Cycloaddition Reactions, 315

9.3 Modification of Substituents, 318

9.3.1 Nonactivated Cyclopropane Precursors, 318

9.3.2 Cyclopropylcarbinyl Activated Precursors, 318

9.3.3 Cyclopropyl Activated Precursors, 323

9.3.4 Cooperatively Activated Precursors, 325

9.4 Retrosynthetic Account, 329

References, 330

10 Cyclooctanes and Larger Carbocycles 333

10.1 Cycloaddition Reactions, 333

10.2 Modification of Substituents, 334

10.2.1 Cyclopropylcarbinyl Activated Precursors, 334

10.2.2 Cyclopropyl Activated Precursors, 338

10.3 Retrosynthetic Account, 340

References, 340

11 Heterocyclic Compounds 341

11.1 Intramolecular Cyclization Reactions, 341

11.1.1 Nonactivated Cyclopropane Precursors, 341

11.1.2 Cyclopropylcarbinyl Activated Precursors, 342

11.1.3 Cyclopropyl Activated Precursors, 378

11.1.4 Cooperatively Activated Precursors, 380

11.2 Cycloaddition Reactions, 387

11.2.1 Cyclopropylcarbinyl Activated Precursors, 387

11.2.2 Cooperatively Activated Precursors, 390

11.3 Modification of Substituents, 400

11.3.1 Cyclopropylcarbinyl Activated Substrates, 400

11.3.2 Cyclopropyl Activated Substrates, 402

11.3.3 Cooperatively Activated Substrates, 402

11.4 Retrosynthetic Account, 409

References, 410

CONCLUSION 415

AUTHOR Index 417

Oleg Kulinkovich was the head of the Department of Organic Chemistry from 1993-2003 and the head of the Laboratory of Organoelement Synthesis at Belarusian State University and visiting professor at Tallinn University of Technology. His seminal work on titanium-catalyzed cyclopropanation of carboxylic esters with Grignard reagents bearing β-hydrogen atoms (Kulinkovich reaction) is very well-known. Dr. Kulinkovich has published several reviews and original articles on organic synthesis in leading international journals.

Used in total synthesis of natural products and other complex molecules, cyclopropanes can be conveniently prepared with different approaches and used as intermediates to make target-directed organic transformations more efficient. The synthetic potential of cyclopropane derivatives is often overlooked but is nonetheless universal and could be more efficient than standard approaches.

This book provides a comprehensive review of cyclopropanes – their properties, preparation, synthesis, and applications. It includes comprehensive references and synopses of review articles on experimental data and theoretical interpretations of the geometry of cyclopropanes and also discusses typical transformations of substituted cyclopropanes, derivatives, and intermediates, with emphasis on highly selective transformations of easily available cyclopropane precursors. The author provides a detailed description of successful applications of cyclopropane approaches in target-oriented syntheses classified by the class of the target structures and transformation type, and mode of the activation of the cyclopropane ring toward its cleavage.

Overall, the book stresses universality, experimental efficiency, and strategic importance of synthetic methodologies based on an efficient preparation of cyclopropane derivatives and their involvement in smooth ring opening or fragmentation reactions with inexpensive reagents. A valuable guide for practicing chemists, this book offers key features that include:

• A resource to help readers better understand cyclopropane applications for the efficient realization of synthetically important organic transformations and popular experimental procedures
• New developments and up-to-date information that will lead to original methodologies for complex organic synthesis
• Focus on the synthetic potential of cyclopropane applications, as well on their planning by retrosynthetic analysis