Donor Acceptor Cyclopropanes in Organic Synthesis

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Donor–Acceptor Cyclopropanes in Organic Synthesis

Donor–Acceptor Cyclopropanes in Organic Synthesis Edited by Prabal Banerjee and Akkattu T. Biju

Editors Prof. Prabal Banerjee

Indian Institute of Technology Ropar Department of Chemistry Rupnagar-140001 Punjab India Prof. Akkattu T. Biju

Indian Institute of Science Department of Organic Chemistry Bangalore 560 012 India Cover Image: Courtesy of the Editors

All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing‐in‐Publication Data

A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2024 Wiley‐VCH GmbH, Boschstraße 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978‐3‐527‐34987‐6 ePDF ISBN: 978‐3‐527‐83563‐8 ePub ISBN: 978‐3‐527‐83564‐5 oBook ISBN: 978‐3‐527‐83565‐2 Typesetting:

Straive, Chennai, India

v

Contents Preface xiii 1

1.1 1.2 1.3 1.4 1.5 2

2.1 2.2 2.3 2.4 2.5 3

3.1 3.2 3.2.1 3.2.2 3.2.3

Introduction to the Chemistry of Donor–Acceptor Cyclopropanes: A Historical and Personal Perspective 1 Hans-Ulrich Reissig Introduction 1 My Personal Entry to Donor–Acceptor Cyclopropanes 3 A Few Principles of the Chemistry of Donor–Acceptor Cyclopropanes 6 Remarks Regarding the Terminology Applied to the Use of Donor–Acceptor Cyclopropanes 10 Conclusions 12 Abbreviations 12 References 13 Understanding the Reactivity of Donor–Acceptor Cyclopropanes: Structural and Electronic Analysis 15 Anu Jacob, Gwyndaf A. Oliver, and Daniel B. Werz Introduction 15 Activated Cyclopropanes 17 Donor–Acceptor Cyclopropanes (DACs) 19 Computational and Kinetic Investigations 22 Concluding Remarks 32 References 32 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes 37 Roman A. Novikov, Denis D. Borisov, and Yury V. Tomilov Introduction 37 Formal [3+2]-Cycloaddition with Carbon–Carbon Multiple Bonds 39 General Aspects 39 Formal [3+2]-Cycloaddition with C=C Double Bond 40 Formal [3+2]-Cycloaddition with Triple C≡C Bond 50

vi

Contents

3.2.4 3.2.5 3.3 3.3.1 3.3.2 3.4 3.4.1 3.4.2 3.4.3 3.4.4 3.4.5 3.4.6 3.5 3.5.1 3.5.2 3.5.3 3.5.4 3.5.5 3.5.6 3.5.7 3.6 3.6.1 3.6.2 3.7 3.7.1 3.7.2 3.7.3 3.7.4 3.7.5 3.8 3.9 3.9.1 3.9.2

[3+2]-Annulation with Aromatic C=C Bond 53 [3+2]-Annulation of D–A Cyclopropanes Involving Aryl/Heteroaryl Donor Substituent 57 Formal [3+2]-Cycloaddition with C=O and C=N Double Bond 59 Formal [3+2]-Cycloaddition with C=O Double Bond 59 Formal [3+2]-Cycloaddition with C=N Double Bond 66 Formal [3+2]-Cycloaddition with Other Heteroatom X=Y Double Bonds 73 Formal [3+2]-Cycloaddition with Cumulenes and Heterocumulenes 73 Formal [3+2]-Cycloaddition with SCN and SeCN 76 Formal [3+2]-Cycloaddition with C=S and C=Se Double Bonds 77 Formal [3+2]-Cycloaddition with N=O and N=N Double Bonds 78 Formal [3+2]-Cycloaddition with C≡N Triple Bonds in Nitriles 80 Formal [3+2]-Cycloaddition and Other Reactions with Three-Membered Heterocycles 80 Formal [3+3]-Cycloaddition and Annulation Reactions of D–A Cyclopropanes 83 General Aspects 83 [3+3]-Annulation with Aromatic Substrates as 1,3-Synthons 84 [3+3]-Annulation with Allenes, Allyl, and Propargyl Derivatives 87 [3+3]-Annulation with Mercaptoacetaldehyde 88 [3+3]-Cycloaddition with Nitrones and Nitronates 89 [3+3]-Annulation/Cycloaddition with Dinitrogen Substrates 93 Formal [3+3]-Cycloaddition with Azides and Diazo Compounds 94 Reactions of Formal [4+3]-Cycloaddition and Annulation with Diene and Heterodiene Systems 96 Dienes as Traps for 1,3-Zwitterions 97 Reactions of [4+3]-Cyclization with Heterodiene Systems and Their Analogs 99 Other Formal [n+m]-Cycloaddition and Annulation Processes 102 Formal [8+3]-Cycloaddition Reactions 102 Other Formal Stepwise “High-Order” Cycloaddition/Annulation Reactions 103 Formal [3+1]- and [3+1+1]-Cycloadditions 105 Cycloaddition/Annulation Reactions Proceed via Generation of β-Styrylmalonates 106 GaCl3-Mediated Cycloaddition/Annulation Reactions via Generation of 1,2-Zwitterionic Intermediates 109 Cyclodimerization Reactions of D–A Cyclopropanes 112 Miscellaneous Reactions, Stepwise Cyclization Reactions, Cyclizations with Involvement of Functional Groups 118 Stepwise Cyclization Using Substrates with Two Nitrogen Atoms 118 Some Other Cascade and Miscellaneous Formal Cycloaddition Reactions for Cyclopropanedicarboxylates 119

Contents

3.9.3 3.9.4 3.9.5 3.9.6 3.9.7 3.9.8 3.9.9 4

4.1 4.2 4.3 4.4 4.5 4.6 5

5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12

Formal Cycloaddition and Cyclization Reactions for 2-Aryl D–A Cyclopropanes Containing Active Substituent in Ortho-Position 122 Cyclization Reactions of D–A Cyclopropanes with Additional CHO Group in Donor Part 123 Miscellaneous Cyclizations with Phenols and Nitrogen-Containing Heterocycles 124 Some Cyclization Reactions of 1,1-Dicyano Cyclopropanes 125 Miscellaneous Cyclizations with Sulfur Reagents 126 Cyclizations of Cyclopropanes Containing Carbonyl Group as an Acceptor with Amine Reagents 127 Miscellaneous Reactions 128 References 129 Activation of Donor–Acceptor Cyclopropanes under Covalent Organocatalysis: Enamine, Iminium, NHC, Phosphine and Tertiary Amine Catalysis 139 Efraim Reyes, Liher Prieto, Luisa Carrillo, Uxue Uria, and Jose L. Vicario Introduction 139 Secondary Amine Catalysis: Enamine Activation 141 Secondary Amine Catalysis: Iminium Ion Activation 144 NHC Catalysis: Activation Through Breslow Intermediates 148 Phosphine or Tertiary Amine Catalysis 157 Conclusion 162 References 162 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes 167 Avishek Guin and Akkattu T. Biju Introduction 168 Enantioselective 1,3-Dichlorination of Formyl Group-Containing Cyclopropanes 168 Ring-Opening 1,3-Dichlorination of D–A Cyclopropanes 169 1,3-Chlorochalcogenation of Cyclopropyl Carbaldehydes 170 1,3-Bisfunctionalization of D–A Cyclopropanes with Arenes and Nitrosoarenes 172 1-Amino-3-Aminomethylation of D–A Cyclopropanes 173 1,3-Halochalcogenation of D–A Cyclopropanes 174 1,3-Aminobromination of D–A Cyclopropanes 175 Reaction of D–A Cyclopropanes with 4,5-Diazaspiro[2.4] hept-4-enes 176 Four-Component Coupling of D–A Cyclopropanes 177 1,3-Aminochalcogenation of Donor–Acceptor Cyclopropanes 178 1,3-Bisfunctionalization of Donor–Acceptor Containing Cyclopropyl Boronic Ester 178

vii

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Contents

5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 6 6.1 6.2 6.3 6.4 6.4.1 6.4.2 6.4.3 6.5 6.6 6.7 7 7.1 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.2.6

1,3-Halogenation–Peroxidation of D–A Cyclopropanes 178 1,3-Aminothiolation of D–A Cyclopropanes Using Sulfenamides 180 1,3-Bisarylation of D–A Cyclopropanes with Electron-Rich Arenes and Hypervalent Arylbismuth Reagents 181 Conversion of D–A Cyclopropanes to β-Hydroxy Ketones 182 1,3-Carbothiolation of D–A Cyclopropanes 183 1,3-Haloamination of D–A Cyclopropanes Employing Copper Salt and N-Fluorobenzenesulfonimide 184 Ring-Opening 1,3-Carbocarbonation of D–A Cyclopropanes 185 1,3-Aminofunctionalization of D–A Cyclopropanes 187 Conclusion 188 References 188 Molecular Rearrangements in Donor–Acceptor Cyclopropanes 191 Igor V. Trushkov and Olga A. Ivanova Introduction 191 Donor–Acceptor Cyclopropane Isomerizations to Alkenes (Cyclopropane–Propene Rearrangement) 192 Vinylcyclopropane–Cyclopentene Rearrangement 197 Cloke–Wilson Rearrangement and Related Processes 202 Rearrangement of Acyl-substituted Cyclopropanes to 2,3-dihydrofurans 202 The Cloke–Wilson Rearrangements Affording Pyrrole Derivatives 208 The Related Rearrangements Affording Other Heterocycles 209 Nazarov Reaction and its Homo-Version 210 The Cope Rearrangement and Related Isomerizations of Donor– Acceptor Cyclopropanes 215 Intramolecular Nucleophilic Ring Opening/Ring Closure and Related Processes 218 References 221 Donor–Acceptor Cyclopropanes with an Amino Group as Donor 227 Ming-Ming Wang and Jerome Waser Introduction 227 Synthesis of DA Aminocyclopropanes 229 Synthesis of DA Aminocyclopropanes from β-Dehydroamino Acids (Route A) 231 Synthesis of DA Aminocyclopropanes from Enamines (Route B) 231 Synthesis of DA Aminocyclopropanes from Acrylates (Route C) 233 Synthesis of DA Aminocyclopropanes from Cyclopropene (Route D1) 233 Synthesis of DA Aminocyclopropanes from 2-Haloethylidene Malonates (Route D2) 233 Synthesis of DA Aminocyclopropanes from Cyclopropylamines (Route E) 234

Contents

7.3 7.3.1 7.3.2 7.4 7.5

Ring-Opening Reactions of DA Aminocyclopropanes 235 Intramolecular Ring-Opening of DA Aminocyclopropanes 236 Intermolecular Ring-Opening of DA Aminocyclopropanes 240 Formal Cycloaddition of DA Aminocyclopropanes 244 Conclusion 250 Abbreviations 250 References 251

8

Reactivity of Cyclopropyl Monocarbonyls 255 Pankaj Kumar, Irshad Maajid Taily, Priyanka Singh, and Prabal Banerjee Introduction 255 Associated Challenges 256 Reduced Reactivity 256 Diastereomers and Controlled Reactivity 257 Perks of Having a Monocarbonyl Substituent on Cyclopropane 258 DAC Monocarbonyls—Not Merely a Three-Carbon Synthon 258 Two Nucleophilic and Two Electrophilic Sites 258 Cyclopropane Mono-Carbonyls in Organocatalysis 259 Methods for the Preparation of Cyclopropyl Monocarbonyls 260 From Olefins 260 Corey–Chaykovsky Reaction 260 Hydroformylation of Cyclopropenes 261 Ozonolysis of Vinyl Cyclopropanes 261 From Homoaldol Adducts 261 From Arylthio Cyclopropyl Carbaldehydes 262 From Diazo Compounds 262 From 1,2-Dicarbonyl Compounds 263 Cyclopropyl Monocarbonyls in Important Heterocyclic Synthesis 264 Metal Catalyzed Annulation Reactions of Cyclopropyl Monocarbonyls 264 Ring Expansion and Ring-Opening Reactions of Cyclopropyl Monocarbonyls 267 Application in Total Synthesis 270 References 270

8.1 8.2 8.2.1 8.2.2 8.3 8.3.1 8.3.2 8.3.3 8.4 8.4.1 8.4.1.1 8.4.1.2 8.4.1.3 8.4.2 8.4.3 8.4.4 8.4.5 8.5 8.5.1 8.5.2 8.6 9

9.1 9.2 9.3 9.3.1 9.3.2 9.3.3 9.3.4

Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes 273 Thangavel Selvi and Kannupal Srinivasan Introduction 273 Synthesis of Aroyl-Substituted D–A Cyclopropanes 274 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes 276 AlCl3 or SnCl4-Mediated Ring-Opening Reactions 276 TiCl4-Mediated Ring-Opening Reactions 278 Ring-Opening Reactions with Hydrazines 278 Ring-Opening Reactions with 1-Naphthylamines 280

ix

x

Contents

9.3.5 9.3.6 9.3.7

9.3.8 9.4 9.5 9.5.1 9.5.2 9.5.3 9.5.4 9.5.5 9.5.6 9.6 10

10.1 10.2 10.3 10.4 10.5 10.6

(3 + 2) Annulations with Nitriles 280 (3 + 3) Annulation with Mercaptoacetaldehyde 282 Conversion of Aroyl-Substituted D–A Cyclopropanes into γ-Butyrolactone-Fused D–A Cyclopropanes and their Synthetic Applications 285 Works from Yang and Sekar Research Groups 286 Synthesis of Nitro-Substituted D–A Cyclopropanes 289 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes 291 BF3-Mediated Ring-Opening Reactions 291 Reactions with Nitriles 292 Reactions with Activated Aromatics 293 Reaction with Mercaptoacetaldehyde Dimer 293 Ring-Opening Reactions with 2-Aminopyridines 294 Works from He, Xia, and Asahara Groups 296 Conclusion 297 References 298 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases, and Thermal Reactions 301 Lijia Wang and Yong Tang Introduction 301 Metal-Free Electrophilic Activation of D–A Cyclopropanes 302 Metal-Free Nucleophilic Activation of D–A Cyclopropanes 313 Catalyst-Free Activation of D–A Cyclopropanes 319 Metal-Free Activation of D–A Cyclopropanes via Radical, SET, and Photopromoted Process 327 Conclusion 329 References 330

Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes 333 Yong Xia, Xiaohua Liu, and Xiaoming Feng 11.1 Introduction 333 11.2 Chiral Lewis Acid-Catalyzed Reactions of D–A Cyclopropanes 334 11.2.1 Asymmetric Reactions of Two-Substituted Cyclopropane-1,1-Dicarboxylates 334 11.2.1.1 Ring-Opening Reactions 334 11.2.1.2 [3 + n] Annulations 337 11.2.2 Asymmetric Reactions of 2-Substituted Cyclopropane-1,1-Diketones 341 11.3 Chiral Low-Valent Transition Metal Promoted Reactions of Vinyl Cyclopropanes 343 11.3.1 Ring-Opening Reactions 344 11.3.2 [3 + n] Annulations 345 11.4 Chiral Organocatalytic Reactions of D–A Cyclopropanes and Miscellaneous 349 11

Contents

11.4.1 11.4.2 11.4.3 11.4.4 11.4.5 11.5

Enamine/Iminium Catalysis Activation 349 Brønsted Base Catalyst Activation 350 Nucleophilic Catalyst Activation 351 Brønsted Acid Catalyst Activation 352 Radical Pathway 353 Conclusion 355 R eferences 355

12

Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products 359 Amrita Saha, Karuna Mahato, Satysen Yadav, and Manas K. Ghorai Introduction 359 Synthesis of Alkaloids 360 Synthesis of Terpene/Terpenoids 379 Synthesis of Miscellaneous Natural Products 403 Conclusion 427 References 427

12.1 12.2 12.3 12.4 12.5

Index 433

xi

xiii

Preface Donor–Acceptor Cyclopropanes (DACs) constitute a preeminent class of building blocks in organic synthesis featuring a strain‐induced incredibly wide variety of reactivity. Besides, the cyclopropanes in general are also decorated with a plethora of structurally and biologically important scaffolds. The book is aimed at focusing on the chemistry involved with DACs and their utilization toward the construction of various carbo‐ and heterocycles of biological and industrial importance. Continuous progress made in the field of DACs, involving (3 + n) annulation, ring‐ opening, molecular rearrangements, and the asymmetric versions of many of these reactions have captured the tremendous interest of organic chemists. Signing up of DACs toward the synthesis of an array of carbo‐ and heterocycles of pharmaceutical importance have proved very beneficial. However, the lack of a book in the area of DACs has prevented chemists from appreciating the complete developments in DAC chemistry. The focus of the book is on recent developments in cycloaddition, ring‐opening, and molecular rearrangements involving DACs. Examples from the literature that have demonstrated the synthetic application of these processes as well as unprecedented contributions that have directed research in the area are included in the book. In addition, the simpler and milder reaction conditions in DAC chemistry will inspire a broad range of organic and medicinal chemists to explore the applications of DACs in their respective fields. The first chapter is documented by Hans‐Ulrich Reissig, who significantly ­contributed to the early phase of this chemistry and coined the term Donor– Acceptor Cyclopropanes. This chapter provides a detailed introduction with a his­ torical and personal perspective on this field. An inward understanding of the structure, bonding, and reactivity plays a central facilitating role in engendering molecules of choice. From this perspective, Chapter 2, authored by Daniel B. Werz and coworkers, demonstrated the bonding and rationale of strain‐induced reactiv­ ity of these three carbon synthons, considering the structural and electronic insights. Chapters 3–12 focus on the chemistry of diverse DACs and their reactivity, including the mechanistic studies and utilization toward the construction of vari­ ous carbo‐ and heterocycles of biological and industrial importance. Chapter 3, written by Roman A. Novikov and coworkers, covers the cycloaddition and annu­ lation reactions of DACs. Moreover, it integrates a number of 1,3‐zwitterionic ­synthons that could be generated from DACs and their responsiveness toward the

xiv

Preface

formation of carbon–carbon and carbon–heteroatom multiple bonds. The advent of organocatalysis has created new opportunities in organic synthesis. In Chapter 4, Jose L. Vicario and Efraim Reyes focus on the organocatalytic in‐situ generation of the DACs to undergo a variety of interesting transformations. In continuation, Chapter 5 by Akkattu T. Biju and coworkers deals with the ring‐ opening 1,3‐bisfunctionalization of DACs. The exercise of bisfunctionalization works through the introduction of two functional groups at the same time to the reacting partner. Rearranging the carbon skeleton is a recognized aspect of organic chemistry and demonstrates an alluring strategy to modify existing structures to construct important molecular frameworks. Chapter 6, authored by Igor V. Trushkov, demonstrates the detailed molecular rearrangements of DACs to produce a broad diversity of products. Because of their structural and pharmaceutical importance, the construction of nitrogenous compounds has always been an attractive area of research for organic chemists. Chapter 7, documented by Jerome Waser and cowork­ ers, introduces DA aminocyclopropanes as a reliable building block and provides an in‐depth description of their synthetic applications in ring‐opening reactions and formal cycloadditions. DACs with one carbonyl group have emerged as interesting molecules with diverse reactivity lines as compared to the classical DACs with diester group as an acceptor. Chapter 8, written by Prabal Banerjee demonstrates the synthetic strategies and reactivity profile of these cyclopropyl carbonyls, followed by a discussion on their exploitation in the total synthesis of complex biologically important molecules. The aroyl‐ and nitro‐substituted DACs are relatively emerging entities in the area of DAC chemistry, and Chapter 9, documented by Thangavel Selvi and Kannupal Srinivasan, focuses on the synthesis of these DACs and their further utilization toward the facile access to various acyclic, carbocyclic, and heterocyclic compounds. Fascinated by the metal‐free activation of DACs, Yong Tang and Lijia Wang have written Chapter 10. In the following chapter, they referred to various strategies for the C─C bond cleavage of the DACs by means of protic acids, non‐metal Lewis acids, bases, thermal reactions, and so on. Asymmetric catalysis has emerged as a robust platform with a huge potential in organic synthesis, despite the tremendous challenges associated. Chapter 11, documented by Xiaoming Feng and coworkers, summarizes the stereospecific transformations or enantioselective reactions of race­ mic, prochiral, or optically enriched cyclopropanes. Cyclopropanation followed by ring‐opening or cycloaddition and cyclopropanation ring‐opening cyclization are attractive strategies widely used in the total synthesis of complex natural products. Chapter 12, authored by Manas K. Ghorai and coworkers, demonstrates the exploi­ tation of DACs in the total synthesis of bioactive natural products over the last two decades. The crafting of this book was possible only because of the outstanding contribu­ tions of all the colleagues engaged in DAC chemistry, and we are very thankful to them. In addition, we thank all the authors for their invaluable contributions, and we appreciate their time and patience. We believe this book will be a source of inspi­ ration for youngsters as well as senior chemists practicing synthetic organic

Preface

chemistry. We are thankful to Katherine Wong and Dr. Sakeena Quraishi at Wiley‐ VCH for their strong support and constructive suggestions in preparing this book. Prabal Banerjee Ropar / Bangalore, November 2023 Akkattu T. Biju 31 May 2023

xv

1

1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes: A Historical and Personal Perspective Hans-Ulrich Reissig Institut für Chemie und Biochemie, Freie Universität Berlin, D-14195 Berlin, Germany

CHAPTER MENU 1.1 1.2 1.3 1.4

Introduction, 1 My Personal Entry to Donor–Acceptor Cyclopropanes, 3 A Few Principles of the Chemistry of Donor–Acceptor Cyclopropanes, 6 Remarks Regarding the Terminology Applied to the Use of Donor–Acceptor Cyclopropanes, 10 1.5 Conclusions, 12 Abbreviations, 12 References, 13

1.1 Introduction During the past 15 years, we have seen tremendous progress in new applications of donor–acceptor cyclopropanes (DACs). Between 1980 and 2005, only a handful of papers per year were published mentioning this term; however, starting in 2006, a constant increase of interest could be observed, and recently, 80–100 articles dealing with this type of cyclopropanes as key compounds were released annually (Figure 1.1). This increasing number of contributions and the growing importance of this field are confirmed by the high number of recent review articles and, of course, by the fact that this book will collect articles from many of the key players in this research area. We introduced the term “donor‐acceptor‐substituted cyclopropane” in 1980 [1] and contributed to this field in its early phase. However, we did not use the term regularly; sometimes, we preferred the more specific name “siloxy‐ substituted cyclopropanecarboxylate,” assuming that it is more precise.

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes

292 238

136

120

Number of publications

2

62 54 40

5 9

8 19

– 80

19

9 19

19

– 90

9 20

07

20

– 00

6 9 3 10 21 01 01 01 20 20 –2 –2 –2 – 4 7 1 0 1 1 1 2 20 20 20 20

20

– 08

Period

Figure 1.1 Number of publications dealing with the topic “donor–acceptor cyclopropane” or synonyma (according to a search in Web of Knowledge on 26 September 2021).

Also, several of the important contributions of Ernest Wenkert do not name their substrates DACs [2]. Therefore, the statistics in Figure 1.1 are not fully representative of the early period of 1980–2005. Why did DACs receive this importance in organic synthesis? For a long time, cyclopropanes were regarded as exotic laboratory curiosa. In 1882, August Freund prepared the parent compound in Lemberg [3]; shortly after, in 1884, William Henry Perkin Jr. synthesized the first functionalized cyclopropane (diethyl cyclopropanedicarboxylate) [4] in the Munich laboratory of Adolf von Baeyer, who recognized the special properties of this type of hydrocarbons and formulated his famous concept of ring strain [5]. Over the years and decades, cyclopropane derivatives with different substituents and functional groups were prepared and investigated; however, in general, the reaction mechanisms involved were at the center of interest. The development of efficient methods for their synthesis was essential for this progress, in particular, the use of carbenes and carbenoids allowed simple and selective approaches to various classes of cyclopropanes. It was only in the 1960s and 1970s that it became evident that cyclopropanes can also serve as building blocks in organic synthesis, and very famous chemists were involved in exploring these possibilities. A systematic treatment of “Methods of Reactivity Umpolung” by Dieter Seebach [6] also included certain aspects of cyclopropane chemistry in this seminal review. Here the phrase “cyclopropane trick” was mentioned and connected with reactivity umpolung. A second early key player in this period was Armin de Meijere, who entered the field as a physical organic chemist but subsequently also provided important synthetic contributions in the cyclopropane field [7]. Very important contributors to the use of cyclopropanes in organic synthesis, in particular, in natural product synthesis, were Samuel Danishefsky, Robert V. Stevens, and Ernest Wenkert. Danishesky et al. exploited cyclopropanes activated by two acceptor substituents

1.2 ­y ersonal ntry to Donor–Acceptor Cyclopropanes

that can be smoothly ring‐opened (homo‐Michael addition), especially in an ­ intramolecular fashion, to give skeletons suitable for further synthetic elaboration [8]. The known Cloke rearrangement of cyclopropyl imines to dihydropyrrole derivatives was further developed by Stevens and applied to natural product synthesis [9]. On the other hand, Wenkert et al. explored the chemistry of oxycyclopropanes for the synthesis of terpenes and alkaloids. His publications also contained a few examples of alkoxy‐substituted cyclopropyl ketones or esters; however, these DACs were semantically not distinguished from the other oxycyclopropanes [2]. Nevertheless, his group should receive the credit for being the first to use DACs in natural product synthesis.

1.2 My Personal Entry to Donor–Acceptor Cyclopropanes After my doctoral studies with Rolf Huisgen [10] at Ludwig‐Maximilians University in Munich, I started a postdoctoral stint in the laboratory of Edward Piers at the University of British Columbia in Vancouver, Canada, in the fall of 1978. In Munich, I worked with diazoalkanes and studied kinetics, as well as the mechanistic aspects of their 1,3‐dipolar cycloadditions. In the group of Piers, I was trained as a synthetic chemist, with a research project dealing with cuprate chemistry, the generation of divinylcyclopropanes, and their Cope rearrangements to cycloheptadiene derivatives [11]. My project and the contemporary literature taught me that cyclopropanes are very suitable compounds to achieve synthetic processes, which are not easily possible by alternative methods. Afterward, I had the chance to start my independent academic career as an associate of the group of Siegfried Hünig [12] in Würzburg, and as my first research project, I suggested to use donor‐acceptor‐substituted cyclopropanes. This idea originated when reading the publications of Danishefsky [8]: instead of an external nucleophile, a directly connected nucleophilic center (donor center) should open the acceptor‐activated cyclopropane ring by a strain‐driven retro‐aldol reaction. For this type of process, only a few related examples could be found in the literature [2]. The original drawing of my grant application to the Fonds der Chemischen Industrie, a very supportive institution in Germany for young scientists, is shown as a copy in Figure 1.2. My proposal was apparently considered to be reasonable, and equipped with a Liebig fellowship, I could start with my project at the end of 1979. In Vancouver, I had learned that silyl enol ethers are very useful starting materials for many synthetic operations, whereas during my doctoral work in Munich, methyl diazoacetate was one of the key compounds. It was, therefore, a nearby idea to combine this knowledge for the synthesis of siloxy‐substituted cyclopropanecarboxylate 2 (Scheme 1.1). They were efficiently available by copper‐catalyzed addition of the carbenoid derived from methyl diazoacetate to the silyl enol ethers 1. As the simplest subsequent reaction, we first studied the ring‐opening with fluoride sources to give 1,4‐dicarbonyl compounds 3 under very mild conditions. In my very first independent paper published in 1980, we used the term “donor‐acceptor‐substituted

3

4

1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes

Figure 1.2 Copy of a hand-drawn scheme in a grant proposal submitted by the author to the Fonds der Chemischen Industrie in the summer of 1979.

N2CHCO2Me

Me3SiO R 1

Cu(acac)2 solvent, Δ

CO2Me

Me3SiO R

NEt3•HF THF, r. t.

2

O

CO2Me

R 3

Donor–acceptor cyclopropanes

Scheme 1.1 Synthesis and ring-opening of siloxy-substituted cyclopropanecarboxylate 2, the first cyclopropanes named DACs.

cyclopropanes” for this type of compound [1], which was later shortened to donor–acceptor cyclopropanes (DACs). I am not entirely sure why I had chosen this name, but my thoughts were probably influenced by the review of Seebach, who classified compounds by donor and acceptor centers [6]. One of the initial ideas of this project – the ring‐opening with fluoride under aprotic conditions and the trapping of the resulting ester enolate with electrophiles – did not work satisfactorily [13]. However, as an excellent alternative, we found a step‐wise method for forming new C─C bonds at the acceptor‐substituted cyclopropane carbon atom. Methyl cyclopropanecarboxylate 2 could be smoothly deprotonated with lithium diisopropylamide (LDA) and subsequently trapped with a broad range of electrophiles (Scheme 1.2). This clean deprotonation reaction was not self‐ evident, since enolates incorporating a cyclopropane ring were essentially unknown around 1980. The reaction with alkyl halides R′‐X occurred with surprisingly high stereoselectivity [14], leading to C‐1 substituted cyclopropanes 4, whose ring‐ opening led to higher substituted 1,4‐dicarbonyl compounds. The trapping of the enolates with aldehydes or ketones furnished highly substituted tetrahydrofuran derivatives 5 (synthetically very useful γ‐lactols) after treatment with fluoride [15]. The reaction of the enolates with carbon disulfide or aryl isothiocyanates, followed by the addition of methyl iodide, provided a nice route to interestingly functionalized thiophene or pyrrole derivatives 6 [16].

1.2 ­y ersonal ntry to Donor–Acceptor Cyclopropanes R′

Me3SiO

R CO2Me

1. LDA

4

2. R′-X CO2Me

Me3SiO R 2

HO R

1. LDA 2. R2′ C=O 3. F

CO2Me R′

O R' 5

1. LDA 2. X=C=S

3. Mel R 4. CF3CO2H X = S or N-Ar

CO2Me SMe

X 6

Scheme 1.2 Deprotonation of siloxy-substituted cyclopropanecarboxylate 2 with LDA and subsequent reactions with electrophiles leading to products such as 4–6.

Me3SiO

1. R'2 C = O CO2Me TiCl4, CH2Cl2

Me3SiO 7

2

Me3SiO

O

R A

TiCl4

Me3SiO

O

–CISiMe3 Cl3TiO

TiCl4 –30 °C

R

R'

CO2Me R' 8

MeO

MeO

MeO

O

2. Δ

R

EtO

R

B Red titanium enolate

O

R C Beige–yellow titanoxycyclopropane

Scheme 1.3 Titanium tetrachloride-promoted ring-opening of siloxy-substituted cyclopropanecarboxylate 2 and reactions with carbonyl compounds leading to dihydrofuran derivatives 8; titanium intermediates A–C involved in this process.

An alternative mode of activation and ring‐opening of the siloxycyclopropanes 2 employed strong Lewis acids such as titanium tetrachloride (Scheme 1.3). This idea was deduced from the results of Kuwajima and Nakamura published in 1977 [17]. They demonstrated that 1‐ethoxy‐1‐(trimethylsiloxy)cyclopropane 7 (an oxycyclopropane bearing no acceptor group) reacts with aldehydes and ketones under TiCl4‐ promotion in a ring‐opening homo‐aldol process to yield γ‐hydroxy carbonyl compounds. Under similar conditions, siloxy‐substituted cyclopropanecarboxylate 2 furnished acyclic products or γ‐lactols in good yield. Through elimination, the intermediate γ‐lactols could be converted into dihydrofuran derivatives 8 [18]. After these preliminary results, a subsequent mechanistic study revealed an equilibrium

5

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1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes

between a TiCl4‐complex A and a red‐colored acyclic titanium enolate B at low temperatures [19]. This type of intermediate is likely responsible for the observed cis‐ trans‐isomerization of siloxy‐substituted cyclopropanecarboxylates at low temperatures [20]. Today, this type of activation is relevant for most reactions of DACs bearing two alkoxycarbonyl groups as activating substituents. By warming A/B to –30 °C, an elimination of chlorotrimethylsilane was observed. This provided a titanoxycyclopropane C, which is probably the reacting species with the carbonyl compound to form the new C–C product, again in a homo‐aldol type process, but now with the support of the acceptor group. Although many more studies were subsequently published by our group in the period between 1980 and 1995, I will conclude my personal story concerning DACs with this rather detailed presentation of basic ideas and early results. We used compounds such as 2 as convenient precursors for 1,4‐dicarbonyl compounds 3, which were in situ trapped by subsequent reactions; for instance, intramolecular Diels– Alder reactions, and in addition, we also studied Ugi and Gewald multicomponent reactions. The results of the first years were already summarized in a review article published in 1988 [21], and later, Reinhold Zimmer and I wrote a second review published in 2003. It was much more comprehensive, including many contributions from other groups, and so far has been cited almost 1200 times [22]. This second review and an article by Brian Pagenkopf published in 2005 [23] were probably responsible for widely popularizing the term DAC because it was used in the titles of these reviews. These articles drew the attention of many research groups to this type of small‐ring compound. Already in 2014, Daniel Werz – one of the current key players in the field – wrote an excellent comprehensive review entitled “A New Golden Age for Donor‐Acceptor Cyclopropanes” [24]. Although only selected review articles published afterward can be listed here [25], they all attest to the high importance DACs gained during the last 40 years. It should also be mentioned that a special issue of the Israel Journal of Chemistry published in 2016 is also exclusively devoted to the chemistry of DACs and the related donor–acceptor cyclobutanes [26].

1.3 A Few Principles of the Chemistry of Donor–Acceptor Cyclopropanes We must start with an unanswerable question: What is a donor, and what is an acceptor substituent? When the author of this chapter introduced the term DAC in 1980, his intention was to apply this name to cyclopropane derivatives bearing relatively strong electron‐donating substituents such as alkoxy, siloxy, amido, or amino groups, in combination with a vicinally positioned electron‐withdrawing substituent, and in most cases this substituent was a carbonyl or a cyano group. Later, the term DAC was less strictly employed, and cyclopropanes with substituents that are able to stabilize a positive or a negative charge can now be generally regarded.

1.3 A eew rinciples of the Chemistry of Donor–Acceptor Cyclopropanes

Figure 1.3 DACs polarized by different donor and acceptor substituents, respectively, and the respective zwitterionic mesomeric formula.

These substituents polarize the bond between the carbon atoms bearing the activating groups, a situation that can be characterized by a zwitterionic mesomeric formula, as depicted in a simplified manner in Figure 1.3. Many substituents can now be included in this (incomplete) list. On the donor side, many more substituents can be considered, in particular, aryl, hetaryl, or alkenyl groups. Even alkyl groups are able to stabilize a positive charge better than a hydrogen atom. The acceptor substituents are generally X Y double bond or X Y triple bond systems containing one or two heteroatoms. However, aryl, hetaryl, alkenyl, and alkynyl groups are also able to stabilize a negative charge and should be added as acceptor substituents in a systematic survey. It is obvious that two donor or two acceptor substituents should have a stronger influence on the reactivity of the cyclopropane than just one of these substituents. A very useful scale of the activating property of many of these substituents has been provided by Werz et al. who performed DFT calculations of the rearrangement of DACs to the corresponding five‐membered ring systems [27]. The effect of substituents on the reactivity of DACs in the presence of Lewis acids was also studied by Werz et al. [28], whereas Ofial et al. examined the reactivity of several acceptor‐substituted cyclopropanes, including a few DACs, in nucleophilic ring‐opening reactions by thiols in the absence of Lewis acids [29]. The reactions of DACs can be roughly classified into the categories of isomerization reactions, ring‐opening reactions, and cycloadditions. In Scheme 1.4, isomerizations are subdivided into reactions under the maintenance of the cyclopropane ring [case a)] cis/trans‐isomerizations and [case b)] racemizations), reactions under ring‐opening [case c)], and rearrangements under ring‐enlargement [case d)]. The latter case can be regarded as a (formal) 1,3‐sigmatropic rearrangement; the 3,3‐sigmatropic Cope‐rearrangements of cyclopropane derivatives bearing two alkenyl groups or their heteroanalogs, which lead to seven‐membered carbo‐ or heterocycles, are not listed here.

7

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1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes Isomerization reactions Acc

(a) Don

Don

Cis/trans isomerization Acc

(b) Don Don

Acc

Don

Racemization

Acc

Don

R R Acc or Don R Don Acc (c) Don Ring-opening under hydrogen shift (d) Don

R

Don

Acc

R

X =Y

Y X Formal 1,3-sigmatropic rearrangement

Scheme 1.4 Isomerization reactions of DACs (presentation in part under disregard of configurational aspects).

Ring‐opening reactions under the incorporation of reagents (Scheme 1.5) can occur through a primary nucleophilic attack at the donor‐substituted carbon [case a)], an electrophilic attack at the acceptor‐substituted carbon [case b)], or the attack of a radical, often observed as the addition of the radical to an alkenyl group as donor substituent [case c)]. Donors such as siloxy groups allow a reaction with fluoride as a nucleophile at the silicon center, delivering a cyclopropoxy anion whose ring opening directly generates a carbonyl group in a retro‐aldol process [case a), also see Scheme 1.1]. Similarly, the reactions of electrophiles can also lead to the formation of a carbonyl group if their counter ion X− reacts with the siloxy group [case b), also see Scheme 1.3]. The ring‐opening of acceptor‐substituted vinylcyclopropanes by palladium or other metal complexes, which affords π‐allyl complexes ready for further reactions with external or internal nucleophiles, is not presented here.

Ring-Opening reactions (a) Don

R

Nu (b) Don

R

R + H Don Acc Attack of nucleophiles Nu Acc

+X

Acc

Acc EI

EI R (c) X•

Scheme 1.5

Acc

+Y •

Attack of radicals X

O

R

Acc Y

Ring-opening reactions of DACs.

or

Acc R

H

Don R

Attack of electrophiles X

or

O

Acc R

EI

1.3 A eew rinciples of the Chemistry of Donor–Acceptor Cyclopropanes

Cycloadditions constitute a particularly important class of reactions of DACs. Only a few can occur without external promoters; however, Lewis acids are generally employed in stoichiometric or catalytic amounts in order to activate the cyclopropanes. Most frequently, the combination of two alkoxycarbonyl groups on the acceptor side and an (electron‐rich) aryl group on the donor side was used. In the simplified Scheme 1.6, only the overall processes are illustrated, showing that (3+2)‐cycloadditions give rise to five‐membered ring systems [case a)], and that several 1,3‐dipoles have been used in (3+3)‐cycloadditions, which furnish six‐ membered heterocycles [case b)]. A few examples of dimerizations of DACs have been reported, which also belong to the category of (3+3)‐cycloadditions. To complete the picture, (3+4)‐cycloadditions of DACs with 1,3‐(hetero)dienes are listed here [case c)], although this process is relatively rare. Higher‐order cycloadditions and reactions where a rearrangement of the DAC occurs before a cycloaddition proceeds have also been studied. Scheme 1.6 Schematic presentation of (3+n)-cycloaddition reactions of DACs (simplified presentation without Lewis acids frequently required in these processes).

(a)

Cycloadditions

R Don

Acc

+ X Y R Don

R Don

Acc +

W Z X Y

Acc

X Y Don R

Acc

X Y Z 1,3-dipole

R

(3 + 2) → 5

+

(b)

(c)

Don

(3 + 3) → 6

X

Acc Y

Z

Don R (3 + 4) → 7

W

X Y

Acc Z

All these basic reactions have been described in detail in the published reviews, and certainly, they will be discussed again in the following chapters. Here, I just want to draw attention to the very interesting early studies reported by Cram and coworkers, starting in 1970. As physical–organic chemists, they carefully studied the isomerizations of specifically substituted cyclopropanes, which are clearly DACs according to our current definition [30]. Scheme 1.7 shows a typical example: the thermal racemization of compound 9 involves zwitterionic intermediate D as a crucial species. Cram et al. called these systems “carbanion‐carbonium ion intermediates,” discussed the character of the intermediates (1,3‐zwitterion vs. singlet 1,3‐diradical), and determined the activation parameters. As expected, the rate of racemization is dependent on the polarity of the solvent, with a relative rate of 1 in benzene and 75 in dimethylformamide in the presence of lithium bromide. The lithium cation acts as a Lewis acid in these reactions, which are more complex due

9

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1 Introduction to the Chemistry of Donor–Acceptor Cyclopropanes

to subsequent ring‐opening and ring‐enlargement steps. In the case depicted in Scheme 1.7, the zwitterion D is a real existing intermediate with a certain lifetime, which is formed by the ring‐opening of 9 or ent‐9. It should not be mixed up with the zwitterionic mesomeric formula presented in Figure 1.3, which expresses the charge distribution of DACs. Ph

CO2Me

CN Δ, solvent Ph

Ph

CO2Me

Ph

CN

Scheme 1.7 Racemization of DAC 9 via zwitterionic intermediate D as studied by Cram et al.

ent-9

9

Ph Ph

CN CO2Me D

This almost forgotten study by Cram et al., published 50 years ago, is presented to emphasize that DAC chemistry is not entirely new and that a lot of information and inspiration can be gained by reading these detailed reports.

1.4 Remarks Regarding the Terminology Applied to the Use of Donor–Acceptor Cyclopropanes The correct use of unambiguous nomenclature and terminology is inevitable to avoid confusion. It facilitates smooth communication between scientists and is particularly important in teaching. Reactions of DACs are often described by applying incorrect or ambiguous terms, and therefore a few of these issues are discussed here. (a) The term “1,3‐dipole” or “1,3‐dipolar synthon” for DACs is misleading and incorrect. Huisgen clearly defined 1,3‐dipoles [31] as conjugated 4π‐system as depicted in Figure 1.4. These species always contain sp2‐ or sp‐hybridized heteroatoms Y in their center, which can bear a positive charge in an electron octet formula. The bonding situation of cyclopropanes can be described by the MO‐model by Walsh, which suggests that the C─C “single” bonds have considerable π‐character (below, σ/π is used to describe this type of bonding). The interaction of cyclopropane bonds with adjacent substituents is therefore stronger than expected [7a, 27]. The zwitterionic mesomeric formula of DACs reflects the polarization of the bond between donor‐ and acceptor‐substituted carbons and the dominating interaction with the substituents, but it has no common feature with 1,3‐dipoles. The central atom is – by definition – a carbon atom and therefore not in strong interaction with the two adjacent carbons.

1.4 ­emarrs ­eeardine the erminoloey Applied to the se of Donor–Acceptor Cyclopropanes

Figure 1.4 1,3-Dipoles according to Huisgen’s systematic classification and polarization of DACs.

(b) Very often, DACs are named “1,3‐dipolar synthons,” which is wrong in two aspects. For the use of “1,3‐dipole,” see the the previous discussion under (a). The term “synthon” was initially introduced by Corey to characterize a hypothetical (charged) unit within a target molecule that represents a potential precursor reagent [32]. However, Corey noted in 1988 that “synthon” has now come to be used to mean “synthetic building block” rather than a retrosynthetic fragment. Since the original meaning of “synthon” is still useful in retrosynthetic analysis, I suggest calling DACs “1,3‐zwitterionic building blocks” (or synthetic equivalents of a “1,3‐zwitterionic synthon”). (c) Surprisingly, the term “(3+n)‐cycloaddition” is inconsistently used when the reactions of DACs are discussed. It should be recalled first that parentheses, for instance, in (3+2)‐cycloaddition, should be used to define the number of centers involved in a cycloaddition, whereas brackets, for instance, in [4+2]‐cycloaddition, denote the number of (π)‐electrons involved in a cycloaddition. For reactions of DACs, several authors prefer the more general term “(3+n)‐annulation” or the even less specific “(3+n)‐cyclizations”. Indeed, the definition of cycloaddition reactions is ambiguous if cyclopropanes are involved. According to the criteria, as collected long ago by Huisgen [33], cycloadditions are ring‐forming reactions with an increase in the number of σ bonds. They are not associated with the elimination of small compounds or with the shift of atoms – at least in the ring‐forming step. The reaction mechanism involved (thermally or photochemically, concerted as pericyclic reactions or step‐ wise via intermediates, uncatalyzed or catalyzed) is irrelevant. Later, IUPAC recommends similar criteria but notes that two or more unsaturated molecules should participate in the formation of a cyclic adduct in which a net reduction of bond multiplicity can be observed [34]. Cyclopropanes are usually not regarded as unsaturated molecules, but their partial π‐character (see the previous discussion under (b)) justifies treating them as ethene homologs and calling the reactions summarized in Scheme 1.6 “real” cycloadditions if all other criteria are met. The prototype

11

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of a (3+2)‐cycloaddition of a cyclopropane to a five‐membered ring (Scheme 1.8) is electronically characterized as a [2σ/π+2π]‐process, in analogy to a (2+2)‐cycloaddition of two alkenes, which is a [2π+2π]‐process. I strongly recommend to act pragmatic and stay with the well‐established and frequently used term “(3+n)”‐ cycloadditions for cyclopropanes if the above‐mentioned criteria are met. Scheme 1.8 (3+2)-Cycloadditions of cyclopropanes to a double bond system X Y.

R + X =Y

(3 + 2) → 5 [2σ/π + 2π]

R Y X 2 new σ-bonds No elimination No bond shifts

1.5 Conclusions This introductory chapter should illustrate how the author was guided to introduce the term DACs and which types of reactions are possible with DACs. Studies conducted in the 1980s already revealed some of the important features of reactivity, for instance, the activation of DACs by Lewis acids. Later, the definition of DACs was expanded to include many new cyclopropane derivatives, particularly compounds with aryl groups as donor substituents. A tremendous development could be observed with many synthetically very useful transformations employing DACs as crucial C3‐building blocks. Impressive examples already exist on catalytic enantioselective processes [25h, 25i], and it can be expected that these will be further advanced. The currently observed increase in electron‐transfer‐promoted reactions may also influence the chemistry of DACs. Recent examples employing electrochemical methods can already be found in the literature [35]. Some functionalized bicyclo[1.1.0]butanes can also be classified as DACs, and a few ring‐opening reactions of these very strained compounds were reported [36]. This compound class is not particularly difficult to access, and therefore, more applications can be expected in the future. Finally, and most importantly, surprising and entirely new reactions of DACs are certainly still possible. The golden age of DACs is not finished.

­Abbreviations Acc DAC Don LDA

acceptor substituent donor–acceptor cyclopropane donor substituent lithium diisopropylamide

References

­References 1 Reissig, H.‐U. and Hirsch, E. (1980). Angew. Chem. Int. Ed. Engl. 22: 813–814. 2 (a) Wenkert, E. (1980). Acc. Chem. Res. 3: 27–31. (b) Wenkert, E. (1980). Heterocycles 14: 1703–1708. (c) For an excellent summary of Wenkert’s contributions to cyclopropane chemistry, see:Hudlicky, T. (2016). Isr. J. Chem. 56: 540–552. 3 Freund, A. (1882). Monatsh. Chem. 3: 625–635. 4 Perkin, W.H. Jr. (1884). Ber. Dtsch. Chem. Ges. 17: 54–59. 5 Baeyer, A. (1885). Ber. Dtsch. Chem. Ges. 18: 2269–2281. The important chapter on strain theory is presented in an appendix on page 2278–2281 of this article about polyacetylenes. 6 Seebach, D. (1979). Angew. Chem. Int. Ed. Engl. 18: 239–258. 7 (a) De Meijere, A. (1979). Angew. Chem. Int. Ed. Engl. 18: 809–826. (b) De Meijere, A. (1987). Chem. Ber. 23: 865–879.8 Danishefsky, S. (1979). Acc. Chem. Res. 12: 66–72. 9 Stevens, R.V. (1977). Acc. Chem. Res. 10: 193–198. 10 (a) Houk, K.N. and Reissig, H.‐U. (2019). Chem. 5: 2499–2505. (b) Giese, B., Mayr, H., and Reissig, H.‐U. (2020). Angew. Chem. Int. Ed. 59: 12228– 12232. 11 Piers, E. and Reissig, H.‐U. (1979). Angew. Chem. Int. Ed. Engl. 18: 791–792. 12 Reissig, H.‐U. (2021). Angew. Chem. Int. Ed. 60: 9180–9191. 13 Kunkel, E., Reichelt, I., and Reissig, H.‐U. (1984). Liebigs Ann. Chem. 802–819. 14 (a) Reissig, H.‐U. and Böhm, I. (1982). J. Am. Chem. Soc. 104: 1735–1737. (b) Reichelt, I. and Reissig, H.‐U. (1984). Liebigs Ann. Chem. 531–551. 15 (a) Brückner, C. and Reissig, H.‐U. (1985). J. Chem. Soc. Chem. Commun. 1512–1513. (b) Brückner, C. and Reissig, H.‐U. (1988). J. Org. Chem. 53: 2440–2450. 16 (a) Brückner, C. and Reissig, H.‐U. (1985). Angew. Chem. Int. Ed. Engl. 24: 588–589. (b) Brückner, C. and Reissig, H.‐U. (1988). Liebigs Ann. Chem. 465–470. (c) Brückner, C., Suchland, B., and Reissig, H.‐U. (1988). Liebigs Ann. Chem. 471–473. 17 Nakamura, E. and Kuwajima, I. (1977). J. Am. Chem. Soc. 22: 7360–7362. 18 (a) Reissig, H.‐U. (1981). Tetrahedron Lett. 22: 2981–2984. (b) Reissig, H.‐U., Reichelt, I., and Lorey, H. (1986). Liebigs Ann. Chem. 1924–1939. 19 Reissig, H.‐U., Holzinger, H., and Glomsda, G. (1989). Tetrahedron 45: 3139–3150. 20 Reissig, H.‐U. and Böhm, I. (1983). Tetrahedron Lett. 24: 715–718. 21 Reissig, H.‐U. (1988). Top. Curr. Chem. 144: 73–135. 22 Reissig, H.‐U. and Zimmer, R. (2003). Chem. Rev. 103: 1151–1196. 23 Yu, M. and Pagenkopf, B.L. (2005). Tetrahedron 61: 321–347. 24 Schneider, T.F., Kaschel, J., and Werz, D.B. (2014). Angew. Chem. Int. Ed. 53: 5504– 5523. 25 (a) de Nanteuil, F., De Simone, F., Frei, R. et al. (2014). Chem. Commun. 50: 10912– 10928. (b) Cavitt, M.A., Phun, L.H., and France, S. (2014). Chem. Soc. Rev. 43: 804–818.

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26 27 28 29 30

31

32 33 34

35

36

(c) Grover, H.K., Emmett, M.R., and Kerr, M.A. (2015). Org. Biomol. Chem. 13: 655– 671. (d) Pagenkopf, B.L. and Vemula, N. (2017). Eur. J. Org. Chem. 2561–2567. (e) Budynina, E.M., Ivanov, K.I., Sorokin, I.D., and Melnikov, M.Y. (2017). Synthesis 49: 3035–3068. (f) Ivanova, O.A. and Trushkov, I.V. (2019). Chem. Rec. 19: 1–21. (g) Singh, P., Varshnaya, R.K., Dey, R., and Banerjee, P. (2020). Adv. Synth. Catal. 362: 1447–1484. (h) Pirenne, V., Muriel, B., and Waser, J. (2021). Chem. Rev. 121: 227–263. (i) Xia, Y., Liu, X., and Feng, X. (2021). Angew. Chem. Int. Ed. 60: 9192–9204. (j) Augustin, A.U. and Werz, D.B. (2021). Acc. Chem. Res. 54: 1528–1541. (k) Gosh, K. and Das, S. (2021). Org. Biomol. Chem. 19: 965–982. (l) Gosh, A., Dey, R., and Banerjee, P. (2021). Chem. Commun. 57: 5359–5373. Introductory editorial for 16 articles: Reissig, H.‐U. and Werz, D.B. (2016). Isr. J. Chem. 56: 367–368. Schneider, T.F. and Werz, D.B. (2011). Org. Lett. 13: 1848–1851. Kreft, A., Lücht, A., Grunenberg, J. et al. (2019). Angew. Chem. Int. Ed. 58: 1955– 1959. Jüstel, P.M., Stan, A., Pignot, C.D., and Ofial, A.R. (2021). Chem. Eur. J. 27: 15928– 15935. (a) Yankee, W.E. and Cram, D.J. (1970). J. Am. Chem. Soc. 92: 6328–6329. (b) Yankee, W.E. and Cram, D.J. (1970). J. Am. Chem. Soc. 92: 6329–6331. (c) Yankee, W.E. and Cram, D.J. (1970). J. Am. Chem. Soc. 92: 6331–6333. (d) Yankee, W.E., Badea, F.D., Howe, N.E., and Cram, D.J. (1973). J. Am. Chem. Soc. 95: 4210–4219. (e) Yankee, W.E., Spencer, B., Howe, N.E., and Cram, D.J. (1973). J. Am. Chem. Soc. 95: 4220–4230. (f) Howe, N.E., Yankee, W.E., and Cram, D.J. (1973). J. Am. Chem. Soc. 95: 4230–4237. (g) Chmurny, A.B. and Cram, D.J. (1973). J. Am. Chem. Soc. 95: 4237–4244. (a) Huisgen, R. (1963). Angew. Chem. Int. Ed. Engl. 2: 565–598. (b) Huisgen, R. (1963). Angew. Chem. Int. Ed. Engl. 2: 633–645. (c) Breugst, M. and Reissig, H.‐U. (2020). Angew. Chem. Int. Ed. 59: 12293–12307. Corey, E.J. (1967). Pure Appl. Chem. 14: 19–37. Huisgen, R. (1968). Angew. Chem. Int. Ed. Engl. 7: 321–328. McNaught, A.D. and Wilkinson, A. (ed.) (1997). IUPAC‐Compendium of Chemical Terminology (the “Gold Book”), 2e; compiled by, 6. Oxford: Blackwell Scientific Publications. (a) Kolb, S., Ahlburg, N.L., and Werz, D.B. (2021). Org. Lett. 23: 5549–5553. (b) Kolb, S., Petzold, M., Brandt, F. et al. (2021). Angew. Chem. Int. Ed. 60: 15928– 15934. (c) Saha, D., Taily, I.M., and Banerjee, P. (2021). Eur. J. Org. Chem. 5053–5057. McNamee, R.E., Haugland, M.M., Nugent, J. et al. (2021). Chem. Sci. 12: 7480–7485.

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2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes: Structural and Electronic Analysis Anu Jacob1, Gwyndaf A. Oliver2, and Daniel B. Werz2 1

Institut für Organische Chemie, Technische Universität Braunschweig, Hagenring 30, D-38106 Braunschweig, Germany Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, D-79104 Freiburg, Germany 2

CHAPTER MENU 2.1 2.2 2.3 2.4 2.5

Introduction, 15 Activated Cyclopropanes, 17 Donor–Acceptor Cyclopropanes (DACs), 19 Computational and Kinetic Investigations, 22 Concluding Remarks, 32 References, 32

2.1 Introduction Cyclopropanes with their strained bonds show great potential for simple and rapid transformations, leading to complexity in very few steps [1]. Although cyclopropanes are highly energetic molecules with a ring strain of about 115 kJ mol−1 [2], the C─C bonds of these molecules are kinetically rather inert and maintain the integrity of the ring. Unlike other saturated carbocycles, cyclopropanes undergo electrophilic reactions in the presence of mineral acids [3, 4] and add oxidatively to transition metals [5, 6]. The bonding and corresponding unique reactivity of cyclopropanes can be rationalized by various models. The strain model provides a simple explanation of how the highly strained system lowers its energy through a ring-opening reaction. For cyclopropane, the internuclear angle is 60°, which is far from the ideal sp3 geometry and minimizes electrostatic repulsion requirements. The geometry of cyclopropane

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

Figure 2.1 Orbitals by Förster, Coulson and Moffitt.

106°

requires co‐planarity of the three carbon atoms. This fact leads to an eclipsed arrangement of the C─H bonds, causing, in addition to the Baeyer strain, a torsional strain (Pitzer strain). Therefore, many explanations for the increased reactivity of cyclopropanes in comparison with other cyclic alkanes are based on the relief of ring strain. However, this model is insufficient to entirely account for the reactivity of cyclopropanes. Another rationale using elaborate bonding models was suggested by Förster [7] and refined by Coulson and Moffitt [8, 9]. They regard the σ‐bonds in cyclopropanes as being bent (Figure 2.1). There is about a 20% reduction in the overlap between two carbon atoms compared to that in ethane. This adds to the increased angular strain, thereby an increased reactivity is observed. Their theory advocates that the C─C bonds are built from sp5‐hybridized orbitals and C─H bonds are built from sp2.3‐hybridized orbitals. This assumption explains the high π character of the ring and leads to an understanding of why similar reactivity to that of alkenes is observed. X‐ray crystallographic data for cyclopropane derivatives validated the concept of bent bonds. The maximum electron density is found outside the conventional bond axes [10]. However, this model was unsuccessful in rationalizing the effect of electron‐donating and withdrawing substituents on the reactivity and stability of cyclopropanes. The Walsh model gives a detailed description of bonding in cyclopropanes [11]. It was assumed that the bonding in cyclopropanes is represented more precisely by the combination of sp2 hybrid orbitals and pz‐orbitals. The in‐phase combination of the three sp2 orbitals produces a molecular orbital (MO) with a large electron density in the center of the ring, which makes up the lowest energy orbital ψ1. The three pz orbitals directed outside to the corners of a hypothetical triangle form a degenerate pair of highest‐occupied molecular orbitals (HOMOs) ψ2 and ψ3. These orbitals are called the Walsh orbitals of cyclopropane (Figure 2.2). Their electron density does not lie along the internuclear axis; they mirror the kind of bent bonds in the model Figure 2.2 Walsh molecular orbitals of cyclopropane.

Ψ6 Ψ4

Ψ5

Ψ2

Ψ3 Ψ1

2.2 Activated Cyclopropanes

of Förster, Coulson, and Moffitt. These orbitals account for the π‐character of the ring; energetically, they are relatively high‐lying orbitals for a saturated hydrocarbon. The lowest unoccupied molecular orbitals (LUMOs) ψ4 and ψ5 are formed similarly to the ψ1 orbital of sp2 orbitals, which are directed to the center of the ring, but in a destructive fashion. The highest‐energy unoccupied orbital ψ6 is formed by the destructive overlap of p‐orbitals. The Walsh orbitals are excellent π‐donors, interacting well with low‐lying vacant orbitals [12]. The presence of electron density at the center of the ring, explained by ψ1, brings forth the concept of σ‐aromaticity of cyclopropanes. The stabilization comes from the aromaticity due to σ‐bonds. The ring consists of six electrons positioned across the three atoms, obeying the (4n+2) rule of Hückel for aromaticity. This stabilization might explain its reactivity toward electrophiles while also explaining the strong localized diatropic ring current due to which a significant shielding of its 1H nuclei (signals at δ = 0.22) is observed in comparison to larger cycloalkanes (signals at δ = 1.44–1.54) [13]. The current understanding of the structure and reactivity of cyclopropanes can be drawn from all the concepts, including ring strain, distorted π‐like bonds, and σ‐aromaticity.

2.2 Activated Cyclopropanes Although cyclopropanes show a significant amount of ring strain, they are kinetically rather inert. Thus, additional functional groups need to be attached to the ring to allow mild and synthetically efficient transformations. Only a few reactions of cyclopropanes – such as some special ring‐opening, ring‐enlargement and pericyclic reactions – take place without the aid of activating substituents; however, harsh conditions are required. Examples of this reactivity are the vinylcyclopropane– cyclopentene or divinylcyclopropane–cycloheptadiene reactions [14]. Cyclopropanes substituted with electron‐withdrawing groups are termed acceptor cyclopropanes. They behave analogously to γ‐carbonyl cation equivalents/homologous Michael acceptors. Cyclopropanes substituted with electron‐donating groups are called donor cyclopropanes, and they act as homologous enolate equivalents [15]. The first example of a ring‐opening reaction of an activated cyclopropane was published by Bone and Perkin in 1895 [16]. They showed the ring‐opening of cyclopropane 1 using an enolate generated from diethyl malonate 2 to obtain 3 in 50% yield (Scheme 2.1). O

EtO2C CO2Et

O

+ EtO 1

Scheme 2.1

OEt 2

CO2Et

NaOEt, EtOH 50%

EtO2C

3

CO2Et CO2Et

Nucleophilic ring-opening of acceptor cyclopropanes.

Homologous Michael reactions of activated cyclopropanes employing a range of nucleophiles such as amines [17], mercaptans [17], enamines [18], and cuprates [19]

17

18

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes O

O

O

O

O O

O

O

O 4

5

O

1,7

O

O O

1,5

O

6

O O 7

(a)

(b)

Figure 2.3 (a) Spiroacylal mode of activation in 5 and 6, (b) modes of attack on a vinyl cyclopropane.

were later explored. However, the harsh reaction conditions and mediocre yields dimmed the utility of these intermolecular reactions. This was however tackled by Danishefsky and coworkers by choosing a spiroacylal for diester activation, instead of 4, where the carbonyl groups are orthogonal to the plane of the cyclopropane (5) [20]. This enables the emerging carbanion to delocalize over the alkoxycarbonyl groups (Figure 2.3). A spiroacylal linkage may allow greater charge separation in the transition state for ring‐opening, reflecting the stabilization of the transition state leading to the presumed intermediate 6 (Figure 2.3a). This fact is easily understood from the relative acidity of Meldrum’s acid (pKa ~ 5) compared to acyclic malonic esters (pKa ~ 14). Investigations into nucleophilic attacks on vinylcyclopropane by Singh and Danishefsky [21] showed that an exclusive 1,5‐attack was observed when spiroacylal was chosen as the acceptor motif as in 7 (Figure 2.3a), whereas a competing 1,5‐ and 1,7‐mode of nucleophilic addition took place in case of 4 (Figure 2.3b). This transformation under mild conditions underscores the value of spiroactivated vinylcyclopropanes in various synthetic strategies. The remarkable electrophilic properties of spiroactivated cyclopropanes suggested a simple synthesis of trans‐fused γ‐lactones 10, improving upon the conventional synthetic route involving epoxidation of olefins followed by the nucleophilic attack by an acetic acid ester carbanion equivalent. This trans‐diaxial solvolysis reaction underlined the effectiveness of this activation mode (Scheme 2.2) [22]. O O

O H

H

H2O Reflux

OH 8

Scheme 2.2

H

H HO2C

H O

HO

H

O

9

H 10

trans-Fused γ-lactone synthesis from activated cyclopropanes.

Total synthesis of (±)‐martinellic acid 14 was reported by Snider et al. in 2001 [23]. Derivatives of 14 have been recognized as antagonists for bradykinin receptors (B1, B2). Activated vinyl cyclopropane 5 was utilized in this total synthesis route. The synthetic strategy included ring‐opening of 5 by substituted aniline 11, followed by lactamization–oxidation to yield vinylpyrrolidone 12. Reaction with N‐benzylglycine and a subsequent intramolecular (3+2)‐cycloaddition deliver 13, a precursor to (±)‐ martinellic acid 14 (Scheme 2.3).

2.3 Donor–Acceptor Cyclopropanes DACss

(a) Br O

O

OH Br

NH2

O

11 Toluene, reflux, 24 h

O

(b) MnO2

O

N

CO2H

N

NHBn Toluene, Δ

O

N Bn 13

12

5

O

Br

HN HN O N HO N H

H N

H N

NH 14 (±)-Martinellic acid

Scheme 2.3 Total synthesis of (±)-martinellic acid 14.

2.3 Donor–Acceptor Cyclopropanes (DACs) A significant breakthrough in the realm of cyclopropane chemistry was realized by substituting the three‐membered ring with donor and acceptor moieties in a vicinal fashion. Donor and acceptor substituents act as a push–pull trigger and activate the ring, thereby enabling the molecule to be vulnerable to even mild reaction conditions. The transformations of this molecule were extensively researched by Wenkert and Reißig in the 1980s [24–31]. All the reactions could be rationalized by taking a 1,3‐zwitterionic relationship into account, wherein the negative charge is stabilized by the electron‐withdrawing group and the positive charge by an electron‐donating group (Figure 2.4). A variety of activation methods are known for donor–acceptor cyclopropanes (DACs), as shown in Scheme 2.4. The most widely studied of these is Lewis acid catalysis [32–36]. However activation by organocatalysis [37, 38], radicals [39], and electrochemical single electron transfer (SET) oxidation [40] are also known and give access to a variety of different intermediates for interesting chemical processes. DACs can be easily activated by Lewis acids, which coordinate with the acceptor motifs and enhance their electron‐withdrawing ability. This polarization weakens the σ‐bond between the donor and acceptor carbon atoms, facilitating various reactions. DACs have been employed for ring‐opening reactions [41–63], cycloadditions [64–85], and rearrangements [86–91]. Scheme 2.5 depicts the general reactions of DACs under Lewis acid catalysis. Figure 2.4 Zwitterionic relationship in vicinally substituted donor–acceptor cyclopropanes 15.

D D

A

A 15

16

19

20

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

Scheme 2.4

D

Known activation strategies for DACs.

δ+ δ– X-Y

A

+

D

–

Nu

A LA

E

Cycloaddition

Activated complex LA = Lewis acid Nu = Nucleophile E = Electrophile

Scheme 2.5

Y

Ring-opening

LA

X

D

A

D

A

Nu

E

D Rearrangement

A

Different reactivities of DACs by Lewis acid catalysis.

2.3 Donor–Acceptor Cyclopropanes DACss

Ring‐opening reactions in DACs are among the most straightforward and efficient ways to construct 1,3‐functionalized structures. Nucleophilic ring‐opening reactions of activated cyclopropanes could be viewed as homologous Michael additions. In contrast, for DACs, such ring‐opening reactions can be considered as bimolecular nucleophilic substitution reactions (SN2), taking into consideration the inversion of configuration at the reactive center. Ring‐opening reactions by electrophiles require umpolung, which is generally achieved by transition metal catalysis of DACs with a vinyl donor [92–95]. Recently, multicomponent reactions where a nucleophile opens the ring and a suitable electrophile is trapped by the malonate anion have attracted the attention of cyclopropane chemists [53–63]. Cycloaddition reactions in DACs deliver highly functionalized four‐, five‐, six‐, or seven‐membered rings. Saturated or partially unsaturated rings are obtained by these (3+n) reactions [64–85]. These reactions are highly regioselective, as the carbon atom bearing the donor motif is preferentially attacked by the more nucleophilic part of the incoming reaction partner. Diastereo‐ and enantioselective versions have been explored with the aid of chiral substrates, chiral Lewis acids, or dynamic kinetic resolutions [96–108]. Rearrangements are another major class of transformation undergone by DACs. Thereby, the acceptor moiety is incorporated into the three‐membered ring. Delocalization of the negative charge from the carbon atom to a heteroatom of the acceptor allows the heteroatom to attack the emerging positive charge next to the donor. The classical rearrangements involving cyclopropanes are cyclopropylimine‐pyrroline and cyclopropylcarbaldehyde‐dihydrofuran rearrangements investigated originally by Cloke [109] and Wilson [110] in 1929 and 1947, respectively. However, the first rearrangement involving a pure hydrocarbon backbone dates back to 1959, when Neureiter transformed 1,1‐dichloro‐2,2‐dimethylcyclopropane to 4,4‐dichlorocyclopentene under pyrolysis conditions [111]. The fact that such harsh conditions are required for the hydrocarbon system can be traced back to the non‐polarized nature of this cyclopropane derivative, which impressively demonstrates how polarization lowers the activation barrier. In contrast, with DACs, numerous rearrangements were realized under very mild reaction conditions. Activation of the acceptor motifs by Lewis or Brønsted acid further lowers the activation barrier for the intramolecular attack on the donor‐substituted carbon of the cyclopropane. Thus, DACs have been subject to a multitude of explorations as versatile synthons [112–115]. Cyclopropanes bearing an aldehyde were first activated by organocatalysis in 2011 by Sparr and Gilmour [37]. In this system, the electron‐withdrawing aldehyde group becomes a donor group upon the formation of iminium/enamine [37, 116]. The initial work with an aldehyde attached directly to the three‐membered ring showed concomitant electrophilic and nucleophilic chlorination. Later works employing a system with an extra CH2 linkage between the cyclopropane and the aldehyde led to cycloadditions [38, 117–119], and in one particularly interesting case by Jørgensen et al. the formation of a [2+2] product rather than the classical 1,3‐dipolar chemistry (Scheme 2.6).

21

22

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

O

O

N

H A

N H

X=Y A A

A

Scheme 2.6

H X

A Y

A

Unexpected [2+2] products formed by organocatalytic activation.

In contrast to the organocatalytic method for the formation of 1,3‐dichlorinated products, the Werz group developed a radical approach for this same reaction [39]. Homolytic cleavage of the polarized C─C bond, leading to a radical intermediate, allowed a reaction with further chlorine radicals. Following this, they went further and developed electrochemical methods for the activation of DACs [40, 120]. Direct anodic SET oxidation of the arene donor group is followed by a homolytic C─C bond cleavage. The resulting radical cation intermediate was then shown to react with triplet oxygen forming β‐hydroxyketones, or with arenes in Friedel–Crafts‐type reactions (Scheme 2.7, please see Chapter 10, Scheme 10.46, 10.47, for more details). Electrochemical SET oxidation Ar

A

+

Ar

O

3O

2

•

A

Ar

OH A

Ar'

Ar' H Ar

A

Scheme 2.7 Electrochemical reactions of DACs.

Investigations on the structural and kinetic properties of different DACs provided quantitative data for their strongly enhanced reactivity. This book chapter compiles the published information about the influence of structure and electronics on the reactivity of these strained, commonly used building blocks in organic synthesis.

2.4 Computational and Kinetic Investigations An astonishing renaissance has been seen in the field of DAC chemistry in the last few decades. Nevertheless, investigations into the physical organic details were not satisfactorily carried out until 2019. In 1974, Danishefsky and Rovnyak investigated the effects of alkyl substituents on the nucleophilic ring‐opening of activated cyclopropanes [121]. They chose compounds 17 and 22 as model substrates and investigated their reactions with pyrrolidine. The nucleophile was observed to attack at the C2 and C3 positions of cyclopropane 17, delivering four products 18–21 (Scheme 2.8). The reaction is rather low‐ yielding and only poorly chemoselective (3:2 ratio of attack at C2 vs. C3). A slow and low‐yielding reaction with pyrrolidine was observed for 22. The emergence of carbonium ion character in the ring‐opening transition state is consistent with the

2.4 Computational and inetic Investigations

preferential attack at the highly substituted carbon. However, the steric hindrance and the Thorpe–Ingold effect caused by the geminal alkyl groups retard the attack of the nucleophile on 22 compared to 17.

Scheme 2.8

Chemoselectivity in reactions of DACs substituted with an alkyl group.

In 2011, the influence of different push–pull combinations of donors and acceptors on ring‐enlargement reactions of DACs was studied by Werz and Schneider using density functional theory (DFT) computations [122]. Figure 2.5 shows the model systems chosen for the study. Eight donor and nine acceptor moieties gave 72 Donors (D) MeO

MeS

(MeO)

(MeS)

D

A Me

MeSe

Me2N

(MeSe)

(Me2N)

D

a 24

Me2P

Me

(Me2P)

(Me)

Ph

CI

(Ph)

(CI)

Acceptors (A)

Me

Me

(CHO)

(COMe)

O

φ X Y

O (COOR) (R = H, Me)

Me X Z

NH (CHNH)

H N

Me

(CHNMe)

Y 25

H

OR Z

via TS24–25

D

H

N O

O

(NO2)

H S (CHS) N O (NO)

Figure 2.5 Donor (D) and acceptor (A) combinations investigated in a rearrangement study by Werz and Schneider.

23

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

250 225 200 175 150 125 100 75 50 25 0

ΔG ‡ (kJ/mol )

24

CI

PM

M

Ph

M S O Me e M e

e

2

e

Se

N

no

Do

r

M e2

e M O OH O C CO NO 2 e M e O Ac C HNM NH ce C O CH CH S pto r CH O N

Figure 2.6 Transition state energies for the ring-enlargement reactions from 24 to 25 derived by B3LYP/6-311G(d) calculations for different combinations of donor and acceptor substituents.

D–A combinations with the cyclopropanes 24 as starting materials and the respective products 25 connected via transition states TS24–25 (Figure 2.5). Figure 2.6 depicts the combinations arranged from the most efficient (Me2N/NO) to the least efficient (Cl/COOMe) system for ring‐enlargement. The activation barrier for the 1‐amino‐2‐nitroso‐substituted cyclopropane is so low that this compound should not exist; rather, it would immediately rearrange to the ring‐enlarged system. In general, low transition state energies are found for the combination of strongly electron‐donating substituents (Me2N, MeO) as donors with rather electron‐withdrawing substituents (NO, CHS, CHO) as acceptors. The data reveals that aromatic groups are better donors than aliphatic groups. Other than the nitroso and thioaldehyde acceptors, which lower the transition state energies to a great extent, relatively small differences were encountered for the other acceptors investigated. The lowest energy pathway from the three‐ to the five‐membered ring is via a concerted process; computations taking into account the involvement of zwitterionic or diradical intermediates showed these pathways to be higher in energy. Natural bond orbital (NBO) analyses translate the computational solutions of the Schrödinger wave equation into a simple and familiar chemical bonding concept [123]. The Wiberg bond index (WBI) [124] obtained from NBO analyses provides a quantification of electron population overlap between two atoms. The WBI of the formal single bond between the donor and the acceptor substituent ranges from 0.86 (24(MeS/ CHS)) to 0.94 (24(Cl/NO2)). In general, a value below 1 indicates a weakened bond. A small WBI for the bond, a (the bond between donor and acceptor) and a large angle ф (see Figure 2.5) in the late transition states are observed in combinations such as (Me2N/CHS) and (MeO/NO). Figure 2.7 depicts the facile ring‐enlargement of 24(Me2N/CHS) to 25(Me2N/CHS) with a late transition state TS24–25.

2.4 Computational and inetic Investigations

60

ΔG (kJ/mol)

40 TS24–25

20 0 –20 –40 –60

25 24 Transition Cyclopentene state reaction coordinate

Cyclopropane

Figure 2.7 Optimized structures of cyclopropane 24(Me2N/CHS), transition state TS24–25, and dihydrothiophene 25(Me2N/CHS) as calculated at the B3LYP/6-311G(d) level. Table 2.1 Comparison of transition state energies (ΔG‡), reaction enthalpies (ΔGR) in vacuo, and different solvents based on the PCM model (calculated at the B3LYP/6-311G(d) level of theory). 24 (D/A)

Solvent

ΔG‡a

ΔΔG‡a,b

ΔGRa

ΔΔGRa,b

(MeO/CHO)

In vacuo

154.4

—

−25.7

­

­

PhMe

146.4

−8.0

−22.1

3.6

­

CH2Cl2

137.8

−16.6

−19.3

6.4

−18.5

7.2

DMSO

134.2

−20.2

(MeO/COOMe)

In vacuo

171.6

­

­

PhMe

164.2

−7.4

14.2

5.9

­

CH2Cl2

154.5

−17.1

18.7

9.8

­

DMSO

148.8

−22.8

18.9

10.9

(Me2N/CHO)

In vacuo

108.2

—

−4.2

­

­

PhMe

92.0

−16.2

8.0

12.2

­

CH2Cl2

74.4

−33.8

10.6

14.7

­

DMSO

67.2

−41.1

11.4

15.5

−1

a) Values are given in kJ mol . b) Differences of ΔG‡ and ΔGR, respectively, to the corresponding values in vacuo.

The role of solvents in the reaction was studied using computational methods. Table 2.1 compares activation barriers (ΔG‡a) and reaction enthalpies (ΔGRa) in vacuo and in three different solvents (toluene, dichloromethane, and dimethyl sulfoxide (DMSO)) for three selected examples. DMSO was found to tremendously

25

26

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

D

Me

Me

R R' A D 26

Figure 2.8

A

A

D

A

D

A D

27

28

R, R' = H, Me D = MeO; D' = NMe2 D'

A = CHO, COOMe

29

Further substitution patterns of D–A cyclopropanes.

Table 2.2 Influence of the methyl group and the stereochemistry of the donor– acceptor-substitution (calculated at the B3LYP/6-311G(d) level of theory). 26 (D/A)

R/R

ΔG‡a

ΔΔG‡a,b

ΔGRa

ΔΔGRa,b

(MeO/CHO)

Me/H

154.4

—

−25.7

­

­

H/H

149.1

−5.3

−34.8

−9.1

­

Me/Me

147.0

−7.4

−26.1

−0.4

(MeO/COOMe)

Me/H

171.6

­

H/H

168.6

−3.0

7.4

−6.2

Me/Me

163.3

−8.4

8.0

−0.6

27 (D/A)

R/R

ΔG‡a

ΔΔG‡a,b

ΔGRa

ΔΔGRa,b

(MeO/CHO)

Me/H

132.8

−21.6

−40.7

15.0

(MeO/COOMe)

Me/H

164.8

−6.8

30.6

22.6

−1

a) Values are given in kJ mol . b) Differences of ΔG‡ and ΔGR, respectively, to the corresponding values for the system with one methyl substituent.

lower the transition state energy. This behavior was attributed to the stabilization of highly polarized transition states in polar aprotic solvents. Studies on the influence of methyl groups as further substituents on the ring and the stereochemistry of the donor–acceptor substitution were conducted (Figure 2.8). It was found that the presence of methyl groups (26) has no significant influence on the energetics of the ring‐enlargement (Table 2.2). cis‐Substituted D–A cyclopropane 27 tends to have a smaller activation barrier than the corresponding trans‐isomer. Furthermore, the effect of additional donors and acceptors on 28 was investigated (Table 2.3). A decrease in transition state energies (ΔG‡) was observed as expected with an increase in substitution, although no significant influence was observed for the reaction enthalpies (ΔGR). In order to access seven‐membered ring 31 starting from a DAC, ring‐enlargement of a cyclopropane with a vinylogous aldehyde acceptor 30 might be a favorable route (Scheme 2.9). An energy gain of 57 kJ mol−1 was computed when a vinylogous aldehyde was employed as the acceptor because of the much less strained transition state TS30–31, compared to the five‐membered transition state that would form when employing a MeO/CHO system.

2.4 Computational and inetic Investigations

Table 2.3 Effects of substitution with an additional acceptor and a further donor, respectively (calculated at the B3LYP/6-311G(d) level of theory). 28 (DD/AA)

ΔG‡a

ΔΔG‡a,b

ΔGRa

ΔΔGRa,b

(MeO/CHO)

154.4

—

−25.7

­

(MeO/(CHO)2)

94.9

−59.5

−60.0

−34.3

((MeO)2/CHO)

85.0

−69.4

−41.9

−16.2

(MeO/COOMe)

171.6

­

(MeO/(COOMe)2)

147.1

−24.5

9.4

1.4

a) Values are given in kJ mol−1. b) Differences of ΔG‡ and ΔGR, respectively, to the corresponding values in system 24.

Me

Me

Me

MeO

MeO O

O

TS30–31

30

Scheme 2.9

MeO O

31

Ring-enlargement of cyclopropane 30 to seven-membered ring 31.

The requirement for a further, detailed kinetic study of several DACs was realized by the same group in 2019 [125]. Werz and co‐workers shed light on the influences of structural and electronic properties on the reactivity of DACs. Physical‐organic data of these molecules, such as bond lengths obtained from X‐ray studies or DFT calculations, and relaxed force constants (RFC), were compared with kinetic rate constants. The (3+2)‐cycloaddition reaction of an aldehyde to a DAC in the presence of SnCl4 to form tetrahydrofuran was chosen as the model reaction for the kinetic investigation of different D–A systems. It was found that there was a first‐ order dependence on reaction rate with respect to the aldehyde. Because the Lewis acid loading is very low, the cyclopropane is found to have a zero‐order dependence on rate at higher concentrations. A pseudo‐first‐order rate law was specified for the above system, d product dt

= k × cyclopropane

0

× aldehyde

1

The rate constants of 18 different D–A cyclopropanes were determined by examining the consumption of aldehyde (Figure 2.9a). This data was logarithmically evaluated by employing the least‐squares fitting method (Figure 2.9b). The rate constants were determined from the slope of this fitting curve. To allow for comparison, the value for the system with a phenyl group as a donor and two geminal methyl esters as acceptors was arbitrarily designated as 1 (krel = 1). Table 2.4 provides the relative rate constants for the reaction of 4‐fluorobenzaldehyde with different D–A cyclopropanes. It was observed that electron‐rich donors on the

27

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes 100 p-CF3-Phenyl

Phenyl

80

p-Br-Phenyl

Naphthyl

p-CI-Phenyl

p-Me-Phenyl

70 60 50 40 30

4.4 4.2 4.0 3.8 3.6

p-CF3-Phenyl

3.4

p-CI-Phenyl

20

3.2

10

3.0

0 (a)

4.6

90

In(c Aldehyde)

c Aldehyde (μmol.ml–1)

28

0

2

4

6 8 t (h)

10

12

14

p-Br-Phenyl Phenyl Naphthyl p-Me-Phenyl

2.8 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 (b) t (h)

Figure 2.9 (a) Plot of consumption of aldehyde over time; (b) logarithmic plot of consumption of aldehyde over time.

cyclopropane such as p‐methoxyphenyl (krel = 49.7) and p‐methylphenyl (krel = 6.32) led to fast reactions. A naphthyl donor with its extended π‐system accelerated the reaction by a factor of 3.12, the same holds true for the cyclopropyl donor with a factor close to 2. It has been observed that halogen‐substituted donors lowered the rate slightly, whereas succinimide reduced the rate to 0.12. A sluggish reaction has been observed when electron‐poor groups such as p‐F3CC6H4 or p‐O2NC6H4 were chosen as donors (krel = 0.0077 and krel = 0.0015, respectively). It should be noted that the cyclopropane with a phthalimide donor reacts about 350 times faster than with a succinimide donor. Investigating the influence of different esters as acceptors revealed that replacing methyl with ethyl or benzyl groups decreased the rate of reaction. Most probably, this is due to the inability of these more sterically encumbered ester groups to efficiently coordinate with Lewis acids. An excellent correlation was observed when the measured logarithmic rate constants (log(krel)) for para‐substituted D–A cyclopropanes were tabulated against Hammett substituent parameters (σ) (Figure 2.10). The slope of the Hammett plot, known as the reaction parameter ρ, provided information about the associated reaction mechanism [126]. The negative slope indicates that there is a build‐up of positive charge during the course of the reaction, and electron‐rich donors influence the rate‐determining step, resulting in a faster reaction. To get a clearer picture of the influence substituents have on the donor moiety, not only electronic but also physical parameters were systematically evaluated. Bond lengths are sometimes considered indicators of bond strengths and are correlated with the reactivity of compounds. Although longer bonds for better donors were expected in this case, the calculated bond lengths in the gas phase or the solid phase obtained from X‐ray analyses showed no correlation with the kinetic trends. Similarly, the 1H‐ and 13C‐NMR shifts of the hydrogen and carbon atoms next to the donor moiety did not provide any correlation with the corresponding rate constants (Table 2.5).

2.4 Computational and inetic Investigations

Table 2.4 The relative reaction rate constants for the reaction of 4-fluorobenzaldehyde with different D–A cyclopropanes.

CO2Me CO2Me

R

O

+

CD2CI2

F

31

CO2Me CO2Me

SnCI4 R

O

32

F 33

Residue

krela

a

p‐MeO‐Phb

49.7

b

Phthalimide

42.0

c

p‐Me‐Ph

6.32

d

o‐MeO‐Ph

3.20

e

Naphthyl

3.12

f

Cyclopropyl

1.92

g

Ph

1.00

h

p‐F‐Ph

0.62

i

o‐Me‐Ph

0.50

j

Phc

0.32

k

p‐Cl‐Ph

0.27

l

p‐Br‐Ph

0.25

d

m

Ph

n

Succinimide

0.12

0.22

o

H2C=CH‐

0.093

p

p‐F3C‐Ph

0.0077

q

m‐O2N‐Ph

0.0017

r

p‐O2N‐Ph

0.0015

Reaction conditions: D–A cyclopropane (1.00 equiv.), 4‐fluorobenzaldehyde (1.00 equiv.), SnCl4 (0.10 M in CD2Cl2, 0.015 equiv.), CD2Cl2 (0.10 M), 298 K. a) krel = kResidue/kPhenyl. b) Fast formation of a side product was observed. c) Benzyl ester instead of methyl ester. d) Ethyl ester instead of methyl ester.

Another physical parameter investigated was the RFC. RFCs measure the force required to distort a coordinate by a unit amount while allowing all other coordinates to relax [132]. The RFCs were calculated for the cyclopropane bond broken during the reaction. This was based on the notion that the second derivative of energy is a more sensitive kinetic descriptor than equilibrium bond lengths (Table 2.5). These data were found to be in congruence with the kinetic trends (Figure 2.11). A higher rate constant generally corresponds to a lower RFC and a weaker bond.

29

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

log(krel)

30

2.0 1.5 1.0 0.5 0.0 –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 –0.4

MeO

Me F

CI H

Br NO2

CF3 –0.2

0.0

0.2

0.4

0.6

0.8

σ

Figure 2.10

Table 2.5

Hammett plot with p-substituted aryl residues.

Comparison of physical parameters for para-substituted D–A cyclopropanes.

Donor

Bond length gas phasea (Å)

NMR shift C-2-H (ppm)

NMR shift C-2 (ppm)

RFCb (mdyn Å−1)

p‐MeO‐Ph

1.561

3.17c

32.1c

2.584

1.559

c

32.4c

2.646

d

d

p‐Me‐Ph

3.19

Naphthyl

1.559

3.38

32.9

2.660

Ph

1.558 (1.539)

3.22c

32.4c

2.688

e

e

p‐F‐Ph

1.558

3.19

31.7

2.674

p‐Cl‐Ph

1.558 (1.537)

3.16f

30.7f

2.688

p‐Br‐Ph

1.558 (1.536)

f

3.21

f

32.6

2.688

p‐CF3‐Ph

1.556 (1.549)

3.25g

29.7g

2.725

1.556 (1.542)

e

e

2.732

p‐NO2‐Ph

3.28

31.5

a)

B3LYP/6‐311G(d,p) level of theory. Bond lengths in the solid state from X‐ray analysis are given in parentheses. b) RFC = relaxed force constant. c) Müller and Fernandez [127]. d) Talukdar et al. [128]. e) Perreault et al. [129]. f) Ghanem et al. [130]. g) Doyle et al. [131].

Further investigations on different cycloaddition reactions of D–A cyclopropanes, even with different catalytic systems, revealed the reproducibility and generality of the observed kinetic trends. (3+3)‐ and (4+3)‐cycloadditions of DACs with either nitrone 35 [97] or isobenzofuran 36 [133] as starting material were investigated (Scheme 2.10). The reactions were followed using an in‐operando IR spectrometer, where the progress of the reaction was analyzed by the decrease in the intensity of characteristic IR bands of the starting materials.

2.4 Computational and inetic Investigations 102

2.75 krel

10

2.7

krel

101 2.65 10–1 2.6

p-NO2

p-CF3

p-Br

p-CI

p-F

H

Naphthyl

p-Me

10–3

p-OMe

10–2

Relaxed force constant (mdyn (Å))

Relaxed force constant

2.55

Figure 2.11 Reaction rate constants (logarithmic scale) vs. relaxed force constants of the bond to be broken.

–3

–3

–2

–2

Me

–1 0

Naphthyl

–1

BrCI

–2 –3

H

CF3

–4 –5 –4 –3 –2 –1 0 In(krel(Aldehyde))

In(krel(Benzofurane))

In(krel(Nitrone))

Scheme 2.10 (3+3)- and (4+3)-Cycloaddition reactions of DACs with nitrone and isobenzofuran.

Naphthyl

–1

Me

0 –1

H

–2 –3

1

2

CF3 –4 –5 –4 –3 –2 –1 0 In(krel(Aldehyde))

1

2

Figure 2.12 Plotting of the logarithmic specific rate constants for the cycloaddition reactions of DACs with aldehydes against those of nitrone and isobenzofuran.

Figure 2.12 was obtained by logarithmic plotting of specific rate constants for the reactions of the aldehyde against the ones with nitrone and isobenzofuran. The linear dependence reflects comparable kinetics. A good correlation was observed in

31

32

2 Understanding the Reactivity of Donor–Acceptor Cyclopropanes

the reaction of DACs with nitrones, whereas a slight deviation in the case of DACs with phenyl and naphthyl donors was noted.

2.5 Concluding Remarks The development of DACs from activated cyclopropanes has brought about a renaissance in the field of cyclopropane chemistry. Transformations involving DACs have found valuable applications in synthetic organic chemistry. Investigations into understanding the influence of structure and electronics on the reactivity of these moieties have enabled chemists to take full advantage of their potential as synthons. Different DACs have been studied by computational means in order to get insights into the activation barriers for the three‐ to five‐membered ring enlargement reactions. These studies also revealed that polar solvents are able to significantly lower the energy of the highly polar transition states. Comparative studies on different DACs gave insights into the strong influence of the type of donor in cycloaddition reaction of DACs. (3+2)-Cycloadditions of DACs with aldehydes were found to be about 30 000 times faster when p‐methoxyphenyl was chosen as donor instead of the p‐nitrophenyl derivative. This observation was found to correlate with the Hammett substitution parameters and was similarly observed for other types of cycloaddition reactions with DACs. Interestingly, such kinetic data could not be correlated with the bond lengths of the bonds to be broken; however, RFCs of the respective bonds allowed a correlation with kinetic parameters determined by experimental means.

References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

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126 Hansch, C., Leo, A., and Taft, R.W. (1991). Chem. Rev. 91: 165–195. 127 Müller, P. and Fernandez, D. (1995). Helv. Chim. Acta 78: 947–958. 128 Talukdar, R., Tiwari, D.P., Saha, A. et al. (2014). Org. Lett. 16: 3954–3957. 129 Perreault, C., Goudreau, S.R., Zimmer, L.E. et al. (2008). Org. Lett. 10: 689–692. 130 Ghanem, A., Lacrampe, F., and Schurig, V. (2005). Helv. Chim. Acta 88: 216– 239. 131 Doyle, M.P., Davies, S.B., and Hu, W. (2000). Org. Lett. 2: 1145–1147. 132 Markopoulos, G. and Grunenberg, J. (2013). Angew. Chem. Int. Ed. 52: 10648–10651. 133 Ivanova, O.A., Budynina, E.M., Grishin, Y.K. et al. (2008). Angew. Chem. Int. Ed. 47: 1107–1110.

37

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Roman A. Novikov, Denis D. Borisov, and Yury V. Tomilov N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Moscow, Russian Federation

CHAPTER MENU 3.1 3.2 3.3 3.4 3.5 3.6

Introduction, 37 Formal [3+2]-Cycloaddition with Carbon–Carbon Multiple Bonds, 39 Formal [3+2]-Cycloaddition with C=O and C=N Double Bond, 59 Formal [3+2]-Cycloaddition with Other Heteroatom X=Y Double Bonds, 73 Formal [3+3]-Cycloaddition and Annulation Reactions of D–A Cyclopropanes, 83 Reactions of Formal [4+3]-Cycloaddition and Annulation with Diene and Heterodiene Systems, 96 3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes, 102 3.8 Cyclodimerization Reactions of D–A Cyclopropanes, 112 3.9 Miscellaneous Reactions, Stepwise Cyclization Reactions, Cyclizations with Involvement of Functional Groups, 118 Acknowledgments, 128 References, 129

3.1 Introduction The cycloaddition and annulation reactions of donor–acceptor (D–A) cyclopropanes are one of the most widespread, important, and most recognizable processes in their chemistry. And often D–A cyclopropanes are associated precisely with cycloaddition reactions. Indeed, the great ability of D–A cyclopropanes to cleavage the three-membered ring to form 1,3-zwitterionic intermediates allows access to an exceptionally wide variety of different cycloaddition processes. Cycloaddition/ annulation reactions are discussed in many review articles on the chemistry of activated cyclopropanes from various points of view and types of transformations [1–8]. The main direction of cycloaddition/annulation processes is the reactivity of D–A cyclopropanes as the 1,3-zwitterionic synthones (I) (Figure 3.1), usually realized

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

38

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes EWG1

Don, Ar = donor group EWG = acceptor group

EWG2

Ar

EWG2

IV GaCl3 EWG1

The most common 1,3-zwitterionic synthone EWG1

Lewis acid

EWG1

Don

Don

EWG2

I

EWG2

Ar

EWG1

V EWG1

EWG2

Ar II

EWG2

Ar III

Figure 3.1 Main types of zwitterionic synthones in cycloaddition/annulation processes of the D–A cyclopropanes.

under the action of Lewis acids, or catalysis with Pd(0) for vinyl cyclopropanes. Generated 1,3-zwitterionic synthones react easily with various types of substrates, of which the most common are formal [3+2]-cycloaddition to multiple bonds, as well as formal [3+3]-cycloaddition with 1,3-dipoles or their synthetic equivalents, and also formal [4+3]-cycloaddition with (hetero)diene systems (Figure 3.2). There are also known a large number of other types of cyclization processes, in which D–A cyclopropanes act as various zwitterionic synthons. Of these, it can be noted the [3+2]-annulation at the aromatic donor substituent in D–A cyclopropane (synthon II), reactions proceeding through the in situ-generation of β-styrylmalonates (synthon III), cyclodimerization reactions of D–A cyclopropanes, and the annulation reactions under the action of GaCl3, in which D–A cyclopropanes act as 1,2and 1,4-zwitterionic intermediate synthons (IV and V) (Figure 3.1). All this leads to a very significant variety of implemented processes. All these aspects of the D–A cyclopropane chemistry are discussed in detail and comprehensively in the current book chapter.

Don

Acc MetLn

Don

Z

Acc Don

Acc

[3+4]

X

Y

[3+3] [3+2]

X Y

Don

Don

Acc Z

Y

X

Acc X Y

Figure 3.2 Three main formal cycloaddition processes of D–A cyclopropanes as 1,3-zwitterionic synthones.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

Malidialle Fonad

3.2 Formal [3+2]-Cycloaddition with Carbon–Carbon Multiple Bonds 3.2.1 General Aspects The formal [3+2]-cycloaddition of D–A cyclopropanes 1 to multiple C–C bonds is one of the main and most common processes in the chemistry of D–A cyclopropanes, and is rightfully considered one of the effective modern methods for creating five-membered carbocycles, including various polysubstituted and polycyclic derivatives, and products with multiple bonds in the cycle. The concept of this method is quite simple and lies in the fact that D–A cyclopropanes, after opening the threemembered ring, act as 1,3-zwitterionic synthons, which are added to multiple bonds via the [3+2]-cycloaddition pathway to form five-membered rings 2,3 (Figure 3.3). There are several different approaches to activating D–A cyclopropanes. The most common is the classical catalysis by Lewis acids, which are coordinated over one or two acceptor groups, followed by polarization of the σ-bond. In this case, the attack of the substrate is usually carried out through the carbocation center formed during the opening of the cyclopropane ring. Separately, we can single out the use of Lewis acids such as MgI2, CaI2, and ZnI2 for activation, in which the iodide anion is initially temporarily attached to cyclopropane 1 and the substrate is further nucleophilically attacked, which allows the use of electron-deficient double bonds (Figure 3.4). Another approach is to use palladium catalysis Pd(0) for vinylcyclopropanes 4 with acceptor groups, or similar Ni(0) catalysis for cyclopropyl ketones. In this case, the activation and the opening of the three-membered ring occur upon coordination of Pd(0) with the vinyl group to form analogous 1,3-zwitterionic synthons and similar types of reactions occur (Figure 3.5). In addition, other approaches

CO2R

Ar 1

CO2R Lewis acid

OR Ar

δ+

δ-

RO

O

E = CO2R, EWG Ar = Donor E

OR Ar

O LA

O RO

I

II

O

E

Ar

LA

1,3-Zwitterionic intermediate

C C

RO2C

E

CO2R E

C C

Ar

Electrophilic C substitution 3 (SEAr) [3+2]-Annulation

C

1,5-Cyclization Ar III

C

C

CO2R CO2R

Ar

2 [3+2]-Cycloaddition

Figure 3.3 Formal [3+2]-cycloaddition reactions of D–A cyclopropanes 1 with multiple C–C bonds under Lewis acid catalysis, and their main mechanistic features.

39

40

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes I

OR CO2R

Ar 1

MIn Ar

CO2R

O

δ-

δ+ RO

O

OR

+ I–

Ar RO

MIn

II

I

O O

Iodideanion RO2C Ar

Figure 3.4

C 2

C C CO2R CO2R

CO2R

C

MIn

I

– I–

Ar C

C III

Catalysis using metal iodides (MgI2, CaI2, ZnI2). MeO2C

CO2Me

Pd(0)

CO2Me

Pd

CO2Me 4

Figure 3.5

CO2Me I

C C C Pd

CO2Me C

MeO2C C

II

CO2Me C

5

Pd(0)-catalyzed formal [3+2]-cycloaddition of the vinyl D–A cyclopropanes 4.

are also known using base catalysis, the use of organocatalysts, examples of radical processes, as well as the use of photocatalysis methods. Many of these processes are already difficult to attribute to the classical chemistry of D–A cyclopropanes, and they often require the use of specific types of substrates.

3.2.2 Formal [3+2]-Cycloaddition with C=C Double Bond 1,3-Dipolar cycloaddition reactions of activated cyclopropanes to alkenes, with the formation of five-membered carbocycles have been known for a very long time. The first examples appeared almost 60 years ago at the turn of the 1960s–1970s and can be considered the first reactions related to the classical well-known D–A cyclopropane chemistry. The scheme shows some early examples of reactions of activated cyclopropanes, developed in 1966–1991, with electron-rich double bonds in compounds such as enamines, enol ethers, ketene acetals, as well as some electron-poor double bonds and non-activated olefins. The first processes focused on the use of fairly simple and reactive substrates that easily enter into formal cycloaddition processes when the most common 2-substituted 1,1-cyclopropane dicarboxylates of our time were not yet actually used. At the same time, Lewis acids, as well as thermal activation, were also often used to activate cyclopropanes. Also, a noticeable bias was observed toward the development of synthetic methods for obtaining natural compounds or their analogs, in which five-membered carbocycles are very common; for example, the terpene class [9–14]. An illustrative example is also the formal [3+2]-cycloaddition of ethyl 2,2-dimethoxycyclopropanecarboxylate 23 to tetracyanoethylene 24, with the formation of a polyfunctional cyclopentanecarboxylate 25 with good stereoselectivity, which proceeds even at room temperature even in the absence of an activator, due to the high reactivity of the alkene component

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

Malidialle Fonad

and cyclopropane itself [15]. Separately, we can note the very important work of B. Snider in 1986, which set a certain tone in the modern chemistry of D–A cyclopropanes, in which the interaction processes of 1,1-cyclopropane dicarboxylates 21 were first developed and described in detail, including several simple 2-alkyl substituted representatives, with various non-activated alkenes using EtAlCl2 as the Lewis acid activator [16]. Also noteworthy are the first examples of Pd(0)-catalyzed cycloaddition of vinylcyclopropanes 4 with acceptor groups to Michael acceptors, as described by J. Tsuji [17] (Figure 3.6). Further, after 2000 and up to the present day, the processes of formal [3+2]-cycloaddition of D–A cyclopropanes to double carbon bonds continued to develop rapidly. Many dozens of papers have already been published, and many various examples of such transformations are known, including their various applied aspects and applications in total syntheses. Moreover, a great diversity is found both in the structures of D–A cyclopropanes and alkene substrates, and in the very methods of activation and opening of the three-membered ring. I. Yokoe in 2001 described the processes of formal [3+2]-cycloaddition of methoxycyclopropane dicarboxylates 27 and various allylsilanes 28 upon activation with a strong Lewis acid, titanium(IV) tetrachloride. The yields of the final cyclopentanes 29 reached 70%, but the diastereoselectivity of the process was very moderate [18] (Figure 3.7). A

NC

D

CO2Et 7

N

N

NC

OSiEt3

R2 R1

CO2Et

16

15

6

R1 R2

KF CH3CN, 80 °C

Ph3P

Xylene, 150 °C

CO2Et

CO2Et 17, 75–91%

8, 41% O

B

R3 9

TMSO

R3 R2O

CH2Cl2, –40 °C

R3

OTMS R1 12

13 OR

5

TiCl4 CH2Cl2, –78 °C

F R3

R4

5

R O

CO2R R1

NC NC

R3

MeO MeO CO2Et 23

RT

CN

CO2Et

MeO NC CN NC CN

25, 80% (dr = 8:1)

E

4 E 26

R3

CO2R4 CO2R4

22, 48–98% E

R

R2 R1

H MeO

CO2R4

21 EtAlCl2, DCE

R2 20

O

CN 24

R4O2C

R1

2

14, 28–75% G

H 19, 85%

18

R4 OR5

2C

O

MsOAc

R2

11, 34–89%

C

MeO

R1

SnCl4 (3 mol%) CH2Cl2, –78 °C

O

OMe

10

R2

R1

E

O

OMe

OTMS

Pd2(dba)3 PRʹ 3 E = CO2Me, EWG

R E

E E 27, 66–89%

Figure 3.6 First reactions and examples of the [3+2]-cycloaddition of alkenes to activated cyclopropanes.

41

42

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes MeO

OMe Me Me

CO2Me CO2Me 27

28

[Si]

TiCl4 (1.1 equiv.) CH2Cl2, 1 h

[Si]

Me Me CO2Me CO2Me 29

SitBuPh2 – 65% (dr = 4/1) SiiPr3 – 70% (dr = 4/1)

[Si] = SiMe3 – 23% (dr = 4/1) SiMePh2 – 48% (dr = 2/1)

Figure 3.7 [3+2]-Cycloaddition with allylsilanes 28.

Another type of such transformations is the well-known work of Liu and Montgomery (2006), which describes the processes of [3+2]-cyclodimerization of cyclopropyl ketones 10, as well as their formal [3+2]-cycloaddition reactions with α, β-unsaturated ketones 30 when initiating the opening of a three-membered ring under the conditions of catalysis with zero-valent nickel-generated in the system of nickel(0) dicyclooctadienyl, N-heterocyclic carbene (NHC), and titanium(IV) tetratert-butoxide [19]. Subsequently, such metal complex approaches were widely developed separately, but in this chapter, they will be considered in passing, since this is a somewhat separate and distinct field of chemistry from D–A cyclopropanes with its own regularities (Figure 3.8). Silyl ethers of enols 12, 33 are a very convenient interceptor for the generated 1,3-zwitterions, which are reactive and easily interact with various types of D–A cyclopropanes, including their low-activity representatives. Therefore, reactions with silyl ethers of enols were studied in some detail in the last century, and examples are presented in the Scheme above. After 2000, active work in this direction continued and expanded to other convenient substrates for developing approaches to asymmetric catalysis, as well as to the introduction of new representatives of D–A cyclopropanes. Earlier examples include the work of M. Ihara et al., which describes the [3+2]-cycloaddition reactions of cyclopropyl ketones 10 and alkoxycyclopropane monocarboxylates 32 under conditions of catalysis with triflimide Tf2NH or its cyclic analog as a strong Brønsted acid [20]. Z. Wang studied in detail the reactions of enol silyl ethers with more classical D–A cyclopropanes, such as 1,2-substituted cyclopropane dicarboxylates or their diketone analogs, in Sc(OTf)3 catalysis using a wide range of both substrates [21] (Figure 3.9). Of other simple alkene substrates, it can be noted that D–A cyclopropanes are capable of reacting with almost any of their representatives. However, if we look specifically at simple alkenes without complex functionalization, then their reactions are rather poorly purposefully systematized in published works with common R3 O

R1

R2 O

10

O

R4 30

Ni(COD)2 NHC t-BuOK Ti(OtBu)4 Toluene, 90 °C

R2 R1 O

NHC = R3 R4

N+

N

31 Cl-

Figure 3.8 Montgomery’s Ni(0)-catalyzed [3+2]-cycloaddition of cyclopropyl ketones 10.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon O[Si] BuO CO2Et 32 or Ph

PMP 10

O

33 Tf2NH (2 mol%) CH2Cl2 –78 °C, 2 h

O[Si] EDG

R

EWG

34 70–94% yields

EWG 1

EWG

TMSO

R1

12

R2

Sc(OTf)3 (20 mol%) CH2Cl2

R2 R

Malidialle Fonad

R1

OTMS EWG EWG

35 60–99% yields

R = aryl, vinyl, i-Pr; EWG = CO2Me, CO2Et, CO2Bn, C(O)Me, C(O)Ph R1 = Ph, Me, i-Bu, OEt; R2 = H, Me, CO2Et; R1,R2 = -(CH2)4-

[Si] = SiMe2tBu, SiMe3, SiiPr3, SiPh2tBu

Figure 3.9 Some reactions with silyl esters of enols.

types of D–A cyclopropanes. Since such substrates were studied quite a lot in the last century, and many scattered examples were published, the novelty and interest in such processes in the 2000s, without an applied bias were already significantly reduced. Not all processes have been studied, given the significant evidence of predicting the course of such transformations. One recent example of such work is the systematic study of the interaction of cyclopropane dicarboxylates 1 with diarylethenes 36 published by the L. Wang group. In addition to cyclopentanes 37, the formation of acyclic addition products has also been described [22] (Figure 3.10). One of the most important directions in the development of formal [3+2]-cycloaddition reactions with alkenes in the last decade is the development of general approaches to asymmetric catalysis for the preparation of optically pure cyclopentane derivatives, which significantly expands and increases the interest in this field of chemistry and corresponds to the general trends in its development. The need for just asymmetric catalysis emphasizes the often impossibility of using optically pure cyclopropanes to obtain optically pure products due to the easy occurrence of racemization processes under catalytic conditions of the processes. Several alternative approaches have been developed for asymmetric catalysis, ­ corresponding to the methods of activation of various types of D–A cyclopropanes. For example, an important work published by the B. Trost group in 2012 presents the development of a method for vinylcyclopropanes 4 in formal cycloaddition reactions with Michael acceptors. Correspondingly, Pd(0) catalysis and the most common chiral phosphine ligands in such cases, phosphine derivatives of diaminocyclohexane, are used for this. However, a particular difficulty for the D–A processes of cyclopropanes is the detailed selection of the reaction conditions and Ar1 CO2Me

Ar

CO2Me 1

Figure 3.10

Ar1

Ar1 36 Sc(OTf)3 (5 mol%) CH2Cl2, 12 h 80 °C

Ar

Ar1 CO2Me CO2Me

37 13–87% yields

Reaction with diarylethenes 36.

43

44

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

O

O

R

38

O EWG 4

EWG

O

Pd2(dba)3·CHCl3 (2.5 mol%) (R,R)-L (7.5 mol%) PhMe, rt

O

O

O R EWG

O

EWG = CO2Me, CO2(CH2CF3), Meldrum's acid R = aryl, hetaryl

O L = Ph2P

PPh2

NH HN O

EWG 39 Up to 81% yields dr up to 19:1 ee up to 96%

Figure 3.11 B. Trost’s asymmetric approach to formal [3+2]-cycloaddition for vinyl cyclopropanes 4.

substituents in both starting substrates, in order to obtain high enantiomeric excess (ee) values, which is often a nontrivial task [23]. (Figure 3.11) Another approach has been developed in parallel by the Y. Tang group for cyclopropane dicarboxylates 1 using Lewis acid catalysis. Reactive cyclic silyl ethers of enols 33 were used as alkene substrates, and an efficient system of copper perchlorate and substituted bisoxazoline ligands was proposed for asymmetric catalysis. Also, sterically loaded 2-adamantyl esters of the starting cyclopropanes were used to achieve the best ee values [24] (Figure 3.12). An extension of this concept was demonstrated by J. Waser for protected aminocyclopropane dicarboxylates 46 using the same chiral catalytic system based on copper perchlorate and bisoxazoline ligands and enol esters, in combination with carefully selected succinimide substituents in D–A cyclopropanes [25]. In general, this is one example from a series of works by the J. Waser group, devoted to the development and introduction to the chemistry of D–A cyclopropanes of new classes based on 2-amino cyclopropane dicarboxylates 41, 44, with various protective groups for an amine (usually succinimide and phthalimide), including derivatives nitrogenous bases (thymine and uracil), and allowing to obtain combination products 43, 45, 47, with a protected amino group. The Lewis acid catalysis is also used for these cyclopropanes, and reactions have been developed with various substrates, of which alkenes are among the basic ones [26, 27] (Figure 3.13). Another direction in the development of formal [3+2]-cycloaddition reactions to alkenes in the last decade has been toward the use of complex polyfunctional Ar

OTBDPS 33

CO2Ad

R 1

CO2Ad

R = aryl, hetaryl, styryl Ad = 2-adamantyl TBDPS = SiPh2tBu

n = 0–2

n = 0–2

Cu(ClO4)2·6H2O (10 mol%) L (11 mol%) CH2Cl2, rt, 4Å MS

R

MeO

Ar OTBDPS CO2Ad

OMe L=

Me

O

CO2Ad

40 Up to 94% yields dr up to 99:1 ee up to 98%

OMe

O N

i-Pr

N i-Pr

Figure 3.12 Y. Tang’s asymmetric approach to formal [3+2]-cycloaddition for cyclopropane diesters 1.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

CO2Me

O

OTIPS Ph

CO2Me

CO2Me Ar

OTIPS

SnCl4 (5–20 mol%) CH2Cl2, –78 °C

O

N

O

O

Boc

41 i

TIPS = Si Pr3

43 Up to 95% yields

R1

O

CO2Me

N

CO2Me O

46

R = Bn, alkyl R1 = H, aryl, hetaryl

TIPSO

CO2Me CO2Me

Ar

42

42

O

N

MeO2C OTIPS MeO2C

Ph

CO2Me

Malidialle Fonad

OR

N N O

R1

42

N

R O

45 51–84% yields

Me Me

OR

O

CO2Me

SuccN

Cu(ClO4)2 (10 mol%) BOX (10 mol%) CH2Cl2, rt, 4 Å MS

Boc

Ar = Ph, styryl

44 R = Me, H, F

N

O

SnCl4 (10 mol%) R CH2Cl2, –20 °C

BOX =

CO2Me 47 Up to 99% yields dr up to 20:1 ee up to 96%

O N

N

i-Pr

i-Pr

Figure 3.13 J. Waser’s [3+2]-cycloaddition of amino-based D–A cyclopropanes and its asymmetric approach.

substrates for the targeted preparation of complex polycyclic or polysubstituted molecules for further applied use in various directions. For example, Trushkov and coworkers describe in detail the interactions of D–A cyclopropanes 1 with various cyclic and acyclic diene systems 48, many of which proceed as formal [3+2] cycloaddition at the C=C double bond [28]. Hyland et al. described the addition of vinylcyclopropanes 4 to the C=C double bond of nitro-substituted enines 51 under the conditions of palladium catalysis [29] (Figure 3.14). In a series of works by Prof. Banerjee’s group, processes were developed for the addition of D–A cyclopropanes 1 to various heterodiene systems containing nitrogen atoms, such as N-sulfoxy-substituted 1,3-azadienes 52, benzofuran-based azadienes 53, enamines with carbonyl substituents 54, and others. In general, a lot depends on the particular heterodiene component used, but many reactions also proceed as formal [3+2]-cycloaddition at C=C bonds, and lead to polyfunctionalized cyclopentane derivatives 55–57. In reactions with diene and heterodiene MeO2C

CO2Me

Ar

R

NO2

CO2Me

Ar

CO2Me

1

LA CH2Cl2

+ R R1 n

48 LA = TiCl4, SnCl4, Sn(OTf)2

R1

49 51–62% yields

MeO2C

CO2Me

Ar n 50 54–65% yields

CO2Et CO2Et 4

EtO2C CO2Et Ar 51

R

Pd2(dba)3·CHCl3 (2–3 mol%) Phen (6–9 mol%) MeCN, rt, 18 h Ar = Ph, 2-thienyl R = Ph, n-C6H13

Figure 3.14 [3+2]-Cycloaddition to dienes and nitroenynes.

Ar

R

NO2 52 Yields up to 81%

45

46

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes RO2S RO2S N RO2S N

Ar1

O 53

CO2Et O

52

56 52–69% yields

1

CO2Et

O

R2N 54

R1

LA (20 mol%) CH2Cl2, rt, 4 Å MS (BOX ligand) LA = Cu(OTf)2, MgI2

Ar = aryl, PhthN, 2-furyl SO2R = Ts, Ns Ar1 = aryl R = Me, -(CH2)2-, Bn R1 = OMe, 2-naphthyl

CO2Et

CO2Et 55 69–81% yields

MgI2 (20 mol%) CH2Cl2, rt

CO2Et

Ar

CO2Me

Ar

Ar1

Ar1

MgI2 (20 mol%) CH2Cl2, rt

CO2Et

Ar

MeO2C

N

Ar1

N SO2R

O R1 Ar

NR2 CO2Et CO2Et

57 Up to 88% yields er up to 8:1

Figure 3.15 Banerjee’s reaction with C=C double bond in complex nitrogen-containing heterodiene systems.

systems, cyclopropanes are usually activated using Lewis acids such as MgI2, Cu(OTf)2, Sn(OTf)2, SnCl4, and TiCl4 [30–32] (Figure 3.15). M. Doyle with coworkers presented an approach to [3+2]-cycloaddition of silyl ethers of enols containing a diazo group 58 and D–A cyclopropanes 1, proceeding under mild catalysis with ytterbium(III) triflate with the retention of the diazo group in the final cyclopentane product 59, which allows using it in final products for their further functionalization [33]. Similar processes for vinyl azides 60, also proceeding with the retention of the azido group in the final cyclopentane 61, and its use for further functionalization, are described in the works of the P. Banerjee and S. Chiba groups [34, 35] (Figure 3.16).

CO2Me OTBS

N2 CO2Me

R 1

CO2Me

R = aryl, hetaryl, BzO, PhthN TBS = SiMe2tBu

N2

58 Yb(OTf)3 (5 mol%) 1,2-DCE, 24 h rt, 4 Å MS

R

CO2Me OTBS CO2Me

CO2Me 59 Up to 84% yields dr up to 20:1

LA (20 mol%) CH2Cl2, rt, 4 Å MS CO2R

Ar 1

CO2R

Ar1

Ar1

+ 60

Ar = aryl, 2-furyl, vinyl R = Me, Et, i-Pr, Bn Ar1 = aryl

Figure 3.16

LA = MgI2, InCl3

N3

Sc(OTf)3 (15–30 mol%) CH2Cl2–MeNO2 (4:1) 0 °C

Ar

N3 CO2R CO2R

61 62–95% yields dr up to 9:1

Reactions with substituted vinyl azides and vinyl diazo compounds.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

Malidialle Fonad

Along with Lewis acids, for the activation of D–A cyclopropanes and their introduction into formal [3+2]-cycloaddition reactions with functionalized alkenes, basic catalysis is also quite widely used. Accordingly, this imposes certain requirements on the structures of the initial D–A cyclopropanes, as well as alkene components, which are usually Michael acceptors, such as α, β-unsaturated dicarbonyl compounds or their analogs with cyano groups, as well as nitroolefins, and so on, because basic catalysis assumes that the reaction proceeds through carbanion intermediates. The work of K. Takeda et al. demonstrates an interesting example of [3+2]-cycloaddition of activated cyclopropanes 62 and Knoevenagel condensation products 63, with the α-para-tosyl anion generated in the presence of LiHMDS, acting as the donor moiety of cyclopropane [36]. K. Jorgensen with coworkers developed an asymmetric approach for base-catalyzed formal [3+2]-cycloaddition between substituted dicyanocyclopropanes 65 and nitroalkenes 66 using a chiral organocatalyst based on disubstituted thiourea [37]. A study by C. Wang et al. demonstrated the possibility of interaction of tetrasubstituted activated cyclopropanes 68 and Knoevenagel adducts 69 in the presence of 1,8-Diazabicyclo(5.4.0)undec-7ene (DBU), which also proceeds as [3+2]-cycloaddition [38] (Figure 3.17). Modern methods of photocatalysis, including those in combination with Lewis acids, are also used to activate D–A cyclopropanes. Although many similar processes are rather difficult to attribute to the classical chemistry of D–A cyclopropanes, several works can still be considered in this aspect. The study by T. Yoon et al. presents an intramolecular variant of [3+2]-cycloaddition of olefins with a cyclopropyl ketone fragment in its structure 71, proceeding under the action of lanthanum(III) triflate in the presence of a ruthenium-based photocatalyst under visible light irradiation [39]. Later, Z. Lu with coworkers developed an intermolecular visible-light photocatalyzed [3+2]-cycloaddition of styrene derivatives 74 and nitrocyclopropanecarboxylates 73 in the presence of a similar ruthenium-based photocatalyst [40]. The mechanisms of the processes and their patterns are discussed in detail in the relevant works (Figure 3.18). R EWG SO2 p-Tol

62

63 CO2Me

Ar2

O

CN 69 CO2Et

CO2Et

Ar 68

CN

Ar, Ar1, Ar2 = aryl

MeO2C

LiHMDS (1.2 equiv.) –80 °C to rt 20–70 min

EWG = CO2Et, CN R = aryl, alkyl, SiMe2Ph

Ar1

R2

CO2Me

DBU (1 equiv.) CH2Cl2, Δ 12 h

R

CN CN

EWG 64 43–91% yields dr up to 4:1

EtO2C

CN Ar2 CN

Ar

CO2Et Ar1

O 70

R1 R1

66 NO2

NO2 R2 CN

BB CN 65 (20 mol%) O R 67 CH2Cl2 71–98% yields –25 °C, 40 h R = Me, aryl dr up to 20:1 R1 = H, Me ee up to 91% R2 = aryl, alkyl, cycloalkyl

R

O

O2N

BB =

S N H

N H

N

79–87% yields

Figure 3.17 Examples of the [3+2]-cycloaddition to C=C double bond under basic catalysis/activation conditions.

47

48

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes O

La(OTf)3 (1 equiv.) TMEDA (5 equiv.) Ru(bpy)3Cl2 (2.5 mol%)

Ar R1 R

MgSO4, MeCN visible light, 12 h

O

71

Ar = Ph, aryl; R1 = H, Me, Et R = t-BuO, EtO, t-Bu, SEt R2 74

O2N

CO2Et

R 73

R = Me, Et Ar = aryl, hetaryl, vinyl R1 = H, alkyl; R2 = H, Me

R

72 Up to 86% yields dr up to 10:1

Ar

R1 R2

R

[Ru(bpy)3(PF6)2] (2.5 mol%) Et3N, LiBF4, MgSO4 MeCN, CFL (18 W)

O

Ar

R1 Ar

R1

O

CO2Et

O2 N

75 42–96% yields dr up to 4:1

Figure 3.18 Photocatalytic [3+2]-cycloaddition of activated cyclopropanes to C=C double bond.

In the works devoted to the chemistry of D–A cyclopropanes, published during the last two or three years, a large number of formal [3+2] cycloadditions to the C=C double bond are also encountered, touching on various interesting aspects of it. In a number of studies, complex substrates are used as the alkene component, in which the double bond required for addition is generated in situ during the reaction, which allows expanding the range of substrates and simplifying the synthetic methodology. These reactions include the works of S. Zhu, describing [3+2]-cycloaddition under the action of ZnI2 to indenones generated from ortho-ethynylbenzaldehydes 76, as well as the work of Trushkov and Voskressensky, devoted to the D–A reaction of cyclopropanes 1 with arylketals 78 under the action of ZnCl2 at microwave irradiation [41, 42] (Figure 3.19). Another direction is the expansion of the range of used D–A cyclopropanes and methods of their activation, including synthetic improvements in the methodologies used. In a joint study by J. Waser and K. Severin, D–A cyclopropanes with a triazene substituent 80 are used as a strong donor moiety. In this work, their interactions with C=C double bonds are studied in sufficient detail. For this, substrates such as tetracyanoethylene 24 and enol silyl ethers 42 are used. Triazene-based D–A CHO MeO2C

CO2Me

EWG

Ar 76

Ar

77

Ar

O

EWG

Up to 86% yields dr up to 99:1

Figure 3.19

EDG

ZnI2 (50 mol%) 1,2-DCE

CO2Me

EDG 1

CO2Me

EDG = aryl, hetaryl, styryl, vinyl Ar = aryl, hetaryl EWG = CO2Me, CO2Et, C(O)Me, C(O)nBu

OMe OMe

Ar

78 CO2R LA (20–200 mol%) Ar MW, 1,2-DCE CO2R 150 °C 79 LA = ZnCl2, Yb(OTf)3 Up to 94% yields EDG = Ph, aryl, 2-thienyl Ar = aryl

Formal [3+2]-cycloaddition to C=C double bond generated in situ.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

NC NC

NC CN CO2Me CO2Me

N N

R N R

R1

NC NC

CN 24

R1

CO2Me

CN

CO2Me

N N

Acetone, 40 °C R N

R

81 Up to 65% yields dr up to 2:1

80

R = Cy, i-Pr R1 = H, 3-thienyl, cyclopropyl [Si] = SiMe3, SiiPr3, SiPh2tBu Ar = aryl

[Si]O

Ar

Ar

42

Malidialle Fonad O[Si] CO2Me CO2Me

N Hf(OTf)4 N (10 mol%) Cy N CH2Cl2 Cy 82 Up to 88% yields dr up to 20:1

Figure 3.20 Using triazene derivatives 80 as D–A cyclopropanes in reactions with alkenes.

cyclopropanes are reactive and easily react under mild conditions or even without a catalyst [43] (Figure 3.20). A recent work by the D. Werz group describes the process of formal [3+2]-cycloaddition of D–A cyclopropanes 1 with acceptor olefins based on Michael acceptors with a cyclic fragment 83, such as derivatives of oxazolone, indandione, barbiturate, and Meldrum’s acid. Despite the use of widely used D–A cyclopropanes, in this study, a rather unusual method of activation by calcium iodide CaI2 is used. This activation occurs due to the addition of the iodide anion to cyclopropane, followed by a nucleophilic attack on the olefin (Michael acceptor), and subsequent cyclization with the elimination of the iodide anion. That is, the actual cycloaddition catalyst is the iodide anion, which makes it possible to introduce acceptor olefins into the reaction, in contrast to the use of donor olefins in classical Lewis acid catalysis through 1,3-zwitterions [44] (Figure 3.21). Another recent work by D. Werz developed a protocol for [3+2]-cycloaddition between cyclopropane dicarboxylates 1 and cyclic dithioacetals 85. At the same time, a similar protocol for acyclic dithioacetals 87 was developed in the work of the M. Wang group. Both processes are perfectly catalyzed by Sc(OTf)3; sulfur-containing spiro derivatives 86 or thiocyclopentenes 88 can be obtained as products [45, 46] (Figure 3.22). Finally, there is a series of works devoted to the use of oxindole derivatives in formal [3+2]-cycloaddition reactions, both as a D–A cyclopropane component 91 and as an alkene substrate 89. The interest in these transformations is due to the R2

A CO2R1

R 1

A

A 83

CO2R1

O = O

Figure 3.21

O O

CO2R1 84

CO2R1

Up to 99% yields dr up to 20:1 O

O

Me Me ;

A

R2

R

CaI2 1,2-DCE

R = aryl, hetaryl, alkyl, NPhth, OPh R1 = Me, Et; R2 = aryl, hetaryl, alkyl A

A

O

; O

Me O

N

N

Me O

;

O N Ph

CaI2-catalyzed [3+2]-cycloaddition to activated acceptor olefins.

49

50

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes EtS R1(O)C

SEt

EtS

CO2Me

R

87

Sc(OTf)3 (3–10 mol%) CH2Cl2, air

CO2Me 88 Up to 96% yields

Figure 3.22

S C(O)R1

S

CO2Me

R 1

CO2Me

R = aryl, NPhth, NSucc R1 = Me, OEt, OMe, Ph

Ph(O)C S

C(O)Ph

85

Sc(OTf)3 (10 mol%) CH2Cl2, rt

S CO2Me

R

CO2Me 86 Up to 99% yields dr up to 4:1

[3+2]-Cycloaddition with dithioacetals. R2(O)C

Ar O

EWG

R 65

EWG

O N 89 R1

R1

Ar N

C(O)R2 CO2Et

O

NaOH (20 mol%) THF, 30 °C, 24 h O

EWG = CO2Et, CN R = Me, 4-NO2C6H4O R1 = Me, Bn; R2 = aryl, alkyl, OEt

CO2Et R

90 Up to 90% yields dr up to 20:1

Ar OHC

R

O R N PG

Ar 92 Up to 92% yields dr up to 2:1; ee up to 99% L=

N H

CHO 26

Pd(OAc)2 (5 mol%) L (20 mol%) PPh3 (10 mol%) AcOH (20 mol%) THF, rt

Ph Ph OTMS

Me

Ar EDG N PG

O

O 91

EDG = vinyl PG = Bn, allyl, MOM, Me R = aryl, 2-thienyl, 2-furyl, Me

93

N

N

Ph Ph

MgI2 (20 mol%) THF, 85 °C

N Me Ar

N

O Ar

O N Me

Ar EDG = aryl, 2-thienyl, 2-furyl 94 PG = Me Up to 98% yields dr up to 2:1

Figure 3.23 Formal [3+2]-cycloaddition reactions of the oxindole derivatives for both substrates under different activation modes to constrain spiro and dispiro heterocycles.

possibility of obtaining complex derivatives of oxindole, which are widely used in the interests of medicinal chemistry. Various polycyclic spiro derivatives 90, 92, as well as dispiro derivatives of oxindole 94 can be excellently prepared by these methods. As activation methods, both Lewis acid catalysis and basic catalysis, as well as metal complex catalysis with zero-valent palladium using vinyl derivatives of cyclopropane, are used. Research in this direction has been noted by B. Zhou, H. Yang, J. Saha, and E. Budynina scientific groups [47–49] (Figure 3.23).

3.2.3 Formal [3+2]-Cycloaddition with Triple C≡C Bond The C≡C triple bond is also a very good reactive trap in reactions of D–A cyclopropanes, although not many reactions with acetylene derivatives are known. Alkynes have been studied much less thoroughly in these reactions than alkenes. The first

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

MeO2C

MeO

95

CO2Me

MeO CO2Et 23

MeO

MeO

CO2Et

MeO

85 °C (~80%)

Malidialle Fonad

+

MeO2C

CO2Me

MeO2C

96

CO2Et

MeO

CO2Me 97

Figure 3.24 First example of the reaction of activated cyclopropanes with C C triple bond.

example of such a process is given by the reaction of ethyl 2,2-dimethoxycyclopropanecarboxylate 23 with acetylenedicarboxylate 95 reported by Graziano and Cimminiello in 1992. The reaction occurs at elevated temperatures in the absence of a catalyst and results in two different compounds in approximately equal amounts, including products of formal [3+2]-cycloaddition to the triple bond [50] (Figure 3.24). In 2004, Yadav and Sriramurthy reported the reaction of terminal acetylenes 99 with silylcyclopropanes 98. Their work was the first example of a systematic study of the reaction of D–A cyclopropanes and alkynes. The reaction occurs as a formal [3+2]-cycloaddition, to give substituted cyclopentenes 100. The use of a strong Lewis acid is required; titanium(IV) tetrachloride was used in this case. The yields of products 100 can reach 85%, while the diastereomer ratio is up to 20/1. The synthetic protocol they developed is also successfully applicable in the intramolecular version, which makes it possible to obtain, for example, annulated indanone 102 [51] (Figure 3.25). Yet another type of process is represented by the [3+2]-cycloaddition of cyclopropyl ketones 103, which occurs under metal complex catalysis conditions. Processes of this type were developed by Ogoshi et al. In 2011, they extended this approach to the reaction of cyclopropyl ketones 103 with acetylenes 104 in the presence of a zerovalent nickel catalyst. This method provides a very good stereoselectivity [52]. The study by Qi and Ready expanded the idea of [3+2]-cycloaddition reactions of D–A cyclopropanes 106 and alkynes 107, including silyl ethers of internal alkynes. This method made it possible to obtain substituted cyclopentenones 108 in fairly good yields after direct treatment of the reaction mixture with pyridinium hydrofluoride, Ar t

BuPh2Si

O 98

R

R = Ph, n-Bu, t-Bu Ar = Ph, 4-ClC6H4, 4-MeOC6H4

99

Ar

TiCl4 (130 mol%) CH2Cl2

tBuPh Si 2

O 100

R

Up to 85% yields dr up to 95:5 O

t

BuPh2Si

TiCl4 O 101

Figure 3.25

(130 mol%) CH2Cl2 SiMe3

tBuPh Si 2

Me3Si

102 85% yield

One of the first systematic formal [3+2]-cycloaddition process with alkynes.

51

52

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes O R1

R3

R2

R4

+

R5

Figure 3.26

R4

105

R5

Ni(0)-Catalyzed formal [3+2]-cycloaddition for cyclopropylketones 103.

R1 R EtO

R1 R2

R3

THF, 50 °C, 3 h

104

103

O

[Ni(cod)2] (10 mol%) Me2AlCl (20 mol%)

TIPS

107

R2

R2

Me2AlCl (1 equiv.) / air then HF·Pyr CH2Cl2, –78 °C

CO2Et 106

O

R

CO2Et R1

108 24–82% yields

R = H, n-Pr, n-Bu R1 = H, alkyl; R2 = alkyl, cycloalkyl

Figure 3.27 Cycloaddition reaction of alkoxy cyclopropanecarboxylates 106.

which resulted in the removal of the silyl group followed by β-elimination. Cyclopropanes with alkoxy donor groups in the cyclopropane moiety were used as the D–A cyclopropanes [53] (Figures 3.26 and 3.27). J. Johnson et al. developed a general approach to the [3+2]-annulation of D–A cyclopropanes 109 using ynamides 110. The process is performed using scandium(III) triflate and provides nearly quantitative yields of the target cyclopentene sulfonamides 111. This process successfully occurs in the case of D–A cyclopropanes, with donor substituents at the aromatic ring, with a heteroaromatic moiety, or with styryl substituents [54]. A little later, Waser et al. demonstrated an approach to [3+2]-cycloaddition between thioalkynes 112, 114 and D–A cyclopropanes 1 in the presence of Hf(OTf)4, giving thiocyclopentene derivatives 113. The yields of the target products varied from 36% to 96%. Moreover, the same team developed an approach where the carbonyl group of phthalimide cyclopropanedicarboxylate underwent cyclization to give a tetracyclic bridged compound 115 [55] (Figure 3.28). Ts R Ar

CO2Me CO2Me 109

Me

Ar = aryl, styryl, 2-furyl R = H, Me, ethynyl; R1 = Ph, n-C5H11

MeO2C MeO2C

O

PhS N

PhS Me

O

115

Up to 78% yields (R1 = NPhth)

114

Ts N Me

110

R

CO2Me

Sc(OTf)3 (10 mol%) CH2Cl2, rt

Ar

CO2Me 111

Up to 99% yields

Me

Sc(OTf)3 (20 mol%) CH2Cl2

R1

R1

N

RS R1 1

CO2Me CO2Me

R = aryl, alkyl, steroid R1 = NPhth, NMal, PMP

112

SiEt3

Hf(OTf)4 (10 mol%) CH2Cl2, rt 15 min

RS

SiEt3 CO2Me

R1

CO2Me

113 Up to 96% yields

Figure 3.28 Johnson’s and Waser’s formal [3+2]-cycloaddition with ynamides and thioalkynes.

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

Malidialle Fonad

O La(OTf)3 (1 equiv.) TMEDA (5 equiv.) Ru(bpy)3Cl2 (2.5 mol%)

Me

O Ph

O

MgSO4, MeCN visible light

117 73% yield; dr 10:1

La(OTf)3 (1 equiv.) TMEDA (5 equiv.) Ru(bpy)3Cl2 (2.5 mol%)

Ph X 116

118 83% yield; dr 9:1

R = Me, Ph; X = CH2, O RO2C CO2R CO2R

R1 O

O

120

Up to 94% yields Me COOH

PhOC SmI2 (2.5 equiv.)

N Ts

THF, rt

N Me 121

Ar

R1

Ar

COPh

Ts

CO2R

Sc(OTf)3 (10 mol%) 1,2-DCE, 4 Å MS

119 Ar = aryl, 2-thienyl R = Me, Et; R1 = alkyl, Cl, Br, OMe

TBSO

Ph

MgSO4, MeCN visible light

R

Ph

O

122

COOH N H

OTBS

81% yield; dr 12:1

(–)-(a)-Kainic acid

Figure 3.29 Intramolecular formal [3+2]-cycloaddition with alkynes.

Yoon et al. studied an intramolecular version of formal [3+2]-cycloaddition of alkynes comprising a cyclopropylketone moiety 116. This process occurs in the presence of lanthanum triflate, and a ruthenium-based photocatalyst under visible light irradiation. The yields of cyclic products 117, 118 were up to 83% with good diastereoselectivity. Moreover, migration of the multiple bonds toward the acceptor group was observed in the reaction with an alkyne with a terminal methyl group [39]. Liang et al. suggested a method for synthesizing the cyclopenta[c]chromene skeleton 120 by a related reaction of intramolecular [3+2]-cycloaddition of D–A cyclopropanes 119 with a C C triple bond catalyzed by scandium triflate [56]. Li et al. used an intramolecular version of [3+2]-cycloaddition in the complete synthesis of (−)-(α)-kainic acid. Samarium(II) iodide was used as the mediator in the cyclization process. This process occurred with high diastereoselectivity and in high yields [57] (Figure 3.29).

3.2.4 [3+2]-Annulation with Aromatic C=C Bond The addition reactions of D–A cyclopropanes 1 to aromatic multiple bonds in heterocycles occurring as [3+2]-annulation with dearomatization and the formation of annulated heterocyclic compounds have been studied rather well. Moreover, the reactions with indole have been studied most thoroughly, since polycyclic derivatives based on the indole skeleton are of considerable interest, both as biologically active compounds and in the complete synthesis of natural substances and their analogs. Indole derivatives are widespread in nature. The first examples related to the development of new methods for the synthesis of polycyclic indole heterocycles

53

54

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Ar

CO2R

R1 1 N

R2

R3 123

CO2R

Yb(OTf)3 (5 mol%)

R1

Ar

CO2R CO2R

N R3

N

R1 = H

Δ R2 = H

R3

R3

R2

CO2R

124, 27–94%

CO2R

N 3

R 125, 55–97%

R2

R1

CO2R CO2R

N

CO2R

R2 I

Ar

Figure 3.30

Ar

R1

Ar

CO2R

126,16–78%

Kerr’s studies of the addition of indoles to D–A cyclopropanes.

involve the use of indoles as the nucleophilic components in the [3+2]-cycloaddition of activated cyclopropanes. M. Kerr et al. developed a series of processes in 1997–2002 and found that the outcome of the reaction strongly depends on the substituents in the starting indole. As a result, three main directions of the reaction that gave [3+2]-cycloaddition products 124 and acyclic products 125, 126 were found [58–60] (Figure 3.30). Subsequently, many scientific teams continued to study and develop processes based on the reactions of various D–A cyclopropanes with indole derivatives, including approaches to asymmetric catalysis and intramolecular transformations. H. Junjappa presented a variant for trapping 1,3-zwitterions, which are generated from cyclopropyl ketones 10 and cyclopropanedicarboxylates 1, by indole derivatives 127 via [3+2]-annulation in the presence of boron trifluoride etherate to give cyclopentaindolines 129, 130 in 70% to 93% yields [61]. In turn, Pagenkopf et al. developed this process for alkoxycyclopropanecarboxylates 16 as D–A cyclopropanes. Trimethylsilyl triflate in nitromethane was used as the activator. This reaction occurred with high diastereoselectivity and also gave tricyclic indole derivatives 131 [62]. Y. Tang developed an efficient asymmetric catalytic approach for the [3+2]-annulation with indoles in the presence of copper(II) salts, namely, Cu(OTf)2 or Cu(SbF6)2, and substituted bisoxazolines as chiral ligands, which allowed a high degree of enantiomeric enrichment of products 132 (up to 98 : 2) to be reached [63]. More recently, Jerome Waser suggested to use D–A cyclopropanes based on aminocyclopropane monoesters 128 in the presence of catalytic amounts of in situ-generated Et3SiNTf2. Careful optimization of the activating amino group was performed to implement the process efficiently and open the cyclopropane ring. TsMeN was found to be the best option that made it possible to perform the reaction with a wide range of indole and cyclopropane substrates [64] (Figure 3.31). Y. Tang et al. developed an efficient protocol for the intramolecular [3+2]-cycloaddition of indoles 134 whose structures comprised a D–A cyclopropane moiety. The process occurs efficiently in the presence of Cu(SbF6)2 and a chelating ligand to give high yields of the final tetracyclic cyclopentane-fused spiroindolines 135 with good diastereoselectivity and enantiospecificity. The use of differently substituted ester groups allowed controlled syntheses of various diastereomers of the resulting

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon R = aryl, hetaryl, styryl, vinyl R1 = H, alkyl; R2 = H, alkyl, vinyl X = H, Me, OMe, Br, Cl

R = Me, n-Bu R1 = H, Me PG = H, Me X = H, OMe, I

R

RO

X

R2

X

N R PG

CO2Me

N R1 CO2Me Bn CO2Me 132 R CO2Me Up to 98% yields 1 Cu(OTf)2 dr up to 20:1 (10 mol%) ee up to 96% BOX (11 mol%) X PhMe, 0 °C PG = Bn

R3

R 128

R N R1 CO2Et 133 PG Up to 95% yields dr up to 95:5

131 51–90% yields dr up to 3:1

Ar R1

1

Ar R2

CO2Et CO2Et

CO2Et CO2Et

N PG

BF3·Et2O or Yb(OTf)3 MeNO2 or MeCN R1 = H; X= H

PG

130 49–90% yields Ar = aryl, styryl R2 = H, Me; PG = H, Me

OTES

Me

R2

X

CO2Et

R2 = H

R2

127

CO2Et

1

TMSOTf, MeNO2

16

N

R4 TsN Ts R4 R3 N

CO2Et OR

Malidialle Fonad

Ar

OMe Me

(25–50 mol%) Tf2NH (2.5–20 mol%) CH2Cl2, –78 °C, 30 min

10

O R

X

BF3·Et2O, MeNO2

Ar R2 1

N R R PG

Ar = aryl, styryl; R = Me, Ph R1,R2 = H, Me; PG = H, Me; X = H, Br

O 129

70–93% yields

Figure 3.31 [3+2]-Annulation of various D–A cyclopropanes with indoles.

compounds to be performed. The CO2(iPr) group (for the trans isomer) and the CO2(2-Ad) group (for the cis isomer) showed the best results [65] (Figure 3.32). Regarding other heterocyclic systems, [3+2]-annulation with derivatives of furans, benzofurans, benzothiazoles, some pyridines, and β-naphthols was studied. The C=C double bond in the furan ring is modified most easily since it has the lowest aromaticity and is most reactive. For example, Trushkov et al. presented a method for the functionalization of 2,5-dimethylfuran 136 with D–A cyclopropanes 1 by single or double formal [3+2]-cycloaddition at C=C bonds to give bi- and tricyclic systems 137, 138 based on tetrahydrofuran, as well as by more complex cascade processes. Lewis acids such as tin(IV) chloride and ytterbium(III) triflate were used as the catalysts in these reactions [66]. M. Vitale’s study presents a related method TsN CO2R CO2R

X N PG

134

R = alkyl and bulky alkyl PG = H, Me X = H, Me, OMe, F, Cl, Br

Cu(SbF6)2 (10 mol%) L (12 mol%) 1,2-DCE

L= Ar N N Ar Ar = 2,6-(i-Pr)2C6H3

TsN X

CO2R N PG

CO2R 135

Up to 95% yields dr up to 96:4 ee up to 99%

Figure 3.32 Intramolecular [3+2]-annulation with indoles.

55

56

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Me Ar 1

CO2Me CO2Me

O 136

Me

MeO2C

MeO2C

CO2Me Ar Me O Me CO2Me 137

LA, CH2Cl2 LA = SnCl4, Yb(OTf)3

Ar = Ph, 2-thienyl

CO2Me Ar HH

Me Ar Me O 138

82–94% yields R

4

R = H, OMe, Br, F, OCF3, Me, t-Bu EWG = CO2Me, CO2i-Pr, CO2CH2CF3, Meldrum's acid, Barbituric acid

Figure 3.33

53–76% yields

O NO2

EWG EWG

CO2Me H

R

EWG EWG

139 Pd2(dba)3·CHCl3 (2.5 mol%) dppe (5 mol%) CH2Cl2, rt, 2 h

O NO2 140 Yields up to 90% dr up to 4.4:1

Formal [3+2]-cycloaddition with furans and benzofurans.

for [3+2]-annulation of 2-nitrobenzofurans 139, but with vinyl cyclopropane dicarboxylates 4 and under palladium catalysis conditions using the Pd2(dba)3·CHCl3 complex. The reaction was also successfully performed with vinyl D–A cyclopropanes comprising various acceptor substituents apart from ester groups [67] (Figure 3.33). Processes of [3+2]-annulation of 2-naphthols 141 in reactions with D–A cyclopropanes 1 are also known. In this case, elimination of an OH group occurs, which results in the reduction of the naphthalene aromatic system to give derivatives of cyclopentanaphthalenes 142. Various conditions for this type of process are known. Prof. Biju used a Bi(III)-based catalytic system: Bi(OTf)3–KPF6, whereas the standard Sc(OTf)3 only led to a simple Friedel–Crafts type reaction without cyclization. At the same time, the reaction was very tolerant to the electronic effects of substituents in the naphthalene core under Bi(III) catalysis conditions [68]. Y. Zhao et al. used a metal-free catalytic system based on a Brønsted acid, TfOH, that showed similar synthetic patterns. However, it is especially successful with vinylcyclopropane dicarboxylates, where Bi(III) catalysis did not perform well enough [69] (Figure 3.34). A few examples of reactions at the aromatic C=N bond in heterocycles that occur as a formal [3+2]-cycloaddition with dearomatization and the formation of R1 R1

R1

OH

R

OH

EWG EWG 142 60–87% yields

141 TfOH (20 mol%) CH2Cl2, 0 °C

R 1

EWG EWG

141 Bi(OTf)3 (10 mol%) KPF6 (20 mol%) CH2Cl2, 30 °C

R = aryl, hetaryl, styryl, vinyl EWG = CO2Me, CO2Et, CO2Bn, CO2i-Pr, CO2t-Bu R1 = Ph, OMe, n-C6H13, Br, OH, CO2Me

Figure 3.34 [3+2]-Annulation with β-naphthols.

R R1

EWG EWG 142 53–87% yields

3.2 ­Formal 3322]-CyalFmaadidFon dit -morFonn-morFon

Et

N

CN 144

Rʹ Rʹ

S N

CO2Me CO2Me

147 R 89–95% yields; ee up to 95%

N 146

MeO n-Pr

Malidialle Fonad CO2Et

NC

CO2Et Me3SiOTf, MeNO2 (52% yield) 143

N

Et

145 n-Pr

S

CO2Me R MgI2 (10 mol%) CO2Me tBuPyBOX (12 mol%) 1 PhCl, 0 °C R = aryl, 2-thienyl, styryl 5 days, 4 Å MS Rʹ = H, Br, Cl, Me, MeO

Figure 3.35 [3+2]-Annulation with aromatic C=N double bond in 4-CN-pyridine and benzothiazoles.

heterocyclic annulated systems are known. For example, examples with 4-cyanopyridine 144 and substituted benzothiazoles 146 were reported [70, 71] (Figure 3.35).

3.2.5 [3+2]-Annulation of D–A Cyclopropanes Involving Aryl/ Heteroaryl Donor Substituent A special place in the wide variety of reactions of formal [3+2]-cycloaddition of D–A cyclopropanes 1 is occupied by the processes of so-called [3+2]-annulation. They proceed with annulation along the aromatic ring, which is used as a donor group for the activation of cyclopropane, while the malonyl center at the acceptor groups remains unused, in contrast to most other processes. There are very few examples of such processes at the moment, and most of them were developed by Prof. Trushkov’s group, but their distinctive features make them worthy of a separate consideration. Usually, these processes occur during the interactions of D–A cyclopropanes with double and triple C–C bonds, or during dimerization. These processes generate active carbocationic centers capable of efficient intramolecular electrophilic substitution at the aromatic ring to the ortho position according to the SEAr type. Moreover, for the selective direction of the process in the desired direction, the use of additional donor substituents in the benzene ring is usually required, for example, MeO groups are especially suitable. It is also preferable to use heteroaromatic substituents as donor groups in D–A cyclopropane. Older similar processes of [3+3]-annulation and [4+3]-annulation are also known, proceeding in a similar way and described by the same features (see Figure 3.36). In 2013, the selective [3+2]-annulation of D–A cyclopropanes 1 and polysubstituted alkenes 148 in the presence of Lewis acids was demonstrated. As noted above, this process directly involves the donor group of cyclopropanes, which is attached to the main three-carbon fragment involved in cycloaddition. Derivatives of indanes 149 or their heterocyclic analogs are obtained as reaction products [72]. The known examples of a similar reaction occurring during the dimerization of D–A cyclopropanes 1 in the presence of Sn(OTf)2, in which [3+2]-annulation is observed between β-styrylmalonate formed in situ and the starting cyclopropane. In this case, this dimerization can also be selectively carried out in a cross-variant between two

57

58

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

CO2R

Ar

Ar

O

CO2R

1

E = CO2R

OR

Lewis acid

RO

O

I

E E

Ar

LA

1,3-Zwitterionic intermediate

C=C or C≡C CO2R

RO2C

E

R

R′

R′

E

Ar R R′

3 [3+2]-Annulation

1,5-Cyclization

Electrophilic substitution (SEAr)

Ar II

R

CO2R CO2R

Ar

2 [3+2]-Cycloaddition

Figure 3.36 [3+2]-Annulation reactions of D–A cyclopropanes with multiple C-C bonds, and their main mechanistic features.

different cyclopropane molecules [73]. In a later study, a similar [3+2]-annulation of arylcyclopropanedicarboxylates 1 and internal alkynes 104 was developed in the presence of Lewis or Brønsted acids. This also requires the use of aryl D–A cyclopropanes with donor substituents in the aromatic fragment. The reaction products are polysubstituted derivatives of indene 151, which can be used as dyes with high extinction coefficients [74] (Figures 3.37–3.39). R

Ar

LA (1.3 equiv.) CH2Cl2, rt

1 Ar = aryl, hetaryl

CO2Me

MeO2C

R R 148

CO2Me CO2Me

Ar

R

R R R R 149 R = cycloalkyl, alkyl, aryl 45–81% yields, dr up to 9:1

LA = SnCl4, BF3·Et2O, Sn(OTf)2

Figure 3.37 [3+2]-Annulation of D–A cyclopropanes 1 with alkenes.

CO2Me CO2Me

Ar

MeO2C Ar

Sn(OTf)2 (10–30 mol%) Solvent, Δ

CO2Me

Ar

1

MeO2C

Ar = aryl Solvent = MeNO 2, PhCl

CO2Me 150

Up to 87% yields; dr up to 4:1

Figure 3.38 [3+2]-Annulation dimerization process of D–A cyclopropanes 1. R CO2Me CO2Me

Ar 1

Ar = aryl, hetaryl R = Ph, PMP Rʹ = Me, Et, Ph, PMP

104

Rʹ

LA (120 mol%) or BA (10 mol%) 4 Å MS, MeNO2

R

Rʹ

CO2Me CO2Me

Ar

151 Up to 85% yields

LA = SnCl4, BF3·Et2O BA = TfOH

Figure 3.39 [3+2]-Annulation of with acetylenes.

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona

3.3 Formal [3+2]-Cycloaddition with C=O and C=N Double Bond 3.3.1 Formal [3+2]-Cycloaddition with C=O Double Bond Of all the variety of reactions, those of D–A cyclopropanes with carbonyl compounds have been studied especially well. Moreover, they are among the first reactions that started the development of the chemistry of these compounds. The process is of extremely general nature and nearly always occurs as a formal [3+2]-cycloaddition to the C=O double bond to give a tetrahydrofuran ring; substrates of diverse types undergo this, although other types of processes are also known in some cases. The first examples of [3+2]-cycloaddition of aldehydes to activated cyclopropanes were reported by H. U. Reissig and I. Kuwajima over 40 years ago, back in 1981 and 1977, respectively [75, 76]. After that, these studies slowly continued to develop, and the use of these reactions gradually became more and more popular. The next turning point came in 2005 when J. Johnson published a [3+2]-cycloaddition with 2-substituted cyclopropane-1,1-dicarboxylates that are now the most popular types of D–A cyclopropanes (along with M. Kerr’s [3+3]-reaction of the same cyclopropanes with nitrones reported in 2003) [77, 78]. In fact, the publication of these reactions in 2003–2005 began the modern era and the chemistry of D–A cyclopropanes. From that time on, this term was introduced into widespread use [1]. Therefore, the significance of [3+2]-cycloaddition reactions with aldehydes can hardly be overestimated. Sometimes this reaction with cyclopropane1,1-dicarboxylates is also called Johnson’s reaction since it became very popular subsequently. At present, more than a hundred works on the reaction of [3+2]-cycloaddition with aldehydes in various implementations have been published. It is one of the most recognizable and representative processes in the chemistry of D–A cyclopropanes. Moreover, the reaction is now widely used in practice since it produces tetrahydrofuran derivatives that are very useful in syntheses. The majority of early studies mainly focused on the use of D–A cyclopropanes comprising alkoxy groups 152, 155, 157 and cyclopropylketones 159. It was sometimes rather difficult to reach high diastereoselectivity in those reactions, especially in the case of sterically loaded cyclic systems. Nevertheless, the reactions occurred successfully with various cyclopropanes and often required highly reactive tin and titanium chlorides as the Lewis acids [75, 79–82] (Figure 3.40). As mentioned above, since 2005, J. Johnson et al. began to intensively study the formal [3+2]-cycloaddition D–A cyclopropanes 1 and aldehydes 160 catalyzed by Lewis acids. Various aromatic, heteroaromatic, as well as alkenyl and alkyl substituents were used as substituents in the initial substrates. A wide range of Lewis acids has been studied using model reactions of 2-phenylcyclopropane-1,1-dicarboxylate with benzaldehyde, as well as some others, leading to the formation of substituted tetrahydrofurans. The product usually forms with high cis-diastereoselectivity. It should be noted that this reaction is well-catalyzed by almost any Lewis acid, although the yield of tetrahydrofurans may not be so high. However, triflates of a number of transition and post-transition metals, such as Sc(OTf)3, Yb(OTf)3,

59

60

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes O

O OTMS

R3

R4

153

R1

MeO2C

R2 152

MeO2C

TiCl4 CH2Cl2, –78 °C then H2O

CO2Me

O O 157

Figure 3.40

R4

R2 MeO2C

153

SnCl4 (10 mol%) CH2Cl2 –78 °C

H O

O

1

R

OH R1

R4 154, 61–95% R

R

O

R4

O R

R3

OR2

EtO2C 155

H O

OR2

O R1 159

158 67–99%; dr >50:1

RS RL 153 TiCl4 CH2Cl2, –78 °C then cat. TsOH

R1

R1

EtO2C RL

O O

RS 156, 61–96%

O

R CO2Me CO2Me

R

1

R2

160

O

H

TiCl4, Bu4NI then Al2O3

R1 O R2 161, 64–94%

Initial reactions of D–A cyclopropanes with aldehydes and ketones.

Ce(OTf)3, Hf(OTf)4, Cu(OTf)2, Zn(OTf)2, Sn(OTf)2, and others, turned out to be the most preferable among them. At the same time, tin(II) triflate was most widely used for catalysis, and for a number of substrates – hafnium(IV) triflate, for less reactive substrates, such as aliphatic aldehydes or cyclopropanes with vinyl or alkyl substituents – SnCl4 and AlCl3 [77, 78, 83, 84]. The process is very easy to experimentally implement. For example, the reaction of 2-phenylcyclopropane-1,1-dicarboxylate with benzaldehyde proceeds very easily using as little as 5% anhydrous Sn(OTf)2 at room temperature and simply mixing the reagents in a suitable solvent (usually methylene chloride), leading to quantitative yields of a tetrahydrofuran product that does not actually require additional purification. At the same time, traces of water, which could potentially interfere with the reaction, are easily removed by adding molecular sieves. The mechanism of this process is classical in the chemistry of D–A cyclopropanes. It is implemented through the coordination of the Lewis acid at two ester groups, which leads to the activation of the σ-bond of the cyclopropane ring and its subsequent opening, generating 1,3-zwitterionic intermediates, which enter into a stepwise [3+2]-cycloaddition reaction with C=O double bond of aldehydes. In this case, we can consider two main extreme options from the possible ways of the process: with the complete opening of the three-membered ring and the generation of 1,3-zwitterionic intermediates as such, or without complete opening, but only with the polarization of the C‒C bond, making it sufficient for nucleophilic attack by an aldehyde molecule. It is believed that polarization of the bond of the cyclopropane ring without opening occurs when milder reaction conditions and less active Lewis acids, such as metal triflates, and full opening occurs when using stronger Lewis acids, such as titanium or tin(IV) chlorides. Although in reality, it turns out to be quite difficult to distinguish one type of mechanism from another. Their significant difference lies, among other things, in the stereochemical result of the reaction, especially when optically active starting cyclopropanes are used since the generation of carbocations leads to significant racemization (Figures 3.41 and 3.42).

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona R–CHO 160

CO2Me

Don

CO2Me 1 Don = aryl, hetaryl, styryl, vinyl R = aryl, hetaryl, styryl, alkynyl, alkyl

O

Don

R CO2Me

Lewis acid CH2Cl2

162

CO2Me

Johnson's main conditions: CO2Me

Ar

CO2Me 1

Arʹ–CHO 160

O

Ar

Arʹ CO2Me

Sn(OTf)2 (5 mol%) CH2Cl2, rt

CO2Me 162 Yields up to 98% dr up to 100:1

Figure 3.41 Johnson’s formal [3+2]-cycloaddition of cyclopropanedicarboxylates with aldehydes.

OR Don

CO2R Lewis acid 1

CO2R

Don δ+

δ-

RO

O

OR Don

O LA

RO

O

LA II

I

R1

O R1

RO2C RO2C III

Figure 3.42

O

O Don

RO2C RO2C 162

R1 O Don

General mechanism of the reaction.

In the work of Johnson et al., a wide range of both substrates with different substituents was studied, and a detailed analysis of a number of dipolarophiles was carried out. The following can be noted from the main regularities: aromatic aldehydes 160 containing donor groups react much more easily than aromatic aldehydes with electron-withdrawing groups. However, when Hf(OTf)4 is used as a catalyst, these aldehydes can also be easily introduced into reactions with cyclopropanes. The effect of substituents in the D–A donor group of cyclopropanes 1 was also studied. Electron-donating aromatic substituents also significantly accelerate [3+2]-cycloaddition, stabilizing the carbocationic center formed as a result of the opening of the cyclopropane ring. The Johnson [3+2]-cycloaddition reaction with aldehydes proceeds with high diastereoselectivity and stereospecificity, which makes it possible to obtain enantiomerically pure tetrahydrofuran derivatives 162 starting from chiral starting cyclopropanes 1. To explain the abnormally high diastereoselectivity and the absence of racemization, Johnson and colleagues performed a detailed study of the reaction mechanism using deuterium labels (Figure 3.43), under mild catalysis with tin(II) or hafnium(IV) triflates. Activation of the σ-bond of the cyclopropane ring under such conditions occurs without the actual opening of the three-membered ring and

61

62

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes D3CO2C Ar

CO2Me Ar

CO2Me

1

R

160

SnXn

H

Sn(OTf)2 (5 mol%) or Hf(OTf)4 (5 mol%) CH2Cl2

Ar, R = aryl, alkenyl, alkyl

MeO2C Ar

+

O

O

R OCD

OMe

D3CO

H

H

XnSn

O

Ar

OMe O

O

H

R

O

O

D3CO

CO2Me

O

H Ar

3

IV

SnXn

O

Ar

O

OMe

I

CO2Me R

162, 54–99% dr 1.5:1 to 100:1 ee 76–99%

D3CO H

H R

O

O

D3CO SnXn

H

O R

120°

Ar III

H

OMe

O

Ar

O

SnXn

O II

OMe

Figure 3.43 Detailed mechanistic investigation and explanation of enantiospecificity by Johnson’s group.

the formation of a carbocation (intermediate II), which practically prevents racemization, but it is sufficient for an effective nucleophilic attack by an aldehyde molecule, similar to SN2 type. Also, during the process, racemization does not have time to occur due to the very rapid formation of a new C─C bond [83]. Despite the enantiospecificity of the reaction with aldehydes, the use of optically pure starting cyclopropanes does not always allow one to transfer chirality and obtain an optically pure product. In cases where less reactive starting D–A cyclopropanes or aldehydes are used, the use of more severe reaction conditions and stronger Lewis acids is required, which leads to significant or complete racemization of the starting cyclopropane during the process. The next step was the development, by the same authors in 2009, of a catalytic asymmetric variant of the cycloaddition reaction of cyclopropane dicarboxylates 1 to aldehydes 160, which is one of the first for D–A cyclopropanes (along with the reaction with nitrones and some others). The ability to convert one enantiomer of cyclopropane to another under the action of Lewis acids makes it possible to implement an effective dynamic kinetic asymmetric resolution (DyKAT) protocol when using racemic cyclopropanes, converting all cyclopropanes into an optically pure product 162 with high ee values (up to >98–99%). A MgI2 complex with chiral PyBOX ligands is used as a catalyst [84, 85]. This protocol and the combinations of Lewis acids and chiral ligands used, have proved to be excellent for various substrates and later became the most common and classic for D–A cyclopropanes and their various asymmetric processes (Figure 3.44). The process of formal [3+2]-cycloaddition of 2-vinyl cyclopropane dicarboxylates 4 to aldehydes 160 can also be considered separately since it proceeds by a different mechanism. This process was also first developed by the J. Johnson group in 2008. It represents another approach to the creation of cyclic systems based on D–A

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona

RCHO 160

CO2Me

R1

CO2Me

PyBOX·MgI2 (10 mol%) CCl4

1

R1

O

Cl

R CO2Me

CO2Me 162 Yields up to 92% dr > 50:1 ee up to 97%

O

N

N tBu

O

N

tBu

PyBOX

Figure 3.44 Asymmetric [3+2]-cycloaddition with aldehydes (DyKAT).

cyclopropanes. The method is based on the formation of stabilized palladium-allyl zwitterionic intermediates (I and II), which implies the use of the corresponding vinylcyclopropanes 4 as starting D–A cyclopropanes. This therefore requires the use of Pd(0) metal complex catalysis, which initiates the activation and opening of the three-membered ring upon initial coordination with the vinyl group and not with acceptor ester substituents. Otherwise, the patterns are broadly similar to those for the analogous Lewis acid-catalyzed process for cyclopropane dicarboxylates. The process is also of a general nature and is well implemented for various aromatic as well as aliphatic aldehydes [86] (Figure 3.45). The formal [3+2]-cycloaddition to the aldehyde’s C=O double bond, producing a tetrahydrofuran ring, is a very general process that can involve diverse types of substrates. After the first publications and a series of works published by J. Johnson’s team, various scientific groups began to actively develop and study this process. The main focus was on the use of various types of D–A cyclopropanes in this reaction. For example, almost any aldehydes, including aromatic and heteroaromatic aldehydes, aliphatic aldehydes, aldehydes with various functional groups, more complex aldehydes based on natural and biological compounds, building blocks, and so on, as well as ketones enter this reaction under a wide range of conditions. The specifics of the reaction are usually governed by the D–A cyclopropane used. Catalysis by various Lewis acids or sometimes Brønsted acids, often under rather mild conditions, is used in the majority of cases. It is this reaction with aldehydes that is often used as a model process for optimizing the use of new types of D–A cyclopropanes. Studies on the [3+2]-cycloaddition with aldehydes are reported in the works of a number of scientific teams, such as those of V. Yadav, J. Johnson, D. Werz, J. Waser, M. Kerr, B. Pagenkopf, Z. Wang, Y. Tang, P. Banerjee, I. Trushkov, R. Novikov, Y. Tomilov, M. Niggemann, N. Maulide, Y, Hua, J. Chai, H. Shao, Z. Chai, J. Zhou, A. Mikhaylov, D. Rawat, and others, many of whom are very well known in the chemistry of activated cyclopropanes and related substrates [25, 27, 87–101].

CO2Me 4

CO2Me

Figure 3.45

Pd2(MeO-dba)3 (cat.) Ph2phen (cat.) toluene 40 °C

O CO2Me

Pd

CO2Me I

R

MeO2C H O Pd

CO2Me R II

Pd(0)-Catalyzed [3+2]-cycloaddition of vinylcyclopropanes.

MeO2C

O

CO2Me R

163, 53–100% dr 69:31 to 98:2

63

64

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Also, the [3+2]-cycloaddition process with aldehydes is very convenient for testing the use of new catalysts in the chemistry of D–A cyclopropanes (for example, cobalt porphyrins [CoTPP] or gallium phthalocyanines [PcGa]) [102, 103] (Figure 3.46). D D

CO2Me

A

R

O R

Me

CO2Me

BnO

R1 = Me; isopropenyl; aryl R2 = Ph; Me; Allyl; Bn

R = Me; n-Pr; BnOCH2; Ph R1 = aryl; alkyl

(V. Yadav, 2006)

Sn(OTf)2 (5 mol%) 1,2-DCE, rt, 20 min

Ca(NTf2)2 (5 mol%) Bu4NPF6 (5 mol%), 1,2-DCE, rt

(J. Johnson, 2011)

(M. Niggemann, 2013)

Boc

CO2R

N

CO2Et

R

O

O

O

CO2R

O

CO2Me O

R

CO2R = CO2Me, CO2Et

R = Me, H, F

AlCl3 (50 mol%) CH2Cl2

FeCl3·Al2O3 (5 mol%) CH2Cl2, rt, 2 h

SnCl4 (10 mol%) or In(OTf)3 (20 mol%) CH2Cl2, –20 °C

(J. Waser, 2012)

CO2Me

N

CO2Me

R, R1 = aryl

(G. Yang, 2011)

(H. Shao, 2013)

CO2Me

N

N

n = 1,2 InCl3 (20 mol%) toluene, 0–4 °C

O

O

CO2Et

Me

n

BnO

R1

Sc(OTf)3 (15 mol%) CH2Cl2, rt

R1

O

O

CO2Et

CO2Me

R1

A

O

R

R2

CO2Me SiPh2tBu

+

Cu(ClO4)2 (10 mol%) t BuBOX (12 mol%) CH2Cl2, 3 Å MS, rt (J. Waser, 2014)

(J. Waser, 2014) Ph

R1

O CO2Et

Ar

Ar

CO2Et Ar = aryl

AlCl3 (50 mol%) CH2Cl2 (G. Yang, 2013)

O

Ar

R2

Ar1

Ar

O

O

O R1 = aryl, H, TMS, cC3H5 R2 = aryl, n-Bu, 2-thienyl

Ar = aryl, hetaryl

Ar, Ar1 = aryl

Sc(OTf)3 (20 mol%) toluene, 4 Å MS, 0 °C

tBuMe SiOTf 2

(10 mol%) EtNO2 or MeNO2

BF3·Et2O (2 equiv.) CH2Cl2

(Z. Wang, 2016)

(N. Maulide, 2016)

Cl

N

O 4-MeC6H4 O

O

Ar

O CO2R

Ar

Sn(OTf)2 (10 mol%) CH2Cl2, rt (D. Werz, 2018)

(D. Rawat, 2017)

Arʹ

N

CO2Me CO2Me

O

PG

O CO2Me

N Ar

N

R1 R2

TsOH (1.1 equiv.), CH 2Cl2

CO2R = CO2Me, CO2Et Ar, Arʹ = aryl, hetaryl

PG = Bn, Cy, Ph Ar = aryl

Sc(OTf)3 (10 mol%) 1,2-DCE

Sn(OTf)2 (1 mol%) 1,2-DCE, 40 °C

Al(OTf)3 (1 mol%) 1,2-DCE, 80 °C

Ar = aryl, hetaryl R1 = Me, Cy, Bn R2 = Me, Et

(J. Zhou, 2017)

(Z. Chai, 2018)

(Z. Chai, 2020)

(A. Mikhaylov, 2020)

Ph

Figure 3.46 Generality of the formal [3+2]-cycloaddition reaction with aldehydes, selected examples of different D–A cyclopropanes.

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona O CO2Bn MeO MeO

CO2Me AlCl3 CO2Me (15 mol%) 164 CH2Cl2 CHO

+ O

O

O O

MeO2C MeO2C

MeO

O

O

MeO

BnO2C OMe

O 165

OMe

OMe

166, 80%, dr 20:1

(+)-virgatusin

OMe

O CO2Me 167 + Me OTMS OHC 168

MABNTf2 (25 mol%) CH2Cl2 rt, 21 h

O

CO2Me

Me OTMS

AcO

HH O

O H

t-Bu

169 76% dr 18:1

O)2AlNTf2 O

HH (+)-polyanthellin A

Me

CEt3 MABNTf2

Figure 3.47 Examples of the application of [3+2]-cycloaddition with aldehydes in total synthesis.

The reactions of formal [3+2]-cycloaddition of aldehydes and D–A cyclopropanes have found wide use in the complete synthesis of natural compounds since the tetrahydrofuran ring and its derivatives are widespread in nature. The use of [3+2]-cycloaddition as a key step in the complete syntheses of compounds such as (+)-virgatusin and (+)-polyanthellin-A in the studies by Jeffrey Johnson can be noted as simple and illustrative examples [104, 105] (Figure 3.47). Ketones exhibit properties similar to aldehydes as dipolarophiles in the formal [3+2]-cycloaddition with D–A cyclopropanes 1, although their activity may be somewhat lower in some cases. The same Lewis acids are usually employed for ketones as for aldehydes, while the reaction diastereoselectivity remains at the same high level, as it was reported in the works of many scientific teams, such as those of J. Johnson, V. Yadav, J. Waser, and others. Highly substituted tetrahydrofuran derivatives 170 can be obtained in the reaction [27, 83, 87]. Both simple acyclic ketones and more complex cyclic representatives, as well as other substituted ketones 171, readily react in this process. Various spiro-linked tetrahydrofurans 172, 174 are obtained as the products in the case of cyclic ketones. For example, even cyclopropenones 173 can be successfully used in the reaction [106]. Special synthetic protocols were also developed for [3+2]-cycloaddition reactions with ketones performed in the enantioselective catalytic version. Y. Tang et al. developed such a protocol for reactions with cyclic ketones under catalysis with copper(II) triflate and bis-oxazoline ligands (SaBOX) [107]. Various functionalized D–A cyclopropanes, for example, those based on γ-butyrolactone, are also successfully used in reactions with ketones [99] (Figure 3.48). A series of works by Z. Wang’s team report a number of interesting intramolecular processes based on formal [3+2]-cycloaddition of the C=O double bond to D–A cyclopropanes to give complex polycyclic systems with a bridging oxygen atom.

65

66

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Don = aryl; NPhth; 2-ferrocenyl R1 = Ph; Et Sc(OTf)3 (10 mol%) R1 CH2Cl2, 0–80 °C, 4 h O O Don R1 CO2R

R1

174 RO2C Yields up to 100%

Don = CH2SitBuPh2; vinyl; aryl; alkyl; N(PG) R1,R2 = alkyl; aryl; cycloalkyl O

173

R = Me, Et, Bn Don

O

Don

Rʹ

BnO2C

CO2Bn

Yields up to 98% dr up to 99:1 ee up to 92%

172

R2

Ar O

n = 0–2

O

Rʹ

171

FG

Ar O N

Cu(OTf)2 (10 mol%) SaBOX (12 mol%) CH2Cl2/THF –20 °C, 4 Å MS

Me

N

SaBOX Me Ar = 3,5-tBu2C6H3

Formal [3+2]-cycloaddition with ketones. CO2R1

X

170 Yields up to 95%

LA = Sn(OTf)2; SnCl4

CO2R

Don = PMP; styryl; hetaryl; Rʹ,Rʺ = H, Me, Et, n-Pr, i-Pr, t-amyl

Figure 3.48

CO2R1

LA (10–20 mol%)

LA CO2R1 (10–20 CO2R1 mol%) R 1,2-DCE 177 O LA = Sc(OTf)3; Yb(OTf)3; Eu(OTf)3

R2 FG

CO2R1 1

CO2R 175 176 R R Yields up to 96% R = H, Me, vinyl, PhC≡C n = 0–2 R1 = Me, Et; R2 = H, Me, OBn, OEt R = H, Me, c-C6H11, n-Bu, c-C3H5, Ph X = CH2, O, S; Y = O, NRʹ LA = Sc(OTf)3, SnCl4, R1 = Me, Et FG = aryl, hetaryl, alkyl Yb(OTf)3, Et3SiOTf CO2R1 Et3SiOTf (20 mol%)

FG

O R

179

R = H, Me, vinyl, PhC≡C R1 = Me, Et; R2 = H, Me, OBn, OEt FG = aryl, hetaryl, alkyl

Figure 3.49

R2 FG

(CO)6Co2

O

MeNO2 R

n

n

Y

1,2-DCE or MeNO2

Y

R2

CO2R

1

Rʺ

n = 0–2

R1

RO2C

LA (5 mol%) CH2Cl2, rt

CO2R

R = Bn

Rʺ

R1 R2 153

R1

R2

O

Don

CO2R1 CO2R1

O CO2R1 180

Yields up to 94% dr up to 95:5

SnCl4 (20 mol%) 1,2-DCE

FG R

181

R = H, Me; R1 = Me, Et FG = aryl, hetaryl, alkyl

CO2R1

O R

CO2R1

178 Yields up to 84%

(CO)6Co2

O CO2R1

FG

CO2R1

R 182 Yields up to 93%

Intramolecular formal [3+2]-cycloaddition with C=O double bond.

Aromatic, alkyl, heteronuclear, heteroaromatic, α,β-unsaturated compounds, and moieties with a triple bond serve as bridges between the carbonyl group and the activated cyclopropane moiety. The range of the developed processes is very wide. The reactions mainly involve aldehydes and ketones, but they can also be successfully expanded to include the corresponding imines, where the C═N double bond is involved in the process [108–111] (Figure 3.49).

3.3.2 Formal [3+2]-Cycloaddition with C=N Double Bond Reactions of formal [3+2]-cycloaddition of activated cyclopropanes with imines result in pyrrolidine heterocycles that are part of many biologically active and natural compounds. For this reason, this class of reactions is of great importance and has

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona

been studied very well to date. Studies of these processes began back at the dawn of the chemistry of D–A cyclopropanes, starting from the end of the past century. At the moment, dozens of papers on this subject have been published, and the variety of reactions performed is simply enormous. The process of [3+2]-cycloaddition of cyclopropanes to the double C=N bond is general in nature and readily occurs under mild conditions. Moreover, it is tolerant to the majority of functional groups, so a wide variety of substrate types can be successfully used in it. These factors determine its widespread use in modern organic synthesis. One of the first synthetically significant processes was developed by Carreira et al. in 1999 for the synthesis of indole spiro derivatives 184 using MgI2 as the catalyst and their subsequent utilization in complete syntheses [112]. In 2002, Olsson et al. demonstrated a similar approach for reactions of cyclopropyl ketones 185 with imines also promoted by iodide anions [113]. Both processes have a mechanism that somewhat differs from the majority of modern variants and occur not via a formal 1,3-zwitterionic intermediate, but via the initial nucleophilic addition of an iodide anion, which determines the choice of the Lewis acid. This reaction path is also encountered in a number of later reactions of D–A cyclopropanes (Figures 3.50 and 3.51). At the same time, the cycloaddition of dimethoxycyclopropanecarboxylates to aldehyde hydrazones in the presence of titanium tetrachloride should be noted as one of the earlier examples (1990). In this case, the reaction involves hydrolysis of two alkoxy groups to give isomeric substituted pyrrolidones in high yields [114] (Figure 3.52). I O N Bn 183

N

MgI2 (10 mol%)

R2

R1

I N

H

R2 O

OMgI

THF, 60 °C

R1

N Bn

N Bn

N

R1 R2 O

N Bn 184, (55–99%) dr 52:48 to 98:2

Figure 3.50 Carreira’s cycloaddition of imines to spiroindolinones 183. R1 R1

O +

185

O

2

R

H

+

186

160

Figure 3.51

R3NH2

O

MgI2 or Et2AlI THF, rt to 80 °C

N R3

R2

187, (16–70%) dr 81:19 to 99:1

Olsson’s cycloaddition of imines to cyclopropyl ketones 185. Ts N R2 188

(1) R 1 R1 MeO

CO2Et OMe 23

Figure 3.52

TiCl4 (2) EtOH

R1 R1 O

CO2Et N

Ts

R2

cis + trans 189, (70–90%)

Early work on the addition of tosyl imines to activated cyclopropanes.

67

68

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

In subsequent years, the [3+2]-cycloaddition with imines was intensively developed and extended, among other compounds, to cyclopropanedicarboxylates with a donor substituent at position 2 that is most commonly used as classical D–A cyclopropanes 1. After that, the wide use of this process in organic synthesis began. The widespread advancement of this reaction was facilitated by studies of the teams well-known in this field of chemistry, such as the teams of M. Kerr and J. Johnson, as well as X. L. Sun and Z. Wang, and were later joined by many others [108, 115–118]. The synthetic features and mechanism of the reaction resemble those of the reaction with aldehydes. Moreover, it also has a predominantly high cis-selectivity and a very wide scope of starting substrates (hundreds of various combinations are known). Both imines 190 with electron-donor and electron-acceptor substituents readily undergo the reaction. Usually, mild conditions are used with Sc, Yb triflates, magnesium iodide, or similar Lewis acids as the catalysts. Many imines are insufficiently stable, and it is inconvenient to work with them in their individual form. Therefore, the approach in which imines were generated in situ from the corresponding aldehydes and ketones and then immediately reacted with a D–A cyclopropane was found to be very successful [115]. In 2010, J. Johnson et al. developed an efficient asymmetric protocol for this reaction in the most practically useful dynamic kinetic asymmetric resolution (DyKAT) variant, involving racemic cyclopropanes [118]. MgI2 complexes with chiral PyBOX ligands were used as the catalysts. At the moment, this is one of the most classical protocols for asymmetric reactions of D–A cyclopropanes that allows high ee values to be achieved. The reaction mechanism and various aspects of controlling its diastereo- and enantioselectivity were also studied in detail. By using imines with a protective group that can be easily removed after the reaction, this approach opens up a remarkable way to the synthesis of chiral pyrrolidines 192 that are widely used in organic synthesis and as biologically active compounds (Figure 3.53). Owing to the general nature of the reaction and its high tolerance to the structure of the starting compounds, complex substrates, both imines and D–A cyclopropanes, can be successfully introduced into formal [3+2]-cycloaddition. For example, the reaction can be performed with acyclic azadienes 193 that react selectively at the C=N bond, as demonstrated by Verma and Banerjee. The diastereoselectivity of the reaction products depends on the Lewis acid used [30]. In the study of E. Budynina’s team, imine oxindoles 195 were involved in the reaction with D–A cyclopropanes 1 as the imine component. A wide range of cyclopropanes with various acceptor groups have been successfully used in the reactions, which made it possible to obtain a variety of spiro[indoline-3,2′-pyrrolidin]-2-one derivatives 196 [119]. In a study by Christie, Jones, et al., a variant of [3+2]-cycloaddition between imines 160 and cyclopropanes was presented, where a dicobalt cluster 197 formed upon coordination of Co2(CO)8 with a triple bond acted as the donor moiety [120]. Chai et al. studied the [3+2]-cycloaddition of D–A cyclopropanes 199 based on γ-butyrolactam with aldehydes and aldimines under catalysis with 1% Al(OTf)3 [100]. Many other examples of the use of various complex substrates in the [3+2]-cycloaddition with C=N bonds are also known (Figure 3.54).

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona X.-L. Sun's [3+2]-cycloaddition with imines (2006) R1 R 1

N 190

CO2Rʹ

Bn N

Bn R

Sc(OTf)3 (10 mol%) CH2Cl2, rt

CO2Rʹ

R1

CO2Rʹ Yields up to 98% 191 CO2Rʹ dr up to 30:1

M. Kerr's three-component [3+2]-cycloaddition (2005) R CO2Me R2 2 R R NH2 2 R CO Me N 2 1 186 N 1 + R Yb(OTf)3 O R1 (10 mol%) MeO2C CO2Me R1 160 191, 62–96% cis : trans = 55:45 to >99:1

Hal

O N t-Bu

J. Johnson's asymmetric DyKAT approach (2010) R1 R 1

CO2Me CO2Me

N

PG PG

R1

Yb(OTf)3 (10 mol%)

CO2Me CO2Me

H2 (1 atm) HCl / MeOH

N

R

(PyBOX)MgI2 (10 mol%) CCl4, rt, 24 h

O

N

H N

R

N t-Bu

PyBOX R1

CO2Me CO2Me 192

191 PG = 2-MeOBn Yields up to 86% dr up to 30:1; ee up to 98%

Figure 3.53 Founding works of the [3+2]-cycloaddition of imines with cyclopropane dicarboxylates.

NAr Ar O

NH

N

R

Arʹ EWG EWG 196 Yields up to 96% dr up to 95:5 ee up to 98%

Arʹ

LA = Cu(OTf)2, Sc(OTf) 3 Ar N Ts 193 R EWG

O

N 195 H

R

LA

1

LA = Yb(OTf)3, Sc(OTf)3

EWG

R = aryl, hetaryl EWG = CO2Me, CO2Et, COMe, NO2, CN, Meldrum's acid, SO2Ph

LA (10–20 mol%) CH2Cl2, rt, 5 h 4Å MS

(OC)3Co Ar

(OC)3Co Co(CO)3 197

N R

198

N

CO2Me

MeO2C CO2Me

Yields up to 91% dr up to 3:1

BF3·Et2O CH2Cl2 R = CO2Et, 4-NO2C6H4

Arʹ R

N 160

Ar

199

Ar

CO2Et CO2Et 194 Yields up to 81% dr up to 4:1

R = aryl, styryl EWG = CO2Et

CO2Me

(OC)3Co

Ts N

PG Ar

O CO2Me

Al(OTf)3 (1 mol%) 1,2-DCE, 80 °C

R N

Arʹ

R = aryl; PG = Bn, Cy, Ph

CO2Me O N PG 200

Up to 87% yields

Figure 3.54 Selected examples of the imine formal [3+2]-cycloaddition with complex substrates.

69

70

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

O

O N

NPh2 NTs

N Ar

NPh2 O N Ar Ts 202, 52–92% 49–86% ee

MgI2

MgI2 (30 mol%) IndaBOX

Ar

H

188 THF, 60 °C

O N Ts

Ar

204 57–85% dr 1.6:1 to 20:1

NPh2

NTs

MgI2, THF 65 °C O

O 201 N Ar

Figure 3.55

188

H

203

S H

Tol

NPh2 O N Ar O S Tol

205 63–94% dr >20:1

Formal [3+2]-cycloaddition of imines with methylene cyclopropanes 201.

The use of methylenecyclopropanes 201 opens up new ways for their chemical conversion upon the addition of imines. Depending on the substituents in cyclopropane and the Lewis acid used, several possible reaction pathways are realized to give five- and six-membered heterocycles. The use of chiral imines makes it possible to obtain optically active pyrrolidines 202. Moreover, an asymmetric catalytic variant of this reaction using a chiral IndaBOX ligand was developed. Magnesium iodide is the best catalyst, although aluminum salts can also be used in some cases [121–123] (Figure 3.55). A number of works are known where cyclic C=N bonds were involved in the [3+2]-cycloaddition process. Catalysis by rare earth metal triflates is used in many cases, of which Yb(OTf)3 is used most commonly. H. Yang demonstrated an example of a reaction with annulated cyclic imines, indolene 206, in particular [124]. In turn, P. Banerjee developed the process of [3+2]-cycloaddition to the C=N bond in the cyclic hydrazone moiety of tetrahydropyridazine 208 [125]. Y. C. Luo et al. presented a method for the synthesis of nitrones 211 by [3+2]-cycloaddition reaction between D–A cyclopropanes 1 and 1,4,2-dioxazoles 210 at the C=N double bond, followed by acetone elimination [126]. M. Kerr reported an elegant way for obtaining compounds 213 with an azabicyclo[3.1.0]hexane skeleton by [3+2]-cycloaddition with 3-phenyl-2H-azirine 212. He used an interesting nontrivial approach to the selection of reaction conditions in order to prevent considerable destruction of three-membered rings containing a nitrogen atom. Trifluoroethylcarboxylate substituents are sometimes used to control the activity of a D–A cyclopropane, while dysprosium triflate, Dy(OTf)3, is used as the catalyst [127] (Figure 3.56). The use of D–A cyclopropanes is a powerful synthetic tool for functionalization, which makes it possible to use, among others, including aromatic C=N bonds in heterocyclic systems. Pagenkopf et al. presented an example of [3+2]-annulation of pyridines at the C=N bond to give dihydroindolizine derivatives [70]. S. L. You et al. developed a process for asymmetric annulation of benzothiazoles using chiral complexes of MgI2 with PyBox ligands [71] (Figure 3.57).

3.3 ­Formal 3322]-CyalFmaadidFon dit -C=O mona -C=N FMralle Fona R1 = aryl, hetaryl, styryl, alkyl O– N+

R

Yb(OTf)3 (10 mol%)

Yb(OTf)3 (10 mol%) 1,2-DCE, Δ, 4 Å MS Me Me

R1

O 210

O N

CO2Rʹ RʹO 2C 211 Yields up to 94%

Ar

R1

N

R

Ar N

206 CO2Rʹ

R

CO2Rʹ

1

Ph N

R

Ph CO2CH2CF3

213 CO2CH2CF3 Yields up to 92%

CO2Rʹ 207 Yields up to 86% dr up to 20:1

RʹO2C

CH2Cl2

PMP

N 212 Dy(OTf)3 (10 mol%) PhMe, 110 °C Rʹ = CH2CF3 Ph

R

N

Ph

N 208 Yb(OTf)3 CH2Cl2, rt, 4 Å MS PMP = 4-MeOC6H4

R = aryl, AcO, vinyl, NPhth, 2-thienyl

PMP N N

RʹO2C

CO2Rʹ

209 Yields up to 73% dr up to 70:30

Rʹ = Me, Et, Bn, allyl; R = aryl, hetaryl, vinyl, alkyl

Figure 3.56

Formal [3+2]-cycloaddition with cyclic C=N double bonds.

N

Et MeO n-Pr

CO2Et

CN 144

CO2Et

NC

Et

N

Me3SiOTf, MeNO2

R 1

R = aryl, 2-thienyl, styryl Rʹ = H, Br, Cl, Me, MeO

145 n-Pr

n-Pr Rʹ

Et

N

(52% yield)

143

CO2Me CO2Me

CO2Et

NC

N 146

S

MgI2/L (10 mol%) PhCl, 0 °C 5 days, 4 Å MS

Rʹ

S N

CO2Me

L= O

CO2Me

N 147 R

O

N

t-Bu

N t-Bu

89–95% yields ee up to 95%

Figure 3.57 Formal [3+2]-cycloaddition with aromatic C=N double bonds.

Simple imines generated in situ from appropriate sources are successfully involved in [3+2]-cycloaddition with D–A cyclopropanes. For example, Sosnovskikh et al. reported an example of a reaction with methanimine generated from spiroanthracenoxazolidine 214 in the presence of MgBr2·Et2O [128]. Prof. Werz suggested using substituted 1,3,5-triazines 216 as sources of imines in the presence of MgI2 [98, 129]. J. K. Liu et al. also applied 1,3,5-triazines 216 as sources of imines, but under different catalytic conditions, in particular, using AlCl3 as the Lewis acid [130]. It should be noted that in order to make 1,3,5-triazines efficiently act as sources of imines under the reaction conditions, rather a fine selection of a suitable Lewis acid is required since they can also react by other pathways. In general, the [3+2]-cycloaddition processes considered above are tolerant to variations of the initial substrates and the electronic effects of substituents in them, while pyrrolidines 215, 217 are usually formed in high yields (Figure 3.58).

71

72

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Me N

MgI2 (10 mol%) CH2Cl2, rt, 1.5 h (up to 93%)

O Me R

N

O 214

CO2Et

MgBr2·Et2O (150 mol%) o-xylene, Δ 3.5 h

215 CO2Et 16–52% yields R = aryl, hetaryl EWG = CO2Et

Figure 3.58

EWG

R 1

EWG

R1

EWG = CO2Me; CO2Et R = aryl, hetaryl, PhO, vinyl, NPhth, c-C3H5 R1 = aryl

R1

R1

N

N

N

R N

216

R1

AlCl3 (20 mol%) CH2Cl2, rt (up to 99%)

EWG EWG 217 EWG = CO2Me; CO2Et R = aryl; R1 = aryl, Bn

Formal [3+2]-cycloaddition with simple imines generated in situ.

Apart from the intermolecular variant of [3+2]-cycloaddition between imines and D–A cyclopropanes considered above, examples of intramolecular transformations also exist. H. Yang presented a method for synthesizing hexahydropyrroloquinoline derivatives 219 by intramolecular cyclization of cyclopropane 218 and an imine moiety in a molecule in the presence of TiCl4 [131]. M. Kerr reported an approach to intramolecular [3+2]-annulation with an oxime moiety 220. The process is stereodivergent and makes it possible to selectively obtain both cis- and trans-isomers under the catalysis of Yb(OTf)3 by varying the process temperature or the reagent mixing sequence [116, 132]. The yields of the final products 219, 221 in both intramolecular processes are high and reach 93% and 99%, respectively. Z. Wang used intramolecular cyclization with imines to synthesize bridged heterocycles [108] (Figure 3.59). Studies on the reactions of [3+2]-cycloaddition with imines have found applications as key steps in the complete syntheses of a number of natural compounds, such as FR901483 (compound 224) and (‒)-spirotryprostatin-B (227) performed by the teams of M. Kerr and E. Carreira. These examples demonstrate both the intermolecular and intramolecular versions of cycloaddition of azomethine derivatives to D–A cyclopropanes 222, 225 and are very representative and well-known in the use of D–A cyclopropanes in complete syntheses [133, 134] (Figure 3.60). O CHO

CO2R

H N

Ar O

2) TiCl4, rt, 20 min 218

R

N

n = 0–2

220 R = aryl, alkyl

CO2Me CO2Me

Ar

NH

N Ph 219 Yields up to 93% dr up to 95:5

CO2R = CO2Me; CO2Et Ar = aryl, hetaryl, styryl, vinyl

O

RO2C

1) PhNH2, TsOH 1,2-DCE, 60 °C

Yb(OTf)3 (5 mol%) Toluene, T

R MeO2C MeO2C

N

O n = 0–2

221 Yields up to 99% selectively cis or trans

Figure 3.59 Intramolecular formal [3+2]-cycloaddition with C=N double bond.

3.4 ­Formal 3322]-CyalFmaadidFon dit =Oitleo leileoFmiFr C=Y FMralle Fonad O P

HO BnO

H

HO

BnO

OBn

N OMe Yb(OTf)3 BnO 1,2-DCE 70 °C 4 Å MS MeO2C CO2Me 223

CO2Me CO2Me

OMe

OMe

(CH2O)n NH2

O

222

HO

O TIPS

N H 225

*HCl

NHMe

N

O

N

MgI2 (20 mol%) THF, 80 °C

O

HN

N

N O

TIPS

N H 226

224 FR901483

N O H 227

(–)-Spirotryprostatin B

Figure 3.60 Examples of the application of [3+2]-cycloaddition with C=N double bond in total synthesis.

3.4 Formal [3+2]-Cycloaddition with Other Heteroatom X=Y Double Bonds 3.4.1 Formal [3+2]-Cycloaddition with Cumulenes and Heterocumulenes Despite its apparent relative exoticism, the reactions of D–A cyclopropanes with cumulene and heterocumulene systems have been studied in great detail. (Hetero) cumulenes are very interesting substrates for the construction of carbo- and especially heterocyclic systems. In this case, the overwhelming majority of processes proceed as formal [3+2]-cycloaddition of a 1,3-zwitterionic intermediate generated under the reaction conditions, resulting in the formation of five-membered rings. Reactions with substrates starting with allenes and ending with various heterocumulenes with oxygen, nitrogen, and sulfur atoms have been studied. The first work on reactions with allenes was published in 2004. Studies on the reactions of “classical” D–A cyclopropanes with heterocumulenes started much later, since 2012, and the main work was carried out in 2016–2021. The only example of earlier work is the pioneering work of M. Graziano with 2,2-dimethoxy cyclopropanecarboxylate, carried out back in 1987–1989. A 2004 paper by V. Yadav and V. Sriramurthy describes a formal [3+2]-cycloaddition between D–A cyclopropanes 98 and allenylsilanes 228 in the presence of Lewis acids such as TiCl4 and Et2AlCl. The process proceeded with high regio- and diastereoselectivity, leading to the formation of silyl-substituted methylidene cyclopentanes 229 in yields up to 90%. The same work also showed the possibility of formal [3+3]-cycloaddition using this reagent system [135] (Figure 3.61).

73

74

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes [Si] H2C C C 228 R1

tBuPh Si 2

C(O)R R1

Figure 3.61

R1 tBuPh

LA (120 mol%) CH2Cl2

98 R = Ph, t-Bu, n-Bu; = H, Me [Si] = Me3Si, tBuPh2Si

[Si] 2Si

C(O)R 229

Up to 90% yields dr up to 95:5

LA = TiCl4, Et2AlCl

Formal [3+2]-cycloaddition with silyl allenes 228.

The reactions of heterocumulenes with D–A cyclopropanes were first described much earlier, in M. Graziano’s pioneering work in 1987. 2,2-Dimethoxy cyclopropanecarboxylate 23 was used as the D–A cyclopropane, which is very rarely used in this role at present. When heated, this cyclopropane easily enters into formal [3+2]-cycloaddition reactions with phenylisocyanate 230 and thioisocyanate 231 at the C=N double bond without any activators. However, since then, until 2012, there have been no mentions of such transformations [136, 137] (Figure 3.62). Formal [3+2]-cycloadditions with ketenes were recently developed by N. Kerrigan’s group. Moreover, the reaction can proceed at both the C=O double bond and the C–C single bond. An efficient regioselective process of interaction between ketenes 234 and standard D–A cyclopropanes 1 at the C=C double bond was developed to form substituted cyclopentanones 235. The authors used a rather unusual catalytic system of Lewis acids InBr3–EtAlCl2. In addition, optically active starting cyclopropanes with the retention of chirality can be successfully used in this reaction [138]. Also, N. Kerrigan et al. developed a protocol for the interaction of vinyl and styryl D–A cyclopropanes 236 and ketenes 234, with selectivity for the carbonyl group Me

Ph

MeO MeO

N

Ph

230 MeO

85 °C O

MeO 23

(38%)

232

Figure 3.62

Me

231

Ph

Me

N C O

CO2Et

MeO

N C S

MeO

85 °C

CO2Et

Ph

(35%)

CO2Et N 233

S

First examples of the reactions with phenyl isocyanate and isothiocyanate. Ar O C C 234 R2

CO2R1

R 1

CO2R1

InBr3 (30 mol%) EtAlCl2 (15 mol%) CH2Cl2, –25 °C

R = Ph, styryl, vinyl; Ar = Ph, aryl R1 = Me, Et, Bn; R2 = Ph, Me, Et, n-Bu

236

EWG

CO2R1 235

CO2R1

Up to 99% yields dr up to 3:1; ee up to 99% R2 R1

O

Pd(PPh3)4 (5 mol%) CH2Cl2, –25 °C

R = H, Ph; EWG = CO2Me, CO2Et, CN R1 = Ph, Me, Et; R2 = Ph, aryl, Et

O

R

R1 O C C 2 234 R

EWG R

Ar R2

EWG

R 237

EWG

Up to 84% yields dr up to 99:1; ee up to 97%

Figure 3.63 Formal [3+2]-cycloaddition with ketenes 234.

3.4 ­Formal 3322]-CyalFmaadidFon dit =Oitleo leileoFmiFr C=Y FMralle Fonad

under palladium catalysis conditions Pd(PPh3)4. The authors also managed to develop an enantioselective version of this reaction [139] (Figure 3.63). The work of D. Werz’s group demonstrates an elegant method for intercepting in situ-generated thioketenes 238 using D–A cyclopropanes 1 through formal [3+2]-cycloaddition reactions under the action of scandium(III) triflate. A wide range of D–A cyclopropanes, both with an aromatic fragment and with alkyl and amine substituents, successfully enter into the reaction, proceeding exclusively at the thiocarbonyl group [140]. Subsequent studies by these authors expanded the limits of applicability of the previously developed method and introduced new substituted thioketenes 240 into these transformations [141]. The possibility of formal [3+2]-cycloaddition between phenyl isothiocyanate and a D–A cyclopropane with a cyclopropyl fragment as a donor was also demonstrated [98]. A. Vidal et al., in turn, developed an effective method for the interception of ketenimines 242 using the formal [3+2]-cycloaddition reaction of D–A cyclopropanes 1, proceeding along the C=N bond [142] (Figure 3.64). B. Stolz et al. presented examples of formal [3+2]-cycloaddition of D–A cyclopropanes 1 with a number of heterocumulenes – isocyanates 244, isothiocyanates 245, as well as carbodimides 246, which have resulted in a whole range of new, previously undescribed heterocyclic products 247–249. The developed processes were successfully carried out in the presence of Lewis acids such as FeCl3 and Sn(OTf)2. These processes are very tolerant to the electronic effects of substituents of substrates, proceed with high regioselectivity, and yield end products up to 99% [143]. In a later work by I. Shibata et al., there is an example of a similar interaction of D–A cyclopropanes with vinyl and methylene fragments as donors with isocyanates 244 under catalysis conditions using the MgBr2–Bu2SnI2 system [144]. The study of Z. Chai’s group added knowledge about the formal [3+2]-cycloaddition of isothiocyanates 245 and carbodimides 246 to D–A cyclopropanes based on γ-butyrolactone under FeCl3 catalysis conditions [145] (Figure 3.65). In the recent joint work of I. Trushkov’s and D. Werz’s groups in 2021, it was possible to carry out an interaction between the source of isothiocyanic acid HNCS 250 and a wide range of D–A cyclopropanes 1. The specificity of this process is that it is

t-Bu S

EWG EWG 241 Up to 92% yields dr up to 82:18

C C S i-Pr 240 Sc(OTf)3 (10 mol%) CH2Cl2, rt

O

Me Me

EWG

R 1

238

Me Me

S R

EWG EWG 239 Up to 99% yields

Sc(OTf)3 (10 mol%) 1,2-DCE, 60 °C, 12 h

EWG

R = aryl, NPhth, NSucc, vinyl, styryl EWG = CO2Me, CO2Et, CO2Bn R1 = Ph, CO2Et; R2 = Ph, Me; Ar = aryl

Figure 3.64

S

t-Bu

i-Pr

R

Me Me

R2 R1 C C N Ar R2 242 Sc(OTf)3 (20 mol%) CH2Cl2, rt, 4 h

Ar N R

R1 EWG

EWG 243 Up to 94% yields

Reactions of D–A cyclopropanes with thioketenes and ketenimines.

75

76

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes R2 R2

N

N

R

R2 CO2Me

CO2Me

249 Up to 99% yields

246 N C N R2

Sn(OTf)2 (1.1 equiv.) R CH2Cl2, rt

R1

CO2Me 1

CO2Me

R1

245 N C S

N S

CO2Me

Sn(OTf)2 (1.1 equiv.) R CH2Cl2, rt

CO2Me

248 Up to 99% yields

R = aryl, vinyl R1 = vinyl, cyclohexyl R2 = Me3Si, i-Pr, Ph R3 = Me3Si, Bn, i-Pr, n-Bu, vinyl

244 R3 N C O

O

R3 N

FeCl3 (1.1 equiv.) CH2Cl2, rt

CO2Me

R

CO2Me

247 Up to 78% yields

Figure 3.65 Formal [3+2]-cycloaddition with isocyanates, isothiocyanates, and carbodimides.

effectively carried out in an ionic liquid – 1-methylimidazolium thiocyanate, which simultaneously acts both as a source of HNCS and as a catalyst for the process. In this case, the reaction proceeds with exceptional regioselectivity for the C=N bond [146]. Concurrently, in the same 2021, D. Werz’s group developed a general approach for the introduction of the S=N double bond into D–A cyclopropanes 1 by the formal [3+2]-cycloaddition reaction, catalyzed by GaCl3 or MgI2, depending on the substrate. N-Sulfinylamines 252 and sulfur diimide derivatives 254 were used as sources of S=N bonds [147] (Figure 3.66).

3.4.2 Formal [3+2]-Cycloaddition with SCN and SeCN Similar transformations also take place upon the addition of thiocyanates and selenocyanates, which have tautomeric forms with a triple bond C N in their structure. This determines the direction of the reaction and differentiates it from the addition of thiocyanic acid, described earlier. P. Singh, A. Goswami et al., proposed organic thio- and selenocyanates 256 as dipolarophiles in the formal [3+2]-cycloaddition reaction with 250 H N C S

EWG

EDG 1

EWG

Ionic liquid 70 °C, 1 h

EDG = aryl, hetaryl, vinyl, styryl, ferrocenyl, NPhth, NSucc EWG = CO2Me, CO2Et, CN PhO2S N N S

254 PhO2S N S N SO2Ph

PhO2S R

255

EWG

EWG

Up to 99% yields dr up to 20:1

Figure 3.66 diimides.

MgI2 (20 mol%) TBABF4, MeCN 70 °C, 18 h

EWG

R 1

EWG

S HN EDG

EWG EWG

251 25–90% yields

252 Ar N S O

Ar

GaCl3 (1.2 equiv.) R 1,2-DCE, –20 °C to rt 22 h

R = aryl, vinyl, NPhth, NSucc, cyclopropyl EWG = CO2Me, CO2Et, CN

N S

O EWG EWG

253

Up to 99% yields dr up to 20:1

Addition of D–A cyclopropanes to thiocyanic acid, sulfinylamines, and sulfur

3.4 ­Formal 3322]-CyalFmaadidFon dit =Oitleo leileoFmiFr C=Y FMralle Fonad

CO2Et

Ar 1 Ar = aryl R = aryl, Me, Bn X = S, Se

CO2Et

RXCN 256

N

Ar

SnCl4 (100 mol%) 1,2-DCE, 40 °C

SR

Ar

CO2Et CO2Et

257

N

258

SeR CO2Et CO2Et

Yields up to 93%

Figure 3.67 Formal [3+2]-cycloaddition with organic thiocyanates 256. R

Se

262

NH2 CO2R1

Yields up to 95%

NMe4SeCN 261 Yb(OTf)3 (60 mol%) THF/MeCN, 65°C

CO2R1

R 1

CO2

R1

NH4SCN 259 Yb(OTf)3 (30 mol%) THF, 75 °C

R

S

260

NH2 CO2R1

Yields up to 93%

R = aryl, vinyl, 2-thienyl, NSucc R1 = Me, Et, Bn, t-Bu

Figure 3.68 Formal [3+2]-cycloaddition with inorganic thiocyanates 259 and selenocyanates 261.

D–A cyclopropanes 1, which proceeds through the C≡N triple bond, by analogy with nitriles, in the presence of tin SnCl4 [148]. The processes of addition of inorganic thiocyanates (thiocyanates) 259 and selenocyanates 261 to D–A cyclopropanes 1 were developed in the works of D. Werz’s and I. Trushkov’s groups. The direction of these reactions differs from organic representatives, and proceeds as nucleophilic addition at the chalcogenide atom, with further cyclization at the C N group, as a result of which the chalcogen atom is in the cycle, in contrast to the products of the A. Goswami’s group. Also, during the process, one of the ester groups is cleaved off. Inorganic thioand selenocyanates are quite active substrates and reactions proceed under mild conditions with Yb(OTf)3 catalysis. Reactions with selenocyanates were subsequently used to obtain substituted selenophenes [149, 150] (Figures 3.67 and 3.68).

3.4.3 Formal [3+2]-Cycloaddition with C=S and C=Se Double Bonds The chemistry of compounds with carbon–chalcogen double bonds in reactions with D–A cyclopropanes is of considerable interest due to heterocyclic products of these transformations that have various practical applications. The first works were carried out quite recently, in 2017, and D. Werz’s group can definitely be considered pioneers of research in this field. Thus, the authors studied in detail the reactions with thiocarbonyl and selenocarbonyl compounds 263, and the corresponding synthetic protocols were developed. These reactions proceed as the classical formal [3+2]-cycloaddition of D–A cyclopropanes 1 to multiple bonds with the transfer of enantioselectivity from the starting cyclopropanes, and aluminum(III) salts are used as catalysts. The reaction is general in nature and tolerant to functional groups, which is proved, for example, by the successful use of thiocarbonyl derivatives of ferrocene 266 [151]. Various cyclopropanes, including nitrogenous, alkyl, and cyclopropyl derivatives, as well as various chalcogen substrates have been successfully used as substrates in this transformation [98, 152]. Reactions of D–A cyclopropanes with tellurium derivatives have not yet been studied (Figure 3.69).

77

78

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Fe S

266 2-ferrocenyl

R 1 R = aryl, hetaryl, vinyl, NSucc, NPhth, c-C3H5

CO2Me CO2Me X = S, Se

R

S

R

S

Sc(OTf)3 CH2Cl2, rt X

R1 R2 263 LA (10–20 mol%) CH2Cl2 LA = Al(OTf)3; AlCl3

R1, R2 = Ad, cyclopropenyl, aryl, hetaryl, Me, alkyl

Figure 3.69

R1

R1 CO2Me 267 CO2Me Yields up to 98% dr up to 100:1 2 R2 Se R R R1 R1 CO2Me CO2Me CO2Me CO2Me 264 265 Yields up to 99% dr up to 4:1; ee up to 92%

Formal [3+2]-cycloaddition with thioketones and selenocarbonyl compounds.

There are also known later works from other research groups in this direction, which have picked up this topic. T. Ohshima et al. succeeded in performing selective [3+2]-cycloaddition at the C=S double bond between various D–A cyclopropanes 1 and thioethers 268, catalyzed by iron(III) triflate, resulting in the formation of alkoxytetrahydrothiophenes 269 [153]. In another study, H. M. Guo et al. presented an example of [3+2]-cycloaddition of thiourea 270 to D–A cyclopropanes 1. The Yb(OTf)3–Rb2CO3 system acts as a catalyst; the process proceeded with the elimination of one of the acceptor groups, leading to the formation of aminodihydrothiophene derivatives 271 [154] (Figure 3.70).

3.4.4 Formal [3+2]-Cycloaddition with N=O and N=N Double Bonds Reactions of formal [3+2]-cycloaddition of heteronuclear electrophiles X=Y with the activation of cyclopropanes have been little studied. Only a few works on the involvement of N=O and N=N double bonds in the reaction with D–A cyclopropanes are known. There is also one known work devoted to reactions with an N=S double bond in heterocumulene structures, such as N-sulfinylamines and sulfur diimide derivatives (as discussed above in Section 3.4.3).

S R

S

271

NH2 EWG

Yields up to 89%

H2N

S

270 NH2

Yb(OTf)3 (20 mol%) Rb2CO3 (20 mol%) 1,2-DCE, 90 °C, 8 h

EWG EWG

R

EWG = CO2Me, CO2Et, CO2Bn, CN R = aryl, Bn, alkyl

1

R1

268 OR2

Fe(OTf)3 (10 mol%) PhMe, rt, 5 h 4 Å MS

R

R1 OR2 CO2Me 269 CO2Me S

Yields up to 91% dr up to 20:1 ee up to 95%

EWG = CO2Me R = aryl, 2-thienyl, styryl, vinyl, NPhth R1 = aryl, hetaryl, 2-ferrocenyl; R2 = Me, i-Pr

Figure 3.70 Formal [3+2]-cycloaddition with thioesters 268 and thioureas 270.

3.4 ­Formal 3322]-CyalFmaadidFon dit =Oitleo leileoFmiFr C=Y FMralle Fonad

Thus, carbon-free dipolarophiles, in particular, nitrosyl chloride, in the reaction of [3+2]-cycloaddition with D–A cyclopropanes 23, were first proposed by M. Graziano, M. Iesce et al. This process proceeded with good yields of the target isoxazoles 272 in the absence of a catalyst, using highly active cyclopropanes such as 2,2-dimethoxycyclopropanecarboxylates [155]. A study by A. Studer’s group presented nitrosoarenes 273 as dipolarophiles under the catalysis of MgBr2. It turned out that many standard Lewis acids, which were used in previous works, give a low yield of the final products 274, and the electronic effects of substituents in the aryl fragment of the electrophilic substrate have the opposite effect in comparison with the previously described dipolarophiles. Also, nitrosoarenes 273 were able to be involved in more complex cascade transformations [156]. R. Varshnaya and P. Banerjee presented their version of the formal [3+2]-cycloaddition between D–A cyclopropanes 1 and nitrosocarbonyl compounds 275, generated in situ from hydroxycarbamates in the presence of MnO2 and MgI2. Isoxalidines 276 are the products of this reaction [157] (Figure 3.71). Other X=Y electrophiles in [3+2]-cycloaddition reactions with activated cyclopropanes 23 are also very little studied. There are isolated cases of such reactions for the N=N double bond in diazenes. Thus, dimethoxycyclopropane 23 without any activators easily undergoes cycloaddition reactions with azodicarboxylate 277 and phenyltriazolinedione 278, resulting in the formation of the corresponding five-membered nitrogen heterocycles 279, 280 with good yields and high stereoselectivity [136, 137]. The study by V. Korotkov and Armin de Meijere, describes azodicarboxylates, azobenzenes, and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) 281 in the reaction of [3+2]-cycloaddition with D–A cyclopropanes 1. It is curious that the authors used gallium trichloride (GaCl3), as a selective and rather specific catalyst, which is not so often used in such transformations. The yields of pyrazolidines 282 are not so high and reach only 63% [158]. Many other types of substrates with N=N double bonds do not undergo formal [3+2]-cycloaddition. For example, PTAD and its analogs usually undergo more complex reactions with fragmentation [159]. Derivatives of 1-pyrazolines are capable of entering into a wide range of different transformations, with the exception of [3+2]-cycloaddition [160] (Figure 3.72). R NOCl OMe OMe

EtO2C

CCl4 R = H, Me, Et

23 O R

O

276

N CO2R CO2Et CO2Et

RʹO

275 NHOH

MnO2, MgI2 CH2Cl2, rt

R

Yields up to 72%

1

CO2R1 CO2R1

O

MeO

N

R

CO2Et 272 Yields up to 60% Ar O N 273 MgBr2 (20 mol%) 1,2-DCE, 90 °C

R

O

N Ar CO2R1 1 CO 2R 274

Yields up to 99%; ee up to 99% R = aryl, hetaryl, vinyl, styryl Rʹ = Me, t-Bu, Bn; R1 = Et

R = aryl, hetaryl, vinyl, n-Bu, OAc, NPhth R1 = Me, Et, t-Bu, allyl; Ar = aryl

Figure 3.71 Formal [3+2]-cycloaddition with nitroso compounds.

79

80

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Me

N N

N N

O N 278 Ph

MeO MeO O

CO2Et

N

O

rt (80%)

O

Me MeO MeO

Ph 280 R1 CO2R CO2R

Ar Ar = aryl; R = Me, i-Pr R1 = CO2iPr, CO2Et, Ph

1

EtO2C

GaCl3 (20 mol%) CH2Cl2, rt

Me CO2Et

70 °C (70%)

CO2Et 23 281 N 1 N R

277 N

N

MeO MeO

CO2Et

N N CO2Et EtO2C 279

R1 Ar

N

1 N R CO2R

282 CO2R Yields up to 63%

Figure 3.72 Formal [3+2]-cycloaddition with N=N double bond.

3.4.5 Formal [3+2]-Cycloaddition with C≡N Triple Bonds in Nitriles The B. Pagenkopf’s group is a pioneer in the field of using nitriles as dipolarophiles with a C≡N triple bond in formal [3+2]-cycloaddition reactions to D–A cyclopropanes under the catalysis conditions of trimethylsilyl triflate, Me3SiOTf. In these studies, a wide range of different D–A cyclopropanes 16, 106, 128, and 283 were used, various ways of obtaining heterocyclic systems with nitrogen atoms were discovered, and the application of this approach for the complete synthesis of (±)-goniomycin (compound 293) was shown [161–166] (Figure 3.73). The later works of K. Srinivasan’s, I. Trushkov’s, and Z. Wang’s groups supplemented the concept of the reactions of the D–A cyclopropanes 109, 295 with nitriles, which were initiated by SnCl4 and TfOH. These reactions usually proceed as formal [3+2]-cycloaddition to the C≡N triple bond to form various 3,4-dihydro-2H-pyrrole derivatives 294, 296. In an attempt to carry out the reaction in an enantioselective variant, a racemate of the final dihydropyrrole was obtained from optically pure cyclopropanes, which is due to the use of strong Lewis acid [167–169]. K. Srinivasan et al. also presented the processes involving the interaction of nitriles 284 with D–A cyclopropanes based on γ-butyrolactone 297 in the presence of SnCl4 as a Lewis acid, to obtain tetrahydro-1H-furo[3,4-c]pyrrol-1-ones 298 [170, 171] (Figure 3.74).

3.4.6 Formal [3+2]-Cycloaddition and Other Reactions with Three-Membered Heterocycles The methodology for intercepting 1,3-zwitterionic intermediates generated from D–A cyclopropanes using three-membered heterocycles began to develop in the mid-2010s. At the same time, it is quite common when a three-membered heterocycle under the reaction conditions acts as a source of synthons with a double bond, such as C=O, C=N, and C=C, which enter into formal [3+2]-cycloaddition reactions, resulting in the formation of the corresponding products with a five-membered ring.

3.4 ­Formal 3322]-CyalFmaadidFon dit =Oitleo leileoFmiFr C=Y FMralle Fonad O

O t-Bu2Si

284 RCN

O

Me3SiOTf CH2Cl2, rt

O

283 O

O

O t-Bu2Si

N R

O O

O

R = aryl, alkyl, alkenyl, styryl

284 RCN

R3 R2O

288 X

NC

R1

R2O

CO2Et Me3SiOTf MeNO2

106

N

R3

R1O

– R2OH

R = aryl, alkenyl, alkyl, styryl R1 = H, Me, Et, sugars, THF R2 = Me, n-Bu, Et R3 = H, Me, n-Bu, Et

H N

R3 R1

NC +

R

TsN

128

R3

289

Yields up to 85%

TsN

R N H 290 Yields up to 95%

Me3SiOTf (100 mol%) EtNO2, –40 °C

OMe

R3

CO2Et

R = aryl, alkyl, styryl, 2-thienyl

OH

O CO2Et

EtNO2 –30 °C

Me

16

R2 EtO2C

284 RCN

CO2Et

Me3SiOTf (105 mol%) NBn

OMe

Me3SiOTf MeNO2

CO2Et

106

CO2Et

O

X

R3

R = H, Me, THF; OR1 = OMe, On-Bu R2 = H, Me, n-Bu, Et; R3 = H; Et; X = S; NH

287 Yields up to 93%

CO2Et

R3

R2

CO2Et

H N

R

R

R

R1 286

285

Yields up to 96%

N H

NBn N H HN

Me

Me

292

291

293, (±)-Goniomitine

Figure 3.73 Reactions of various D–A cyclopropanes with nitriles developed by B. Pagenkopf group.

R1

CO2Me

R

CO2Me 109

284 R2CN TfOH (50 mol%) rt, 5 min

R

N

R1

R2 CO2Me

CO2Me 294 Yields up to 98%

R1

O CO2Et

284 R2CN

Ar

O N

R2 CO2Et

R1 SnCl4 CO2Et (100 mol%) O 296 1,2-DCE, rt, 7 h Yields up to 92% R1 = Ph; 4-NO2C6H4; 2-thienyl R2 = Ph, Me, 4-MeOC6H4 Ar

CO2Et 295

R

Ar

R = Ph, Bn, vinyl R1 = H, Me; R2 = aryl, alkyl, alkenyl, styryl

Ar

284 RCN

O SnCl4 (1 equiv.) CO2Et 1,2-DCE, 40 °C 297 Ar = aryl R = aryl, n-Bu

N Ar

CO2Et O O

Ar

298 15–75% yields

Figure 3.74 Reactions of D–A cyclopropanes with nitriles developed by K. Srinivasan, I. Trushkov, and Z. Wang groups.

81

82

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes PG1 Ar

N

Ph

Ph

CO2Et 302 CO2Et Yields up to 67%

EtO2C

O

O 301

N

MgI2 (20 mol%) CH2Cl2, 30 °C 4 Å MS

CO2Et

Ph

N PG2

301

299

PG1 Ar 1

304

R1

O

303 Yields up to 67%

300 Yields up to 88%

Ar

OH CO2Et

R2

PG2

BF3·Et2O (50 mol%) CH2Cl2, rt, 4 Å MS Ar = aryl Ar1 = Ph, 4-MeOC6H4 R1 = aryl; R2 = Me, Ph PG1 = Me, i-Pr, c-C6H11, methylBn PG2 = Ts, Bs, t-Bu

Ar

CO2Et CO2Et

R1 R2

O N

Ar Ar1

InCl3 (10 mol%) 4 Å MS, DCE, 60 °C

CO2Et CO2Et

Ar1

O

CO2Et 305 Yields up to 71% dr up to 3:1

Figure 3.75 Formal [3+2]-cycloaddition with oxiranes and oxaziridines.

Methods for the preparation of substituted tetrahydrofurans 300 and pyrrolidines 302 in reaction with oxiranes 299 and oxaziridines 301, which act as sources of aldehydes and imines, are presented in the works of P. Banerjee’s group. In these processes, Lewis acids such as InCl3 and MgI2 act as catalysts [172, 173]. Another study by the same group described the interaction of D–A cyclopropanes 1 with disubstituted oxiranes 304 in the presence of boron trifluoride etherate. It turned out that the process proceeds as a formal [3+2]-cycloaddition to the C=C double bond, resulting in the formation of substituted cyclopentanols 305 [174] (Figure 3.75). More complex cascade processes with aziridines 306, [175] formal [3+2]-cycloaddition with diaziridines 307, [176], as well as formal [3+2]-cycloaddition at the C=N double bond with 2H-azirines 212 [127] are also known (These transformations are described in more detail in other relevant sections.) (Figure 3.76).

R = aryl, AcO, vinyl, NPhth, 2-thienyl CO2R′ = CO2 CH2CF3 Ts EtO2C CO Et 2 Ts OEt N O Ar´ EtO2C Ar 308 Yields up to 65%

212 Ph

N Ar

CO2Et 306 CO2Et

MgI2 (20 mol%) 4 Å MS, 1,2-DCE, rt R, Ar′ = aryl

CO2R′

R 1

R

N

Ph

N

CO2CH2CF3 CO2CH2CF3 310

Dy(OTf)3 (10 mol%) PhMe, 110 °C

Yields up to 92%

CO2R′

R3 R1 N R2 N Ni(ClO4)2·6H2O 307 3 4 Å MS, CH2Cl2, Δ R

R3 R3 Ar

R = aryl, hetaryl; CO2R′ = CO2 Me R1 = aryl, Me, H, Et, alkenyl, c-C3H5 R2 = H, Me; R3 = -(CH2)3-, -(CH2)4-, Et

N

N

R1 R2 CO2Me CO2Me 309 Yields up to 88% dr up to 95:5 ee up to 99%

Figure 3.76 Reactions of D–A cyclopropanes with aziridines 306, diaziridines 307, and 2 -azirines 212.

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled

3.5 Formal [3+3]-Cycloaddition and Annulation Reactions of D–A Cyclopropanes 3.5.1 General Aspects Formal [3+2]-cycloaddition reactions of D–A cyclopropanes 1 were known as far back as the last century, beginning in the 1970s–1980s and quite a lot of examples with different types of substrates were known before the 2000s. In contrast to [3+2]-cycloaddition reactions, [3+3]-cycloaddition/annulation reactions of D–A cyclopropanes started to develop much later. Similar reactions involving nitrones and activated cyclopropanes were described by Kerr et al. in a series of papers (links from Section 3.5.5), starting in 2003. And then, these types of transformations quickly gained popularity and turned into a very important synthetic approach for creating six-membered carbo- and heterocyclic systems. At present, [3+3]-annulation reactions of D–A cyclopropanes 1 are one of the main and most representative types of transformations for these, and many dozens of reactions and a huge number of works with various substrates are known. This, however, is not surprising, since the main type of reactivity for D–A cyclopropanes is positioned acting as 1,3-zwitterions. And they perform well in this role in coupling reactions with various other 1,3-dipoles and other compounds acting as 1,3-synthons. These reactions with 1,3-dipoles as nitrones, nitronates, nitrilimines, azomethine imines, and related dipoles, azides, diazo compounds, and so on, as well as various aromatic, heteroaromatic substrates, and substrates with multiple bonds act as three-carbon 1,3-synthons. The mechanisms of such transformations are typical for cycloaddition reactions of D–A cyclopropanes 1 and proceed according to a stepwise ionic mechanism consisting of the following stages (Figure 3.77): Lewis acid coordination/opening of a three-membered ring/nucleophilic addition to the 1,3-dipole/1,6-cyclization, leading to the final ring closure in the product.

OR

OR CO2R

Don

Lewis acid Don δ+

CO2R

δ-

RO

1

O

O

Don

O

LA

RO

O

Z XYZ = CCC, CCN, CCO, CCS, CNO, CNN, NNN

Y

311 [3+3]-Cycloaddition

X

CO2R

Z X

Y

CO2R

RO2C CO2R

Don

LA

II

I

1,6-Cyclization

Don

X Y

Z

III

Figure 3.77 [3+3]-Annulation/cycloaddition reactions of D–A cyclopropanes and their mechanism.

83

84

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

3.5.2 [3+3]-Annulation with Aromatic Substrates as 1,3-Synthons There are many [3+3]-annulation reactions with aromatic substrates that act as 1,3-synthons. In these cases, the annulation occurs at the α-position of the substituent on the aromatic ring and in its ortho-position (or a similar position for heteroaromatic substituents). The largest number of reactions is known for indole derivatives, which are especially actively studied because of the high practical attractiveness of the heterocyclic products of such transformations. Thus, in the work of Kerr et al., an example of [3+3]-annulation of cyclopropane dicarboxylates 1 and indoles 312 containing an alkyne fragment in the 2nd position is presented. This process is catalyzed by a rather strong Lewis acid based on Zn2+ cations, zinc triflimide Zn(NTf2)2, in an amount of only 5 mol%, which allows the entire process to be carried out in one stage, although there are other less efficient catalytic systems [177]. Y. Tang describes a similar process for unsubstituted indolylacetylenes 314, implemented in an enantioselective variant and carried out stepwise in two stages. For this, the following catalytic system is successively used: “Cu(OTf)2/ BOX – InBr3/DBU.” The authors achieved good ee (94%) [178]. M. Ghorai developed a similar method for intercepting the D–A of cyclopropanes 1 using Knoevenagel adducts and nitroolefins with an indole fragment (instead of indolyl acetylenes) 316. Such transformations proceed as a [3+3]-annulation reaction, are excellently catalyzed by ytterbium(III) triflate, and are well-implemented, including for sterically loaded substrates [179] (Figures 3.78 and 3.79). In the most recent works of 2021, E. Ruijter described the processes of [3+3]-annulation of indolecarbaldehydes 319, 322, and related nitrogenous heterocycles with various types of D–A cyclopropanes 318, 321 containing a phosphonate acceptor group. The latter extends their synthetic functionality and allows the phosphonate group to be used to create an additional double bond via Horner–Wadsworth– Emmons (HWE) olefination. For this, a double catalytic system “Sc(OTf)3–Cs2CO3” is used for aryl-substituted cyclopropanes and a catalytic system based on Pd(0) for R1 CO2Me

Ar 1

CO2Me

Ar

R N 312 PG Zn(NTf2)2 (5 mol%) 1,2-DCE, Δ

Ar = aryl, hetaryl, styryl, vinyl R = H, CO2Me; R1 = Me, CO2Me, CF3 PG = Me, Bn, H

1

R

CO2Me N

PG R 313 Yields up to 95%

Ar

R CO2Me

Ar 1

CO2Me

Ar = aryl, hetaryl, styryl R = H, Me, OMe, Cl, F

Figure 3.78

CO2Me

N 314 Me (1) Cu(OTf)2/BOX (10 mol%), PhMe (2) InBr3 (20 mol%) DBU (10 mol%)

R

CO2Me N

Me 315 Yields up to 87% ee up to 94%

[3+3]-Annulation with indolyl acetylenes.

CO2Me

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled R Ar

EWG N Ar 1

CO2Me

316

Me

CO2Me

CO2Me

N EWG Me R 317 Yields up to 90%

Yb(OTf)3 (20 mol%) 1,2-DCE

CO2Me

Ar = aryl, hetaryl, styryl R = H, CO2Me; EWG = NO2, CO2Me

Figure 3.79 [3+3]-Annulation with acceptor indolyl olefins 316.

vinyl cyclopropanes. The use of various nitrogenous heterocycles in the annulation process makes it possible to implement various types of coupling with cyclopropanes and to carry out annulation both at the NH-group and at the CH-bond of the heterocycle [180, 181]. P. Banerjee, in his study, presented an example of [3+3]-annulation with a rearrangement between D–A cyclopropanes 1 and carbinols with an indole fragment 324. The process efficiently proceeds with InCl3 catalysis and was accompanied by good yields of final tetrahydrocarbazole products 325, which can be easily transformed into the corresponding substituted carbazoles [182] (Figures 3.80 and 3.81). R

CO2Et

Ar 318

PO(OiPr)2

CHO

N

319

Ar

R

PG CO2Et

Sc(OTf)3, Cs2CO3 THF, 50 °C

N PG

R = H, Cl, Br, F, Me, OMe, OBn PG = Me, i-Pr; Ar = aryl X X 1

CO2R 321

PO(OR1)2

R1 = Me, Et; X = CH, N R = H, Cl, F, Me, OMe

320

Yields up to 72% CHO NH X

R

CO2R1

X

322

X

Pd2(dba)3, L LiCl, water, t-BuOK THF, 50 °C

R

O O

N

L=

X

P O

323 Yields up to 73%

Figure 3.80 [3+3]-Annulation of phosphonate-derived D–A cyclopropanes with indole carbaldehydes. R

N Ar 1

EWG EWG

Ar = aryl, hetaryl, styryl R = H, Br, F; PG = H, Me, Bn EWG = CO2Me, CO2Et

PG

R

EWG EWG

OH 324

InCl3 (20 mol%) CH2Cl2, rt

N PG 325 Yields up to 73%

Ar

Figure 3.81 [3+3]-Annulation with indolylmethyl alcohols.

85

86

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Lewis acid MeNO2

CO2R

Ar 1

CO2R

3-indolyl CO2R RN

CO2R

CO2R CO2R

Dimerization

X

CO2R Ar

CO2R

Ar

Ar

CO2R

Ar = aryl, hetaryl, indolyl; R = Me, Et LA = SnCl4, Sn(OTf)2, Ga(OTf)3, etc.

RO2C

Ar

RO2C

326

327

CO2R

RO2C 328

CO2R

Figure 3.82 Dimerization of D–A cyclopropanes with [3+3]-annulation on aromatic ring.

Many D–A cyclopropanes 1 themselves can also participate in the [3+3]-annulation reaction at the aromatic ring in the absence of substrates, with the involvement of an aryl or heteroaryl substituent in the 2nd position. Such cyclodimerization processes have been actively studied by the group of I. Trushkov and also by the group of Novikov and Tomilov. Moreover, a lot of data on cyclodimerization reactions were obtained on 2-indolyl-substituted cyclopropanes and analogous cyclopropane derivatives of furan and thiophene [183, 184] (Figure 3.82). Other [3+3]-annulation reactions with aromatic substrates that are not indole derivatives are also known. S. Sin and S. G. Kim, in their work, presented a variant of such an interaction between D–A cyclopropanes 1 and α,β-unsaturated aromatic ketones 329 with an NMe2 donor group in the aromatic ring in the presence of Yb(OTf)3, proceeding as a cascade of Friedel–Crafts/Michael addition and leading to NMe2-substituted tetralin derivatives 330. Along with α,β-unsaturated, similar derivatives of methylidenemalonates also enter into this reaction [185]. The work of A. Studer is devoted to the study of [3+3]-annulation between D–A cyclopropanes 1 and various nitrosoarenes 273, which proceeds as a complex multi-stage process and leads to tetrahydroquinoline derivatives 331. The Lewis acid in these transformations is MgBr2 with the addition of 3,5-di-tert-butyl-4-hydroxytoluene (BHT), and the solvent is 1,2-dibromoethane (1,2-DBE) [186]. T. Punniyamurthy with coworkers proposed another variant for the synthesis of tetrahydroquinolines 333 via the oxidative [3+3]-annulation reaction between D–A cyclopropanes 1 and N-alkylanilines 332 in the presence of copper triflate in air. Unlike Studer’s process, the products have a different arrangement of substituents from the original cyclopropane, which is very useful in practical terms [187] (Figures 3.83 and 3.84).

Me2N CO2R1

Ar 1

CO2R1

Figure 3.83

329

O

R

O

Yb(OTf)3 (10 mol%) CHCl3, 60 °C, 4 Å MS

Ar = aryl; R1 = Me, Et, Bn R = aryl, hetaryl, t-Bu, c-C3H5

NMe2

R

Ar

CO2R1 CO2R1

330 Yields up to 91% dr up to 16:1

[3+3]-Annulation with α,β-unsaturated aryl ketones 329.

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled

Ar 273

1

CO2R

R 1

CO2R1

R = aryl, alkenyl; R1 = Me, Et, Bn Ar = aryl

Ar

CO2R 1

CO2R

Figure 3.84

PG NH 332

Cu(OTf)2 (10 mol%) K2CO3 (1 equiv.) DMF, 100 °C, air

Ar = aryl, 2-thienyl; R = Me, Et Ar1 = aryl; PG = Me, Et, Bn, PMB, Ph, etc.

tBu

NH

MgBr2 (2 equiv.) BHT (0.2 equiv.) 1,2-DBE, 65 °C

Ar1

OH

Ar

NO

CO2R1 CO2R1 331 Yields up to 91% dr up to 16:1 R

Ar1 N RO2C RO2C

tBu

BHT = Me

PG Ar

333 Yields up to 78% ee up to 99%

[3+3]-Annulation with anilines and nitrosoarenes.

3.5.3 [3+3]-Annulation with Allenes, Allyl, and Propargyl Derivatives V. Yadav and V. Sriramurthy provided an example of formal [3+3]-cycloaddition of D–A cyclopropanes 98 to allenylsilanes 228 in the presence of Lewis acids such as TiCl4 and Et2AlCl. The process proceeds with the migration of the silyl fragment of cumulene, resulting in it acting as a three-carbon synthon in the coupling reaction [135]. M. Kerr et al. presented a method for the preparation of substituted methylenecyclohexanes 336 by [3+3]-annulation of D–A cyclopropanes 1 to chloromethyl allylsilanes 335, which are usually used as 1,3-three-carbon synthons in the synthesis. The process is carried out sequentially in two stages through cyclopropane opening/ring closure. In the first step, TiCl4 is used, and in the second, sodium hydride is used for the final cyclization at the malonyl fragment [188] (Figure 3.85).

Figure 3.85 Formal [3+3]-cycloaddition with silylallenes 228 and chloromethyl allylsilanes 335.

87

88

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

K. Mondal and S. Pan investigated the [3+3]-annulations of D–A cyclopropanes 1 and allyl alcohols 337 in the presence of Sc(OTf)3, which proceeds with the ­ participation of the OH group and leads to tetrahydropyran derivatives 338 [189]. A similar [3+3]-annulation with the formation of methylenetetrahydropyrans 340 was described earlier in the M. Kerr’s group for propargyl alcohols 339. The synthetic protocol turned out to be very tolerant to substituents and was implemented for a wide range of D–A cyclopropanes. At the same time, a complex system is used for catalysis – In(OTf)3 with additions of Et3N and ZnBr2 [190]. Finally, Z. Wang’s group described an intramolecular variant of [3+3]-annulation between the allyl fragment and the D–A system of cyclopropane in the initial substrate 341. The process is also catalyzed by Lewis acids and leads to the formation of a bicyclo[2.2.2]octane system 342 annelated with the benzene ring with good diastereoselectivity [191] (Figures 3.86 and 3.87).

3.5.4 [3+3]-Annulation with Mercaptoacetaldehyde A series of studies are known on the use of mercaptoacetaldehyde derivatives in reactions with D–A cyclopropanes developed by K. Srinivasan, X. Feng, and J. Zhou. In this case, mercaptoacetaldehyde 343, introduced into the reaction in the form of a stable dimer (1,4-dithiane-2,5-diol) 344, acts as a source of 1,3-synthon with a sulfur atom in the processes of formal [3+3]-cycloaddition to D–A cyclopropanes proceeding stepwise, which leads to the formation of derivatives of tetrahydrothiopyran 345, 348, 349. That is, the main proceeding process in all cases is the same, but the original D–A cyclopropanes differ greatly in nature. The first information on the use of the acetaldehyde 343 as a dipolarophile in these reactions appeared in the work of K. Srinivasan, who used in this role 2-aryl cyclopropanedicarboxylates 295 R1

R1

339

O OH

O R 340

CO2Me CO2Me

Up to 97% yields

In(OTf)3 (20 mol%) Et3N (1 equiv.) ZnBr2 (3 equiv.) PhMe

R 1

R = aryl, hetaryl, vinyl, Me R1 = H, Me

O

Sc(OTf)3 (20 mol%) CH2Cl2

Ar

R1

CO2Me CO2Me

Sc(OTf)3 or SnCl4 1,2-DCE

R 341 Ar = aryl R = Me, Et, n-Pr, i-Pr, t-Bu, Bn R1 = H, Me

CO2Me CO2Me 338 Up to 93% yields dr up to 3.5:1

R

R = aryl, 2-thienyl R1 = aryl, hydrocinnamic

Figure 3.86 [3+3]-Annulation with allyl and propargyl alcohols. R1

Ar

R1

OH

R1

CO2Me CO2Me

O

337

CO2Me R CO2Me 342

Up to 96% yields dr up to 3.9:1

Figure 3.87 Intramolecular [3+3]-annulation with allyl derivatives.

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled

with an additional arylketo group in the 3rd position under the action of AlCl3. The reaction products were used further to obtain substituted thiophenecarbaldehydes 346 [192]. X. Feng managed to carry out the interaction between 2-arylcyclopropane-1,1-diketones 347, and using enantioselective catalysis. The process was catalyzed by scandium(III) triflate and chiral N,N’-dioxide as a ligand [193, 194]. J. Zhou’s group presented their version of the process using cyclopropane with an oxindole moiety as one acceptor and an N-phosphonate group as the other acceptor. This time, indium(III) chloride turned out to be the most effective catalyst [97] (Figure 3.88).

3.5.5 [3+3]-Cycloaddition with Nitrones and Nitronates Nitrones are particularly good interceptors for the 1,3-zwitterion generated from D–A cyclopropanes, and in many respects, they are classical, since it was from them that the well-known modern chemistry of D–A cyclopropanes began to develop. The first works were made by the Michael Kerr group back in 2003, and this direction quickly gained popularity [195–200]. In general, nitrones are convenient and widespread 1,3-dipoles used in various cycloaddition reactions in organic synthesis. In this regard, D–A cyclopropanes 1 were no exceptions; it turned out that they perfectly entered into [3+3]-cycloaddition processes with various nitrones 350. The activation of D–A cyclopropanes is usually carried out under mild conditions with Lewis acid catalysis. The most widespread Lewis acids in these reactions include

S

OHC Ar1

DBU S

Ar

346

OH

Ar

CO2R CO2R

Ar1(O)C

345 Up to 74% yields dr up to 9:1 Ar = aryl; R = Me, Et; Ar1 = aryl, hetaryl

CO2R SH C(O)Ar1

Ar

O 343

CO2R CO2R 295

AlCl3 (50 mol%) CH2Cl2, rt

S HO Cl

S 344

OH

Ar

C(O)Ar′ 347

C(O)Ar′

S Ar

Sc(OTf)3 (10 mol%) L (10 mol%) TCE, 50 °C, 4 Å MS

S Ar N

O

OH

349 PO(OEt)2 93%; dr 5:1

O

91

N

O– N+

PO(OEt)2

InCl3 (10 mol%) 1,2-DCE Ar = 4-MeC6H4

L= O

NH Tipp

–O

CO2R CO2R

348 Up to 80% yields dr up to 19:1 ee up to 99%

Ar, Ar′ = aryl

Ar Cl

OH

N+ HN

O

Tipp

Tipp = 2,4,6-(iPr)3C6H2

Figure 3.88 [3+3]-Annulation reactions with mercaptoacetaldehyde 343.

89

90

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Yb(OTf)3, Ni(ClO4)2, MgI2, and others. Usually, the reactions are carried out with acyclic nitrones 350, which are easily obtained in various ways, for example, from the corresponding aldehydes and hydroxylamines, or by other methods. Tetrahydrooxazine heterocycles 351 are formed as reaction products in high yields and cis-selectivity. It is assumed that these transformations proceed according to a stepwise mechanism, like other D–A reactions of cyclopropanes. The use of disubstituted cyclopropane dicarboxylates 353 also exhibits high stereoselectivity. In addition, optically pure starting cyclopropanes can be used in these transformations without any loss of ee. The formed tetrahydrooxazine heterocycles 354 are widely used in further syntheses. In addition, in further works, the authors (C. Jasperse group, Y. Tang group) managed to carry out processes in an enantioselective variant using chiral ligands based on oxazolines (Figures 3.89 and 3.90). In 2005, the C. Jasperse group developed the first example of a catalytic asymmetric [3+3]-cycloaddition reaction of D–A cyclopropanes 21 using a Ni catalyst with a chiral Ph-DBFOX ligand. Later, Y. Tang with coworkers developed a slightly different approach to the asymmetric synthesis of tetrahydrooxazines 351 using the same initial substrates, also using nickel catalysis, but with a different tris-oxazoline ligand (TOX) (Figure 3.91) [201] [202]. Johansen and Kerr succeeded in using [3+3]-cycloaddition between D-A cyclopropanes 236 and nitrones 356 to obtain a building block 357 for the synthesis of yuremamine core, which occurs in a number of natural compounds (Figure 3.92). Further work by M. Kerr et al., K. Nolin et al., D. Werz et al., and others expanded the concept of applicability of [3+3]-cycloaddition processes in D–A reactions of cyclopropanes and acyclic nitrones [98, 203–205]. R1 EWG

R 1

EWG

R1

R2 O 350 N

O

LA, solvent

R = aryl, styryl, vinyl, c-C3H5 R1 = Me, aryl R2 = aryl, hetaryl, styryl EWG = CO2Me, CO2Et, CO2Bn, CO2allyl

R2

N

EWG

R 351

EWG

Up to 99% yields dr up to 99:1 ee up to 97%

Main LA = Ni(ClO4)2, Yb(OTf)3, Ca(OTf)2, MgI2

Figure 3.89 Formal [3+3]-cycloaddition of D–A cyclopropanes with nitrones – general reaction.

O

N

R2

R3

N

Ph

1

Ph Me MeO2C CO2Me 354

Figure 3.90

Me 353

Yb(OTf)3 (10 mol%) (43%)

O Ph

N 352

Ph

N

O

R3

R1 R4O2C CO2R4 351, 27–99%; dr 4:1 to 15:1

Ph

CO2Me CO2Me

R2

or MgI2 (10 mol%) THF, rt

CO2R4

Ph O

CO2R4

+

R1 350

Ph

Yb(OTf)3 (5 mol%) CH2Cl2, rt

Me

CO2Me CO2Me 353

Yb(OTf)3 (10 mol%) (51%)

Kerr’s examples of individual reactions.

Ph

N

O

Ph

Ph Me MeO2C CO2Me 354

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled

O

R2

N

CO2R3

+

CO2R3

R1 350

21

R3

CO2R2 CO2R2 1

Ph-DBFOX = R2

N

O O

R1 R3O2C CO2R3

4 Å MS CH2Cl2, rt

O

355, >90% 71–96% ee O

R1

Ni(ClO4)2 (10 mol%) Ph-DBFOX (10 mol%)

N

N

N

Ph

Ph

O

R4

350

R1

Ni(ClO4)2 (10 mol%) IndTOX (11 mol%) DME, rt

R4 CO2R2 CO2

R2

+

IndTOX = N

O

O

R1

R3 R2O2C CO2R2 351, s = 13–97

N O

O N

N iPr

iPr

Figure 3.91 Asymmetric approach to formal [3+3]-cycloaddition with nitrones 350.

NMe2

N 356

OH

R2

R2

I

5 steps O

+

N

OH

N R1

MeO2C 236

CO2Me

R1 357

OH CO2Me HO HO

OH Yuremamine

Figure 3.92 Example of application in total synthesis.

As can be seen, the reactions of [3+3]-cycloaddition of nitrones with D–A cyclopropanes have been studied very well since 2003. This is due to the fact that tetrahydrooxazines 351, the products of these transformations, can be easily transformed with high stereoselectivity into polysubstituted pyrrolidines, which are found as fragments in many natural compounds. In subsequent years, the methodology of [3+3] cycloaddition of nitrones and D–A cyclopropanes continued to be actively developed and extended to more complex substrates, as well as to applications in applied syntheses. For example, a study by Zhang et al. extended the methodology of [3+3]-cycloaddition of nitrones 350 to polysubstituted D–A cyclopropanes 358 with an alkyne fragment, which is successfully realized in the presence of Sc(OTf)3 and phenanthroline as a ligand [206]. The J. Zhou group used cyclopropanes 91 with an oxindole moiety as one acceptor and an N-phosphonate group as another acceptor in the same [3+3]-cycloaddition reaction with nitrones 350. Nickel(II) triflate proved to be the most effective catalyst, which allows obtaining spiro derivatives of 2-indalinones 360 in high yields [97] (Figure 3.93). In another study, various methods of in situ generation of functionalized nitrones and their intramolecular transformations. Dhote and Ramana’s work

91

92

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes 2 R R N+

Cl

R2

Ar1 O– 350

O

N

Ar1

Me

R

Ar

Sc(OTf)3 Ar R1 (10 mol%) O 1,10-phenantroline 359 (10 mol%) Up to 93% yields 1,2-DCE, 4 Å MS dr up to 16:1

R1

Ar O 358

N PG

91

O

R Cl O– 350

N Me

Ni(OTf)2 (10 mol%) 1,2-DCE

N

R O

PG 360 Yields up to 96% dr up to 20:1

Ar = 4-MeC6H4 PG = H, Bn, COMe, COPh, Ts, PO(OEt)2 R = aryl, hetaryl, alkyl

Ar = Ph, PMP; R = aryl, alkyl; R1 = Me, Et, Ph Ar1 = aryl, styryl, 2-furanyl; R2 = Ph, Bn

Figure 3.93

O

Ar N+

Reactions with complex cyclopropane substrates.

demonstrated [3+3] cycloaddition between D–A cyclopropanes 1 and bicyclic nitrones generated via in situ intramolecular cyclization of ortho-nitro arylalkines 361 in the presence of AuCl3 [207]. A study by Pagenkopf and the Kerr group demonstrated an elegant method of generating acyclic nitrones through the reaction between D–A cyclopropanes 1 and nitrosoarenes 273 followed by further fragmentation. The generated nitrone interacts with the second cyclopropane molecule by [3+3] cycloaddition reaction. The described process undergoes in the presence of ytterbium(III) triflate [159]. M. Kerr group demonstrated the intramolecular [3+3]-cyclization D–A of cyclopropanes 364 with nitrones. In these works, nitrone is generated in situ from an aldehyde fragment in a cyclopropane structure and hydroxylamine. The resulting nitrone undergoes the cyclization reaction in the presence of ytterbium(III) triflate to obtain various bicyclic structures 365 [208, 209] (Figure 3.94). R

O AuCl3 (5 mol%)

Ar

1,2-DCE

NO2

R

Ar N O

361 Ar = aryl; R = aryl, n-pentyl Ar1 = aryl; EWG = CO2Me, CO2Et

CO2Me

Ar 1

CO2Me

Ar = Ph, 2-thienyl Ar1 = aryl

Ar1

N

O

Ar1

1 EWG

Ar N O

Sc(OTf)3 (10–15 mol%) 1,2-DCE

R EWG EWG

Ar1

362 Up to 92% yields

Ar

273

Yb(OTf)3 (10 mol%) 1,2-DCE, Δ – CH2=C(CO2Me)2

Ar1 N

RNHOH EWG Toluene, 4 Å MS CHO 364

Ar

Ar1

CO2Me 1 CO2Me

O

N

CO2Me

Ar

O

Ar

363

CO2Me

Up to 91% yields

R N

EWG

EWG

O

EWG N O R

R = Me, Bn, PMB, Ph, n-heptyl EWG = CO2Me, CO2Et; linker = alkyl, alkenyl, aryl, hetaryl

Figure 3.94

O

EWG

Yb(OTf)3 (10 mol%)

EWG EWG

365 Up to 98% yields

Generation of nitrones in situ and intramolecular [3+3]-cycloaddition.

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled R1 R4

EDG 1

CO2Me

= H, aryl R2 = Me, n-Pr, Ph, CH2Cl 3 = H, Me R R4 = H, Me, Et R5 = alkyl, aryl R6 = H, alkyl EDG = aryl, hetaryl, styryl, vinyl

TBSO

R1

R6 N

367

O

Yb(OTf)3

R6 R5 TBSO

N

CO2Me R4 CO2Me

R2 N O O EDG R3 368 Up to 94% yields dr up to 3.5:1

Yb(OTf)3 4 Å MS, solvent

R5 R1

N R2 O O R3 366

CO2Me

CO2Me CO2Me O

EDG

369 56–98% yields

Figure 3.95 Formal [3+3]-cycloaddition with cyclic and acyclic nitronates.

In a series of joint studies by Tabolin, Mikhaylov, Ioffe, Novikov, and Tomilov, general protocols for formal [3+3]-cycloaddition reactions between D–A cyclopropanes 1 and cyclic and acyclic nitronates 366, 367, which usually proceed under ytterbium(III) triflate catalysis, were developed. The total coverage of substrates and functional groups used was found to be very broad. The general patterns of reactions are similar to those with nitrones. As a result, various cyclic nitronates and their derivatives are obtained as products, which can be used in further reactions, for example, as 1,3-dipoles, as well as in other transformations, which are very diverse, well-developed, and useful for the subsequent functionalization of nitronate derivatives 368, 369 [210–212] (Figure 3.95).

3.5.6 [3+3]-Annulation/Cycloaddition with Dinitrogen Substrates The application of various substrates with two nitrogen atoms as 1,3-synthons in different capacities in formal [3+3]-cycloaddition reactions with D–A cyclopropanes are well studied. The use of hydrazides and their analogs in formal [3+3]-cycloaddition reactions was first proposed by D. Werz et al. under the catalysis with TiCl4 and imidazole for in situ generation of nitrile imines as intercepted 1,3-dipoles. Hydrazoyl chlorides 370 of various natures were reacted with cyclopropanedicarboxylates 1 to give tetrahydropyridazine derivatives 371 [213]. In the work of T. Punniyamurthy, another variant of the synthesis of tetrahydropyridazines 373 by means of the formal [3+3]-cycloaddition reaction of D–A cyclopropanes 1 to hydrazones 372 under oxidizing conditions is proposed. This process can be successfully carried out in an enantioselective manner [214] (Figure 3.96). I. Trushkov’s group has developed an elegant process of combining two different types of three-membered rings, proceeding as formal [3+3]-cycloaddition, while generating 1,3-zwitterionic intermediates from both starting substrates. Diaziridines 307, three-membered rings with two nitrogen atoms, which open in a similar manner, were used as the second component to D–A cyclopropanes 1. The process takes

93

94

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Ar2 Ar2 Ar

N

N

HN

Ar3 EWG EWG

373 Yields up to 81% ee up to 98%

N 372

Ar1

Ar3 EWG

Ar

Cu(OTf)2 (10 mol%) 1,2-DCE 50 °C, air

H N

Cl N 370

R

TiCl4 (20 mol%) Imidazole CH2Cl2

EWG 1

Ar1

N

N

Ar

R EWG EWG

371 Yields up to 92%

Ar = aryl; EWG = CO2Me, CO2Et, CO2iPr, CO2Bn R = aryl, 2-thienyl, Me, c-C3H5 Ar1, Ar2 = aryl; Ar3 = aryl, 2-thienyl, styryl

Figure 3.96

Formal [3+3]-cycloaddition with nitrilimines and hydrazones.

place under mild conditions under the catalysis of nickel(II) perchlorate with high diastereoselectivity. The reaction products are functionalized tetrahydropyridazines 309. It should be noted that diaziridines, in this sense, are the only three-membered heterocycles that enter into formal [3+3]-cycloaddition with cyclopropanes. Other three-membered heterocycles react differently (see Section 3.4.6) [176] (Figure 3.97). There are also several known cycloadditions with other 1,3-dipoles containing two nitrogen atoms. In the new work of R. Sonawane et al., a variant of the interception of D–A cyclopropane 1 by azomethine imines 372, proceeding as a formal [3+3]-cycloaddition, is presented. The process requires the use of a strong Lewis acid, EtAlCl2, and the yields of the final products are low, which is associated with the usually dominant alternative routes of interaction [215]. In a study by H. Guo et al., a method of interaction with phthalazinium dicyanomethanides 374 under the action of scandium(III) triflate with the formation of annelated six-membered nitrogen heterocycles 375 is proposed [216]. Other similar heterocycles 377 are obtained by Ni(ClO4)2-catalyzed formal [3+3]-cycloaddition with aromatic azomethine imines 376, developed by the A. Charette’s group [217] (Figure 3.98).

3.5.7 Formal [3+3]-Cycloaddition with Azides and Diazo Compounds Azides 378 as 1,3-dipoles for coupling with generated 1,3-zwitterionic intermediates in formal [3+3]-cycloaddition reactions with D–A cyclopropanes 1 were successfully used in the work of P. F. Xu’s group. The authors managed to involve a wide range of cyclopropanes in the developed process. To introduce azides into the reaction, stringent conditions are required: TiCl4 is the initiator of this process. The yields of the R

R

CO2Me

Ar

CO2Me 1

N

R1

N

R2 307

Ni(ClO4)2·6H2O 4 Å MS, CH2Cl2, Δ

Ar = aryl, hetaryl R,R = -(CH2)3-; -(CH2)4-; Et,Et R1 = aryl, Me, H, Et, alkenyl, c-C3H5 R2 = H, Me

R R Ar

N

N

R1 R2 CO2Me CO2Me

309 Yields up to 88% dr up to 95:5 ee up to 99%

Figure 3.97 Formal [3+3]-cycloaddition with diaziridines 307.

3.5 ­Formal 3332]-CyalFmaadidFon mona ononMalmidFon lemyidFond Fo n -CyalFioFimonled O N 372

CO2R

Ar 1

CO2R

Ar

O

N

N

EtAlCl2 (2 equiv.) 1,2-DCE, 0 °C

Ar = aryl, 2-thienyl; R = Me, Et

CO2R N CO2R 373 Yields up to 38%

CN

X CO2Me N

CO2Me

NBz R

377

11–87% dr up to 6.6:1

N

N+ 376

NBz

Ni(ClO4)2 (10 mol%) 4 Å MS, THF, r.t.

CO2R′

R 1

CO2R′

R = Donor group

CN

N 374 Sc(OTf)3 (10 mol%) 1,2-DCE, rt X = H, Me, OMe, SMe, Cl, CF3, Ph

Ar NC

CO2Et

NC

N

CO2Et

N X 375 Yields up to 99% dr up to 95:5

Figure 3.98 [3+3]-Annulation processes of D–A cyclopropanes 1 with azomethine imines 372, aromatic azomethine imines 376, and phthalazinium dicyanomethanides 374.

final tetrahydrotriazines 379 ranged from 49% to 94%. At the same time, during the reaction, the extrusion of the nitrogen molecule does not occur, although this can be achieved if necessary [218] (Figure 3.99). Diazo compounds are other commonly used 1,3-dipoles in cycloaddition reactions, but they are not nearly as good as azides. Despite their active study in reactions with D–A cyclopropanes 1, so far it has not been possible to obtain tetrahydropyridazines 381 or their isomeric forms, which are the simplest reaction products of the formal [3+3]-cycloaddition of a diazo compound 380 as a 1,3-dipole. In many respects, the problem lies in the instability of the diazo compounds themselves under the conditions of inherent catalysis by Lewis acids. But as a result, many other directions of interaction with diazo compounds were realized [219, 220]. Thus, M. Doyle, a distinguished specialist in diazo compounds, presented an approach to another formal [3+3]-cycloaddition of silyl ethers of enols 58 containing a diazo group and D–A cyclopropanes 1. The process proceeds efficiently in the presence of the Yb(OTf)3– Rh2(cap)4 catalytic system and is sufficiently tolerant to the electronic effects of donor substituents in cyclopropane. At the same time, diazoester formally acts as a source of three-carbon synthon with the elimination of the nitrogen molecule. In reality, the process proceeds in two stages: through the initial addition of cyclopropane to the double C=C bond and further rhodium-catalyzed rearrangement [33]. Another very elegant way of using diazocarbonyl compounds 383, 384 in

CO2Me

R 1

CO2Me

R = aryl, vinyl R1 = Bn, n-C10H21

378 R1N3

R1

TiCl4 Solvent

R

N

N

N

CO2Me CO2Me

379 49–94% yields

Figure 3.99 Formal [3+3]-cycloaddition with azides.

95

96

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

A

D 1

R +

N2

A

N

N

R (unknown)

380

D 381

A A

Figure 3.100 Hypothetical formal [3+3]-cycloaddition with diazo compounds, not yet experimentally realized. CO2Me

R 1

CO2Me

CO2Me

58 (1) Yb(OTf)3 (5 mol%) 1,2-DCE, 24 h rt, 4 Å MS (2) Rh2(cap)4 (2 mol%) PhMe, Δ, 24 h

R = aryl, hetaryl, BzO, PhthN

OTBS

OTBS

N2 CO2Me

CO2Me 382 Up to 73% yields

N2

MeO2C

CO2Me

R

CO2Me

O OH MeO

383

CO2Me

384

N2 O

O MeO

O O CO2Me Rh (OAc) (2 mol%) Rh2(OAc)4 (2 mol%)] 2 4 EDG MeO2C EDG Sc(OTf)3 (10 mol%) 1 CO2Me EDG Sc(OTf)3 (10 mol%) CO2Me Yb(OTf)3 (0.5 mol%) Yb(OTf)3 (0.5 mol%) 386 385 CH2Cl2, 30 °C, 4 Å MS PhMe, 30 °C, 4 Å MS Yields up to 93% Yields up to 98% EDG = aryl, 2-thienyl, NPhth dr up to 5:1 dr up to 20:1

MeO2C

Figure 3.101 [3+3]-Annulation processes with different 1,3-synthones generated from diazo compounds.

cycloaddition reactions with D–A cyclopropanes 1 is presented in the work of D. Werz’s group. Diazocarbonyl compounds 383, 384 are used to generate carbonyl ylides – 1,3-zwitterions with an oxygen atom in the middle, which are introduced into further formal [3+3]-cycloaddition with cyclopropanes. To generate carbonyl ylides, an intramolecular process of diazoketone decomposition is used, which requires catalytic amounts of Rh(I), and therefore, for the reaction as a whole, a double catalytic system Rh2(OAc)4–Sc(OTf)3 is used, similar to what Doyle used. Even better ones are achieved by doping scandium triflate by 5% ytterbium. The implementation of this process leads to the synthesis of polysubstituted tricyclic pyrans 385, 386 [221] (Figures 3.100 and 3.101).

3.6 Reactions of Formal [4+3]-Cycloaddition and Annulation with Diene and Heterodiene Systems The reactions of D–A cyclopropanes 1 with diene and heterodienic systems and their analogs, which occur as formal [4+3]-cycloaddition, annulation, or cyclization reactions, are of particular interest since they open new approaches to the synthesis of a wide range of various seven-membered cyclic structures that are not so easy to

3.6

lemyidFond Fo ­Formal 4332]-CyalFmaadidFon mona ononMalmidFon dit dleonle mona leileoFadleonle Cdilerd OR

OR CO2R

Don

1

CO2R

Lewis acid Don δ+

δ–

RO

Don

O

O

LA

O RO

O

LA

II

I X

Don = Ar, HetAr

Y R

Ar

CO2R

Y

X

CO2R 387 R

CO2R CO2R

Don

X, Y = C, N, S

[4+3]-Annulation

R

388

Formal [4+3]-cycloaddition

Figure 3.102 Formal [4+3]-cycloaddition and annulation reactions of D–A cyclopropanes with dienes/heterodienes.

obtain even now. At first approximation, the formal [4+3]-cycloaddition is a homoanalog of the Diels–Alder reactions which, however, nearly always occurs stepwise by an ionic mechanism [222]. In this case, the D–A cyclopropane acts as a 1,3-zwitterionic synthon that is coupled with a diene system. In terms of the mechanism, these reactions are typical of D–A cyclopropanes and occur by opening the threemembered ring to give a 1,3-zwitterionic intermediate; hence, they require catalysis with Lewis acids. Conceptually, further, there are two main pathways of [4+3]-coupling, that is, with cyclization on the malonyl moiety or with annulation at the aromatic ring. In the latter case, an annulated system with a seven-membered ring is formed [223]. The [4+3]-cyclization reactions of D–A cyclopropanes often occur in good yields and under mild conditions; therefore, they are very attractive for building seven-membered rings (Figure 3.102).

3.6.1 Dienes as Traps for 1,3-Zwitterions The first conceptual data on the reactions of dienes and D–A cyclopropanes 1 were obtained by Trushkov et al. in 2008. Isobenzofuran 391, which is well known in this role and is widely used as a highly reactive diene system in organic synthesis, was used as a cyclic diene in the reactions with D–A cyclopropanes 1. The process occurs as [4+3]-cycloaddition, ytterbium(III) triflate is used as the process catalyst, and the yields of the final products 392 reach 92%. It should be noted that, as a rule, D–A cyclopropanes 1 with donor groups in the aromatic moiety successfully react in this process [222, 224]. In another work published by the same team, a formal [4+3]-cycloaddition reaction of D–A cyclopropanes 1 and other cyclic diene systems 389, anthracene and tetracene in particular, in the presence of TiCl4 was developed. The process was carried out with a series of aromatic and heteroaromatic D–A cyclopropanes, resulting in fairly good yields of final products 390. In the case of D–A cyclopropanes 1 with a thiophene moiety or several methoxy substituents at the aromatic ring, cyclization also involves these moieties in the D–A cyclopropane [225] (Figure 3.103).

97

98

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes 389

Ar CO2R

RO2C Ar 1

CO2R CO2R

TiCl4 CH2Cl2 390 Yields up to 85%

Ar = Ph, 4-FC6H4 R = Me, Et Ph 391 O CO2R

Ar

CO2R 1

Ph

Ph O

Yb(OTf)3 (5 mol%) CH2Cl2

Ar = aryl, hetaryl R = Me, Et

CO2R CO2R

392 Ph

Ar

Yields up to 92%, dr up to 86:14

Figure 3.103 Formal [4+3]-cycloaddition of D–A cyclopropanes to anthracene/tetracene and isobenzofuran.

Y. Tang et al. presented a more general version of formal [4+3]-cycloaddition between D–A cyclopropanes and conjugated dienes containing a donor OSiPh2tBu group (OTBDPS), including cyclic and acyclic dienes 393, 394. They succeeded in developing an efficient cyclization process, also in the enantioselective version, using Cu(II) salts as the catalyst and cyclohexyl-TOX or BOX as the chiral ligands. The yields of the target products 395, 396 reached 96%, and this process is mainly successful with cyclopropanes 1 containing donor substituents at the aromatic ring [226]. It should be noted that many simple cyclic and acyclic dienes without an activating donor group do not enter [4+3]-cyclization with D–A cyclopropanes but react like ordinary alkenes in simpler [3+2]-reactions [28] (Figure 3.104). OTBDPS EDG TBDPSO

R1

TBDPSO

R1 R2

CO2R CO2R

396 Yields up to 96% ee up to 98% (Asymmetric)

EDG

394

393

R2

TBDPSO

R1

EDG

Cu(ClO4)2·6H2O (10 mol%) TOX (11 mol%) MS 4A

CO2R CO2R Cu(SbF ) (10 mol%) 6 2 1 BOX (11 mol% )

EDG = aryl, hetaryl, styryl, vinyl R = 2-Ad, Bn; R1 = H, Me, Et, Ph; R2 = H, cyclo

N

Me O

TOX

N c-C6H12

395

CO2R CO2R

Yields up to 96% (Racemic)

Me Me O

O

O N

c-C6H12

c-C6H12

R1

N

N BOX

Figure 3.104 Cu(II)-catalyzed formal [4+3]-cycloaddition with dienes and its asymmetric version.

3.6

lemyidFond Fo ­Formal 4332]-CyalFmaadidFon mona ononMalmidFon dit dleonle mona leileoFadleonle Cdilerd OMe OMe

(Het)Ar

CO2R CO2R

1 +

MeO2C MeO2C

TiCl4

OMe

EtO2C S EtO2C

CH2Cl2 –40 °C 397 (70%)

389

398 (71%)

Ar = 3,4,5-(MeO)3C6H2

CO2R CO2R

CO2R CO2R

399

LA (5–10 mol%) CH2Cl2, 4 Å MS

X 402 Yields up to 68% dr up to 80:20

Figure 3.105

X

X

403

Ar = 2-thienyl

CO2R CO2R

CO2R

400

CO2R X

LA (5–10 mol%) CH2Cl2, 4 Å MS

X = S, O, NTs, NMe R = Me, Et LA = Yb(OTf)3, Sn(OTf)2

401 Yields up to 81% dr up to 95:5

[4+3]-Annulation at aromatic rings with anthracene and cyclopentadiene.

Apart from the direct formal [4+3]-cycloaddition that is a homo-analogue of the Diels–Alder reaction, the related less common [4+3]-cyclization of D–A cyclopropanes with annulation at the aromatic ring was also implemented. In particular, the [4+3]-annulation with cyclopentadiene 403 under “mild” catalysis with Yb(OTf)3 or Sn(OTf)2 was studied in detail. As a rule, this reaction involves D–A cyclopropanes 399, 400 with a heterocyclic moiety as a strong donor. The cyclization direction can be controlled by varying the position of the cyclopropyl moiety in the heterocycle; in this case, more complex cascade reactions giving tri- and tetracyclic annulated systems can be performed. The yields of the final products 401, 402 are up to 81% [223]. In the case of D–A cyclopropanes 1 with a thiophenyl substituent or with a few methoxy groups at the phenyl ring, a similar [4+3]-cyclization with annulation at the aromatic ring of a D–A cyclopropane can be carried out using anthracene 389 as the diene component (Figure 3.105).

3.6.2 Reactions of [4+3]-Cyclization with Heterodiene Systems and Their Analogs Since formal [4+3]-cycloaddition reactions with 1,3-dienes were found to occur very well with D–A cyclopropanes, quite a few approaches were developed in the subsequent years (2016–2021) to perform [4+3]-cyclization reactions with the participation of heterodiene systems since this is a very convenient and attractive tool for creating seven-membered heterocycles, many of which are not easy to obtain by alternative methods. Suitable heterodiene systems are structures with nitrogen and sulfur atoms in various positions, such as substrates as cyclic azadienes, anthranils, thiodienes, and bisthioquinones. Related cyclization reactions can also occur with

99

100

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

triazines, salicylic, and anthranilic aldehydes. On the other hand, α, β-unsaturated ketones do not undergo [4+3]-cyclization with D–A cyclopropanes. A study by Y. C. Luo et al. is the first example of a [4+3]-cycloaddition reaction between D–A cyclopropanes 1 and anthranils 404 as cyclic azadienes. A broad range of anthranils and cyclopropanes, including those with an alkyl substituent as a donor, are readily involved in this process to give final products 405 in yields above 90%. The reaction is catalyzed by scandium triflate Sc(OTf)3, which is a typical catalyst for these reactions. The authors also successfully performed this reaction in the enantioselective version using optically active starting D–A cyclopropanes 1 for this purpose. It should be noted that the use of simpler substituted azadienes in this reaction under the conditions studied failed [227]. In a study by Z. Chai et al., the reaction with anthranils 404, 406 was developed using D–A cyclopropanes 11 obtained from γ-butyrolactones. In the case of unsubstituted anthranil 406, the process occurred as [4+3]-cycloaddition, while in the presence of a phenyl substituent in the heterocycle, it resulted in tetrahydroquinolines 407. The reaction is also catalyzed by scandium(III) triflate, and the process can be carried out with the transfer of chirality of the starting D–A cyclopropane [228] (Figure 3.106). Of particular interest are the reactions with thiodienes developed by D. Werz’s team, which open access to seven-membered sulfur-containing heterocycles. For example, thiochalcones 409 were successfully used in [4+3]-cycloaddition to D–A cyclopropanes 1. The process is catalyzed by Sc(OTf)3. It is tolerant to various functional groups in D–A cyclopropanes and thiochalcones, and the yields of the final tetrahydrothiepins 410 reach 87% [229]. In another work, the researchers succeeded in performing formal [4+3]-cycloaddition reactions with D–A cyclopropanes 1 using benzodithioloneimines 411 as sources of cyclohexadienedithiones 413 that served as dipolarophiles in the reaction. The process is of general scope. The electronic effects of substituents in the starting substrates weakly affect the process,

404

R

Ar CO2Me CO2Me

EDG

Ar

1

O O

Ar2

Ar1 N H

Ph

O

Ar

407

Yields up to 76%

404

N

EDG

405

Yields up to 90% ee up to 99% (Using chiral cyclopropane)

Ph

Ar2

CO2Me CO2Me O

Sc(OTf)3 (5 mol%) 1,2-DCE, rt, 4 Å MS

EDG = aryl, vinyl, Et R = H, Me; Ar = aryl

RO2C

R

O N

406 O

Ar1

O

O

N Sc(OTf)3 (10 mol%) 1,2-DCE, 60 °C

CO2R Ar

11

2

Ar

Ar

N Sc(OTf)3 (5 mol%) 1,2-DCE, rt

R = Me, Et Ar = aryl; Ar1 = H, aryl; Ar2 = aryl

Figure 3.106 Formal [4+3]-cycloadditions with anthraniles.

Ar1

O Ar2

O N RO2C

408

O O

Yields up to 94% ee up to 99% (Using chiral cyclopropane)

3.6

lemyidFond Fo ­Formal 4332]-CyalFmaadidFon mona ononMalmidFon dit dleonle mona leileoFadleonle Cdilerd S

EDG

1

409

CO2R CO2R

CO2R CO2R

EDG

Ar1

Ar

Ar

S

EDG

1

CO2R CO2R

410

Yields up to 87%

EDG = aryl, 2-thienyl, vinyl, NSucc, NPhth R = Me, Et, Bn; Ar = aryl, 2-thienyl, 2-ferrocenyl Ar1 = aryl, 2-thienyl

CO2R CO2R

EDG

NH S 411

Ar

Ar1

S

Sc(OTf)3 (20 mol%) CH2Cl2, 40 °C, 2 h

S

S

S

TiF4 (10 mol%) Cs2CO3 (3 equiv.) THF, 60 °C, 16 h

NH

– “HCN”

Ar

Ar

S

S Ar

413

412

411

Yields up to 91% ee up to 87% (Using chiral cyclopropane)

EDG = aryl, vinyl, NSucc, NPhth, OBn, c-C3H5 R = Me, Et; Ar = aryl, hetaryl

Base

S

Figure 3.107 Formal [4+3]-cycloadditions with thiodienes and bistioquinones.

which is a great advantage. The reaction results in dihydrobenzodithiepine derivatives 412 in up to 91% yields. A double catalytic system “TiF4 – Cs2CO3”, which is unusual in the chemistry of D–A cyclopropanes, is used as the catalyst. It should also be noted that the reaction occurs with the retention of the asymmetric center configuration in the initial cyclopropane [98, 230] (Figure 3.107). In other studies published by D. Werz et al., they reported an interesting example of cyclization of D–A cyclopropane 1 with triazines 216, catalyzed by Sc(OTf)3. It should be noted that the process occurs as a formal [4+3]-cycloaddition, with the formal dimer of N-arylmethaneimine 415 acting as the 1,4-synthon. A wide range of both D–A cyclopropanes and triazines were involved in the process. In these cases, the yields of the final products were up to 94%. 1,3-Diazepines 414 were subsequently used in the aminal cleavage process in order to obtain the products of 1-amino-3-aminomethylation of the starting D–A cyclopropanes 1 [231] (Figure 3.108). A study by E. Ruijter et al. (2021) presented a reaction of salicylic aldehydes 416 and vinyl-substituted D–A cyclopropanes 321, in which the phosphonate group Ar N

216 CO2R CO2R

EDG

1

Ar

N

N

CO2R CO2R

EDG Ar Ar

Sc(OTf)3 (10 mol%) CH2Cl2, rt, 14 h

N N

414

Ar

Yields up to 94%

EDG = aryl, vinyl, 2-thienyl R = Me, Et; Ar = aryl Ar N Ar

N

N

216

Figure 3.108

Ar

– Ph–N=CH2

Ar

N

N

Ar

415

Formal [4+3]-cycloaddition with triaryl triazines 216.

101

102

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes OHC

416 CO2R

417 Ar

HO

OHC

PGO2S

RO2C CO2R Ar

PO(OR)2

PdCl2 (10 mol%) L (20 mol%) LiCl, water, t-BuOK 321 THF, rt R = Me, Et; Ar = aryl

PO(OR)2

O

418 Yields up to 99% ee up to 83%

321

Pd2(dba)3, L LiCl, water, t-BuOK THF, 50 °C

R = Me, Et; PG = Me, aryl

Me

L=

CO2R

N H

O P N O Me

N PGO2S

419

Yields up to 72% O

O L=

P O

Me

Figure 3.109 [4+3]-Annulation reactions of vinyl D–A cyclopropanes with salicylic and anthranylaldehydes.

acted as one of the acceptor moieties. The [4+3]-annulation occurs with a wide range of initial substrates. The yields of the final product 418 reach 99%. In this process, palladium catalysis was used for cyclopropane opening. Its use was found to be necessary due to the presence of a reactive vinyl group in cyclopropane. This process was successfully implemented in the enantioselective version using chiral phosphonate ligands [232]. Later on, the same team expanded their approach to reactions of anthranyl aldehydes 417 with D–A cyclopropanes 321, where the same phosphonate group acted as an acceptor moiety. The formal [3+4]-annulation can also be performed with a wide range of initial substrates. The yields of the final product 419 reached 72%. Pd2(dba)3 with the addition of the trifurylphosphine ligand served as the catalyst for this process [233] (Figure 3.109).

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes 3.7.1 Formal [8+3]-Cycloaddition Reactions M. Sierra et al. presented an example of the reaction of 2-substituted tropones 420 as dipolarophiles and D–A cyclopropane 41, comprising a phthalimide activating donor group. The reaction did not occur as a [3+2]-cycloaddition at the carbonyl group or one of the C=C double bonds, but strictly as an [8+3]-cycloaddition with exceptionally high regio- and diastereoselectivity. The process was catalyzed by SnCl4. The yields of the end products 421 reached 72% [234]. It should be noted that this process is classified as an [8+3]-cycloaddition according to the number of electrons of the conjugated system of double bonds involved in the reaction, though formally it can also be considered as a [3+3]-annulation since a six-membered ring is formed in the reaction. In the same year, J. Carretero’s team independently published a similar process for usual 2-substituted cyclopropanedicarboxylates 1 with

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes PhthN O CO2Et

PhthN

+

SnCl4 (5 mol%)

R

CH2Cl2, rt, 16 h

CO2Et

41

O CO2R1

+

CO2R1 1

R2

CO2Et CO2Et

420 R = Cl, Br, Ar, ORʹ

R2

O R

= Ar, HetAr, Alk, NPhth

421, yields up to 71%

Ni(ClO4)2 (10 mol%) CH2Cl2, 70 °C, 12–24 h

422

O

R2

1 R1O2C CO2R

423, yields up to 92%

Figure 3.110 Formal [8+3]-cycloadditions of D–A cyclopropanes with tropones 420, 422.

an unsubstituted tropone 422 catalyzed by nickel perchlorate Ni(ClO4)2 that also occurred as an [8+3]-cycloaddition followed by migration of double bonds in the cycloheptatriene ring [235] (Figure 3.110).

3.7.2 Other Formal Stepwise “High-Order” Cycloaddition/ Annulation Reactions A few other reactions that do not fit into the classification presented above and occur with the formation of seven- and eight-membered rings are also known for D–A cyclopropanes 1. For example, processes of stepwise addition of D–A cyclopropanes to vinyl and allyl derivatives of indole with acceptor groups at the double bond were reported. X. T. Xu et al. succeeded in performing the [3+4]-annulation of Knoevenagel adducts comprising an indole moiety 424 with D–A cyclopropane 1, with possible efficient employment of a wide range of D–A cyclopropanes to give high yields of end products 426 with high diastereoselectivity. The process is catalyzed by ytterbium(III) triflate [236]. A. Nishida et al. developed a similar protocol for a formal [5+3]-cycloaddition of D–A cyclopropanes 1 and substituted indoles 425 with an allylcarboxylate substituent at position 2. The process can be carried out either by a one-pot technique or sequentially to give an acyclic product. The yields of end products 427 reached 91% [237] (Figure 3.111). Recent publications from Novikov and Tomilov’s team reported a rare example of formal [6+2]-cycloaddition of 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) 278 to D–A cyclopropanes 428, 431 based on the bicyclopropane system to give a 1,2-diazacyclooctane moiety [238, 239]. These substrates are highly reactive and occur under mild catalysis conditions using 5–10% Yb triflate. Apart from the formal [6+2]-cycloaddition, a number of other processes occur in this case, including those accompanied by further transformations with the addition of two or three PTAD moieties. Moreover, the same team reported a rare selective example of [4+3]-cyclodimerization of (9-anthracenyl)cyclopropanedicarboxylate 433 in the presence of GaCl3 to give a tetracyclic 1,2,3,4-tetrahydrocyclohepta[de]anthracene skeleton 434 [240] (Figures 3.112 and 3.113).

103

104

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes RO2C N

RO2C

Yb(OTf)3 (10 mol%) 1,2-DCE, 60 °C

1

Ar = aryl, hetaryl R = Me, Et, Bn; PG = Me, allyl, Bn

PG

Ar

N

426 Yields up to 96% dr up to 20:1

R

EWG

425

CO2Me CO2Me

PG

(1) Yb(OTf) 3 (5 mol%) 1,2-DCE, 80 °C (2) NaH, rt, 24 h

1

CO2Me CO2Me

EDG

R

N EDG

CO2Me CO2Me

424

CO2Me CO2Me

Ar

CO2R

RO2C

PG

N

EWG

PG

427 Yields up to 91% dr up to 8:1

EDG = aryl, 2-thienyl, styryl, vinyl EWG = CO2Me, C(O)Me; R = H, OMe; PG = Me, Bn

Figure 3.111 Formal stepwise [4+3]- and [5+3]-annulation reactions of D–A cyclopropanes to vinyl and allyl indole derivatives.

CO2Me CO2Me

N

+ Ar

278

428

Yb(OTf)3 (10 mol%)

NPh

N

CO2Me CO2Me

O

O

1,2-DCE 60 °C

O

PhN

N

NPTAD

O

NH

N

O

N

+

NPTAD

NPh

429

430

O Ar 22–60%, cis/trans up to 10/1

PTAD

MeO2C

CO2Me O N NPh N

Ph

O

Up to 10–15%

NPTAD = 4-Ph-1,2,4-triazolidine-3,5-dione-1-yl

MeO2C CO Me 2

O N

+ Ph

NPh

N

278

O

CH2Cl2 20 °C

PTAD

431

CO2Me CO2Me O N

Yb(OTf)3 (5 mol%) N Ph

PTAD

NPh

Further transformations

O 65%

432

Figure 3.112 Formal [6+2]-cycloadditions of the activated D–A bi(cyclopropanes) to PTAD 278.

CO2Me CO2Me

GaCl3 (40 mol%)

MeO2C CO Me 2

CO2Me CO2Me

15 °C, 24 h CH2Cl2 (45–55%)

433

434

Figure 3.113 [4+3]-Cyclodimerization of anthracene-derived D–A cyclopropane 433.

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes R2

O Ar

350

Ar

Ph3PAuOTf (2 mol%) CH2Cl2, rt

R1

O

R

Ar1

N

R

358

O

R2

N

O

435

Ar = Ph, PMP; Ar1 = aryl, styryl, 2-furanyl R = aryl, alkyl; R1 = Me, Et, Ph; R2 = Ph, Bn

R1

1

Ar

Up to 99% yields dr up to 20:1

Figure 3.114 Formal [4+3]-cycloaddition with nitrones under Au(I)+ catalysis conditions.

J. Zhang et al. developed a methodology for the formal [4+3]-cycloaddition of nitrones 350 with polysubstituted D–A cyclopropanes 358, in which an acetylene moiety was present at the cyclopropane ring. The process was successfully implemented under metal complex catalysis conditions using a gold complex, Ph3PAuOTf. The yields of the final product 435 reached 99%, and the process occurred with extremely high diastereoselectivity [206]. In these reactions, rearrangement also occurred in addition to the formal cycloaddition. Moreover, cyclopropane itself acted as a source of a four-carbon synthon in the cyclization (Figure 3.114). T. Hayashi et al. described Pd-catalyzed [4+3]-annulation between cyclopropanedinitriles 436 and 5-methyliden-3-methoxycarbonyl-3-phenyltetrahydropyran2-one 437. The reaction proceeds through the formation of allylpalladium intermediate complex which then undergoes decarboxylation. This process leads to the formation of 1,4-zwitterionic intermediate, which reacts with cyclopropanedinitrile to form substituted cycloheptane 438 [241] (Figure 3.115).

3.7.3 Formal [3+1]- and [3+1+1]-Cycloadditions Formal [3+1]-cycloaddition processes involving D–A cyclopropanes are very rare, and only a few reactions can be attributed to them at the moment. From the formal point of view, a carbene intermediate should add to a D–A cyclopropane molecule

CN Ph

CN

(Ph or H) 436

O

+ 437

Ar

NC CN

CpPd(η 3-C3H5) (5 mol%)

O

Ph CO2Me Ar 438

CO2Me

O

P

O

CN

NiPr2 (10 mol%) PdII

Ph

CN 436

PdII

O O Ar

CO2Me

– CO2 Ar

CO2Me

Figure 3.115 [4+3]-Cycloaddition of D–A cyclopropane 436 to methylene tetrahydropyranone 437.

105

106

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Ar

1

Pr(OTf)3 Ar

CO2R

δ+

O

RO

I CO2R CO2R Ar

N Ar1

440

Ar

O

δ–

439

OR

OR CO2R

[Pr]

439 Ar1NC:

Ar1NC:

O O

RO

[Pr]

II Ar N Ar1

Ar

CO2R CO2R N Ar1

Ar1

CO2R CO2R

N H

441

N Ar1

442

Figure 3.116 Formal [3+1]- and [3+1+1]-cycloadditions of isonitriles to D–A cyclopropanes.

in the course of [3+1]-cycloaddition, but reactions of this kind were found to be unrealizable in real life. The most popular and convenient variant for the generation of carbene intermediates via various diazo compounds combined with D–A cyclopropanes results in a wide range of various reactions but not the formal [3+1]-addition of carbene [33] [219–221] [242]. However, a few reactions of this kind are known. In 2006, Armin de Meijere’s team implemented a process of addition of isonitriles 439 to D–A cyclopropanes 1 catalysis by praseodymium triflate Pr(OTf)3 under mild conditions [243]. In this case, isonitrile exhibits the properties of a carbene and adds to a D–A cyclopropane by the [3+1]-cycloaddition type to give an unstable four-membered ring, which immediately adds the second isonitrile molecule in a similar way to give a five-membered ring 441 resulting from formal [3+1+1]-cycloaddition. (Figure 3.116) A couple of formal [3+1]-cycloadditions of nitrene synthons to D–A cyclopropanes, resulting in the formation of azacyclobutane skeleton, are also known. However, in reality, processes of this kind occur either stepwise in two stages or by a more complex multistage mechanism. In 2014, P. F. Xu et al. succeeded in achieving this goal by first entering a D–A cyclopropane 1 into formal [3+3]-cycloaddition with azides 378 and then performing their thermal de-diazotization [218]. Later, P. Banerjee et al. suggested an alternative approach, where N-substituted 3-phenyl-1,2-oxaziridines 301 were used as nitrene synthons that eliminated a benzaldehyde molecule in the reaction [173] (Figure 3.117).

3.7.4 Cycloaddition/Annulation Reactions Proceed via Generation of β-Styrylmalonates The main type of reactivity of D–A cyclopropanes is the opening of the three-membered ring with the generation of 1,3-zwitterionic intermediates or their synthetic equivalents, followed by their trapping by various substrates. An essential part of this chapter covers processes of this type. However, even though reactions of D–A cyclopropanes 1 that occur by the generation of other types of intermediates are much less common, they are no less interesting and deserve special attention. One of these important types of processes involves the generation and trapping of β-styrylmalonates 443 as active synthons that determine the overall reaction

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes RO2C CO2R

378 R1 N N N

R

TiCl4 CO2R

R

1

N

RO2C CO2R

N

Xylene, Δ

N

– N2

N R1

R1

R

379

303

CO2R R2

301

MgI2

RO2C CO2R

N O Ph

– PhCHO

N R2 R

303

Figure 3.117 Approaches to obtain azetidine derivatives 303 via formal addition of nitrene synthon to D–A cyclopropanes 1.

pathway. β-Styrylmalonates 443 are isomers of D–A cyclopropanes 1 formed through direct isomerization by opening the three-membered ring in a complex with a Lewis acid followed by proton migration. They can be generated directly in situ in the course of the reaction or can be obtained separately. At the moment, there is only one convenient way to obtain them, exactly from D–A cyclopropanes. Depending on the substituents, Me3SiOTf, Sn(OTf)2, or GaCl3 are used as Lewis acids for isomerization [244] [245]. In terms of the mechanism of the subsequent reactions with substrates, styrylmalonates 443 resemble D–A cyclopropanes 1 and are also activated due to complexation with Lewis acids at two ester groups, and often reacting as malonyl anion. The subsequent pathway of their reactions with substrates usually involves an ionic stepwise mechanism via formal cycloaddition or annulation at the C=C double bond of the β-styrylmalonate, although more complex cascade cyclization processes also occur (Figures 3.118 and 3.119). Not so many examples of reactions of D–A cyclopropanes that occur through the generation of β-styrylmalonates are known to date. In the study by Prof. Banerjee et al., cyclic chalconimines 444, 445 were used as traps for D–A cyclopropanes 1. The process was performed in the presence of MgI2 as the catalyst. It occurred as [4+2]-cycloaddition by the hetero-Diels–Alder reaction of intermediate β-styrylmalonates 443 generated in situ. The yields of end products 446, 447 were up to 86%; the reaction showed moderate diastereoselectivity. The process

Ar

CO2R

1

CO2R

CO2R

Lewis acid Isomerization in situ

Ar

Substrate

CO2R

443

(i) TMSOTf, PhCl, 130 °C (ii) Sn(OTf)2, conditions (iii) GaCl3, CH2Cl2, then Pyr

Figure 3.118 The type of reactivity of D–A cyclopropanes 1 realized via generation of isomeric styrylmalonates 443 as key intermediates.

107

108

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

Ar

CO2R

H

Ar

Processing

CO2R

– LA

III

β-Styrylmalonate

443

O

CO2R

Ar

1

CO2R

Ar

O

– H+

+ H+ OR

O

Complexation and ring opening

RO

O

LA

RO

OR Lewis acid

OR

LA

Ar – H+

II

1,3-Zwitterion

Substrate

O RO

LA

O

LA complex of the β-Styrylmalonate

I

Figure 3.119 General mechanistic features of styrylmalonate-type processes.

was successfully performed with a wide range of substrates [246]. The reaction using pre-synthesized β-styrylmalonates 443 reported by Novikov and Tomilov’s team, instead of D–A cyclopropanes 1, makes it possible to expand the range of substrates even further and use simple α,β-unsaturated imines 448 in this [4+2]-cycloaddition, while in the standard version the latter react with D–A cyclopropanes 1 by the [3+2]-cycloaddition type [247] (Figure 3.120). In 2013–2021, the teams of R. Sonawane, L. Wang, and I. Trushkov developed reactions of formal [3+2]-annulation and cycloaddition of D–A cyclopropanes 1 that also occurred via generation of β-styrylmalonates 443, in which D–A cyclopropanes acted as two-carbon synthons in ring formation. N-Benzylic sulfonamides 450 [248] and azomethine imines 372 [215] were used as 1,3-substrates to give indane 451 and diazabicyclooctane 452 derivatives, respectively. Moreover, I. Trushkov’s team developed a process of homo- and cross-[3+2]-cyclodimerization of D–A cyclopropanes 1 where one of the two molecules reacted as a styrylmalonate synthon, also to give indane derivatives [73]. Yet another type of process involves the reaction of β-styrylmalonates 443 with aromatic aldehydes 160, which has been R′

448 CO2R Ar

Lewis acid

Isomerization

PG

Ph

Ts N

CO2Et CO2Et

447

79% yield

444

445 Ph

MgI2 (20 mol%) 3,4-(MeO)2C6H3 Solvent Ph

CO2Me

N

CO2Me Ar2

Ph 449 Up to 95% Up to single diast.

N

N Ph

N PG R′

CO2R Sc(OTf)3 or Sn(OTf)2 (20–40 mol%) R′ = H, Ph

443

PG

PG

Ar2

Ar

n = 1,2

CO2R

1 CO2R

MgI2 (20 mol%) Solvent

Ar = aryl Ar1, Ar2 = aryl R = Me, Et PG = Ts, Ns, aryl-SO2

PG Ar1

RO2C CO2R

N

Ar n = 1,2

Ar1

446 Yields up to 86% dr up to 2:1

Figure 3.120 Formal [4+2]-cycloaddition reactions via generation of styrylmalonates.

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes RO2C

450 RO2C CO2R Ar1

RO2C Ar

CO2R

RO2C Ar1

451

CO2R

1

O

150

N

O

–

N

372

Ar R1

AlCl3 1,2-DCE

CO2R

Ar

Sn(OTf)2 PhCl

Ar2

R1

Ar2

443 CO2R

CO2R

NHTs

RO2C

+

N

Ar

N

Sc(OTf)3, DCE, 100 °C

CO2R

452

Figure 3.121 Formal [3+2]-cycloaddition/annulation reactions via generation of styrylmalonates 443.

intensely developed by Novikov and Tomilov’s team since 2016. Styrylmalonates 443 pre-synthesized from D–A cyclopropanes 1 are usually employed in this case to give noticeably higher product yields in comparison with generation in situ. However, as a rule, both variants do not change the type of the process. Reactions of this class are usually characterized by the utilization of GaCl3 as a Lewis acid and the occurrence of complex cascade reactions that give five- and six-membered ­ carbocycles and lactones 453–455, as well as polycyclic systems 456 [249–253] (Figure 3.121). The most typical representatives of this class of processes are shown in Figure 3.122.

3.7.5 GaCl3-Mediated Cycloaddition/Annulation Reactions via Generation of 1,2-Zwitterionic Intermediates The use of anhydrous gallium trichloride (GaCl3) makes it possible to realize a completely separate type of D–A reactivity of cyclopropanes 1, which is not observed for other Lewis acids. Due to a combination of a number of unique properties, gallium(III) leads to a rapid 1,2-hydride shift in the classical 1,3-zwitterionic

Ar2

O

Ar1

O

Ar1

CO2Me

453

GaCl3

Ar2

CO2Me

BF3·Et2O

443

+ Ar2

CO2Me

Ar2

CO2R

454

Ar1

Ar2 = 5-Ph-2-thienyl H

S

456

Ar2

Ar1 O O

CO2Me

GaCl3

Ar1 MeO2C

CO2Me

S

160

GaCl3

Ar2

O

H CO2Me

Ar1

CO2Me CO2Me

455

Figure 3.122 Various cascade cyclization reactions of the styrylmalonate 443 with aromatic aldehydes 160.

109

110

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes H CO2Me GaCl3

Ar

1

OMe

Ar

CO2Me

O MeO

I

O

OMe

1,2-Hydride shift Ar

GaCl3

II

O MeO

O

GaCl3 CO2Me

Ar

1,2-Zwitterionic intermediate

CO2Me

II C=C or C≡C Rʹ

Rʹ

R

R CO2Me

CO2Me Ar

CO2Me

458 [4+2]-Annulation

Electrophilic substitution (SEAr)

CO2Me

Ar

III

Z

Y

n = 0–2

X CO2Me CO2Me

Ar X

Y

Z n = 0–2

457 Formal [n+2]-cycloaddition

Figure 3.123 1,2-Zwitterionic reactivity type of D–A cyclopropanes in annulation reactions.

intermediates I, resulting in the formation of the main reactive 1,2-zwitterionic intermediate II as a gallium complex. This intermediate undergoes further reactions with various substrates, especially in the annulation reactions with multiple bonds. The 1,2-zwitterionic intermediate II is strongly stabilized by the coordinated gallium cation, in comparison to the previous 1,3-zwitterionic intermediate I. This fact explains such a type of reactivity of D–A cyclopropanes 1 in the presence of gallium salts, which is completely different from the classical chemistry of D–A cyclopropanes. This type of reactivity of D–A cyclopropanes is actively developed by the Novikov and Tomilov research group [220] [254–263] (Figure 3.123). This gallium complex II is highly reactive and has a very rich chemistry, including various types of transformations initiated by carbocation attack. One of the key reactions is formal cycloaddition and annulation with various substrates; in particular, reactions with alkenes and acetylenes are well studied. In these reactions, D–A cyclopropanes 1 act as sources of “even” 1,2- and 1,4-zwitterionic synthons instead of the classical “odd” 1,3-synthons. The two main types of such processes are realized, one with the cyclization at the malonyl center (products 457), and the other with the electrophilic attack at the aromatic substituent in D–A cyclopropane, leading to the formation of annulated products (458). One of the first developed processes was [4+2]-cyclodimerization of D–A cyclopropanes 1 in the presence of GaCl3, which proceeded with the formation of tetralin derivatives 459. Later, it turned out that this [4+2]-annulation reaction is common when using GaCl3. The process was extended to the reaction of D–A cyclopropanes 1 with various sources of multiple bonds: alkenes, acetylenes, dienes, and other substrates. The resulting products of these interactions were the derivatives of tetralin 460 or dihydronaphthalene 461, as well as more complex products based on them. Formal [n+2]-cycloaddition reactions with the cyclization at the malonyl carbon

3.7 Other Formal [n+m]-Cycloaddition and Annulation Processes

atom are more characteristic of other types of substrates, since, upon addition of a multiple C–C bond, it should lead to the formation of an unfavorable cyclobutane ring ([2+2]-cycloaddition). So, only one selective example is known in the reaction with bicyclobutylidene. Apparently, various allyl derivatives, azides, and also other sources of 1,3-dipoles react in this direction along the [3+2]-cycloaddition pathway. In addition, dienes also react in this direction – along the path of ionic [4+2]-cycloaddition, as well as diazo compounds – along the path of ionic [2+1]-cycloaddition. It should also be noted that a large number of more complex cascade processes occur based on these transformations [220, 254–263] (Figures 3.124, 3.125, and 3.126).

CO2Me

Ar 1

R1

CO2Me

R

GaCl3 (70 mol%)

Ar

1

CO2Me 109

[4+2]-Cyclodimerization

CO2Me

(1) GaCl3 2 (2) R

R4

R3

R5

(2) R2

R

CO2Me R3

104

CO2Me 459

2 461 R

R1

R2 CO2Me

GaBr3

CO2Me

R1

CO2Me Cl

R4

CO2Me

Ar

3

463

462

CO2Me

460

(1) GaCl3

Ar MeO2C

R5 R2 R3

R1

CO2Me

Ar

Ar

148

CO2Me

CO2Me

R2

464

CO2Me

Cl

Figure 3.124 [4+2]-Annulation of D–A cyclopropanes with multiple C-C bonds under the action of GaCl3.

380 OMe CO2Me

Ar

1

GaCl3

Ar

CO2Me

R2 MeO2C CO2Me

471

R2 R

O

MeO2C

R2 48

Ar

R3

1

470

R N3 378

3 469 R

MeO2C CO Me 2

R2 R1

465

466

GaCl3

R1

R1

CO2Me CO2Me

Ar

O MeO

Ar

RO2C CO2R

N2

MeO2C

Ar

MeO2C

CO2Me

Ar 467

N N N R 468

Figure 3.125 Various formal [n+2]-cycloadditions with gallium 1,2-zwitterionic intermediate.

111

112

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes R1 R1

CO2Me

Ar

109

CO2Me

CO2Me

(1) GaCl3

(2) R

2

R

Ar

3

48

CO2Me 2

R

R3

472

Figure 3.126 GaCl3-Mediated cascade of the double [4+2]-annulation reactions.

3.8 Cyclodimerization Reactions of D–A Cyclopropanes The dimerization of organic compounds is an important tool in organic synthesis. Dimerization processes can be used to obtain compounds with high molecular complexity in a single synthetic step. It should be noted that these processes often occur with high regio- and diastereoselectivity and yield high quantities of the final products. One of the trademarks of D–A cyclopropanes is their considerable liability to selective dimerization reactions in the absence of substrates if Lewis acids are present. This differs them from the majority of other cyclopropane molecules. D–A cyclopropanes quite readily enter a wide range of diverse and controlled dimerization processes and related reactions. These processes yield complex polyfunctional molecules in one stage from simple and accessible cyclopropanes, so dimerization proved to be very attractive for organic synthesis. Dimerization processes have been described in most detail for 2-aryl and 2-hetaryl-cyclopropane-1,1-dicarboxylates. Basic data on dimerization processes were obtained in parallel by Trushkov’s and Novikov and Tomilov’s scientific teams beginning in 2011 [240]. These processes were later developed in studies by other scientific teams [234, 264–266]. At the moment, at least 10 main selective dimerization pathways and over 2 dozen minor and specific reactions are known, and more than 20 scientific papers on this topic have been published. Historically, it may be considered that V. Huch et al. studied one of the first examples of dimerization of D–A cyclopropanes. In their works, reactions of [3+3]-cyclodimerization of cyclopropylketones 473 containing an indole substituent as a donor were developed in 2002. In this case, the presence of a donor indole substituent played a key role since electrophilic substitution with cyclization occurred at that substituent. The yields of annulated cycloadducts 474 were up to 83%. If activation was performed by SnCl4, the process often did not stop at the stage of dimers 474, which easily underwent further transformations [267] (Figure 3.127). A few years later, Liu and Montgomery discovered the process of [3+2]-cyclodimerization using simpler cyclopropyl ketones 10 as an example. The process occurred under metal complex catalysis with cyclooctadienyl nickel(0) complex and with the addition of NHC ligands. The yields of the final cyclopentanes 475 in these reactions were rather moderate, and only a few examples were presented [19] (Figure 3.128).

3.8 Cyclodimeriiation Reactions of D–A Cyclopropanes Ar O

O

X Ar

X

SnCl4 (1.5 equiv.) MeNO2

O

N PG

Ar

X

N PG

473

474

PG = Me, Bn; X = H, Br; Ar = Ph, PMP

N PG

Yields up to 83%

Figure 3.127 [3+3]-Cyclodimerization of (3-indolyl)cyclopropylketones 473.

O Ni(COD)2

Ar

R 10

NHC, t-BuOK Ti(O-iPr)4 PhMe, 90 °C

O

R = Me, H

Et

Ar

N+

Ph

R 475

O

N

Cl–

NHC

Figure 3.128 Ni(0)-Catalyzed [3+2]-cyclodimerization of some simple cyclopropylketones 10.

The main studies on the dimerization of D–A cyclopropanes were performed much later, beginning in 2011, independently by I. Trushkov’s team and by Novikov and Tomilov’s team. Trushkov et al. demonstrated an example of [3+2]-cyclodimerization of D–A cyclopropanes 1 catalyzed by Sn(II) and Sc(III) triflates that generated β-styrylmalonate, which acted as a trap of another cyclopropane molecule. The process occurred in good yields and showed moderate diastereoselectivity in the final cyclopentanes 476 [268]. Concurrently, Novikov, Tomilov et al. reported a different approach for performing the same type of dimerization, namely, in the presence of catalytic amounts of GaCl3 [269] (Figure 3.129). Later, a method was developed for dimerization of D–A cyclopropanes 1 in the presence of Sn(OTf)2, in which [3+2]-annulation of β-styrylmalonate formed in situ and the original D–A cyclopropane occurs. This reaction occurs with cyclopropanes containing donor groups at the aromatic ring or with heteroaromatic substituents such as thiophene or benzofuran. The yields of the final indanes 150 range from 42% to 87%. Dimerization protocols have been developed both in the RO2C Ar 1

CO2R CO2R

Ar = aryl, 2-thienyl R = Me, Et

Ar

LA (5–20 mol%) Solvent conditions

Ar

CO2R CO2R CO2R

476 Up to 80% yields dr up to 4:1

LA = Sn(OTf)2, Sc(OTf)3, GaCl3; Solvent = CH2Cl2, 1,2-DCE, PhCl

Figure 3.129 [3+2]-Cyclodimerization process of D–A cyclopropanes 1.

113

114

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Ts N R2 R1 MeO2C

Ar CO2Me CO2Me CO2Me 477

Yields up to 85%, single diast. Ar = substituted N-Ts-3-indolyl R1, R2 = H, F, Cl, Br, CN

CO2Me

Sn(OTf)2 CO2Me (10–30 mol%)

BF3·Et2O (200 mol%) 20–40 °C CH2Cl2

Ar

1

Solvent, Δ Solvent = MeNO2, PhCl

Ar = aryl with EDG groups, hetaryl

MeO2C Ar

Ar MeO2C

CO2Me

CO2Me 150

Yields up to 87% dr up to 4:1

Figure 3.130 [3+2]-Cyclodimerization of D–A cyclopropanes 1 with annulation at the aromatic ring.

standard homo-variant and in a cross-variant where two molecules of different D–A cyclopropanes can be selectively combined [73]. A selective protocol of this [3+2]-cyclodimerization in the presence of BF3·Et2O was developed for N-tosylprotected 3-indolyl D–A cyclopropanes, which makes it possible to obtain tetrahydrocyclopenta[b]indole derivatives 477 [270] (Figure 3.130). However, the main and most characteristic type of dimerization of D–A cyclopropanes 1 is the [3+3]-cyclization in the presence of various Lewis acids. These ­processes were thoroughly developed and studied in detail in a series of papers mainly published in 2011–2016. Researchers developed three more main selective pathways for dimerization reactions, namely, direct formal [3+3]-cycloaddition to give cyclohexane derivatives 478, as well as single or double annulation to the aromatic ring in D–A cyclopropanes. These reactions allowed them to obtain bi- and tricyclic systems 327, 328, and moreover, the dimerization direction could be controlled. Numerous diverse examples and reaction conditions were reported, and aspects of their diastereoselectivity were described. It should be noted separately that D–A cyclopropanes with heteroaromatic substituents have a considerable susceptibility to dimerization that opens access to efficient construction of complex annulated heterocyclic systems [183, 184, 240] (Figure 3.131). Based on the [3+3]-cyclodimerization of 2-phenylcyclopropanedicarboxylate 1, a protocol for deeper oligomerization realized under the action of the SnCl4·THF complex was developed. In this case, the degree of polymerization and the chain length can be controlled fairly well by the concentrations of the reagents. Moreover, the trimer and tetramer 479 can be obtained quite selectively (Figure 3.132) [269]. An interesting example of selective [4+3]-cyclodimerization of D–A cyclopropane 480 in the presence of the GaCl3·THF complex was also reported by Novikov, Tomilov et al., which resulted in a seven-membered annulated carbocycle 481 in moderate yields and with an equimolar ratio of diastereomers. A 1-naphthyl substituent was used as the donor moiety in cyclopropane. These processes also make it possible to easily obtain the [3+2]- and [3+3]-cyclodimerization products described above; therefore, the process requires careful selection of reaction conditions (Figure 3.133) [271]. The Trushkov’s team reported an interesting process of domino-ipso-cyclodimerization of D–A cyclopropanes 1 containing an indole or para-methoxyphenyl

3.8 Cyclodimeriiation Reactions of D–A Cyclopropanes RO2C

CO2R Ar

SnCl4, Ga(OTf)3, Sn(OTf)2

Ar SnCl4, Sn(OTf)2 Ga(OTf)3

CO2R CO2R

Ar

MeNO2

RO2C

CO2R 327 Yields up to 78% dr up to 95:5

MeNO2 CO2R CO2R

Ar

1 Ar = aryl, hetaryl R = Me, Et

RʹO N

Rʹ

OMe

CO2R CO2R

MeO RO2C RO2C

OMe

N

MeO

328 Yields up to 80% dr up to 95:5 CO2R CO2R

Ar

CO2Me

O

CO2Me CO2Me CO2Me

CO2Me CO2Me

CO2Me CO2Me

RʹO

20% (60 mol% Sn(OTf)2)

CO2Me

CO2Me

R1

MeO2C R3 N R2

MeO2C S N R3 CO2Me

R1

75–83% (SnCl4, GaCl3)

Ar 478 Yields up to 86%

O

OMe

Rʹ

58–86% (SnCl4, TiCl4)

CO2R

ORʹ

40–71% (SnCl4) CO2R CO2R OMe Rʹ

Rʹ

AlCl3, SnCl4, TiCl4 MeNO2

RʹO

Rʹ

RO2C RO2C

RO2C

RO2C RO2C

Selected examples of dimers and its conditions Rʹ

Ar

R2

S CO2Me CO2Me

MeO2C 70–79% (20 mol% Ga(OTf)3)

68% (30 mol% Sn(OTf)2)

Figure 3.131 Three main different types of the [3+3]-cyclodimerization of D–A cyclopropanes 1. E E

Ph

CO2Me 1

H

SnCl4·THF (200 mol%)

CO2Me

E E

20 °C, 12 h

Concentration-controlled oligomerization

Ph E = CO2Me

Figure 3.132 process.

n–2

479 n = 2 (80%), dr 3:1 n = 3 (42%), dr 9:3:3:1 n = 4–8 (35–2%)

Oligomerization of D–A cyclopropane 1 based on [3+3]-cyclodimerization

CO2Me CO2Me 480

Figure 3.133

Ph E E

GaCl3·THF CH2Cl2 (40%)

CO2Me CO2Me CO2Me CO2Me 481

Example of the [4+3]-cyclodimerization of D–A cyclopropanes 480.

115

116

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

moiety as the donor. Tin tetrachloride acts as the catalyst in the process, and moreover, substituted 2-indolylcyclopropane-1,1-dicarboxylates readily enter the reaction to give a tetracyclic octahydropentaleno[1,6a-b]indole skeleton. The yields of the final product 482 are up to 75% [183, 272]. Subsequently, a similar transformation resulting in the pentaleno[6a,1-a]naphthalene skeleton was implemented for a D–A cyclopropane-1,1-diester 1 with a 1-naphthyl substituent as the donor. The process was performed using 20 mol% GaCl3 with tetrasubstituted 1-pyrazoline (3,3-dimethylpyrazoline-3,3-dicarboxylate) as the organocatalyst. However, unlike the examples discussed above, the tetracyclic product 482 formed with inversed diastereoselectivity with respect to the aryl substituent in the five-membered ring [271] (Figure 3.134). Yet another interesting type of cascade dimerization of D–A cyclopropanes 1 involving one of the ester groups, which is encountered rather rarely for cyclopropanedicarboxylates, was also reported. Specific conditions of cooperative catalysis with GaCl3 with a tetrasubstituted 1-pyrazoline as the organocatalyst were also used for this purpose. The process occurs with high diastereoselectivity and yields dimers that are 2-oxabicyclo[3.3.0]octane derivatives 483 with an acetal moiety in rather good yields [273] (Figure 3.135).

MeO2C CO2Me Ar

1

CO2Me CO2Me

Lewis acid Solvent Ar

Ar

CO2Me CO2Me 482

Yields up to 75%

Ar = 3-indolyl, 4-MeOC6H4, 1-naphthyl

Solvent = MeNO2, CH2Cl2, C6H6; Lewis acid = SnCl4, GaCl3·pyrazoline R1 CO2Me CO2Me H R2

N

CO2Me CO2Me H CO2Me

MeO

CO2Me

H CO2Me

CO2Me

H CO2Me

CO2Me N H R2

R1

CO2Me CO2Me H

O

Figure 3.134 Cascade ipso-type dimerization of D–A cyclopropanes 1.

CO2Me CO2Me

Ar 1

GaCl3 (20 mol%) L (20 mol%)

MeO2C MeO2C

OMe O Ar

30 °C, CH2Cl2 Ar

CO2Me

L=

Me EtO2C N N

CO2Me Me

483 Yields up to 74% Single diast.

Figure 3.135 GaCl3/pyrazoline cooperative catalyzed dimerization of D–A cyclopropanes 1 involving CO2Me-group with the formation of the 2-oxabicyclo[3.3.0]octane skeleton 483.

3.8 Cyclodimeriiation Reactions of D–A Cyclopropanes

In terms of the mechanism, the main dimerization processes occur through the formation of zwitterionic intermediates that can be expressed most clearly as synthons I–III, which in turn react with each other to give dimers with various structures 150, 327, 328, 476, 478, 482. Therefore, it is quite convenient to characterize reactions of these types directly by their reaction products. Two pathways of [3+2]-cyclodimerization (with and without annulation), three pathways of [3+3]-cyclodimerization, and the ipso-type of cyclodimerization can be distinguished. Each of them may be the main pathway of reactions of the 1,3-zwitterionic intermediate (I) initially generated from D–A cyclopropane 1 in the presence of a Lewis acid. The generated 1,3-zwitterionic intermediate I dimerizes to intermediate IV, which further follows a number of possible transformation pathways, depending on the conditions and substituents used. Yet another pathway of dimerization involves the isomerization of a fraction of D–A cyclopropane 1 into β-styrylmalonate intermediate II followed by its reaction with 1,3-zwitterion I. It should be noted that the foundations of this classification and analysis of the mechanisms of DAC dimer formation were laid in the works by Trushkov et al [183, 268] (Figure 3.136). E

E

E E E

Ar E

Ar 150 Synthons II+III

E Ar

Ar 476 Synthons I+II

E

Coupling of intermediates I+II

CO2R

Ar

OR

Lewis acid δ+

Ar

CO2R

RO

1

δ-

LA

O

OR

OR Ar

O

RO

I

– H+

LA

O

II

O RO

O

LA

E

E Ar

Ar

O

E = CO2R

E

Ar

E I

Synthon III

E

E

E

E Ar

Synthons I+I

328

E

E Ar

327

E

E E

E Ar Ipso-attack

E

Synthons III+III

E E

E

Ar

Ar

1,6-Cyclization

Ar

E

478

Dimerization coupling

E

Ar

E E Synthons I+III

Electrophilic substitution (SEAr)

Ar IV

Ar

Ar

E E 482

Figure 3.136 General mechanism of the main types of dimerization reactions for 2-(het) aryl cyclopropanedicarboxylates 1 as an example.

117

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3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

3.9 Miscellaneous Reactions, Stepwise Cyclization Reactions, Cyclizations with Involvement of Functional Groups The chemistry of D–A cyclopropanes is very rich. Since cyclization reactions are one of its main parts, a huge number of types of cyclizations are known, which are rather difficult to reduce to any simple unified classification. The main processes of cycloaddition and annulation are discussed in detail in the previous sections. We will briefly look at the main examples and types of existing reactions with the formation of a new cycle in this section. These transformations include stepwise two-stage cyclization reactions, related processes, more complex cascade cyclizations, cyclizations involving functional groups in cyclopropane, and so on. Some of the transformations are discussed in more detail in other chapters by other authors.

3.9.1 Stepwise Cyclization Using Substrates with Two Nitrogen Atoms The reactions of coupling with substrates comprising a few nitrogen atoms followed by cyclization are of interest for creating nitrogen heterocycles with two or more nitrogen atoms. A few reactions of this kind are known, with substrates such as substituted ureas, hydrazines, and pyrimidines. They are performed in two stages or by a one-pot protocol. Prof. Banerjee et al. developed an approach to the [3+3]-coupling of standard D–A cyclopropanes 1 with benzyloxyureas 484 in successive stages, that is, cyclopropane opening and cyclization. The process was carried out both in two-stage and one-pot versions. The yields of the resulting substituted tetrahydropyrimidinones 486 reached 95% [274]. I. Trushkov’s team developed an approach to the synthesis of pyrimidoazepinetriones 489 by successive opening of the D–A ring in cyclopropane 1 followed by cyclization, first using scandium(III) triflate and then sodium methoxide. The process was implemented only with D–A cyclopropanes containing donor substituents in the aromatic moiety [275] (Figure 3.137). Somewhat earlier, a two-stage method was presented for synthesizing hexahydropyridazines 490 by the reaction of D–A cyclopropanes 1 with phenylhydrazine catalyzed by nickel(II) perchlorate with the initial addition of hydrazine followed by cyclization on the ester group. A similar process for the synthesis of tetrahydroindenopyridazinones 492 from spirocyclopropaninedenones 491 was also reported [276] [277]. H. U. Reissig et al. developed a method for synthesizing pyridazinones 494 by the reaction of activated cyclopropane 493 with substituted hydrazines. It is interesting that the starting cyclopropanes can have a perfluoroalkyl group as a substituent, which allows polyfluorinated pyridazinones to be obtained [278] (Figure 3.138).

ement H H N N BnO R1 484 O

CO2R CO2R

Ar

O R1

InCl3 (30 mol%) CH2Cl2, rt

1

N H

Ar

O

CO2R

N

CO2R

CH2Cl2, rt

OBn

485 Yields up to 94%

Ar = aryl, 2-furyl, styryl; R = Me, Et, i-Pr R1 = OBn, Bn, Ph, 4-NO2C6H4CH2O

R1

I2, DBU

N

N

RO2C RO2C

OBn Ar

486 Yields up to 95%

O R

N

O

N

Me 487 CO2Me CO2Me

Ar 1

Sc(OTf)3 (10 mol%) MeCN, Δ

Ar

O

NHR1 R

CO2Me CO2Me

N

O

(2) LiCl, H 2O DMSO, Δ

NHR1

N

(1) MeONa MeOH, Δ

Me

O

N N Me

N H

O

489 Yields up to 72%

488 Yields up to 97%

Ar = aryl, hetaryl, styryl R = H, Me; R1 = H, n-Bu

O Ar Me

Figure 3.137 Two-step cyclization reactions of BnO-urea 484 and pyrimidines 487.

Ar 1

CO2Me CO2Me

(1) PhNHNH 2 Ni(ClO4)2·6H2O CH2Cl2, Δ (2) NaBH3CN, AcOH, MeOH, Δ

Ar Ph

CO2Me N

N H

Ar = aryl, styryl O

491

O

490 Yields up to 88% dr up to 2:1

O

PhNHNH2 Sc(OTf)3, CH2Cl2 EDG

O

H EDG

(47–68%)

N N 492

Ar = aryl, alkenyl

Ph

R2 R1 EWG

TMSO R

2

R NH NH2 TsOH·H2O

493 R = H, CF3, n-C5F11, C6F5 R1 = H, CF3; EWG = CO2Me, CO2Et R2 = H, Ph

N R

N

O R1

494

Yields up to 90%

Figure 3.138 Cyclization reactions with hydrazines.

3.9.2 Some Other Cascade and Miscellaneous Formal Cycloaddition Reactions for Cyclopropanedicarboxylates A series of works by I. Trushkov’s team concerning the reactions of D–A cyclopropanes 1 with simple furan derivatives and the use of D–A cyclopropanes with a furyl substituent as the donor moiety appears to be very interesting. The high reactivity of

119

120

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

the furan ring makes it possible to perform cascade cyclizations with its participation and reactions with its subsequent opening. An interesting example of the cascade cycloaddition of a D–A cyclopropane 1 to 2,5-dimethylfuran 136 in the presence of SnCl4 to afford the tetracyclic system of hexahydro-3,5-methanocyclopenta[c] isochromene 495 was reported. Yet another tetracyclic annulated system, hexahydro-3H-5,8-methanocyclopenta[a]azulene 497, was obtained by the reaction of cyclopentadiene 403 with (5-methyl-2-furyl)cyclopropanedicarboxylate 496 with furan ring opening [66] [223]. A recent work by Borisov, Novikov, Tomilov et al. reported the reaction of furyl-2-carbaldehydes 498 with β-styrylmalonates 443 generated from D–A cyclopropanes 1 that occurred under the action of GaCl3. The process also occurs with the opening of the furan ring and is accompanied by the formation of cyclopentene derivatives 499 [252] (Figure 3.139). A study by P. Banerjee et al. presented an example of the reaction of D–A cyclopropanes 1 with other three-membered rings, namely, aziridines 306. The reaction does not occur as the expected formal [3+3]-cycloaddition of two generated 1,3-zwitterionic intermediates, but as a more complex cascade process to give furopyrrole derivatives 308. The process is catalyzed by MgI2 and involves one of the D–A ester groups in cyclopropane, which is rather a rare example [175]. Ghorai, Tiwari et al. developed an approach for synthesizing substituted cyclopentenes 502 and 503 by the domino-ring-opening-cyclization (DROC) protocol in reactions of D–A cyclopropanes 1. The reaction gives high yields of end products, and a wide range of cyclopropanes can be involved in the process. It is noteworthy that the introduction of substituted malonodinitriles 501 into such reactions resulted in regioisomeric cyclopentenones 503 in good yields and with high diastereoselectivity of the final products [279–281] (Figures 3.140 and 3.141).

Ar 1

136 Me

CO2Me CO2Me

O O

Ar Me MeO2C MeO2C

SnCl4, CH2Cl2 (71–76%)

Ar = 3,4,5-(MeO)3C6H2, 2-thienyl

Me

Me

495 O

Me

O

CO2Me CO2Me

Me

403 Yb(OTf)3, CH2Cl2

MeO2C

(63%)

496

MeO2C

497

O CO2Me CO2Me

Ar 1

Lewis acid

CO2Me CO2Me

Ar 443

498 O

CHO

O

Ar

GaCl3, CH2Cl2 MeO2C

CO2Me 499

Figure 3.139 Reactions of furane derivatives.

3.9 Miscellaneous Reactions, Stepwise Cycliiation Reactions, Cycliiations with Involvement Ts 306

N

Ar 1

CO2Et CO2Et

EtO2C CO Et 2 Ts OEt N O Ar1 EtO2C Ar 308 Yields up to 65%

CO2Et CO2Et

Ar1

MgI2 (20 mol%) MS, 1,2-DCE, rt

Ar, Ar1 = aryl

Figure 3.140 Cascade reaction of D–A cyclopropanes 1 with aziridines 306. R1 NC

R1

Ar

NH2

NC

CO2Me

503 Yields up to 86% dr up to 20:1

500

501 CN

Yb(OTf)3 (20 mol%) NaH, THF

CO2R CO2R

Ar 1

NC

CN

Yb(OTf)3 (20 mol%) NaH, THF

Ar = aryl, hetaryl, styryl; R = Me, Et R1 = Me, Bn, Ph, vinyl

NC Ar

NH2 CO2R CO2R

502 Yields up to 93%

Figure 3.141 Reactions with malonodinitriles 500, 501.

D. Werz et al. developed a protocol for benzoquinone 504 annulation using D–A cyclopropanes 1 in the presence of SnCl2 followed by oxidation of the product with manganese(IV) oxide. The yields of the final 9-hydroxy-4H-cyclopenta[b]naphthalen-4-one derivatives 505 that find use as new dyes were up to 88% [282]. Z. He et al. continued a study of the reactions of D–A cyclopropanes 506 with diazenes 507. It was shown that if an additional acceptor nitro group was incorporated into a D–A cyclopropane 506 and triphenylphosphine was present, a cascade reaction occurred with the conversion of one of the ester groups to give pyrazolines 508. The process gave high yields of the end products with good diastereoselectivity [283] (Figures 3.142 and 3.143). O

O

Ar 1

CO2Me CO2Me

(1) SnCl2 (2) DBN, MnO2

Reaction with naphthoquinone.

NO2

t-BuO2C

CO2Me R

CO2Me 506

507

N

N

CO2t-Bu CO2t-Bu

Ph3P (2.5 equiv.) CH2Cl2, rt

R = aryl, hetaryl, styryl, n-C6H13

Figure 3.143

CO2Me

OH 505

(88% yield)

Figure 3.142

Ar

504 O

R MeO2C t-BuO2C

N

N OMe

508 Yields up to 95%

Reaction with tert-butyl azadicarboxylate.

121

122

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

3.9.3 Formal Cycloaddition and Cyclization Reactions for 2-Aryl D–A Cyclopropanes Containing Active Substituent in Ortho-Position A number of works are known where 2-arylcyclopropanedicarboxylates substituted at the ortho-position were used as a reaction center. These reactions occurred as formal cycloaddition/annulation/cyclization. In fact, Mikhaylov, Ioffe et al. demonstrated an approach to the synthesis of cyclic nitronates 511 by C–C coupling of ortho-bromo substituted D–A cyclopropanes 509 and primary nitro compounds 510 catalyzed by Pd(0) salts. The reaction products, that is, cyclic annulated nitronates 511 obtained in up to 82% yields, were used in further transformations, including reactions of their cycloaddition (Figure 3.144) [284]. E. Budynina et al. studied the formal [4+2]-cycloaddition of alkenes 513 and D–A cyclopropanes 512 comprising an OH group at the ortho-position that acted as the C4-component. The process efficiently occurs in the presence of boron trifluoride etherate, and rather a wide range of alkenes enter the reaction. These D–A cyclopropanes act as sources of synthetic equivalents of ortho-quinone methides I that are very interesting in reactions of this kind. It appears that these D–A cyclopropanes can also be used in the same role in other reactions, but only this process that results in chromane derivatives is known to date (Figure 3.145) [285]. An acetylene moiety at the ortho-position is also used to expand the functional capabilities of 2-arylcyclopropanedicarboxylates. M. Kerr et al. reported a method for synthesizing triazole 516 derivatives by a tandem combination of the opening of D–A cyclopropane 515 and the click-coupling of azides comprising a triple bond [286]. K. Reddy et al. presented a method for synthesizing derivatives of isoquinolines 518 by a similar tandem reaction of the same ortho-acetylene containing cyclopropanes 517 with amines. The process is based on the opening of cyclopropane with amines, CO2Me CO2Me CO2Me

Ar Br

510

R

CO2Me

NO2

Pd(dba)2 (10 mol%) JohnPhos (20 mol%) Cs2CO3 (2 equiv.) 1,4-Dioxane

509

Ar = aryl R = Me, (CH2)2CO2Me, Et, CH2Bn, CH2PMP

O

Ar 511

N+

O–

R

Yields up to 82%

Figure 3.144 Formal [3+3]-annulation of ortho-bromo cyclopropanes 509 with nitro compounds 510. CO2Me CO2Me CO2Me Ar

OH

512

R1

R2

513 BF3·Et2O (1.5 equiv.) CH2Cl2, rt, 5 min

Ar = aryl with H, Cl, Br, MeO R1 = aryl, alkenyl, vinyl; R2 = H, Me, Ph

Ar O 514

MeO

CO2Me CO2Me

MeO2C R2 R1

Yields up to 74% dr up to 4:1

OH CO2Me

OH Ar

Ar 512

O I

Figure 3.145 Formal [4+2]-cycloaddition of ortho-OH substituted cyclopropanes 512 with alkenes 513.

3.9 Miscellaneous Reactions, Stepwise Cycliiation Reactions, Cycliiations with Involvement

CO2Me CO2H

515

N

R

N N

NaN3, NH4Cl MeOCH2CH2OH –H2O (10:1)

R

CO2Me 516

R = H, aryl, hetaryl, n-C4H9

Yields up to 80% R Ar1

CO2Me CO2Me

Ar1 517

R

R = aryl, n-C5H11; Ar, Ar1 = aryl

N

ArNH2 Ni(ClO4)2·6H2O (10 mol%) CuI (10 mol%) 1,2-DCE, Δ

Ar

MeO2C CO2Me 518 Yields up to 68%

Figure 3.146 Cyclization reactions of 2-aryl D–A cyclopropanes 515, 517 with acetylene fragment in ortho-position.

followed by cyclization on the triple bond, and requires double catalysis with Ni(II) and Cu(I)/Ag(I) salts. The reaction successfully occurs with donor substituents. Acceptor substituents in the amine and additional substituents in the D–A cyclopropane decrease the yield of the final products [287] (Figure 3.146).

3.9.4 Cyclization Reactions of D–A Cyclopropanes with Additional CHO Group in Donor Part The presence of a reactive group, in particular, an aldehyde group, in the donor part of D–A cyclopropane promotes various cyclization reactions. A study by J. Vicario presented a method for the interaction of DAC 519 with α,β- and β,γ-unsaturated compounds 89, 520 in the presence of NHC. The process proceeded as a formal [4+2]-cycloaddition with almost quantitative yields of the final products 521, 522 with high enantio- and diastereoselectivity [288] (Figure 3.147). R2 EtO2C

CO2Et

R3

R1 520 R3

O

CO2R

NHC (10 mol%) O (i-Pr)2NEt EtO2C 521 (20 mol%) Yields up to 85% CH2Cl2, 4 °C dr up to 20:1 ee up to 99%

89

CO2R

OHC 519

R = Me, Et, allyl, i-Pr, CH2-c-C6H11, (CH2)4OBn R1 = H, Me, OMe R2 = CO2Et, CO2t-Bu, CO2Bn, C(O)Ph R3 = aryl, hetaryl, alkyl PG = Boc, Fmoc, Cbz, Me, Ac

CO2R

R2

N PG

R1 O

NHC (10 mol%) (i-Pr)2NEt (20 mol%) CH2Cl2, rt

N PG

N

N BF4

N+ –

O 522

Yields up to 99% ee up to 99%

O NHC =

CO2R

RO2C

O

O

Mes

Figure 3.147 Cyclization reactions of D–A cyclopropanes 519 with Michael acceptors 89, 520.

123

124

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes O O Ar OHC 523

CO2 R CO2R

R = Me, Et, Bn, i-Pr Ar = aryl PG = Trt, Bn

O

O

N 524 PG NHC (20 mol%) Et3N (20 mol%) CHCl3, 35 °C, 24 h

NHC =

CO2R

O Ar N

O

N

N

CO2R

N+

BF4–

PG 525 Up to 83% yields dr up to 20:1 ee up to 99%

Ph

NO2

Figure 3.148 Cyclization reaction of D–A cyclopropanes 523 with isatin derivatives 524.

Y. Chi et al. developed a protocol for the annulation of isatine derivatives 524 with D–A cyclopropane 523, which have an aldehyde group in the donor part of the cyclopropane. The process successfully proceeded in the presence of NHC. The yields of the final product 525 were up to 83% [289] (Figure 3.148).

3.9.5 Miscellaneous Cyclizations with Phenols and Nitrogen-Containing Heterocycles In a number of works described below, unusual transformations of D–A cyclopropanes in reactions with phenols and nitrogen-containing heterocycles are presented. It should be noted that these transformations occur as cascades of ring-opening/ cyclization reactions. P. F. Xu et al. demonstrated an interaction of D–A cyclopropanes 526 with phenols 527, 528 containing donor groups. The process proceeds as a formal [4+2] annulation, with the cyclopropane acting as the C4 component. The process proceeded in the presence of Sc(OTf)3. The yields of the final product 529 reached 98%. The authors also successfully developed a protocol for the preparation of spiro-fused quinones 530 with 90% yields of the final products (Figure 3.149) [290]. The Liu work complements the information on [4+2]-annulation reactions in which cyclopropane 526 acts as a C4 component. They developed a protocol for the interaction of D–A cyclopropanes with nitrogen-containing heterocycles 531, 532. The process proceeded in the presence of p-TSA as the Bronsted acid. The yields of final products 533, 534 reached 99% in some cases [291]. J. Vicario et al. developed a regioselective method for the [4+2]-cyclocondensation of D–A cyclopropanes 526 and indoles 535. The process was catalyzed by OH

O Me

Me Ar

O R EWG

530 Yields up to 90%

Me

OH

Me 528

(1) Sn(OTf)2 (10 mol%) HFIP, 0 °C (2) Et3N, PhI(OAc)2

(EDG)2 EWG

Ar

R O 526

527 Sc(OTf)3 (10 mol%) HFIP, 0 °C to rt

(EDG)3

R EWG

Ar 529 Yields up to 98%

Ar = aryl; R = Me, n-C 5H11 EWG = CO2Me, CN, CO2 iPr EDG = Me, OMe, OH

Figure 3.149 Cyclization reactions of D–A cyclopropanes 526 with phenols.

ement Ar EWG

Ar

OMe

Ar

N 532 Me

Me N Me EtO2C

531

Me

p-TsOH (10 mol%) MeCN, 60 °C

Me

Me

Me N

R O 526

534 65% yield Ar = aryl R = Me, c-C3H5, aryl EWG = CO2Me, CO2Et, CO2Bn, H R1 = H, Me R2 = alkyl, aryl, Bn

R2

R2

Ar

R

533 Yields up to 99%

p-TsOH (10 mol%) MeCN, 60 °C

EWG

Ar

N R1

R1

Ar

Ar N

N 535 H (PhO)2P(O)NHTf (10 mol%) PhMe, 100 °C

R

1

R 536 Yields up to 94%

Figure 3.150 Examples of cyclization reactions of D–A cyclopropanes 526 with nitrogencontaining heterocycles.

(PhO)2P(O)NHTf as the Brønsted acid. The yields of the final product 536 reached 94% (Figure 3.150) [292].

3.9.6 Some Cyclization Reactions of 1,1-Dicyano Cyclopropanes The presence of reactive cyano groups in the acceptor part of D–A cyclopropanes makes it possible to carry out cascade transformations with various substrates. A study by Q. Fu and C. G. Yan et al demonstrated a method for synthesizing polysubstituted pyrroles 538 by the reaction of cyclopropane 537 and aromatic imines 160 in the presence of Co(ClO4)2. The yields of the final product 538 were up to 82% (Figure 3.151) [293]. An unusual example of cyclodimerization of D–A cyclopropanes 539 with nitrile groups was presented in a study by C. G. Yan. The process made it possible to obtain polysubstituted indolizine derivatives 540 in a single synthetic step, with good yields of the final products [264]. C. Wang et al. demonstrated a protocol for the annulation of D–A cyclopropanes 539 with thiourea 270 to form substituted pyridines 541. The process was catalyzed by potassium carbonate, and a wide range of starting substrates with aromatic substituents were involved in the reaction. The yields of the final products 541 reached 95% (Figure 3.152) [294]. Ar R

CN CN O2N

Ar1

Ar1 N

Co(ClO4)2 (20 mol%) THF, Δ

537 1

R = OMe, Me; Ar = aryl; Ar = aryl

CN

N

160

N R

NO2 Ar

538

Up to 82% yields

Figure 3.151 Cyclization reactions of 1,1-dicyano cyclopropanes 537 with aromatic imines 160.

125

126

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes Ar1 CN Ar

N

270 H2N

S NH2

Ar

541 Yields up to 95%

O

CN 539

CN

N

NC

Et3N

CN

K2CO3 DMF, 110 °C

NH2

NH

O

Ar1

Ar

0–10 °C Ar1 Cyclodimerization

Ar

1

Ar O 540 Yields up to 57%

Figure 3.152 Cascade transformations of 1,1-dicyano cyclopropanes 539.

3.9.7 Miscellaneous Cyclizations with Sulfur Reagents The use of sulfur-containing compounds in ring-opening/cyclization reactions of D–A cyclopropanes makes it possible to obtain a number of polysubstituted organosulfur compounds in a single synthetic step. The presence of a cyano group in the acceptor moiety of cyclopropane is necessary for providing these transformations. C. Wang et al. presented an example of [4+1]-annulation, in which cyclopropane 542 acts as a C4 component. The process proceeds in the presence of DBU as a base. The yields of the final polysubstituted thiophenes 543 were up to 94% [295]. C. G. Yan et al. carried out the Gewald reaction with cyclopropane 544, which made it possible to obtain a series of substituted aminothiophenes 545. The yields of the final thiophenes were up to 83% [296]. Sundaravelu and Sekar proposed a method for the synthesis of thioflavones 547 and thioflavotions 548 from D–A cyclopropanes 546 and xanthan in the presence of copper diacetate. It was possible to involve a wide range of D–A cyclopropanes in the process, both with donor and acceptor groups in the aromatic ring (Figure 3.153) [297]. The work of D. Gladow and H. U. Reissig demonstrated a method for the synthesis of substituted pyrroles 550 and thiophenes 551 from cyclopropanes 549 containing a perfluoroalkyl moiety. This process proceeded with high yields of products and could also be carried out as a one-pot reaction (Figure 3.154) [298].

CO2R

NC

Ar1

Ar 542

Ar

O

270 H2N

S NH2

Ar

or CS2 DBU (80 mol%) DMF, 115 °C, 24 h

Ar

S NH2

Ar1

CO2R 543 Yields up to 96% O

O Hal

546

S8, morpholine

S

DMF, 60 °C 544

EWG = CO2Et, CN

O 2N 545 Yields up to 83%

Figure 3.153 Reactions with sulfur reagents.

KS

KS

O

OEt

Ar

S Cu(OAc)2 (10 mol%) Na2S2O3 (2 equiv.) 547 DMSO, 110 °C Yields up to 99%

S

NH2

Ar

CO2R

S

CO2R

EWG EWG CN

O2N

CO2R

S OEt

Cu(OAc)2 (10 mol%) AcOH (2 equiv.) DMF, 110 °C

CO2R S

Ar 548 Yields up to 84%

Ar = aryl; R = Me, Et; Hal = I, Br

ement CO2Me

CO2Me F3C

S

CS2

551 62% yield

CO2Me

F3C

(1) LDA (2) MeI (3) Pyr, POCl3

SMe

RNCS

TMSO

549

F3C

(1) LDA (2) MeI (3) Pyr, POCl 3

SMe

N R

550 Yields up to 85%

R = aryl, Et, c-C3H5

Figure 3.154 Reaction of perfluoroalkyl-substituted cyclopropanes with sulfur reagents.

3.9.8 Cyclizations of Cyclopropanes Containing Carbonyl Group as an Acceptor with Amine Reagents The presence of a carbonyl group in the acceptor fragment of D–A cyclopropane makes it possible to carry out cascade ring-opening/cyclization reactions in a single synthetic step. S. France et al. developed an efficient protocol for the opening/cyclization of cyclopropane 552 in the presence of amines. This process utilizes a wide range of cyclopropanes and amines The yields of the final pyrrolines 553 were up to 96% [299]. The work of T. Yakura extended this approach to the ring-opening/cyclization of D–A cyclopropanes 554 in the presence of amines. Thus, cyclopropane with a cyclohexane-1,3-dione fragment as an acceptor was used. It should be noted that the process proceeded in the absence of a catalyst with excellent yields of pyrrolines 555 (Figure 3.155) [300]. D. Werz et al. presented a work devoted to the synthesis of pyrroles 557 and 558 from cyclopropanes 556. A wide range of amines were used in the reaction. Amines containing an acceptor fragment led to the formation of a mono-product 557, while the remaining amines yielded bis-polysubstituted pyrroles 558 [301] (Figure 3.156).

R2 R1

EWG

EDG

R

552 O

R2

R3–NH2

EWG

R–NH2

O

R N R3 553 Yields up to 96% R1

Ni(ClO4)2·6H2O (15 mol%) Solvent, Δ

EDG

EDG = aryl, n-Bu, TMSCH2 EWG = CO2Me, COMe R = Ph, Me, Et, 2-thienyl, OH R1 = H, Me; R2 = H, Me R3 = alkyl, alkenyl, alkynyl, Ph, Bn

Me

O

EDG

Me

554

Me

O

Me

THF, rt 555 R

N EDG

Yields up to 98%

EDG = aryl, n-Bu R = Bn, aryl, alkyl, H

Figure 3.155 Cascade transformations of carbonyl-containing cyclopropanes with amines.

R2 R1 O

R

R O

R1 O

556

N

R2–NH2 p-TsOH (5 mol%) Benzene, 80 °C

R = H, Me, Ph; R1 = alkyl, Ph, hetaryl R2 = aryl, SO2aryl

R O

R1

O

R1

557 Yields up to 69%

R2 N

+ R1 N R2

R1

R 558 Yields up to 81%

Figure 3.156 Cascade transformations of cyclopropanes 556 based on tetrahydrofuran ring with amines.

127

128

3 Cycloaddition and Annulation Reactions of Donor–Acceptor Cyclopropanes

O

O O S

O S NH

560 N 562

Ar

R1

CO2Et 563 Yields up to 86%

DBU (2 equiv.) 2-MeTHF, 80 °C or Cs2CO3 (1.5 equiv.) MeCN, 80 °C

O

559

R1

X

Cl

Ar R1

CO2R

O O S N

DBU (2 equiv.) 2-MeTHF 70 °C

Ar = aryl, hetaryl R = Et, t-Bu R1 = H, Me, Et, Ph, n-C7H15, n-C5H11OPh X = H, Me, MeO, Br, Cl

O

Ar

X R1 561 Yields up to 74%

CO2R

Figure 3.157 Reaction of cyclopropane 559 with sulfonylketenimines. NH2 Ar

Ar

n = 0,1 n = 0,1

CO2Et

Ar1 O

CO2Et 564

565

R

R

Sc(OTf)3 (10 mol%) PhMe, Δ

Ar = aryl, hetaryl; Ar1 = Ph, 4-MeC6H4 R = H, Br, NO2

R N 566 Yields up to 70%

Figure 3.158 Reaction of cyclopropanes 564 with 1-naphthylamines 565.

3.9.9

Miscellaneous Reactions

There are a number of data in the literature on unusual transformations of D–A cyclopropanes, which are difficult to attribute to specific classes of transformations. Thus, S. Samantha et al. developed an approach for synthesizing cyclopentachromenes 561 and thiazepines 563 by annulation of D–A cyclopropanes 559, which contain chlorine as a substituent in the cyclopropane ring with sulfonylketenimines. It should be noted that the ring size of the starting sulfonylketenimine defines the direction of the reaction. Thus, if six-membered ketenimine 560 undergoes the reaction, then products 561 are selectively formed in 74% yields. In the case of using five-membered ketenimines 562, the reaction proceeds with the formation of products 563 in 86% yields [302] (Figure 3.157). Thangamani and Srinivasan presented a method for the preparation of dibenzacridins 566 by the reaction of substituted 1-naphthylamines 565 and cyclopropanes 564, which act as a source of the C1 fragment. The process proceeded in the presence of scandium(III) triflate with good yields of the final acridines 566 [303] (Figure 3.158).

Acknowledgments The authors are grateful to the Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences for the opportunity to conduct this analytical research and for the support of the Russian Science Foundation (grant No. 22-13-00418).

References

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34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66

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281 Saha, A., Bhattacharyya, A., Talukdar, R., and Ghorai, M.K. (2018). J. Org. Chem. 83: 2131–2144. 282 Luecht, A., Sobottka, S., Patalag, L.J. et al. (2019). Chem. – Eur.J. 25: 10359– 10365. 283 Yang, C., Liu, W., He, Z., and He, Z. (2016). Org. Lett. 18: 4936–4939. 284 Mikhaylov, A.A., Dilman, A.D., Novikov, R.A. et al. (2016). Tetrahedron Lett. 57: 11–14. 285 Ivanov, K.L., Bezzubov, S.I., Melnikov, M.Y., and Budynina, E.M. (2018). Org. Biomol. Chem. 16: 3897–3909. 286 Flisar, M.E., Emmett, M.R., and Kerr, M. (2014). Synlett 25: 2297–2300. 287 Unnava, R., Chahal, K., and Reddy, K.R. (2021). Org. Biomol. Chem. 19: 6025–6029. 288 Prieto, L., Sanchez-Diez, E., Uria, U. et al. (2017). Adv. Synth. Catal. 359: 1678–1683. 289 Nie, G., Huang, X., Wang, Z. et al. (2021). Org. Chem. Front. 8: 5105–5111. 290 Luo, Y.-C., Ma, H., Hu, X.-Q., and Xu, P.-F. (2017). J. Org. Chem. 82: 1013–1023. 291 Liu, C., Zhou, L., Huang, W. et al. (2016). Tetrahedron 72: 563–570. 292 Ortega, A., Uria, U., Tejero, T. et al. (2021). Org. Lett. 23: 2326–2331. 293 Fu, Q. and Yan, C.-G. (2011). Tetrahedron Lett. 52: 4497–4500. 294 Wang, S., Xie, Z., Li, M., and Wang, C. (2020). ChemistrySelect 5: 6011–6015. 295 Su, Z., Qian, S., Xue, S., and Wang, C. (2017). Org. Biomol. Chem. 15: 7878–7886. 296 Han, Y., Tang, W.-Q., and Yan, C.-G. (2014). Tetrahedron Lett. 55: 1441–1443. 297 Sundaravelu, N. and Sekar, G. (2019). Org. Lett. 21: 6648–6652. 298 Gladow, D. and Reissig, H.-U. (2014). J. Org. Chem. 79: 4492–4502. 299 Martin, M.C., Patil, D.V., and France, S. (2014). J. Org. Chem. 79: 3030–3039. 300 Nambu, H., Fukumoto, M., Hirota, W., and Yakura, T. (2014). Org. Lett. 16: 4012–4015. 301 Kaschel, J., Schneider, T.F., Kratzert, D. et al. (2013). Org. Biomol. Chem. 11: 3494–3509. 302 Prakash, M., Lodhi, R., and Samanta, S. (2021). J. Org. Chem. 86: 6721–6733. 303 Thangamani, M. and Srinivasan, K. (2021). J. Org. Chem. 86: 1172–1177.

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4 Activation of Donor–Acceptor Cyclopropanes under Covalent Organocatalysis: Enamine, Iminium, NHC, Phosphine and Tertiary Amine Catalysis Efraim Reyes, Liher Prieto, Luisa Carrillo, Uxue Uria, and Jose L. Vicario University of the Basque Country (UPV/EHU), Department of Organic and Inorganic Chemistry, Bº Sarriena s/n. 48940 Leioa, P.O. Box 644, 48080, Bilbao, Spain

CHAPTER MENU 4.1 4.2 4.3 4.4 4.5 4.6

Introduction, 139 Secondary Amine Catalysis: Enamine Activation, 141 Secondary Amine Catalysis: Iminium Ion Activation, 144 NHC Catalysis: Activation Through Breslow Intermediates, 148 Phosphine or Tertiary Amine Catalysis, 157 Conclusion, 162 Acknowledgments, 162 References, 162

4.1 Introduction The advent of organocatalysis has released new opportunities in organic synthesis with enormous potential to unveil new reactivity patterns or to implement known reactions under cheaper or safer conditions [1]. The ability of small organic molecules that do not contain a metal center in their active site to activate a given starting material toward a subsequent transformation has become a well-established area in asymmetric catalysis, which often provides a complementary approach to synthetic problems not easily faced through enzymatic and metal catalysis. In particular, those reactions in which the substrate and the catalyst interact through reversible covalent bonding (also referred to as covalent organocatalysis) constitute a particular class among organocatalytic reactions in which the strong nature of the substrate–catalyst interaction greatly enhances the probability to tune the electronic ­ and steric properties of the activated starting material. This is of evident relevance when trying to implement enantioselective variants of a given reaction, given the enhanced ability of the catalyst to transfer stereochemical information through Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

140

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis

such a strongly bonded intermediate. For this reason, it is not surprising to find that the use of organocatalysts that interact through covalent bonding with the substrate has gained a great deal of popularity when developing catalytic and enantioselective versions of important reactions, including those involving donor–acceptor cyclopropanes (DAC) or acceptor cyclopropanes as substrates [2]. The extraordinary synthetic versatility of this simple concept has been recognized very recently, with the Nobel Prize in Chemistry to B. List and D. W. C. MacMillan for their pioneering contributions to this area [3]. The different possibilities for the activation of a DAC through covalent organocatalysis are illustrated in Scheme 4.1. At first hand, primary and secondary amines, together with N-heterocyclic carbenes (NHCs), belong to the privileged class of covalent organocatalysts due to their ability to condense in a reversible manner with carbonyl compounds. The first ones generate an active azomethine intermediate after interacting with an aldehyde or ketone substrate I or II to form either an electron-donating enamine moiety or an electron-withdrawing iminium ion species, respectively. When combined with the appropriate substitution pattern at the starting cyclopropane derivative, a catalytically generated DAC is generated with the potential to undergo a subsequent chemical transformation in which the aminocatalyst has been involved in the activation of the starting material and also ­provides the opportunity for asymmetric induction if a chiral aminocatalyst is employed [4]. On the other hand, N-heterocyclic carbenes can form a dienol intermediate (also known as Breslow intermediate) or an acyl azolium enolate species upon condensation with substrates I and II, respectively, also generating either an electron-donor or an electron-withdrawing moiety that, in combination with the

R

N H

R R or

EDG

Secondary amine catalysis

I

R

O

II R

N

Donor

Acceptor

Acceptor Iminium ion

Acceptor

Donor

O N

EWG

N

EWG

R N

R′ EDG

N-Heterocyclic carbene (NHC) catalysis

R′

EWG

R R

N

N

O

N

Donor

Donor

Acceptor

Breslow intermediate

Enamine

N

EDG

OH

Acyl azolium enolate

Phosphine or tertiary amine catalysis R

R R

R

X EWG Acceptor

X=P, N

R X

EWG

X

EWG

Betaine intermediate

Scheme 4.1 The different possibilities for the activation of cyclopropanes through covalent organocatalysis.

4.2 Secondary Amine Catalysiss: Enamine Activation

correct substitution pattern at the cyclopropane, again leads to an activated intermediate able to undergo a variety of transformations [5]. In a different context, the ability of phosphines and tertiary amines to participate as nucleophilic catalysts that are able to interact with an electrophilic cyclopropane and therefore form a betaine intermediate is an appealing possibility for the activation of this type of cyclopropanes through covalent interaction with an organocatalyst [6]. In the following sections, the most relevant examples reported in the literature that imply any of these activation manifolds will be discussed following the classification shown in Scheme 4.1.

4.2 Secondary Amine Catalysis: Enamine Activation The generation of enamine species in cyclopropylacetaldehyde-containing substrates through the condensation of a primary or secondary amine activates the substrate for a cyclopropane ring-opening event to take place. This was pioneered by Jørgensen and coworkers, who initially studied the system with the help of computational tools. Indeed, calculations showed that methods for the formation of the enamine intermediate also implied an increase in C–C bond lengths in several cyclopropane substrates through the formation of the proposed cyclopropylenamine intermediate in comparison with the starting cyclopropylacetaldehyde or its corresponding iminium ion (Figure 4.1) [7]. In particular, the presence of such a catalytically generated electron-donating substituent (the enamine) in combination with electron-withdrawing substituents (R1 and R2 = CO2Me) led to the formation of a DAC in which an increase in the bond length of the C–C sigma bond within the cyclopropane moiety was maximized with respect to activated cyclopropylenamine intermediates with other substituents of different nature. Moreover, calculations also showed the presence of a predominant conformation in which the π-orbital of the enamine and the σ*C–C orbital of the cyclopropyl moiety lied in a parallel arrangement, thus favoring a hypothetical C–C bond cleavage event.

C1–C2 bond length (Å)

N

O 1

N 1

R1 R2

2

R1 = R2 = H

1.506

R1 = H; R2 = CO2Me

1.512

R1 = R2 = CO2Me

1.517

1

R1 R2

2

R1 R2

2

N

1.509

MeO2C

1.508

1.530

MeO2C σ* H

1.522

1.559

1.500

π

Figure 4.1 Selected bond distances in several cyclopropyl-containing species and the preferred conformation of enamine containing cyclopropanedicarboxylate.

141

142

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis 1. Ph Ph OTMS 3a (10 mol%), PhCO2H (10 mol%), CHCl3, −20 °C N H

R2

O +

R3 O

CO2R1 CO2R1

X R4 2

(±)-1

2. Ph3PCHCO2Et, CHCl3, rt

CO2R1

R3

R2

R4

X

CO2Et

Yield: 55–86% d.r.: 5.1:1 to 13.9:1 e.e: 75–97%

O

4 (14 examples)

Enamine activation

3a

CO2R1

Michael/Michael (formal [2+2])

3a R4

N

R1O2C R1O2C

Ph Ph OTMS

Ring opening

N

Ph Ph OTMS

2

R1O2HC

CO2R1

X O

Dienamine formation

Iminium ion formation

R3

N

Ph Ph OTMS

R2

R1O2C

CO2R1

R1 = Me, Et R2 = COMe, COPh, CO2Me, P(O)O2Et R3 = H, Me, MeO, Cl, Br, I R4 = H, Me, Br X = NH, NBoc, O

Scheme 4.2 Asymmetric formal [2+2] cycloaddition between cyclopropylacetaldehyde dicarboxylates and alkylideneoxindoles or alkylidenebenzofuranones.

With this preliminary information in hand, the same group demonstrated the concept by reacting cyclopropylacetaldehyde dicarboxylates 1 with alkylideneoxindoles and alkylidenebenzofuranones in the presence of chiral secondary amine catalyst 3a (the so-called Jorgensen–Hayashi catalyst) [8], leading to the formation of sterically congested and densely functionalized cyclobutanes 4 (Scheme 4.2) [7]. The reaction consists of the initially projected ring-opening event of the activated cyclopropylenamine intermediate, leading to an α,β-unsaturated iminium ion intermediate that subsequently equilibrates with a tautomeric nucleophilic dienamine species. This participates in a formal [2+2] cycloaddition step with the highly electrophilic alkylideneoxindole or benzofuranone reagent in a sequence that is mechanistically explained as a Michael/intramolecular Michael cascade process that generates the cyclobutane scaffold [9]. The final hydrolysis of the cyclobutylenamine intermediate regenerates the catalyst and releases the final product, which was isolated in high yield. In addition, the ability of the chiral catalyst 3a to block one of the diastereotopic faces of the dienamine intermediate by steric shielding as well as to achieve efficient control over the conformational preferences of the dienamine scaffold turns into an overall process that takes place with high diastereo- and enantioselectivity. The same type of cyclopropylacetaldehydes 1 has been employed in the direct synthesis of dihydroquinolines 6 through reaction with o-aminobenzaldehydes 5 (Scheme 4.3) [10]. In this particular case, the authors made use of the electrophilic

4.2 Secondary Amine Catalysiss: Enamine Activation Ph Ph OTMS 3a (10 mol%), 4-NO2C6H4CO2H (20 mol%) N H

O CHO 1

CO2R CO2R1

Yield: 69–99% e.e: 79–97%

Ring Ph opening Ph 5 OTMS Iminium ion formation

CHO N

CO2R1

6 (15 examples)

H

O 7

3a

Enamine activation

N

R1O2C R1O2C

N H 1 R O2C

CHCl3, rt

NH2 5

(±)-1 3a

+ R2

CHO one-pot R2

R2

O R2

H

N

Ph Ph OTMS

aza-Michael/ Aldol condensation

NH2

R1O2C

CO2R1

R1 = Me, Et, Bn R2 = H, 3-Me, 4-Me, 5-Me, 4-CF3, 3-MeO, 4-MeO, 4-F, 4-Cl, 5-Cl, 4-Br, 5-Br, benzo[d]

Scheme 4.3 Asymmetric synthesis of dihydroisoquibnolines through cascade ring-opening/aza-Michael reaction/intramolecular aldol condensation.

nature of the unsaturated iminium ion formed after the ring-opening event to initiate a cascade process that involved an initial aza-Michael-type reaction of the aniline moiety followed by intramolecular aldol condensation [11]. As in the previous example, the catalyst was highly effective in providing high stereocontrol to the overall process. Moreover, the dihydroisoquinoline compounds obtained could be easily transformed into synthetically useful pyrroloisoquinolines 7 through a threestep set of reactions that took place in a one-pot manner. The group of Christmann has also combined the principle of vinilogy [12] with this specific reactivity profile and has developed a particular variant of the Cope rearrangement using cyclopropanes 7 as substrates (Scheme 4.4) [13]. Condensation of the amine catalyst 3a with the enolizable conjugated enal substituent of the cyclopropane substrate led to the formation of a dienamine intermediate that spontaneously underwent the [3.3] sigmatropic rearrangement with the participation of the vinyl substituent at the C-2 position, allowing the preparation of differently substituted cycloheptadienes 8 in good yields and excellent cis-diastereoselectivity. Interestingly, only cis-configured cyclopropane substrates 8 were found to be reactive in this transformation, which is consistent with the proposed sigmatropic rearrangement process. This finding, together with the fact that the reaction was found to be completely enantiospecific, ruled out the possibility of a ring-opening/ring closure alternative mechanism to participate. In fact, the cycloheptadiene products 9 were isolated in all cases as racemic materials, even though the reaction proceeded with the participation of a chiral catalyst such as 3a. Moreover, when an enantioerniched starting material was employed, its enantiomeric purity was preserved in the final product, demonstrating the enantiospecific nature of the process and further supporting the mechanistic proposal.

143

144

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis Ph Ph OTMS 3a (20 mol%) N H

H

O R

CH2Cl2, rt

H

(±)-8 3a

Dienamine activation

9 (19 examples)

Ph Ph OTMS H

R

R

Yield: 29–96% cis:trans from 2:1 to >20:1 e.e. 0% (98% starting from (+)-8 >99% e.e.)

Ph Ph OTMS N

O

Cope rearrangement H

H

N

3a R

H

R = H, Ph, 4-MeC6H4, 4-(t-Bu)C6H4, 2-CF3C6H4, 3-CF3C6H4, 4-CF3C6H4, 4-NO2C6H4, 4-MeOC6H4, 2-FC6H4, 3-FC6H4, 4-FC6H4, 3-ClC6H4, 4-ClC6H4, tiophen-2-yl, CO2Et, CN, Ph(CH2)2, Ph(CH2)2CH=CH

Scheme 4.4 Diastereoselective divinylcyclopropane-cycloheptadiene rearrangement using under dienamine activation.

4.3 Secondary Amine Catalysis: Iminium Ion Activation The first evidence of the possibility of performing a cyclopropane ring-opening reaction through iminium activation was demonstrated by the Wang group in 2007 [14]. During their research directed toward the organocatalytic preparation of differently substituted cyclopropanes such as 12 from enals 10 and dimethyl bromomalonate, they observed the formation of byproduct 13, which resulted to be formed after a ring-opening event from the cyclopropanecarbaldehyde products 12. This reaction was further studied in detail and optimized for the selective formation of the ring-opening product, which could be obtained quantitatively and as a single diastereoisomer by careful selection of the base employed. The proposed mechanism consisted of the activation of the formylcyclopropane 12 through iminium ion formation by its condensation with the aminocatalyst 3a, which subsequently had to undergo α-deprotonation by the Brønsted base additive incorporated into the reaction. This would generate a cyclopropylidenamine intermediate with the ability to undergo the ring-opening reaction through a retro-Michael-type process. This proposal was supported by a set of experiments that, for example, showed that the yield of this ring-opening product 13 was drastically decreased when either the catalyst 3a or the Bronsted base (NaOAc) were not present in the media and also when p-nitrocinnamaldehyde (which can compete with 12 to condense with catalyst 3a) was added to the reaction mixture (Scheme 4.5). After this previous example that advanced the possibility for formylcyclopropanes to undergo a ring-opening event through iminium ion activation, several other

4.3 Secondary Amine Catalysiss: Iminium Ion Activation

N H

O Br

+

NO2

10

CO2Me

3a (10 mol%), Et3N (1.1 equiv.)

CO2Me

CH2Cl2, rt

CHO O2N (±)-12 Iminium ion activation

MeO2C CO2Me CHO +

Ph Ph N H OTMS (±)-3a (10 mol%), NaOAc (2 equiv.)

O 2N

N

Scheme 4.5 activation.

MeO2C

CO2Me

13

N O 2N

CO2Me

CHO

CDCl3, rt Yield: 100% Z:E >19:1

H

Ph TMSO Ph

MeO2C 13

MeO2C CO2Me

AcO

O 2N

12

MeO2C CO2Me

O2N

CHO

O2N

Yield: 88% 12:13: 17:1

11

MeO2C CO2Me

(±)-3a

Ph Ph OTMS

Ph TMSO Ph

retro-Michael

3a

The ring-opening reaction of cyclopropanecarbaldehydes under iminium ion

examples appeared in which the increase of the polarization of the cyclopropane C–C bond upon formation of a cyclopropyliminium ion intermediate was explored to develop a variety of transformations. In fact, the formation of the iminium ion increases the ability of the formylcyclopropane to participate as an electrophile in ring-opening reactions triggered by the attack of an external nucleophile on the polarized cyclopropane C–C bond. The first example of this type of reactivity was described by the Wang group in 2009, who studied the ring-opening reaction of 2-substituted formylcyclopropanes 14 with benzenothiols 15 using (S)-proline 16 as a catalyst [15]. This reaction was carried out under very mild reaction conditions and led to the formation of the homo-Michael-type adduct 17 in low to moderate yields. Despite the use of an enantiopure catalyst such as proline, in all cases, racemic materials were obtained. Importantly, functionalized o-mercaptosalicylaldehydes 18 could also be employed through this reaction scheme, playing the role of bifunctional nucleophilic/electrophilic reagents able to be involved in a cascade process toward the synthesis of benzo[b]thiepines 19. In this case, the enamine generated after the ring-opening step undergoes intramolecular aldol condensation to provide the final products in moderate to good yields. This reaction was also found to be enantiospecific, as observed when an enantioenriched cyclopropane was used as the starting material. As a consequence, the ring-opening event should have to take place through an SN2-type reaction on the electrophilic activated carbon atom of the polarized cyclopropyliminium ion intermediate (Scheme 4.6).

145

146

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis

CO2H N H 16 (40 mol%), 4 Å MS

HS R1

CHO

+

CHO

+

18 16

R2

R1 SH

CHO

THF, rt

R2

OHC

(±)-14

17 (16 examples)

16 (40 mol%), 4 Å MS

HS R1

R2

Yield: 15–61%

15

CHO S

THF, rt

R2

(±)-14

R1

S

Yield: 34–56% e.e. 0% (88% e.e. from (+)-14 92% e.e.)

19 (11 examples)

Iminium ion activation

Aldol condensation

N

N

O CO2H

CHO

R1

homo-Michael

R2

CO2H S

R1

16

R1 = H, Ph, 4-MeOC6H4, 4-FC6H4 R2 = H, Me, F, Cl

Scheme 4.6 Ring-opening reaction of formylcyclopropanes promoted by benzenethiol derivatives under iminium ion activation.

The first enantioselective version of this type of cyclopropane ring-opening reaction that converted an achiral formylcyclopropane starting material into an enantioenriched addition product was described two years later by the group of Gilmour (Scheme 4.7, top) [16]. In this case, they took advantage of the use of ­meso-2,3-disubstituted formylcyclopropanes 20 for performing the homo-Michaeltype reaction using chloride as the nucleophile that initiates the ring-opening process. Because of the initial addition, the overall process takes place with concomitant desymmetrization of the starting material, in which the chiral imidazolidinone catalyst 23a is involved in the stereodifferentiation of the two prostereogenic electrophilic carbon atoms of the formylcyclopropyliminium ion intermediate. In addition, an electrophilic chlorine source such as perchlorinated quinone 22 was also incorporated into the reaction scheme for the electrophilic trapping of the intermediate enamine that is formed after the ring-opening event. The overall chloride anion-initiated ring-opening reaction/α-clorination cascade process delivered a series of β-branched α,γdichlorinated aliphatic aldehydes 24 with high yields and diastereo- and enantioselectivities. An extension of this methodology was presented by the group of Werz, who reported the direct chlorosulfenylation of the same type of meso-formylcyclopropanes 20, this time using a variety of arylsulfenyl chlorides 25 as external electrophiles engaged in the reaction with the enamine intermediate generated after the chlorideinitiated nucleophilic ring-opening step (Scheme 4.7, bottom) [17]. In this case,

4.3 Secondary Amine Catalysiss: Iminium Ion Activation Me

O N

Me

O

CHO + R

R

Me

N H

20

Cl Me

Cl

Cl Cl

Cl

Cl

+

Me N Me H 23a·TFA (20 mol%) Bn

CDCl3, rt

Cl

Yield: 67–72% d.r.: 86:14 to >95:20:1 e.e.: 66–96%

3b

Ar OSiPh Me 2 Ar O H H N O O R1

R1

R2

Ar Ar

Ar OSiPh Me 2 Ar O H N H O R1

R1

R1

O R2

O

CHO R1

28 (24 examples) 3b

Ar OSiPh Me 2 Ar N O R2

R1 R1

O

O R2

R1 = Et, Ph or R1-R1 = (CH2)3, (CH2)4, (CH2)5, benzo[c](CH2)4, -CH2CH=CHCH2R2 = Me, ClCH2, furan-2-yl, Ph, 2-MeC6H4, 4-MeC6H4, 2,4,6-(Me)3C6H2, 2,4,6-(i-Pr)3C6H2, 2-(NO2)C6H4, 4-(NO2)C6H4, 2-(OH)C6H4, 2,6-(MeO)2C6H3, 3-MeOC6H4, 2-FC6H4, 4-FC6H4, Bn

Scheme 4.8 Asymmetric desymmetrizative ring-opening reaction of formylcyclopropanes promoted by carboxylates under iminium ion activation.

intermediate (kinetically a single step), that forms the subsequent enamine species with complete control in both the enantioselectivity and diastereoselectivity under catalyst control that is able to differentiate between the two prostereogenic C2 and C3 atoms of the cyclopropane scaffold. The applicability of this methodology as a tool in synthesis has been demonstrated with the total synthesis of speciosin H (Scheme 4.9), which is a metabolite isolated from the basidiomycete fungus Hexagonia speciosa that grows in subtropical areas of China [19]. The initial enantioselective ring-opening step took place with excellent yield and enantiocontrol and at a synthetically useful gram-scale. This ringopening adduct was converted into the target natural product in an additional 6 steps using standard and reliable reactions.

4.4 NHC Catalysis: Activation Through Breslow Intermediates The generation of the Breslow intermediate upon condensation of an N-heterocyclic carbene with a formylcyclopropane converts the electron-withdrawing formyl group into an electron-donating enaminol moiety. In this sense, a cyclopropane containing both an electron-withdrawing group and a formyl substituent (an acceptor/

4.4

Ar Ar OSiPh2Me Ar: 3,5-(CF3)2C6H3 ent-3b (20 mol%) N H

CHO H

HC Catalysiss: Activation hrough Bresloow Intermediates

O

H +

Ar OH (Ar=2-OHC6H4)

28

2. LAH

O

O

93%

Ar O

31 m-CPBA, NaHCO3 CH2Cl2, r.t.

2. concd. HCl Acetone/H2O

H

Speciosin H

82%

33

Ar

O

1. LiBH4, THF, −30 °C

O

O

Neat, r.t.

93% d.r. 1.6:1

O

Ar

O

O

pTSA

O

30

HO

72%

O

H

Yield: 94% d.r.: >20:1 e.e.: 92%

1. Ph3P=CMe2, THF, r.t.

HO

O

CHCl3, 50 °C or

29

OH

Ar

O

O O

O O

32 (59% isolated yield)

Scheme 4.9 Application of the carboxylate-initiated enantioselective ring-opening of formylcyclopropanes to the total synthesis of (-)-speciosin H.

acceptor cyclopropane) leads to the formation of an activated DAC in which the polarization of the C–C bond has been significantly increased, therefore favoring a ring-opening event that generates an acyclic zwitterionic intermediate (Scheme 4.10).

CHO A-A cyclopropane

EWG X R N

Base

R N

N R

N R

NHC R

N

EWG OH

D-A cyclopropane

N R

Breslow intermediate R

γ

α N R

OH

EWG

R

N

R Nu

EWG O

R N

Nu− γ N R

EWG

E

O

N R

O

EWG

E+

E

N

E+ E

N N R

R

α EWG

O

N N R

Nu−

E Nu

EWG O

R N

N R

Scheme 4.10 General reactivity of formylcyclopropanes under NHC activation.

149

150

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis

This zwitterion can now react through the γ-carbon with an electrophile or equilibrate to the corresponding acyl azolium enolate via proton transfer, the latter showing a nucleophilic character at the α-position. Once these intermediates react with an external electrophile, an acyl azolium intermediate is generated that subsequently has to react with a nucleophile (either inter- or intramolecularly) in order to enable catalyst turnover. As a consequence, this reactivity platform is very suitable for the formation of polifunctionalized molecules through cascade or domino processes, provided that all selectivity issues are conveniently controlled. The first use of N-heterocyclic carbenes in this chemistry was described by the group of Bode in 2006 (Scheme 4.11, top) [20]. In this study, chiral cyclopropanes 34 were converted into α,β-disubstituted δ-oxo carboxylic acid derivatives through activation with the carbene derived from triazolium salt 35 in the presence of alcohols, water, or thiols. In this particular case, the zwitterionic enolate/acyl azolium ringopening intermediate underwent protonation assisted by the Brønsted acidic pronucleophile, the latter being subsequently engaged in the catalyst turnover step that generates the carboxylic acid moiety (ester, thioester, or carboxylate). The reaction was also found to be enantioconservative, enabling the formation of products 36 when enantioenriched cyclopropanes were used as starting materials with no loss of optical purity. The scope of this reaction was further extended to substrates that contain different types of electron-withdrawing groups, such as 2-nitrocyclopropyl carbaldehyde [20, 21] or 2,4-dinitrophenylcyclopropyl carbaldehyde [22], which demonstrated to be compatible with this methodology, observing similar performance. Importantly, primary or secondary aliphatic and aromatic amines can also be used as nucleophilic reagents in this transformation, enabling the synthesis of α,β-disubstituted δ-oxoamides in a single step from the same cyclopropanes 34 (Scheme 4.11, bottom) [23]. As an alternative, when the same substrates 34 are reacted with the same catalyst derived but in the absence of any external nucleophile, the ring-opened intermediate can undergo recyclization, with the enolate moiety acting as an O-nucleophile involved in catalyst turnover. This turns out to be a very efficient method to convert cyclopropanes 34 into the corresponding lactones 38 under similar reaction conditions as those employed in Scheme 4.11 (Scheme 4.12, top) [24]. The generated lactones are obtained in good to excellent yields; it is also possible to obtain them in an enantioenriched form when enantiopure starting materials are used. In a similar way, formylcyclopropane 39 containing two carbonyl acceptor groups can also be converted into the corresponding lactone 41 under similar reaction conditions, in this case using imidazolium-derived catalyst 40a (Scheme 4.12, bottom) [25]. Using salicylicaldehydes 42 in combination with cyclopropanecarbaldehydes 39, the Wang group has developed an efficient protocol for the preparation of coumarin2-ones 43 in a single operation (Scheme 4.13) [26]. In this case, after the ring-opened zwitterionic intermediate undergoes protonation, catalyst turnover takes place through the participation of the salicylaldehyde phenol moiety as a nucleophile. A final intramolecular Knoevenagel condensation accounts for the formation of the cumarine final adducts. This transformation was studied for a variety of cyclopropanes 39 containing different substituents at the ketoester moiety in combination with a family of

4.4

HC Catalysiss: Activation hrough Bresloow Intermediates N N Mes Cl 35 (5 mol%), DBU (20 mol%) N

R2 R3 CHO

R1

+

Nu H

R3 R1

THF, rt

O

Nu R2

O

O

Yield: 81−99% 34

36 (11 examples) 35

35 + DBU

Nu H R2 R3 N

R1 O

OH

R3

N

N Mes

O

R2

Nu H

N

R1 O

N

N Mes

R3

N

R1 O

R2

O

N N Mes

Breslow intermediate R1 = t-Bu, Ph, NMe(OMe), OEt R2 = H, Me, n-Pr, CH3CH=CH, Ph or R1-R2 = (CH2)2 R3 = H, Me Nu-H = MeOH, H2O, C12H25SH N N R2 R3 CHO

R1 O

R4 +

N R5 H

N Mes Cl

35 (5 mol%), DBU (20 mol%) Imidazole (1.1 equiv.) THF, rt

R3

R4

R1

N O

R2

R5

O

Yield: 54–99% 34

37 (10 examples)

R1 = t-Bu, Ph, OEt R2 = H, Me, Ph R3 = H, Me R4-NH-R5 = BnNH2, n-C8H17NH2, BnONH2, PhNH2, NH2-Phe-Ot-Bu, piperidine

Scheme 4.11 Cyclopropane ring-opening reaction promoted by an NHC and an external nucleophile.

substituted salicylaldehydes 42, obtaining good yields in almost all cases, which demonstrates the wide scope of the reaction. An extension of this methodology was presented by the same group using, in this case, 2-indolinecarbaldehydes 44a as the functionalized pronucleophile engaged in the catalyst turnover step (Scheme 4.14) [26]. This reaction, when applied to differently substituted indoles and cyclopropanecarbaldehydes 39, allowed the preparation of a wide family of pyrrolo[1,2-a]indol-3-ones 45 in good to moderate yields.

151

152

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis N N

35 (5 mol%), DBU (30 mol%), 4 Å MS

R2 R1

N Mes BF4 O O

Dioxane, 65 °C

CHO O

R2

Yield: 30−92%

R1

38 (11 examples)

34

35

35 + DBU

R2 N R1 OH

O

N

N Mes

N R1 O

R2

OH

N

N Mes

N R1 O

R2

O

N N Mes

Breslow intermediate R1 = t-Bu, Ph, 4-MeC6H4, 4-MeOC6H4, 4-BrC6H4 R2 = H, Me, n-Pr, Ph, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4

Mes N O

40a (10 mol%), DBU (20 mol%),

O

Me

OEt CHO 39

Cl N Mes

THF, 55 °C Yield: 72%

O O Me CO2Et 41

Scheme 4.12 Conversion of formylcyclopropanes 34 and 39 into δ-lactones through NHC catalysis.

Optimization of the reaction conditions indicated that bezimidazolium precatalyst 40b was the most effective one for this particular case, performing much better than the original imidazolium precatalyst 40a. 3-Indolinecarbaldehydes 44b bearing a chlorine atom at C-2 have also been employed as bifunctional reagents able to engage in a similar cascade process when reacting with formylcyclopropanes 39 under similar reaction conditions (Scheme 4.15) [27]. In this particular case, the acyl azolium intermediate formed after the ring-opening event reacted with the NH group of the indolinecarbaldehyde reagent, forming the corresponding amide and releasing the NHC catalyst. Next, intramolecular formal nucleophilic aromatic substitution between the malonate moiety and the 2-chloroindole site (being proposed to occur through conjugate addition/elimination) took place to form the final adduct 46 in moderate to good yields. This reaction involved the use of modified 3-phenyltriazolium salt 40c as a precatalyst that performed much better than the benzimidazolium salt 40b used in the previous reaction with simple indolinecarbaldehydes.

4.4

HC Catalysiss: Activation hrough Bresloow Intermediates Cl N Mes

Mes N O

O

R1

CHO OR2

+

R3 OH

CHO

CO2R2 R3

THF, 55 °C

O

Yield: 51–99%

42

39

40a (20 mol%), DABCO (30 mol%), DBU (70 mol%) O

COR1

43 (14 examples) Knoevenagel

38a + DBU

38a

O O R1

OR2 Mes N OH

R2O

O Mes

N

R1 N Mes

O

42 H+

OH

O Mes

R2O

N Mes

O

O

N Mes

N

R1 OH R3

CHO

Breslow intermediate R1 = OMe, OEt, Oi-Pr, Me R2 = Me, Et, i-Pr R3 = H, 5-NO2, 3-Me, 3-MeO, 4-MeO, 5-MeO, 3-OCF3, 3-F, 5-F, 5-Cl, 5-Br

Scheme 4.13 Reaction of cyclopropanecarbaldehydes and salicilaldehydes under NHC catalysis. Me N

O

O R3 OR2 +

R1

CHO 39

CHO N H 44a

I N Me 40b (40 mol%), DBU (1 equiv.) 4 Å MS Toluene, 60−70 °C Yield: 28–62%

R3

N

COR1

O

CO2R2

45 (9 examples)

R1 = OMe, OEt, Oi-Pr R2 = Me, Et, i-Pr R3 = H, 5-Me, 5-Et, 5-i-Pr, 5-MeO, 5-Cl

Scheme 4.14 Reaction of cyclopropanecarbaldehydes and indolinecarbaldehydes under NHC catalysis.

Recently, our group has disclosed the potential use of chiral NHC in this chemistry that could enable the use of racemic formylcyclopropanes 39 as starting materials, leading to enantioenriched final products. In particular, chiral triazolium salt 48a or its enantiomer was employed as a precatalyst in the reaction between 39 and alkylideneoxindoles or β,γ-unsaturated α-oxoesters for the enantioselective synthesis of pyranoindolones 49 and pyranones 51, respectively (Scheme 4.16) [28].

153

154

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis Ph ClO4 N Ph

Ph N O

CHO

O OR2 + R3

R1

40c (40 mol%), DBU (2 equiv.)

Cl

39

R3

Toluene, rt

N H 44b

CHO

CHO COR1 CO2R2 N O

Yield: 36−76%

46 (13 examples)

40c DBU

R 2O

- Cl

O

Ph

Ph N

R1 O

OH

N Ph

44b 40c DBU

R2O

O

CHO

Cl

R1

R3 N

O

O

R3

CHO Cl COR1 CO2R2 N O

Ring opened intermediate R1 = OMe, OEt, Oi-Pr R2 = Me, Et, i-Pr R3 = H, 5-Me, 7-Me, 4,6-Me2, 5-Et, 5-i-Pr, 5-MeO, 5-Cl, 6-Cl, 5-Br, 5-I

Scheme 4.15 Reaction of formylcyclopropanes and 2-chloroindolinecarbaldehydes under NHC catalysis.

A subsequent report studied the mechanism of this transformation in detail, confirming the initial proposal (Scheme 4.17) [29]. Thus, the reaction takes place after the condensation of cyclopropane 39 condenses with the carbene catalyst derived from 48a, generating the Breslow intermediate that is responsible for the cyclopropane ring-opening reaction. In this sense, ELF analysis indicates that this ringopening reaction alleviates the high electron density between the two contiguous atoms at cyclopropane. Afterwards, hydrogen shift occurs from the malonate moiety to the enaminol site, generating an enolate, the last acting as a dienophile in an hetero Diels–Alder reaction under inverse electron demand with the alkylideneoxindole or the β,γ-unsaturated α-oxoester reagents, which participate as oxodienes. A final α-elimination has to take place in order to generate the free carbene catalyst and the final adducts. In a different approach, 2-acetylcyclopropanecarbaldehydes 52 have been used in enantioselective cascade reactions under chiral NHC activation, in this case being involved as a C4 component in a [4+2] cyclocondensation reaction with highly electrophilic sulfonimines such as 53 (Scheme 4.18) [30]. In this transformation, after the cyclopropane ring-opening event, the formed enolate undergoes an intermolecular Mannich reaction with imine 53, followed by cyclization through the reaction of the imide moiety with the acyl azolium site, which enables catalyst turnover. The reaction provides a family of benzoisothiazolo[2,3-a]pyridin-7-one 5,5-dioxides 54 in good yields and high disastereo- and enantioselectivities. The authors also demonstrate that the reaction involves a DYKAT-type process in which the diastereomeric purity of the starting material 52 does not affect isomer composition of 54.

4.4

HC Catalysiss: Activation hrough Bresloow Intermediates H O

N BF4 N Mes

N H O

R4

O

R1

48a (10 mol%), i-Pr2NEt (20 mol%)

3

+

OR2

R

N R5

CHO 39

47

O

R1CO R4

R3

CH2Cl2, rt Yield: 6–99% d.r.: >20:1 e.e.: 91–>99%

N R5

O

CO2R2

O

49 (16 examples)

R1 = OMe, OEt, Oi-Pr, OAllyl, OCH2c-C6H11, O(CH2)4OBn R2 = Me, Et, i-Pr, Allyl, CH2c-C6H11, (CH2)4OBn R3 = H, 5-Me, 5-MeO R4 = CO2Et, CO2t-Bu, CO2Bn, COPh R5 = Boc, Fmoc, Cbz, Me, Ac H O N H O

O

1

OR2

R

CHO 36

+

ent-48a (10 mol%), i-Pr2NEt (20 mol%)

O R3

CO2

50

N BF4 N Mes

R4

CH2Cl2, 4 °C Yield: 58–85% d.r.: 2:1–>20:1 e.e.: 97–>99%

R4 CO2R2 R2O2C

O

O

COR1

51 (15 examples)

R1 = OEt R2 = Et R3 = Me, i-Pr, PhCH2CH2, BnOCH2, Ph, 2-MeC6H4, 3-MeC6H4, 4-MeC6H4, 4-MeOC6H4, 3,4-OCH2O-C6H3, 4-FC6H4, 2-furyl, 2-thienyl R4 = Me, Et

Scheme 4.16 Reaction of formylcyclopropanes with alkylideneoxindoles or β,γunsaturated α-oxoesters under chiral NHC catalysis for the enantioselective synthesis of δ-lactones.

Additional remarkable features are the fact that the chiral catalyst is able to exert an efficient facial and simple selectivity control despite the fact that it is located somewhat far away from the reaction site. In addition, it is also able to control the face selectivity in the protonation of the enol moiety, which also generates an additional stereogenic center if this position of the starting material is also substituted. Cyclopropanes 55 have been employed in a photo/NHC co-catalyzed reaction directed to the synthesis of γ-substituted-α,β-unsaturated esters by the group of Ye (Scheme 4.19) [31]. This reaction combines the formation of an activated acyclic dienol-type Breslow intermediate after the ring-opening of the cyclobutane substrate with the generation of a malonyl radical species from α-substituted dialkylbromomalonates 56 upon activation of the latter by Ru(bpy)32+ by light irradiation in

155

156

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis H O N N

N H

BF4 Mes EtO2C EtO2C

48a O

i-Pr2NEt

O

EtO

OEt

H O

CHO 39 H O N H

N N

N H

O N Boc 49

Mes H O

N N Mes

N H

HO EtO2C

H O N H

CO2Et

O CO2Et

N N Mes

Boc N

H O N H

HO CO2Et

N Boc

N N Mes O

CO2Et

CO2Et CO2Et

N N Mes

O

CO2Et

O Boc N

EtO2C

O

CO2Et CO2Et CO2Et

O

47

Scheme 4.17 Mechanism proposed for reaction of formylcyclopropanes 39 with alkylideneoxindoles catalyzed by 48a.

the photoredox cycle. Radical addition to the nucleophilic Breslow intermediate generates a radical-enolate intermediate, which is reduced by the Ru2+ species to generate an acyl azolium species and regenerates the photoredox catalyst. The reaction of the former with an alcohol incorporated into the reaction scheme enables the turnover of the carbene catalyst and releases the final product 57. The reaction is remarkably wide in scope, tolerating a wide variety of substitution patterns at both the bromomalonate reagent and the alcohol additive, showing good to excellent yields in most of the cases. The enantioselective version has also been studied using different chiral NHC catalysts, but observing low enantioselectivities. Cyclopropylacetaldehydes bearing two electron-withdrawing groups, such as 58, are another type of cyclopropyl substrates that have been evaluated as starting materials for promoting a cascade reaction initiated by ring-opening under NHC

4.5 Phosphine or ertiary Amine Catalysis H O N H

N N

Ar

BF4

R1

2

H

R CHO

+

R3

Ar: 2,6,6-Cl3C6H2 48b (20 mol%), K2CO3 (20 mol%), 4 Å MS

O O S N

O 52

R3

THF, 25 °C

CO2R4

Yield: 54−88% d.r.: 3:1– >20:1 e.e: 80–>99%

53

O O S N

R2

R4O2C O R1 54 (27 examples)

48b + K2CO3

48b

Ar R1

H O

O

R2

R2

N N

OH

H

N

O H

O

Ar

R2

N N

OH

H

N

53 O H Mannich

R1

Breslow intermediate

O R1 R4O2C

Ar

N N

H O N S O O

N

O H

R3

R1 = thienyl, Ph, 4-(CF3)C6H4, 4-(NO2)C6H4, 4-MeC6H4, 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 2-FC6H4, 4-FC6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4, 3-BrC6H4, 4-BrC6H4, 4-IC6H4 R2 = H, Me, Et, 4-(NO2)C6H4CH2 R3 = H, 5-Me, 5-i-Pr, 5-t-Bu, 7-CF3, 5-MeO, 5-F, 7-F, 5-Cl, 7-Cl, bezo[e] R4 = Me, Et

Scheme 4.18 Reaction of 2-acylcyclopropanecarbaldehydes with sulfonimines under chiral NHC catalysis.

catalysis (Scheme 4.20) [32]. In this particular case, a ring-opening event takes place from a cyclopropylmethylenaminol Breslow intermediate that undergoes intramolecular nucleophilic addition to the electrophilic cyclopropane moiety, generating a cyclopropanol intermediate facilitated by the formation of a stable malonate-type enolate. Proton shift generates an alcoxide anion that undergoes a second spontaneous ring-opening, generating a homoenolate-type enol species, which is the one reacting with the isatin electrophile 59 through 1,2-addition followed by intramolecular reaction to release the catalyst and to generate the spirocyclic lactone moiety. The reaction proceeded generally with moderate to excellent yields and good stereoselectivity for a wide variety of isatin reagents employed using modified chiral triazolium salt 48c as the most effective precatalyst.

4.5 Phosphine or Tertiary Amine Catalysis As mentioned earlier, a Lewis base can act as a nucleophilic catalyst that triggers the ring-opening event on a cyclopropane substrate with an electrophilic character. In particular, cyclopropanes with two electron-withdrawing substituents are highly reactive substrates for activation with a tertiary amine or a phosphine. A good

157

158

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis H O N N

N H

Mes

BF4

EtO2C

CO2Et

+

EtO2C

(±)-48a (10 mol%), Ru(bpy)3(PF6)2 (20 mol%), CsOAc (2 equiv.) R2OH (2 equiv.)

CO2Et

55

Yield: 55−95%

56

CO2Et

EtO2C

Ar

N N

OH

Ar

CO2Et EtO2C

O

EtO2C

Blue LED, DCE, 25 °C

Br R1

CHO

H

H

O H

EtO2C OH +

R2

55

EtO2C

R1

CHO

EtO2C

H

N

O H

CO2Et R1

Ru(bpy)3+2 Blue LED [*Ru(bpy)32+] EtO2C

CO2Et

CO2Et Ar CO2Et N N O

EtO2C

CO2Et CO2Et

57

N

N N O H

R1

57 (21 examples)

Breslow intermediate

N

CO2R2

EtO2C

EtO2C Ru(bpy)33+

R1

Ru(bpy)32+

CO2Et Ar CO2Et N N

EtO2C O

H

N

O H

Ru(bpy)33+

CO2Et

Br R1 56 R1 = Me, n-Pr, n-Bu, i-Bu, Allyl, EtO2CCH=CHCH2, Bn, 4-(Bpin)C6H4CH2, 2-MeC6H4CH2, 4-MeC6H4CH2, 4-(NO2)C6H4CH2, 3-ClC6H4CH2, 4-BrC6H4CH2, 2-NpCH2 R2 = Me, Et, n-Pr, CF3CH2, c-C3H5, c-C4H7, Cl(CH2)2CH2, CH2=CHCH2CH2

Scheme 4.19 Ring-opening reaction of cyclopropyl acrylaldehydes and subsequent reaction with malonyl radicals under NHC/photoredox catalysis.

example of this behavior is shown in Scheme 4.21, in which electrophilic cyclopropanes 61 have been used as starting materials for performing a Cloke–Wilson rearrangement catalyzed by DABCO (Scheme 4.21) [33]. Experimental data together with additional computational information [34] have demonstrated that the mechanism of the reaction involves the addition of DABCO to the electrophilic C-2 site of the cyclopropane, generating a zwitterionic enolate (that could be isolated) that subsequently underwent cyclization to provide the final dihydrofurane products 62. Surprisingly, the reaction was not found to be enantiospecific since enantioenriched cyclopropanes delivered racemic products, which was interpreted in terms of possible racemization processes occurring due to the need for high temperatures and a remarkable high amount of DABCO for the reaction to take place.

4.5 Phosphine or ertiary Amine Catalysis H O N N

N H

Ph

BF4 NO2 O R1O2C

CO2R1 CHO

R2

+

O N R3

58

59

CO2R1 R1O

Ph

N N

2C

OH

CO2R1

Ph

R1O2C O

H

N

R2

CO2R1

N R3 60 (18 examples)

N N

OH

H

60

N

CO2R1 CHO 58

CO2R1 Ph N N

R1O2C R2

N R3

N N H

R1O2C

O H

Breslow intermediate O H

CO2R1

O

Yield: 37–83% d.r.: 5:1–>20:1 e.e.: 74−98%

N

CO2R1

O

CH2Cl2, 35 °C

Ph

R1O2C

O

48c (20 mol%), Et3N (20 mol%)

O O

O

H

N

O H

O

O H

Ph R1O2C R1O2C

R2

N N

OH

H

N

O H

O 59

N R3

R1 = Me, Et, i-Pr, Bn R2 = 5-Me, 5-NO2, 5-MeO, 6-MeO, 4,6-F2, 5-F, 5,6-F2, 6-F, 5-Cl, 6-Cl, 4-Br, 5-Br, 6-Br, 5-I R3 = Bn, Trt

Scheme 4.20 NHC catalyzed ring-opening reaction of cyclopropyl acetaldehydes.

Taking advantage of the manifold depicted in Scheme 4.21, the same group has extended this reactivity to the incorporation of an external electrophilic alkene 65 able to react with the zwitterionic enolate formed after the ring-opening event (Scheme 4.22) [35]. In this case, catalyst release took place with the participation of an amide incorporated at one of the electron-withdrawing substituents of the electrophilic cyclopropane reagent 63, leading to the formation of γ-lactam 66 as the final product of the reaction. As an alternative possibility, a Michael acceptor was incorporated as one of the electron-withdrawing substituents that activate the electrophilic cyclopropane reagent 67 (Scheme 4.23) [36]. In this type of substrate, DABCO first had to undergo conjugate addition to the Michael acceptor site, and it was the enolate moiety that triggered the ring-opening event in an intramolecular fashion with the participation of the oxygen as the nucleophile. Subsequent ring closure, as in the standard

159

160

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis O

O

R2

DABCO (50 mol%)

R1

R2

DMSO, 120 °C

R3

R1

Yield: 42−99%

61

62 (25 examples)

DABCO

DABCO

O

O

O δ

R1

R3

O

R1 R3

R2 R3 δ

R1

O δ

R2

R2

O 3

R

δ

N N

N N

O

N N

R1 = Me, Ph, 4-MeC6H4, 4-MeOC6H4 R2 = Me, Ph, 4-MeC6H4, 4-MeOC6H4, OEt, NHPh R3 = H, Me, CH2=CH, Ph, 4-MeOC6H4, 4-ClC6H4

Scheme 4.21 DABCO catalyzed Cloke–Wislon rearrangement of electrophilic cyclopropanes.

O

O

R1

NHR2

64

+

DABCO (20 mol%) EWG

MeCN, 60 °C Yield: 61–97%

65

R3

R1

O

O

N R2 66 (15 examples)

DABCO O

DABCO O

R1

NHR2 N N

EWG 65

O

O

R1 EWG

O NHR2

N N

O

R1 EWG

NR2 N N

R1 = Me, Ph R2 = Ph, 4-MeC6H4, 2,4-Me2C6H3, 2-(NO2)C6H4, 4-MeOC6H4, 2-ClC6H4, 4-ClC6H4, 2-Cl-4-MeOC6H3, 2-pyridyl, 1-naphthyl R3 = CN, CO2Et, CO2n-Bu, CO2t-Bu, SO2Ph, CONMe2

Scheme 4.22 DABCO-catalyzed cyclopropane ring-opening/Michael/cyclization cascade reaction.

Cloke–Wilson-type rearrangement already shown in Scheme 4.21, delivered the final dihydrofurane products 68. Finally, the use of electrophilic vinylcyclpropanes 69 in combination with phosphines as catalysts produces cyclohepenones 70 as rearrangement products in high yields (Scheme 4.24) [37]. This transformation started with the nucleophilic

4.5 Phosphine or ertiary Amine Catalysis O

O

R2

DABCO (20 mol%)

R1

NHR2

DMSO, 110 °C

R3

R1

Yield: 43−94%

67

68 (15 examples)

DABCO

DABCO

N N R

R3

O

O

N N

O

1

NHR

R3 O

R1

2

R3

N N

O

R1

R3

NHR2

O

O

NHR2

R1 = 2-thienyl, 2-furyl, Ph, 4-MeC6H4, 3-(NO2)C6H4, 4-MeOC6H4, 3,4-(OCH2O)C6H3, 2-ClC6H4, 4-ClC6H4, 4-pyridyl R2 = Bn, 4-MeC6H4CH2, 4-MeOC6H4CH2, 2-ClC6H4CH2, 4-ClC6H4CH2 R3 = H, Me

Scheme 4.23 DABCO catalyzed ring-opening reaction of enoylcyclopropanes.

ring-opening reaction of the cyclopropane 69, triggered by the vinylogous addition of the phosphine to the terminal position of the olefin, and generated a zwitterionic enolate. This subsequently had to equilibrate to a second, less stable enolate, the second undergoing intramolecular SN2’ type displacement, which is preferred to a disfavored 5-endo-trig cyclization from the initially generated and more stable enolate. In fact, both enolates coexist in the reaction, as observed by the authors by 31 P-NMR. DFT studies have also supported this mechanism [38]. O

O

R1

PBu3 (20 mol%)

R2 R4 R3

Toluene, 110 °C Yield: 47−90% d.r.: 1.5:1–3.5:1

69

R2

R4 R3 70 (21 examples)

PBu3

O R1

PBu3 O

O R

R4 R3

O

R1

2

Bu3P

O

O

R1

O R2

O

R1

R2

R4

R4 R3

PBu3

R3

PBu3

R1 = H, Me, Et, n-Pr, i-Pr, n-Bu, n-C6H13, Bn, allyl, Ph, MeO R2 = Me, Ph, NHPh, NH(4-ClC6H4), NH(4-MeOC6H4), OMe, OEt, Oi-Pr R3 = H, Me R4 = H, n-Bu, n-C6H13, n-C10H21, Ph

Scheme 4.24 Phosphine catalyzed rearrangement of electrophilic vinylcyclopropanes.

161

162

4 Activation of Donor–Acceptor Cyclopropanes Under Covalent Organocatalysis

4.6 Conclusion The possibility for organocatalysts to interact with activated cyclopropanes through the formation of new covalent bonds in intermediates that can subsequently undergo ring-opening events has experienced a true renaissance in the last few years and has opened new venues to find untrodden reactivity patterns that enable carrying out transformations that cannot be performed using standard chemistry. An evident advantage of this type of activation manifold is the strong nature of the catalyst–substrate interaction, which allows very efficient control of the electronic and steric properties of the reaction intermediates by the catalyst. This means that selectivity issues can be very efficiently controlled in a very reliable manner, which is particularly evident with respect to the possibility of performing these reactions in an enantioselective fashion. Nevertheless, and despite the impressive advances in the field, the portfolio of reactions that have been discovered or optimized up to date is still somewhat narrow, and therefore, venues for new exciting findings in the near future are fully open.

Acknowledgments Financial suupport by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU) through projects FEDER-PID2020-118422-GB-I00 and FEDERCTQ2017-83633-P and by the Basque Government (Grupos IT908-16) is gratefully acknowledged.

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Fernandez, M., Vicario, J.L., Reyes, E. et al. (2012). Chem. Commun. 48: 2092. (f) Lee, S.-J., Youn, S.-H., and Cho, C.-W. (2011). Org. Biomol. Chem. 9: 7734. (g) Bae, J.-Y., Lee, H.-J., Youn, S.-H. et al. (2010). Org. Lett. 12: 4352. (h) Hong, L., Sun, W., Liu, C. et al. (2010). Chem. Eur. J. 16: 440. (i) Enders, D., Wang, C., and Raabe, G. (2009). Synthesis 41: 4119. (j) Yoshitomi, Y., Arai, H., Makino, K., and Hamada, Y. (2008). Tetrahedron 64: 11568. (k) Li, H., Wang, J., Xie, H. et al. (2007). Org. Lett. 9: 965. (l) Sundén, H., Rios, R., Ibrahem, I. et al. (2007). Adv. Synth. Catal. 349: 827. Fuson, R.C. (1934). Chem. Rev. 16: 1. Apel, C., Hartmann, S.S., Lentz, D., and Christmann, M. (2019). Angew. Chem. Int. Ed. 58: 5075. Xie, H., Zu, L., Li, H. et al. (2007). J. Am. Chem. Soc. 129: 10886. Li, L., Li, Z., and Wang, Q. (2009). Synlett 11: 1830. Sparr, C. and Gilmour, R. (2011). Angew. Chem. Int. Ed. 50: 8391. Wallbaum, J., Garve, L.K.B., Jones, P.G., and Werz, D.B. (2016). Chem. Eur. J. 22: 18756. Diaz, E., Reyes, E., Uria, U. et al. (2018). Chem. Eur. J. 24: 8764. Jiang, M.-Y., Zhang, L., Liu, R. et al. (2009). J. Nat. Prod. 72: 1405. Sohn, S.S. and Bode, J.W. (2006). Angew. Chem. Int. Ed. 45: 6021. Vesely, J., Zhao, G.-L., Bartoszewicz, A., and Cordova, A. (2008). Tetrahedron Lett. 49: 4209. Meazza, M., Ashe, M., Shin, H.Y. et al. (2016). J. Org. Chem. 81: 3488. Bode, J.W. and Sohn, S.S. (2007). J. Am. Chem. Soc. 129: 13798. Li, G.-Q., Dai, L.-X., and You, S.-L. (2009). Org. Lett. 11: 1623. Du, D. and Wang, Z. (2008). Eur. J. Org. Chem. 2008: 4949. Li, L., Du, D., Ren, J., and Wang, Z. (2011). Eur. J. Org. Chem. 2011: 614. Du, D., Li, L., and Wang, Z. (2009). J. Org. Chem. 74: 4379. Prieto, L., Sanchez-Diez, E., Uria, U. et al. (2017). Adv. Synth. Catal. 359: 1678. Wang, Y., Qiao, Y., Lan, Y., and Wei, D. (2021). Cat. Sci. Technol. 11: 332. Lv, J., Xu, J., Pan, X. et al. (2021). Sci. China Chem. 64: 985. Day, L. and Ye, S. (2020). Org. Lett. 22: 986. Nie, G., Huang, X., Wang, Z. et al. (2021). Org. Chem. Front. 8: 5105. Zhang, J., Tang, Y., Wei, W. et al. (2017). Org. Lett. 19: 3043. Shi, Q., Wang, Y., and Wei, D. (2018). Comput. Theor. Chem. 1123: 20. (a) Lin, S., Li, L., Liang, F., and Liu, Q. (2014). Chem. Commun. 50: 10491.for a related example, see (b) Du, D. and Wang, Z. (2008). Tetrahedron Lett. 49: 956. Li, M., Lin, S., Dong, Z. et al. (2013). Org. Lett. 15: 3978. Wu, J., Tang, Y., Wu, Y. et al. (2018) . Angew. Chem. Int. Ed. 57: 6248. Wu, Y., Li, M., Jin, L., and Zhao, X. (2020) . ACS Omega 5: 2957.

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5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes Avishek Guin and Akkattu T. Biju Indian Institute of Science, Department of Organic Chemistry, Bangalore, 560012, India

CHAPTER MENU 5.1 Introduction, 168 5.2 Enantioselective 1,3-Dichlorination of Formyl Group-Containing Cyclopropanes, 168 5.3 Ring-Opening 1,3-Dichlorination of D–A Cyclopropanes, 169 5.4 1,3-Chlorochalcogenation of Cyclopropyl Carbaldehydes, 170 5.5 1,3-Bisfunctionalization of D–A Cyclopropanes with Arenes and Nitrosoarenes, 172 5.6 1-Amino-3-Aminomethylation of D–A Cyclopropanes, 173 5.7 1,3-Halochalcogenation of D–A Cyclopropanes, 174 5.8 1,3-Aminobromination of D–A Cyclopropanes, 175 5.9 Reaction of D–A Cyclopropanes with 4,5-Diazaspiro[2.4]hept-4-enes, 176 5.10 Four-Component Coupling of D–A Cyclopropanes, 177 5.11 1,3-Aminochalcogenation of Donor–Acceptor Cyclopropanes, 178 5.12 1,3-Bisfunctionalization of Donor–Acceptor Containing Cyclopropyl Boronic Ester, 178 5.13 1,3-Halogenation–Peroxidation of D–A Cyclopropanes, 178 5.14 1,3-Aminothiolation of D–A Cyclopropanes Using Sulfenamides, 180 5.15 1,3-Bisarylation of D–A Cyclopropanes with Electron-Rich Arenes and Hypervalent Arylbismuth Reagents, 181 5.16 Conversion of D–A Cyclopropanes to -Hydroxy Ketones, 182 5.17 1,3-Carbothiolation of D–A Cyclopropanes, 183 5.18 1,3-Haloamination of D–A Cyclopropanes Employing Copper Salt and N-Fluorobenzenesulfonimide, 184 5.19 Ring-Opening 1,3-Carbocarbonation of D–A Cyclopropanes, 185 5.20 1,3-Aminofunctionalization of D–A Cyclopropanes, 187 5.21 Conclusion, 188 References, 188

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

5.1 Introduction Donor–acceptor (D–A) cyclopropanes are strained molecules, which are highly electrophilic in nature. In 1980, Reissig originally coined the term D–A cyclopropanes [1]. The strain energy for cyclopropane is around 27.5 kcal/mol. A high degree of polarization of the C─C single bond is induced within the D–A cyclopropane system because of the push‐pull effect of the nearby electron‐donating and electron‐accepting units. Polarization can be further enhanced with the existence of Lewis acid [2–8]. Thus, suitable nucleophiles can add to the D–A cyclopropane, which leads to the opening of the strained three‐membered ring. Consequently, a stable carbanion is generated at the acceptor terminus of D–A cyclopropane. If the carbanion is quenched with the proton source, it will lead to mono functionalization of D–A cyclopropane, and this chemistry is very well explored in D–A cyclopropane field. But if the in situ generated carbanion is slaked with an appropriate electrophilic source, 1,3‐bisfunctionalization of D–A cyclopropane is achieved. 1,3‐Bisfunctionalization of D–A cyclopropane is highly important because it can introduce two functional groups at the same time. However, it is also highly challenging because of the appropriate nucleophile‐ electrophile combination used for the process. Sometimes compatibility of nucleophiles and electrophiles in the same reaction flask is an issue. Consequently, very few reactions for ring‐opening 1,3‐bisfunctionalization of D–A cyclopropane are reported to date. The noteworthy reactions involving ring‐opening 1,3‐bisfunctionalization of D–A cyclopropane will be discussed in the following sections.

Nu-E

Lewis acid or Brønsted acid catalysis, radical additions, or electrocatalytic ring-opening R2 R1

Nu– E+

R2

R2 R2

R1 Nu

E

1,3-Bisfunctionalization New C–C or C–X bond formation

5.2 Enantioselective 1,3-Dichlorination of Formyl Group-Containing Cyclopropanes Synthetic organic chemists used D–A cyclopropanes as versatile intermediates for more than 40 years. However, selective bisfunctionalization of D–A cyclopropanes was rarely obtained in the early days. In 2011, Sparr and Gilmour smartly designed an enantioselective 1,3‐dichlorination of cyclopropanes containing a formyl group [9]. The reaction was initiated with the formation of cyclopropyl iminium intermediate 7. Nucleophilic chloride ion 2 adds to the γ position of intermediate 7 and generates the effective secondary enamine intermediate 3. This can be considered as formal

5.3 Ring-Opening 1,3-Dichlorination of D–A Cyclopropanes

umpolung through the use of a secondary amine, to utilize nucleophilic chloride for γ‐functionalization, which furnishes intermediate 3. The enamine intermediate further adds through α‐attack to electrophilic chlorine 4 to furnish the intermediate 5. Hydrolysis of intermediate 5 yields the expected enantioselective 1,3‐dichlorination of cyclopropanes 6 (Scheme 5.1). Since enamine formation is the main criterion for this 1,3‐dichlorination of cyclopropanes, this reaction is limited to reactive formyl groups as substitutions.

CHO + R

R

CI

+ N

Me

H

–

Bn

Me

N H

• Me TFA

CI 3

H

O

N

N Me

Bn

R

(20 mol%)

H 2

1

Me N Me

O

Me

Me

R

Me O

CI

CI R

H

CI

R CI Bn CHO

CI R

CI R

6

5

+ NHR2

O 1

CI

CI

Hydrolysis

5

CHO

CI

H

+

CI

CI

6

H CI

NR2

3 CI

O

CI

CI

7

CI

CI

CI 4

N Me N + Me Me –

NHR2

CI

CI

O

NR + 2

CI

Me CHO

68% yield 70% yield er = 91 : 9, dr = 94 : 6 er = 86 : 14, dr = 92 : 8

Me CHO

CI Me

70% yield er = 89 : 11, dr = 86 : 14

Scheme 5.1 Enantioselective 1,3-dichlorination of cyclopropanes [9].

5.3 Ring-Opening 1,3-Dichlorination of D–A Cyclopropanes Inspired by the above enantioselective 1,3‐dichlorination of cyclopropanes, later Werz and coworkers developed a general method for the 1,3‐dichlorination of D–A cyclopropanes using iodobenzene dichloride 9 as a chloride source [10]. Several D–A cyclopropanes were transformed with the readily obtainable iodobenzene dichloride into the corresponding ring‐opened 1,3‐dichlorinated compounds. Most of the transformations ­ yielded moderate‐to‐high yields of the desired 1,3‐dichlorinated compounds. Dichloromethane was found to be the optimum solvent for this

169

170

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

transformation. The reaction proceeds with the homolytic cleavage of the I─Cl bond of iodobenzene dichloride 9 to release the Cl atom. This very reactive radical species adds to the weakest bond between D–A cyclopropanes to generate another delocalized radical intermediate 13. Intermediate 13 can either abstract Cl from PhICl2 or merge with a Cl atom 11 or with a PhICl radical 12, releasing PhI (Scheme 5.2). +

EWG

R

PhICI2

EWG

CI

I

•

10 EWG

R

Ph

•

I 12

•

CI

CI

12

13

CI

Ph CI

10

PhI

CI

Ph CI

CI Ph 65% dr = 10 : 1 CI

CO2Et CO2Et

88%

CI

CO2Et CO2Et

NC

Scheme 5.2

CI

O

CI O

O

93% dr = 1 : 1

93%

EWG

CI

CI

CI

R

EWG

R

11

Ph

CI

CI

9

CI

9

R

16 h, 45 °C

8

CI

CH2CI2

79%

CI O

CI

CO2Et CO2Et

53%

Ring-opening 1,3-dichlorination of donor–acceptor cyclopropanes [10].

5.4 1,3-Chlorochalcogenation of Cyclopropyl Carbaldehydes Interestingly, Werz and coworkers further developed regio‐, diastereo‐, and enantioselective 1,3‐chlorochalcogenation of cyclopropyl carbaldehydes in 2016 [11]. In the presence of an organocatalyst, meso‐cyclopropyl carbaldehydes reacted with sulfenyl or selenyl chlorides to furnish 1,3‐chlorochalcogenated products. This conversion was successfully attained by merging iminium–enamine catalysis with aldehyde‐substituted cyclopropanes. The target products were delivered through enantioselective desymmetrization reactions, leading to three adjacent stereocenters in complete regioselectivity and moderate‐to‐high diastereo‐ and enantioselectivities. Mechanistically, the reaction is similar to 1,3‐dichlorination of cyclopropanes as demonstrated by Sparr and Gilmour [9]. The reaction proceeds with the formation of iminium intermediate 17. Sulfenyl chloride attacks at the 3‐position by the chloride

5.4 ­1,3-ChloloChhologehatle lo -CohlooloCh -horhhlgCClges

ion to the in situ generated intermediate 17, to furnish the enamine intermediate 18. The further addition of the enamine to positively charged sulfenylium ion, followed by hydrolysis, yields the expected 1,3‐chlorochalcogenation product of cyclopropyl carbaldehydes 16 (Scheme 5.3). Me N

O (1)

• DCA Ph EtOAc, –4 °C

CHO + R

14

RXCI

R

15

R

N H

O

R

Me N + N H2

CHO R

R

H2O

H2O

Me N

O

CH2OH

R 16

(X = S, Se)

CHO

XR

CI

(2) NaBH4, EtOH, –4 °C

XR

CI

R

O

N+

Me N N+

RX 19

H R

R

R

CI

R 17

RXCI O

Me N

RX

+

N R R

Br Ph CI

CH2OH 84% yield er = 90 : 10, dr = 3.5 : 1

CI CI

STol CH2OH

CI

H

Ph

70% yield er = 81 : 19, dr = 5.2 : 1

18

O

H

CI

STol CH2OH

65% yield er = 71 : 29, dr = 2.1 : 1

BocN

H

STol CH2OH

48% yield er = 50 : 50, dr = 1.6 : 1

Scheme 5.3 1,3-Chlorochalcogenation of cyclopropyl carbaldehydes [11].

171

172

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

5.5 1,3-Bisfunctionalization of D–A Cyclopropanes with Arenes and Nitrosoarenes Multicomponent 1,3‐bisfunctionalization of D–A cyclopropanes with arenes and nitrosoarenes as the coupling partners was uncovered by Studer and coworkers in 2016 for the synthesis of γ,γ‐disubstituted N‐arylated α‐amino esters [12]. AlBr3 acts as both the Lewis acid and the bromide anion donor in the regioselective arene bromination step for this transformation. This methodology involves the formation of C─C, C─N, and C─Br bonds in a single flask reaction. This multicomponent 1,3‐ bisfunctionalization strategy has a broad substrate scope with variations on all three components, and the target products are formed in moderate‐to‐good yields. Mechanistically, the reaction proceeds with the Friedel‐Crafts type alkylation at the para‐position of the toluene ring with D–A cyclopropanes 20 to furnish the enolate 24. The resulting enolate 24 reacts with p‐methoxy nitrosobenzene to generate the intermediate 25. The methoxy group assists the cleavage of the N─O bond to form a new intermediate 26. The addition of bromide ion from AlBr3 to intermediate 26 followed by tautomerization, delivers the expected γ,γ‐disubstituted N‐arylated α‐amino esters 23 (Scheme 5.4).

CO2R2 R1

NO +

R3

CO2R2 20

+

5 R5 Cs CO (0.5 equiv.) R 2 3 rt, 4–8 h

21

+

CO2Et

EtO

O

+

23 N –

Ph HN

Br

Me CO2Et CO2Et

OAIBr3

Friedel-Craft alkylation

Br Me 58%

HN OMe

Br Me

– Ph – OAIBr2 CO2Et – Br– CO2Et 26

46%

Ph

OEt 24 Ar–NO

Me OMe

Ph CO2Et N CO2Et OAIBr3

MeO

CO2Et CO2Et HN Br

–

OAIBr3

Me

CO2Et CO2Et

O

EtO Me

Me

MeO

23

CH3 –

CO2Et AIBr3 Ph

R4

22 EtO

CO2R2 CO2R2 HN R3 Br

R1

AIBr3 (2 equiv.) AI2O3 (1 equiv.)

R4

25

–

Ph HN

CO2Et CO2Et

Br

OMe

OPh

Me 50%

Scheme 5.4 1,3-Bisfunctionalization of D–A cyclopropanes with arenes and nitrosoarenes [12].

44%

5.6 1-Amino-3-Aminomethylation of D–A Cyclopropanes

5.6 1-Amino-3-Aminomethylation of D–A Cyclopropanes In 2017, Werz and coworkers demonstrated a facial ring‐opening reaction of D–A cyclopropanes to afford 1,4‐diamines [13]. The primary reaction was the (4 + 3) cycloaddition of D–A cyclopropanes 20 with triazinanes 27 in the presence of scandium triflate as a Lewis acid catalyst for the synthesis of 1,3‐diazepanes. Acid treatment of 1,3‐diazepanes led to the efficient cleavage of the aminal moiety, producing the desired 1,4‐diamines 28. The one‐pot reaction was also performed, which includes an amine and an aminomethyl group to the former cyclopropane, with ring‐opening at the first and third positions, respectively (Scheme 5.5). The reaction advances under very mild conditions and tolerates many functional groups. A library of 1,4‐diamine compounds can be synthesized using this efficient protocol. Mechanistic investigation indicates that the reaction is stereospecific, with an initial SN2 attack of triazinane opens the activated cyclopropane to yield the expected diamine product 28 (Scheme 5.5).

CO2R2 R1

CO2R2

Ar N + Ar

20

N

Sc(OTf)3, CH2CI2 25 °C, 14 h N

Ar

then 1 M HCI in MeOH 25 °C, 10 min

Ar

NH

NH

NH OMe

65%

CO2Me (S)-20a (95% ee)

NH

NH

+ Ph

N

N

Sc(OTf)3, CH2CI2 25 °C, 14 h Ph

NH

OMe CF3

F3C

79%

Ph N

Ar

CO2Me CO2Me

CO2Et CO2Et

Me

NH

CO2Me

NH

28

27

CO2Me CO2Me

Ph

CO2R2 CO2R2

R1

then 1 M HCI in MeOH 25 °C, 10 min

78%

CO2Me CO2Me

Ph Ph

NH

NH Ph (R)-28a

27a

(70% 95% ee)

Scheme 5.5 1-Amino-3-aminomethylation of D–A cyclopropanes [13].

173

174

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

5.7 1,3-Halochalcogenation of D–A Cyclopropanes Inspired by the results of 1,3‐chlorochalcogenation of cyclopropyl carbaldehydes, the Werz group developed a more general method for the 1,3‐halochalcogenation of D–A cyclopropanes for the synthesis of γ‐halogenated α‐thiolated malonic diester derivatives 30 [14]. Although in this case no iminium catalysis was involved, MgI2 as a Lewis acid catalyst was used for the desired transformation. D–A cyclopropanes 20 bearing two geminal carboxylic esters are reacted with chalcogenyl chlorides or bromides 29 to furnish the ring‐opened products 30, having the halogen atoms adjacent to the donor and the chalcogenyl residue next to the two acceptor groups. Several D–A cyclopropanes were transformed with either readily available sulfenyl chlorides, selenyl chlorides, or sulfenyl bromides. The use of several other donors such as oxygen, nitrogen, and even aromatic systems are all well tolerated. In the presence of the enantiopure D–A cyclopropane 20a, the 1,3‐halochalcogenated product 30a was obtained with inversion of configuration, which indicates that the transformation is stereospecific and proceeds in SN2‐like fashion (Scheme 5.6).

CO2R2

CO2R2 +

R1

R3SX

20

Mgl2, CH2CI2, 25 °C

CI

S

CI

S

CO2Me CO2Me CI

CO2Me CO2Me OMe S 90%

O

O N S

CO2Me CO2Me

R3

O

Me 83%

83%

CI

S

CO2R2 CO2R2

30

NO2

N O

CI

CO2Me Ph CO2Me Br Se

S

CO2Me CO2Me

Tol

Br 83%

91% CIS CO2Me +

Ph

X

29 CO2Et CO2Et

O

R1

Mgl2, CH2CI2, 25 °C

CO2Me

70% CO2Me CO2Me

Ph

NO2

CI

S NO2

(S)-20a

29a

(95% ee)

Scheme 5.6

1,3-Halochalcogenation of D–A cyclopropanes [14].

(R)-30a (100% 88% ee)

5.8 ­1,3-AtelrolAtehatle lo D- -Cohlooloheges

5.8 1,3-Aminobromination of D–A Cyclopropanes In 2017, Studer and coworkers reported the Sn(OTf)2‐catalyzed 1,3‐aminobromination of D–A cyclopropanes with different sulfonyl amides or electron‐poor anilines 31 and N‐bromosuccinimide 32 for the synthesis of γ‐aminated α‐brominated malonic diesters 33 [15]. The reaction proceeds under mild conditions and these reactions occurred with complete regio‐ and stereospecificity (Scheme 5.7). This methodology can tolerate various functional groups and in most cases moderate‐to‐good yields of γ‐aminated α‐brominated malonic diesters were obtained. These products functioned as valuable substrates for the subsequent reactions to afford substituted γ‐lactams and azetidines in good yields. The reaction with anilines 31a proceeded with complete stereospecificity. Simple experimentation, ready access to starting materials, and good yields of products are the notable features of this transformation. O CO2R2 R1

CO2R2 20

HN

N Br

+ R3R4NH +

DCE, 25 °C, 17 h

O 31

Ts

CO2Et CO2Et Br

Ph

F

NH

33

F3C

HN

F

CO2Me CO2Me Br

N

61%

+

(>99% ee)

O2N

N Br

31a

O

CO2Et CO2Et Br

74%

Ph

Sn(OTf)2 (5 mol%) DCE, –5 °C, 17 h

NO2 (S)-20a

N

O +

CO2Me

Ph

Br Me

NO2

NH2 Ph

CO2Et CO2Et Br HN Ts 76%

CO2Et CO2Et

Ph

92%

CO2Me

Ts

CO2Me CO2Me Br

79%

F

F

CO2R2 CO2R2 Br N R4 R3 R1

32

98% F

Sn(OTf)2 (5 mol%)

CO2Me CO2Me NH Br

O2N

32

(R)-33a (82%, >99% ee)

Scheme 5.7 1,3-Aminobromination of D–A cyclopropanes [15].

175

176

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

5.9 Reaction of D–A Cyclopropanes with 4,5-Diazaspiro[2.4]hept-4-enes In 2018, Tomilov and coworkers uncovered a unique 1,3‐bisfunctionalization reaction of D–A cyclopropanes and 4,5‐diazaspiro[2.4]hept‐4‐enes for the synthesis of highly functionalized pyrazolines [16]. EtAlCl2 has dual roles in this reaction. In the presence of EtAlCl2, activation of D–A cyclopropane takes place. Also, the positively charged intermediate adds to the azocyclopropane system of the pyrazoline, leading to the opening of the second three‐membered ring, along with the addition of a halide anion from the EtAlCl2. Depending upon the ratio of the D–A cyclopropane or pyrazoline, a twofold addition can take place for both components. Product 36 was formed when a 5 : 1 ratio of D–A cyclopropane 34 and pyrazoline 35 were used, and in this case, 1,3‐bisfunctionalization was achieved for one D–A cyclopropane moiety and the other D–A cyclopropane monofunctionalization was attained. The use of allyl bromide as the electrophilic third component, instead of another molecule of D–A cyclopropane, was also tested; in this case, product 38 was formed with a 63% yield and a diastereomeric ratio of 1.2 : 1 (Scheme 5.8).

CO2Me CO2Me

Ph

+

N N

R2 N

CO2Me Me N N

Ph CO2Me CO2Me

Ph MeO2C

Ph MeO2C

CO2Me

CO2Me 34

+

N N 35

R1 CI

Ph MeO2C

36

CI

CO2Me CO2Me

N N

CO2Me

CO2Me Me Ph

CO2Me CO2Me

Ph

CO2Me

20% NMR yield

CO2Me

N

MeO2C

MeO2C

73%

Ph

Ph CO2Me CO2Me

CI

Ph N

EtAICI2 (3 equiv.) 0–5 °C, 15 min, CH2CI2

N 35

34

CI

R2

R1

CO2Me Me +

Br 37

87%

CI EtAICI2 (2 equiv.) 0–5 °C, 15 min CH2CI2

N

N

CO2Me Me Ph

CO2Me CO2Me 38 (63%, dr 1.2 : 1)

Scheme 5.8

Reaction of D–A cyclopropanes with 4,5-diazaspiro[2.4]hept-4-enes [16].

5.10 our-Component Coupling of D–A Cyclopropanes

5.10

Four-Component Coupling of D–A Cyclopropanes

For the first time, Studer and his coworkers disclosed a four‐component coupling reaction of D–A cyclopropanes 20 involving indolyl boron ate complexes and alkyl halide 41 [17]. Scandium triflate was found to be the optimum Lewis acid catalyst, with THF being the best solvent for this transformation. The reaction progressed with complete diastereoselectivity, to afford indolines. The formation of three C─C bonds and the construction of three contiguous stereocenters are notable features of this transformation. The reaction performed using enantiomerically enriched D–A cyclopropane 20a, showed complete stereospecificity, to deliver highly enantiomerically enriched indoles and indolines in a single flask (Scheme 5.9). The present transformation can tolerate several valuable functional groups, and in most cases,

CO2R2 R1

CO2R2

R3 +

N Me

20

Li + Ar B(pin) + RX

40

Me CO2Me CO2Me

R3

41

Br

64%

41%

CO2Et CO2Et

B(pin) Ph

N Me

F3C

N Me 71%

N Me

CO2Et CO2Et

CO2Et CO2Et B(pin) Ph

B(pin) Ar 42

B(pin) Ph

B(pin) Ph

N Bu

2 R CO2R CO2R2

N Me CO Me 2Me CO2Me

Me CO2Et CO2Et

B(pin) Ph

S

R1

THF, 20 h

39

N Me 62%

Sc(OTf)3

B(pin) Ph

F3C

60%

N Me 53%

Me CO2Et CO2Et CO2Et Ph

CO2Et

(S)-20a (>99% ee)

+

N Me 39a

Li + Ph

B(pin) + CH3I

Sc(OTf)3

Ph

THF, 20 h

N B(pin) Me 40a

41a

(S, S, S)-42 74%, >99%

Scheme 5.9 Four-component coupling of D–A cyclopropanes with indolylboron ate complexes and alkyl halide [17].

177

178

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

the expected product is formed in moderate‐to‐good yields. The beneficial boron moiety is retained in the product, thus offering useful options for further transformation.

5.11 1,3-Aminochalcogenation of Donor–Acceptor Cyclopropanes Inspired by the 1,3‐aminobromination of donor–acceptor cyclopropanes demonstrated by Studer and his coworkers, Werz and coworkers later disclosed the 1,3‐ aminochalcogenation of donor–acceptor cyclopropanes using the multicomponent strategy [18]. Sn(OTf)2 was established to be the Lewis acid of choice for this three‐ component coupling strategy. Sulfonamide 43 was found to be the nucleophile for this three‐component coupling. The 1,3‐aminothiolation or 1,3‐aminoselenation of D–A cyclopropanes could be achieved depending on the electrophile used. Various donors, including electron‐rich and electron‐deficient aryl moieties, were well tolerated, and in most of the cases, the desired products were obtained in good yields. Interestingly, the formation of a racemic product, even in the presence of enantiopure D–A cyclopropane 20a, was observed. Further studies revealed that enantiopure D–A cyclopropane racemizes under the reaction conditions, even when other substrates are not present in the system, and this accounts for the formation of racemic products (Scheme 5.10).

5.12 1,3-Bisfunctionalization of Donor–Acceptor Containing Cyclopropyl Boronic Ester In 2019, Aggarwal and coworkers disclosed the enantiospecific coupling reaction, including organolithium reagents and enantioenriched cyclopropyl boronic esters [19]. This transformation progresses via a boronate complex with an activated cyclopropane in the α position. The presence of two ester groups in the β position and strain in the cyclopropane is crucial for 1,2‐metalate rearrangement to take place. Employing methyl iodide as an electrophilic coupling partner furnished a three‐component coupling product with a 77% yield (Scheme 5.11). The use of allyl iodide and Eschenmoser’s salt as the third components was also successful and the multicomponent products 49 were observed in good yield and excellent enantioselectivity.

5.13 1,3-Halogenation–Peroxidation of D–A Cyclopropanes Saha and coworkers revealed the use of hydroperoxides as the nucleophilic trigger in the multicomponent coupling reaction of D–A cyclopropanes [20]. This is the

5.13 1,3--alogenation––erooidation of D–A Cyclopropanes O R2

CO2

+ TsNH2 + CO2R2

R1

20

N

R1

Sn(OTf)2

XR3

DCE, 25 °C, 12 h O

43

Ts

CO2R2 CO2R2 NH XR3

44

45

F F

F

CO2Me CO2Me F HN SPh Ts

CO2Me CO2Me SPh F HN Ts

93% Ph Ts

NH S

CO2Me CO2Me HN SPh Ts 86%

54% CO2Me CO2Me

Ph Ts

74%

Me

CO2Et CO2Et NH SePh Ts

77% O

Ph

CO2Me + TsNH + 2 CO2Me (S)-20a

43

N SPh

Ts

CO2Me CO2Me NH SPh

(R)-45a

44a

(78%, 10% ee)

(99% ee)

Ph

Scheme 5.10

61%

Ph

Sn(OTf)2 DCE, 25 °C, 12 h

O

CO2Me CO2Me NH SePh

CO2Me

Sn(OTf)2

CO2Me

DCE, 25 °C, 12 h

CO2Me Ph

CO2Me

(S)-20a

(S)-20a

(99% ee)

(8% ee)

1,3-Aminochalcogenation of donor–acceptor cyclopropanes [18].

first example of constructing highly functionalized γ‐peroxy carbonyls through an ionic process and is distinctive from the previously reported radical methodologies. Operationally, a simple ring‐opening 1,3‐halogenation–peroxidation was achieved in the presence of hydroperoxide and an appropriate halogenating agent. Sc(OTf)3 was found to be the choice of Lewis acid for the desired three‐component coupling. The reaction was conducted at 0 °C in the presence of dichloromethane as the solvent. This multicomponent approach can tolerate several functional groups and shows variations for all three components, with products formed in moderate‐to‐ good yields (Scheme 5.12). Enantiopure products were obtained when chiral D–A cyclopropane was used, which indicates the SN2 nature of the addition of hydroperoxides to D–A cyclopropanes. Various synthetic transformations of 1,3‐halogenation– peroxidation products were performed, which makes this methodology more attractive to synthetic organic chemists.

179

180

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

CO2tBu CO2tBu

PinB

er: 97 : 3 46

BPin R1

1. PhLi (1.2 equiv.) THF, –78 °C to rt, 16 h

CO2tBu CO2tBu

49

2. R1-I (2 equiv.) MgBr2·Et2O (0.2 equiv.) –78 °C to rt, 16 h MgX2

PhLi

Pin B

CO2tBu CO2tBu

Ph 47

R1-I

Li+ tBuO

LiX

BPin Ph

BPin Me CO2tBu CO2tBu

77%, er = 97 : 3

BPin

tBu

O

MgX O 48 OtBu BPin

CO2 CO2tBu

88%, er = 97 : 3

NMe2 CO2tBu CO2tBu

72%, er = 97 : 3

Scheme 5.11 1,3-Bisfunctionalization of D–A cyclopropane-containing cyclopropyl boronic ester [19].

5.14 1,3-Aminothiolation of D–A Cyclopropanes Using Sulfenamides Considering the efficiency of 1,3‐bisfunctionalization of D–A cyclopropanes, Biju and coworkers uncovered the Yb(OTf)3‐catalyzed mild and regioselective ring‐ opening 1,3‐aminothiolation of D–A cyclopropanes, utilizing sulfenamides for the construction of γ‐aminated α‐thiolated malonic diester derivatives 54 [21]. The Lewis acid‐catalyzed formation of C─N and C─S bonds was the key feature of this methodology. DCE was found to be the optimum solvent for this transformation. Under optimized conditions, various D–A cyclopropanes and sulfenamides were tested, and in all cases, the desired products were obtained in moderate‐to‐good yields (Scheme 5.13). Notably, in this case, enantiopure D–A cyclopropane yielded a chiral product with an inversion of configuration, which indicates that the nucleophilic attack of the sulfenamide proceeds in an SN2‐like fashion. Mechanistic studies revealed the role of 4‐substitution on the N‐methyl aniline moiety of 53 for the insertion to take place. In the absence of the 4‐substitution on the N‐methyl aniline moiety, sulfenamide can rearrange in the presence of Yb(OTf)3, and thus N–H insertion of the rearranged product was observed as the sole product. The cross‐over

5.15 1,3-Bisarylation of D–A Cyclopropanes with Electron-Rich O CO2R2 R1

+ ROOH

CO2R2

+

N X

CH2CI2, 0 °C

50

CO2Me CI CO2Me O

O tBu

O

CO2Me CO2Me

N O

Br O tBu

O

77%

CO2Me (S)-20a ( >99% ee)

Scheme 5.12

O

+

tBuOOH

50a

+

NBr O 32

CI

66%

Ph CO2Me CO2Me CI

CO2Me CO2Me Br O O Me

O tBu

71%

CO2Me

52

tBu

62%, dr = 25 : 1

O

Ph

O

Br

62% O

N

X

CO2Me CO2Me

S

tBu

57% O

O

O R

51

CO2Me CO2Me

O

O

O

20

O

CO2R2 CO2R2

R1

Sc(OTf)3

Sc(OTf)3 CH2CI2, 0 °C

CO2Me CO2Me

Ph O

Br O tBu

(R)-52a (72%, >99% ee)

1,3-Halogenation–peroxidation of D–A cyclopropanes [20].

experiments employing differently substituted sulfenamides revealed the formation of four γ‐aminated α‐thiolated malonic diester products, shedding light on the stepwise pathway for insertion and the intermolecular nature of the sulfur group migration.

5.15 1,3-Bisarylation of D–A Cyclopropanes with Electron-Rich Arenes and Hypervalent Arylbismuth Reagents In 2020, Saha and coworkers disclosed a new catalytic procedure for the tandem 1,3‐bisarylation of D–A cyclopropanes 20, employing electron‐rich arenes 55 as the nucleophile and hypervalent aryl bismuth components 56 as the electrophilic source of arene [22]. The formation of Lewis acid‐catalyzed C─C bond using a multicomponent approach was the key highlight for this efficient transformation. Sc(OTf)3 was found to be the choice of Lewis acid, and diethyl ether was the optimal solvent.

181

182

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes Me N

CO2R2 R1

Ar

+

CO2R2

S

R3

R3 53

S Me Ph

Me

N

S Me Ph

Me

CO2Me CO2Me

Ph

CO2Me CO2Me

O

73%

N

Me

S Me CI

75%

46%

Me CO2Me Ph

N

(>99% ee)

S Ph

+

CO2Me (S)-20a

Ph

Yb(OTf)3 (10 mol%)

N

DCE, 10 °C, 12 h Me

S Me Ar 54

CO2Me CO2Me N

N

DCE, 25 °C, 12 h

20

CO2R2 CO2R2

R1

Yb(OTf)3 (10 mol%)

CO2Me CO2Me

S Me Ph

Me 53a

(R)-54a (68%, >99% ee)

Scheme 5.13 1,3-Aminothiolation of D–A cyclopropanes using sulfenamides [21].

Notably, this methodology was not only limited to D–A cyclopropanes, but D–A cyclobutanes 58 were also well tolerated under the present reaction conditions and furnished the 1,4‐bisarylated products 59 in moderate‐to‐good yields (Scheme 5.14). Mechanistic studies revealed that this transformation is stereospecific.

5.16 Conversion of D–A Cyclopropanes to β-Hydroxy Ketones Werz and coworkers demonstrated an electrochemical strategy for the ring‐opening of D–A cyclopropanes by single electron transfer (SET) initiation [23]. Although there are many ways to break the C─C bond of D–A cyclopropanes, including the use of Lewis acids, Brønsted acids, and breaking by radical addition, but there are not many reports for the electrocatalytic opening of D–A cyclopropanes by anodic oxidation. The use of triplet oxygen as the reaction partner was considered because of its abundance, cheapness, and diradical character. Interestingly, under the optimized conditions, the expected β‐hydroxy ketones 60 were formed in moderate‐to‐ good yields (Scheme 5.15). Remarkably, this methodology could be further extended toward D–A cyclobutanes and in this case, the expected γ‐hydroxy ketones were formed in good‐to‐excellent yields. The reaction proceeds with the oxidation of the arene ring of the D–A cyclopropane at the anode, and the formation of radical cation 62 via the breaking of the C─C bond of cyclopropane. Radical combination with

5.­7 ­1,3-horlaCtlhhatle lo D- -Cohlooloheges R3

R1

R3 +

FG +

CO2R2 CO2R2 20

Sc(OTf)3 tBuOK

CI Bi 3 CI

55

R1

CO2R2

Et2O

CO2R2 FG

56

57

MeO Ph

S

CO2Me CO2Me N

Ph CO2Me CO2Me

CO2Me CO2Me N

Me 86%

Me

88%

OMe 71% R3

R1

CO2Me CO2Me

FG

R3 +

+

58

55

CI Bi 3 CI

Sc(OTf)3 tBuOK Et2O

CO2Me CO2Me

R1

56

59 FG

MeO CO2Me CO2Me

BnO CO2Me CO2Me MeO

N

OMe

OMe

Me 78%

Scheme 5.14

81%

1,3-Bisarylation of D–A cyclopropanes [22].

triplet oxygen, followed by intramolecular 5‐exo‐trig cyclization, furnished another radical cation intermediate 64, which formed dioxolane 65 via the chain propagation step. Deprotonation of dioxolane, followed by O─O bond cleavage, yielded the expected β‐hydroxy ketones 60. Notably, in 2021 Banerjee and coworkers also independently demonstrated the same strategy for the synthesis of β‐hydroxy ketones [24].

5.17 1,3-Carbothiolation of D–A Cyclopropanes Biju and coworkers disclosed a two‐step ring‐opening 1,3‐carbothiolation of D–A cyclopropanes utilizing alkyl halides and in situ generated dithiocarbamates (from amines and CS2) [25]. This reaction is easy to operate and works with good functional group compatibility. The key highlight was the formation of three new bonds,

183

184

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

CO2R2 R1

CO2R2

3O2-Balloon, TBABF4

O GC

20

O 88% E

CO2Me CO2Me OH

E E H O

O

O 64%

Chain propagation

E

GC CO2Me CO2Me OH

CO2R2 CO2R2 OH 60 CO2Me CO2Me O OH 42% E

E E 61

SET

65

O

S

+ Anode +

E

R1

E 62 3O2

E E O

E

O

64

O

O

E

63

E 60 OH

Scheme 5.15 Conversion of D–A cyclopropanes to β-hydroxy ketones [23].

including C─N, C─S, and C─C bonds. The reaction proceeds via the formation of dithiocarbamate by the addition of amine to CS2 (Scheme 5.16). This in situ‐ generated dithiocarbamate opened the cyclopropane ring in the presence of Lewis acid, thus forming the monofunctionalized ring‐opened intermediate. Under the base treatment, this monofunctionalized intermediate underwent alkylation using alkyl halide, thus resulting in the formation of the 1,3‐bisfunctionalized product. This strategy was not only limited to alkyl halide as the electrophilic component but Michael acceptors such as ethyl acrylate or acrylonitrile were also used as the electrophilic fourth component. Enantiospecific study revealed the SN2 mode of addition of dithiocarbamate to D–A cyclopropanes.

5.18 1,3-Haloamination of D–A Cyclopropanes Employing Copper Salt and N-Fluorobenzenesulfonimide Li and coworkers uncovered a protocol for the divergent copper salt‐controlled reactions of D–A cyclopropanes 20 and N‐fluorobenzenesulfonimide (NFSI) 72 [26]. In the presence of CuX2 (X = Cl, Br), which acts as both a mediator and a halide source, the cyclopropanes underwent 1,3‐aminohalogenation via a free radical‐mediated ring‐ opening process, to yield 1,3‐aminochlorination and 1,3‐aminobromination products 73 in moderate‐to‐good yields (Scheme 5.17). Interestingly, 1,3‐aminohalogenation was a formal umpolung reaction, with the halogen anion directly connected to an electron‐rich carbon center with two strongly electron‐withdrawing groups. Mechanistically, the reaction proceeds with the generation of Cu(I) intermediate from

5.­9 ­teo3-ogeteo ­1,3-horlohorlehatle lo D- -Cohlooloheges

R2

CO2

R1

CO2R2

+ CS2

(ii) Cs2CO3, R–X THF, 25 °C, 12 h

N

Me

R4

67 CO2Me CO2Me

S

S

S N

N

R

Ph

CO2Me CO2Me

S

S

S

S R3

Ph

CO2Me CO2Me

CO2R2 CO2R2

R1

66

20 OMe

S

(i) Yb(OTf)3 THF, 25 °C, 16 h

H + N R3 R4

N Me

81%

92%

84% CO2Me CO2Me

Yb(OTf)3 20 MeO O

67

BnBr Cs2CO3

S

H

S

CO2Me CO2Me

O MeO 69

N 71

S +

Scheme 5.16

Yb(OTf)3

S 70 NH

H +N

CO2Me – CO2Me

S

– S 68

+ CS2 N H 66

1,3-Carbothiolation of donor–acceptor cyclopropanes [25].

Cu(II) species via the disproportionation of Cu(II) salt. Next, the NFSI underwent homolysis to produce phenylsulfamide nitrogen radical 74. This radical 74 adds to D–A cyclopropane 20 to furnish intermediate 75, which combines with CuX2 via oxidative addition to generate metal–carbon species 76. In the next step, product 73 was generated from intermediate 76 via the reductive elimination and simultaneously the active catalyst (Cu(I)) was regenerated. Thus, this methodology offers an alternative strategy for 1,3‐haloamination proceeding via a radical pathway.

5.19 Ring-Opening 1,3-Carbocarbonation of D–A Cyclopropanes Very recently, Werz and coworkers demonstrated the 1,3‐carbocarbonation of D–A cyclopropanes by employing Grignard reagent as the nucleophilic trigger [27]. Using copper catalysis, the ring‐opening addition with a Grignard reagent progressed

185

186

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes CO2R2 +PhO2S N SO2Ph CO2R2 F

R1 20

1.0 equiv. CuX2

(PhO2S)2N

CI

CO2R2 O N CO2R2 2

R1

Ar, 60 °C

72

(PhO2S)2N

CI

X

(PhO2S)2N

MeCN:DCE (1 : 1)

CO2R2 CO2R2

73

CO2R2 CO2R2

Br

(PhO2S)2N

CO2R2 CO2R2

CI

F 58% (PhO2S)2N

42% X 73

CO2Me CO2Me

(PhO2S)2N

X

55%

NFSI

CuI

X CuIII CO2Me CO2Me

N(SO2Ph)2 + CuII 74 CO2Me CO2Me

76

IICuX 2

(PhO2S)2N

CO2Me CO2Me 75

Scheme 5.17 1,3-Haloamination of D–A cyclopropanes employing copper salt and NFSI [26].

smoothly; after this, the intermediate was transformed into the final product 77 by the reaction with appropriate carbon‐based electrophiles under basic conditions. Grignard reagents originated from sp3‐, sp2‐, and sp‐hybridized carbon residues were successfully utilized as nucleophiles, whereas various aliphatic bromides and ethynylbenziodoxolone (EBX) derivatives (for sp moieties) functioned as electrophiles (Scheme 5.18). 1) RMgX, Cu(OTf)2 (cat.) 2) R'Br, DBU

CO2R2 CO2R2

R1

THF then DMSO, 0–43 °C 18 h

R1 R

CO2R2 CO2R2 R'

20 Ph Me

77 CO2Me Ph CO2Me

CO2Me Ph CO2Me

CO2Me CO2Me Me

73%

OMe

CO2Me CO2Me Me

OMe 48%

54%

34%

Scheme 5.18 Ring-opening 1,3-carbocarbonation of D–A cyclopropanes [27].

OMe

5.20 1,3-Aminofunctionalization of D–A Cyclopropanes

5.20 1,3-Aminofunctionalization of D–A Cyclopropanes Very recently, Biju and coworkers devised 1,3‐aminofunctionalization of D–A cyclopropanes via three‐component coupling reactions using benzotriazoles as the nucleophilic trigger [28]. Under the optimized reaction conditions, benzotriazoles 78 were added to D–A cyclopropanes 20 in the presence of catalytic Yb(OTf)3, and the in situ generated intermediate was trapped with various types of electrophiles. First, the scope of 1,3‐aminohalogenation leading to the product 79 (employing N‐halosuccinimides as electrophiles) was investigated and in each case, the expected products were formed in good‐to‐excellent yields. Later, the scope of the reaction was further expanded using different carbon‐based electrophiles. Although the direct three‐component coupling was not successful in that case, the one‐pot strategy was successful. Several electrophiles, including alkyl/benzyl halides, Michael acceptors, EBX derivatives, and even Selectfluor, were used under the optimized conditions. The synthetic utility of the products was shown via some selected functional group interconversions (Scheme 5.19). R1

R1

20

F

CO2R2 + R3 CO2R2

N

N N

N N H

78

N N

CO2Me CO2Me

N N

N H 78

CO2Me CO2Me Ph

Ph N N

Me

N

CI

F

N

Yb(OTf)3 (15 mol%) DCE, 25 °C, 12 h

N N

80%

79 CO2Me CO2Me

N

N N

Br

75% CO2Me CO2Me

Ph

then CS2CO3 (2.5 equiv.) R–X (2.0 equiv.) 25 °C, 12 h

CO2Me CO2Me

N N

Ph

F

61%

+

20

CO2Me CO2Me

Ph N

CI

84%

Ph

77%

R3

51

N

N

t-Bu-Ph, 25 °C, 12 h

CO2Et CO2Et

CO2Me Ph CO2Me N Br

49%

N

Yb(OTf)3 (15 mol %)

N + NXS

CO2R2 CO2R2 X

N

N N

R

80

CO2Me Ph CO2Me

Ph N

CO2Me

N N

CO2Me CO2Me N

Ph

57%

Scheme 5.19 1,3-Aminofunctionalization of D–A cyclopropanes [28].

N N

61%

F

187

188

5 Ring-Opening 1,3-Bisfunctionalization of Donor–Acceptor Cyclopropanes

5.21 Conclusion In this chapter, the application of D–A cyclopropanes in ring‐opening 1,3‐bisfunctionalization reactions has been summarized. Ring‐opening 1,3‐bisfunctionalization reactions can be achieved in two ways. The first approach is the multicomponent approach, and the second type is the insertion reaction, which is not well explored in the D–A cyclopropane field. Various nucleophiles and electrophiles can combine with D–A cyclopropanes and produce several useful organic compounds by using this strategy. It is expected that the efficiency of 1,3‐bisfunctionalization reactions in D–A cyclopropanes will continue and will result in remarkable outcomes for innovative 1,3‐bisfunctionalizations in the future. It is realistic to believe that the potential of this 1,3‐bisfunctionalization reaction is still not completely exposed, and more significant developments will be disclosed in the upcoming future.

References 1 Reissig, H.‐U. and Hirsch, E. (1980). Angew. Chem. Int. Ed. Engl. 19: 813–814. 2 Werz, D.B. and Biju, A.T. (2020). Angew. Chem. Int. Ed. 59: 3385–3398. 3 Schneider, T.F., Kaschel, J., and Werz, D.B. (2014). Angew. Chem. Int. Ed. 53: 5504–5523. 4 Ghosh, K. and Das, S. (2021). Org. Biomol. Chem. 19: 965–998. 5 Singh, P., Varshnaya, R.K., Dey, R., and Banerjee, P. (2020). Adv.Synth. Catal. 362: 1447–1484. 6 Carson, C.A. and Kerr, M.A. (2009). Chem. Soc. Rev. 38: 3051–3060. 7 Reissig, H.‐U. and Zimmer, R. (2003). Chem. Rev. 103: 1151–1196. 8 De Nanteuil, F., De Simone, F., Frei, R. et al. (2014). Chem. Commun. 50: 10912–10928. 9 Sparr, C. and Gilmour, R. (2011). Angew. Chem. Int. Ed. 50: 8391–8395. 10 Garve, L.K.B., Barkawitz, P., Jones, P.G., and Werz, D.B. (2014). Org. Lett. 16: 5804–5807. 11 Wallbaum, J., Garve, L.K.B., Jones, P.G., and Werz, D.B. (2016). Chem. ‐ Eur. J. 22: 18756–18759. 12 Das, S., Daniliuc, C.G., and Studer, A. (2016). Org. Lett. 18: 5576–5579. 13 Garve, L.K.B., Jones, P.G., and Werz, D.B. (2017). Angew. Chem. Int. Ed. 56: 9226–9230. 14 Wallbaum, J., Garve, L.K.B., Jones, P.G., and Werz, D.B. (2017). Org. Lett. 19: 98– 101. 15 Das, S., Daniliuc, C.G., and Studer, A. (2017). Angew. Chem. Int. Ed. 56: 11554– 11558. 16 Novikov, R.A., Borisov, D.D., Zotova, M.A. et al. (2018). J. Org. Chem. 83: 7836–7851. 17 Das, S., Daniliuc, C.G., and Studer, A. (2018). Angew. Chem. Int. Ed. 57: 4053–4057. 18 Augustin, A.U., Jones, P.G., and Werz, D.B. (2019). Chem. ‐ Eur. J. 25: 11620–11624. 19 Gregson, C.H.U., Ganesh, V., and Aggarwal, V.K. (2019). Org. Lett. 21: 3412–3416.

References

20 Singh, K., Bera, T., Jaiswal, V. et al. (2019). J. Org. Chem. 84: 710–725. 21 Guin, A., Rathod, T., Gaykar, R.N. et al. (2020). Org. Lett. 22: 2276–2280. 22 Mondal, B., Das, D., and Saha, J. (2020). Org. Lett. 22: 5115–5120. 23 Kolb, S., Petzold, M., Brandt, F. et al. (2021). Angew. Chem. Int. Ed. 133: 24 25 26 27 28

16064–16070. Saha, D., Maajid Taily, I., and Banerjee, P. (2021). Eur. J. Org. Chem. 5053–5057. Guin, A., Deswal, S., and Biju, A.T. (2022). J. Org. Chem. 87: 6504–6513. Liu, L., Wang, X., Xiao, W. et al. (2022). Chem. Eur. J. e202202544. von Köller, H.F., Jones, P.G., and Werz, D.B. (2022). Chem. Eur. J. e202203986. Deswal, S., Guin, A., and Biju, A.T. (2023). Org. Lett. 25: 1643–1648.

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191

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes Igor V. Trushkov1 and Olga A. Ivanova2 1 N.D. Zelinsky Institute of Organic Chemistry RAS, Laboratory of Directed Functionalization of Organic Molecular Systems, Leninsky Av., 47, Moscow, 119991, Russia 2 M.V. Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow, 119991, Russia

CHAPTER MENU 6.1 Introduction, 191 6.2 Donor–Acceptor Cyclopropane Isomerizations to Alkenes (Cyclopropane–Propene Rearrangement), 192 6.3 Vinylcyclopropane–Cyclopentene Rearrangement, 197 6.4 Cloke–Wilson Rearrangement and Related Processes, 202 6.5 Nazarov Reaction and its Homo-Version, 210 6.6 The Cope Rearrangement and Related Isomerizations of Donor–Acceptor Cyclopropanes, 215 6.7 Intramolecular Nucleophilic Ring Opening/Ring Closure and Related Processes, 218 Acknowledgment, 221 References, 221

6.1 Introduction An amazing feature of donor–acceptor (D–A) cyclopropanes is their ability to produce a broad diversity of products in reactions involving no other educts. The fine tuning of reaction conditions allows each of the products to be obtained in high yields and selectivity. Among such processes are: (1) cis-trans isomerization [1–4] as well as racemization of the optically active substrates [4–8]; (2) various dimerizations that were reviewed recently [9, 10]; (3) oligo- and polymerization [11–15]; and (4) various molecular rearrangements producing isomers of the starting compounds with different carbon skeletons. It is the molecular rearrangements of D–A cyclopropanes that are discussed in this chapter. Seven major types of these processes can be distinguished. The simplest one is the cyclopropane-to-alkene isomerization (Section 6.1). Another important process is vinylcyclopropane-to-cyclopentene Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

192

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

isomerization (Section 6.2), its analogs with heteroatom in double bond, i.e. formation of 2,3-dihydrofuran and 2,3-dihydropyrroles from acylcyclopropanes and their imines, respectively, (the Cloke–Wilson rearrangement) as well as the related processes (Section 6.3), homo-Nazarov cyclization (Section 6.4), and homo-version of 3,3-sigmatropic shifts (Section 6.5). Intramolecular cycloadditions can also be considered as a type of molecular rearrangement, but these processes are discussed in Chapter 3; therefore, this subject is not covered here. At last, intramolecular nucleophilic ring opening–ring closure (INRORC) processes can be considered as molecular rearrangement of D–A cyclopropanes. Some examples of these processes are discussed in Section 6.6. In general, we do not discuss here domino reactions wherein molecular rearrangement is one of the steps and other steps represent the addition or elimination of some molecules (group of atoms) except for rare examples given to better understand the subject of this chapter.

6.2 Donor–Acceptor Cyclopropane Isomerizations to Alkenes (Cyclopropane–Propene Rearrangement) The isomerization of cyclopropane-to-propene was reported for the first time 100 years ago [16]. This reaction was proven to proceed via homolysis of the C–C bond [17] and required heating at 500–600 °C. Similar isomerization of D–A cyclopropanes was found to proceed under milder conditions; however, still requires very high temperatures. Thus, heating cyclopropa[b]thiophene 1 in toluene-d8 at 150 °C in a sealed NMR tube failed to induce any reaction. However, 1 was converted to 2-thienylacetate 2 under treatment with iodine at room temperature (Scheme 6.1) [18]. 150 °C Toluene-d8

CO2Et Me

Scheme 6.1

I2

Toluene r.t., 18 h

S 1

Me

CO2Et S 2, 69%

Iodine-induced rearrangement of cyclopropa[b]thiophene 1.

The isomerization of 2-alkoxycyclopropanecarboxylates 3 to the corresponding vinyl ethers 4 can be performed at relatively mild conditions in the presence of copper bronze or transition metal complexes, such as (PtCl2∙2PhCN) and [Rh(CO)2Cl]2 (Scheme 6.2) [19, 20]. R3 R2

R3 CO2Et

[Rh(CO)2Cl]2 110 °C

R1O

3

R2

CO2Et OR1

and/or isomers

Scheme 6.2 Transition metalcatalyzed isomerizations of 2-alkoxycyclopropanecarboxylates.

4, 46–98%

However, these are Lewis and Brønsted acids that are most commonly used to initiate the isomerization of D–A cyclopropanes to the corresponding propenes. Thus, Reissig described the transformation of 2-siloxycyclopropanecarboxylates 5 to the corresponding alkenes 6 under catalysis with trimethylsilyl iodide (Scheme 6.3) [21].

6.2 ­DoDor–AAcepDo CAcDeoDepoc IDocoripprDoI pD –clcocI R2 R1

R1 CO2Me

Me3SiO

Me3SiI CHCl3, r.t.

R3 5

CAcDeoDepocr–oDecoc cpooponcocopt

R2

Me3SiO

CO2Me R3 6, 49–95%

Scheme 6.3 Trimethylsilyl iodide-induced isomerization of 2-siloxycyclopropanecarboxylates 5.

D–A cyclopropanes, bearing carbamates and related groups as donor substituents, behave similarly. Thus, cyclopropanes 8, obtained from 2,3-dehydropiperidines 7 and vinyl acetates or silyl ethers, were rearranged to 3-acetonyl-2,3-dehydropiperidines 9 under treatment with 10-camphorsulfonic acid (10-CSA) in CH2Cl2 at 0 °C (Scheme 6.4). It should be noted that the rearrangement of corresponding cyclopropanecarboxylate (R2 = OEt) required reflux in toluene [22]. R1

3 steps

N CO2Et 7

Scheme 6.4

R1 N CO2Et 8

O

10-CSA

CH2Cl2, 0 °C R2

R1

O R2

N CO2Et 9, 69–97%

Camphorsulfonic acid-initiated rearrangement of cyclopropapiperidines 8.

Brönsted acids were also applied for the rearrangement of D–A cyclopropanes bearing arylsulfanyl groups as donors. Kulinkovich showed that 1-acyl-2,2bis(phenylsulfanyl)cyclopropanes 10 isomerized to ketene dithioacetals 11 under treatment with p-toluenesulfonic acid (TsOH). The reaction should be carried out under anhydrous conditions to prevent hydrolysis of the products (Scheme 6.5) [23]. Scheme 6.5 TsOH-induced isomerization of cyclopropanes 10 to ketene dithioacetals 11.

R2 R1 O

10

O

SPh

TsOH

SPh

CH2Cl2, r.t.

R1

R2 SPh

SPh 11, 74–94%

The important examples of D–A cyclopropanes with heteroatom-based functionality as donors are cyclopropanated heterocycles. In general, the cyclopropane-topropene isomerization of these compounds can afford acyclic compounds, the corresponding heteroaromatic molecules, or products of ring expansion, depending on the nature of starting cyclopropanes. The trap of ring expansion products with alkenes and alkynes affording 8-aza- and 8-oxabicyclo[3.2.1]octane derivatives was reported by Reiser et al. [24]. These processes do not belong to the class of molecular rearrangements and are not discussed here in detail. Indoles 12 cyclopropanation with ethyl diazoacetate 13 in the presence of TpBr3Cu(NCMe), where TpBr3 is hydrotris(3,4,5-tribromopyrazolyl)borate, produced D–A cyclopropanes 14, which isomerized to (indol-3-yl)acetates 15 during column chromatography on silica gel (Scheme 6.6) [25]. Heating the related N-acetylcyclopropa[b]indole with HCl in ethanol yielded predominantly 3-indolylacetate; this ring opening was accompanied by N-deacetylation [26].

193

194

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

R3

R2 N Me 12

R1 +

N2

TpBr3Cu(NCMe)

CO2Et

CO2Et

R2

SiO2

N R Me

CH2Cl2, r.t.

13

CO2Et

R2

1

N Me

14

R1

15, 40–99% for two steps

Scheme 6.6 Synthesis of 3-indolylacetic acids 15 by the rearrangement of cyclopropa[b]indoles 14.

Nevertheless, 2-H-3-substituted indoles under the same conditions produced derivatives of (indol-2-yl)acetic acid, while NH-indoles afforded a mixture of 1,3-dialkylated and two monoalkylated products. Similarly, under acidic conditions, cyclopropa[b]benzofuran 16 rearranged to (benzofuran-2-yl)acetate 17 [27], while substrate 18 produced (benzofuran-3-yl)acetic acid 19 [28] (Scheme 6.7).

OH CO2Me

Me O 16

H

HO BF3·OEt2

Me

CO2H

CO2Me

C6H6, 0 °C

O

O 18

17, 68%

CO2H

conc. HCl AcOH

Δ

Ph

O 19, 80%

Ph

Scheme 6.7 Cyclopropane–propene isomerizations of cyclopropa[b]benzofurans 16 and 18.

In the last few years, 2-aryl- and 2-alkenylcyclopropane-1,1-dicarboxylates, as well as their analogs with other electron-withdrawing groups, have been the most studied D–A cyclopropanes. Their studies showed that the moderately active 2-arylcyclopropane-1,1-diesters 20 isomerize to (E)-styrylmalonates 21 under reflux with trimethylsilyl triflate (TMSOTf) in chlorobenzene; the more reactive substrates 20 afford polymeric products at the same reaction conditions, while they yield styrylmalonates 21 in the presence of less activating Lewis acids such as Sn(OTf)2. On the contrary to substrates studied in that work, 2,4,6-trimethylphenyl-derived cyclopropane 22 isomerizes mainly to alkylidenemalonate 23 (Scheme 6.8) [29]. It is noteworthy that without Lewis acid, the rearrangement of the active substrate 20 bearing a 4-methoxyphenyl group as a donor to the corresponding styrylmalonate required heating at 290 °C [30].

CO2Me Ar

CO2Me 20

TMSOTf PhCl, ∆ or Sn(OTf) 2 various conditions

Ar

CO2Me CO2Me 21, 56–88%

Me

CO2Me CO2Me

Me

Me 22

Me

Me

SnCl4

CO2Me

C6H6, ∆

CO2Me

Me 23

Scheme 6.8 Rearrangement of 2-arylcyclopropane-1,1-diesters 20 to styrylmalonate 21; isomerization of 2,4,6-trimethylphenyl-substituted analog 22 to 2-arylethylidenemalonate 23.

6.2 ­DoDor–AAcepDo CAcDeoDepoc IDocoripprDoI pD –clcocI

CAcDeoDepocr–oDecoc cpooponcocopt

On the other hand, the broad variety of alkylidenemalonates 24 were synthesized by the treatment of cyclopropanes 20 with GaCl3 in methylene chloride for 5–15 min at 0 °C (Scheme 6.9) [11, 31]. Ar

CO2Me

GaCl3

CO2Me

CH2Cl2 0 °C, 5–15 min

Ar

CO2Me CO2Me 24, 72–98%

20

Scheme 6.9 Isomerization of cyclopropanes 20 to 2-arylethylidenemalonates 24 in the presence of GaCl3.

The increase in the reaction time led to the decomposition of 24 and its partial isomerization to styrylmalonates 21. This isomerization can be performed by stirring 24 with Lewis acids or bases, with pyridine being the most efficient additive for this goal (Scheme 6.10) [32]. Although for the preparation of styrylmalonates from substrates with highly donor substituents, this approach is less efficient than the direct isomerization described earlier, it allows one to involve cyclopropanes bearing acceptor group(s) in the aromatic ring in the desired transformation. Thus, the two approaches complement each other. Scheme 6.10 Two-step isomerization of cyclopropanes 20 to styrylmalonates 21.

Ar

CO2Me

1) GaCl 3 (1.4 equiv) CH2Cl2, 0−40 °C

CO2Me

2) Pyridine (10 equiv) CH2Cl2, 25 °C

Ar

20

CO2Me CO2Me 21, 22−72%

Vinilogous (2-phenylcyclopropyl)methylenemalonate 25 rearranged to diene 26 under stirring at room temperature with GaCl3 while it gave cyclopentene 27 under heating with Sc(OTf)3 (Scheme 6.11) [33]. CO2Me

Ph

CO2Me

GaCl3 20 °C, CH2Cl2 0.5 h

CO2Me 26, 89%

Ph

CO2Me 25

Ph Sc(OTf)3 110 °C, PhCl 6h

CO2Me CO2Me 27, 98%

Scheme 6.11 Rearrangements of 2-phenylcyclopropylmethylenemalonate 25 to diene 26 and cyclopentene 27.

Another type of vinylogues of 20, i.e. 2-styrylcyclopropane-1,1-dicarboxylates, under treatment with Lewis acids isomerized usually to cyclopentenes (Section 6.2). However, compound 28, bearing an o-nitrophenyl group, in the presence of GaCl3, afforded diene 29. Diene was also formed in the rearrangement of ­2-vinylcyclopropane-1,1-diester 30, albeit in low yield (Scheme 6.12) [34]. NO2

CO2Me CO2Me 28

CO2Me

NO2 GaCl3

CH2Cl2 ∆, 1 h

CO2Me 29, 38%

CO2Me CO2Me 30

GaCl3 CH2Cl2 ∆, 1 h

CO2Me CO2Me 31, 18%

Scheme 6.12 Rearrangements of 2-alkenylcyclopropane-1,1-dicarboxylates 28 and 30 to dienes 29 and 31.

195

196

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

The chemoselectivity of the isomerization of the related cyclopropanes 32 bearing an acyl group at the C(3) atom of the three-membered ring was found to depend on the Lewis acid applied. Under initiation with TiCl4, they rearranged to dienones 33; SnCl4 induced their transformation to cyclopentenes 34 (Scheme 6.13) [35]. Again, the presence of the nitro group in the styryl moiety prevented the formation of the cyclopentene ring.

Scheme 6.13 Isomerization of 3-aroyl-2-styrylcyclopropane-1,1-diesters 32 to dienes 33 and cyclopentenes 34.

The introduction of the phenyl group at the C(3) atom of styrylcyclopropanes also influences the reaction output; in the presence of titanium(IV) or iron(III) chlorides, these substrates 35 rearranged to but-3-enylidenemalonates 36 [36, 37]. Based on the deuterium label distribution, the authors concluded that this rearrangement proceeds via selective (C1)—C(2) bond heterolysis followed by aryl group 1,2-migration (Scheme 6.14). It is noteworthy that the formation of dienes 36 was proved to be reversible; the extension of the reaction time led to the formation of cyclopentenes 37. Among other things, these experiments demonstrate that the styryl moiety stabilizes carbocation more efficiently than the related aryl group. Ar 2 Ar1

MeO

TiCl 4

CO2Me (1 equiv.) CO2Me 35

CH 2Cl2 r.t., 15 min

Ar1

O

TiCl4 O

Ar2 OMe

Ar2

~ Ar 2 – TiCl4

Ar1

CO2Me CO2Me

36, 15–100% 18 examples

TiCl 4 (1 equiv.) CH 2Cl2 r.t., 24 h

Ar1 CO2Me CO2Me Ar 2 37, 26–93% 10 examples

Scheme 6.14 Rearrangement of 3-aryl-2-styrylcyclopropane-1,1-dicarboxylates 35 to skipped dienes 36 and 2,5-diarylcyclopent-3-ene-1,1-dicarboxylates 37.

2’-Phenylbicyclopropyl-1,1-dicarboxylate 38 was found to produce a broad diversity of isomerization products 39–44 depending on the reaction conditions (Scheme 6.15). According to these data, of the two three-membered rings, phenyl-bound cyclopropane undergoes ring opening first; diene 44 is presumably a kinetic product that rearranged to 42 with the increase of reaction time and temperature and to 39 (after stirring with neutral alumina) [33, 38]. At last, the isomerization of D–A cyclopropane 45 was used in the total synthesis of rhodomolleins XX and XXII. The treatment of ketoester 45 with TMSOTf and (CH2OTMS)2 led to both three-membered ring opening and acetal protection of the ketone moiety-producing compound 46 (Scheme 6.16) [39].

6.3 Vinylcyclopropane–Cyclopentene Rearrangement CO2Me Ph 44, 65% 0 °C 0.3 h

Ph

CO2Me CO2Me 43, 10% (+41, 14%)

BF 3·OEt 2 CH2Cl2 GaCl3 CH2Cl2

CO2 Me

Al 2O3 (neutral)

CO2Me GaCl 3 CH 2Cl2

Ph

20 °C 10 min

Ph

39, 90%

CO2Me CO2Me 38

20 °C 1.5 h

40−80 °C

CO2Me CO2Me

SnCl 4 CH2Cl2

Sc(OTf)3

Ph 40, 62%

C 6H 6

CO2Me

CO2Me Ph

CO2 Me

Ph

CO2Me 42, 60%

CO2Me 41, 72%

Scheme 6.15 A diversity of isomerization pathways for 2’-phenylbicyclopropyl-1,1dicarboxylate 38.

O

CO2Et

TMSOTf (CH2OTMS)2

OMe Me Me H

OTIPS

O

O

CO2Et

Me H O HO OMe

R Me

OTIPS

CH2Cl2, 0 °C 70%

Me Me

45

OH Me H

Me OH

HO

R = OH, rhodomollein XX R = H, rhodomollein XXII

46

Scheme 6.16 The rearrangement of benzylcyclopropane 45 in the total synthesis of rhodomolleins XX and XXII.

6.3 Vinylcyclopropane–Cyclopentene Rearrangement Vinylcyclopropane–cyclopentene rearrangement (VCR) was described for the first time in 1959 by Neureiter, who reported that the vacuum pyrolysis of 1,1-dichloro2-vinylcyclopropane 47 at 500 °C (5 mm) produced 3,3-dichlorocyclopentene 48, a product of its dehydrochlorination 49, as well as 1,1-dichloropenta-1,3- and 1,4-dienes 50, 51 (Scheme 6.17) [40]. Cl

500 °C 5 mm

Cl 47

Cl

Cl Cl

Cl +

+ 48

49

Cl Me +

Cl 50

Cl 51

Scheme 6.17 The first example of vinylcyclopropane–cyclopentene rearrangement.

Already, this study demonstrated that thermal rearrangements of vinylcyclopropanes produce a complex mixture of products, the most common side products being dienes, resulting from the cyclopropane–propene rearrangement. Despite this, VCR began to be intensively studied immediately after its discovery; these ­ reactions were considered as a very good approach to “dissonant” five-membered carbocycles, which are abundant in nature and have a broad application, including medicine. The results of these investigations were summarized in a series of reviews [41–47]. The introduction of donor and acceptor substituents into a three-membered ring decreases the energy barrier for VCR; moreover, this decrease is larger than expected

197

198

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

based on the supposition of the stepwise mechanism with a biradical intermediate [48–50]. However, even D–A cyclopropanes, for which the stabilization of the zwitterionic intermediate should be the most important, were rearranged under rather harsh thermal conditions. For example, without a Lewis acid, cyclopropane 52 rearranged to cyclopenta[b[benzofuran 53 under heating at 150 °C in a sealed tube for four days, the conversion being less than 50% (Scheme 6.18) [51]. Ph CN

150 °C sealed tube

CN O 52

Ph O MeO CN CN

Toluene, 4 d conversion ca. 50%

OMe

53, 33%

Scheme 6.18 Thermal rearrangement of 2-(benzofuran-3-yl)cyclopropane-1,1dicarbonitrile 52.

Other examples of thermal VCR of D–A cyclopropanes were reported by Buchert and Reissig. They showed that diastereomerically pure cyclopropanes 54 were converted to mixtures of four diastereomers of 55 under heating at 190 °C in decalin or benzonitrile, with the reaction in more polar solvent being significantly faster. Cyclopropanes 54 are stable under heating at 150 °C in DMF. Bicyclic analogs 56 demonstrated higher reactivity; their rearrangements at 150 °C also produced mixtures of isomers 57 (Scheme 6.19) [52]. CO2Me

Ph OMe ∆

R

CO2Me

CO2Me

R

Decalin or benzonitrile

n

54

Scheme 6.19

H Ph OMe

Ph OMe

55, 71–95%

Ph OMe

∆ DMF

H 56, n = 1, 2

CO2Me n

57, quantitative

Thermal rearrangement of cyclopropanes 54 and 56.

There are restricted examples of D–A cyclopropanes that undergo rearrangement to cyclopentene derivatives under relatively mild conditions. Thus, 1-phenyl-2,2divinylcyclopropanecarboxylic acid, its esters, and amides 58 isomerized to cyclopentenes 59 under reflux in toluene solution (Scheme 6.20) [53]. O

Ph

X

O ∆

Ph

X

PhMe

58

Scheme 6.20 Isomerization of 1-phenyl-2,2divinylcyclopropanecarboxylic acid and its derivatives (58).

59, 73–91%

The use of transition metal catalysis was supposed to decrease the reaction temperature to provide reaction conditions more appropriate for the preparative synthesis. For example, butadienyl-substituted cyclopropane-1,1-dicarboxylate and their analogs 60 rearranged to cyclopentenes 61 in the presence of a catalytic amount of Pd(PPh3)4 at 25–60 °C (Scheme 6.21) [54, 55].

6.3 Vinylcyclopropane–Cyclopentene Rearrangement

R4

R2

R1

R1 CO2R EWG

R3

Pd(PPh3)4 DMSO 25–60 °C

R3

60

CO2R EWG R2

R4 61, 28–96%

dr from 1:1 to 3:1

Scheme 6.21 Pd(PPh3)4-catalyzed isomerization of (butadienyl)cyclopropanes 60 to cyclopentenes 61.

The VCR of similar substrates 62 was also carried out under radical conditions [56]. Refluxing a benzene solution of substrate with Ph3SnH (Bu3SnH, PhSH) and AIBN produced cyclopentenes 63 in reasonable to excellent yields (Scheme 6.22). Scheme 6.22 Rearrangement of alkenylcyclopropanes 62 to cyclopentenes 63 under radical conditions.

R2

R1

R1

R3

EWG

Ph3SnH or PhSH

CO2R

Benzene, Δ

CO2R EWG R2

R3

63, 70–98%

62

It is noteworthy that the related isomerization of 1-acyl-2-alkenylcyclopropanes 64 produced the corresponding cyclopentens 65 in low yields, if at all, even though the rearrangement was carried out at 120 °C in the presence of nickel complexes with N-heterocyclic carbenes (NHC) (Scheme 6.23). This demonstrates that one acyl and one alkenyl group is not enough to provide a significant polarization of the C–C bond between endocyclic atoms bearing donor and acceptor substituents [57]. Scheme 6.23 Ni(NHC)-catalyzed isomerization of alkenylcyclopropanes 64 to cyclopentenes 65.

Cl

O

R2 n

R N

Ni(COD)2 t-BuOK toluene, 120 °C

R1

64, n = 1, 2

O

H

R2

N R

R1 n

H 65, 0–38%

Lithium iodide induced the rearrangement of 2-oxo-6-vinylbicyclo[3.1.0]hexane1-carboxylate 66 to pentalene derivative 67. Its decarboxylation produced compound 68, a useful building block for the synthesis of various natural cyclopentanoids (Scheme 6.24). At the same time, substrate 69, containing no ester functionality, as well as the corresponding bicyclo[4.1.0]heptanes 70 failed to isomerize under these conditions [58]. On the other hand, compounds 69, 70, and related bicyclic alkenylcyclopropanes were isomerized to bicyclo[3.3.0]octenones under thermolysis at 600 °C [59–61]. O

CO2Me

H 66

LiI (2 equiv.) DMF 110 °C, 3 h

O

O

CO2Me

H

135 °C

H 67

4.5 h 70% for two steps

H 68

LiI (2 equiv.) DMF 110 °C, 3 h 0%

O

H

H 69

Scheme 6.24 LiI-initiated rearrangement of cyclopropane 66 to bicyclo[3.3.0]oct-6-ene-1carboxylate 67.

199

200

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

7-Alkenyl-2-oxobicyclo[4.1.0]heptanes 70 with anti-arrangement of the alkenyl group failed to form the product of VCR not only under treatment with lithium iodide but also under such standard procedures as pyrolysis, transition metal, and Lewis acid catalysis. However, these substrates rearranged to the corresponding cyclopentenes 72 under mild heating (40 °C) in acetonitrile in the presence of 1.5 equiv of MgI2 (Scheme 6.25). The mechanism of this transformation, proposed by the authors, includes the reversible nucleophilic addition of iodide-ion to β-carbon atom of the double bond, followed by the cyclization of (Z)-isomer of intermediates 71 to products 72 and (E)-71 to 70 [62]. LiI-induced rearrangements were supposed to proceed by the same mechanism; the different behavior of studied substrates in the presence of LiI and MgI2 was not explained.

R1

O

R2

R3 R4

CO2Me

MgI2 (1.5 equiv.) MeCN 40 °C

R5

H 70

Scheme 6.25

R1 R2 R3 R4

O

I Mg

O OMe I

(Z)-isomer

R1 R2 R3 R4

O

CO2Me R5

H 72, 74−86%

71

MgI2-induced isomerization of alkenylcyclopropanes 70 to compounds 72.

Ila et al. described SnCl4-initiated rearrangement of aryl 2-[4,4-bis(methylthio) butadienyl]cyclopropyl ketones 73 to the corresponding cyclopentenes 74 and their spirocyclic analogs to spirocyclopentenes (Scheme 6.26) [63]. X

O

Me

SnCl 4

SMe n

SMe

CH3NO2, 0 °C

SMe SMe

n

73, n = 0–3

Scheme 6.26

Me O

X

74, 61–85%

Tin(IV) chloride-induced rearrangement of cyclopropanes 73.

Recently, the rearrangement of 2-styrylcyclopropane-1,1-dicarboxylates 75 and their analogs with other acceptor groups was studied in detail [34]. It was shown that yields of target cyclopentenes 76 in the reaction of highly reactive cyclopropanes bearing an electron-rich aromatic group in the styryl substituent are the largest when moderately activating Lewis acids (Ni(ClO4)2∙6H2O or Sc(OTf)3) are applied. On the other hand, for substrates with unsubstituted styryl or halogenostyryl groups, cyclopentenes were formed in the best yields using more activating GaCl3, SnCl4, or TiCl4 (Scheme 6.27). When styryl had an alkyl substituent at the α-position to the cyclopropyl moiety, two types of products were obtained depending on the reaction conditions applied. EWG (Het)Ar

EWG 75

Lewis acid CH2Cl2

EWG EWG (Het)Ar 76, 51–98%

Scheme 6.27 The Lewis acid-initiated isomerization of styrylmalonates 75 to cyclopentenes 76.

6.3 Vinylcyclopropane–Cyclopentene Rearrangement

When methylene chloride solutions of substrates 77 were heated under reflux with tin(IV) chloride, 2,3-disubstituted cyclopent-3-ene-1,1-dicarboxylates 78 were obtained, while under heating with gallium(III) chloride, the isomeric cyclopent2-ene-1,1-diesters 79 were prepared (Scheme 6.28). Scheme 6.28 Rearrangement of 2-(1-alkyl-2-(het)arylvinyl) cyclopropane-1,1-diesters 77.

SnCl4 CH2Cl2, Δ

GaCl3 70–85% CH2Cl2, Δ

CO2Me

R 77

(Het)Ar

78, 67–80%

CO2Me (Het)Ar

CO2Me CO2Me

R

CO2Me CO2Me

GaCl3 CH2Cl2, Δ

R

(Het)Ar 79, 67–75%

The investigation of the reaction stereochemistry revealed that Et2AlCl-induced rearrangement of 1-alkenyl-2-alkoxycyclopropanecarboxylates 80 in CH2Cl2 proceeds with a significant loss of enantiomeric excess (Scheme 6.29), but the introduction of the additional group at the C(3) atom (compound 82) was accompanied by a significant increase of the product ee [64]. OEt CO 2Me EtO R 80, ee 93–94%

Et2AlCl CH 2Cl2 −78 °C to r.t.

Me

OEt CO 2Me

R EtO CO 2Me 81, 66–71% ee 9–11%

Ph

Et2AlCl CH 2Cl2 −78 °C to r.t.

82, ee 65%

Ph

R CO 2Me 83, 72% ee 43%

Scheme 6.29 VCR of the optically active substrates 80 and 82.

Moreover, the conformationally rigid analogs with cyclopropane annulated to tetrahydrofuran (84) and tetrahydropyran (86) afforded the corresponding products 85 and 87 without loss of enantiomeric purity (Scheme 6.30). H O

H

CO 2Me R

H

84, ee 86%

CO 2Me

H

Et2AlCl CH 2Cl2 −78 °C to r.t.

O

H

R 85, 66–72% ee 85–86%

O

H

CO 2Me

CO 2Me

Et2AlCl

R H

86, ee 87–88%

CH 2Cl2 −78 °C to r.t.

O H R 87, 80–87% ee 82–84%

Scheme 6.30 Asymmetric synthesis of cyclopentafurans and -pyrans 85 and 87 from cyclopropanes 84, 86.

These results were used for the asymmetric synthesis of complex polycyclic compounds. Thus, 1-alkenylcyclopropanecarboxylates 88 annulated to 2,3-dihydrobenzofuran fragments were isomerized to the corresponding cyclopentenes 89 using AlCl3 as a Lewis acid (Scheme 6.31) [65]. Similar rearrangements were performed for the related compounds, wherein the same cyclopropane is annulated to the C(2)—C(3) bond of tetrahydrofuran, tetrahydropyran, and N-Boc-indoline using Et2AlCl.

201

202

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes H

H CO Me 2 Br

O

H

Me

AlCl3 CH2Cl2 –20 °C 80%

H CO Me 2 O

O

OMe

H

Br H 88

Me

O

OMe

CO2Me H Br H OMe Me CO2Me H H Me

Br OMe

89

Scheme 6.31 AlCl3-induced rearrangement of alkenylcyclopropanes 88 to cyclopentenes 89.

6.4 Cloke–Wilson Rearrangement and Related Processes The rearrangement of cyclopropylimines 90 or their hydrochloride to 2,3-dihydropyrroles ­ 91 was disclosed by Cloke in 1929 [66]. In 1947, Wilson reported that cyclopropylcarbaldehyde 92 and 2,3-dihydrofuran 93 transform into each other upon heating (Scheme 6.32), with the initial focus on the transformation of 93 to cyclopropane 92 and products of its further decomposition [67]. R NH 90

H

Δ

N H 91

R

O 92

O 93

Scheme 6.32 Seminal studies of the Cloke–Wilson rearrangement.

Later, however, the attention of researchers was predominantly paid to expanding cyclopropyl ketones to 2,3-dihydrofurans, while only a few works were devoted to the synthesis of pyrrolines from cyclopropylimines as well as other related processes. All these rearrangements of cyclopropane derivatives to the corresponding fivemembered heterocycles are now referred to as the Cloke–Wilson rearrangement.

6.4.1 Rearrangement of Acyl-substituted Cyclopropanes to 2,3-dihydrofurans Without an activation with the appropriate catalyst, cyclopropanes underwent the Cloke–Wilson rearrangement only at high temperatures [30, 68]. For example, 1-acetyl-1-methyl-2-phenylcyclopropane isomerized to 4,5-dimethyl-2-phenyl-2,3dihydrofuran under heating above 250 °C with Ea of 48.1 kcal/mol. The introduction of the additional methyl group to the C(3) atom of the three-membered ring (94) allowed one to conclude that dihydrofurans are formed with the predominant retention of the relative stereochemistry of substituents at the C(2) and C(3) atoms (Scheme 6.33). Stereoisomers of the initial cyclopropane and isomeric enones were also formed under these conditions, demonstrating that under thermal conditions this process proceeds via a stepwise mechanism through 1,3-biradical intermediate,

6.4 R Ph

O 285 °C

Me

O

Ph R

Me 94a,b

cDlcr–rcIDo cpooponcocop pond ccppcnd –oDAcIIcI Me

Me Ph

Me

O Me

285 °C

Me

Me 94c

95a,b 30–37% dr 85:15 to 97:3

O

Ph

Me Me

95c, 40% dr 70:30

Scheme 6.33 Thermal rearrangement of 1-acetyl-2-phenyl-1-methyl- and -1,3-dimethylcyclopropanes 94.

wherein bond rotation competes with the ring closure step, and, as a result, it is non-chemoselective [68]. Similar results were also obtained under irradiation of compounds 94. Moreover, Dauben and Shaffer found that the irradiation of the solution of chrysantemal 96a and the corresponding methyl ketone 96b in t-butanol led to both dihydrofurans 97 and a series of side products (Scheme 6.34) [69]. Me

Me

Me Me O

Me 96

R

hν t-BuOH

R

Me

O

Me

+ side-products

Me

97, 51–61%

Scheme 6.34 Photochemical rearrangement of chrysantemal 96a and the related methyl ketone 96b.

Similar to other transformations of D–A cyclopropanes, the Cloke–Wilson rearrangements ­ proceed efficiently in the presence of Lewis or Brønsted acid. For example, Alonso and Morales reported that 2-(4-methoxyphenyl)-1-acetyl-3-Rcyclopropanecarboxylates 98 converted completely to 5-aryl-2-methyl-4-R-4,5dihydrofuran-3-carboxylates 99 after stirring with neutral alumina (activity III) in chloroform for 24 h, the process proceeding with complete retention of cyclopropane stereochemistry (Scheme 6.35) [70].

Scheme 6.35 Isomerization of 1-acetyl-2-(4-methoxyphenyl)cyclopropanecarboxylates.

This study stimulated further investigations of the acid-induced Cloke–Wilson rearrangements. Thus, it was shown that spiro[cyclopropane-1,2’-cyclohexane-1’,3’diones] 100 rearranged efficiently to 2,3,6,7-tetrahydrobenzofuran-4(5H)-ones 101 in the presence of TMSI, TMSOTf, Sc(OTf)3, MgI2, BF3∙OEt2, or TsOH∙H2O (Scheme 6.36) [71, 72]. This approach was used by the authors in the total synthesis Scheme 6.36 Acid-initiated rearrangement of spiro[cyclopropane-1,2’-cyclohexane-1’,3’diones] 100.

O

O R1

R2 R3

O 100

TsOH·H2O CH2Cl2, r.t.

R1 R2 O R3 101, 72–98%

203

204

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

of cuspidan B [72]. Even substrates having an alkyl group as a donor were found to be highly reactive. Nevertheless, yields in the reactions of alkyl-substituted cyclopropanes are lower than those for cyclopropanes with an aryl group as a donor. The ease of this rearrangement was additionally confirmed by the isolation of tetrahydrobenzofuran-2-ones 101 during the synthesis of cyclopropanes 100 [73, 74]. At the same time, the efficiency of TsOH-induced rearrangement was low for spirocyclopropanes obtained from cyclopentane-1,3-dione, and various acyclic 1,3-diones [72]. The acid-induced isomerization was used by Werz et al. for the synthesis of tricyclic bisacetals and bishemiaminals 103 by double isomerization of dicyclopropanes 102, wherein carbon atom of three-membered ring, connected to an acceptor group, is quaternary. Oppositely, if the second substituent at this atom is hydrogen, compounds 102 rearranged to 3,4-bis(acylmethyl)furans and -pyrroles 104; these processes are examples of cyclopropane-to-propene rearrangement (Scheme 6.37) [75]. O

O

R2

R2

1

R2 R

TsOH THF, 80 °C R1 = H

X

O

H H

O

R1 R2

R1 X

H

TsOH THF, 80 °C

H

O H

HH X

R1 R2 O H

103, 59–97%

102

104, 29–93%

R2

Scheme 6.37 TsOH-induced rearrangement of biscyclopropatetrahydrofurans and -pyrrolidines 102.

The high efficiency of the rearrangement of cyclopropanecarbaldehyde to dihydrofuran was used for the synthesis of the related polycyclic compounds (105, 106, etc.), with both odd and even numbers of tetrahydrofurans annulated via C(2)—C(3) bonds containing up to nine rings (Scheme 6.38) [76, 77]. H 1) N2CHCO2Et Cu powder toluene, 100 °C

HH O H

O

O H

103a

2) LiAlH4, THF 3) IBX, DMSO

HHHH

O H

O H

O 105

O O

H

H

1) N2CHCO2Et Cu powder toluene, 100 °C

1) N2CHCO2Et Cu powder toluene, 100 °C

2) LiAlH4, THF 3) IBX, DMSO

2) LiAlH4, THF 3) IBX, DMSO

O

O

HH H H HHHH

H O H

O

O H

O 106

H O H O

O

H

H

Scheme 6.38 Synthesis of annelated THF moieties by cyclopropanation-modificationisomerization sequence.

The use of BINOL-based phosphoric acids allowed to perform the asymmetric transformation of a broad series of cis-1-acyl-2-arylcyclopropanecarboxylates 107 to 2-aryl-2,3-dihydrofuran-4-carboxylates 108 in 48–95% yield and enantiomeric ratio (er) between 83:17 and 96:4 (Scheme 6.39) [78]. The efficiency of this rearrangement depended crucially on the nature of acyl functionality: cyclopropanes containing acetyl, propionyl, butyryl, and isobutyryl groups produced dihydrofurans in good-to-excellent yields, while cyclopropanes with benzoyl group failed to produce the target products. Moreover, the introduction of the second substituent to the C(2) atom of the three-membered ring led to a decrease in er.

6.4

cDlcr–rcIDo cpooponcocop pond ccppcnd –oDAcIIcI

R3 O O P O OH

O R2 Ar CO2R1 107

R3 R3 = 9-phenanthryl m-xylene, DCE –30 °C or –40 °C

R2

O

Ar

R1O2C 108, 96% er from 83:17 to 96:4

Scheme 6.39 Chiral phosphoric acid-catalyzed isomerization of cis-1-acyl-2arylcyclopropanecarboxylates 107 to the optically active dihydrofurans 108.

It is noteworthy that 1-acyl-2-arylcyclopropanes 109 also underwent an asymmetric transformation to the optically active 2-aryl-2,3-dihydrofurans 110 in 75–92% yields and good enantioselectivity (er from 90:10 to 95:5) (Scheme 6.40) [78]. The reversible cyclopropane ring opening under the reaction conditions is responsible for the success of this asymmetric transformation, as the stereochemical information of the starting substrates is lost during the process, and the stereochemical result of the reaction was determined exclusively by the chiral phosphoric acid used as a catalyst. R' O O P O OH

O Ar

R 109

m-xylene, DCE –30 °C or –40 °C

O

R

R' R' = 1-naphthyl

Ar

110, 75–92% er from 90:10 to 95:5

Scheme 6.40 Asymmetric synthesis of 2-aryl-2,3-dihydrofurans 110.

The Cloke–Wilson rearrangement was carried out for a broad range of D–A cyclopropanes. For example, substrates 111, wherein the silylmethyl group serves as a donor group, isomerize to dihydrofurans 112 (Scheme 6.41) [79]; spiro[cyclopropane– barbiturates] 113 rearranged to furo[2,3-d]pyrimidines 114 (Scheme 6.42) [80, 81], etc. Scheme 6.41 The rearrangement of 2-silylmethyl-1-EWG-substituted cyclopropyl ketones 111.

Scheme 6.42 The Cloke-Wilson reaction of cyclopropane, spiro connected to barbituric acid moiety, 113 to furopyrimidine 114.

EWG

t-BuPh2Si

O R1 111

EWG TiCl4

N

R1

O

112, 70–96% O

O Me

t-BuPh2Si

CH2Cl2

N

O

Me

Me AlCl3

O

EWG 113

CH2Cl2 r.t.

O

N

N

Me O EWG

EWG EWG 114, 69–99%

205

206

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

The Cloke–Wilson rearrangement can also be induced by nucleophiles. For example, it was shown that 2-aryl-1-(tri- or difluoroacetyl)cyclopropanecarboxylates 115 isomerized efficiently to the corresponding dihydrofurans at room temperature under treatment with 10 equiv of NaI in acetone while at 60 °C (Scheme 6.43). Moreover, this rearrangement proceeded quantitatively in the presence of only 5 mol.% of NaI [82]. Scheme 6.43 NaI-induced isomerization of trans-1-acyl-2-arylcyclopropanecarboxylates 115 to 116.

CO2Me Ar O 115

CO2Me

NaI

Rf

Acetone 60 °C, 12 h Rf = CF3, CHF2

Ar

Rf

O

116, >99% 8 examples

The stepwise mechanism was proposed for these processes. The initial nucleophilic attack of the iodide ion leads to the three-membered ring opening providing an acyclic intermediate containing an enolate anion. Then enolate serves as a nucleophile while iodide serves as a leaving group, affording dihydrofuran as a cyclization product. When this isomerization was performed for the optically active substrate 117, product 118 was obtained with the retention of the configuration of the benzylic carbon atom, which confirms the double inversion mechanism; some loss of enantiomeric purity can be explained by either partial racemization of substrate 117 during the reaction or the contribution of iodide substitution by another iodide ion (Scheme 6.44) [83]. Br

CO2CMe3 CHO 117, dr 92:8 ee 98%

NaI (10 equiv) Acetone 60 °C, 72 h

CO2CMe3

Br O

118, 74% 82% ee

Scheme 6.44 The isomerization of the enantiomerically pure cyclopropane 117.

A similar mechanism was proposed for Bu4N[Fe(CO)3(NO)]-catalyzed isomerization of 1,1-diacyl-2-vinylcyclopropanes 119 to the corresponding dihydrofurans 120 based on the results of DFT calculations [84]. Experimentally, this isomerization was carried out either under reflux in methylene chloride or under irradiation at room temperature in acetonitrile, the photochemical conditions being typically preferable (Scheme 6.45) [85]. The relative arrangement of substituents in the threemembered ring as well as substituents at the C=C bond influence the reaction efficiency insignificantly. Compounds with methyl group(s) at the C(3) atom of a small ring under thermal conditions yielded dihydrofurans with lower yields, but these groups had no effect on the reaction output under photochemical conditions. It is especially important that nucleophilic catalysis be equally efficient for a broad series of substrates, including substrates that failed to give dihydrofurans under Lewis/ Brönsted acid catalysis.

6.4

R2 R1

R4 R5

O 119

Bu4N[Fe(CO)3(NO)] A) CH2Cl2, Δ B) hν, MeCN, 180 W (Hg lamp), r.t.

O

R7 R3 R6

R6 R7O

R3

cDlcr–rcIDo cpooponcocop pond ccppcnd –oDAcIIcI

R4 R5

R2

O

R1

120, 75–98% 15 examples

Scheme 6.45 Bu4N[Fe(CO)3(NO)]-catalyzed isomerization of 1,1-diacyl-2vinylcyclopropanes 119.

1,1-Diacyl-2-arylcyclopropanes 121 and the corresponding ketoesters behave similarly but require harsher reaction conditions. Under catalysis with Bu4N[Fe(CO)3(NO)], they rearranged into the corresponding dihydrofurans 122 either under heating in DMF at 120 °C or under irradiation with UV light for 24 h. For these substrates, yields under thermal conditions are typically higher than under irradiation (Scheme 6.46) [85]. O O X

R2 R1 O 121

Bu4N[Fe(CO)3(NO)] A) DMF, 120 °C, MW B) hν, DMF UV light, r.t., 24 h

R2

X O

R1

122, 77–99% 12 examples

Scheme 6.46 Bu4N[Fe(CO)3(NO)]-catalyzed rearrangement of cyclopropanes 121.

Tertiary amines can also induce the Cloke–Wilson rearrangement of D–A cyclopropanes, but the DABCO-initiated process requires heating in DMSO at 120 °C (Scheme 6.47) [86]. Scheme 6.47 DABCO-initiated rearrangement of 1,1-diacyl-2-aryl/alkenylcyclopropanes 119 and 121.

O

O R3

R1

R2 O

119, 121

R3

DABCO DMSO 120 °C

R1

O

R2

120, 122, 42–99% 21 examples

When the starting substrate contains two different acceptor substituents, the reaction chemoselectivity is determined by their nature. For example, the acyl group participates in the process while ester or amide groups remain intact. Cyclopropanes bearing acetyl and benzoyl groups as acceptors produced a mixture of two products with a small excess of 3-benzoyl-2-methyl-4,5-dihydrofurans. In the reactions discussed above, the anionic Fe complex induced the Cloke– Wilson rearrangement, serving as a nucleophile. At the same time, alkenylcyclopropanes 123 bearing two acceptor groups at the vicinal position (one of them is an acyl) were shown to undergo the rearrangement to 5-vinyl-4,5-dihydrofurans 124 under common transition metal catalysis (Scheme 6.48) [87, 88].

207

208

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes Ni(COD)2 ligand CH3CN, r.t.

X

R2

O

R3

O R3

or Rh(PPh3)3Cl AcOH, THF 100 °C

O R1 123

X

R2

1

R O 124, 76–99%

Scheme 6.48 Transition metal-catalyzed isomerization of 1-acyl-2alkenylcyclopropanes 123.

6.4.2 The Cloke–Wilson Rearrangements Affording Pyrrole Derivatives There are only scarce examples of cyclopropylimine-to-pyrroline rearrangements for D–A cyclopropanes that can be related to the competition of imine hydrolysis with the Cloke–Wilson rearrangement. For example, highly active cyclopropane 125 during column chromatography was transformed into aldehyde 126, pyrroline 127, and dihydrofuran 128 (Scheme 6.49) [89]. In this reaction, silica gel served as an acidic catalyst, inducing both imine hydrolysis and rearrangement. Ph OMe

Ph OMe

SiO2

N

R

CMe3

hexane/EtOAc

125

+

O

R

MeO Ph

CMe3 N +

R 127, 17–20%

126, 20–25%

MeO Ph

O

R 128, 34–36%

Scheme 6.49 The competition of imine hydrolysis and rearrangement for cyclopropyl imines 125.

6,7-Dimethoxy-1-(2-phenylcyclopropyl)-3,4-dihydroisoquinoline 129 is a quite stable compound and did not rearrange to the corresponding pyrroloisoquinoline derivative. However, its methylation afforded salt 130, which contains a much more efficient electron-withdrawing group and underwent the Cloke–Wilson rearrangement affording pyrroloisoquinolinium salt 131 even at the boiling point of acetone (Scheme 6.50) [90]. It is noteworthy that the related cyclopropane without phenyl group under the same reaction conditions did not isomerize to pyrroloisoquinolinium salt. MeO

MeO N

MeO

129

Scheme 6.50 salt 130.

MeO

MeI Acetone 25 °C

Ph

N

MeO

130

Me

Ph

Acetone Δ

MeO

N

Me Ph

131, 64%

Synthesis and isomerization of 1-cyclopropyl-2-methylisoquinolinum

On the other hand, 1-(2-pyridyl)-2-styrylcyclopropanecarboxylates 132 afforded dihydroindolizine derivatives 133 under catalysis with Pd(PPh3)4; most of the rearrangement products were isolated after aromatization [91]. A single example of the isolation of 133 was described (Scheme 6.51).

6.4

cDlcr–rcIDo cpooponcocop pond ccppcnd –oDAcIIcI

Cl Cl

N

N

Pd(PPh3)4 DCE, 50 °C

CO2Et

CO2Et 133

132

Scheme 6.51 Palladium-catalyzed rearrangement of 1-(pyridin-2-yl)-2styrylcyclopropanecarboxylate 132.

6.4.3 The Related Rearrangements Affording Other Heterocycles Not only C=O and C=N groups can participate in the rearrangement of this type. For example, various nitrocyclopropanes were rearranged to the corresponding isoxazoline N-oxides [92–96]. An example of this reaction is given in Scheme 6.52. Scheme 6.52 Isomerization of ethyl 2,2-dimethyl-1nitrocyclopropanecarboxylate 134.

NO2

Me

CO2Et

Me

O

BF3·OEt2 CH2Cl2, r.t.

N O

Me

Me CO2Et 135, 100%

134

It is worth noting that the rearrangement of 2-aryl-1-nitro-1-(1-nitro-2-arylvinyl) cyclopropane 136 to the corresponding isoxazoline N-oxides 137 can be accompanied by an unusual shift of nitro group, affording 5-aryl-3-(2-aryl-2-nitrovinyl)isoxazoline N-oxides 138 (Scheme 6.53) [96]. NO2 Ar

Ar

O

NaI

N O

DMSO, 60 °C

O

NaI

Ar

DMSO, 60 °C

Ar

O2N

N O

Ar

Ar

NO2

O2N

136

138, 32–80%

137, 68–98%

Scheme 6.53 Unusual shift of nitro group accompanying the rearrangement of cyclopropanes 136.

It is also possible to point out that 1-nitroso-2-phenylcyclopropane 140, formed as an intermediate in the 2-phenylcyclopropylamine 139 oxidation, undergoes in situ rearrangement to 5-phenyl-4,5-dihydroisoxazoline 141 (Scheme 6.54) [97]. DMDO

Ar

NH2 139

acetone, r.t.

Ar

NO 140

Ar

O

N

141, 42%

+

Ar

NO2 142, 7%

Scheme 6.54 The formation of 4,5-dihydroisoxazoline 141 and 1-nitro-2phenylcyclopropane 142 in the oxidation of 139.

The relative efficiency of various Cloke–Wilson-like rearrangements has been studied by the DFT method under the supposition of a concerted mechanism for this transformation. In general, the trend of reactivity for diverse donor groups was found to be Me2N > OMe > SMe, SeMe, Ph > Me, PMe2, Cl. The analogous trend for diverse acceptor groups is N=O > CH=S > C(R)=O, CH=NR, NO2 > C(O)OR,

209

210

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

despite the fact that the relative reactivity in these sequences depends on the vicinal substituent. The lowest energy barrier was found for cyclopropane bearing a nitroso group as an acceptor and a dimethylamino group as a donor, while methyl 2-chlorocyclopropanecarboxylate ­ has the largest activation energy [98].

6.5 Nazarov Reaction and its Homo-Version D–A cyclopropanes bearing an aroyl group as an acceptor substituent can be involved not only in the Cloke–Wilson rearrangement but also in the homo-Nazarov cyclization, i.e. the acid-stimulated cyclization of alkenyl/aryl cyclopropyl ketones to cyclohexenones. This process proceeds by a stepwise mechanism with the intermediate cyclopropane ring opening, which facilitated by a donor group at the vicinal position to the carbonyl function. Therefore, these were D–A cyclopropanes that were predominantly involved in the homo-Nazarov cyclization. These studies are summarized in a number of reviews [99–101], although it should be noted that only one of them [101] is devoted exclusively to the homo-Nazarov cyclization. The investigation of this process was started by Murphy and Wattanasin in the early 80s. In a series of articles [102–105], they reported that aryl 2-arylcyclopropyl ketones 143 rearrange to 4-aryltetralones 145 through the intermediate oxonium cation 144, if aroyl moiety contains an electron-releasing group facilitating the Friedel–Crafts alkylation. 4-Aryl-4-hydroxybutyrophenones 146 were also formed after quenching the reaction mixtures before the reaction was over or if the aroyl moiety contained no substituent, directing the electrophilic attack to the orthoposition to the carbonyl group (Scheme 6.55).

X

SnCl4

R Y

X

X

X

O

CH3NO2 or C6H6

O

O

R

O

R

+

R

Y

143

Y

Y

144

OH

145

146

Scheme 6.55 Homo-Nazarov rearrangement of 1-aroy-2-arylcyclopropanes 143.

The developed method was used for the synthesis of (±)-picropodophyllone: cyclopropane 147 isomerized to tetralone 148, whose three-step transformation yielded the target product (Scheme 6.56) [106]. O

O O

CO2Et

O

OMe MeO

OMe

O

O BF3·OEt2

O

CO2Et

CH3NO2 r.t., 15 d

MeO

1) KOH, MeOH, 95% 2) CH2O, NaOH H2O, r.t., 30 h, 80%

Scheme 6.56

O

O

3) Jones reagent acetone, 50 min, 72%

OMe OMe

147

O

148, 57%

Total synthesis of (±)-picropodophyllone.

O MeO

OMe OMe picropodophyllone

6.5 Nazarov Reaction and its omo-Version

At the same time, the belonging of cyclopropane 147 to the class of D–A cyclopropanes raises certain doubts as two acceptor groups at the vicinal carbon atoms decrease the mutual polarization of C—C bonds in a three-membered ring. Oppositely, cyclopropanes 149 can definitely be referred to as D–A ones. Under reflux of their dichloroethane (DCE) solution with titanium(IV) chloride, they underwent homo-Nazarov cyclization, affording 1-hydroxy-3,4-dihydronaphthalene derivatives 150 (Scheme 6.57) [107]. Optically active cyclopropanes 149 afforded the corresponding dihydronaphthalenes with retention of the absolute configuration of chiral atoms and without loss of enantiomeric excess. OH CO2R1

O

CO2R1

TiCl4

R2

X

X R2

DCE, 83 °C

Y

Y

150, 31–92%

149

Scheme 6.57 Homo-Nazarov cyclization of 1-aroyl-2-arylcyclopropanecarboxylates 149.

Cyclopropanes with heteroaroyl group as acceptor behave similarly to benzoylsubstituted cyclopropanes. Thus, under treatment with SnCl4, 2-furyl- and 2-thienyl 2-arylcyclopropyl ketones 151 rearranged to 4-aryl-4,5,6,7-tetrahydrobenzofuran and -benzothiophene 152 (Scheme 6.58) [108, 109]. It should be noted that 4-methoxyphenyl derivative 151 isomerized at room temperature, while the cyclization of phenyl-substituted 151 required heating at 80 °C. Scheme 6.58 SnCl4-initiated isomerization of 2-arylcyclopropyl 2-furyl- and 2-thienyl ketones 151.

O X

X

SnCl4

Ar O

C6H6, r.t. or DCE, 80 °C

Ar 152, 54–94%

151

Heating was also needed for homo-Nazarov cyclization of cyclopropanes, wherein the silylmethyl group served as a donor substituent (Scheme 6.59). Substrates 153 with 5-R-2-furyl-, 2-thienyl-, and 2-indolyl-groups produced benzofuran, benzothiophene, and carbazole derivatives in 70–85% yields. It is interesting that for the corresponding reactions of substrates 155 with 3-furyl-, 3-thienyl-, and 3-indolyl-groups the reported yields were the same (80%) independently of the nature of heterocycles [109]. The reactivity of the related 1-(hetarylcarbonyl)cyclopropanecarboxylates 157 and 159 (hetaryl is 2- and 3-furyl, 2- and 3-thienyl, benzofuran-2- and 3-yl, 1-methylindol-2O X

SnCl4

X

O X

SnCl4

DCE, 80 °C

O 153

SiR3

DCE, 80 °C

SiR3 154, 70–85%

O 155

SiR3

X 156, 80%

SiR3

Scheme 6.59 Cyclization of 1-heteroaroyl-2-silylmethylcyclopropanes 153 and 155.

211

212

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

and -3-yl) with diverse donor groups (aryl, silylmethyl) is much higher, which allowed ­ performing their cyclizations to the corresponding annulated derivatives 158 and 160 under catalysis with milder Lewis acid, In(OTf)3 (Scheme 6.60). At the same time, the presence of the second acceptor had some drawbacks: products were formed as mixtures of diastereomers [110, 111]. O CO2Me

X

EDG CH2Cl2, r.t .

EDG

CO2Me

X

O

CO2Me

Yb(OTf) 3 CH2Cl2, r.t.

X

EDG

O 158, 63–91% dr from 1.1:1 to 2.4:1

157

O CO2Me

X

Yb(OTf) 3

159

EDG

160, 61–83% dr from 1.1:1 to 1.7:1

Scheme 6.60 Homo-Nazarov cyclization of cyclopropanes 157, 159.

Two specific examples should be pointed out. The first one is the reaction of substrate 161, bearing 2-bromo-3-thienylcarbonyl group as an acceptor group. In this compound, α-position was blocked by the bromine atom, and atom C(4) was included in the reaction providing benzo[c]thiophene derivative 162. The second one is the reaction of cyclopropane 163 with an alkoxy group as a donor substituent; the elimination of alcohol from the initially formed ring leads to its aromatization furnishing 7-hydroxybenzothiophene 164 (Scheme 6.61) [110]. Br S

O

Br O CO2Me

Yb(OTf) 3 CH2Cl2, r.t.

CO2Me S

S

161

Yb(OTf) 3 CH2Cl2, r.t.

OEt

PMP 162, 56%

PMP

O CO2Me

163

S

CO2Me OH 164, 51%

Scheme 6.61 Atypical examples of homo-Nazarov cyclization of thenoylcyclopropane derivatives 161, 163.

Homo-Nazarov cyclization was used by Waser et al. for the synthesis of indolo[2,3h]quinoline derivatives 166 from 7-(indol-2-ylcarbonyl)-1-azabicyclo[4.1.0]heptanes 165. (Scheme 6.62) [112, 113]. O N Me 165

R

H

Cbz N

Cbz N H TsOH MeCN, r.t.

R

Scheme 6.62 Homo-Nazarov cyclization in the synthesis of octahydroindolo[2,3-h]quinolines 166.

N O Me 166, 90–100%

The authors applied the developed procedure for the synthesis of some natural products. They synthesized the related NH-indoles 167 and introduced them into the homo-Nazarov reaction. Surprisingly, two products were formed: the expected products 168 and the products of cyclization with the participation of N-atom of the indole ring 169 (Scheme 6.63). Optimization of reaction conditions allowed for preparing all of them in good yields [112–114]. Moreover, it was shown that

6.5 Nazarov Reaction and its omo-Version R1 R2 R3

O N H

H

R2

Cu(OTf)2 MeCN, r.t.

Cbz N

R1 R2

Et

+

R3

or TsOH DCM, r.t.

Et

Cbz R1 N H N H

167

O N H Cbz N

R3

O

Et

169, 82–88%

168, 78–85%

Scheme 6.63 Two ways for rearrangement of D–A cyclopropanes 167.

compound 169 can rearrange to isomeric 168 in high yield under prolonged treatment with copper(II) triflate [113]. Deprotection of 168a (R1 = R2 = R3 = H) accomplished the formal synthesis of (±)-aspidospermidine. On the other hand, substrate 170 was converted to indolo[2,1h]quinoline derivative 171, which was transformed in 4 steps to (±)-goniomitine (Scheme 6.64) [112]. (i-Pr) 3SiO

(i-Pr) 3SiO O N H

H

Cbz N

TsOH

N H Cbz N

DCM, r.t.

Et 170

HO

O 4 steps

Et

171, 93%

N H HN

Et

(±)-goniomitine

Scheme 6.64 Formal homo-Nazarov reaction in the total synthesis of (±)-goniomitine.

At last, homo-Nazarov cyclization of D–A cyclopropane 172 affording indoloquinoline derivative 173 was a key step in the total synthesis of jerantinine E (Scheme 6.65) [114]. MeO MeO

O N H 172

Et

H

Cbz N

Cu(OTf)2

MeO

Cbz N H

MeCN, r.t.

MeO

N H 173

Et

O

N 7 steps

Et

MeO MeO

CO2Me N H jerantinine E

Scheme 6.65 Homo-Nazarov cyclization in the total synthesis of jerantinine E.

The transformation of 1-(indol-2-ylcarbonyl)-2-amidocyclopropane 168, 170 to indolo[2,1-h]quinolines 169, 171 can be classified as either nucleophilic ring opening/cyclization ­ or as homo-Nazarov cyclization, accounting for the involvement of the N(1)—C(2) bond in the aromatic system of the indole ring that implies the partial double bond character of this bond. The same problem is faced when choosing the type of process, which includes the cyclizations of (indol-1-yl)carbonyl- and (pyrrol-1-yl)carbonylcyclopropanes 174 to the corresponding indolizine derivatives 175. For ease of comparison, we included these reactions in this section (Scheme 6.66). It was found that for indole-derived cyclopropanes, the best yields were obtained using indium(III) triflate as a catalyst [115, 116], while for pyrrolederived analogs, the best results were achieved with Al(OTf)3 [117]. Various aryl groups, silylmethyl, amino, alkoxy, arylsulfanyl groups, and two alkyl substituents were used as donors; cyclopropanes with electron-abundant aromatic groups

213

214

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes R3 R2

N O 174

R3

In(OTf)3 DCM, r.t. (for indoles)

R1 CO2Me

or Al(OTf) 3 MeCN, 84 °C (for pyrroles)

R1

R2

N O CO2Me 175, 48–99% dr from 1.1:1 to 7.1:1

Scheme 6.66 Cyclization of (indol-1-yl)- and (pyrrol-1-yl)carbonylcyclopropanes 174 to indolizines 175.

rearranged more efficiently than those with phenyl or 4-halophenyl substituents, while 4-nitrophenyl derivative was found to be unreactive. The developed procedure was applied for the synthesis of (±)-deethyleburnamonine (Scheme 6.67). Formal homo-Nazarov cyclization of cyclopropane 176 afforded tetracyclic compound 177, which was converted to the target product in two steps only [116]. Br Br In(OTf)3

N O

Boc H N

N

Boc

N

DCM, r.t.

H CO2Me 177, 71%, dr 3:1

CO2Me

O

176

1) CF3CO2H r.t., 87%

N N

2) NaCl, H 2O DMSO, ∆ 85%

H H

O

deethyleburnamonine

Scheme 6.67 Synthesis of (±)-deethyleburnamonine using formal homo-Nazarov cyclization.

It should also be noted that continuous flow cyclopropanation/formal homoNazarov cyclization of indoles 174 to indolizine derivatives 175 was developed opening the way for the potential use of this transformation in the industry [118]. Not only (het)aroyl-substituted D–A cyclopropanes can be involved in homoNazarov cyclization. Cyclopropanes with various α,β-unsaturated acid moieties can also participate in this transformation giving rise to substituted cyclohexenones. In the first study of this cyclization polyphosphoric acid in benzene was used for the reaction initiation, however under these conditions some side processes proceeded also, and yields of the corresponding cyclohexenones were from low to moderate [119]. More recently, TsOH was used for the cyclization of substrates 178, bearing dihydropyran and dihydrofuran as fragments containing nucleophilic C—C bonds, to the corresponding bicyclic compounds 179 (Scheme 6.68) [120]. Simple alkenes 180 failed to give product of homo-Nazarov cyclization under these conditions. They reacted in the presence of In(OTf)3, however, the expected products 181 O

O R

O

TsOH MeCN, r.t. n n = 1, 2

EDG 178

Scheme 6.68

R3

O

O Me

O MeO 2C n

EDG 179, 15–100%

R2

EDG 180

In(OTf)3

MeO 2C

CH2Cl2, r.t.

OH Me MeO2C + R1

EDG 181, 0–31%

R1 EDG 182, 45–92%

Alkenyl cyclopropyl ketones 178 and 180 in homo-Nazarov cyclization.

6.6 ­Tc Dec cpooponcocop pond ccppcnd IDocoripprDoI Do ­DoDor–AAcepDo CAcDeoDepocI

were formed as minor products if at all. Their isomers 182 with exocyclic C—C double bonds were obtained as major or exclusive products [121]. All these processes demonstrate the large perspectives for using homo-Nazarov cyclization of D–A cyclopropanes. However, D–A cyclopropanes can also participate in the Nazarov cyclization itself. 2-Alkenyl-2-arylcyclopropane-1,1-diesters 183 under treatment with strongly activating Lewis acids underwent a three-membered ring opening, producing 1,3-zwitterionic intermediates, whose positively charged part is analogous to that in the common Nazarov cyclization. As a result, indenes or their heterocyclic analogs 184 were formed in good to excellent yields (Scheme 6.69). Similarly, 2,2-bis(β-methylstyryl)-substituted cyclopropane afforded the corresponding cyclopentadiene [122].

X

CO2Me CO2Me R1

Y 183

R2

MeO BF3·OEt 2 CH2Cl2 –78 °C

X

OBF3 CO2Me R1

Y R2

CO2Me X

CO2Me R1

Y R2 184, 76–99%

Scheme 6.69 Formal Nazarov cyclization of D–A cyclopropanes 183.

Moreover, it was shown that TiCl4 promoted rearrangement of 3-aroyl-2arylcyclopropane-1,1-dicarboxylates 185 to (3-aryl-1-oxoindan-2-yl)malonates 186 via coordination of Lewis acid to both ester groups, leading to the C(1)–C(2) bond breaking, producing α-aroylstyrylmalonates (Section 6.1), and aroyl oxygen, inducing Nazarov cyclization (Scheme 6.70) [123].

Scheme 6.70 TiCl4-promoted rearrangement of cyclopropanes 185 to indanones 186.

6.6 The Cope Rearrangement and Related Isomerizations of Donor–Acceptor Cyclopropanes The rearrangement of 1,2-divinylcyclopropanes to cycloheptadienes has been studied since 1960 [124]; the results of these investigations were summarized in some reviews [125, 126]. It should be noted that cis-1,2-dialkenylcyclopropanes rearrange usually under very mild conditions, which complicates the study of this process. Nevertheless, some examples of the Cope rearrangement of D–A cyclopropanes are known. Thus, compound 187, a product of the furan cyclopropanation, can be isolated in a pure form, but it rearranged to 8-oxabicyclo[3.2.1]octadiene 188 as well as acyclic products 189 even at room temperature (Scheme 6.71) [127].

215

216

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes Me Me

CN r.t.

O

Me

Me

187

O 188

Scheme 6.71

CN CHO +

CN

189

Rearrangement of cyclopropa[b]furan 187.

Another example of the Cope rearrangement was described relatively recently [128]. Namely, 2-vinylspiro[cyclopropane-1,3’-oxindoles] 190 rearranged to cyclohepta[cd]indoles 191 when vinyl and phenyl groups have cis-arrangement while another diastereomer was unreactive (Scheme 6.72) [128]. Me

Me

N R

O

Me

60 °C PhH

N R

O

O N R 191, 55–58%

190

Scheme 6.72

The Cope rearrangement of 2-vinylspiro[cyclopropane-1,3’-oxindoles] 190.

2-Alkenyl-1-arylcyclopropanecarboxylates, -phosphonates, and related compounds 191 can isomerize to either benzocycloheptenes 192 via 3,3-sigmatropic shifts or 4-arylcyclopentenes 193 via VCR. It was found that substrates, bearing two electronwithdrawing substituents in the vicinal position to the alkenyl group, underwent the Cope rearrangement; oppositely if the electron-withdrawing ability of these two ­substituents is not enough, VCR competes or predominates (Scheme 6.73) [129]. EWG

Me X

Me

EWG

Me

Me

Δ PhCN

Me X

191

Me

+ EWG X

192, X = NO2

193, X = H, OMe

Scheme 6.73 The aromatic Cope rearrangement of D–A cyclopropanes 191.

The phosphine-catalyzed isomerization of 2-alkenylcyclopropyl ketones 194 to cycloheptenones 195 was proposed by Xu et al. [130]. Despite this process is not a real 3,3-sigmatropic shift, the products correspond to the formal Cope rearrangement of the enol form of the starting cyclopropane (Scheme 6.74). R2

R1

EWG R2

O 3

R

R1

194

Scheme 6.74

n-Bu3P PhMe 110 °C

EWG

O R3

EWG PBu3

PBu3 O

R3

O R3

EWG

R2

R2 R1

R1 195, 47–90%

Isomerization of 2-alkenylcyclopropyl ketones 194 to cycloheptenones 195.

This approach was used in the total syntheses of daphenylline (Scheme 6.75) [131].

6.6 ­Tc Dec cpooponcocop pond ccppcnd IDocoripprDoI Do ­DoDor–AAcepDo CAcDeoDepocI Me

Me

t-Bu3P

Me

N

PhCl 110 °C

O O 196

N

Me

7 steps

H

H

Me N

O O 197

H

H

daphenylline

Scheme 6.75 Rearrangement of alkenylcyclopropyl ketone 196 in the total synthesis of daphenylline.

Heteroatom analogs of the Cope rearrangement have also been investigated. It was shown that cis-2-vinylcyclopropanecarbaldehyde 198 is in equilibrium with 2,5-dihydrooxepine 199; the ratio of the two isomers being 95:5 in favor of cyclopropane (Scheme 6.76) [132]. Similarly, syn-bicyclo[3.1.0]hex-2-ene-6-carbaldehyde 200 was found to be in equilibrium with 2-oxabicyclo[3.2.1]octa-3,6-diene 201 [133]. On the other hand, for 2-phenyl-2-vinylcyclopropanecarboxaldehyde 202, this ratio is 28:72 [134]. Some other examples of the related equilibriums were reported [135, 136]. O

H

Ph

Ph O

O H

O

95:5

198

199

O

7:3

200

H

201

O

28:72

203

202

Scheme 6.76 Equilibrium between 2-alkenylcyclopropanecarbaldehydes and oxepines

When 2-alkenylcyclopropanecarbaldehydes are less stable than oxepines, they rearranged usually so fast that only oxepines can be isolated during attempts to ­synthesize aldehydes. Thus, Swern oxidation of 2-alkenyl-2-(t-butyldimethylsiloxy) cyclopropylmethanols 204 afforded oxepines 205 (Scheme 6.77). It should be noted that the formed 2,5-dihydrooxepines isomerized to 2,3-dihydrooxepines under acidic conditions and to 2-alkenyl-2-siloxy-2,3-dihydrofurans 206 under basic conditions. Moreover, some starting cyclopropylmethanols produced directly dihydrofurans [137, 138]. R3 R4

t-BuMe2SiO R2 R1

HO 204

Swern oxidation

R3

t-BuMe2SiO R2 R1

R3 R4

O

205, 49–87%

Base

t-BuMe2SiO R2 R1

R4 O

206

Scheme 6.77 Swern oxidation of cyclopropylmethanols 204 to 2,5-dihydrooxepines 205.

On the other hand, oxepines, obtained by oxidation of cyclopropylmethanols, under treatment with Lewis acid rearranged to cyclopentenecarbaldehydes [132, 139]. In other words, 2-alkenylcyclopropanecarbaldehydes are in equilibrium with dihydrooxepines, 2-alkenyl-2,3-dihydrofurans, and cyclopentenecarbaldehydes; the predominant structure is determined by substituents in D–A cyclopropane and reaction conditions [140–144]. The competition of 3,3-sigmatropic shifts with other transformations of the starting D–A cyclopropanes was investigated by quantum chemical methods [138, 145–147].

217

218

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes

Similarly, under heating at 140 °C, tosylimines of 2-alkenyl-1-arylcyclopropanecarbaldehydes underwent rearrangement to both dihydroazepines and 2-alkenylpyrrolines [148]. At last, 2-alkynylcyclopropanecarbaldehyde 207 rearranged into the corresponding alkylideneoxepine 208 under heating at 130–150 °C (Scheme 6.78) [149, 150]. C4H9

H

C4H9

130–150 °C

O H

207

Scheme 6.78

CCl4 sealed tube

O

O

C3H7

208

Rearrangement of 2-alkynylcyclopropylcarbaldehyde 207.

6.7 Intramolecular Nucleophilic Ring Opening/Ring Closure and Related Processes One more important type of molecular rearrangement of D–A cyclopropane is represented by intramolecular nucleophilic ring opening, taking into account the fact that intermolecular reactions with diverse nucleophiles are, apparently, the most studied type of D–A cyclopropane reactions. Thus, Kerr et al. showed that the treatment of 2-aminooxyethyl-substituted cyclopropane 209 with Yb(OTf)3 induced the cyclization affording isoxazolidine 210. An interesting consequence of this process is the ability to control the diastereoselectivity of the transformation of cyclopropane 209 to pyrrolo[1,2-b]isoxazole derivatives 211. The reaction of 210 with aldehydes afforded a new ring with cis-arrangement of substituent, while the initial formation of imine from aldehyde and amino group followed by (3+2)-cycloaddition furnished trans-211 (Scheme 6.79) [151].

Scheme 6.79 Intramolecular D–A cyclopropane opening with O-alkyl hydroxylamine moiety.

Other examples of both intramolecular nucleophilic opening of D–A cyclopropanes and a two-process dichotomy were reported by Li et al. [152]. They found that the treatment of 2-(biphenyl-2-yl)cyclopropane-1,1-diester 212 with a large excess of trifluoromethanesulfonic acid at room temperature or with catalytic quantities of this acid under heating produced (9H-fluoren-9-yl)methyl malonates 213 while at 0 °C in the presence of a catalytic quantity of TfOH dihydrophenanthrenes 214 were formed (Scheme 6.80). The authors explained the obtained results by the different intermediates formed during the reaction: protonation of cyclopropane 212 produced benzylic carbocation that alkylates the neighboring

6.7 opopoDccAccpo cAccDeTrcrA ron ecorong ron cDIcoc pond ccppcnd –oDAcIIcI

aromatic group; under milder conditions, this cation was transformed into alkylidene malonate; and products 214 were formed via intramolecular Michael ­addition (see also Scheme 6.83). CH(CO2Et)2 Ar

Ar'

HFIP, 0 °C

214, 68–87% 11 examples

CH(CO2Et)2

CO2Et

TfOH (0.2–1 equiv.)

TfOH (6 equiv.) HFIP, 20 °C or TfOH (0.1 equiv.), HFIP, 70 °C

CO2Et

Ar

Ar'

Ar

Ar'

213, 34–96% 22 examples

212

Scheme 6.80 Rearrangements of D–A cyclopropanes 212 to fluorenes 213 and dihydrophenanthrenes 214.

A new class of potentially active β-lactam antibiotics, containing an azeto [2,3-d]isoxazolidine skeleton, was synthesized by intramolecular D–A cyclopropane ring opening by the amide functionality in compounds 215 (Scheme 6.81) [153]. This reaction is a rare example of a four-membered ring formation based on the D–A cyclopropanes reactivity. Scheme 6.81 Annulated β-lactams 216 formation by base-induced rearrangement of D–A cyclopropanes 215.

R4 O N R1

CO2R3

t-BuOK, 20 °C

CO2R3 CONHR2 215

R4

CH(CO2R3)2 R2 N

O

O N R1 216, 48–80% 9 examples

Nevertheless, the formation of four-membered rings is typically inefficient, and some concurrent processes proceed faster when furnishing other types of products. For example, MgBr2-promoted rearrangement of 2-(2-hydroxyaryl)cyclopropane1,1-diesters 217 produced 2,3-dihydrobenzofurans 218 (Scheme 6.82). O-Alkylated substrates can be also involved in this process. Moreover, dihydrobenzothiophene was synthesized by this method using thiophenol derivatives bearing 4-methoxybenzyl group at the sulfur atom [154]. Scheme 6.82 The rearrangement of 2-hydroxyaryl-substituted cyclopropanes 217 to dihydrobenzofurans 218

EWG EWG'

Ar OH 217

MgBr2·OEt2 NH4OAc, PhCl, Δ

EWG Ar

O

EWG'

218, 22–72% 16 examples

The proposed mechanism for dihydrobenzofurans 218 formation is shown in Scheme 6.83. The key steps of this rearrangement are the generation of magnesium dienolate and intramolecular Michael addition of phenolate ion to the electrophilic C═C bond. Similar isomerizations were reported for 1-benzoyl-2-hydroxyphenyl-3,3dimethylcyclopropane 219 affording dihydrobenzofuran 220 and related o-carboxamide 221 furnishing isoquinolone derivative 222 (Scheme 6.84) [155, 156].

219

220

6 Molecular Rearrangements in Donor–Acceptor Cyclopropanes MeO

OH

CO2Me CO2Me

O

OH

MgBr2

MeO

MgBr2 O

-H

O

O

H

O

O

~H

OMe

-MgBr2

MeO

MgBr2 O

MgBr2 O

218

OMe

OMe

217

Scheme 6.83

Proposed mechanism for 2,3-dihydrobenzofurans 218 formation.

Me Me Ph O

OH

or t-BuOK, MeOH 50 °C, 67%

O

O CONH2

Me Me NH

H2SO4

Ph

Ph Me Me

220

219

COPh

Me Me

O H2SO4,MeOH 20 °C, 76%

MeOH, 20 °C 87%

O 222

221

Scheme 6.84 Rearrangements of D–A cyclopropanes 219, 221 bearing a nucleophilic group at the ortho-position of the aromatic donor substituent.

The last result seems to be unexpected as the nucleophilic attack on the benzylic carbon atom, providing a five-membered ring, is allowed here. For example, 2-hydroxymethyl-substituted substrate 223 rearranged to isobenzofuran derivative 224 (Scheme 6.85) [154]. Presumably, acid-induced three-membered ring opening in 221 leads to the formation of tertiary carbocation, which is more stable than benzylic cation, especially due to the negative effect of ortho-carbamoyl moiety. CO2Me

MeO2C CO2Me

CO2Me

LA

O

OH

223

224, up to 94%

Scheme 6.85 Lewis acid-induced rearrangement of ortho-hydroxyphenyl-substituted cyclopropane 223.

All these processes belong to the well-known type of n-exo-tet cyclizations. Oppositely, endo-tet cyclization of D–A cyclopropanes was reported recently. Lewis acid-promoted rearrangement of 2,N-diaryl-1-carbamoylcyclopropanecarboxylates 225 produced benzazepines 226, products with cis-arrangement of substituents were formed after one to two hours, but trans-isomers were obtained after one to two days (Scheme 6.86) [157]. Evidently, molecular rearrangements of D–A cyclopropanes are not limited to the reactions discussed above; some interesting transformations are not included, but some other ones were disclosed. Ar N

R

O EWG

EDG 225

Scheme 6.86

LA DCM, 1–2 h MS 4Å, r.t.

R N

R N

O

Ar

EWG

EDG cis-226

LA DCM, 1–2 h MS 4Å, r.t.

O

Ar

EWG

EDG trans-226

Endo-tet cyclization of D–A cyclopropanes 225 yielding benzazepines 226.

References

­Acknowledgment The preparation of this chapter was supported by the Russian Science Foundation (grant 21-13-00395).

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131 Wang, B., Xu, B., Xun, W. et al. (2021). Angew. Chem. Int. Ed. 60: 9439–9443. 132 Rhoads, S.J. and Cockroft, R.D. (1969). J. Am. Chem. Soc. 91: 2815–2816. 133 Rey, M. and Dreiding, A.S. (1965). Helv. Chim. Acta 48: 1985–1987. 134 Hofmann, B. and Reissig, H.-U. (1994). Chem. Ber. 127: 2327–2335. 135 Downing, W., Latouche, R., Pittol, C.A. et al. (1990). J. Chem. Soc. Perkin Trans. 1: 2613–2615. 136 Mahon, M.F., Molloy, K., Pittol, C.A. et al. (1991). J. Chem. Soc. Perkin Trans. 1: 1255–1263. 137 Boeckman, R.K., Shair, M.D., Vargas, J.R., and Stoltz, L.A. (1993). J. Org. Chem. 58: 1295–1297. 138 Zhang, W., Baudouin, E., Cordier, M. et al. (2019). Chem. Eur. J. 25: 8643–8648. 139 Nasveschuk, C.G. and Rovis, T. (2005). Angew. Chem. Int. Ed. 44: 3264–3267. 140 Allegre, K. and Tunge, J. (2019). Tetrahedron 75: 3319–3329. 141 Zhang, W. and Nay, B. (2020). Eur. J. Org. Chem. 2020: 3517–3525. 142 Hofmann, B. and Reissig, H.-U. (1993). Synlett 1993: 27–29. 143 Yamaguchi, S., Arisawa, A., Katoh, N. et al. (1997). Bull. Chem. Soc. Jpn. 70: 2215–2219. 144 Piotrowski, M.L. and Kerr, M.A. (2018). Org. Lett. 20: 7624–7627. 145 Sperling, D., Reissig, H.-U., and Fabian, J. (1997). Liebigs Ann. 1997: 2443–2449. 146 Sperling, D., Reissig, H.-U., and Fabian, J. (1999). Eur. J. Org. Chem. 1999: 1107–1114. 147 Wu, Y., Li, M., Jin, L., and Zhao, X. (2020). ACS Omega 5: 2957–2966. 148 Shang, H., Wang, Y., Tian, Y. et al. (2014). Angew. Chem. Int. Ed. 53: 5662–5666. 149 Bourelle-Wargnier, F., Vincent, M., and Chuche, J. (1979). J. Chem. Soc. Chem. Commun. 584–585. 150 Bourelle-Wargnier, F., Vincent, M., and Chuche, J. (1980). J. Org. Chem. 45: 428–435. 151 Jackson, S.K., Karadeolian, A., Driega, A.B., and Kerr, M.A. (2008). J. Am. Chem. Soc. 130: 4196–4201. 152 Wang, D., Zhao, J., Chen, J. et al. (2019). Asian J. Org. Chem. 8: 2032–2036. 153 Tran, T.Q., Savinkov, R.S., Diev, V.V. et al. (2013). Tetrahedron 69: 5173–5177. 154 Ivanova, O.A., Andronov, V.A., Vasin, V.S. et al. (2018). Org. Lett. 20: 7947–7952. 155 Zheng, G., Zhou, Z., Zhu, G. et al. (2020). Angew. Chem. Int. Ed. 59: 2890–2896. 156 Wu, M., Lin, S., Zhu, G. et al. (2020). Org. Lett. 22: 1295–1300. 157 Vartanova, A.E., Plodukhin, A.Y., Ratmanova, N.K. et al. (2021). J. Am. Chem. Soc. 143: 13952–13961.

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7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor Ming-Ming Wang and Jerome Waser Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015, Lausanne, Switzerland

CHAPTER MENU 7.1 7.2 7.3 7.4 7.5

Introduction, 227 Synthesis of DA Aminocyclopropanes, 229 Ring-Opening Reactions of DA Aminocyclopropanes, 235 Formal Cycloaddition of DA Aminocyclopropanes, 244 Conclusion, 250 Abbreviations, 250 References, 251

7.1 Introduction The chemistry of donor–acceptor (DA)‐substituted cyclopropanes (DA cyclopropanes) [1-4] has underwent an impressive renaissance in the last two decades because of their versatility either as building blocks in organic synthesis [5-14] or as substrates for asymmetric catalysis [15-18]. As a subclass of DA cyclopropanes, DA cyclopropanes with an amino group as donor (DA aminocyclopropanes) share many reactivity similarities with aryl‐ and alkoxy‐substituted DA cyclopropanes. In addition, the importance of the nitrogen atom in biomolecules and pharmaceutical compounds makes aminocyclopropanes (acceptor‐substituted or not) attractive starting materials for accessing more value‐added products [19-21]. For example, with the formal [3 + 2] cycloaddition methods described in this chapter, cyclopentanes with an amino group can be synthesized. Such structures can be found in many bioactive compounds such as the anti‐HIV drug Abacavir (1), and Ramipril (2), which is used to treat high blood pressure, heart failure, and diabetic kidney disease (Figure 7.1). Natural products can also be accessed by using DA aminocyclopropanes as key Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

228

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor NH N

N

NH2 HO2C

N

N

CO2Et

HN

O

N H Me

HN H

Ph

Et

H H N Et

N N

H

OH

HO Abacavir (1) Anti-HIV

Figure 7.1 products.

Ramipril (2) Anti heart failure

Goniomitine (3) Natural product

Aspidospermidine (4) Natural product

Examples of nitrogen-containing synthetic bioactive compounds and natural

(a) Simplest geminal an vicinal DA aminocyclopropanes not synergistic D A

Geminal

H2N CO2H

Simplest example

5 1

Vicinal

D

2

Simplest example H2N

A

CO2H

6

push–pull effect

D

A

H2N

CO2H

H2N

CO2H

H2N

CO2H

H2N

CO2H

cis-6

(b) Degradation of cyclopropane 6 OH

H2N 6

O

trans-6

OH H2N+ I

H2O

O–

O O

OH 7

(c) Classification of DA aminocyclopropanes A R2N

A

mono-acceptor

A gem-di-acceptor

NR2

A R2N A vic-di-acceptor

R2N

A meso

A

Scheme 7.1 Classification and reactivity of DA aminocyclopropanes.

intermediates in cyclization and annulation reactions, such as the alkaloids Goniomitine (3) and Aspidospermidine (4) [22]. In general, DA aminocyclopropanes can be divided into two types: geminal DA aminocyclopropanes and vicinal DA aminocyclopropanes (Scheme 7.1a) [1]. The former, such as acid 5, lack synergistic activation for the C─C bond of the cyclopropyl ring and are of importance mostly as rigid nonnatural amino acid cores [23, 24], so they will not be covered in this chapter. Vicinal DA aminocyclopropanes can be considered

7.2 Synthesis of DA DAminocycloorooanes (a) Reaction of alkenes with carbenes R2N CHNR2

c

A

a

CH2

a

c R2N

A

b A

CHA b

R2N (b) Functionalization/cyclization approaches d1 or d2

X

A

HNR2 A

d R2N

e A

A R2N

e

Scheme 7.2 Retro-synthetic analysis of DA aminocyclopropanes.

as 1,3‐dipolar synthons because the C1─C2 bond is activated via an electronic push– pull effect. 2‐Amino cyclopropanecarboxylic acid (6) [25], the simplest example of vicinal DA aminocyclopropanes, has two stereogenic centers and therefore four isomeric forms [26]. The high reactivity of vicinal DA aminocyclopropanes can compromise their stability. For example, 6 is prone to undergo ring opening, leading to aldehyde 7 in the presence of water via imine I (Scheme 7.1b) [27]. Therefore, protection of the nitrogen atom to reduce its electron density is necessary in order to have a good balance between reactivity and stability. Common protecting groups include succinimide, phthalimide, an acyl group, carbamates, sulfonamides, imines, and nitrogen‐containing heterocycles. The acceptor is usually one or two electron‐ withdrawing groups, which can be an ester, an aldehyde/ketone, a cyanide, a nitro group, etc. Based on the number of donor/acceptor groups and their distribution on the cyclopropyl ring, DA aminocyclopropanes described in this chapter can be classified as mono‐acceptor aminocyclopropanes, gem‐di‐acceptor aminocyclopropanes, vic‐di‐acceptor aminocyclopropanes, or meso aminocyclopropanes (Scheme 7.1c). In this chapter, we will start by giving a brief summary of the synthetic methods to access DA aminocyclopropanes (Section 7.2). Their use as starting materials either in ring‐opening reactions (Section 7.3) or in formal cycloadditions (Section 7.4) will then be described in detail.

7.2 Synthesis of DA Aminocyclopropanes DA cyclopropanes are most commonly prepared by the addition of carbenes or their equivalents to alkenes, namely formal [2 + 1] cycloaddition or cyclopropanation (Scheme 7.2a). In this case, there are three different routes for constructing a cyclopropyl ring with the alkene partners being DA type alkenes such as β‐dehydroamino acids (disconnection a), donor type alkene like enamines (disconnection b), or acceptor type alkenes such as acrylates (disconnection c), respectively [26]. It is also possible that all three carbon atoms come from one reaction partner, in which case

229

230

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor (a) Cyclopropanation with dimethylsulfoxonium methylide (10) O Me O – Me2S CH2 + +

TrO

N

O

N O

10

O Me TrO

O

11

O O

O O

CO2Me

neat

CO2Me

N

120 °C

O 13

12, 80% 7 : 3 d.r.

O

N

+

O CO2Et

CO2Et

14

H

Me Me

O MeO

N O

Me Me (b) Cyclopropanation with 2-methoxyfuran (13)

O

H

N

CO2Me

15, 56%

(c) Cyclopropanation with a vinylcarbene derived from cyclopropene 16

Ph Me

Me

Ts

Ts N

Rh2(OAc)4

Ph

Me

Me O

Ph

O 16

N

Ph 18, 93%, 6.4 : 1 d.r.

17

Scheme 7.3 Cyclopropanation from β-dehydroamino acid with different reagents. (a) Cyclopropanation of N-protected pyrroles 19 CO2R1 N H

CuBr or CO2R1 Cu(OTf)2/PhNHNH2 N N2CHCO2R2

H

19

CO2R2

20, R1 = me, R2 = Et, 17% 21, R1 = tBu, R2 = Me, 45%

(b) Enantioselective cyclopropanation of indole 22 H

CuOTf 3-O-Ac glucoBOX N Boc

N2CHCO2Et

H

N Boc 23, 57%, 72% ee

22

Me Me O

O

CO2Et

O

N

O

O Ph

O

N

O

OAc

AcO

O

3-O-Ac glucoBOX

Ph

(c) Enantioselective cyclopropanation of enecarbamates 24 Cbz

N R

24

Ru(II)-Pheox N2CHCO2Et

Cbz

N

CO2Et

R 25, R = H, 99%, 70:30 d.r., 90% ee 26, R = Bz, 90%, 92:8 d.r., 97% ee 27, R = Me, 97%, 93:7 d.r., 99% ee

(NCCH3)4 Ru+ N

PF6– Ph

O Ru(II)-Pheox

Scheme 7.4 Diastereoselective and enantioselective cyclopropanation of heterocycles and enamides.

7.2 Synthesis of DA DAminocycloorooanes

there are two disconnections for introducing either an amino group (disconnection d) or an acceptor (disconnection e) (Scheme 7.2b). For the introduction of an amino group, there are two reported routes depending on the substrate: a cyclopropene bearing an acceptor group (disconnection d1) or 2‐haloethylidene malonates (disconnection d2). Therefore, based on the starting materials, there are currently six straightforward routes for the synthesis of DA aminocyclopropanes. Each route will be briefly introduced below with selected examples.

7.2.1 Synthesis of DA Aminocyclopropanes from β-Dehydroamino Acids (Route A) This cyclopropanation of DA‐substituted olefins—β‐dehydroamino acids—with a carbene gives DA aminocyclopropanes. The most convenient source of carbene equivalents is diazo compounds, which readily generate a carbenoid after reaction with a transition metal catalyst. Acceptor‐substituted diazoalkanes were frequently used for the synthesis of DA cyclopropanes because they can be prepared easily and cyclopropanation with electron‐rich alkenes is efficient. For example, vic‐di‐acceptor aminocyclopropane 9 can be synthesized by the copper‐catalyzed cyclopropanation of 8 with diazoester in an intermolecular fashion (Eq. 7.1) [28]. Intramolecular cyclopropanation for this type of substrate has also been reported, with diazoalkane attached to the nitrogen atom to produce a bicyclic vic‐di‐acceptor aminocyclopropane [29]. Copper‐catalyzed cyclopropanation of alkene 8 to give vic‐di‐acceptor aminocyclopropane 9. CO2Me

Ph N



O

H 8

Ph

Cu(acac)2

N

N2CHCO2Me O

CO2Me CO2Me 9, 84%



(7.1)

A Corey–Chaykovsky reaction with dimethylsulfoxonium methylide 10 can also be used to construct the cyclopropyl ring. For example, starting from protected uridine 11, uridine analog 12 containing a cyclopropyl ring was isolated in 80% yield as a mixture of diastereoisomers in a ratio of 7 : 3 (Scheme 7.3a) [30]. 2‐Methoxyfuran 13 has also been used for the cyclopropanation of electron‐deficient olefins [31] such as alkene 14 [32], although no synthetic utility of the corresponding products has been disclosed so far (Scheme 7.3b). In 2019, the Loh group reported a cyclopropanation reaction of enaminone 17 with a vinylcarbene intermediate, which was generated in situ from cyclopropene 16 (Scheme 7.3c) [33]. The obtained product 18 was then subjected to hydrolysis under acidic conditions, and an α‐vinyl aldehyde was formed after ring opening.

7.2.2

Synthesis of DA Aminocyclopropanes from Enamines (Route B)

Cyclopropanation of enamines with acceptor‐substituted diazoalkanes is a straightforward way of synthesizing DA aminocyclopropanes. N‐protected pyrroles 19 were versatile starting materials to react with diazoacetates for the synthesis of DA

231

232

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

aminocyclopropanes 20–21, and exclusive formation of the exo diastereoisomer was recorded with carbamate as protecting group on the nitrogen atom (Scheme 7.4a) [34, 35]. An asymmetric version of this reaction was reported by the Reiser group in 2003, with poor enantioselectivity obtained using a copper catalyst and a chiral bis(oxazoline) ligand [36]. In 2017, the Reiser group revisited this reaction, and good enantioselectivity was obtained by using a copper catalyst and an aza‐BOX ligand [37]. In 2019, the Reiser group in collaboration with the Davies group further reported a Rh(II)‐catalyzed cyclopropanation reaction of N‐tosyl pyrroles [38] or cyclic enecarbamates [39], with monocyclopropanation products isolated in good yields and high enantioselectivity in both cases. In 2012, the Boysen group reported an enantioselective cyclopropanation of N‐Boc indole 22 by using CuOTf as a catalyst and a carbohydrate‐based ligand, 3‐O‐Ac glucoBOX, and the corresponding indole‐derived DA aminocyclopropane 23 was obtained in good enantioselectivity (Scheme 7.4b) [40]. In 2017, an intramolecular enantioselective cyclopropanation of indoles was reported by the Zhu and Zhou groups [41]. Excellent yield and enantioselectivity were achieved by using copper or iron complexes with chiral spiro‐BOX ligands as catalysts. The asymmetric cyclopropanation of acyclic vinylcarbamates 24 with diazoesters was also realized by the Iwasa group in 2013 by using a Ru(II)‐ Pheox catalyst, giving products such as 25–27 in excellent enantioselectivity (Scheme 7.4c) [42]. However, the diastereoselectivity of the reaction depended on the substrates, with higher diastereoselectivity observed for N,N‐disubstituted vinylamines compared to N‐monosubstituted vinylamines. Indeed, achieving high diastereoselectivity can be difficult in the cyclopropanation of certain enamines [43, 44]. Switching to diazomalonates allows for avoiding diastereoselectivity issues and leads to the formation of gem‐di‐acceptor aminocyclopropanes. For example, starting from N‐vinyl‐phthalimide 28 or N‐vinyl‐ succinimide 29 and dialkyl diazomalonate, DA aminocyclopropanes 30–32 were synthesized in gram scale using 0.1 mol% Rh2(esp)2 as catalyst (Eq. 7.2) [45, 46]. Using a phthalimide or a succinimide group, the electron density on the nitrogen atom is decreased, resulting in good stability for 30–32. Synthesis of gem‐di‐acceptor aminocyclopropanes 30–32. O N O 28

O or

N O 29

Rh2(esp)2

O

N2C(CO2R)2

CO2R CO2R

N

O 30, R = Me, 78% 31, R = Et, 90% or O N

CO2Me CO2Me

O



32, 79%

(7.2)

7.2 Synthesis of DA DAminocycloorooanes

7.2.3

Synthesis of DA Aminocyclopropanes from Acrylates (Route C)

The synthesis of DA aminocyclopropanes starting from acrylates requires the use of aminocarbenes to assemble the cyclopropyl ring. As the donor‐type diazo compound having an α‐amino group does not exist [47], precedence is focused on Fischer carbenes. Amino‐substituted Fischer carbenes can be easily prepared by replacing the alkoxy group of alkoxycarbene complexes with amines [48]. However, the reaction between most aminocarbene complexes and electron‐deficient alkenes gave only byproducts, which arose from [2 + 2 + 1] cycloaddition [49] or ring‐ opening isomerization [50]. DA aminocyclopropane 35 was obtained only when using pyrrolocarbene complexes 33 or 34, with pyrrole acting as a masked amino group (Scheme 7.5) [51]. Conversion of the pyrrole into other nitrogen‐containing functionalities has been demonstrated by an ozonolysis‐reduction sequence, which provided a formamide group in 36. Other synthetic routes starting from simple acrylates involved several functional group interconversions, such as cyclopropanation followed by reduction of a nitro group [52] or Curtius rearrangement of a carboxylic group [53]. These examples of multi‐step syntheses from simple acrylates are less efficient and will not be discussed. CO2Me N (CO)5M

Methyl acrylate

Ph

1) O3

N

2) (H2N)2C=S

Ph

M = Mo (33) or W (34)

35, 59–62%

CO2Me Ph NHCHO 36, 73%

Scheme 7.5 Synthesis of cyclopropanes 35 and 36 from Fischer carbenes 33 or 34.

7.2.4 Synthesis of DA Aminocyclopropanes from Cyclopropene (Route D1) In 1988, it was reported that 1,4‐addition of amines such as morpholine to cyclopropene carboxylates 37 occurred readily under mild conditions to form DA aminocyclopropanes such as 38–40 (Scheme 7.6a) [54]. Cyclopropene I can also be formed in situ from bromocyclopropane 41 after 1,2‐elimination, and the addition of N‐methylacetamide furnishes DA aminocyclopropane 42 in good yield and high diastereoselectivity, as reported by the Rubin group in 2013 (Scheme 7.6b) [55]. The scope of amides was limited to secondary amides, while products from primary amides were not stable, leading to the formation of aldehydes after ring opening and hydrolysis. Besides, nitrogen‐containing heterocycles, such as pyrrole, indole, pyrazole, and anilines, were well tolerated in this formal substitution reaction.

7.2.5 Synthesis of DA Aminocyclopropanes from 2-Haloethylidene Malonates (Route D2) 2‐Haloethylidene malonates could be used for a cyclopropanation reaction via an addition‐substitution mechanism under basic conditions with amine nucleophiles.

233

234

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor O CO2Me

Me

(a)

Me

(b)

R 37

N H Et2O, 20 °C

Me

NHtBu MeCONHMe

Br

18-crown-6 KOH/THF

O 41

CO2Me

Me

N R

O

38, R = H, 70% 39, R = Me, 80% 40, R = CO2Me, 54%

O Me

NHtBu

NHtBu N Me O 42, 88%, 11:1 d.r.

I O Intermediate

Scheme 7.6 Addition of amines to (in situ formed) cyclopropenes. (a) Synthesis of purine derived DA aminocyclopropane CI CI N

N H2N

N 43

CO2Et

+

CO2Et

Br

N H

DMF

N

N

K2CO3 H2N

N

N

45, 87% 8:1 r.r CO2Et

44

CO2Et

(b) Synthesis of imine derived DA aminocyclopropane Ph Ph2C=NH 46

+

Me Me CO2Me Br 47

CO2Me

Et3N

Ph N CO2Me

tBuOH, refux Me

Me

48, 61%

CO2Me

Scheme 7.7 Synthesis of DA aminocyclopropanes from 2-bromoethylidene malonates.

An elegant synthesis of purine‐derived DA aminocyclopropane 45 was reported by the Geen group in 1992 by mixing 2‐amino‐6‐chloropurine 43 with 2‐bromoethylidene malonate 44 under basic conditions (Scheme 7.7a) [56]. Similarly, treating diphenylmethylidenamine 46 with 2‐bromoethylidene malonate 47 in the presence of triethylamine provided 48 as a different class of DA aminocyclopropanes, as reported by the De Kimpe group in 2005 (Scheme 7.7b) [57].

7.2.6 Synthesis of DA Aminocyclopropanes from Cyclopropylamines (Route E) Lithiation at the β position of cyclopropylcarbamate 50, which was synthesized via an α lithiation cyclization sequence form 49, has been observed, and further treatment with dimethyl carbonate for introducing an ester group as acceptor produced DA aminocyclopropane 51, as reported by the Beak group in 1996 (Scheme 7.8) [58]. In contrast to other routes discussed above, cis DA aminocyclopropanes were

7.3

ing-Ooening eactions of DA DAminocycloorooanes

CI s-BuLi/TMEDA

1) s-BuLi/TMEDA N 2) dimethyl carbonate Boc MeO2C

N Boc 49

N Boc

51, 64% over 2 steps

50, 91%

Scheme 7.8 Synthesis of DA aminocyclopropane 51 by two subsequent lithiationsalkylations from 49.

obtained rather than trans products. The deprotonation is directed by the carbamate group leading to cis stereospecific β‐lithiation. To summarize this section, synthetic routes from six types of substrates have been well established for the efficient synthesis of DA aminocyclopropanes. Nevertheless, it would be still attractive to develop alternative synthetic routes in the future starting from other commercially available compounds, especially when compared with the more mature synthesis of aryl‐substituted DA cyclopropanes [59]. For example, DA aminocyclopropanes could be accessed if a C(sp3)–H amination reaction can be developed by using electrophilic aminating reagent [60], inspired by the recently reported C(sp3)–H arylation of cyclopropyl carboxylic acids for accessing aryl‐ substituted DA cyclopropanes [61, 62]. Alternatively, the synthesis of DA aminocyclopropanes by aminocarbonylation of cyclopropenes might also be possible, based on a recent example of palladium‐catalyzed intermolecular aminocarbonylation of alkenes [63].

7.3 Ring-Opening Reactions of DA Aminocyclopropanes Similar to other types of DA cyclopropanes, heterolytic cleavage of the C1─C2 bond is a facile process, leading to the formation of 1,3‐formal dipoles. Thermal epimerization of compound 52 indicated that the ring‐opening step can be reversible [64] (Eq. 7.3). Thermal epimerization of DA aminocyclopropane 52. H

H

CN Decalin

N CO2Et



52

Reflux, 15 h

NC

CN

H

+ N

N CO2Et

CO2Et ~ 50 : 50

(7.3)

Depending on the addition of external nucleophiles or not, this section is divided into two parts describing the ring‐opening reactions of DA aminocyclopropanes in an intramolecular fashion or an intermolecular fashion, respectively.

235

236

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

7.3.1

Intramolecular Ring-Opening of DA Aminocyclopropanes

The simplest ring‐opening reaction of DA aminocyclopropanes is the isomerization of enamine products. Depending on the substituents on the nitrogen atom, the isomerization can take place spontaneously with dialkyl substituents [65], or require some activation if the electron density on the nitrogen atom is decreased [66, 67]. For example, the isomerization of DA aminocyclopropane 53 to indomethacin 54 was reported to occur efficiently at 160 °C (Eq. 7.4) [66]. Thermal rearrangement of 53 into indomethacin 54. MeO

MeO

H

CO2H

CO2H N

Me

160 °C, 3 min

O

O CI



53

Me

N

90% CI

Indomethacin (54)

(7.4)

Although some ring‐opening reactions took place under mild basic conditions, acidic conditions were more frequently used for the activation of DA aminocyclopropanes. In some cases of DA aminocyclopropane synthesis, the desired product was accompanied by the formation of ring‐opened byproducts because of the presence of the catalyst, which could also act as a Lewis acid to activate the DA aminocyclopropanes [68, 69]. Apart from isomerization into enamine, the iminium species after ring opening can also undergo deprotonation to form an imine product [40] or can be trapped by nucleophiles. Nucleophiles can be internal functional groups, such as the oxygen atom of a carboxylic acid (55, Scheme 7.9a) [70]/ester (56, Scheme 7.9b) [71, 72]/carbonyl (I generated in situ from 57 via oxidation, Scheme 7.9c) [73, 74] group, or the nitrogen atom of cyanide (58, Scheme 7.9d) [75] group, leading to the formation of five‐membered heterocycles 59–63. It is important to note that these ring‐opening reactions can be potentially used in the synthesis of complex molecules. For example, based on the reaction illustrated in Scheme 7.9b, the Wenkert group reported first in 1978 the total synthesis of the natural products Eburnamonine and Aspidospermidine [71, 72]. By extending this reaction to the oxygen analog, the Wenkert group reported in 1981 the total synthesis of Quebrachamine, Vincadine, and epi‐Vincadine [76]. The use of other internal nucleophiles to react with the in situ‐generated iminium intermediates continues to be developed. For example, the Qin group reported in 2006 that after copper‐catalyzed intramolecular cyclization of 64, the reduction of a pendant azido group in 65 by tributylphosphine released a free amino group, which then attacked the iminium after cyclopropane ring opening (Scheme 7.10) [77, 78]. The desired product 66 was obtained in 83% yield as a single diastereoisomer, which was a key intermediate in the total synthesis of the natural product Communesin F (67). This application showcased the potential of DA aminocyclopropanes for the synthesis of complex molecules. Since 2020, this strategy has also been utilized by the Sen group for the synthesis of spirocyclic indole derivatives [79, 80].

7.3

ing-Ooening eactions of DA DAminocycloorooanes

(a) O attack from carboxlic acid 55 CO2H EtO2C

O 6 N HCI, rt, 72 h

N

HO2C

Cbz

55 (b) O attack from ester 56 Et

O

N Cbz 59, 87% Et

H2SO4, reflux, 18 h (a)

CO2Me

O O N R a, 60 (R = CO2Me), 90% b, 61 (R = H), 88%

N CO2Me

or KOH, 100 °C 12 h (b)

56, exo/endo 67 : 33 (c) O attack from aldehyde I Boc BzO

OH

NH

Boc NH O

NalO4, THF, H2O, rt

OH

BzO 62, 51%

57 Boc NH BzO

Boc + NH

O

O–

BzO

I (d) N attack from cyanide 58

II Me

Me CN

PPA, 60–70 °C

N Me CO2Et 58

O

NH N Me CO2Et 63, 85%

85%

Scheme 7.9 Ring opening followed by reaction with internal nucleophiles. Br

Br O N3

O N Me

N2

N

N

Me 65, 88%

Br O

Me

Me

N N3

PBu3, 0 °C, 0.5 h

Ac N

O

CuOTf, rt, 1 h

64

Me

O

O H H N H

N H Communesin F (67)

N Me 66, 83%

Scheme 7.10 Ring-opening cyclization with azide as a masked amino group for the synthesis of Communesin F (67).

237

238

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor MeO2C

NHTs N2 CO2Me N Boc

CuOTf

NHTs N

O

Boc

68

OH

N N H Minfiensine (70)

O

I

MeO2C

O

Me N NTs Boc 69, 50%

Scheme 7.11 Cyclopropanation and ring-opening cascade with pendant sulfonamide as a nucleophile for the synthesis of Minfiensine (70).

The pendant nucleophile can also be a sulfonamide or carbamate group [81]. With these protecting groups, the nitrogen atom is deactivated, and therefore interference with the cyclopropanation step is avoided. The structural complexity can be increased by developing cascade reactions involving cyclopropanation and subsequent ring opening, with DA aminocyclopropanes as non‐isolated intermediates. For example, starting from tryptamine derivative 68, a copper‐catalyzed cyclopropanation‐ring opening‐cyclization sequence provided directly tetracyclic product 69 in 50% yield via cyclopropane I, showing the efficiency of this cascade reaction (Scheme 7.11) [82]. This reaction was used by the Qin group as a key step in the total synthesis of the natural products Minfiensine (70) and Vincorine [83]. Starting from l‐tryptophan, a good diastereoselectivity can be achieved by performing the cascade reaction at low temperature [81], which was later applied in the total synthesis of the indole alkaloid (−)‐Ardeemin [84]. When the side chain contains an electron‐rich aromatic ring, it can react as a carbon nucleophile with the iminium intermediate to form a new C─C bond. In several cases, an indole was attached to the acceptor carbonyl group as an internal carbon nucleophile. The Waser group studied thoroughly this reaction with acyl indole‐ substituted DA aminocyclopropane 71. Ring opening and subsequent cyclization occurred at either the C3 or at the N1 position of the indole if the nitrogen was not protected [85]. They found that the use of Cu(OTf)2 in MeCN strongly favored the formation of 72 as a result of alkylation at the C3 position, while switching to TfOH in dichloromethane gave predominantly 73 as a product (Scheme 7.12). The Waser group also successfully applied this selective cyclization as a key step for the total synthesis of the natural product Goniomitine (3), the formal synthesis of Aspidospermidine (4) [22, 86] and the total synthesis of Jerantinine E (74) [87]. This strategy was also used in the total synthesis of Deethyleburnamonine (75) by the France group [88]. In addition, the formed imine can also be engaged in a formal

7.3 O

H N

Cu(OTf)2

72, 85%

Cbz N Cbz

TfOH

HN

MeCN

H N Cbz

HN H

H

O Et

ing-Ooening eactions of DA DAminocycloorooanes

Et

CH2CI2

71

Et

H H N

N

H N

N Aspidospermidine (4)

O

H N

Et

N

MeO

OH Goniomitine (3)

Et

73, 80%

Et

N

N H

N HO Jerantinine E (74)

H

O

Deethyleburnamonine (75)

Scheme 7.12 Ring opening with internal indole and its application in total synthesis of indole alkaloids. O

O Boc

N

N

Toluene, 200 °C

Et

O

Et 76

Melokhanine E (77), 88%

O

OMgI

O

HN

N

N

N

O

N Et

Scheme 7.13

H

N

O

I

N

Mgl2, µwave

Et

HO II

N

H Et

O III

Ring-opening cascade with enolate for the synthesis of melokhanine E (77).

[3 + 2] cycloaddition with a cyclopropane, as demonstrated by the Pierce group in the total synthesis of melokhanine E (Scheme 7.13) [89]. In a rare example reported in 2012 by the Reiser group, a furan migration product 81 was observed for endo‐80 after a Povarov reaction between 78 and 79, while only isomerization into polycyclic imine 82 was observed for exo‐80 (Scheme 7.14) [90]. The authors proposed a plausible mechanism that involves the formation of intermediate I in the presence of Sc(OTf)3 and subsequent furan migration to intermediate II via a spiroannulated intermediate. The unusual C‐N bond cleavage is compensated by the rearomatization of a quinoline ring in intermediate III, which

239

240

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

N O

Boc N H

+

H 79

78

HN

Sc(OTf)3 rt

CO2Me

O

H + N Boc

H H

H

O

H

MeO

H N Boc +

H N Boc

H O H

H CO2Me

CO2Me endo-80

HN

HN

3.5:1 d.r.

exo-80

Sc(OTf)3, reflux N Fur

OSc(OTf)3

H

I

N Boc

H MeO

II

MeO Fur OSc(OTf)3

N O III

N

OtBu

HN

O O

Se (OTf)3

HN

O 81

O

H

H N

CO2Me 82

Scheme 7.14 Ring opening with or without furan migration of cyclopropane 80 obtained from the Povarov reaction of aryl imine 78 and enamide 79.

further undergoes N‐Boc hydrolysis and lactamization to form 81. However, other aromatic substituents instead of furan, including para‐methoxyphenyl, 1‐naphthyl, and 2‐thionyl, gave only polycyclic imines without migration, indicating that both a furan moiety and the specific conformational arrangement of endo‐80 are necessary for the rearrangement to proceed.

7.3.2

Intermolecular Ring-Opening of DA Aminocyclopropanes

External nucleophiles can also be employed to transform the iminium intermediate into amine products. The smallest nucleophile is a hydride, resulting in the reduction of DA aminocyclopropanes. For example, NaBH4 was used as a reductant in a one‐pot synthesis of γ‐aminobutyric acid (GABA) amides [91]. A pyrrolidin‐2‐one 83 was obtained when the reduction was carried out on 48, which resulted from two subsequent reductions and intramolecular condensation (Scheme 7.15) [57]. The cyclopropanation/ring‐opening/reduction cascade is useful to construct cyclic systems and can thereby find applications in the synthesis of complex molecules [92]. For example, a domino cyclopropanation‐ring opening‐reduction has been applied as a key step in the total synthesis of Lyconesidine B, which was accomplished by the Takemoto group [93]. When water was employed as a nucleophile, an aldehyde was usually formed as a result of hydrolysis of the iminium intermediate [33], which is most often an undesired side reaction because of the loss of nitrogen. With alcohols as nucleophiles, the in situ‐formed iminium intermediate can be stabilized in the form of an N,O‐ acetal, and the Qin group used this strategy in 2017 for the total synthesis of Kopsia indole alkaloids [94]. The Gharpure group reported in 2014 that thiophenol was a good nucleophile as well, which afforded an N,S‐acetal as a product after ring opening [29].

7.3

ing-Ooening eactions of DA DAminocycloorooanes

Ph Ph

N

CO2Me Me

NaBH3CN (2.5 equiv.)

O

MeO2C

Ph N

Me Me 83, 88%

CO2Me Me 48

Ph

Ph Ph

HN Me

CO2Me

CO2Me MeO2C N Me Me CO2Me Me I

Ph Ph MeO2C

II

CO2Me

Ph

N Me Me H

Ph

III

Scheme 7.15 Reduction of imine-substituted DA aminocyclopropane 48 followed by lactamization.

In 2019, the Saha group reported a Sc(OTf)3‐catalyzed ring opening of DA cyclopropanes by hydrogen peroxide [95]. Extension of this reaction to DA aminocyclopropanes was successful, resulting in the formation of α‐amino peroxides as products with amino groups varying from phthalimide, succinimide to even maleimide. With peracid as a nucleophile, the α‐amino peroxide formed from 84 was further fragmented to give pyrrolidin‐2‐one 85 (Eq. 7.5) [29]. Formation of pyrrolidinone 85 by reaction of DA aminocyclopropane 84 with mCPBA.

HO

CO2Et N H Ts



O

H

84

TMSOTf, mCPBA CH2CI2, –10 °C to rt

O H

H N Ts 85, 74%

O

(7.5)

Carbon nucleophiles have also been successfully incorporated into the α‐amino position in the presence of Lewis acid catalysts. In 2013, the Waser group reported a Friedel–Crafts reaction between DA aminocyclopropane 86 and indole 87, leading to the formation of indole C3 alkylation product 88 (Scheme 7.16a) [96]. In the presence of C3‐substituted indoles, C2 alkylation was observed. Pyrroles were also tested, and the regioselectivity between C2/C3 alkylation can be tuned by changing protecting groups on the pyrrole nitrogen atom. Other electron‐rich aromatic compounds, such as anisole or phenol, can also be used but usually give a mixture of products with poorer regioselectivity. The Gharpure group reported in 2014 one example of nucleophilic attack by 1,3,5‐trimethoxybenzene on 84 in the presence of the Lewis acid TMSOTf, forming a Friedel–Crafts alkylation product with high yield and diastereoselectivity [29]. In 2018, the Wang and Guo group developed the

241

242

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor CF3H2CO2C (a)

CO2CH2CF3

Sc(OTf)3 (10 mol%)

+

CO2CH2CF3

PhthN

N H

86

(b)

Et2O, rt N H

88, 87%

87

CO2Me SuccN

CO2Me

Cu(OTf)2 (10 mol%) L1 (12 mol%)

+

32 O

L1

+

91

Scheme 7.16 2-naphthols.

tBu

CuCI2 (20 mol%) AgSbF6 (38 mol%) L2 (24 mol%)

N TBS

CO2Me

MeO2C

N

N

89

N Piv

OH O

tBu

Piv N

CO2Me

MeO2C SuccN

Bn Bn O

(c)

CO2CH2CF3

PhthN

Me Me O

92

O

N N Ph Ph BnO Ph Ph OBn L2

90, 78%, 95% ee Piv

MeO2C

O N

N Piv

MeO2C N TBS

93, 80%, 88% ee

Friedel–Crafts reaction between DA aminocyclopropanes and indoles or

Friedel–Crafts alkylation of DA aminocyclopropane 32 with 2‐naphthol 89 as a nucleophile (Scheme 7.16b) [97]. With Cu(OTf)2 and BOX ligand L1, GABA derivative 90 was obtained in good yield and enantioselectivity by using 2‐naphthol as a limiting reagent. They also showed that this is a kinetic resolution process, and unreactive 32 can be recovered with excellent enantioselectivity by decreasing the ratio between 32 and 2‐naphthol to 1 : 1. In 2018, the Waser group reported an example of enantioselective desymmetrization based on the previously described Friedel– Crafts alkylation reaction (Scheme 7.16c) [98]. Starting from 1H‐imidazol‐2(3H)‐one, meso‐diaminocyclopropane 91 was prepared by cyclopropanation with diazo malonate using Rh2(OAc)4 as catalyst. The combination of a copper catalyst and the fine‐tuned BOX ligand L2 enabled the conversion of 91 into an enantioenriched, diastereomerically pure urea derivative 93. In addition to aromatic compounds, organometallic reagents can also be used as nucleophiles. For instance, Me2CuLi was used to introduce a methyl group by the Prieto and Pérez group in 2014 for C2, C3‐difunctionalization of 1‐methylindole 94 via an unstable indole‐derived DA aminocyclopropane 95 (Eq. 7.6) [99]. Ring‐opening reaction using Me2CuLi as nucleophile. N2CHCO2tBu

CO2tBu

TpBr3Cu (1 mol%) N Me 94

N Me 95

Me2CuLi

CO2tBu Me N Me 96, 81%, 7:3 d.r.

(7.6)

7.3

ing-Ooening eactions of DA DAminocycloorooanes

Apart from monofunctionalization of the DA aminocyclopropanes, 1,3‐difunctionalization has also been reported in the presence of an electrophile. In 2014, the Werz group reported a 1,3‐dichlorination of DA cyclopropanes by iodobenzene dichloride under mild conditions (Scheme 7.17a) [100]. The donor group could vary from succinimide, phthalimide, alkyl, aryl, etc., and the acceptors were usually diesters or dinitriles. A radical pathway, rather than an ionic process, was proposed to explain the mechanism of this reaction. Following this work, the Werz group reported a 1,3‐halochalcogenation with magnesium iodide as a Lewis acid catalyst (Scheme 7.17b) [101]. The strongly polarized bonds of sulfenyl or selenyl halides were exploited for the incorporation of a chalcogen and a halogen atom into the nucleophilic and electrophilic sites of 30, forming 100 or 101 in good yields. A similar strategy was utilized by the Studer group in 2017 for the ring‐opening 1,3‐ aminobromination [102] of 31 as well as by the Saha group in 2019 for 1,3‐haloperoxygenation [95] of 30 (Scheme 7.17c). In these cases, p‐toluenesulfonamide or tert‐butyl hydrogen peroxide were used as nucleophiles for the ring‐opening reaction with the help of a Lewis acid catalyst, leading to the formation of 102 or 103. In 2020, the Saha group also reported a bisarylation reaction of 30, using 1‐methylindole and an arylbismuth(V) reagent as nucleophile and electrophilic arylating agents, respectively (Scheme 7.17d) [103]. To summarize this section, ring‐opening reactions of DA aminocyclopropanes have been discussed, including isomerization, cyclization, monofunctionalization O

A

N

(a) O2N

PhlCl2 (1.2 equiv.) CH2Cl2, 45 °C

O

(b)

O2N

CO2Me

CI

Ar

CO2Me CO2Me

100, X = S, Ar = ToI, 91% 101, X = Se, Ar = Ph, 83% CO2R CO2R

N

X

PhthN

CH2Cl2, 25 °C

O

O

O

ArXCI, Mgl2

30

(c)

A A

98, A = CO2Et, 92% 99, A = CN, 80% CO2Me

N

CI

N

97

O

CI

O

A

or TBHP, NBS, Sc(OTf)3 (Saha)

O

Nu

TsNH2, NBS, Sn(OTf)2 (Studer)

Br CO2R CO2R

PhthN

102, Nu = TsNH, R = Et, 60% 103, Nu = tBuOO, R = Me, 77% O (d)

CO2Me N

CO2Me O 30

PhthN

Sc(OTf)3, tBuOK 1-Methylindole, Ph3BiCl2

Ph

CO2Me CO2Me

N Me

104, 82%

Scheme 7.17 Ring-opening 1,3-difunctionalization reactions with electrophiles.

243

244

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

as well as 1,3‐difunctionalization. In all these cases, only classic bond cleavage involving the C1─C2 bond was observed. In addition to these reports, rare examples of ring‐opening reactions involving non‐classic bond cleavage were also disclosed [104-107].

7.4 Formal Cycloaddition of DA Aminocyclopropanes In 1996, the Beak group reported a formal [3 + 2] cycloaddition between 51 and tetracyanoethylene (TCNE, 105) (Eq. 7.7) [58]. In an attempt to broaden the synthetic utility of this reaction, less activated electrophiles including fumaronitrile, dimethyl maleate, and acrylonitrile were tested. However, no corresponding products were observed, and only the starting material was recovered. This may suggest that the first elementary step with tetracyanoethylene could be single electron transfer [20]. Formal [3+2] cycloaddition of 51 with tetracyanoethylene.

N Boc

MeO2C

NC

CN

NC

CN

+

51

CH2CI2, rt

TCNE (105)



NBoc CN MeO2C CN NC CN 106, 99%, single diastereoisomer

(7.7)

In 2020, the Reiser group explored the possibility of activating DA aminocyclopropanes by single‐electron oxidation [108]. Using Fukuzumi dye as a catalyst under blue light irradiation, polycyclic endoperoxide 108 was formed as a result of the formal [3 + 2] cycloaddition between DA aminocyclopropane 107 and molecular oxygen. The obtained polycyclic endoperoxides were tested for antimalarial activity, given their close analogy to the active principle of approved drugs such as artemisinin (Eq. 7.8). Formal [3+2] cycloaddition of 107 with molecular oxygen. H Ph CO2Me

H N H CO2Ph



Ph CO2Me

107

[MesAcr]CIO4 (8 mol%) hv455 nm, O2, MeCN, rt

O N

O

H CO2Ph

108, 37%, 5.3:1 d.r.

(7.8)

While examples of DA aminocyclopropanes activation involving a radical pathway remain scarce, polar mechanism has been widely exploited for developing cycloaddition reactions. In 2011, the Waser group reported a catalytic [3 + 2] annulation of DA aminocyclopropanes with silyl/alkyl enol ethers (Scheme 7.18) [45, 109]. Several DA aminocyclopropanes have been synthesized to compare their reactivity and stability. It was found that mono‐acceptor aminocyclopropanes 112– 114 were not reactive under the examined conditions, while gem‐di‐acceptor

7.4 Formal Cycloaddition of DA DAminocycloorooanes

CO2Et PhthN

CO2Et

+

Lewis acid (20 mol%) TIPSO

31

Ph

O CO2Et CO2Et

PhthN

or

OTIOS Ph 110 EtO2C

109

Ph NPhth CO2Et

111

with SnCI4, –78 °C, 110 : 111 > 20 : 1 with ln(OTf)3, rt, 110 : 111 < 1 : 20 Selected scope

Substrate screening No reaction O

Decomposition O

N

O

112

CO2Et N

CO2Et

O

CO2Et

CbzHN

115

CO2Et

PhthN Br

CO2Et CbzHN

113

116

O

O N

114

CO2Et N

CO2Et

CO2Et

117

PhthN Me

CO2Et PhthN H

O

CO2Et N

PUSH

CO2Et O

PULL

Scheme 7.18

PhthN 31

Me Me

CO2Me CO2Me OTIPS 118, 92%, > 20 : 1 d.r.

CO2Me CO2Me OTIPS 119, 92%, 20 : 1 d.r. Ph CO2Me CO2Me OTIPS 120, 91%, 10 : 1 d.r.

CO2Me CO2Me121, 81%, 4 : 1 d.r. OTIPS Ph

Catalyst-tuned ring opening/cycloaddition with enol ether.

aminocyclopropanes 115–117 were not stable and decomposed directly after cyclopropanation. In the end, a balance between reactivity and stability was found when the nitrogen atom was protected as a phthalimide group to reduce its electron density (31), leading to the formation of cyclopentylamine 110. Product 110 was obtained in 98% yield and with more than 20 : 1 diastereoselectivity using SnCl4 as catalyst, while an acyclic product 111 arising from nucleophilic ring opening was formed when In(OTf)3 was used as catalyst. This reaction was stereospecific in relation to the configuration of enol ether and enantiospecific. The size of the silyl group on the enol ether and the substituent on the benzene ring of the aminocyclopropane almost had no influence on the yield or selectivity of the products, as shown in the case of 118. For trisubstituted or tetrasubstituted enol ethers, a drop in diastereoselectivity in the products 119–121 was observed. Interestingly, the opposite diastereoisomer was formed in the case of product 120, while in other cases, products having nitrogen in anti‐relationship with oxygen were determined as the major diastereoisomer. In 2012, the Waser group also reported catalytic [3 + 2] annulations between DA aminocyclopropanes and carbonyl compounds such as aldehydes [110] or ketones [111], giving access to aminotetrahydrofurans. Built upon these results, the Waser group further reported in 2014 a dynamic kinetic asymmetric (DYKAT) [3 + 2] annulation reaction of 32 with enol ethers or aldehydes 122 to form

245

246

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

CO2Me PhthN

CO2Me

OTBS CO2Me

+

2) Rh2(cap)4 (2 mol%)

N2 125

30

OTBS CO2Me

1) Yb(OTf)3 (5 mol%)

CO2Me CO2Me 127, 64%, over 2 steps

PhthN

Yb(OTf)3 [3 + 2]

Ring expansion

CO2Me

TBSO PhthN 126

Scheme 7.19

TBSO

Rh2L4

N2 CO2Me CO2Me

PhthN I

CO2Me

TBSO

Rh2L4 CO2Me CO2Me

PhthN II

CO2Me Rh2L4 CO2Me CO2Me

Formal [3+3] cycloaddition of 30 with enoldiazoacetate 125.

five‐membered cyclic compounds such as 123 and 124 (Eq. 7.9) [46]. The combination of a copper catalyst and the commercially available bisoxazoline ligand L1 was key to the success of this reaction, which provided products in high yield, good diastereoselectivity, and excellent enantioselectivity under mild conditions. The dynamic process can be speculated to proceed via reversible ring opening/closing, as racemization of enantio‐enriched 32 was observed in the absence of enol ether. This DYKAT process represents a straightforward approach to convert the easily accessible racemic DA aminocyclopropanes into enantio‐enriched nitrogen building blocks, which may be useful for the synthesis of bioactive compounds. Dynamic kinetic asymmetric [3+2] annulation reaction of 32. O

O

CO2Me CO2Me

N O

32, 50 : 50 e.r.

Cu(CIO4)2/L1

X

+ R

Ph

122, X = O, CH2

CH2CI2, rt

N O

X

CO2Me CO2Me

R Ph 123, R = OBn, X = CH2, 97%, 92% ee 124, R = H, X = O, 82%, 84% ee (7.9)

In 2015, the Doyle group reported a formal [3 + 3] cycloaddition of enoldiazoacetate 125 with DA cyclopropanes, which was extended successfully to DA aminocyclopropane 30 (Scheme 7.19) [112]. This reaction was realized by a tandem reaction, first with a Lewis acid‐catalyzed [3 + 2] cycloaddition to form 126, followed by a subsequent rhodium‐catalyzed ring expansion to afford the six‐membered cyclic compound 127 as the final product. In addition to enol ethers/aldehydes/ketones, formal [3 + 2] cycloadditions with thioalkynes [113] and ynamides [114] were also reported. Based on previous studies from the Waser group [115], thioalkynes were easily synthesized from thiophenols and ethynylbenziodoxolones (EBX reagents). Annulation reactions of 30 and triethylsilyl substituted thioalkyne gave access to highly substituted cyclopentene 128 in high yield and regioselectivity (Scheme 7.20a), while a different product was

7.4 Formal Cycloaddition of DA DAminocycloorooanes

CO2Me CO2Me

PhthN

SPh

TES

TES

SPh

Hf(OTf)4 (20 mol%)

(a)

(d)

S

NH

PhthN S

Cs2CO3, TiF4 THF, 60 °C

128, 73% 13 : 1 r.r. CO2Me CO2Me

PhthN Ph

N

N

131, 84% N3iPr2 Ph

(b)

N iPr Sc(OTf)3 (10 mol%)

iPr

CO2Me CO2Me S

S

30 or 31

(e)

CO2Me

NH4SCN

PhthN S NH2 132, 22%

Yb(OTf)3, 75 °C

CH2Cl2, 7 d

129, 42%

PhthN

CO2Et CO2Et O N Ph 130, 90%

PhNO MgBr2 (20 mol%) DCE, 90 °c

(c)

(f)

Me N

NH

NCS PhthN

70 °C

CO2Me CO2Me N S H 133, 77%

Scheme 7.20 Formal cycloaddition with thioalkynes, ynamides, nitrosobenzenes, benzodithioloimines, thiocyanates, or isothiocyanic acid.

formed with aliphatic thioalkynes [113]. 1‐Alkynyltriazenes were synthesized by the Severin group, and their synthetic utility was demonstrated in several types of transformation, including the [3 + 2] annulation with 30 to form cyclopentene 129 (Scheme 7.20b) [114]. In 2014, the Studer group reported a formal [3 + 2] cycloaddition of 31 with nitrosobenzene to form 130 (Scheme 7.20c) [116]. The Werz group reported in 2016 a formal [4 + 3] cycloaddition of 30 with amphiphilic benzodithioloimine as surrogate for ortho‐bisthioquinone to give 131 (Scheme 7.20d) [117], as well as a formal [3 + 2] cycloaddition of 30 with selenocyanate [118] or thiocyanate to form 132 (Scheme 7.20e) [119]. In 2021, the Trushkov group in collaboration with the Werz group reported a formal [3 + 2] cycloaddition of 30 with isothiocyanic acid to produce 133, in which case an untypical N‐attack took place (Scheme 7.20f) [120]. Apart from annulation of DA aminocyclopropanes with the dipolarophiles mentioned above, dearomative [3 + 2] annulation reactions have also been studied. In 2017, the Waser group described a dearomative [3 + 2] annulation of N‐heterocycles with DA aminocyclopropanes (Scheme 7.21a) [121]. In this case, imido‐substituted DA cyclopropanes exhibited superior reactivity compared to aryl or alkoxy‐substituted DA cyclopropanes. Several different N‐heterocycles, including pyridines, quinolines, and isoquinolines, were well tolerated. An asymmetric dearomative [3 + 2] cycloaddition reaction of DA aminocyclopropane 136 with benzazole 137 was later disclosed by the Guo and You group, forming tricyclic product 138 in good yield and enantioselectivity (Scheme 7.21b) [122]. In 2019, the Guo group successfully extended the asymmetric dearomative [3 + 2] cycloaddition to purines [123]. In 2019, the Wang group developed a cooperative RhII/InIII catalytic system for the cyclopentannulations of indole 139 to tetracyclic indolines (Scheme 7.22a) [124]. By tuning the reaction parameters carefully such as solvent and temperature, three structurally divergent tetracyclic indolines, cis‐140, trans‐140, and 141, were synthesized with good yield and excellent selectivity. Mechanistic studies indicated an

247

248

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

(a)

CO2Me PhthN

CO2Me

Yb(OTf)3 (5 mol%)

+ N

30 O

CO2Et

N

+

137

138, 83%, 97% ee

NTs

CO2Me N H CO2Me PMB

Rh2(esp)2 InCI3

N PMB

MeO2C

N2(CO2Me)2

139

NTs N H PMB cond. C: DCM, –15 °C 141, 78%, 97:3 r.r.

OSiEt3

Me

N Ts

142

Scheme 7.22

CO2Et

+

N Me 94

OMe Me

Tf2NH (2.5 mol%) CH2Cl2, –78 °C

CO2Me

or

cond. A: 1,3,5-triethylbenzene, 30 °c cis-140, 75%, 94:6 d.r., 93:7 r.r. cond. B: DCE, 70 °C trans-140, 80%, single isomer

Me

(b)

Me CO2Et

Dearomative [3 + 2] cycloaddition reactions.

NTs

(a)

CO2Et

S

136

O

N N

S

O

Scheme 7.21

O

Cu(OTf)2/L1

Me

CO2Me CO2Me

PhthN 135, 95%

134 CO2Et

N

(b)

CH2Cl2, rt

H N

TsN H

Me PMB CO2Et

N H Me 143, 95%, 93:7 d.r.

Intra- and intermolecular dearomative [3 + 2] annulations of indoles.

intramolecular annulation of the indole with an in situ‐formed aminocyclopropane. In 2021, the Waser group reported an intermolecular [3 + 2] dearomative annulation reaction between mono‐acceptor aminocyclopropanes and indoles (Scheme 7.22b) [125]. Getting rid of one acceptor group was not easy, as a balance between reactivity and stability needed to be found. Protecting the amino group with a tosyl group and a methyl group as in 142 gave an optimal reactivity. The choice of the in situ formed triethylsilyl triflimide as catalyst was also crucial and led to the formation of tricyclic indoline product 143 with excellent yield and stereoselectivity. Annulations with tropones were also explored. For example, the Sierra group reported in 2013 a formal [8 + 3] cycloaddition reaction between DA aminocyclopropane 31 and tropone, which produced amino‐substituted tetrahydrocyclohepta[b]pyran 144 with complete regio‐ and diastereoselectivity (Eq. 7.10) [126]. Density functional theory (DFT) calculations revealed that the transformation proceeds stepwise through a zwitterionic intermediate, which is stabilized by some

7.4 Formal Cycloaddition of DA DAminocycloorooanes

degree of π‐aromaticity of the tropyl cation. The regio‐ and diastereoselectivity are controlled in the ring closure step. In the same year, the Adrio and Carretero group also reported a nickel‐catalyzed formal [8 + 3] cycloaddition of tropones with 1,1‐ cyclopropanediesters, including DA aminocyclopropane 30 [127]. Formal [3 + 2] cycloaddition of 31 with tropone. O PhthN O

CO2Et PhthN



CO2Et

CO2Et CO2Et

SnCI4 (5 mol%)



31

(7.10)

In addition to the commonly used imide‐substituted DA cyclopropanes, the Waser group also developed an efficient synthesis of thymine/uracil‐substituted DA cyclopropanes 145 and their subsequent formal [3 + 2] cycloaddition with enol ethers/ aldehydes/ketones 146 for the synthesis of nucleoside analogs 147 (Scheme 7.23a) [128, 129]. Based on the recent progress in the synthesis of alkenyltriazene 148 [130], the Severin group in collaboration with the Waser group has synthesized triazene‐ derived DA cyclopropane 149 by cyclopropanation with diazomalonate. They illustrated the reactivity of 149 by developing ring‐opening reaction with methanol to form 150 or by developing a formal [3 + 2] cycloaddition with TCNE or enol ethers to form five‐membered cyclic products 151 or 152, respectively (Scheme 7.23b) [131].

O

O O

(a)

O

HN

R1

HN

R1 +

N

O N H

CO2Me CO2Me

R1 = H (Uracil) R1 = CH3 (Thymine)

X R2

(b)

N

N N

Cy

145

Cy N

N N

Hf(OTf)4

Scheme 7.23

N N N NC CN

OTIOS Ph

N N N Cy

Cy Cy

149, 87%

N

OMe CO2Me Cy

Cy TCNE (105)

O

R2 MeO2C R3 MeO2C 147, 51–97%

146

CO2Me CO2Me 148

Lewis acid R3

X = O, CH2

MeOH

Cy

R1

HN

Cy N N N Cy

CO2Me

CO2Me CO2Me

150, quant

151, 65%

CN CN CO2Me CO2Me Ph OTIPS

152, 76% 4 : 1 d.r.

Thymine/uracil- and triazene-substituted DA cyclopropanes 145 and 149.

249

250

7 Donor–Acceptor Cyclopropanes with an Amino Group as Donor

7.5 Conclusion Activating the C─C bond of cyclopropane, in spite of its high ring strain, is challenging and usually requires the use of noble metal catalysts. Nevertheless, attaching an amino group as donor and one (or two) electron‐withdrawing group(s) as acceptor to the vicinal carbon atoms of the C1─C2 bond makes it strongly polarized and prone to cleavage to give a formal 1,3‐dipole. As an important subclass of DA cyclopropanes, DA aminocyclopropanes share many similarities with aryl‐ or alkoxy‐substituted DA cyclopropanes in terms of activation methods and reaction patterns. Nevertheless, the nitrogen atom of DA aminocyclopropanes endows them with some unique properties. Their utility has now been demonstrated in organic chemistry, especially in the field of total synthesis of natural products and their analogs. Challenges, however, still remain for the future, including among others the synthesis of medium‐sized rings by formal cycloaddition, the development of new diastereoselective and enantioselective reactions for mono‐acceptor aminocyclopropanes, the use of other amino donor groups, and the further extension of the developed concepts to DA aminocyclobutanes [132-136], which have been only scarcely investigated so far.

Abbreviations



triphenylmethyl

eferences

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8 Reactivity of Cyclopropyl Monocarbonyls Pankaj Kumar, Irshad Maajid Taily, Priyanka Singh, and Prabal Banerjee Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar, Punjab, 140001, India

CHAPTER OUTLINE 8.1 8.2 8.3 8.4 8.5 8.6

Introduction 255 Associated Challenges 256 Perks of Having a Monocarbonyl Substituent on Cyclopropane 258 Methods for the Preparation of Cyclopropyl Monocarbonyls 260 Cyclopropyl Monocarbonyls in Important Heterocyclic Synthesis 264 Application in Total Synthesis 270 References 270

8.1 Introduction Over the years, carbonyl groups have proven to be amazing acceptors in molecules where reactivity depends upon the resonance-induced electron-withdrawing nature of a suitably substituted functional group. Carbonyls work as useful withdrawing groups in aromatic systems, unsaturated molecules, and for activation of strained carbon─carbon bonds, like in small ring systems of cyclopropanes, aziridines, epoxides, and cyclobutanes. Considering cyclopropanes in particular, carbonyl compounds are among many other functional groups that have been used as acceptors to activate the cyclopropane ring. Some of the well-known acceptors are diesters, keto-esters, nitro, nitro-esters, nitriles, etc (Scheme 8.1a). Among all these, the most widely studied acceptor group for the cyclopropane chemistry is the diester group. Cyclopropane diesters are easy to prepare and are stable at room temperature. Cyclopropane diesters can be easily activated in the presence of Lewis acids, which particularly activate them through binding to the diester site of the cyclopropane [1]. This extensive study of the cyclopropane diesters has proven this molecule to be the

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

256

8 Reactivity of Cyclopropyl Monocarbonyls Generally employed acceptors for DACs:

(a)

CO2R

C(O)R

CO2R D

(Diketone)

CN

NO2

D

C(O)R

D

CO2R (Diester)

CN

D

(Nitro-ester)

(Dinitrile)

General reactivity of DACs:

(b)

D

A D

A

NuE

A

E

D Nu

A (1,3-dipole)

A

A

(c) O

NuH R

D (R = Alkyl, Aryl, H)

O D

R Nu

O

+ D

Further reactions Nu

R

Scheme 8.1 (a) Generally employed acceptors for DACs; (b) common reactivity of DACs; and (c) reactivity of cyclopropane monocarbonyls.

best choice for the (3 + n) type of formal cycloaddition processes (Scheme 8.1b). This predictable reactivity of cyclopropane diesters being a three-carbon synthon, besides being an advantage, seems to saturate the versatile scope of this otherwise interesting molecule. However, the removal of one of the two ester groups on the vicinally substituted cyclopropane molecule or having a ketone/aldehyde functionality in place of the diester can make the reactivity of these donor–acceptor cyclopropanes even more exciting. With cyclopropane carbaldehyde or ketone, the carbonyl group is also a pertinent reactive center that can undergo a number of reactions and, so, can make the donor–acceptor chemistry of the cyclopropane molecule even more fascinating (Scheme 8.1c).

8.2 Associated Challenges Donor–acceptor cyclopropane monocarbonyls have come up with specific reactivity advantages, but there are also some challenges associated with these molecules. They are listed in the following section.

8.2.1

Reduced Reactivity

The first and major challenge that is associated with the cyclopropane monocarbonyls is their fairly reduced reactivity compared to other donor–acceptor cyclopropane (DAC), in particular the cyclopropane diesters. Clearly, the bond between the vicinal substituents will be more reactive when we have two ester groups to pull (with the alkyl/aryl group to push) rather than one ester (carbonyl) group for the pull/withdrawing effect (Figure 8.1). As a result, the cyclopropane ring-opening

8.2 ­ssociated Challenges

Figure 8.1 Reduced polarization of reactive carbon─carbon bond in cyclopropane monocarbonyls.

A

A A

D

D A = C(O)R

Figure 8.2 A general comparison of reactivity in various cyclopropane monocarbonyls.

OR

D

O

O

O D

R

D

Reactivity of various cyclopropane mono-carbonyls

becomes more difficult in the case of cyclopropane mono-carbonyls, and we may have to use harsh reaction conditions or modify the reaction conditions accordingly. However, the reduced reactivity of these cyclopropanes makes them more selective for specific reaction conditions in order to undergo ring-opening transformations. On the other hand, the reactivity of DAC mono-carbonyls can be further improved by having a more electron-withdrawing carbonyl group as an acceptor. Evidently, aldehydes and ketones are significantly more electron-withdrawing than the esters [2]. Consequently, DA cyclopropane carbaldehydes/ketones would be more reactive than the DA cyclopropane monoesters (Figure 8.2). In this chapter, we will have a thorough discussion on the reactivity of DA cyclopropane carbaldehydes and DA cyclopropyl ketones.

8.2.2

Diastereomers and Controlled Reactivity

At first, cyclopropane monocarbonyls seem to be similar to the other DACs, but actually they come with a few practical challenges that need to be addressed before one starts to work with these molecules. In aryl substituted cyclopropane monocarbonyls, the first challenge resides in their diastereomeric nature. There are two stereo centers in the molecule, and the two substituents in the vicinal positions of the cyclopropane can be cis or trans to each other. Depending on the relative geometry of these two substituents that work in synergy, the molecule can be reactive for some transformation only in one geometry. So, tuning the geometry of these cyclopropane mono-carbonyls according to the designed transformation is the first challenge to be worked on before we move further with the reactivity. Having this choice of diastereomers in the cyclopropane molecule can sometimes also be helpful. For instance, trans-geometry of the DA cyclopropane monocarbonyls would be preferred in the following scenario: (i) Reaction with a binucleophile would prefer the trans-geometry for a sterically favored approach (Scheme 8.2a) [3]. (ii) If the nucleophilic species (approaching C─C bond of the cyclopropane) would have any interaction with the acceptor carbonyl group, or if the electrophilic center of the dipolar species (approaching C─C bond of the cyclopropane) would have any interaction with the donor group (Scheme 8.2a).

257

258

8 Reactivity of Cyclopropyl Monocarbonyls

O

(a)

R

D

Nu1–Nu 2

Nu2 Nu1

Nu

O R

D

O

D (cis)

R

R1–Nu

E

O

D R1 Nu

R

D

(trans)

(b)

O

R

O

D

R X Y

Scheme 8.2 (a) Steric factors would favor the trans-geometry, while (b) Donor group assistance and concerted cycloaddition would favor the cis-geometry of DA cyclopropane monocarbonyls.

On the other hand, cis-geometry of the DA cyclopropane monocarbonyls would be preferred in cases like; (i) If the transformation is designed in such a way that the catalyst/reagent can activate/assist the carbonyl group as well as the donor substituent on the cyclopropane ring. (ii) If there is any donor group assistance to the nucleophilic attack on the carbonyl center (Scheme 8.2b). (iii) For a concerted cycloaddition process, where both nucleophilic and electrophilic ends of the dipolar species need to approach the cyclopropane from the same side (Scheme 8.2b).

8.3 Perks of Having a Monocarbonyl Substituent on Cyclopropane 8.3.1

DAC Monocarbonyls—Not Merely a Three-Carbon Synthon

Unlike Cyclopropane diesters, cyclopropane mono-carbonyls are not merely a three-carbon dipolar species; but the carbonyl group here is also reactive on its own. In many cases, it is seen that the carbonyl center, especially the aldehyde and ketone groups, is more reactive than the cyclopropane ring, and the nucleophilic center of a partner substrate first reacts on the carbonyl center rather than on the cyclopropane ring [4]. This unique property of the acceptor group being involved in reactions of cyclopropyl mono-carbonyls makes them rather interesting to work with.

8.3.2 Two Nucleophilic and Two Electrophilic Sites As is known very clearly, DACs have an electrophilic (e1) and a nucleophilic center (n1) on the vicinal positions of the cyclopropane ring. In addition to these reactive centers, cyclopropane mono-carbonyls also have two more fairly reactive centers on the carbonyl group – an electrophilic carbonyl carbon (e2) and a nucleophilic carbonyl oxygen (n2). Thus, this class of cyclopropanes now possesses four highly

8.3 Perrs of aving a Monocarbonyl ubstituent on Cyclopropane

reactive centers that can be used to design numerous transformations with these cyclopropanes. However, it is noteworthy that the vicinal positions of the cyclopropane are comparatively less reactive than the diester-based DACs as there is only one acceptor group here. With all these structural properties, DA cyclopropane mono-carbonyls can be expected to undergo a number of transformations depending on the type of substrate partner/reagent used. Firstly, it can undergo the classical Cloke–Wilson type rearrangement on its own or in the presence of a nucleophilic species (Scheme 8.3a) [5]. This transformation can be catalyzed by a Bronsted acid, a Lewis acid, or by heating. Being a type of DAC, these cyclopropanes are also expected to undergo the most studied (3 + n) formal cycloaddition process of the DACs with a dipolarophile (Scheme 8.3b) [1]. These two processes are also well known with the other DACs, except for the fact that the cyclopropane C─C bond for DAC monocarbonyls is far less activated, and it should be challenging to make it undergo the requisite cleavage. The most fascinating part about the reactivity of DAC monocarbonyls is something that is not feasible with the other DACs. For instance, these cyclopropanes are also open to an unexpected (5 + n)-type formal cycloaddition process where the cyclopropane moiety could behave as a five-atom contributor to an even larger ring system (Scheme 8.3c). Intriguingly, these cyclopropanes are also apt to undergo annulation with a bi-nucleophilic species, making use of both of their electrophilic centers (Scheme 8.3d) [3]. Unlikely, in such a scenario, the cyclopropane would behave as a four-carbon contributor toward the annulation process. R' Nu +

R'–Nu Cloke-Wilson-type cyclization

D

NuE

D

O

R

D

O

R

(a)

O n2 O D

[3 + n] Cycloaddition

O R

e1 n1 e2

D

R

E

(b)

D Nu–E [5 + n] Cycloaddition Nu–Nu Binucleophilic annulation

Scheme 8.3

R

Nu

Nu

E O

R

(c)

R

(d)

D Nu

Nu

Possible reactions of DA cyclopropane monocarbonyls.

8.3.3 Cyclopropane Mono-Carbonyls in Organocatalysis There have been some great advancements in the field of chiral phosphoric acid as well as iminium ion catalysis with aldehydes and ketones for asymmetric synthesis, but unfortunately, iminium ion activation of the cyclopropane ring has not been explored much. With cyclopropyl carbaldehydes or with cyclopropyl ketones, this area of research has immense scope to work on (Scheme 8.4).

259

260

8 Reactivity of Cyclopropyl Monocarbonyls O O P O O H

O R

D

O D

H

O O P O

O

R

Ring opening via iminium ion catalysis

N D

Scheme 8.4

D

CPA induced ring opening

N H

R

O

R

N D

R

Organocatalytic activation of DA cyclopropane monocarbonyls.

8.4 Methods for the Preparation of Cyclopropyl Monocarbonyls There are a number of versatile methods available for the synthesis of cyclopropane carbaldehydes. However, only two approaches have become popular for the same—(i) those based on diazo compounds and (ii) those using sulfur ylides (Corey–Chaykovsky reaction). Nevertheless, a few other methods have their own strengths and applicability.

8.4.1

From Olefins

8.4.1.1 Corey–Chaykovsky Reaction

The Corey–Chaykovsky reaction is one such reaction that has been extensively exploited for the synthesis of DACs [6]. It was discovered by A. William Johnson in 1961 and developed significantly by E. J. Corey and Michael Chaykovsky. This method involves trimethylsulfoxonium [Me2S(O)CH2] ylide (Corey ylide) as a methylenating agent. It involves the base-mediated deprotonation of trimethylsulfoxonium iodide to generate the ylide. The ylide undergoes Michael addition on the electrophilic alkene ester, followed by cyclization due to the attack of the anionic center on the ylide methylene group with the elimination of DMSO. Finally, the ester group is transformed to the corresponding aldehyde by a series of reduction and oxidizing agents (Scheme 8.5).

I-

CO2Et

O +

S

CO2Et

NaH or tBuOK R

LiAlH4

CO2Et

CHO

PCC

R

– Me 2SO

Scheme 8.5

Corey–Chaykovsky synthesis of cyclopropane carbaldehydes.

R

R

8.4 Methods for the Preparation of Cyclopropyl Monocarbonyls

8.4.1.2

Hydroformylation of Cyclopropenes

The hydroformylation of cyclopropenes was first demonstrated by Orchin in 1981 by employing Mn- and Co-complexes, albeit in low yield [7]. Noyori in 1995 used HMn(CO)5 complex, which somewhat improved the yield (Scheme 8.6) [8]. Stoichiometric HMn(CO)5

Scheme 8.6 Mn- and Co-catalyzed hydroformylation of cyclopropenes.

Ph

or HCo(CO)4

Ph

CHO Ph

Ph

However, Rubin et al. reported the first catalytic diastereo- and enantioselective hydroformylation of prochiral cyclopropenes toward the synthesis of substituted cyclopropanecarbaldehydes under mild conditions and very low catalyst loading (Scheme 8.7) [9]. Scheme 8.7 Diastereo- and enantioselective hydroformylation of cyclopropenes.

Rh (I)-cat Ph

Ph

H2, CO

*

Ph

*

CHO

8.4.1.3 Ozonolysis of Vinyl Cyclopropanes

It involves the oxidative cleavage of vinyl cyclopropane to cyclopropylaldehydes by employing O3/PPh3 (Scheme 8.8) [10]. Scheme 8.8

Ozonolysis of vinyl cyclopropanes.

O3, then PPh3 Ph

Ph

8.4.2

O

From Homoaldol Adducts

Taylor developed an efficient two-step homologation of aldehydes to cyclopropylaldehydes with excellent trans/cis selectivity in 2003 [11]. The protocol involves the activation of homoaldol adducts obtained from O-enecarbamates and N-enecarbamates to generate the heteroatom stabilized cyclopropylcarbinyl cationic intermediate to finally furnish the cyclopropane carbaldehydes (Scheme 8.9).

OTES

(i) sec-BuLi (ii) BaI 2 (iii) RCHO

OH

Activating agent

R OTES

base

R

O

activating agent/base = Tf 2 O/2,6-lutidine at –78 °C or Ms 2O/iPr 2NEt at rt

Scheme 8.9

Two-step homologation of aldehydes to cyclopropylaldehydes.

Moreover, the same group in 2004 disclosed the stereospecific cyclization of enantiomerically enriched homoaldol adducts to furnish enantiomerically enriched and diastereomerically pure 1,2,3-trisubstituted cyclopropyl aldehydes by asymmetric metalation [12].

261

262

8 Reactivity of Cyclopropyl Monocarbonyls

8.4.3

From Arylthio Cyclopropyl Carbaldehydes

The stoichiometric metalation of arylthio ethers followed by trapping with formamides is the main route of their synthesis (Scheme 8.10a) [13–15]. The hydrolysis of cyclopropane carbonitriles could also be used to access these cyclopropanes (Scheme 8.10b) [13b]. In 2018, Secci et al. demonstrated the Bronsted acid-catalyzed facile synthesis of these carbaldehydes via addition/ring contraction reaction sequence of 2-hydroxycyclobutanones. The methodology exhibited wide substrate scope under mild reaction conditions (Scheme 8.10c) [16]. SPh Cl

(a)

1. KNH2

SPh

2. NCS

Cl

SPh

(b)

n-BuLi

CN

Br

OH

O

(c)

Br

+

HO

H

1. n-BuLi

SPh

2. N(Me)2CHO

CHO

SPh

1. NaBH4

CN

2. H3O

SR

OH

RSH

Scheme 8.10

8.4.4

SPh

+

RS

CHO

OH

SR CHO

Synthesis of arylthio cyclopropyl derivatives.

From Diazo Compounds

The synthesis of cyclopropane carbaldehydes has well exploited the carbene chemistry, as most of the methods for their synthesis are based on the addition of in situ generated carbenes or their equivalents to alkenes (Scheme 8.11) [17]. Diazo compounds (diazomethane, diazo carbonyls), which, in the presence of a metal catalyst (usually transition metals like Rh, Pd, Cu, Au, etc.) generate reactive carbenes, are utilized to bring out this transformation. The in situ generated carbenes undergo simultaneous [2 + 1] cycloaddition with the olefins to construct the three-carbon ring. Diazomethane is the easiest and most convenient source of carbenes for the cyclopropanation of alkenes that have both substituents. However, the diazo compound could also bear either of the donor or acceptor substituents. DACs with high Scheme 8.11 Synthesis of cyclopropane carbaldehydes from diazo compounds.

R Y(O)C

R

LnM

Ln M

N2

O CHC

Y

N2

O CHC

Y

8.4 Methods for the Preparation of Cyclopropyl Monocarbonyls

yields and absolute stereoselectivity (cis/trans) could be obtained by designing the catalyst and the substituents in the reactants. Diazo compounds with electronwithdrawing groups (acetates, malonates) and alkenes with electron-donating groups are commonly employed as starting materials for the synthesis of DACs. This methodology has been found equally efficient in the case of alkyl vinyl ethers, vinyl sulfides, enamines, and other similar compounds where a heteroatom acts as a donor group. Moreover, this methodology has found its application at the industrial scale and in the flow chemistry. Alkyl diazoacetates are readily dediazotized in presence of the catalyst and are thus commonly utilized among alkyl diazocarbonyls. This method has found its use in the synthesis of a number of chiral DACs by employing a chiral metal catalyst. Apart from these, the diazo compounds with two EWGs, like α-cyano- and α-nitro-diazocarbonyl compounds, have also been studied. In 2016, the Lawasa group diastereo- and enantioselective Ru(II)–Amm–Pheox complex catalyzed stereoselective cyclopropanation of diazo Weinreb amides with olefins to furnish the corresponding chiral cyclopropyl Weinrebamides (Scheme 8.12) [18]. These Weinrebamides could be easily transformed to the corresponding aldehydes, ketones, and alcohols.

O Cat.

+

PF6–

O R

LiAlH4

+

H

Ru

N (NCCH3)4

O N2

R

O Ph

Cat. = Ru(II)-Pheox

Scheme 8.12 Asymmetric cyclopropanation of various olefins.

8.4.5

From 1,2-Dicarbonyl Compounds

Keeping in view the potentially explosive nature and multi-step synthesis of diazo compounds, Zhuo et al. recently in 2021 reported molybdenum-catalyzed deoxygenative cyclopropanation of 1,2-dicarbonyl compounds (Scheme 8.13) [19]. The protocol elegantly presented the carbonyl group as the carbene precursor and furnished cyclopropanes with exclusive regioselectivity in up to 90% yield. Phosphines (or silanes) act as both a mild reductant and a good oxygen acceptor and bring about the reduction of Mo-oxo complexes to regenerate the Mo catalyst. Scheme 8.13 Molybdenum-catalyzed deoxygenative cyclopropanation of 1,2-dicarbonyls.

O R O

MoO2Cl2 DPPB

R1

O R R1

O R

R1

263

264

8 Reactivity of Cyclopropyl Monocarbonyls

8.5 Cyclopropyl Monocarbonyls in Important Heterocyclic Synthesis Similar to other types of DACs, aryl substituted cyclopropyl carbonyls, due to the vicinal arrangement of the functional groups, also undergo C─C bond cleavage, leading to the formation of 1,3-zwitterionic species. Various transformations such as cycloaddition, ring-opening, rearrangement, and ring-expansion reactions toward the formation of diverse high-value open-chain and cyclic compounds have been achieved through the formed 1,3-dipoles. This section of the chapter is mainly focused on the reactivity of cyclopropyl carbonyls toward different reactive partners.

8.5.1 Metal Catalyzed Annulation Reactions of Cyclopropyl Monocarbonyls Among various cyclopropane derivatives, Lewis-acid catalyzed reactions of DACs have been studied widely [20], whereas the reactions of cyclopropane carbaldehydes are scarce. So in an attempt to explore the Lewis acid catalyzed reactivity of cyclopropane carbaldehydes, in 2018, Banerjee and group represented facile access to tetrahydropyridazines 3 via Lewis acid catalyzed annulation of cyclopropane carbaldehydes 1 and aryl hydrazines 2 (Scheme 8.14a) [3a]. The product tetrahydropyridazine 3 was also subjected to a [3 + 2] cycloaddition reaction with 2-aryl cyclopropane 1,1-dicarboxylate 4 to render hexahydropyrrolo[1,2-b]pyridazine derivatives 5a and 5b (Scheme 8.14b). Furthermore, these two reactions were also performed in one pot by a sequential manner to synthesize hexahydropyrrolo[1,2-b] pyridazine derivatives 5a and 5b. In the annulation step, InCl3 was the most effective catalyst, whereas in cycloadditions step, Yb(OTf)3 was the most efficient catalyst. (a)

O +

Ar1 1 R=H

R

HN Ar2 H 2N

Ar1

InCl3, 4 Å MS DCM, rt up to 75% yield

Ar2

2

N

N 3

Ar1 = Ph, 4-FC6H4, 4-MeC6H4, 4-OMeC6H4, 2,6-(OMe)2C6H3, 1-napthyl, 2-furyl Ar2 = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CNC6H4, 4-MeC6H4, 4-IPC6H4

(b)

Ar2

PMP

PMP

Ar1 N

+ N 3

Ar1 = PMP Ar2 = Ph

R1 4

CO2R2

Yb(OTf)3, 4 Å MS

CO2R2

DCM, rt up to 73% yield up to 70 : 30 dr

Ph

N

N

CO2R2 CO2R2 +

Ph

N

R1 5a (cis) Major

N

CO2R2 CO2R2

R1 5b (trans) Minor

R1 = Ph, 4-FC6H4, 4-OMeC6H4, 3,4-(OMe)2C6H3, 4-MeC6H4, 2-MeC6H4, 2-furyl, 2-thienyl R2 = Me, Et, Bn

Scheme 8.14

Annulation reaction of cyclopropane carbaldehyde and aryl hydrazine.

8.5 Cyclopropyl Monocarbonyls in Important eterocyclic ynthesis

Extending the Lewis acid catalyzed reactivity of cyclopropane carbaldehydes toward the Prins-type cyclization, Banerjee group subsequently in same year reported a versatile single-step TiX4-mediated route to nine-membered ring (E)-hexahydrooxonines 8 or a fused bicyclic system octahydrocyclopenta[b]pyrans 9, simply by picking up an appropriate alcohol. When cyclopropane carbaldehydes 1 were made to react with 3-buten-1-ol 6 through non classical Prinstype cyclization resulted in the highly stereoselective construction of relatively strained (E)-hexahydrooxonines 8. While switching the alcohol to 3-butyn-1-ol 7 prompted a similar route, augmented by another classical Prins-type cyclization within a nine-membered ring to afford a bicyclized product (4,4-dihalo-5aryloctahydrocyclopenta[b]pyran) 9 (Scheme 8.15) [3b]. Easy transformation of the resulting geminal dihalide to a vinyl halide and a ketone further supplemented the synthetic scope of this proposed approach.

R 1

O

TiCl4(1 equiv.)

O

Ar1

6

OH

4 Å MS, DCM, –78 °C 0.5–0.7 h 30–78% yield

Ar

Cl 8

Ar1 = 4-OMeC6H4, 4-OBnC6H4, 4-MeC6H4, 4-i-PrC6H4, 3,4-(OMe)2C6H3, 2,4,6-(Me)3C6H2 X X O

Ar1 1

R

TiX4 (1.5 equiv.) HO 7

4 Å MS, DCM, –78 °C 0.3–0.5 h 40–80% yield >99% dr

O

H

Ar

H

9 (major)

X X

H

Ar

O H 9' (minor)

Ar1 = Ph, 4-OMeC6H4, 4-OBnC6H4, 4-MeC6H4, 2,4,6-(Me)3C6H2, 4-i-PrC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 2-napthyl X = Cl, Br

Scheme 8.15 Prins-type annulation between cyclopropane carbaldehydes and alkenols/ alkynols.

In contemporary time, the thought of exploring the metal-free reactivity of the cyclopropanes led us to test the ability of Bronsted acids to activate cyclopropane carbaldehydes. In 2019, our group reported a p-toluenesulphonic acid (pTSA) mediated mild and eco-friendly ring-opening/domino ring-opening cyclization reaction of cyclopropane aldehyde 1 and N-benzyl aniline 10 toward the construction of substituted 4-aminobutanal 11/2,3-dihydro-1H-benzo[b]azepine 12 derivatives. The formation of 4-aminobutanal 11 or 2,3-dihydro-1H-benzo[b]azepines 12 depends upon the presence of methoxy substituent at the 3 position of phenyl ring of N-benzyl aniline 10. The reaction proceeds through the formation of open chain 4-aminobutanal 11 via the nucleophilic ring-opening with N-benyl aniline 10 and cyclopropane aldehyde 1 in the presence of pTSA. Further, the aldehyde functionality of 11 gets activated by pTSA to undergo an intramolecular Friedel–Crafts type

265

266

8 Reactivity of Cyclopropyl Monocarbonyls

reaction to form the desired benzoazepines 12 (Scheme 8.16). A broad range of substrate scope was supported by the optimized reaction conditions, affording the designed compounds moderate to good yields [3c]. O

Ar1 Ar1

CHO N

Bn

R=H 4 +

PTSA (20 mol%) R1 R2

DCM, rt 14–50 h 45–73% yield

Bn

R

H N

R1 2

R

11

Ar1 PTSA (1.2 equiv.) DCM, rt 3–5 d 45–70% yield R2 = OMe

Bn

N

R1

R2 12

10

Ar1 = Ph, 4-OMeC6H4, 4-OBnC6H4, 4-ClC6H4, 4-CH3C6H4, C6H4CH = CH-, 2-napthyl R1 = H, OMe, Br, I, F, NO2 R2 = H, OMe

Scheme 8.16 Synthesis of 4-aminobutanal/2,3-dihydro-1 -benzo[b]azepine derivatives.

Further investigating the Bronsted acid-catalyzed reactivity of cyclopropane carbaldehydes, Banerjee and group also disclosed a highly regioselective synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one derivatives 14 by reacting cyclopropane carbaldehyde 1 with N′-aryl anthranil hydrazides 13 in the presence of pTSA. The reported transformation follows a domino imine formation and intramolecular cyclization to form 2-arylcyclopropyl-2,3-dihydroquinolin-4(1H)-one 15, which, on nucleophilic ring-opening of cyclopropyl ring, afforded the desired tetrahydropyrrolo[1,2-a]quinazolin-5(1H)one 14 in good to excellent yield with complete regioselectivity (Scheme 8.17) [3d]. One-pot sequential and gram scale synthesis of the desired pyrroloquinazolinones also revealed the industrial utility of the reported protocol. The proposed methodology tolerates a great variety of functional groups and thus provides a simple and step-efficient method for the synthesis of pyrroloquinazolinones. O

O O

Ar1 R R=H 1

+

N H NH2 13

R1

PTSA (30 mol%) dry DCM, rt 8–18 h 70–85% yield upto 20 : 80 dr

N N Ar1 H 14 (trans) minor

O

R1 H

O N

+ N

R1

N

H N H

Ar1 H 14' (cis) major

R1

Ar1 15

Ar1 = Ph, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, 4-OMeC6H4, 3,4-(OMe)2C6H3, 4-Ch = CHC6H4, 2-napthyl, 2-furyl R1 = Ph, Bn, 4-FC6H4NH-, 4-ClC6H4NH-, 4-BrC6H4NH-, 4-MeC6H4NH-, 4-i-PrC6H4NH-, C6H5CH2NH-

Scheme 8.17 PTSA catalyzed synthesis of tetrahydropyrrolo[1,2-a]quinazolin-5(1 )ones.

In continuation of this, Banerjee and group in 2020, put forward a convenient additive-free synthesis of dihydro-4H-1,2-oxazines 7 via a Cloke−Wilson-type ring expansion of aryl substituted cyclopropane carbaldehydes 1/1′ with the hydroxylamine salt 16 (Scheme 8.18a) [3e]. Here, hydroxylamine salt 16 acted as a precursor

8.5 Cyclopropyl Monocarbonyls in Important eterocyclic ynthesis (a)

O

Ar1 R

1/1' R = Aryl, H

R

NH2OSO3H (16, 1.5 equiv.) benzene, rt, open flask 4–72 h 25–82% yield

Ar1

O

N

17

Ar1 = Ph, 4-OMeC6H4, 4-OBnC6H4, 4-MeC6H4, 2,4,6-(Me)3C6H2, 4-i-PrC6H4, 2-MeC6H4, 3,4,5-(OMe)3C6H2, 3,4-(OMe)2C6H3, 3,4-(OCH2O)C6H3, 2-napthyl R = Ph, 4-MeC6H4, 4-ClC6H4

(b) Ar1

O

N

17

+

R1 4

CO2R2

Cu(OTf)2

CO2R2

4 Å MS, dry CH2Cl2 1–72 h 33–72% yield upto >99% dr

CO2R2 CO2R2 Ar1

O

CO2R2 CO2R2 +

N R2

18 (major)

Ar1

O

N

R2 18' (minor)

R1 = Ph, 4-FC6H4, 4-NO2C6H4, 4-OMeC6H4, 3,4-(OMe)2C6H3, 3,4,5-(OMe)3C6H2, 4-CH = CHC6H4, CH = CH2 R2 = Me, Et

Scheme 8.18 Annulation reaction of cyclopropane carbaldehyde with hydroxylamine salt.

of cyclopropyl aldoximes and underwent rearrangement for the effortless construction of 6-aryl-5,6-dihydro-4H-1,2-oxazine 17. Further to check the synthetic feasibility of the protocol, cyclopropyl ketones 1′ were also subjected to the standard conditions in the presence of catalytic p-toluene sulfonic acid monohydrate. The conversion rates were found to be very low as were the percentage yields, which could be due to the less reactivity of ketones as compared to the aldehydes. The transformation is performed in an open-air as it shows negligible sensitivity toward air/moisture. Dihydro-4H-1,2-oxazines 17 when subjected to cycloaddition with the cyclopropane diester 4 afforded a trouble-free formulation of the valued hexahydro2H-pyrrolo[1,2-b][1, 2]oxazine derivatives 18 (Scheme 8.18b).

8.5.2 Ring Expansion and Ring-Opening Reactions of Cyclopropyl Monocarbonyls Opening of the three-membered ring of cyclopropyl carbonyls under acidic conditions, followed by the attack of a nucleophile, is an area of considerable interest in organic synthesis. Several reports have been found in the literature discussing the ring-opening and ring expansion of the cyclopropane aldehydes. Acylsilanes are a useful class of compounds in organic synthesis, and a number of methods for the synthesis of acylsilanes have been developed in the past [21]. Especially, cyclopropyl silyl ketones are expected to exhibit the specific reactivities of the silylcarbonyl group and the three-membered ring. However, the chemical behavior of cyclopropylacylsilanes has not yet been fully clarified because of their synthetic difficulty. In 1986, Nakajima and group reported for the first time the ring-opening reaction of cyclopropylacylsilanes 19 in the presence of Lewis acids or hydrogen chloride (HCl). The reactions were performed at a lower temperature and led to the formation of either 3-chloropropyl trimethylsilyl ketones 20 or 2-trimethylsilyl-4,5-dihydrofurans 21, depending upon the substituents on the three-membered ring and the acids used (Scheme 8.19). The alkyl substituted

267

268

8 Reactivity of Cyclopropyl Monocarbonyls R3 R2

Si

R1

Si

Cl

DCM, –70–25 °C 2–4 h, 41–85% yield

O Si = SiMe3 19

R3

R1 R2

Lewis acid or HCl

R3

R2 R1

or

O

21

20

R1 = H, Me

R2 = H, Me, Ph

Si

O

R3 = H, Me

Scheme 8.19 Ring-opening and synthesis of silyl-dihydrofurans.

cyclopropylsilanes afforded only the ring-opened 3-chloropropyl trimethylsilyl ketones 20 in the presence of TiCl4/HCl whereas SnCl4 and BF3. OEt2 gave exclusively 2-trimethylsilyl-4,5-dihydrofurans 21. While aryl substituted cyclopropylsilanes in the presence of TiCl4/HCl furnished ring enlarged dihydrofurans 21 only [22]. In connection with the above findings, in 1995, Nakajima and group also reported that cyclopropylacylsilanes 19 react with strong acids having a low nucleophilic counter anion in aprotic solvents to yield two types of ring-enlargement products, cyclobutanones 23 or 2-silyl-4,5-dihydrofuran derivatives 21, depending upon the substituents on the three-membered ring of 19 or the acids used. Aryl substituted cyclopropylsilanes 19 in the presence of H2SO4 in DME/THF gave cyclobutanones 23 only, while alkyl substituted cyclopropylsilanes 19 led to the formation of 2-silyl-4,5-dihydrofuran derivatives 21. When solvent changed from DME/THF to MeOH, the formation of trimethylsilyl ketones 20 was observed (Scheme 8.20a) [23].

R3

H2SO4 R3

R1 R2 Si

MeO R3

O

R2

H2SO4

R MeOH, 20 °C 2–6 h, 94–96% yield

20

R1 = H, Me

Si

1

O

Si = SiMe3 19 R2 = H, Me, Ph

R3 = H, Me

DME/THF 60 °C, 1–9 h 51–85% yield

R2

R3

DME/THF 0–20 °C, 0.5–5 h 20–69% yield

Si 19

(b)

O

R1 = R 3 = H R2 = Ph, 4-ClC6H4, 4-MeC6H4

R2 R1

R3 O 21

2 + R Si R1

O 22

OH Si

R1 = R3 = H or Me R2 = Me

CF3SO3SiMe3

R1

R 23

O

R3

H2SO4 or TfOH

(a)

R2

1

DCM, –78 °C, 5 min 24->99% yield

R3 R2 R1

O

Si

21

Si = SiMe3, SiMe2t-Bu, SiMe2Ph R1 = H, Me R2 = H, Me, Ph R3 = H, Me

Scheme 8.20 Ring enlargement of cyclopropylacylsilanes to cyclobutanones and 2-silyl-4,5-dihydrofuran.

8.5 Cyclopropyl Monocarbonyls in Important eterocyclic ynthesis

Futher, they have also put forward that the treatment of cyclopropyl silyl ketones 19 with trimethylsilyl trifluoromethanesulfonate (CF3SO3SiMe3) as a strong acid with a low nucleophilic counter anion gives exclusively the corresponding 5-silyl2,3-dihydrofuran derivatives 20 regardless of substituents on the cyclopropane ring or silicon atom (Scheme 8.20b). To check the synthetic utility of the reported compounds, subsequent reactions with electrophilic reagents or Heck-type reactions were also carried out [24]. In 2011, Sparr and Gilmour for the first time, reported an unprecedented enantioselective strategy for the synthesis of 1,3-dichlorides 24 via organocatalytic activation of the meso-cyclopropane carbaldehyde 22. Not only does activation of cyclopropane carbaldehyde 22 by union with a secondary amine (MacMillan catalyst) I facilitate the ring-opening using pyridinium chloride A as a nucleophilic chlorinating source, it also generates a second reactive enamine 23 that can be intercepted by an electrophilic chlorinating reagent (perchlorinated quinone) B. The communicated protocol constitutes a formal 1,3-addition of Cl2 across the C1─C2 bond of cyclopropyl carbaldehyde compounds 22 (Scheme 8.21) [25]. O

Me

Cl

CHO R

R 22 R = Ph

+

Me

N H A O

H Bn

Cl

Cl

Me

Me

R NR'2

Cl R

Me N Me H (20 mol%) I

23

Cl Cl

–

Cl Cl B CDCl3 rt

R

Cl

Cl

CHO R 24

Scheme 8.21 Organocatalytic desymmetrization of meso-cyclopropane carbaldehydes.

Organofluorine compounds have become very important in a wide variety of fields, and many useful reactions for their syntheses have been developed recently [26]. Ring-opening fluorination of cyclopropane derivatives can be an attractive method for their synthesis. In this context, Kirihara et al. disclosed the reaction of arylated cyclopropane carbaldehydes 1 with diethylaminosulfur trifluoride (DAST), effectively causing the ring-opening fluorination to produce homoallylic fluorides 25. The proposed reaction proceeded via a carbocation intermediate. DAST reacted with cyclopropane carbaldehydes 1 having electron-donating aromatic substituents to cause ring-opening fluorinations with the addition of two fluorine atoms to afford 1,4-difluorobut-1-enes 25, while cyclopropane carbaldehyde having a p-nitrophenyl/alkyl group did not produce the ring-opening product but a (difluoromethyl)cyclopropane 26 was obtained (Scheme 8.22) [27]. An electron-donating aromatic substituent was found essential for the ring-opening fluorination to occur.

269

270

8 Reactivity of Cyclopropyl Monocarbonyls

R

Ar1 O 1 Ar1

DAST (2 equiv.) DCM, –78 °C to rt 4.2–23.7 h, 56–98% yield

Ar1

F

or

F

Ar1

F

F 25

26

= Ph, 4-OMeC6H4, 4-BrC6H4, 4-NO2C6H4, CH2CH2C6H5

Scheme 8.22 Ring-opening fluorination of cyclopropane carbaldehydes with DAST.

8.6 Application in Total Synthesis Functionally activated cyclopropanes are versatile synthetic intermediates in organic chemistry because they may undergo facile and predictable ring-opening reactions. Factors contributing to the stereo- and regioselectivity of cyclopropane carbonyls opening under reductive and nucleophilic conditions have been described for a number of systems. In 1997, Huang and Forsyth reported a trimethylsilyl halide induced ring-opening of spiro-fused cyclopropane carbaldehyde, which resulted in the total synthesis of the sesquiterpene natural products trifarienols A and B (Scheme 8.23) [28]. Oxidation to cyclopropyl aldehyde 28 activated the cyclopropane toward dissolving metal reduction, which gave 13-methyl aldehyde 29. However, the potential use of TMSI/TMSCl for the direct conversion of 29 into a 13-(halo)methyl silyl enol ether derivative 30 appeared to be an attractive alternative towards the formation of Trifarienols A and B. O

H3CO

O

CH3 O

H

O CH3

H

CH3

CH3

Li NH3

CH3

H

CH3

28

27

CH3

29

R3SiX X R3SiO

CH3

+ R3SiO

CH3 31

CH3

CH2X CH3

CH3 30

CH3

HO OH

CH3

Trifarienols A & B

Scheme 8.23 Total synthesis of trifarienols A and B.

­References 1 Selected reviews on donor-acceptor cyclopropanes: (a) Reissig, H.-U. and Zimmer, R. (2003). Chem. Rev. 103: 1151–1196. (b) Schneider, T.F., Kaschel, J., and Werz, D.B. (2014). Angew. Chem. Int. Ed. 53: 5504–5523. (c) Pandey, A.K., Ghosh, A., and Banerjee, P. (2016). Isr. J. Chem. 56: 512–521. (d) Budynina, E.M., Ivanov, K.L., Sorokin, I.D., and Melnikov, M.Y. (2017). Synthesis 49: 3035–3068. (e) Singh, P., Varshnaya, R.K., Dey, R., and Banerjee, P. (2020). Adv. Synth. Catal. 362: 1447–1484. (f) Ghosh, A., Dey, R., and Banerjee, P. (2021). Chem. Commun. 57: 5359–5373.

References

2 Kharasch, M.S. and Cooper, J.H. (1945). J. Org. Chem. 10: 46–54. 3 (a) Dey, R., Kumar, P., and Banerjee, P. (2018). J. Org. Chem. 83: 5438–5449. (b) Kumar, P., Dey, R., and Banerjee, P. (2018). Org. Lett. 20: 5163–5166. (c) Dey, R. and Banerjee, P. (2019). Adv. Synth. Catal. 361: 2849–2854. (d) Singh, P., Kaur, N., and Banerjee, P. (2020). J. Org. Chem. 85: 3393–3406. (e) Kumar, P., Kumar, R., and Banerjee, P. (2020). J. Org. Chem. 85: 6535–6550. (f) Dey, R., Rajput, S., and Banerjee, P. (2020). Tetrahedron 15: 131080. 4 (a) Burgi, H.B., Dunitz, J.D., Lehn, J.M., and Wipff, G. (1974). Tetrahedron 30: 1563–1572. (b) Burgi, H.B., Dunitz, J.D., and Shefter, E. (1973). J. Am. Chem. Soc. 95: 5065–5067. 5 (a) Cloke, J.B. (1929). J. Am. Chem. Soc. 51: 1174–1187. (b) Wilson, C.L. (1947). J. Am. Chem. Soc. 69: 3002–3004. (c) Hudlicky, T. and Reed, J.W. (2010). Angew. Chem. Int. Ed. 49: 4864–4876. 6 (a) Corey, E.J. and Chaykovsky, M. (1962). J. Am. Chem. Soc. 84: 867. (b) Corey, E.J. and Chaykovsky, M. (1965). J. Am. Chem. Soc. 87: 1353. 7 (a) Nalesnik, T.E. and Orchin, M.J. (1981). Organomet. Chem. 222: C5. (b) Nalesnik, T.E., Freudenberger, J.H., and Orchin, M.J. (1982). Organomet. Chem. 236: 95. (c) Matsui, Y. and Orchin, M.J. (1983). Organomet. Chem. 244: 369. 8 Jessop, P.G., Ikariya, T., and Noyori, R. (1995). Organometallics 14: 1510. 9 Sherrill, W.M. and Rubin, M. (2008). J. Am. Chem. Soc. 130: 13804–13809. Melancon, B.J., Perl, N.R., and Taylor, R.E. (2007). Org. Lett. 9: 1425–1428. 10 11 Taylor, R.E., Risatti, C.A., Engelhardt, F.C., and Schmitt, M.J. (2003). Org. Lett. 5: 1377–1379. 12 Risatti, C.A. and Taylor, R.E. (2004). Angew. Chem. Int. Ed. 43: 6671–6672. 13 (a) Trost, B.M., Vladuchick, W.C., and Bridges, A.J. (1980). J. Am. Chem. Soc. 102: 3548. (b) Trost, B.M. and Jungheim, L. (1980). J. Am. Chem. Soc. 102: 7910. 14 (a) Cohen, T., Daniewski, W.M., and Weisenfeld, R.B. (1978). Tetrahedron Lett. 47: 4665. (b) Bernard, A.M., Frongia, A., Piras, P.P. et al. (2005). Org. Lett. 7: 4565. 15 (a) Tanaka, K., Uneme, H., Matsui, S. et al. (1980). Chem. Lett. 287. (b) Bernard, A.M., Cadoni, E., Frongia, A. et al. (2002). Org. Lett. 4: 2565. (c) Bernard, A.M., Frongia, A., Guillot, R. et al. (2007). Org. Lett. 9: 541. 16 Porcu, S., Luridiana, A., Martis, A. et al. (2018). Chem. Commun. 54: 13547–13550. (a) Doyle, M.P., Mckervey, M.A., and Ye, T. (1998). Modern Catalytic Methods for 17 Organic Synthesis With Diazo Compounds: From Cyclopropanes to Ylides. New York, Chichester, Weinheim, Brisbane, Singapore, Toronto: Springer. (b) Moss, R.A. and Doyle, M.P. (ed.) (2014). Contemporary Carbene Chemistry. Hoboken, NJ: Wiley. 18 Chanthamath, S.H., Mandour, S.A., Tong, T.M.T. et al. (2016). Chem. Commun. 52: 7814–7817. 19 Cao, L.Y., Luo, J.N., Yao, J.S. et al. (2021). Angew. Chem. Int. Ed. 60: 15254–15259. 20 (a) Zhang, J., Jiang, H., and Zhu, S. (2017). Adv. Synth. Catal. 359: 2924–2930. (b) Zhu, X., Hong, G., Hu, C. et al. (2017). Eur. J. Org. Chem. 2017: 1547–1551. 21 For recent reviews on the synthesis and reaction of acylsilanes, see: (a) Brook, M.A. (2000). Silicon in Organic, Organometallic, and Polymer Chemistry. New York: John Wiley & Sons. (b) Bonini, B.F., Comes Franchini, M., Fochi, M. et al. (1998). Organomet. Chem. 567: 181–189. (c) Qi, H. and Curran, D.P. (1995). Acyl silicon,

271

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8 Reactivity of Cyclopropyl Monocarbonyls

germanium, or boron functions. In: Comprehensive Organic Functional Group Transformations: Synthesis: Carbon with Two Attached Heteroatoms with at Least One Carbon-to-Heteroatom Multiple Link, vol. 5, Chapter 5.09, (ed. A.R. Katrizky, O. Meth-Cohn, C.W. Rees, and C.J. Moody), 409–433. Oxford: Pergamon Press. (d) Cirillo, P.F. and Panek, J.S. (1992). Org. Prep. Proced. Int. 24: 553–582. (e) Page, P.C.B., Klair, S.S., and Rosenthal, S. (1990). Chem. Soc. Rev. 19: 147–195. (f) Ricci, A. and DeglInnocenti, A. (1989). Synthesis 647–660. 22 Nakajima, T., Miyaji, H., Segi, M., and Suga, S. (1986). Chemistry Lett. 15: 181–182. 23 Nakajima, T., Segi, M., Mituoka, T. et al. (1995). Tetrahedron Lett. 36: 667–1670. 24 Honda, M., Naitou, T., Hoshino, H. et al. (2005). Tetrahedron Lett. 46: 7345–7348. 25 Sparr, C. and Gilmour, R. (2011). Angew. Chem. Int. Ed. 50: 8391–8395. 26 (a) Kirsch, P. (2013). Modern Fluoroorganic Chemistry. Weinheim: Wiley-VCH Verlag GmbH & Co KGaA. (b) Bégué, J.-P. and Bonnet-Delpon, D. (2008). Bioorganic and Medicinal Chemistry of Fluorine. Hoboken: John Wiely & Sons Inc. (c) Uneyama, K. (2006). Organofluorine Chemistry. Oxford: Blackwell Publishing Ltd. (d) Inoue, M., Sumii, Y., and Shibata, N. (2020). ACS Omega 5: 10633. 27 Kirihara, M., Kikkawa, Y., Nakamura, R. et al. (2021). Tetrahedron Lett. 64: 152655. 28 Huang, H. and Forsyth, C.J. (1997). Tetrahedron 53: 16341–16348.

273

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes Thangavel Selvi and Kannupal Srinivasan School of Chemistry, Bharathidasan University, Tiruchirappalli, Tamil Nadu, 620024, India

CHAPTER MENU 9.1 9.2 9.3 9.4 9.5 9.6

Introduction, 273 Synthesis of Aroyl-Substituted D–A Cyclopropanes, 274 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes, 276 Synthesis of Nitro-Substituted D–A Cyclopropanes, 289 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes, 291 Conclusion, 297 Acknowledgments, 297 References, 298

9.1 Introduction The fascinating chemistry of donor—acceptor (D–A) cyclopropanes continues to attract the attention of numerous chemists around the globe [1–12]. The exploration of the reactivity of different D–A cyclopropanes has resulted in the discovery of novel synthetic routes to a wide variety of acyclic products, carbocycles, heterocycles, and natural products. The horizons of the field are ever expanding with the introduction of new D–A cyclopropanes, reaction partners, reagents, catalysts, and synthetic strategies in the field. Aroyl‐ and nitro‐substituted D–A cyclopropanes 1 and 2 (Figure 9.1) are relatively new entrants in the area of D–A cyclopropane chemistry [13]. Although few derivatives of 1 and 2 were reported many decades ago [14, 15], their synthetic potential has been intently being investigated in the past decade. Apart from the usual aryl donor and diester acceptor substituents in vicinal positions, the presence of an extra substituent (aroyl/nitro) in the third position of these cyclopropanes makes them unique building blocks in the field. Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

274

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes RO2C Ar

RO2C

CO2R Ar2

1

1

Figure 9.1 Structures of aroyl- and nitro-substituted D–A cyclopropanes.

CO2R NO2

Ar 2

O

9.2 Synthesis of Aroyl-Substituted D–A Cyclopropanes Aroyl‐substituted D–A cyclopropanes 1 have been invariably synthesized (in both racemic and chiral forms) by Michael initiated ring closure (MIRC) methodology, as summarized in Scheme 9.1. Accordingly, these cyclopropanes were synthesized by the reactions of (i) vinyl sulfonium salts 3 with dialkyl malonate 4 in the presence of NaOH in ethanol [14], (ii) arylidene malonates 5 with α‐chloroacetophenones 6 in the presence of K2CO3 in xylene [16], (iii) α‐bromochalcone 7 with dialkyl malonate 4 in the presence of K2CO3 in DMSO [17], and (iv) chalcones 8 with dialkyl bromomalonate (9) in the presence of cinchona alkaloid‐derived chiral phase transfer catalysts and K2CO3 in mesitylene [18], or carbohydrate‐derived chiral crown ethers and Na2CO3 in diethylether‐THF [19]. They were also synthesized by the oxidative cyclization of Michael adducts of chalcones with malonates 10 using iodosobenzene and Bu4NI in MeOH [20] or Bu4NI and TBHP in THF [21]. CO2R O Ar1

CO2R

Ar2 3

4

NaOH, EtOH

SMe2

RO2C RO2C

CO2R Ar2

Ar1 1

O

K2CO3, Xylene CO2R Ar1 5

CO2R

4, K2CO3 DMSO

O +

Cl

Ar2 6

Br

Ar1

Ar2 10

Cinchona alkaloid-derived chiral PTC (10 mol%), K2CO3, Mesitylene (or) Carbohydrate-derived chiral crown ether, Na2CO3, Et2O-THF O

Ar2 7

Scheme 9.1

(or) Bu4NI, TBHP, THF

O Ar1

CO2R O

PhIO, Bu4NI, MeOH

Ar2

Ar1 8

CO2R

+ Br 9

CO2R

Literature methods for the synthesis of aroyl-substituted D–A cyclopropanes.

When we started our research work in the area of D–A cyclopropanes in 2010, we required a variety of aroyl‐substituted D–A cyclopropanes 1 for our work. So, we developed a convenient procedure for the synthesis of these cyclopropanes from Michael adducts of chalcones with dialkyl malonates 10 (Table 9.1) [22]. Accordingly, when Michael adducts 10 were treated with 2 equiv. each of iodine and DBU in toluene or DCM, D–A cyclopropanes 1 were obtained in yields of 86–95%. The reaction tolerated the presence of electron‐donating, electron‐withdrawing, and halogen substituents on both aromatic rings, and also heteroaromatic rings. Mechanistically, the base (DBU) first abstracts the more acidic malonate proton of 10, and the resulting carbanion attacks iodine to give iodinated Michael adduct 11 as an intermediate. Next, the base removes the other acidic proton (adjacent to the keto group) in 11 and the anion so formed displaces iodide in an intramolecular SN2 attack to give

9.2 Synthesis of Aroyl-Substituted D–A Cyclopropanes

Table 9.1

Synthesis of various aroyl-substituted D–A cyclopropanes. RO2C

CO2R O

Ar1

I2 (2 equiv.) DBU (2 equiv.) PhMe, rt 15–20 min

Ar2 10

EtO2C

CO2Et Ph

11

CO2Et

CO2R Ar2

Ar1

Ar2

1

O

CO2Et

EtO2C

R

R2

O R1 1j-m R1, R2 = Me, OMe, Cl, NO2; 89–92%

1f-i O R = Me, MeO, Cl, NO2; 91–95% EtO2C

CO2Et

MeO2C

CO2Et Ar2

Ar1

S

Ar

RO2C

CO2R O

Ph

1a-e R = H, Me, MeO, Cl, NO2; 90–95% EtO2C

I

Ar1

EtO2C

O

R

RO2C

Ar

Ar = Ph, 4-MeC6H4, 4-MeOC6H4; 89–91%

Ar2 O

O 1q: Ar1 = Ph, Ar2 = 3,4-Cl2C6H3; 92% 1 = 3-FC H , Ar2 = Ph; 92% 1r: Ar 6 4 1s: Ar1 = 2-thienyl, Ar2 = 4-MeC6H4; 90%

1n-p O

CO2Me

1

1t: Ar1 = Ar2 = Ph; 90% 1u: Ar1 = Ph, Ar2 = 2-thienyl; 86%

cyclopropanes 1. The advantages of our procedure include the use of readily accessible Michael adducts as starting materials and the formation of products as single trans‐diastereomers in good‐to‐excellent yields. The exclusive formation of trans‐ diastereomers in these reactions is attributed to DBU‐induced isomerization of cis‐ isomers, formed if any, to more stable trans‐isomers. The above‐mentioned methodology could also be extended to Michael adducts derived from other chalcone‐like compounds. For example, Michael adducts of vinylogous chalcones with diethyl malonate 12 (obtained by the condensation of cinnamaldehydes with acetophenones followed by Michael addition of diethyl malonate) yielded a series of vinyl D–A cyclopropanes 13 under the same reaction conditions (Table 9.2) [23]. Table 9.2

Synthesis of aroyl-substituted vinyl D–A cyclopropanes. EtO2C

CO2Et O

Ar1

EtO2C

I2 (2 equiv.) DBU (2 equiv.)

Ar2

PhMe, rt, 0.5 h

Ar1

CO2Et

R

CO2Et Ar2 13 O

12 EtO2C

CO2Et

EtO2C

Ph

EtO2C

CO2Et

Ph

O 13a-e R = H, Me, MeO, Cl, NO2; 89–93%

O 13f-h R = Me, Cl, NO2; 91–94%

R

EtO2C

CO2Et

R1 R 1, EtO2C

13i-j R2 =

CO2Et

Ph 13k O 88%

S

13l-m

O

R = H, Cl; 88–90%

O

Me, Cl; 88–92% R

R2

275

276

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Similarly, Michael adducts 14, obtained from diarylideneacetones, also furnished the corresponding D–A cyclopropanes 15 on treatment with iodine and DBU (Scheme 9.2) [24]. EtO2C

CO2Et O Ar

Ar

I2 (2 equiv.) DBU (2 equiv.)

EtO2C

PhMe, rt, 0.5 h

Ar

14

CO2Et Ar

O 15a: Ar = Ph; 71% 15b: Ar = 4-MeC6H4; 74% 15c: Ar = 4-OMeC6H4; 67%

Scheme 9.2

Synthesis of acryloyl-substituted D–A cyclopropanes.

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes 9.3.1 AlCl3 or SnCl4-Mediated Ring-Opening Reactions D–A cyclopropanes, when treated with Lewis acids, are capable of forming putative 1,3‐zwitter ionic intermediates, which may undergo further transformations to yield useful products. With this view, aroyl‐substituted D–A cyclopropanes 1 were treated with stoichiometric amounts of various Lewis acids. When these cyclopropanes were treated with 1 equiv. of AlCl3 (or SnCl4) in dichloromethane (or 1,2‐DCE) at room temperature, they furnished 2‐pyrones 16 (Table 9.3) [24]. A mechanism has Synthesis of 2-pyrones from aroyl-substituted D–A cyclopropanes.a

Table 9.3

CO2R

RO2C

2

Ar

Ar1 1

CO2R

AlCl3 (1 equiv.)

Ar1

DCM, rt, 7–12 h

CO2R Ar1

Ar2

O

O

Ar2

O

CO2R

CO2R 18

17 Ar1

RO2C O

O OR 19

Ar1

RO2C

Ar2

O

O 16

Ar2

Selected examples: RO2C O

O

Ph

EtO2C

Ph

O

16a: R = Me, 80% 16b: R = Et, 86%

NO2

Ph EtO2C O O

Cl

16c, 75%

O

Ph

16d, 93%

NO2 EtO2C O

Cl EtO2C

O

O

O

OMe 16e, 82%

a)

EtO2C

Ph

16f, 84%

Cl Cl

O

O S

16g, 74%

In the mechanism, the Lewis acid coordination is not shown in the intermediate structures for clarity.

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

been formulated for the transformation, which involves the formation of 1,3‐zwitterionic intermediate 17 through ring‐opening, and this intermediate undergoes fragmentation to give ion pair 18, followed by recombination of the fragments to form δ‐keto ester 19 and lactonization of 19 to give 2‐pyrone 16. Except for a cyclopropane having p‐nitrophenyl group as Ar1 (because, p‐nitrophenyl group is not capable of stabilizing the positive charge of the respective zwitterionic intermediate), all other cyclopropanes yielded 2‐pyrones 16 in good‐to‐excellent yields. Not only aroyl‐substituted D–A cylopropanes 1 but also acryloyl‐substituted D–A cyclopropanes 15 also gave the corresponding pyrones 19 in good yields (Scheme 9.3) [24]. The double bond of the acryloyl moiety remained unchanged during the transformation. Scheme 9.3 Synthesis of 2-pyrones from acryloyl-substituted D–A cyclopropanes.

O

Ar

DCM, rt, 7 h

CO2Et

Ar

EtO2C

AlCl3

CO2Et

15

Ar

O

O

Ar

19a: Ar = Ph, 70% 19b: Ar = 4-MeC6H4, 71% 19c: Ar = 4-OMeC6H4, 80%

On the other hand, vinyl D–A cyclopropanes 13 upon treatment with SnCl4 in dichloromethane, formed cyclopentenes 20 (Table 9.4) [23]. The transformation is basically a vinylcyclopropane–cyclopentene rearrangement, and it proceeds through the formation of 1,3‐zwitterionic intermediate 21, followed by cyclization to give cyclopentene 22, which being a β,γ‐unsaturated ketone, automatically rearranges to more stable α,β‐unsaturated ketone, that is, cyclopentene 20. However, the transformation does not work for a cyclopropane having a p‐nitrophenyl group as Ar1. Table 9.4

Synthesis of cyclopentenes from aroyl-substituted vinyl D–A cyclopropanes.

EtO2C

SnCl4 (1 equiv.)

CO2Et Ar2

Ar1 13

CH2Cl2, rt

O

Ar2

Ar1

Ar2

Ar2 Ar1

Ar1

O CO2Et 21

O EtO2C CO2Et

O EtO2C CO2Et

EtO2C

20

22

Selected examples:

NO2

Ph Ph

O EtO2C CO2Et

Ph

Ph Cl

MeO

O EtO2C CO2Et

O EtO2C CO2Et 20b, 80%

20a, 92%

20c, 70%

Cl

Ph

O EtO2C CO2Et 20d, 67% Cl

Ph Me O EtO2C CO2Et

O EtO2C CO2Et

20e, 76%

20f, 82%

S O EtO2C CO2Et 20g, 71%

277

278

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

9.3.2 TiCl4-Mediated Ring-Opening Reactions During the course of the above‐mentioned studies, we observed that the cyclopropanes yielded very different products when treated with TiCl4 [24]. Thus, aroyl‐ substituted D–A cyclopropanes 1 when treated with 1.5 equiv. of TiCl4 in dichloromethane at room temperature, they furnished 1‐indanones 23 (Table 9.5). The transformation takes place through a partial cleavage of the C─C bond of 1 in between the Ar1 and diester groups, SNi‐like attack of chloride ion of TiCl4 on the incipient carbocation to give an intimate ion‐pair 24, E2‐like elimination of HCl from 24 to yield E‐alkene 25 stereoselectively, and subsequent Nazarov cyclization to give the products 23. Surprisingly, a cyclopropane having p‐nitrophenyl group as Ar1 was also compatible for the transformation. When the above‐mentioned procedure was extended to vinyl D–A cyclopropanes 13, the transformation stopped at the alkene stage, and the subsequent Nazarov cyclization did not take place (Table 9.6) [23]. Nevertheless, a series of E,E‐1,3‐ dienes 26, which are versatile synthetic intermediates, were obtained in good yields in the transformations.

9.3.3

Ring-Opening Reactions with Hydrazines

Nucleophilic ring‐opening reactions of D–A cyclopropanes with nitrogen nucleophiles provide access to various heterocyclic compounds [8, 10]. Generally, the nucleophile attacks the carbon to which the donor group is attached, resulting in the ring‐opening of the cyclopropanes, and the intermediates so formed further undergo cyclization to give the products. When aroyl‐substituted D–A cyclopropanes 1 were heated under reflux conditions with aryl hydrazines 27 in EtOH, they gave 4,5‐trans‐substituted dihydropyrazoles 28 (Table 9.7). The products were obtained from the reaction mixture by Table 9.5

Synthesis of 1-indanones from aroyl-substituted D–A cyclopropanes.

O

CO2Et

EtO2C

TiCl4 (1.5 equiv.)

Ar2 DCM, rt, 12–24 h

Ar1 1

O Cl4Ti

E2

Ar2 R

Selected examples: O

O

OEt O δ– O H δ+ Ar1 OEt

CO2Et CO2Et

Ar2 H

CO2Et

Cl

H 24

H

Ar1

O Nazarov cyclization

CO2Et R

CO2Et

CO2Et

CO2Et

CO2Et

Ph 23a, 78%

CO2Et

Ar2

1 23 Ar

O

O

CO2Et

SNi

TiCl4

Ar1

25

CO2Et

O

CO2Et

O CO2Et Cl

CO2Et Ph 23d, 65%

23b, 72%

OMe

23c, 60%

NO2

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

Table 9.6

EtO2C

Synthesis of E,E-1,3-dienes from aroyl-substituted vinyl D–A cyclopropanes.

CO2Et Ar2

TiCl4 (1 equiv.)

13 O

Ar1

Ar2 H

O

H δ+

DCM rt, 12 h

OEt O δ– O OEt

CO2Et

O

CO2Et

2

Ar

TiCl4 SNi

EtO2C

E2

Cl

H

Ar2

H

Ar1

CO2Et

Ar1 O

26

Ar1

Selected examples: EtO2C

CO2Et MeO

Ph

CO2Et O2N

EtO2C

Ph O

Ph

O

EtO2C

EtO2C

CO2Et

26e, 78%

O 26d, 75% EtO2C

Ph

CO2Et Ph

S O

O

O

Cl

CO2Et

Me

CO2Et

Ph

O

26c, 83%

26b, 80%

EtO2C

CO2Et

Ph

26a, 86% Me

EtO2C

26g, 77%

26f, 70%

Table 9.7 Synthesis of dihydropyrazoles from aroyl-substituted D–A cyclopropanes. EtO2C

CO2Et Ar2

Ar1 1

O

Ar2 EtO2C

H

EtO2C 1

3

Ar

2

H 1

Ar2

Ar3NHNH2 27

EtO2C

EtOH, reflux 8–12 h

EtO2C

O

N

H

H N

Ar3

H

CO2Et Ar2

EtO2C

SN2

N N 3 Ar 28

Ar1

Ar1 29

Selected examples:

Me

CO2Et Ph

EtO2C

N N Ph

Ph

CO2Et Ph

EtO2C

N N Ph

MeO

28a, 92%

EtO2C

EtO2C EtO2C

MeO

N N Ph 28e, 95%

EtO2C

28d, 90% Cl

EtO2C

EtO2C

N Ph

N

N NO2

28f, 89%

Br

28g, 92%

Me EtO2C

EtO2C N

N N Ph

Ph

28c, 88%

CO2Et Ph

Ph

EtO2C

CO2Et Ph N N Ph

Cl

28b, 95% OMe

EtO2C

NO2

S

28h, 92%

N

N NO2

NO2

simple crystallization and did not require any column chromatographic purification. More importantly, the reaction did not require the assistance of any catalyst. The transformation proceeds through the formation of arylhydrazone 29 as an intermediate and subsequent intramolecular attack of the other nitrogen of hydrazone moiety on the carbon attached to the Ar1 group in SN2 fashion to give the products 28 diastereoselectively.

279

280

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Table 9.8 EtO2C

Synthesis of pyridazinones from aroyl-substituted D–A cyclopropanes. CO2Et Ar2

Ar1 1

O

Ar1

H2NNH2 .H2O, AcOH, reflux, 5–7 h

H

(or)

MeNHNH2 .H2SO4, Et3N, EtOH, reflux, 9 h

Ar2

H

CO2Et

EtO2C

O

EtO2C Ph H

O NH N

Ph 30a, 43%

EtO2C Ph

EtO2C

O N N

Me F

NH N

H

H

Ph 30b, 43%

O

OEt NNHR

EtO2C

H

R

H 2 30 Ar

O

Ph

N N

Ar1

31 Selected examples:

O

NH Me N

EtO2C

O NH N

H S

30c, 57% Me

30d, 57%

30e, 57%

The scope of the above transformation was also investigated for hydrazine and methyl hydrazine (Table 9.8). Accordingly, when D–A cyclopropanes 1 were heated under reflux conditions with methyl hydrazine in ethanol or hydrazine in AcOH, cyclopropane‐fused pyridazinones 30 were produced through the intermediates 31 in moderate‐to‐good yields. It may be noted that when hydrazine in ethanol was used, the reactions led to the corresponding pyrazoles.

9.3.4

Ring-Opening Reactions with 1-Naphthylamines

The ring‐opening reactions of aroyl‐substituted D–A cyclopropanes were further investigated with different amines, such as anilines, naphthylamines, and alkylamines. Though most of the reactions gave complex mixtures, the reaction of D–A cyclopropanes 1 with 2 equiv. of 1‐naphthylamine 32 in the presence of Sc(OTf)3 yielded dibenzo[c,h]acridines 33 (Table 9.9). During the transformation, 1‐naphthylamine 32 acts as a C‐nucleophile, and attacks the carbon attached to the Ar1 group, to give the ring‐opened intermediate 34. The intermediate undergoes rearomatization, and subsequent fragmentation, to yield malonate derivative 36 and intermediate 37. Another molecule of 1‐naphthylamine 32 attacks 37 to give intermediate 38, which undergoes electrocyclic ring‐closure followed by aromatization to give dibenzo[c,h]acridine 33. It may be noted that the diester and aroyl groups of 1 are not incorporated into the final products during this intriguing transformation. The scope of the transformation was also examined for vinyl D–A cyclopropanes 13 and they too furnished the corresponding dibenzo[c,h]acridines 40 (Table 9.10).

9.3.5

(3 + 2) Annulations with Nitriles

The (3 + 2) annulation of D–A cyclopropanes with nitriles is an efficient strategy for the stereoselective synthesis of 1‐pyrroline derivatives [7]. Other nitrogen heterocycles such as pyrroles and pyrrolidines, could also be easily accessed via 1‐pyrrolines based on this strategy. The seminal work of Pagenkopf and coworkers on (3 + 2) annulation of carbohydrate‐derived D–A cyclopropanes with various nitriles has acted as a stimulus for various works in this area [28].

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

Table 9.9

Synthesis of dibenzo[c,h]acridines from aroyl-substituted D–A cyclopropanes.

O

A L

O

EtO

OEt

Ar1 R

Sc(OTf)3 Ar2 (10 mol%) H N 2

1

PhM e reflux 8–10 h

O

NH2

H

CO2Et Ar1

CO2Et

O 34

32

H 2N

CO2Et

Ar1

LA O

Ar2

Ar1 NH2

NH2

Selected examples:

N

H2

33

39

NO2

OMe

Ph

Ar1

N

NH3

Ar2 36

O

Ar1

N H NH2 LA 38

37

CO2Et

Ar2

35

R Ar1

CO2Et

CO2Et

Ph O2 N N

Br

NO2

Br

N

N

33a, 68%

N

N

33c, 60%

33e, 52%

33d, 50%

33b, 66%

Table 9.10 Synthesis of dibenzo[c,h]acridines from aroyl-substituted vinyl D–A cyclopropanes. Ar1

EtO2C

NH2

CO2Et Ar2

Ar1 13

O

+ 32 R

Sc(OTf)3 (10 mol%)

R

R N

PhMe, reflux 8–10 h

40

Selected examples: Ph

Ph

S

NO2

O2N N 40a, 70%

Br

Br

N 40b, 62%

N

N 40d, 61%

40c, 66%

When aroyl‐substituted D–A cyclopropanes 1 were subjected to (3 + 2) annulation with aliphatic and aromatic nitriles 41 in the presence of 1 equiv. of SnCl4 in 1,2‐ DCE, they readily yielded the corresponding 1‐pyrroline derivatives 42 in a highly diastereoselective manner (Table 9.11) [22]. The diastereoselectivity observed in the products could be explained as follows. The coordination of SnCl4 to the diester moiety weakens the C1─C3 bond of the cyclopropane, and the nitrile 41 attacks the

281

282

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Table 9.11 Synthesis of 1-pyrrolines from aroyl-substituted D–A cyclopropanes.

EtO2C

Ar2

CO2Et Ar2

Ar1

+

SnCl4

N

2

H

1,2 DCE rt, 7 h

41

O

1

R

O EtO O SnCl4 H 1 O 3

OEt

Ar1 R

1

N 41

EtO

O

Ar2

O

H H

Ar1

R

H

OEt

EtO Ar1

O

120°

N

O

Ar2

43

O

O H

N R

CO2Et CO2Et

Ar2

O

Ar1

R

N 42

OEt

Selected examples: O

Ph

O

O CO2Et CO2Et

Ph

Me

N

CO2Et CO2Et

Ph

42a, 89%

Ph

42b, 86%

O

N

N 42e, 51%

Ph MeO

Me

Ph

N

OMe

Cl

42f, 67%

N

Ph

42d, 66%

S

CO2Et CO2Et

Ph

CO2Et CO2Et

Ph

42c, 90% O

CO2Et CO2Et

Ph

Cl

O2N

Me

N

Cl

O CO2Et CO2Et

O CO2Et CO2Et N

OMe

42g, 59%

cyclopropane carbon attached to the Ar1 group in SN2 fashion, resulting in the 1,5‐ dipolar intermediate 43. The groups attached to C3 of 43 undergo 120° rotation in order to facilitate the attack of malonate anion on the nitrile carbon. The ensuing cyclization affords 42 with Ar1 and Ar2 groups pointing in cis‐orientation. The 1‐pyrroline derivatives 42 synthesized as shown above could be transformed into other products using standard imine chemistry. For example, a simple reduction of pyrrolines 42 with sodium cyanoborohydride in the presence of acetic acid in methanol at room temperature gave the 2,4,5‐cis‐substituted pyrrolidines 43 in excellent yields (Table 9.12) [22]. The (3 + 2) cyclopropane–nitrile annulation strategy could also be extended to aroyl‐substituted vinyl D–A cyclopropanes 13 for the access of 5‐vinyl‐1‐pyrroline derivatives 44 (Table 9.13) [27].

9.3.6

(3 + 3) Annulation with Mercaptoacetaldehyde

As compared with (3+2) annulations of D–A cyclopropanes, only less number of (3 + 3) and other higher‐order annulations have been reported in the literature [3]. Especially, for aroyl‐substituted D–A cyclopropanes such higher‐order annulations largely remain unexplored.

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

Table 9.12 Conversion of 1-pyrrolines to pyrrolidines. O

O CO2Et CO2Et

Ar2 Ar1

MeOH/AcOH (3 : 1) rt, 1 h

R

N 42

O

O CO2Et CO2Et

Ph

Me

N H

Cl

Ar1

O CO2Et CO2Et

Ph

Ph

O

CO2Et CO2Et

Ph Ph

N H

43b, 92%

43a, 90%

R

N H 43

CO2Et CO2Et

Ph

Me

N H

O 2N

CO2Et CO2Et

Ar1

NaCNBH3

N H

OMe

43c, 93%

S

43d, 85%

Table 9.13 Synthesis of vinyl pyrrolines from vinyl D–A cyclopropanes. O EtO2C

CO2Et Ar2

Ar

1

1

+

R

N 41

O

SnCl4 1,2 DCE rt, 12 h

Selected examples: O CO2Et CO2Et

CO2Et CO2Et

Ph

Me

N

Ph

N

Ph

44b, 86% O

N

N

44c, 76%

44d, 80% O

N

S

Ph

O CO2Et CO2Et

CO2Et O 2N CO2Et

Ph

Ph

CO2Et CO2Et

Ph

N

O CO2Et CO2Et

Ph

R

O CO2Et CO2Et

Ph

Ph

Ph 44a, 88%

Ar

N 44

1

O

O

Ph

44h, 65% CO2Et CO2Et

Ar2

Ph

N

CO2Et CO2Et

Ph

Ph

N

Ph S

MeO 44e, 78%

44f, 72%

S

O2 N 44g, 68%

1,4‐Dithiane‐2,5‐diol (45), also called mercaptoacetaldehyde dimer, is an interesting synthetic precursor and capable of releasing the monomer, mercaptoacetaldehyde (45′) in situ when treated with tertiary amines or certain organocatalysts (Scheme 9.4) [30, 31]. Scheme 9.4 in situ.

Generation of mercaptoacetaldehyde

S HO

OH S 45

Base

O

2 HS 45′

We envisaged that the treatment of 45 with a suitable Lewis acid would also form the monomer 45′ in situ (through coordination with sulfur), and the

283

284

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Table 9.14 Synthesis of thiophenes from aroyl-substituted D–A cyclopropanes.a Ar2 RO2C

H

CO2R

S

Ar2

Ar1

1

+ HO

AlCl3

OH

O

45

CO2R RO2C O Ar1 O S Ar2

H

DCM rt, 24 h

S

Ar1

S

O R HO

S

H

CHO

CO2 ROH

B

Ph

Ar1

DBU

Ar2 Ar1

H

CO2R Ar1

120°

S

O Ar2

O S

RO2C

S

49

Ar

1

Ar2

Ar1

H2

O

RO2C

RO2C

CHO

S 50

CO2R

H

CO2R CO2R O H

O

CHO

S 48

Ph

EtO2C

O

47

CO2R Ar2

Ar2

Ar1

Ar1

Ar2

45′

DCM rt, 12 h

46

RO2C

SH

O

O RO2C CO2R OH Ar2

O

RO2C

OR O AlCl3 O OR

O

Ph

EtO2C

Ph

EtO2C F

Ph

S

CHO

48a: R = Me, 70% 48b: R = Et, 72%

CHO

S

Me

48c, 74%

EtO2C

EtO2C Ph

Ph

CHO

S

Cl

CHO

Ph

48g, 75%

48f, 68%

48e, 63% Me

EtO2C S

CHO

S

48d, 77%

OMe

Me

CHO

S

Cl

EtO2C S

CHO Cl

48h, 73%

CHO

S

48i, 72%

OMe

MeO

S

CHO

48j, 71%

a)

S

EtO2C

EtO2C

Ph

S

CHO

48k: R = Me, 79% 48l: R = Et, 78%

S

EtO2C

Cl

S

CHO

48m, 82%

S

EtO2C

O2 N

S

CHO

48n, 55%

Isolated overall yield.

monomer could be used for (3 + 3) annulation with aroyl‐substituted D–A cyclopropanes 1 under the same reaction conditions. Accordingly, when D–A cyclopropanes 1 were reacted with 45 in the presence of AlCl3 in DCM, they smoothly underwent the desired (3 + 3) annulation and yielded tetrahydrothiopyranols 46 (Table 9.14). The reaction proceeds through an SN2 attack of mercaptoacetaldehyde (45′) on the cyclopropane carbon attached to the Ar1 group to give intermediate 47, followed by 120° rotation of groups attached to C3 of 47 and subsequent cyclization to give tetrahydrothiopyranol 46. Unfortunately, the products were produced as inseparable diastereomeric mixtures in most of the cases and hence, we decided to convert them into other useful compounds. Fortunately, when the diastereomeric mixtures of tetrahydrothiopyranols 46 were treated with DBU in

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

DCM, they yielded tetrasubstituted thiophenes 48 in excellent yields. The conversion takes place via DBU‐induced ring‐opening of 46 to give anionic intermediate 49, followed by cyclization, elimination of carbon dioxide and alcohol, and subsequent aromatization to give thiophene 48. It is interesting to note that bis‐ thiophenes 48k‐n were also accessible by this methodology by employing cyclopropanes having a thiophene ring as Ar2.

9.3.7 Conversion of Aroyl-Substituted D–A Cyclopropanes into γ-Butyrolactone-Fused D–A Cyclopropanes and their Synthetic Applications In order to expand the synthetic potential of aroyl‐substituted D–A cyclopropanes 1 to new venues, we decided to convert them into γ‐butyrolactone‐fused D–A cyclopropanes 51 via reductive cyclization process. This kind of fusion of another ring to the D−A cyclopropane skeleton is expected to enhance or alter the reactivity of such cyclopropanes. Thus, when aroyl‐substituted D–A cyclopropanes 1 were treated with NaBH4 in MeOH at 0 °C, they underwent reductive cyclization to afford γ‐ butyrolactone‐fused D–A cyclopropanes 51 as single diastereomers in good yields (Table 9.15) [32]. When γ‐butyrolactone‐fused D–A cyclopropanes 51 were reacted with nitriles 41 in the presence of SnCl4 in 1,2‐DCE at 40 °C, γ‐butyrolactone‐fused 1‐pyrrolines 52 having four contiguous stereocenters, were produced in good yields (Table 9.16) [32]. The reaction takes place through a mechanism analogous to the one depicted in Table 9.11. Table 9.15 Synthesis of γ-butyrolactone fused D–A cyclopropanes from aroyl-substituted D–A cyclopropanes. EtO2C

CO2Et NaBH4

O

Ar1 1

Ar1

MeOH, 0 °C 30–45 min

Ar2

CO2Et H

H

OEt

Ar2

H

O

Ar1

Ar2 OH

O

EtO2C

H

51

O

Selected examples: H

Ph O

Ph

H

O

MeO

EtO2C

EtO2C

O 51a, 79%

O

51f, 87%

Cl

O 2N

EtO2C

O

51g, 76%

Ph

Ph

H

O

EtO2C

EtO2C

O 51c, 76%

O 51d, 82%

O EtO2C

O 51e, 83%

Cl

H

H O

Ph

H

O

O

H O

Ph

F

H

EtO2C

H

51b, 83% Me

Ph

Ph

O

Ph EtO2C

O

51h, 79%

O

MeO EtO2C

S

H

O

51i, 76%

O

Me EtO2C 51j, 73%

O

285

286

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Table 9.16 Synthesis of γ-butyrolactone fused 1-pyrrolines from γ-butyrolactone fused D–A cyclopropanes. Ar2

H Ar1

+

O

EtO2C 51

N

R 41

O

H Ar1

EtO H

SnCl4 (1 equiv.))

Ar1

1,2-DCE 40 °C 4–24 h

R

H

O N

O

H

Ar1

N

O

Ar2

N

H

2

O O

O

H

CO2Et

Ar1

O

R

R

R

O

H CO2Et Ar2

H CO2Et Ar2

120°

SnCl4

O

Ar1

O

1

2

N

H CO2Et Ar2

O Ar2

3

R

N 52

Selected examples: O

Ph Ph

O

Ph

O

H

H

CO2Et

Ph N 52a, 73%

O

Ph

H

O

H MeO

Ph Ph

N

OMe

O

O

H Br

O

Ph

Ph Cl

52f, 62%

52c, 58% O

H

O

H Ph

N

N

Ph

52g, 52%

O CO2Et

nBu N 52e, 75%b

52d, 42%

O 2N

CO2Et

O

Ph

CO2Et

Cl

CO2Et N

O CO2Et

Ph

N 52b, 68%

Ph

O

Ph

CO2Et

O H Ph

H

CO2Et N

Ph

52h, 55%

O

Ph

O

Me

O CO2Et

N

Me

52i, 59%

During the course of the above‐mentioned investigation, we found that γ‐ butyrolactone‐fused D–A cyclopropanes 51 when reacted with wet aliphatic nitriles in the presence of AlCl3 in 1,2‐DCE at 60 °C furnished 3,4,5‐trisubstituted γ‐ butyrolactones 53 exclusively, instead of the expected 1‐pyrroline derivatives (Table 9.17) [33]. The products are likely produced through a Ritter‐type mechanism, involving the nucleophilic addition of water to the nitrilium ion intermediate 54, before the usual cyclization. The study clearly demonstrates how the fusion of the γ‐butyrolactone ring influences the reactivity of the D–A cyclopropanes.

9.3.8 Works from Yang and Sekar Research Groups Yang and coworkers have reported a handful of annulation and ring‐opening reactions of aroyl‐substituted D–A cyclopropanes 1, as well as γ‐butyrolactone‐fused D–A cyclopropanes 51 [34–40]. The (3 + 2) annulation of D–A cyclopropanes 1 with aromatic aldehydes 55 in the presence of 0.5 equiv. of AlCl3 in DCM gave 2,5‐diaryl‐4‐aroyl‐tetrahydrofuran‐3,3‐ dicarboxylates 56 with good diastereoselectivities, depending on the electronic nature of the aromatic aldehydes employed (Scheme 9.5) [34]. Thus, the use of neutral or electron‐poor aldehydes yielded 2,5‐cis products, whereas the use of electron‐ rich aldehydes furnished 2,5‐trans products.

9.3 Synthetic Applications of Aroyl-Substituted D–A Cyclopropanes

Table 9.17 Synthesis of 3,4,5-trisubstituted γ-butyrolactones from γ-butyrolactone fused D–A cyclopropanes.

Ar2

O

O

H

CO2Et Ar

H

RCN 41

1

51

CO2Et Ar2

Ar2

H Ar1

AlCl3 (1 equiv.) 1,2-DCE H2O, 60 °C 3–5 h

O N

Ar1

O

O

CO2Et NHCOR

R 54

H 2O

O

53

Selected examples: Ph Ph

O

Ph

O Me

CO2Et NHCOR

O Ph

F

O

CO2Et NHCOMe

Ph

53g, 83%

O

CO2Et CO2Et

Ph Ph

O

Ar3

Ph

CO2Et NHCOMe

Electron-rich Ar3CHO 55 AlCl3 (0.5 equiv.) DCM, 30 °C

EtO2C

Ar2

Ar1 O

When Ar1 = Ar2 = Ph

Neutral (or) electron-poor Ar3CHO 55 AlCl 3 (0.5 equiv.) DCM, 0 °C

O

53f, 73%

53e, 74%

Cl

O

O

CO2Et NHCOMe

O

CO2Et NHCOMe

O

CO2Et NHCOMe

MeO

53j, 83%

53i, 81%

CO2Et

1

Ph

O

CO2Et NHCOMe

O

O

53h, 78%

56d: Ar3 = 4-MeC6H4, 88% 56e: Ar3 = 3,4-(MeO)2C6H3, 90%

Scheme 9.5

Cl

53d, 89%

O

O

Ph

O

CO2Et NHCOMe

53a: R = Me, 85% 53b: R = nBu, 76% 53c: R = Bn, 81% MeO

O

O

CO2Et CO2Et

Ph Ph

O

Ar3

56a: Ar3 = Ph, 88% 56b: Ar3 = 2,4-Cl2C6H3, 90% 56c: Ar3 = 4-O2NC6H4, 43%

(3 + 2) Annulation of aroyl-substituted D–A cyclopropanes with aldehydes.

The above‐mentioned (3 + 2) cyclopropane–aldehyde annulation procedure has been extended to cis‐diastereomers of D–A cyclopropanes 1 (Scheme 9.6) [35]. Unlike their trans‐counter parts, these D–A cyclopropanes yielded only one type of diastereomers, irrespective of the electronic nature of the aromatic aldehydes used. Moreover, the products were produced comparatively in higher yields. The methodology was later expanded to cyclic ketones 57 to obtain spirotetrahydrofurans 58 in a highly diastereoselective manner [36]. The cis‐diastereomers of D–A cyclopropanes 1 also underwent (3 + 2) annulation with aromatic and aliphatic isothiocyanates in the presence of 2 equiv. of AlCl3 in nitromethane at 30 °C (Scheme 9.7) [37]. The products, 2‐iminodihydrothiophenes, were produced as single trans‐diastereomers in moderate‐to‐excellent yields. The ring‐opening reaction of aroyl‐substituted D–A cyclopropanes 1 with PCl5 has also been reported by the Yang group (Scheme 9.8) [38]. Accordingly, when D–A cyclopropanes 1 were treated with 5 equiv. of PCl5 in chlorobenzene at 80 °C, they underwent ring‐opening through the intermediate 59, to give tri‐substituted vinyl chlorides 60 stereoselectively.

287

288

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes O

EtO2C

CO2Et Ph

Ar1 cis-1 O

AlCl3 Ar1 Ar2 O (0.5 equiv.) 1 2 DCM, 0 °C or 30 °C 56f: Ar = Ph, Ar = 4-ClC6H4, 87% 56g: Ar1 = Ph, Ar2 = 2,4-(MeO)2C6H3, 87% 56h: Ar1 = 4-O2NC6H4, 4-MeOC6H4, 82% O O

AlCl3 (0.5 equiv.) DCM, 0 °C

Scheme 9.6 ketones.

CO2Et Ph

Ar cis-1 O

CO2Et CO2Et

Ph

( )n 57

EtO2C

CO2Et CO2Et

Ph

Ar2CHO

Ar1

O

( )n

58a: Ar1 = Ph, n = 1, 90% 58b: Ar1 = Ph, n = 2, 93% 58c: Ar1 = Ph, n = 3, 77% 58d: Ar1 = 4-ClC6H4, n = 2, 94%

(3 + 2) Annulation of cis-D–A cyclopropanes with aldehydes and cyclic

O

R N C S 57

CO2Et CO2Et

Ph

AlCl3 (2 equiv.) DCM, 30 °C

Ar

N R 58a: Ar = R = Ph, 71% 58b: Ar = 4-ClC6H4, R = 4-MeOC6H4, 70% 58c: Ar1 = 4-O2NC6H4, R = Cyclohexyl, 64% S

Scheme 9.7 (3 + 2) Annulation of cis-D–A cyclopropanes with isothiocyanates.

EtO2C

CO2Et Ar2

Ar1 1

O

Scheme 9.8

PCl5 PhCl, 80 °C

EtO2C

CO2Et Ar2

Ar1 Cl

Cl 59

OPCl4

Cl

Ar2

Cl

Ar1 EtO2C CO2Et 60a: Ar1 = Ar2 = Ph, 82% 60b: Ar1 = 4-MeC6H4, Ar2 = Ph, 74% 60c: Ar1 = Ph, Ar2 = 3-O2NC6H4, 53%

Ring-opening of aroyl-substituted D–A cyclopropanes with PCl5.

Yang and coworkers have also reported FeCl3‐promoted (3 + 2) annulation of γ‐ butyrolactone‐fused D−A cyclopropanes 51 with isothiocyanates 57 and carbodiimides 61 (Scheme 9.9) [39]. A large number of bicyclic γ‐butyrolactone‐fused thioimidates 62 and γ‐butyrolactone‐fused amidines 63 having four contiguous stereocenters were obtained as single diastereomers in excellent yields in the reactions. The Yang group has also explored the (3 + 2) annulation reaction of γ‐ butyrolactone‐fused cyclopropanes 51 with aldehydes 55 and ketones 64, in the presence of a catalytic amount of Sn(OTf)2 in 1,2‐DCE (Scheme 9.10) [40]. This reaction provided highly substituted γ‐butyrolactone‐fused tetrahydrofurans 65 or 66, with excellent yields and diastereoselectivity. Recently, Sekar and Sundarvelu have reported that 2‐iodobenzoyl‐substituted D–A cyclopropanes 67 upon treatment with 3 equiv. of potassium ethyl xanthate in the presence of a catalytic amount of Cu(OAc)2 and 2 equiv. of AcOH in DMF

9.4 Synthesis of Nitro-Substituted D–A Cyclopropanes O

Ar2 H

O CO2Et

R N C N R 61

FeCl3 (2 equiv.) N MeNO2, rt N R R 63 63a: Ar1 = Ar2 = Ph, R = cyclohexyl, 99% 63b: Ar1 = Ph, Ar2 = 4-BrC6H4, R = isopropyl, 97%

Ar2

H Ar1

Ar1

O

EtO2C

O

R N C S 57

O

Ar2 H

FeCl3 (2 equiv.) MeNO2, rt

O CO2Et

Ar1

N R 62a: = = R = Ph, 97% 1 2 62b: Ar = Ar = Ph, R = allyl, 99% 62c: Ar1 = 4-O2NC6H4, Ar2 = Ph, R = 4-MeOC6H4, 94%

51

Ar1

S

Ar2

Scheme 9.9 (3 + 2) Annulation of γ-butyrolactone-fused D–A cyclopropanes with isothiocyanates and carbodiimides. O O

Ar2 H Ar1

O

O CO2Et R1 R2

R1 R2 64 Sn(OTf)2 (5 mol%) 1,2-DCE 40 °C

Ar2

H Ar1

O

EtO2C

O 51

66a: Ar1 = Ar2 = Ph, R1 & R2 = Me, 91% 66b: Ar1 = Ar2 = Ph, R1 & R2 = cyclohexyl, 99% 66c: Ar1 = 4-MeOC6H4, Ar2 = Ph, R1 = Ph, R2 = Me, 90%

Ar3CHO 55

Ar2

O

H

O CO2Et

Sn(OTf)2 Ar3 Ar1 (5 mol%) O 1,2-DCE 40 °C 65a: Ar1 = Ar2 = Ar3 = Ph, 98% 65b: Ar1 = Ar2 = Ph, Ar3 = E-styryl, 92% 65c: Ar1 = 4-BrC6H4, Ar2 = Ar3 = Ph, 96% 65d: Ar1 = Ph, Ar2 = 4-O2NC6H4, Ar3 = Ph, 99%

Scheme 9.10 (3 + 2) Annulation of γ-butyrolactone-fused D–A cyclopropanes with aldehydes and ketones. O CO2Et I 67

Ar

CO2Et

KSC(S)OEt (3 equiv.) Cu(OAc)2 (10 mol%) AcOH (2 equiv.) DMF, 110 °C

O

S

CO2Et

S

Ar

CO2Et S

Ar

CO2Et

69

S

CO2Et

S

Ar

CO2Et

70

68a: Ar = Ph, 82% 68b: Ar = 4-MeOC6H4, 76% 68c: Ar = 3-NCC6H4, 77% 68d: Ar = 1-naphthyl, 72%

Scheme 9.11 Synthesis of thioflavothiones from 2-iodobenzoyl-substituted D–A cyclopropanes.

at 110 °C, yielded thioflavothiones 68 (Scheme 9.11) [41]. The reaction proceeds through in situ formation of thiolate intermediate 69, followed by ring‐opening to give thione 70, and subsequent decarbethoxylation and oxidation to give 68.

9.4 Synthesis of Nitro-Substituted D–A Cyclopropanes Nitro‐substituted D–A cyclopropanes 2 (both in racemic and chiral forms) were also routinely synthesized by the MIRC methodology (Scheme 9.12). Thus, they have been obtained by the following approaches: (i) the reaction of β‐bromo‐β‐ nitrostyrenes 71 with dialkyl malonates in the presence of K2CO3 in DMSO [15], (ii) the conjugate addition of halomalonates 9 to β‐nitrostyrenes 72 in the presence

289

290

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Ar 71

4

CO2R

NO2

Ar

1)

CO2R

RO2C

K2CO3, DMSO

Br

CO2R

X

CO2R

9 CO2R Chiral catalyst

NO2

Ar

2) Base

NO2

2

72

PhI(OAc)2, Bu4NI, PhMe (or) PhI, m-CPBA, Bu4NI, KOtBu, CF3CH2OH RO2C

CO2R NO2

Ar 73

Scheme 9.12 Literature methods for the synthesis of nitro-substituted D–A cyclopropanes. Table 9.18 Synthesis of various nitro-substituted D–A cyclopropanes. EtO2C Ar

EtO2C Ph

CO2Et NO2 73

CO2Et

2e, 92%

EtO2C

CO2Et

MeO MeO

NO2 I 2i, 85%

EtO2C

EtO2C

CO2Et NO2

NO2

EtO2C

CO2Et

MeO MeO

CO2Et

2c, 86%

MeO

EtO2C

NO2 2

EtO2C

2b, 89%

CO2Et

CO2Et

Ar

NO2

NO2 Me

EtO2C

CO2Et

Ar

CO2Et

NO2

NO2 O2N

EtO2C

DCM, rt 10–25 min

EtO2C

2a, 94% EtO2C

I

I2 (2 equiv.) DBU (2 equiv.)

NO2 2f, 89%

CO2Et

MeO

OMe EtO2C

NO2

2g, 82%

CO2Et

EtO2C

CO2Et

Cl

NO2

Cl

2h, 97%

EtO2C

NO2 O

2j, 98%

CO2Et NO2

MeO

2d, 96%

Cl

CO2Et NO2

S 2k, 58%

2l, 49%

of various chiral catalysts, followed by base‐mediated ring closure [42–44], and (iii) the oxidative cyclization of Michael adducts of nitrostyrenes with malonates 73 using iodobenzene diacetate and Bu4NI in toluene [45] or iodobenzene, m‐CPBA, Bu4NI, and KOtBu in trifluoroethanol [46]. In our research group, we have prepared nitro‐substituted D–A cyclopropanes 2 by iodine/DBU‐mediated cyclization of Michael adducts of nitrostyrenes with malonates 73 (Table 9.18) [47]. Accordingly, when the Michael adducts were treated with iodine (2 equiv.) and DBU (2 equiv.) in DCM at room temperature, D–A cyclopropanes 2 were produced as single trans‐diastereomers in good yields. The reaction tolerated the presence of phenyl rings with neutral, electron‐donating, and electron‐ withdrawing groups, naphthyl rings, and heteroaromatic rings.

9.5 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes

9.5 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes In the realm of D–A cyclopropanes, nitro‐substituted D–A cyclopropanes are known for their characteristic chemical reactivity. They normally undergo ring‐opening reactions and a few ring‐expansion reactions, but they seldom take part in annulation reactions.

9.5.1

BF3-Mediated Ring-Opening Reactions

In order to understand the reactivity patterns of nitro‐substituted D–A cyclopropanes 2 with Lewis acids, they were treated with a range of Lewis acids, such as AlCl3, SnCl4, BF3·OEt2, FeCl3, ZnCl2, TiCl4, InCl3, MgI, AgOTf, Cu(OTf)2, In(OTf)3, Sc(OTf)3, and Yb(OTf)3 in different solvents. Among these, BF3·OEt2 effectively transformed D–A cyclopropanes 2 into synthetically useful aroylmethylidene malonates 74 in DCM at room temperature, with yields up to 94% (Table 9.19). Other Lewis acids, such as AlCl3, SnCl4, and FeCl3, were also capable of affording 74, but the yields were poor. As expected, nitrocyclopropane (2e), having a p‐ nitrophenyl ring, did not yield the corresponding aroylmethylidene malonate. This transformation takes place through the formation of 1,3‐dipolar intermediate 75, fragmentation of 75 to form ion‐pair 76, recombination of 76 to give nitro compound 77, and the Nef reaction of 77 finally furnished 74. The products of the above‐mentioned transformation, aroylmethylidene malonates 74, were found to be versatile synthetic precursors for the access of various heterocyclic compounds as depicted in Scheme 9.13 [47]. Thus, 74 reacted Table 9.19 Synthesis of aroylmethylidene malonates from nitro-substituted D–A cyclopropanes. F3 B O

O

EtO Ar

2

O

EtO OEt BF3 •OEt 2

NO2

DCM rt, 24 h

NO2

O

Ar

Ar

NO2 OEt

Selected examples: O Ph

O

CO2Et

O

CO2Et

CO2Et

O

CO2Et

Me

74b, 86%

CO2Et CO2Et

MeO

O MeO MeO

OMe 74e, 94%

CO2Et 74

CO2Et

O

CO2Et MeO

74c, 86%

I 74f, 85%

O

CO2Et CO2Et

Cl

74d, 79%

CO2Et CO2Et

CO2Et

Ar

77

CO2Et

CO2Et 74a, 81%

MeO

Ar

76

75

O

NO2 CO2Et

CO2Et

O

CO2Et CO2Et

74g, 80%

S

CO2Et CO2 Et

74h, 27%

291

292

9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes O

CO2Et CO2Et 74

Ar

CH3 H3N Cl

NH

Et3N, DCM rt, 1 h

HN

R

H2N

R

N

Ar

HS EtOH, rt 15 min

R

N

N

Ar EtO2C

R

79a: Ar = Ph, R = H, 90% 79b: Ar = 4-MeC6H4, R = H, 95% 79c: Ar = 4-OMeC6H4, R = H, 97% 79d: Ar = Ph, R = Me, 92%

CH3 78a: Ar = Ph, 95% 78b: Ar = 4-ClC6H4, 93%

Scheme 9.13

H2N

EtOH, rt, 15 min

CO2Et

Ar

H2N

N

S CO2Et

80a: Ar = Ph, 85% 80b: Ar = 4-MeC6H4, 96%

Synthetic utility of aroylmethylidene malonates.

with (i) acetamidine hydrochloride in the presence of Et3N in DCM to give imidazole derivatives 78, (ii) o‐phenylenediamines in ethanol to afford quinoxalines 79, and (iii) o‐aminothiophenol in ethanol to furnish benzo[1,4]thiazine derivatives 80 through a nucleophilic addition and cyclocondensation sequence.

9.5.2

Reactions with Nitriles

With a view to extend the (3 + 2) D–A cyclopropane–nitrile annulation strategy to nitro‐substituted D–A cyclopropanes 2, we treated them with various aliphatic and aromatic nitriles 41 in the presence of SnCl4 in 1,2‐DCE at room temperature. Instead of the expected 1‐pyrrolines, the reactions yielded a wide variety of 2,4,5‐trisubstituted oxazole derivatives 81 (Table 9.20) [48]. A mechanistic study revealed that D–A cyclopropanes 2 formed aroylmethylidene malonates 74 in situ, and 74 underwent Table 9.20 Synthesis of oxazoles from nitro-substituted D–A cyclopropanes.

EtO2C

CO2Et

Ar

NO2

2

O

RCN 41

O Ar

SnCl4 1,2-DCE rt, 1–7 h

R N

Ar EtO H

(RCN)

CO2Et

CO2Et (SnCl4)

O

74

CO2Et

EtO2C

OEt

N

Ar

O Sn 82 Cl4

O

R

81

Selected examples: EtO2C Ph

CO2Et

EtO2C

N O

Ph

Cl

81b, 85%

EtO2C

N

81f, 88%

Ph S

MeO

EtO2C

N Me

81g, 75%

Ph

CO2Et

EtO2C

N O

MeO

CO2Et

O

EtO2C

Ph

O

CO2Et

O

N

Ph

81a, 89%

EtO2C

CO2Et

CO2Et

Ph

O

81c, 89%

CO2Et

81h, 78%

EtO2C MeO

Ph

81d, 83%

Br

N O

EtO2C

N

CO2Et

Ph

N

N O

81e, 75%

EtO2C

CO2Et N O

O 81i, 72%

CO2Et

CN

81j, 62%

NO2

9.5 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes

conjugate addition with nitriles 41 to give nitrilium ion intermediates 82, which upon cyclization yielded oxazoles 81. The literature methods reported for the generation of nitrilium ion intermediates involve the reaction of α‐functionalized ketones with nitriles (the α‐functionalization of ketones could be achieved only by using reagents based on transition metal or hypervalent iodine) [49–52] and, thus, the current method affords a hitherto unknown route to nitrilium ion intermediates.

9.5.3

Reactions with Activated Aromatics

The above work indicated that the treatment of nitro‐substituted D–A cyclopropanes 2 with Lewis acids would result in the in situ formation of aroylmethylidene malonates 74, which could be converted into other useful products by reaction with suitable reaction partners in the same flask. Such a sequential one‐pot synthesis is better than the corresponding two‐step synthesis, as it avoids the separation and purification of the intermediate products. We envisaged that the conjugate addition of carbon nucleophiles to in situ‐generated aroylmethylidene malonates would give β‐ketomalonates, which are potential synthetic intermediates [54]. Accordingly, nitro‐substituted D–A cyclopropanes 2 were treated with 1 equiv. of BF3·OEt2 in DCM at room temperature for 24 hours to form aroylmethylidene malonates in situ, and then the intermediates were reacted with activated aromatics 83 (indoles, carbazole, pyrrole, thiophenes, methoxybenzenes, and benzodioxole) by adding a catalytic amount of In(OTf)3 in the same reaction vessel to obtain the respective adducts (β‐ketomalonates) 84 (Table 9.21). It is interesting to note that both mono‐ and bis‐ Michael adducts of aroylmethylidine malonates with 2,2′‐bithiophene, 84i and 84k, could also be achieved by this methodology.

9.5.4

Reaction with Mercaptoacetaldehyde Dimer

By applying a similar sequential one‐pot synthetic strategy as a key step, we also devised a two‐step synthesis for the access of 2,3‐disubstituted thiophenes, which are difficult to access by direct electrophilic or metalation procedures [56]. Accordingly, in the first step, nitro‐substituted D–A cyclopropanes 2 were treated with BF3·OEt2 in DCM to form aroylmethylidene malonates in situ, and then reacted with mercaptoacetaldehyde (45′) generated in situ from 1,4‐dithiane‐2,5‐diol (45) in the presence of Et3N, to obtain tetrahydrothiophenes 85 in a sequential one‐pot manner (Table 9.22). A minimum of 2 equiv. of Et3N was necessary for the reaction in order to neutralize the Lewis acid as BF3·OEt2‐Et3N complex and also for the generation of the monomer 45′ from mercaptoacetaldehyde dimer. The products 85 were formed as inseparable diastereomeric mixtures via the thia‐Michael addition of 45′ to aroylmethylidene malonates followed by an aldol reaction. In the second step, tetrahydrothiophenes 85 were treated with p‐TsOH in toluene at 90 °C to obtain 2,3‐disubstituted thiophenes 86 through dehydration, followed by monodecarbethoxylation and aromatization (Table 9.23).

293

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9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

Table 9.21 Synthesis of β-ketomalonates from nitro-substituted D–A cyclopropanes. EtO2C CO2Et Ar1

1) BF3·OEt2 (1 equiv.) DCM, rt, 24 h

NO2

2

Ar2H,

2) 83 (1.1 equiv.) In(OTf)3 (5 mol %), 1–4 h

Selected examples: O CO2Et Ph MeO

Ar2

84

via

CO2Et

CO2Et

Ph

CO2Et

HN

CO2Et

S

CO2Et

Me 84c, 80%

CO2Et

Ph

CO2Et

84d, 81%

CO2Et

CO2Et O

O

O

S

CO2Et

N H

N H 84g, 78%

84f, 75%

84e, 83%

S

CO2Et

CO2Et

CO2Et

MeO

O

S

O

O

S

O

CO2Et

O

CO2Et

CO2Et

CO2Et 74

O

N H 84b, 77%

O

Ph

CO2Et

Ar1

Ph

CO2Et

N H 84a, 89%

MeO

O

CO2Et

O Ph

CO2Et

Ph

O Ar1

EtO2C

CO2Et

89%

CO2Et

S

Ph

O

84i, 89%

S

S

EtO2C

CO2Et

S

84h, 89%

CO2Et

Ph

O

84k, 85%b

84j, 72%

Table 9.22 Synthesis of tetrahydrothiophenes from nitro-substituted D–A cyclopropanesa (step-1). O EtO2C

CO2Et

Ar

NO2

2

1) BF3 ·OEt2, DCM, rt

Ar

Selected examples: EtO2C EtO2C O Ph

2) 45, Et3N

EtO2C EtO2C O

OH

EtO2C EtO2C O

OH

OH

O via Ar

S 85

HS

CO2Et

OH

CO2Et

O

O

S Ar

EtO2C EtO2C O

S

OH

EtO2C EtO2C O

OH S

S

S

85a, 83%

45′ EtO2C

Et3N

74

EtO2C EtO2C O

S

CO2Et

S Me 85b, 80%

MeO

OMe

85c, 87%

Cl

85e, 25% b

85d, 74%

a) The dr values ranged from 1 : 1.1 to 1 : 2.2. b) The reaction was carried out at −15 °C.

9.5.5

Ring-Opening Reactions with 2-Aminopyridines

While investigating the ring‐opening reactions of nitro‐substituted D–A cyclopropanes 2 with different amines, we observed that they undergo tandem ring‐opening/ cyclization with 2‐aminopyridines 87 to yield pyrido[1,2‐a]pyrimidin‐4‐one derivatives 88 (Table 9.24). Water was found to be a better solvent for this transformation

9.5 Synthetic Applications of Nitro-Substituted D–A Cyclopropanes

Table 9.23 Conversion of tetrahydrothiophenes into thiophenes (step-2). EtO2C EtO2C O

OH S 85

Ar

EtO2C EtO2C O

p-TsOH PhMe, 90 °C 15–24 h

O

O S

Ar

EtO2C

EtO2C S

Ar

S 86

Ar

Selected examples: EtO2C EtO2C

EtO2C

EtO2C

O

O

O S

O

EtO2C O S

S

S

S

Ph

S

86a, 72%

Me

OMe

MeO

86b, 68%

Cl 86d, 63%

86c, 81%

86e, 61%

Table 9.24 Synthesis of pyridopyrimidinones from nitro-substituted D–A cyclopropanes. X R N EtO2C Ar

CO2Et

NH2

EtO2C

X = CH or N 87

CO2Et H

NO2 H2O, reflux, 0.5–2 h

2

EtO2C

NO2 R

Ar

N

89

X

N H

O

EtO

EtO2C N

N

CO2Et NO2

X

Ar

90

X R H2N

N

Ar

O

R

CO2Et

N

CO2Et N H

+

O2 N

X

H2N R

CO2Et

X

Ar

N 88

Ar

Selected examples: O

O CO2Et

N

N

Ph

N

O

CO2Et

N 88e, 80%

OMe

O CO2Me

N

N

N

O CO2Et

N N

88f, 68%

Ph

F

88d, 78% O

NH2 O CO2Et

N

CO2Et

N

88c, 72% O

Br

CO2Et

N

88b, 76%

88a, 90%

N

O

CO2Et

N OH 88g, 72%

Ph

CO2Et

N N

88h, 69%

Ph

CO2Et

N N

N

Ph

88i, 70%

as compared to organic solvents such as MeOH, EtOH, AcOH, toluene, DCM, 1,2‐ DCE, THF, 1,4‐dioxane, MeCN, MeNO2, DMF, and DMSO. In addition, these reactions did not require any other reagent or catalyst to take place. Mechanistically, 2‐aminopyridine initially removes the acidic proton of cyclopropane at C3 to give a ring‐opened intermediate 89. The addition of 2‐aminopyridine to intermediate 89, followed by the elimination of the nitro group, forms a new intermediate 90, which upon cyclization, affords pyridopyrimidinone 88.

295

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9 Chemistry of Aroyl- and Nitro-Substituted Donor–Acceptor Cyclopropanes

9.5.6 Works from He, Xia, and Asahara Groups He and coworkers have reported that nitro‐substituted D–A cyclopropanes 2, when treated with azodicarboxylates 91 in the presence of triphenylphosphine in DCM, furnished 3‐alkoxypyrzolines 92 in good‐to‐excellent yields (Scheme 9.14) [58]. The Huisgen zwitterion, produced by the attack of PPh3 on 91, served as a base and removed the acidic proton of cyclopropane at C3, resulting in the respective ring‐ opened intermediate, which underwent cyclization, followed by the elimination of Ph3PO, to afford the product. If one of the ester groups in the products was t‐ butoxycarbonyl, the products were further converted into pyrazoles 93 by acid hydrolysis using TFA, followed by decarboxylation. Xia et al. have disclosed that nitro‐substituted D–A cyclopropanes 2 formed allene intermediates 94 upon treatment with Cs2CO3 via base‐mediated ring‐opening, followed by the elimination of the nitro group (Scheme 9.15) [59]. These intermediates yielded the dimerization products 95 when the reactions were performed in H2O in the presence of soybean lecithin (a surfactant), whereas they furnished the R 1O2C Ar

CO2R1 NO2

2

CO2R1

R1O2C

CO2R2

Ar

N N PPh3 CO2R2

R2O2C

N N

+

91

R1O2C Ar

R1O2C

PPh3, DCM, rt

Ar

CO2R2

CO2R2 OR1 O N PPh3 N CO2R2

R1O2C Ph3PO

Ar

CO2R1 NO2

H

PPh3 N CO2R2 N CO2R2 CO2R1

CO2R2 1 OR 1) TFA, DCM, rt N N CO2R2

2) DMF, reflux When R1 = Me & R2 = CO2tBu

92a: Ar = Ph, R1 = Me, R2 = tBu, 88% 92b: Ar = 3-MeO6H4, R1 = Me, R2 = tBu, 92% 92c: Ar = 3-pyridyl, R1 = Me, R2 = tBu, 89%

Ar

N H

N

93a: Ar = Ph, 78% 93b: Ar = 2-furyl, 58%

Scheme 9.14 Synthesis of 3-alkoxypyrzolines and pyrazoles from nitro-substituted D–A cyclopropanes. EtO2C Ar CO2Et Ar

EtO2C

CO2Et

Cs2CO3

Ar

NO2

solvent

2

via:

CO2Et

94

H2O, soybean lecithin, rt, 4 h

CO2Et NO2

Ar 95a: Ar = Ph, 86% 95b: Ar = 3,5-(MeO)2C6H3, 89% 95c: Ar = 2-thienyl, 61%

CO2Et

Ar

CO2Et CO2Et CO2Et

CH2(CO2Et)2

EtO2C Ar

CPME, rt, 2 h EtO2C

CO2Et CO2Et

96a: Ar = Ph, 88% 96b: Ar = 4-F3CC6H4, 80% 96c: Ar = 2-naphthyl, 76%

Scheme 9.15 Synthesis of enynes and enesters from nitro-substituted D–A cyclopropanes.

Accnooleddments O SnCl2 2H2O

EtO2C Ar

CO2Et

2

NO2

N

EtO2C

Ar THF, 100 °C sealed tube EtO2C CO2Et (or) 97 PhH, 100 °C PNO, sealed tube

Ar

Ar

CO2Et NO2 72

O

N

98a: Ar = Ph, 70% 98b: Ar = 4-MeOC6H4, 62% 98c: Ar = 2-naphthyl, 55% O

CO2Et

SnCl2 2H2O PhH, 100 °C sealed tube

CO2Et

O

Ar

CO2Et CO2Et

74b: Ar = 4-MeC6H4, 33%

Scheme 9.16 Synthesis of isoxazolines and aroylmethylidene malonates from nitrosubstituted D–A cyclopropanes.

nucleophilic addition products 96 when the reactions were carried out in cyclopentylmethyl ether (CPME) in the presence of diethylmalonate. Recently, Asahara and coworkers have reported that nitro‐substituted D–A cyclopropanes 2 could undergo two types of ring‐opening with SnCl2·2H2O, depending upon the solvent or ligand employed (Scheme 9.16) [60]. Thus, when the reactions were performed in THF or benzene in the presence of pyridine‐N‐oxide (PNO), the C2─C3 bond of 2 underwent cleavage to give 1,3‐dipolar intermediates 97, which upon cyclization, yielded isoxazolines 98. On the other hand, the cyclopropanes underwent the usual C1─C2 bond cleavage to give aroylmethylidene malonates 74 through intermediates 72, when the reactions were carried out in benzene in the absence of PNO.

9.6 Conclusion The investigation of the reactivity of aroyl‐and nitro‐substituted D–A cyclopropanes has revealed that the former undergo all the routine reactions of D–A cyclopropanes, such as ring‐opening, ring‐opening/cyclization, and annulation reactions, while the later undergo only ring‐opening and ring‐opening/cyclization reactions. These studies have provided efficient synthetic routes to a range of acyclic, carbocyclic, and heterocyclic products, including medicinally important compounds [61, 62]. The presence of the extra aroyl‐ or nitro‐groups in these cyclopropanes, along with regular D–A substituents, indeed make them unique and versatile building blocks in the field of D–A cyclopropane chemistry.

­Acknowledgments K.S. thanks the Science and Engineering Research Board (SERB) and Council of Scientific and Industrial Research (CSIR), India, for financial support. T.S. thanks the Department of Science and Technology (DST) for a Women Scientist Fellowship (WOS‐A).

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Nagayoshi, K. and Sato, T. (1983). Chem. Lett. 1983: 1355–1356. Lee, J.C. and Hong, T. (1997). Tetrahedron Lett. 38: 8959–8960. Ishiwata, Y. and Togo, H. (2009). Tetrahedron 65: 10720–10724. Saito, A., Hyodo, N., and Hanzawa, Y. (2012). Molecules 17: 11046–11055. Selvi, T. and Srinivasan, K. (2015). Adv. Synth. Catal. 357: 2111–2118. Liu, G., Shirley, M.E., Van, K.N. et al. (2013). Nature Chem. 5: 1049–1057.

55 Selvi, T., Vanmathi, G., and Srinivasan, K. (2015). RSC Adv. 5: 49326–49329. 56 O’Connor, C.J., Roydhouse, M.D., Przybyl, A.M. et al. (2010). J. Org. Chem. 75: 2534–2538. Selvi, S. and Srinivasan, K. (2017). Eur. J. Org. Chem. 2017: 5644–5648. Yang, G., Liu, W., He, Z., and He, Z. (2016). Org. Lett. 18: 4936–4939. Zhou, Z.‐Y., Xu, Z.‐Y., Shen, Q.‐Y. et al. (2021). Chem. Commun. 57: 6424–6427. Asahara, H., Kamidate, R., and Nishiwaki, N. (2021). Heterocycles 103: 379–391. Kandasamy, S., Subramani, P., Srinivasan, K. et al. (2020). J. Mol. Struct. 1214: 128177. 62 Meenakshi, M., Antojenifer, P., Karthikeyan, M. et al. (2022). J. Heterocycl. Chem. 58: 351–358.

57 58 59 60 61

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301

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases, and Thermal Reactions Lijia Wang1 and Yong Tang2 1 East China Normal University, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Department of Chemistry, 3663 North Zhongshan Road, Shanghai, 200062, China 2 The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China

CHAPTER MENU 10.1 10.2 10.3 10.4 10.5

Introduction, 301 Metal-Free Electrophilic Activation of D–A Cyclopropanes, 302 Metal-Free Nucleophilic Activation of D–A Cyclopropanes, 313 Catalyst-Free Activation of D–A Cyclopropanes, 319 Metal-Free Activation of D–A Cyclopropanes via Radical, SET, and Photopromoted Process, 327 10.6 Conclusion, 329 References, 330

10.1

Introduction

Donor–acceptor (D–A) cyclopropanes are very useful three-carbon synthons in modern organic synthetic chemistry, which have been widely applied in the total synthesis of biologically active natural products as well as important pharmaceutical intermediates. Aiming at efficient transformations of D–A cyclopropanes, various activation strategies have been developed. In this chapter, metal-free activations of the D–A cyclopropanes by means of protic acids, non-metal Lewis acids, bases, thermal reactions, and so on, are discussed. Four main sections based on different modes of activation with abundant examples are reviewed, including electrophilic activation, nucleophilic activation, catalyst-free activation, and activation of D–A cyclopropanes via radical processes.

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

302

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases Catalyst-free activation

Electrophilic activation +δ

–δ

D

A Radical process

Nucleophilic activation

10.2 Metal-Free Electrophilic Activation of D–A Cyclopropanes Electrophilic activations on the carbonyl groups of D–A cyclopropanes, employing catalytic protic acids such as trifluoromethanesulfonic acid (TfOH), could increase the C─C bond polarization of the cyclopropane, which allowed the following nucleophilic ring-opening in an SN1 or SN2 manner, depending on both the catalyst acidity and the electronic nature of substituents on the cyclopropanes (Scheme 10.1a). Besides, other non-metal catalysts or regents, such as trivalent boron species, TMSOTf, and so on, that promote electrophilic activations of D–A cyclopropanes, are also reviewed in this section. An alternative strategy of metal-free electrophilic activation of D–A cyclopropanes in the concept of iminium–enamine activation (Scheme 10.1b) is also included and discussed. H O H

O

R2

Nu–H

R1

H

Nu

H

(a)

R1

Increase in C–C bond polarization

O R2

R

2

R1 NR'2 HNR'2

R

2

NR'2 R1

Nu

R1 R2 * Nu

NR'2 E

E R2

*

R1

(b)

* Nu

Iminium–enamine activation

Scheme 10.1 Metal-free electrophilic activation of D–A cyclopropanes.

Moran and coworkers developed a TfOH-catalyzed nucleophilic ring-opening of D–A cyclopropanes with a wide range of nucleophiles, including arenes, indoles, azides, diketones, and even alcohols (Scheme 10.2) [1]. The reaction worked very efficiently in an expanded cyclopropane scope, where D–A cyclopropanes with diester groups (1) or single ketoacceptor groups (2), and those bearing electrondeficient aryl groups, could all react at room temperature within 3 hours in the presence of 10 mol% of TfOH as catalyst. Mechanistic study, employing an enantiopure cyclopropane under standard conditions, delivered a configuration-inverted ringopening product, suggesting that the nucleophilic ring-opening via a predominantly SN2-like pathway. The fluorinated alcohol solvent, hexafluoroisopropanol (HFIP),

10.2 Metal-Free lectrophilic Activation of D–A Cyclopropanes CO2R Ar

Nu

CO2R 1

+

or

Nu H

Ar

H+ (cat.)

or

HFIP, rt, 3h

R

CO2R CO2R

Ar

O

Nu

R Ar

O

3

4

40 examples 79% average yield

2 Selected examples MeO

OMe

MeO

OMe

CO2Me OMe Ph

O

O Ph

CO2Me

CO2Me

O Ph

OMe Ph 3b, 98% [2.5 mmol scale: 99%]

3a, 95%

Ph

Ph

CO2Me

3c, 78%

MeN

O CO2Me

Ph

O

Ph

CO2Me

Me 3d, 85%

Cl 4a, 90%

Scheme 10.2 TfOH-catalyzed nucleophilic ring-opening of D–A cyclopropanes.

was found to play an important role. Zhang and Feng performed density functional theory (DFT) calculations to better understand the detailed mechanisms of this reaction [2]. Computational studies indicate that the explicit solvation effect of HFIP significantly lowered the activation free energy from 29.5 kcal/mol to 20.5 kcal/ mol, which suggested the cooperative role of TfOH and HFIP in facilitating the ringopening step. Similar to the metallic Lewis acid catalysis, in the case of Brønsted acids activated reactions of D−A cyclopropanes, the strained ring with highly polarized C─C bond could also be considered as an equivalent of 1,3-dipole (type I and II), which allowed [3 + n] annulation of D−A cyclopropanes with various dipolarophiles. In 2015, Budynina and coworkers developed a TfOH-catalyzed [3 + 2] annulation of arylcyclopropane-1,1-diesters with alkynes, which led to facile access to various functionalized indenes (5) (16 examples) in yields up to 89% at room temperature (Scheme 10.3a) [3]. As a solvent with strong polarity, MeNO2 was used in this reaction. In their studies, Lewis acids such as BF3 · Et2O could also promote this [3 + 2] annulation; however, stoichiometric Lewis acids were needed. In 2022, Goswami and coworkers reported a BF3 · OEt2-mediated [3 + 2] annulation of cyclopropane1,1-diesters with alkynylnitriles in a chemoselective manner for the synthesis of propargylic cyclic imines (6) (28 examples) in yields up to 93% (Scheme 10.3b) [4]. In 2021, Zhai and Zhao reported a Brønsted acid-catalyzed formal [3 + 2] dehydration cycloaddition of vinyl substituted D–A cyclopropanes (7) with 2-naphthols in CH2Cl2 (Scheme 10.4) [5]. TfOH was employed as the catalyst and delivered the naphthalene-fused cyclopentanes (8) in moderate-to-good yields (55–87% yields) with

303

304

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

EWG

Ar

EWG

Ar

EWG

Ar II

I CO2R

CO2R CO2R

R2

R1

Ar

RO2C

Lewis or Bronsted acid

1

Ar R1

Ar = electron abundant Ar or Het R1=Ar, R2=Ar.Alk

R1

CO2R2 + R3 CO2R2

(a)

R2 5

16 examples up to 89% yield

BF3·OEt2 (150 mol%) CN

CO2R2 CO2R2 (b)

R1 N

1,2-DCE, 60 °C 3–10 h

1

R3

6

28 examples up to 93%

Scheme 10.3 [3 + 2] annulation of D−A cyclopropanes with alkynes and alkynylnitriles.

OH R1

CO2R2 CO2R2

+ 7

TfOH

CO2R2 CO2R2

R1 8

up to 87% yield H EtO O CO2Et OEt OH OH

H

OH OH OEt

Selected examples

CO2Et CO2Et

CO2Et CO2Et

CO2Me CO2Me

NC

Br

n.d

8b 83%

8a 77%

O CO2Me CO2Me

CO2Me CO2Me

8c 71%

8d 75%

Scheme 10.4 TfOH promoted formal [3 + 2] dehydration cycloaddition of D–A cyclopropanes with 2-naphthols.

10.2 Metal-Free lectrophilic Activation of D–A Cyclopropanes

high regioselectivity in a metal-free catalysis. Both vinyl- and aryl-cyclopropane-1,1diesters worked well with 2-naphthols bearing many different substituents, while electron-withdrawing cyano-substituted 2-naphthol decreased the performance of the reaction. In this reaction, the polarization of the C─C bond increased by TfOH enabled the nucleophilic ring-opening of the cyclopropane by 2-naphthol, followed by an intermolecular aldol reaction to form the cyclopentane intermediate, which eliminated H2O to generate the naphthalene-fused cyclopentane. In 2020, Baranov and Mikhaylov developed a Brønsted acid-promoted [3 + 2] annulation of D–A cyclopropanes (9) with aldehydes. In the reaction, stoichiometric TsOH was employed, and imidazol-5-one was introduced as an acceptor group of the spirocyclopropanes. Products 10 and 10′ in 51–92% yields with moderate diastereoselectivity were obtained over 25 examples (Scheme 10.5) [6]. Computational insight into the mechanism of the [3 + 2] annulation between D–A spirocyclopropane and different aldehydes was revealed by Xue and coworkers in 2022 [7], which showed that electron-rich aldehydes are more nucleophilic and have a relatively lower Gibbs free energy barrier in the rate-determining step during the reaction, which is more favorable for the reaction to occur. Ar

R2

N N O 9

R

3

R1CHO TsOH (1.1 equiv.)

Ar O

CH2Cl2 3–240 h

• Brønsted acid activation

Ar

R2

N N R1 O 10

+

O 3 N R

O

R3

R1

N

R2

10'

• 25 examples, 51–92% combined yields • Easily separable diastereomers • dr up to 6:1 for R1 = aliphatic or EWG

Scheme 10.5 TsOH promoted [3 + 2] annulation of D–A cyclopropanes with aldehydes.

In 2012, Werz and coworkers developed a TsOH-promoted domino approach of ring-enlargement of D–A cyclopropanes [8–10]. Ketone-substituted cyclopropanes (11) were transformed into corresponding imines, which underwent the intramolecular ring-opening rearrangement to build up 3,3′-linked oligopyrroles (12). In addition, the in situ-generated highly nucleophilic bispyrroles could react with a Michael acceptor to afford pyrrolo[3,2-e]indoles (13) (Scheme 10.6). R3 R3NH2, p-TsOH, ΔT H

1

R2 R O

H

H

O 11

R1 O H

R2

–3 H2O

R2

R1

R2

N N R1

R3

12

O R3NH2,

p-TsOH, ΔT

–4 H2O O

R3 N R3 N

O R2

R2

R1 R1 13

Scheme 10.6 TsOH-promoted domino approach to bispyrroles.

305

306

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

Protic ionic liquid (PIL) as a Brønsted acid was found to be useful to promote reactions of D–A cyclopropanes. In 2021, Werz, Trushkov, and coworkers developed a metal-free formal [3 + 2]-cycloaddition of D–A cyclopropanes with isothiocyanic acid by employing thiocyanate-based PILs as the sources of nucleophile, the solvent, and the Brønsted acid catalyst. The substrate scope of this reaction is quite broad that various D–A cyclopropanes (33 examples) could be attacked by the nucleophilic 1-methylimidazolium thiocyanate, resulting in the formation of corresponding pyrrolidine-2-thiones (14) in good yields. The PIL could be recovered and the reaction scale could be enlarged to 3 grams without the loss of efficiency and sustainability (Scheme 10.7) [11]. R2

R O

R1

B:•HNCS 70 °C

R3

H B O NCS

R3

R1

[NCS] path a

O

R R1

R3 N H

~H

S

path b

N

S C N

R

R S

OH R1

OH R1

R3

B

A

14

R3

Selected examples

MeO2C MeO MeO

N H

CO2Me S

O

MeO2C N

N H

O 14a 89%

14b 77%

MeO2C

CO2Me S MeO

N H

CN S

14c 42%

Scheme 10.7 PIL-promoted formal [3 + 2] cycloaddition of D–A cyclopropanes with isothiocyanic acid.

In 2009, Waser and coworkers developed a catalytic formal Homo–Nazarov cyclization of D–A cyclopropanes. Various vinyl-cyclopropyl ketones served as substrates in the presence of Brønsted acid catalysts such as TsOH, which were activated by protons to form the cyclopropane ring-opening intermediates, followed by the intramolecular electrophilic addition of olefin to complete the cyclization (Scheme 10.8) [12–14]. Polar solvents such as acetonitrile were found to be more appropriate solvents. Mechanistic studies suggest that this reaction is not in a classical concerted Nazarov cyclization process; in contrast, it undergoes a stepwise mechanism that the ring-opening of D–A cyclopropanes is probably the ratelimiting step.

10.2 Metal-Free lectrophilic Activation of D–A Cyclopropanes O

O a R

X a

ß ß

R

X

TsOH (20 mol%) CH3CN

Ar

Ar

R = CH3 or H X = O, NR1, CHSiMe3

up to quantitive yield

Ar = electron-rich aromatic group Catalytic formal homo-Nazarov Cyclization O a R3

EDG a R1

ß

ß

R2

H

O

R1 R2 –H

H OH R3

EDG R1 R2 I

R3

EDG

OH R3

EDG R1 R2 II

Scheme 10.8 TsOH-promoted formal Homo–Nazarov cyclization of D–A cyclopropanes.

In 2006, Pagenkopf and coworkers demonstrated an annulation of mono-acceptor D–A cyclopropanes with electron-deficient pyridines and quinolones, leading to the synthesis of indolizines (15) and benzoindolizines (Scheme 10.9) [15]. The ringopening reaction of D–A cyclopropanoate esters with pyridines or quinolines was promoted by TMSOTf as a Lewis acid, followed by the intramolecular Mannich annulation to form 2,3-dihydroindolizines, which underwent rapid autooxidation to generate indolizines or benzoindolizines.

Scheme 10.9 TMSOTf-promoted annulation of mono-acceptor D–A cyclopropanes with pyridines.

In 2010, Melnikov and coworkers developed a TMSOTf-catalyzed isomerization of 2-arylcyclopropane-1,1-dicarboxylates, which provided a facile access to 2-styrylmalonates (16) (Scheme 10.10) [16]. A variety of D–A cyclopropanes bearing both electron-donating groups and electron-withdrawing groups on the aryl substituents were tolerated, leading to the corresponding products in moderate-togood yields.

307

308

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases TMSOTf

CO2Me CO2Me

Ar

O

MeO

PhCl, 4 Å MS reflux

Ar

16

TMSOTf

CO2Me

Ar

CO2Me CO2Me

CO2Me OMe

Ar

OH

H

Time (h)

Yield (%)

C6H5

1

67

2

4-BrC6H4

3

80

3

4-FC6H4

1

63

4

4-MeC6H4

1

56

5

2-MeO-5-(O2N)C6H3

1

59

6

α-naphthyl

1

78

7

β-naphthyl

1

86

8

biphenyl-4-yl

2

73

Entry

Ar

1

Scheme 10.10

TMSOTf-promoted isomerization of 2-arylcyclopropane-1,1-dicarboxylates.

In 2014, Budynina and coworkers developed a Lewis acid-promoted [3 + 2] cyclodimerization of D–A cyclopropanes. In the presence of stoichiometric boron trifluoride etherate (BF3 · Et2O) as a Lewis acid, a variety of 2-(3-indolyl)cyclopropane-1,1-dicarboxylic acid diesters were activated to form the corresponding 1,3-zwitterions, which could isomerize to propenes, followed by the [3 + 2] annulations of 1,3-zwitterions with the propenes to produce the 3-indolyl-derived cyclopenta[b]indoles (17) (Scheme 10.11) [17]. The resulting tricyclic ­ system of the cyclopenta[b]indoles is a useful structural fragment in various biologically active indole diterpenoids. In 2016, Csákÿ and coworkers developed the ring-opening of cyclopropane1,1-dicarboxylates with the in situ-generated electron-deficient trivalent boron species, which was promoted by trifluoroacetic anhydride (TFAA) from boronic acids and potassium organotrifluoroborates under metal-free conditions. Electrophilic activation formed by the in situ-formed boron species may occur by coordinating with one of the ester groups of the cyclopropane, followed by the internal nucleophilic attack to form the ring-opening product. The in situ-generated boron species could be considered as synthetic equivalents of alkenyl, alkynyl, and allyl carbon

10.2 Metal-Free lectrophilic Activation of D–A Cyclopropanes

CO2Me

R1 R2 N Ts

OMe

MeO2C

BF3•Et2O CO2Me CH2Cl2 4 Å MS, rt

O

MeO2C

BF3•Et2O

H migration

R1

R1

NTs

R2

CO2Me

NTs

R2 AdE

BF3•Et2O MeO

MeO2C

O

R1

CO2Me

MeO2C

CO2Me

SEAr

R2

R1 R2

CO2Me

MeO2C

N Ts

NTs

R1

CO2Me N Ts

NTs

R1 R2

Entry

Product

R1

R2

Time (min)

Yield (%)

1

17a

H

H

100

85

2

17b

Cl

H

100

76

3

17c

Br

H

90

72

4

17d

CN

H

210

35

5

17e

H

F

120

74

6

17f

H

Cl

120

70

Scheme 10.11

17a-f

R2

BF3 · Et2O-promoted [3 + 2] cyclodimerization of D–A cyclopropanes.

nucleophiles, producing the corresponding ring-opening products (18) in good yields (Scheme 10.12) [18]. Besides the direct electrophilic activation of D–A cyclopropane by Brønsted acid or Lewis acid, an alternative masked D–A strategy via electrophile-induced C─C bond activation of vinylcyclopropanes was developed by Chandrasekaran and coworkers (Scheme 10.13) [19]. An in situ-generated electrophilic bromine acted on the double bond of the vinylcyclopropane to form a π-complex, which could be considered as a D–A cyclopropane analog to accept the attack of a nucleophile leading to the ringopening product. Treatment of chloramine-T with a catalytic amount of phenyltrimethylammonium tribromide (PTAB) resulted in the in situ generation of an interhalogen compound like BrCl, which was usually used as the electrophilic activation catalyst. By applying the masked D–A strategy, Chandrasekaran and coworkers explored several tandem annulation reactions of vinylcyclopropanes bearing a donor group for the synthesis of various bicyclic amidines and Z-alkylidenetetrahydrofurans.

309

310

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases R-B(OH)2 R-BF3K R-BF3K or or + + + BF3 TFAA TFAA

Ar

CO2Me

Ar

R-BX2

H R

CO2Me

H

X

CO2Me OMe B

Ar

+

H

CO2Me

CO2Me 18 Ar = Electron-donor R = Alkenyl, Alkynyl, Allyl R

O X

Selected examples Ph CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

S

CO2Me

OMe OMe

OMe 18b 82%

18a 94%

18c 85%

Ph

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me OMe

OMe

OMe OMe

OMe 18d 65%

18e 75%

18f 81%

Scheme 10.12 The in situ-formed boron species promoted ring-opening of D–A cyclopropanes. D

E

Nu

Olefin activation

D

E D

E

Nu

π-complex D–A Cyclopropane analog

Chloramine-T + PTAB OH EtO Br X (π-complex)

Scheme 10.13

Br-X X = Cl, Br or Nu

OH EtO

Br X

(π-complex)

Electrophile-induced C─C bond activation of vinylcyclopropanes.

In 2011, they reported a tandem ring-opening/cyclization of vinylcyclopropane derivatives with various cyanides through a Ritter-type rearrangement to give enantiomerically pure [4.4.0] and [4.3.0] bicyclic amidine derivatives (19) in good yield

10.2 Metal-Free lectrophilic Activation of D–A Cyclopropanes

(Scheme 10.14a) [19, 20]. In 2013, they demonstrated a highly diastereoselective synthesis of Z-alkylidenetetrahydrofurans (20) from a variety of vinylcyclopropanes bearing a hydroxyl group. A plausible mechanism has been presented explaining the Z-selectivity observed during the product formation (Scheme 10.14b) [21].

Scheme 10.14

Reaction of vinylcyclopropane with chloramine-T. Ts = p-toluenesulfonyl.

An alternative strategy of metal-free electrophilic activation of D–A cyclopropanes was developed in the concept of iminium–enamine activation to form the highly electrophilic three-membered ring intermediate, which was attacked by the nucleophilic reagent and then the electrophilic reagent, successively. In this type of reaction, cyclopropanes bearing an aldehyde group are essential, and chiral secondary amines served as catalysts to promote the ring-opening of cyclopropanes (Scheme 10.15). In 2011, Gilmour and Sparr reported the first cyclopropyl iminium activation of D–A cyclopropanes for the asymmetric synthesis of 1,3-dichlorides (22) in an enantioselective desymmetrization of meso-cyclopropanecarbaldehyde compounds (21). A variety of secondary amine organocatalysts could promote this reaction, and the first-generation MacMillan catalyst (Cat.-1) was found to be the best one.

311

312

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

O

R

NR'2

HNR'2 R R

NR'2 Nu

R * * R Nu

R

E

E *

NR'2

R * * R Nu

Iminium–enamine activation

Scheme 10.15

Iminium–enamine activation of D–A cyclopropanes.

Reagents A and B were employed as the sources of Cl− and Cl+, respectively. Several meso-cyclopropanecarbaldehydes could work well in this reaction system, leading to the optically active 1,3-dichloraldehydes in good yields with up to 96:4 enantiomeric ratio (er) and up to > 95:5 diastereomeric ratio (dr) (Scheme 10.16) [22]. A

CHO R

NR'2

Cl

Cat.-1·TFA (20 mol %)

R

B

R

CDCl3 RT

R

R

Cl CHO

Cl R 22

21

Entry

Product[b]

Substrate CHO

1

H

2

H

Cl

CHO

Cl

H

Me

Me

Et

A

86 : 14

92 : 8

70

89 : 11

86 : 14

72

84 : 16

95 : 5

68

91 : 9

93 : 7

67

96 : 4

> 95 : 5

CHO

CHO

Cl nPr Ph Cl

CHO Ph O

–

+

68

Cl

Cl

Ph

N H

CHO

nPr Cl

Me Me

94 : 6

Et

nPr

Ph

91 : 9

CHO

Et

CHO 6

70

Cl

Cl

Et

nPr

CHO

Me

CHO 5

d.r.

Cl

Cl

CHO 4

H

e.r.

Me Cl

CHO 3

H

H

Yield[%][c]

Cl Me

Cl

Cl Cl Cl

Cl Cl B

O Me N Me H Bn N Me H Cat.-1

Scheme 10.16 Iminium activation of D–A cyclopropanes for the asymmetric synthesis of 1,3-dichlorides

10.3 Metal-Free NNcleophilic Activation of D–A Cyclopropanes

In 2016, Werz and coworkers developed another cyclopropyl iminium activation reaction of meso-cyclopropyl carbaldehydes. Sulfenyl and selenyl chlorides were employed as both the nucleophilic and the electrophilic reagents to give the corresponding 1,3-bisfunctionalization products (23) bearing three adjacent stereocenters in 42–84% yields with up to 93:7 e.r. and 15:1 d.r. in complete regioselectivity (Scheme 10.17) [23]. 1)

Ph

H

RXCl (X = S, Se)

Selected examples Product Cl

H

S(p-C6H4OMe) CH2OH

Cl

Cl

H

XR CH2OH

2) NaBH4, EtOH, –4°C 23

Yield [%]

d.r.

e.r.

63

5.7 : 1

87 : 13

70

5.2 : 1

81 : 19

65

2.1 : 1

71 : 29

(23b)

Ph H

N H

(23a)

Ph STol CH2OH

Cl

Me N

·DCA EtOAc, –4°C

CHO H

O

STol CH2OH (23c)

O

Scheme 10.17 Iminium activation reaction for the asymmetric synthesis of 1,3-bisfunctionalization products.

When a nitro group was introduced in the D–A cyclopropane as an acceptor group, the urea catalysis based on hydrogen bonding activation of D–A cyclopropane was developed by Mattson and coworkers. In 2012, boronate urea was employed as a catalyst for the activation of nitrocyclopropane carboxylates (24) in the nucleophilic ring-opening reactions with various amines, generating a wide range of γ-amino nitro esters (25) in 58–99% yields (Scheme 10.18a) [24]. In 2013, they developed formal [3 + 3] cycloaddition reaction of nitrocyclopropane carboxylates with nitrones via the same hydrogen bonding activation strategy with a urea catalyst (Scheme 10.18b) [25]. This method provided an efficient approach to a large family of highly functionalized oxazinanes (26) in 25–99% yields.

10.3 Metal-Free Nucleophilic Activation of D–A Cyclopropanes In contrast to the electrophilic activation approaches based on lowest unoccupied molecular orbital (LUMO) lowering strategies using Lewis acids or Brønsted acids, the nucleophilic approach for activation of cyclopropanes is based on a highest

313

314

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases R'NH2 Urea cat. (10 mol%)

NO2

CH2Cl2, CF3CH2OH 23 °C, 48 h R

R NO2 CO2Me

OMe

O

(a) 25

NHR'

12 examples, 58–99% yields

24

Urea cat. (15 mol%)

Ph

toluene, 80 °C, 24 h

R'

O R'

N

Ph

N

O

R (b)

O2N CO2Me 26 14 examples, 25–99% yields

H CF3

BF2 O N H O

N CF3 H Urea cat. N

O CO2Me

Ph

Scheme 10.18

Urea catalysis based on hydrogen bonding activation of D–A cyclopropane.

occupied molecular orbital (HOMO)-raising strategy. In this field, many different electrophilic activation strategies have emerged, including direct abstraction of the α-hydrogen of a carbonyl group with base, as well as enamine-activation for D–A cyclopropanes bearing an aldehyde unit (Scheme 10.19). R H

O

O EWG EWG

Base

R

H

N H

N R

EWG EWG

Base

Brønsted base activation

Scheme 10.19

EWG EWG Enamine-activation

Metal-free nucleophilic activation of D–A cyclopropanes.

In 2009, Jørgensen and coworkers reported an organocatalytic asymmetric desymmetrization of diethyl 3-oxobicyclo[3.1.0]hexane-6,6-dicarboxylate (27), involving a metal-free nucleophilic activation of D–A cyclopropane with quinidine-derived thiourea catalyst (cat.-2). Cyclopentenone (28) was obtained in an 84% yield with a 96% enantiomeric excess (ee) (Scheme 10.20) [26]. A direct D–A cyclopropane activation strategy based on the abstraction of α-hydrogen from ketones by a Brønsted base was developed by Jørgensen and coworkers. This type of activation was found to be more suitable for di-cyano-substituted cyclopropylketones than di-ester ones, because in the di-cyano system, an increased polarization of the labile carbon–carbon bond was determined by 13C NMR experiment, as well as the more stabilized anion from the ring-opening of the di-cyano cyclopropane according to the pKa values of the related acids (Scheme 10.21) [27].

10.3 Metal-Free NNcleophilic Activation of D–A Cyclopropanes

O

O

N

cat.-2 (10 mol%)

MeO

H N

Ar

S

CO2Et

CH2Cl2 EtO2C

EtO2C CO2Et 27

N Ar = 3,5-(CF3)2C6H3

28 84% yield 96% ee

Scheme 10.20

H H N

cat.-2

Quinidine-derived thiourea catalyzed ring-opening of D–A cyclopropane. CN CN

CO2Me CO2Me R

R

O EWG EWG

H

Base

O EWG EWG

H

Less polarized C—C bond

More polarized C—C bond

Base Brønsted base activation

MeO2C

CH2O2Me

Less stablized anion

Scheme 10.21

NC

CN

More stablized anion

Brønsted base activation of D–A cyclopropanes.

In 2017, Jørgensen and coworkers developed a metal-free direct activation of D–A cyclopropanes with Brønsted base catalysis (cat.-3) in the [3 + 2] cycloaddition reaction of di-cyano cyclopropylketones (29) with mono- and polysubstituted nitroolefins, providing functionalized cyclopentanes with three contiguous stereocenters (30) in yields up to 98% with >20 : 1 d.r. and up to 91% ee. A proposal for a mechanistic pathway that explains the high stereoselectivity, as well as chemoselective transformations of optically active cyclopentanes, was also demonstrated in their studies (Scheme 10.22) [27]. O R1 O

NC CN

NO2 + R2

R1

cat.-3 (20 mol%)

R4

NC NC

R3 29

O2N

S N H

N H

N

NO2 R4 R2 R

3

30 up to 98% yield up to 91% ee >20 : 1 dr

cat.-3

Scheme 10.22 nitroolefins.

[3 + 2] cycloaddition reaction of di-cyano cyclopropylketones with

In 2022, Jørgensen and coworkers developed a chiral Brønsted base activated ringopening of D–A cyclopropanes in a formal [8 + 3] cycloaddition of di-cyano cyclopropylketones (29) with tropone. This nucleophilic activation strategy employed a bifunctional thiourea (cat.-4) bearing a tertiary amine moiety as a catalyst; a broad

315

316

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

scope of D–A cyclopropanes was well tolerated, leading to the desired cycloadducts (31) in moderate-to-good yields with good-to-excellent enantioselectivity (Scheme 10.23) [28]. R O O

NC CN

O

cat.-4 (20 mol%) +

TCE/CH2Cl2 (2 : 1 v/v) –10 °C

R 29

CN NC 31

S Ar

N H

O

N H

NMe2 Ar=4-(NO2)C6H4 cat.-4 Chiral brønsted base

Selected examples Me R=

Me

76% 90% ee

Cl

Me

83% 90% ee

78% 92% ee

F

52% 86% ee

Scheme 10.23

70% 90% ee Me

51% 85% ee

Me

78% 93 : 7 dr

Formal [8 + 3] cycloaddition of di-cyano cyclopropylketones with tropone.

Another type of metal-free nucleophilic activation of D–A cyclopropanes was developed by Wang and coworkers. Such type of activation is characterized by carbonyl-substituted D–A cyclopropanes with an α-hydrogen atom on the strained ring, which are likely to undergo ring-opening rearrangement to form the anionic intermediate A or B under basic conditions (Scheme 10.24a). In 2016, they reported a [3 + 2] cycloaddition of D–A cyclopropanes with aldehydes in the presence of 1.0 equiv. of DABCO as base under solvent-free conditions. This method allowed efficient preparation of various fully substituted furans from corresponding D–A cyclopropanes (32) with both aromatic and aliphatic aldehydes in yields up to 98% over 24 examples (33) (Scheme 10.24b) [29]. In 2020, they developed ring-opening reactions of the same type of D–A cyclopropanes with various haloalkanes by employing DBU as a base, leading to a wide range of functionalized chalcones (34) containing a quaternary carbon group in up to 94% yield (Scheme 10.24c) [30]. Jørgensen and coworkers developed a metal-free enamine-activation of cyclopropanes, in which the donor moiety of a D–A cyclopropane is in situ formed via ­condensation with a chiral secondary amine to generate an enamine intermediate. Computational studies revealed that the C1─C2 bond length of the cyclopropane was obviously elongated by the formation of the enamine intermediate.

10.3 Metal-Free NNcleophilic Activation of D–A Cyclopropanes

EWG

EWG

Ar2

Ar2

Ar1

Ar O

O

EWG

EWG

EWG

EWG

Ar2

Ar1

H

O

EWG

1

EWG Ar1

Ar2 O

A

(a)

B

base R2 O

DABCO Solvent-free

O + (R)Ar

CN CO2Et R1

H

NC

R1

24 examples up to 98%

(R)Ar

Ar CN CO2Et

Ar'

R2

33

32

O

(b) O

+

H NC R

DBU RX

80 °C

CO2Et

Ar O

(X = Cl, Br, I)

(c)

Ar'

34 26 examples up to 94%

32

Scheme 10.24

Brønsted base activation for carbonyl-substituted D–A cyclopropanes.

Especially, when the cyclopropane bearing two acceptor groups, the C1─C2 bond length was elongated from 1.517 Å to 1.559 Å, indicating that the enamine-activation strategy was very effective (Scheme 10.25) [31]. By applying of this enamine-activation strategy, Jørgensen and coworkers demonstrated the enantioselective formal [2 + 2] cycloaddition reactions of D–A

O

N H EWG EWG

N

EWG EWG R1, R2

C1–C2 bond length (Å)

O 1 3

2

R1 R2

N 1 3

2

R1 R2

Scheme 10.25

R1, R2 = H, H

1.506

R1, R2 = H, CO2Me

1.512

1,

R

R2 =

CO2Me, CO2Me

1.517

R1, R2 = H, H

1.509

R1, R2 = H, CO2Me

1.530

R1, R2 = CO2Me, CO2Me

1.559

Enamine-activation of cyclopropanes.

317

318

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

cyclopropanes (35) with 3-olefinic oxindoles (36) or benzofuranones (36′), using trimethylsilyl (TMS)-protected prolinol (cat.-5) as a catalyst, resulting in multifuctionalized spirocyclobutaneoxindoles (37) or spirocyclobutanebenzofuranones (37′) in good yields, with good-to-excellent diastereoselectivity and excellent enantioselectivity (Scheme 10.26) [31]. EtO2C 1) cat.-5 (10 mol%) MeO2C PhCO2H (10 mol%) CHCl3, –20 °C MeO2C

O

O R1

X

+ CO2Me CO2Me

2) Ph3PCHCO2Et CHCl3, rt

R2

N H

X = NBoc, O Selected examples:

37/37'

EtO2C MeO2C

MeO2C

MeO2C O

MeO2C PhOC

NBoc

R2

OTMS cat.-5

EtO2C

EtO2C

X

R1

Ph Ph

36/36'

35

O

O

MeO2C PhOC

O

MeO2C

NBoc

NBoc

PhOC

Cl 37a 80% yield 10.0 : 1 d.r., 95% ee

37b 79% yield 9.0 : 1 d.r., 97% ee

37c 86% yield 11.0 : 1 d.r., 97% ee

EtO2C

EtO2C O

MeO2C MeO2C MeO2C

O NBoc

37d 70% yield 5.1 : 1 d.r., 95% ee

MeO2C

MeO2C MeO2C (EtO)2OP

O NBoc

37e 76% yield 11.1 : 1 d.r., 75% ee

MeO2C PhOC

O O

37'a 73% yield 13.4 : 1 d.r., 93% ee

Scheme 10.26 Enantioselective formal [2 + 2] cycloaddition reactions of D–A cyclopropanes.

By employing the enamine activation strategy to activate the D–A cyclopropane, in 2016, Vicario, Reyes, and coworkers developed the synthesis of highly enantioenriched pyrrolo[1,2-a]quinolones (38) via a domino cyclopropane ring-opening/azaMichael/aldol reaction, followed by acid-promoted lactamization, and 48–86% yields with 75–97% ee were obtained (Scheme 10.27) [32]. In 2017, a nucleophilic activation of D–A cyclopropane in the presence of an N-heterocyclic carbene catalyst (cat.-6) was developed by Vicario, Reyes, and coworkers, which enabled the formal [4 + 2] cycloaddition of formylcyclopropanes with alkylideneoxindoles, resulting in yields up to 99% with up to >99% ee (Scheme 10.28) [33].

10.4 Catalyst-Free Activation of D–A Cyclopropanes cat.-5 (20 mol%) p-NO2-PhCO2H (20 mol%)

O O

+ R

H

R

OHC

Ph Ph N H

O N

CHCl3, rt, then AcOH, reflux

NH2

CO2Et CO2Et

EtO2C

38 48–86% yields 75–97% ee

OTMS cat.-5

Scheme 10.27 Enamine activation of D–A cyclopropane for the synthesis of pyrrolo[1,2-a]quinolones. Donor EtO2C EtO2C

CHO

cat.-6 (10 mol%) iPr NEt (20 mol%) 2

H O N H

N N Ar

Acceptor EtO2C

N EtO2C EtO2C

X cat.-6 Ar = Mes, X = BF4

N

OH

EtO2C

N Ar

N N Ar

N

OH

R1 CO2Et R2

EtO2C R1 O O

R2

N PG

O N PG Formal [4 + 2] cycloaddition

EtO2C EtO2C

N

N N Ar

O

39 up to 99% yield >99% ee

Scheme 10.28 cyclopropane.

N-heterocyclic carbene-promoted nucleophilic activation of D–A

10.4 Catalyst-Free Activation of D–A Cyclopropanes Kerr and coworkers developed a new mode of metal-free activation for D–A cyclopropanes. By employing cyclopropane hemimalonates as substrates, the intramolecular hydrogen bond forced coplanarity of the hemimalonate carbonyls that facilitated the nucleophilic ring-opening of the D–A cyclopropanes under highpressure conditions (Scheme 10.29).

NuH

R

H O

Scheme 10.29 Cyclopropane hemimalonates promoted ring-opening of D–A cyclopropanes. O O

H

MeO

In 2011, they reported a non-catalytic reaction of cyclopropane hemimalonate (40) with indole as a nucleophile under high-pressure (13 kbar) conditions at 50 °C. A variety of indoles with different substituents were compatible with this reaction.

319

320

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

Both aryl and heteroaryl-substituted cyclopropanes were well-tolerated and produced the corresponding ring-opening products (41) in good yields. Fifteen examples with 50–97% yields were demonstrated (Scheme 10.30) [34]. R2

R2

R1

+

N H

CO2H

50 °C/13 Kbar

CO2Me CO2H

CO2Me

CH3CN

NH

R1

40

41 15 examples 50–97% yields

Selected examples: HO2C

CO2Me

CO2H

CO2H

CO2Me Me

NH

N H

41a 87% yield

CO2Me

Me

Br

NH

41b 97% yield

41c 67% yield

MeO CO2H

CO2H

CO2Me NH 41d 65% yield

Scheme 10.30

CO2H

S

CO2Me NH 41e 72% yield

CO2Me NH 41f 50% yield

A non-catalytic reaction of cyclopropane hemimalonate with indole.

In 2012, Kerr and coworkers developed a tandem ring-opening decarboxylation of cyclopropane hemiaminoglycate with sodium azide at 125 °C, furnishing 4-azido carboxylic acid esters (42) in moderate-to-excellent yields (Scheme 10.31) [35]. A possible involvement of an acyl azide mechanism, including a [3,3]-sigmatropic rearrangement to yield a ketene intermediate, was proposed. An SN2′ ring-opening process proved that an optically enriched phenyl cyclopropane (90% ee) underwent this transformation to give the ring-opening product with full retention of enantiopurity. This catalyst-free method provided a technically simple approach for the nucleophilic ring-opening of cyclopropane hemimalonates under ordinary pressure. In 2014, by delicate designing of the substrate to introduce an alkynyl moiety, they developed a catalyst-free tandem ring-opening/click reaction of cyclopropane1,1-hemimalonate (43) with sodium azide, providing a facile access to various interesting linear tricyclic triazoles (44) in 30–80% yields (Scheme 10.32) [36]. In 2013, Kerr and coworkers demonstrated a catalyst-free tandem reorganization/ dealkoxycarbonylation reaction of D–A cyclopropane hemimalonate under microwave irradiation at 150 °C, leading to a facile synthesis of γ-substituted butanolides (12 examples, 39–90% yields). The retention of stereochemistry in this transformation enabled the total synthesis of the natural product (R)-dodecan-4-olide in a fourstep 67% overall yield from enantioenriched dimethyl ester vinyl cyclopropane (Scheme 10.33) [37].

10.4 Catalyst-Free Activation of D–A Cyclopropanes R

NaN3, NH4Cl

CO2Me CO2H

CO2Me 42 12 examples, 46–95% yields

40

CO2Me O

R

N3

MeOCH2CH2OH H2O, reflux

N N N

R

R

CO2Me

N3

C

O

H2O

R

CO2Me

N3

CO2H

Selected examples: N3

N3

N3 CO2Me

CO2Me MeO

CO2Me NC

42a 78% yield, 90% ee

42b 95% yield

42c 56% yield

CO2Me

N3

N3

N3

CO2Me

CO2Me O

S

N Ts

42e 79% yield

42d 63% yield

Scheme 10.31 sodium azide.

42f 63% yield

Ring-opening decarboxylation of cyclopropane hemiaminoglycate with

NaN3 (1.2 equiv.) NH4Cl (1.4 equiv.) R CO2Me CO2H

N N N

MeOCH2CH2OH-H2O 10 : 1

CO2Me 44 8 examples, 30–80% yields

43

N3 HO2C

R

R2

CO2Me

N3

R2

CO2Me

Selected examples: N N N

CO2Me

44a 80% yield

N N N

44b 77% yield

CO2Me

N

N N N

CO2Me

44c 30% yield

Scheme 10.32 Tandem ring-opening/click reaction of cyclopropane-1,1-hemimalonate with sodium azide.

321

322

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases O

R

LiCl, Me3N•HCl CO2Me CO2H DMF, 150 °C, μW

O

O

O

R 45 12 examples 39–90% yields (R)-dodecan-4-olide

40

Scheme 10.33 Reorganization/dealkoxycarbonylation reaction of D–A cyclopropane hemimalonates.

In 2005, Charette and coworkers developed a catalyst-free ring-opening of 1-nitro1-cyclopropyl ketones, a D–A cyclopropane (46) bearing two strong acceptors, with primary amines, followed by intramolecular condensation of the ring-opening products to yield dihydropyrroles (47) (Scheme 10.34) [38]. By using another electron-withdrawing group as an acceptor such as the cyano group, the reaction was also tolerated, leading to the corresponding 4-cyano-dihydropyrroles in good-to-excellent yields. R1

R2 N R

R1

EWG + R2-NH2 COR

Toluene, reflux

EWG 47

4–15 h

18–99% yields

EWG = NO2, CN 46 R1 R2HN

EWG COR

R1

R2 N OH R EWG

R = Me, n-propyl, Ph, c-C3H5 R1 = Ph, 4-F-C6H4, 1-naphthyl, phenethyl R2 = Ph, allyl, benzyl, t-Bu, 4-Cl-C6H4, 4-MeO-C6H4, et al.

Scheme 10.34

Catalyst-free ring-opening of 1-nitro-1-cyclopropyl ketones.

In 2008, Charette and coworkers reported a nucleophilic ring-opening of methyl 1-nitrocyclopropanecarboxylates with phenoxyanions in situ-generated in the presence of Cs2CO3 as base (Scheme 10.35) [39]. The reaction was compatible with a variety of substituents on both the phenols and the cyclopropanes, providing the ring-opening products in 53–84% yields. When entantio-enriched cyclopropanes were employed, complete preservation of the enantiomeric excess at C4 was observed. R2 O R1

NO2 + R2 CO2Me 24 90–95% ee

OH Cs2CO3 (2.5 equiv.) THF, 65 °C, 12 h

R1

4

NO2 2

CO2Me

48 53–84% yields 90–95% ee

Scheme 10.35 Nucleophilic ring-opening of methyl 1-nitrocyclopropanecarboxylates with phenoxyanions.

10.4 Catalyst-Free Activation of D–A Cyclopropanes

In 2015, Budynina, Trushkov, and coworkers developed a catalyst-free ringopening of D–A cyclopropanes with sodium azide, delivering a broad scope of polyfunctional azides (49) in up to 91% yield (Scheme 10.36) [40]. It is noteworthy that in this reaction for certain D–A cyclopropanes, the introduction of indolyl groups as the donor moiety or nitro group or diketone group as the acceptor moiety, high reaction temperatures were not required. DFT calculations indicate that the optimized transition state corresponds to an SN2-like mechanism, while the nucleophilic attack on the unsubstituted C3 atom has a significantly higher energy barrier than the donorsubstituted C2 atom. In the application of this method, five-, six-, and seven-membered N-heterocycles were synthesized with high diversity, including the total synthesis of (−)-nicotine as well as the formal total synthesis of atorvastatin.

Ar

EWG

NaN3, Et3N•HCl

EWG'

DMF, Δ

N3 Ar

Azide N3

CO2Me CO2Me

N3

Ph

CO2Me

N3

Ph

100

4

88

100

2

80

100

4

75

50

3

91

55

2

76

90

1

90

25

6

85

(49b)

(49c)

(49d)

CO2Et NO2

(49e)

CO2Et COiPr (49f)

4-FC6H4

N3

Yield [%]

(49a)

CO2Me

N3

t [h]

CO2Me

NBn

Ph

T [ °C]

CO2Me

O

N3

Atorvastatin

CO2Me CO2Me

N3

(–)-nicotine

EWG'

49 32 examples 43–91% yields

Selected examples:

Ph

EWG

O (49g) O

Scheme 10.36

A catalyst-free ring-opening of D–A cyclopropanes with sodium azide.

In 2018, Budynina and coworkers developed a catalyst-free ring-opening reaction of D–A cyclopropane (50) with cyanate ion as a fresh N-nucleophile under microwave irradiation at 150 °C (Scheme 10.37) [41]. The substrate scope of this method

323

324

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

R'' O

R N R'

H N

1. KNCO (2 equiv.) Et3N·HCl (1 equiv.) DMF, 150 °C (mW.)

R

2. KNCO (2 equiv.) DMF, 150 °C (μW)

O N R'

50

51

H N

R''

O

R

O N PMB

R = Me R'' = Ph 10 h, 63% yield

R''

O

1 : 1 dr

R=F R'' = Ph 120 min, 64% yield

R = Cl R'' = Ph 100 min, 50% yield

R=F R'' = 4-EtO2CC6H4 120 min, 42% yield

R = Br R'' = Ph 100 min, 63% yield

Scheme 10.37 Catalyst free ring-opening reaction of D–A cyclopropane with cyanate ion.

was broad with various substituents involved in the oxyindole and the cyclopropane units, furnishing the interesting spiro[pyrrolidone-3,3′-oxindoles] skeleton (51) in good yields but with poor diastereoselectivity. In 2016, Chandrasekaran and co-workers demonstrated a series of catalyst-free ring-opening reactions of D–A cyclopropanes in the presence of benzyltriethylammonium tetrathiomolybdate {[BnNEt3]2MoS4} as the sulfur transfer reagent at room temperature under ordinary pressure. Various sulfur-containing molecules such as symmetrical disulfides (52), monosulfides (53), unsymmetrical disulfides (55), and so on were synthesized under mild reaction conditions (Scheme 10.38) [42]. R

2(

S

Ar

NO2

52 3 examples 50–70% yields

ArS-SAr Ph3P, NBS CHCl3, r.t., 3 h R = H, Me, Br

Ph O

S

NO2 CO2Et

54 60% yield

EWG

EWG

R

R

S

EWG

EWG MeCN r.t., 2–7.5 h EWG = CN, CO2Et 53 CONH2, Ac 7 examples Rϒ⌈= H, CN, Cl, NO2 55–75% yields

+ [MoS4]2–

Ar

PhCOOH

ArCH2S-SCH2Ar

Ph3P, NBS CHCl3, r.t., 5 h

MeCN, r.t., 3.5 h R = H, Me, Br Rϒ⌈= H, OMe, Me, Cl

R

S

S

NO2 CO2Et

55 6 examples 50–75% yields

Scheme 10.38 Catalyst-free ring-opening of D–A cyclopropanes in the presence of [BnNEt3]2MoS4.

In 2021, Ofial and coworkers studied the kinetics of the ring-opening reactions of D–A cyclopropanes with thiophenolates in DMSO at 20 °C (Scheme 10.39) [43]. Parabolic Hammett relationships were observed, verifying the electronic properties of substituents on the phenyl groups of cyclopropanes, suggesting that the inherent SN2 reactivity of electrophilic cyclopropanes is activated by electron-rich π-systems owing to the more advanced C─C bond polarization in the transition state. Conversely, ­ electron-poor π-systems facilitate the attack of anionic nucleophiles due to attractive electrostatic interactions, resulting in a lowering of the energetic barriers.

10.4 Catalyst-Free Activation of D–A Cyclopropanes H,Ar S X

Acc Acc

Ar

+

DMSO, r.t.

Acc S

aq.workup

M

56

X H,Ar

Acc

Acc S

Acc

M

X

SAr H

δ-

A

A

δ+

SAr H

A

δ+

A

or

δ-

δ+

EDG

EDG

Attractive electrostatic interactions

Enhanced C—C bond polarization

Scheme 10.39

Ring-opening reactions of D–A cyclopropanes with thiophenolates.

In 2009, Werz and coworkers developed a new approach in the synthesis of ­anti-fused oligoannelated tetrahydrofuran (THF) (57) via a synthetic sequence of cyclopropanation/reduction/oxidation/ring-opening rearrangement of D–A cyclopropanes (Scheme 10.40a) [44]. The key step is the ring-opening rearrangement of cyclopropane, which relied on the elaborate design of in situ formation of the cyclopropane bearing both strong electron-push and electron-pull substituents in a highly strained three-membered ring. In 2013, a similar strategy was applied to the synthesis of bisthiophenes (58) by Werz and coworkers (Scheme 10.40b) [45]. With Lawesson’s reagents, the ketone moieties were converted into the thiocarbonyl acceptor, which could favor the immediate ring-enlargement process by heating [46]. H N2CHCO2Et

O

H

H

EtO2C

[Cu]

CO2Et H

O

H

OH

LiAlH4 HO

H

O

H

H H

H

H

O H

O

H

O

IBX

H

O

O

H O O

O

HHHH H H HH

H

H

O

HH

H

O H

R

H

H

H

– H 2O

O

Lawesson's R reagent H

Δ

O

R

S S 58

Scheme 10.40 THF unit.

H

S R

H

H O

R H

S

HH

R S H

O

H O H

(a)

O O H

O 57

O

O

R S H

(b) R

Catalyst free ring-opening rearrangement of cyclopropane based on a

325

326

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

The study on of D–A cyclopropanes dates back to the 1990s. Pioneered by Pirrung and coworkers, a rhodium-catalyzed cyclopropanation of diazo-1,3-dione (59) with dihydrofuran was conducted, followed by a spontaneous ring-enlargement to furnish the racemic bicyclic acetals (60) (Scheme 10.41a) [47]. Müller and coworkers explored the asymmetric version of this reaction but only obtained moderate levels of ee value (Scheme 10.41b) [48–50]. O

O

O N2

59

O

O Rh2(OAc)4

O

O

(a)

O

O

60 84% yield

CO2Me N2 O

CO2Me *

O

Chiral Rh cat.

*

MeO2C

O * O

O

MeO2C *

*

(b) O * O

O

Moderate ee

Scheme 10.41

Spontaneous ring-enlargement of D–A cyclopropanes.

In 2020, Tang, Wang, and coworkers reported a highly enantioselective synthesis of various chiral heterobicyclic molecules, including fused bicyclic acetals and spiroaminals under mild reaction conditions, involving spontaneous ringenlargements of in situ-generated D–A cyclopropanes [51]. The donor unit of this type of D–A cyclopropane was expanded from oxygen-based moiety such as THF to nitrogen-based moiety such as pyrrolidine. An extremely broad substrate scope was developed, leading to 23 examples of fused bicyclic acetals (61) in up to 91% yield with up to 99% ee, as well as diverse chiral spiroaminals (62) in up to 99% yield with up to 96% ee (Scheme 10.42). R2

n

X

R3 X

R2 R1

*

X

*

R1 O

R3 X = O; NTs;

1 R3 R

(a)

61 23 examples up to 91% yield up to 99% ee

chiral Cu cat. N2

O

n

2 * R O

n

n = 1,2,3

n

N Ts n = 1,2

n

N Ts

*

R2 O *

R1

R2 (b)

n

N O Ts

R1

62 10 examples up to 99% yield up to 96% ee

Scheme 10.42 Spontaneous ring-enlargement of D–A cyclopropanes in an enantioselective process.

10.5 Metal-Free Activation of D–A Cyclopropanes via Radical, S E, and Photopromoted Process

For donor-substituted nitrocyclopropanes, the immediate ring-enlargement could occur in mild conditions (25 °C). In 2013, Werz and coworkers reported a rhodiumcatalyzed cyclopropanation of donor-substituted alkenes with α-diazo-α-nitro ethyl acetate, and the in situ-generated nitrocyclopropane immediately underwent the ring-enlargement to form the cyclic nitronates (63) (Scheme 10.43) [52]. Interestingly, the nitro group was inserted in all cases, while the ester group, as the other acceptor unit, was not involved in the ring-opening rearrangement process. O2N

CO2Et N2

EDG

[Rh] or [Ru]

EDG

EDG

CO2Et NO2

N O CO2Et

(EDG = OR, NR2, SR, Ar)

Scheme 10.43

O

63

Ring-enlargement of donor-substituted nitrocyclopropanes.

In 2022, Afonso, Candeias, and coworkers developed a formal [4 + 1] cycloaddition via photopromoted siloxycarbene-involved cyclopropanation/ring-opening/ annulation processes, leading to a broad range of highly functionalized cyclopentene scaffolds (64) in up to 90% yield (Scheme 10.44) [53]. DFT calculations revealed that in this metal-free process, the energy requirements for the cyclic expansion of cyclopropane to cyclopentene are similar for both diastereomeric cyclopropanes. NC

O Ar1

Si

+

CN

Ar2 CO2Et

Si

419 nm

Si O NC Ar1

CN

Ar2 CO2Et

Scheme 10.44

NC CN O Ar1

Ar2 CO2Et

64 16 examples 40–90% yields

Formal [4 + 1] cycloaddition via photopromoted siloxycarbene.

10.5 Metal-Free Activation of D–A Cyclopropanes via Radical, SET, and Photopromoted Process In 2014, Werz and coworkers developed a radical 1,3-dichlorination reaction of D–A cyclopropanes with iodobenzene dichloride (Scheme 10.45) [54]. A variety of D–A cyclopropanes (22 examples) could undergo ring-opening process to furnish the corresponding 1,3-dichloro carbonyl compounds and carboxylic acid derivatives (65) in 53–95% yields. Different acceptor groups, such as ketone, diester, and dinitrile, Scheme 10.45 Radical 1,3-dichlorination reaction of D–A cyclopropanes with iodobenzene dichloride.

327

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

worked well; however, the single ester group as acceptor proved insufficient to proceed with the ring-opening reaction. The scope of the donor groups for the D–A cyclopropanes are very wide, including aliphatic groups, oxygen-functional groups, nitrogen-functional groups, and the aromatic groups. A plausible mechanism was proposed that by thermolysis or photolysis, the homolytic cleavage of the I─Cl bond released the chloride radical, which attacked the C(sp3)─C(sp3) bond between the adjacent donor and acceptor moieties in the D–A cyclopropane, opening the strained ring and generate a delocalized radical intermediate, followed by abstracting a second chloride radical to form the 1,3-dichlorination product. In 2021, Banerjee and Werz research groups in their individual explorations discovered an electricity-driven 1,3-oxohydroxylation of D–A cyclopropanes, which provide a mild and straightforward access to β-hydroxy ketones (66) (Scheme 10.46) [55 a,b]. Under the electrochemical conditions, the anodic oxidation of D–A cyclopropane occurred, generating an arene radical cation I, which underwent a homolytic cleavage to form a ring-opening intermediate II, followed by the trapping of molecular oxygen to render intermediate III, and then generated the endoperoxide intermediate IV. IV then accepts an electron, leading to intermediate V. Finally, the 1,3-oxohydroxylation product was furnished by the deprotonation of intermediate V. The substrate scope of this reaction was studied, and 17 examples succeeded in 41–94% yields. A strong electronic effect was observed, where the electron-rich aryl groups could benefit the reactivity. In contrast, when the NO2 group was introduced, the reaction could not occur. A A

D

+

O2

CO2Me CO2Me

+

A O

Bu4NPF6, CH3CN rt, 12–24 h

O

A

D

C(+)//C(–)

I

CO2Me CO2Me

H

CO2Me CO2Me OH

O O

V

+e–

1,3-oxohydroxylated product

–e–

OH

66 17 examples 41–94% yields

D = Ar; A = CO2Me, CO2Et

Anode

328

CO2Me CO2Me

CO2Me CO2Me

O O IV CO2Me

I

Scheme 10.46

CO2Me

CO2Me

CO2Me CO2Me

O2 II

Trapping of molecular oxygen

O O

CO2Me III

Electricity-driven 1,3-oxohydroxylation of D–A cyclopropanes.

In 2021, Werz and coworkers described a general electrochemical method in the ring-opening of D−A cyclopropanes with arenes via Friedel−Crafts-type reaction (Scheme 10.47) [56]. This electrosynthesis of various γ,γ-diaryl dicarboxylic esters

10.6 ConclNsion Electrochemical SET oxidation Ar

A

via

Ar H

Ar

A

Ar

Friedel-Crafts- Ar type arylation

A

67 21 examples up to 93% yield

E E

+

Ar H

(E = CO2Me)

Anode

SN2 SET (–e–)

E

E E

E

H

Ar H

E

S N1

I

II Ar

E

III E

Rearomatization E H (from solvent)

Scheme 10.47 Electrochemical-promoted ring-opening of D−A cyclopropanes with arenes.

(67) highlights scalability with a broad reaction scope, including 21 examples in 17−93% yields. A plausible mechanism was proposed that C(sp3)−C(sp3) cleavage of the D−A cyclopropanes was promoted by the direct anodic oxidation of the strained carbocycles to radical cations, followed by the Friedel−Crafts-type reaction with electron-rich arenes.

10.6 Conclusion In summary, in the past decades, remarkable progress has been made in the field of metal-free activation of D−A cyclopropanes. Compared to the classic activation pattern of D−A cyclopropanes by means of Lewis acid catalysts, activations with protic acids result in more diverse reaction sites owing to the demand for carbocation stability. The masked D−A strategy via electrophile-induced C─C bond activation of vinylcyclopropanes provides new thoughts for the metal-free activation of D−A cyclopropanes. For D−A cyclopropanes bearing an aldehyde moiety as the acceptor unit or donor unit, the concepts of iminium activation and enamine activation bring about new opportunities in the enantioselective transformation of cyclopropanes. Studies on the catalyst-free ring-opening of D−A cyclopropanes revealed that the electric effect of the D–A system could influence the C─C bond polarization of the cyclopropane, and thus enabling the ring-opening to occur under mild reaction conditions. By elaborate substrate design, the spontaneous ring-enlargement of D−A cyclopropanes could build up interesting and complex molecular structures. The metal-free activations of D−A cyclopropanes have great vitality and promising

329

330

10 Metal-Free Activation of the Donor–Acceptor Cyclopropanes: Protic Acids, Bases

prospects from an environmentally friendly point of view. New activation patterns concerning more general and flexible D–A moieties as well as more precise control of the stereochemistry are promising research directions.

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53 Vale, J.R., Gomes, R.F., Afonso, C.A.M., and Candeias, N.R. (2022). J. Org. Chem. 87: 8910–8920. 54 Garve, L.K.B., Barkawitz, P., Jones, P.G., and Werz, D.B. (2014). Org. Lett. 16: 5804–5807. 55 (a) Saha, D., Maajid Taily, I., and Banerjee, P. (2021). Eur. J. Org. Chem. 2021: 5053–5057; (b) Kolb, S., Petzold, M., Brandt, F. et al. (2021). Angew. Chem. Int. Ed. 60: 15928–15934. 56 Kolb, S., Ahlburg, N.L., and Werz, D.B. (2021). Org. Lett. 23: 5549–5553.

333

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes Yong Xia, Xiaohua Liu, and Xiaoming Feng Sichuan University, Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Chengdu, 610064, China

CHAPTER MENU 11.1 Introduction, 333 11.2 Chiral Lewis Acid-Catalyzed Reactions of D–A Cyclopropanes, 334 11.3 Chiral Low-Valent Transition Metal Promoted Reactions of Vinyl Cyclopropanes, 343 11.4 Chiral Organocatalytic Reactions of D–A Cyclopropanes and Miscellaneous, 349 11.5 Conclusion, 355 References, 355

11.1

Introduction

Due to the ease of synthesis and high reactivity, donor–acceptor (D–A) cyclopropanes have proven to be powerful synthetic building blocks in organic synthesis. In particular, the enantioselective transformations of D–A cyclopropanes provide easy access to a myriad of optically active carbo-, heterocycles, as well as γ-functionalized carbon scaffolds, and have garnered extensive attention from the synthetic chemistry community. Due to the breaking C─C bond the three-membered ring via various pathways, the stereo-arrangement in D–A cyclopropanes might be preserved or destroyed. Thus, stereospecific transformations from optically enriched cyclopropanes, or enantioselective reactions from racemic or prochiral cyclopropanes, are two general approaches for accessing chiral targets. Efforts toward asymmetric catalytic transformations can be traced back to Scheffold and Troxler’s desymmetrization-fragmentation of meso-cyclopropanes in 1994 [1]. A decade later, an important breakthrough in chiral Ni(II)/BOX complexcatalyzed asymmetric [3 + 3] cycloadditions of nitrones and cyclopropane-1, 1-diesters, was achieved by Sibi et al., in which tetrahydro-1,2-oxazines were synthesized in good enantioselectivity but low diastereoselectivity [2]. Afterwards, Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

334

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

Tang’s group improved the diastereoselectivity of such a reaction by employing a chiral Ni(II) catalyst with an arm-side trioxazoline ligand [3], which was proven to be useful for enantioselective ring-opening of D–A cyclopropanes with a number of nucleophiles. The low-valent transition metal-catalyzed asymmetric reactions of vinylcyclopropanes (VCPs) via π-allyl-metal intermediates were introduced by the groups of Johnson, Krische, and Trost in 2011 [4, 5]. Since then, tremendous strategies of enantioselective transformations of D–A cyclopropanes have been developed and also been applied to the construction of complex molecules. Related reviews have been dedicated to this topic [6]. In this chapter, we aim to give a picture of recent advances in asymmetric catalytic transformations of D–A cyclopropanes. The developed reactions will be classified by a chiral catalyst in connection with the activation modes: Lewis acid activation (Section 11.2); low-valent transition metal catalyst activation (Section 11.3); organocatalyst activation and miscellaneous (Section 11.4).

11.2 Chiral Lewis Acid-Catalyzed Reactions of D–A Cyclopropanes Chiral Lewis acid activation occupies a preeminent position in enantioselective reactions of D–A cyclopropanes. The LUMO energy of cyclopropane can be lowered by a Lewis acid catalyst through coordination with the acceptor moiety and the chiral information is thus loaded meanwhile. Due to the fact that D–A cyclopropanes are often chiral themselves, a dynamic kinetic asymmetric transformation (DYKAT) or a kinetic resolution is usually involved in chiral Lewis acid-promoted reactions [7]. A DYKAT has an interconversion between two Lewis acid-activated diastereomeric intermediates of cyclopropanes, while there is no or much slow conversion between these two diastereomers in a kinetic resolution. Stereospecific SN2like attack by a nucleophile to the activated intermediates leads to the reversed stereocenter on the donor site of cyclopropanes.

11.2.1 Asymmetric Reactions of Two-Substituted Cyclopropane-1,1-Dicarboxylates 2-Substituted cyclopropyl diesters, as one of the most common types of D–A cyclopropane, have been widely used in enantioselective ring-opening and annulation reactions. The ring-opening of such a three-membered ring with heteroatom and electron-rich arene nucleophiles is one of the simplest and most efficient synthetic approaches to homoconjugated addition products. D–A cyclopropanes also serve as formal 1,3-zwitterions in asymmetric [3 + n] annulations, leading to enantioenriched carbocycles and heterocycles. 11.2.1.1

Ring-Opening Reactions

Taking the advantage of side-arm strategy [8], Tang and coworkers developed a Ni(II)/L1-catalyzed asymmetric reaction of cyclopropyl diesters with secondary

11.2 CCiral eeis AciidCatalyyei eactions of D–A Cyclopropanes

aliphatic amines, yielding γ-aminobutyric acid (GABA) derivatives. The introduction of an extra oxazoline group as the side arm of the chiral ligand is crucial for regulating the rate and stereocontrol of the reaction, which underwent the ringopening process in a kinetic resolution manner. Due to the steric repulsion between the donor group of the (R)-enantiomer of cyclopropane 1 and the ligand L1 (Scheme 11.1, TS2), (S)-cyclopropane was preferentially activated to perform the attack of secondary amine to deliver (R)-product 2, leaving the less-matched (R)-cyclopropane in high optical purity (Scheme 11.1) [9].

CO2R1 1

R CO2R 1 (2.2 equiv.) R: Ar, vinyl, styryl R1: CH2tBu L1

R2

N H

R3

O

H R1O

O R'' =

4 Å MS DME, 40 °C

R

H O

R3

N

2, 59–99% 80–98% ee H O

TS 2 N

O O N Cu N O O L H

N

R2

CO2R1 CO2R1

N

N

N

R2

TS 1

R'' O

L1/Ni(ClO4)2 (1.2 : 1, 10 mol%)

H R1O

OR1 H N

O O N Cu N O O L

Favored R3

R2

H N

OR1

H R3

Disfavored

Scheme 11.1 Asymmetric ring-opening of cyclopropyl diesters with secondary amines. Source: Modified from Tang et al. [9].

Direct ring-opening of cyclopropane with primary amines might be accompanied by the overreaction raised from the competitive nucleophilic attack of the formed secondary amine product. Using chiral bimetallic Lewis acid catalysis, Wang and coworkers realized an asymmetric ring-opening of cyclopropanes with primary anilines (Scheme 11.2) [10]. Optically active γ-amino acids 4 were produced in good yield and enantioselectivity by treatment with excessive racemic cyclopropanes. The combination of Y(OTf)3 and (R)-Yb[P]3 greatly enhanced both activity and enantioselectivity in comparison with employing each metal salt. This reaction was

CO2R Ar1

CO2R

3 (5.0 equiv.) R: Me, Et

+

Ar2NH

2

Y(OTf)3 (5 mol%) (R)-Yb[P]3 (10 mol%)

Ar2

H2O, 5 Å MS, 0 °C

Ar1

NH CO2R CO2R

O O P O Yb O

4, 35–93% 47–99% ee

Scheme 11.2 Asymmetric ring-opening of cyclopropyl diesters with anilines. Source: Modified from Wang et al. [10].

3

335

336

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

proposed to proceed via a two-step SN2/proton transfer mechanism, and the initial step was the rate- and enantio-determining step. Asymmetric ring-opening with oxygen-containing nucleophiles yields enantioenriched γ-hydroxybutyric acid (GHB) derivatives. Tang and coworkers successfully developed a chiral L2/Cu(II)-catalyzed ring-opening of D–A cyclopropanes with aliphatic alcohols, providing optically active GHB products 6 in high enantioselectivity. They then investigated the reaction with water nucleophiles, which is particularly challenging, as its nucleophilicity is quite weak and the obtained alcohol products can react further. Here, the Cu(ClO4)2·6H2O acted as both a Lewis acid and a buffer for the water nucleophile source. A DYKAT dominated this process for electron-rich aromatic substituted racemic cyclopropanes (Scheme 11.3) [11].

R1 R

O

CO2Ad

CO2Ad 6, 70–92% 90–96% ee

R1OH Cu(OTf)2 (10 mol%) L2 (12 mol%) R 4 Å MS, 0 °C

CO2Ad CO2Ad 5

Cu(ClO4)2•6H2O (15 mol%) L2 (18 mol%) DME, rt

OH CO2Ad R

CO2Ad 7, 70–96% 82–95% ee

O

L2

N O

O N Cy

Cy

N Cy

Scheme 11.3 Asymmetric ring-opening of cyclopropyl diesters with water and alcohols. Source: Modified from Tang et al. [11].

Carbon nucleophiles-initiated ring-opening mostly relies on Friedel-Crafts alkylations with electron-rich arenes. In 2013, Johnson et al. developed an L3/ MgI2-promoted Friedel-Crafts alkylation of cyclopropyl diesters with indoles. The use of sterically hindered and/or electronically deactivating TBS-protected indoles was important to reach high stereocontrol. Electron-rich aromatically substituted racemic cyclopropanes underwent the reaction via a DYKAT process, in which each isomer could be transformed into the product 9 through the chiral Lewis acid-mediated enantiomer interconversion. However, for less active phenylcyclopropane, the reaction was sluggish and underwent a kinetic resolution process, in which the (S)-cyclopropane consumed faster than its enantiomer (Scheme 11.4a) [12]. A desymmetrization process was involved by using meso-diaminocyclopropanes. With a modified bis(oxazoline) ligand L4/Cu(II) catalyst, chiral urea products 11 were harvested in high enantio- and diastereoselectivities by using indole or pyrrole nucleophiles (Scheme 11.4b) [13]. Wang and Guo also developed an enantioselective ring-opening reaction of aminocyclopropanes 12 with β-naphthols via a dearomatization/rearomatization sequence. C-nucleophilic opening products 13 were obtained in good yields and enantioselectivities, accompanied by O-nucleophilic ring-opening products in some cases. Anthracen-2-ol, 1,3,5-trimethoxybenzene, as well as N-methylindole, were suitable nucleophiles under this catalytic system (Scheme 11.4c) [14].

11.2 CCiral eeis AciidCatalyyei eactions of D–A Cyclopropanes

CO2Me R

+

CO2Me

N CCl4, 4 Å MS, rt R1 TBS (1.7 equiv.)

8, (1.0 equiv.) R: styrenyl electron-rich aryl

H R

MgI2 (10 mol%) L3 (12 mol%)

Cl

CO2Me CO2Me O

N TBS

R1

9, 38–96% 70–94% ee

O

N N

N L3

tBu

tBu

(a) R1

O PivN

NPiv

N or TBS

+

MeO2C CO2Me meso-10 (1.5 equiv.)

O

1 CuCl2 (20 mol%), R AgSbF6 (38 mol%)

L4 (12 mol%) toluene

PivN N

Si

N TIPS

L4

O

O

NPiv

N

N

CH(CO2Me)2 Ar Ar HO Ar Ar OH 11, 60–84% Ar: 3,5-Me2C6H3 78–93% ee

(b)

CO2Me CO2Me

R

OH

+

12 (3.0 equiv.)

Bn Bn

CH(CO2Me)2 OH

O

O N

PhCl, 4 Å MS –20 °C

SuccN

(c)

SuccN L5/Cu(OTf)2 (1.2 : 1, 10 mol%) R H

13, 71–98% 90–98% ee

tBu

N L5

t

Bu

Scheme 11.4 Asymmetric alkylation of cyclopropyl diesters with arenes.

11.2.1.2

[3 + n] Annulations

One of the most important synthetic applications of D–A cyclopropanes has been serving as 1,3-zwitterionic synthons in [3 + n] annulations, resulting in a variety of carbo- and heterocyclic products. In 2009, Johnson and coworkers developed a chiral L3/MgI2-catalyzed asymmetric [3 + 2] cycloaddition of racemic cyclopropanes 8 with aldehydes, allowing the synthesis of optically active cis-2,5-disubstituted tetrahydrofurans 14 (Scheme 11.5) [15]. The authors ascribed the high diastereoselectivity to an unusual SN2 mechanism. A DYKAT dominated the reaction for electron-rich aromatic substituted cyclopropanes, while a kinetic resolution was observed when less active phenylcyclopropane was used.

CO2Me + CO2Me R

8

L3/MgI2 (1.1 : 1, 10 mol%)

O R1

H

(2–4 equiv.)

CCl4, rt >50 : 1 d.r.

MeO2C 5

CO2Me 2

R1 R O 14, 48–92% 82–94% ee

Scheme 11.5 Asymmetric [3 + 2] cycloaddition of cyclopropyl diesters with aldehydes. Source: Modified from Johnson et al. [15].

The same group later finished an enantioselective [3 + 2] cycloaddition of (E)-aldimines with cyclopropanes. Enantioenriched 2,5-cis-disubstituted pyrrolidines

337

338

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

15 were obtained by employing a chiral L6/MgI2 catalyst via a DYKAT. Electronneutral and electron-rich aryl aldimines performed well in the reaction. However, electron-poor aryl, alkenyl aldimines, as well as aliphatic ones, were not successful substrates (Scheme 11.6a) [16].

R

L7/MgI2 (1.2 : 1, 10 mol%)

S

N

PhCl, 4 Å MS, 0 °C >20 : 1 d.r.

R

8 (2.4 equiv.) R1 R: Aryl, thienyl, styrenyl R1 CO2Me

SuccN

(c)

CO2Me +

12 (4.0 equiv.)

Scheme 11.6

N

X

R (X: S, O)

L8/Cu(OTf)2 (1.2 : 1, 10 mol%) DCM, 4 Å MS 0 °C >20 : 1 d.r.

Br

CO2Me 1

R

R N PG 15, 66–86% 86–96% ee

PG: 2-MeOC6H4CH2

CO2Me CO2Me +

(b)

CCl4, rt 6.7 : 1–11.5 : 1 d.r.

(1.1 equiv.)

8

(a)

MeO2C

L6/MgI2 (1.1 : 1, 10 mol%)

PG CO2Me N CO2Me + H R1

O

O

N N

tBu

N

L6

tBu

R

R1 N

CO2Me H CO2Me 16, 87–97% 86–97% ee

O

S

O

N N

N tBu

tBu

L7

NSucc

R N X

R1

CO2Me CO2Me

17, 40–99% 62–99% ee

O

O N

tBu

N L8

tBu

Asymmetric [3 + 2] cycloaddition of cyclopropyl diesters with C═N bonds.

Unsaturated C═N bonds in heterocycles have successfully served as dipolarophiles in [3 + 2] cycloadditions, and the dearomatization of heterocycles has led to the generation of fused-ring systems. The groups of Guo and You jointly developed a chiral L7/MgI2 complex-catalyzed dearomative [3 + 2] cycloaddition with benzothiazoles via a kinetic resolution process, yielding hydropyrrolo[2,1-b]thiazoles 16 in excellent enantioselectivities (Scheme 11.6b) [17]. D–A aminocyclopropane has also been used by the same groups in an L8/Cu(OTf)2-facilitated [3 + 2] annulation with two-substituted benzothiazole dipolarophiles. Optically active hydropyrrolobenzazoles 17 bearing quaternary stereogenic centers were obtained via kinetic resolution even using highly reactive aminocyclopropane 12. Two-substituted benzothiazoles, benzoxazoles, as well as two-unsubstituted benzimidazoles, were suitable dipolarophiles (Scheme 11.6c) [18]. Five-membered carbocycles were accessed by [3 + 2] annulations of cyclopropanes with strongly polarized C═C double bonds. Tang and coworkers developed a chiral L9/Cu(II) complex-catalyzed [3 + 2] annulation with cyclic silyl enol ethers, allowing the formation of enantioenriched [n.3.0] carbocycles 18. The key to success was the use of a steric bulky chiral ligand and large adamantyl ester groups on the cyclopropanes. The employment of TBDPS-protecting group suppressed the single ring-opening side reaction, to finally yield the desired annulated products. This [3 + 2] annulation was indeed a stepwise nucleophilic ring-opening and intramolecular cyclization sequence (Scheme 11.7a) [19].

11.2 CCiral eeis AciidCatalyyei eactions of D–A Cyclopropanes OSi

CO2Ad CO2Ad +

R

R1 1-3

5 R: thienyl, styrenyl electron-rich aryl

Si: TBDPS (1.5 equiv.)

AdO2C CO Ad 2 SiO

L9/Cu(ClO4)2 (1.1 : 1, 10 mol%) CH2Cl2 4 Å MS, 30 °C 4 : 1- >19 : 1 d.r.

R2

CO2Me

R

+ N Bn

R1

8 (1.5–3.0 equiv.)

R3

R2

toluene, 0 °C R1 3.3 : 1->19 : 1 d.r.

(b)

N

iPr

iPr L9 2 R : 3,4,5-(MeO)3C6H2CH2

18, 45–98% 91–99% ee

L10/Cu(OTf)2 (1.1 : 1, 10 mol%)

O N

R1 R

1-3

(a)

CO2Me

R2 O

R O CO2Me

N R3 CO2Me Bn 19, 45–98% 80–96% ee

R4

R4

N

N

O

L10 R4: 3,5-tBu2C6H3CH2

Scheme 11.7 Asymmetric [3 + 2] annulation of cyclopropyl diesters with enol ethers.

As illustrated in Section 11.2.1.1, acyclic ring-opened products could be obtained from three-nonsubstituted indoles, whereas the reaction of three-substituted indoles with D–A cyclopropanes led to the annulated products. Tang and coworkers described the first asymmetric variant to the synthesis of enantioenriched C2, C3-fused indolines 19 by using an L10/Cu(II) catalyst. The cagelike BOX ligand L10 with two sterically hindered tert-butyl groups at the meta-positions of the pendant benzyl groups is essential to achieve high diastereo- and enantioselectivity. The reaction was also a DYKAT with electron-rich aromatically substituted cyclopropanes and a kinetic resolution with less active cyclopropanes (Scheme 11.7b) [20]. Aminocyclopropane has been used by Waser and coworkers in copper-catalyzed asymmetric annulations with enol ethers or aldehydes through a DYKAT process, leading to enantioenriched cyclopentanes or tetrahydrofurans (20 or 21). High levels of enantio- and diastereoselectivity were observed with a broad range of dipolarophiles. Aromatic aldehydes, cinnamaldehyde, as well as aliphatic aldehydes, were well-tolerated (Scheme 11.8) [21]. CO2Me CO2Me + NSucc 12

RO

R1

or O

(2.0 equiv.)

L8/Cu(ClO4)2 (10 mol%) CH2Cl2, rt R1 3 Å MS, 1.5 : 1->20 : 1 d.r.

MeO2C CO2Me R1 OR

SuccN 20, 73–97% 89–96% ee

MeO2C or SuccN

CO2Me O

R1

21, 69–97% 82–96% ee

Scheme 11.8 Asymmetric [3 + 2] cycloaddition of aminocyclopropanes with enol ethers and aldehydes. Source: Modified from Waser et al. [21].

The asymmetric [3 + 3] annulations of D–A cyclopropanes with 1,3-dipoles are valuable tools for the synthesis of six-membered-ring systems. As early as 2005, Sibi and coworkers disclosed a chiral L11/Ni(II)-catalyzed [3 + 3] cycloaddition of nitrones with cyclopropyl diesters, resulting in enantioenriched tetrahydro-1,2oxazines 23 (Scheme 11.9a). Excellent yield and enantioselectivity were observed with activated cyclopropanes 22. However, the use of two-substituted 22 as substrates led to low diastereoselectivity [2]. Two years later, Tang and coworkers

339

340

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

R1

CO2

R2

CO2R1 R

(b)

CO2R1

+

N

L11/Ni(ClO4)2 (1 : 1, 10–30 mol%)

R4

CH2Cl2, 4 Å MS, rt

R3 (1.3 equiv.)

O

+

R2

1 (2.2 equiv.) R: vinyl, Ph, cinnamyl

R1

(c)

O

CO2 22 R, R1: H, alkyl, Ph R3: alkyl R

(a)

R2

R O

N

N

R3

R1

L12/Ni(ClO4)2 (1.1 : 1, 20 mol%) CH2Cl2, 4 Å MS, rt 4 : 1–13 : 1 d.r.

L13/Ni(OTf)2 (1.1 : 1, 10 mol%)

R3 CO2R2 CO2R2

R 23, 54–99% 71–99% ee

1 : 0.8–1 : 1.4 d.r.

O + N THF, 3 Å MS, 0 °C R2 R3 PG >20 : 1 d.r. PG: PO(OEt)2 (0.55 equiv.) 25 (1.0 equiv.)

Scheme 11.9

O

R4 N

O O

R3 N

R3 N O R1 R2 O N PG 26, 34–48% 90–98% ee

R

O

Ph L11 Ph O

L12 R2 1 CO2R O CO2R1 R N 24, 62–99% 80–97% ee i Pr O

N

N

N O N i

Pr

O

O N

N L13

Asymmetric [3 + 3] cycloaddition of cyclopropyl diesters with nitrones.

greatly improved the diastereoselectivity by using the chiral trisoxazoline ligand L12, which contained an extra pendant oxazolinyl group at the bridging carbon atom of the BOX backbone. This trisoxazoline ligand/Ni(II) catalyst was also used in the kinetic resolution of racemic 1, providing access to optically active cyclopropanes (Scheme 11.9b) [3]. Spirocyclic tetrahydro-1,2-oxazines 26 could be accessed by an asymmetric nickel(II)-catalyzed cycloaddition of spirocyclopropyl oxindoles 25 with nitrones, as reported by Zhou and coworkers (Scheme 11.9c) [22]. Both aldonitrones and ketonitrones engaged in the reaction to form 26 in good enantioselectivity via the kinetic resolution process. Utilizing the side-arm strategy, Tang and coworkers developed a chiral L1/Ni(II) complex-catalyzed [3 + 3] cycloaddition of azomethine imines with cyclopropyl diesters, providing enantioenriched tetrahydropyrazines 27. The enantiocontrol was ascribed to the π–π stacking interaction between the indane group of the ligated sidearm and the 2-aryl group combined with a sterically hindered neopentyl ester group of the cyclopropanes (Scheme 11.10a) [23]. The Tang group also described a tandem ring-opening/cyclization sequence for the one-pot construction of chiral tetrahydrocarbazoles 28 from cyclopropyl diesters and 2-alkynyl indoles. A chiral Cu(II)/L14 catalyst promoted the nucleophilic ring-opening of electron-rich aryl cyclopropanes with indoles to provide enantioenriched acyclic 29, which underwent subsequent conia-ene cyclization by InCl3 and DBU catalyst, leading to the formation of optically active carbazoles 28 (Scheme 11.10b) [24]. [4 + 3] Annulation of D–A cyclopropanes with common dienolsilyl ethers meets the competitive pathways, such as [3 + 2] annulation and ring-opening. Tang and coworkers successfully achieved such a transformation of formal 4π-component

11.2 CCiral eeis AciidCatalyyei eactions of D–A Cyclopropanes

CO2R1 CO2

R1

R 1 (2.2 equiv.)

(a)

CO2Me

R

N

+

8 (1.5 equiv.) R: electron-rich aryl, furyl, thienyl, styrenyl (1)

R

R1

R

R1O2C

N

CO2Me CO2Me

N

(b)

NCOR2

R

R1

(2) InCl3 (20 mol%) DBU (10 mol%) toluene, 120 °C

N

N

R1O2C

27 81–99% 86–98% ee

(1) L14/Cu(OTf)2 (10 mol%) toluene, 40 °C

R1

R3

4 Å MS, DME, 40 °C 3 : 1->20 : 1 d.r.

NCOR2

R2: o-CF3C6H4-

R1: CH2tBu

CO2Me

L1/Ni(ClO4)2 (1.2 : 1, 10 mol%)

3 + R

R'

R'

O

CO2Me CO2Me

O N

N

Cy Cy L14 R': 4-tBuC6H4CH2

28, 63–87% 57–94% ee (2)

29

Scheme 11.10 Asymmetric [3 + 3] annulation of cyclopropyl diesters with azomethine imines and 2-alkynyl indoles.

silyl ethers by using a chiral Cu(II)/L2 catalyst. Seven-membered cyclic products 30 were obtained in good diastereoselectivity and enantioselectivity. Experimental studies suggested this reaction proceeded through a kinetically controlled [3 + 2] cycloaddition, followed by an unusual rearrangement of cyclopentane intermediate 31 to yield the thermodynamically favored [4 + 3] annulated product 30 (Scheme 11.11) [25]. OSi CO2Ad CO2Ad

R 5

+

R1 R2 Si: TBDPS (1.5 equiv.)

L2/Cu(ClO4)2 (1.1 : 1, 10 mol%) CH2Cl2, 4 Å MS, 40 °C 4 : 1–10 : 1 d.r.

SiO

R

R2 R1

R1

CO2Ad CO2Ad R2 30, 58–95% 88–99% ee

OTBDPS R

CO2Ad CO2Ad 31

11.2.2 Asymmetric Reactions of 2-Substituted Cyclopropane-1,1-Diketones As a kind of D–A cyclopropane derivatives, cyclopropyl diketones also allow enantioselective ring-opening to synthesize γ-functionalized carbonyls. However, more complex domino sequence might occur with the ketone units, to construct complex and interesting heterocycles in a straightforward fashion. Chiral N,N'-dioxide/ Sc(III) complexes have been found to be efficient in enabling these transformations. The enantioselection raised from kinetic resolution of the racemic substrates, often requires excessive cyclopropyl diketones. An enantioselective ring-opening between cyclopropyl diketones and various nucleophiles catalyzed by chiral N,N'-dioxide L-PiPr3/Sc(OTf)3 complex was developed by Liu and Feng (Scheme 11.12a) [26]. Thioethers were obtained in good yields

341

342

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes COAr1 COAr1

+

R2XH

R1

32 (2.5–4.0 equiv.)

(a)

R2

LiCl (1.0 equiv.) CHCl2CHCl2, 60 °C

R

X

R1

H

COAr1

X

N O

N

N O

ArOC

X

N X R2 MgCl2 (1.0 equiv.) L-PiPr3/Sc(OTf)3 (10 mol%) CHCl3, 35 °C

R1

32 (2.2 equiv.) R Aryl, vinyl

COAr

R1

COAr COAr

O N

Ar2 H H L-PiPr3: Ar: 2,4,6-iPr3C6H2

Ar2

OH

COAr

N R2 34, 52–99% 73–94% ee

O

COAr1

33

X=S 55–97%, 86–95% ee X=O 60–94%, 50–92% ee X = COO 90–99%, 72–83% ee

R1: Ar, vinyl ArOC

(b)

L-PiPr3/Sc(OTf)3 (10 mol%)

LiCl (1.0 equiv.) L-PiPr3 /Sc(OTf) 3 (10 mol%) EtOAc, 60 °C

1:

H

X

OH

35, 52–99% 53–97% ee

Scheme 11.12 Asymmetric ring-opening of cyclopropyl diketones with hetero- and carbon-nucleophiles.

and generally high enantioselectivity by using thiol nucleophiles. Both aromatic thiophenols and aliphatic structures were well-tolerated. In addition, alcohol nucleophiles also worked well to give optical active γ-oxy diketones 33. Relative lower enantioselectivity was obtained when carboxylic acid was used as the nucleophile. This catalytic system was then applied to asymmetric Friedel−Crafts alkylation of indoles with cyclopropyl diketones, resulting in enantioenriched alkylated products (Scheme 11.12b). N–H, N–Me, and N–TBS-protected indoles were suitable substrates. The MgCl2 greatly increased both reactivity and enantioselectivity, which was proposed to be a promoter through counterion exchange [27]. A dearomatization/ rearomatization process was involved in alkylation with 2-naphthol nucleophiles. Due to the lower nucleophilicity of 2-naphthols, higher temperatures and longer reaction times were required [28]. The [3+3] annulation of cyclopropyl diketones with mercaptoacetaldehyde can lead to the formation of six-membered cycloadducts. The mercaptoacetaldehyde generated in situ from 1,4-dithiane-2,5-diol reacted with cyclopropane through a ring-opening/aldol reaction to yield enantioenriched tetrahydrothiopyranols 36 (Scheme 11.13) [29]. COAr COAr R1 32 (5.0 equiv.)

S

+ HO

S

OH

L-PiPr3 /Sc(OTf)3 (1 : 1, 10 mol%) 4 Å MS CHCl2CHCl2, 50 °C 7.8 : 1->20 : 1 d.r.

R

COAr COAr S OH 36, 38–80% 84–99% ee

Scheme 11.13 Asymmetric [3 + 3] annulation of cyclopropyl diketones with mercaptoacetaldehyde. Source: Modified from Feng et al. [29].

Optically active 2,3-dihydropyrroles could be accessed by a domino ring-opening/ cyclization/dehydration reaction of cyclopropyl ketones and primary amines (Scheme 11.14a) [30]. Chiral N,N'-dioxide L-PiPr3/Sc(OTf)3 selectively activated

11.3 CCiral oed-alent ransition COR1 O + R2NH 2

R

(a)

R1

LiCl (1.0 equiv.) CHCl2CHCl2, 35 °C

R 32

R1

H2N

(b)

L-PiPr3 /Sc(OTf)3 (5 mol%) LiCl (30 mol%) SH CHCl2CHCl2, 45 °C 1 : 1–15.7 : 1 d.r.

R

(c)

32

R1

H2 N

Scheme 11.14

37, 16–98% 66–97% ee SH

NH2

CHCl2CHCl2 35 °C

R1

NH COR1

R2

COR1

R 38

COR1

N

N R2

R 43

R

COR1

39 R1 COR1

S N R2

R

H R1 COR1 N

HO R1 R2 N

Michael addition

R 40, 36–89% 38–96% ee

42

L-PiPr3/ScCl3 •6H 2O (10 mol%)

R2 COR1 O +

R2

COR1

R

32 (4.0 equiv.)

R2 COR1 O +

R1

R2 N

L-PiPr3/Sc(OTf)3 (1 : 1, 10 mol%)

etal romotei eactions of -inyl Cyclopropanes

RetroMannich

N R1

N

R2

COR1 R 41, 56–99% 62–97% ee

Asymmetric ring-opening of cyclopropyl diketones with amines.

the (S)-enantiomer of cyclopropane 32 to perform the attack of amines in an SN2 fashion, to generate (R)-38. Subsequent cyclization gave hemiaminal 39 and further dehydration delivered 2,3-dihydropyrroles 37 as the final products. An asymmetric ring-opening/cyclization/thio-Michael cascade reaction of cyclopropyl diketones with 2-aminothiophenol was also realized by the same chiral catalyst. Upon the formation of 2,3-dihydropyrrole 42, a thio-Michael reaction occurred to produce enantioenriched benzothiazole derivative 40 containing quaternary stereogenic centers (Scheme 11.14b) [31]. However, in the case of aryl-1,2-diamine nucleophile, once the tricyclic intermediate 43 was produced, a retro-Mannich process occurred to provide the thermodynamically favorable benzimidazole 41. Here, various aryl-, vinyl-, as well as aliphatic-substituted cyclopropanes were welltolerated (Scheme 11.14c) [32].

11.3 Chiral Low-Valent Transition Metal Promoted Reactions of Vinyl Cyclopropanes Low-valent transition metal complexes were able to facilitate the ring-opening of VCPs to form transient π-allyl metal intermediates, which could react with electrophiles or Michael acceptors to give acyclic or cyclic targets. Chiral palladium and iridium catalysts have proven to be efficient in rendering these transformations enantioselectively. Since reactions usually begin with low-valent metals complex-mediated ring cleavage of VCPs, these transformations generally underwent a dynamic kinetic process. Although a few significant accomplishments have been made in this area, the most frequent transformation by far is the [3 + 2] annulation. Less common ringopening and [4 + 3] annulation have been reported in some instances.

343

344

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

11.3.1

Ring-Opening Reactions

Trost and coworkers described in 2018 a Pd-catalyzed allylic alkylation of C3-substituted 1H-indoles and tryptophan derivatives with VCP. When VCP 44 was exposed to Pd2(dba)3 and Trost ligand L15, a zwitterionic π-allyl-palladium intermediate 47 was formed, which served as electrophiles and reacted with 3-alkylated indole nucleophiles to provide various indolenines 45. The obtained indolenine products bearing an imine, an internal olefin, as well as a malonate motif could be readily transformed into complicated polycyclic skeletons 46 via a tandem cyclization (Scheme 11.15) [33]. CO2Me

R1

R2

CO2Me +

BEt3 (1.2 equiv.) CHCl3, 4 °C

N H

44 [Pd]

Pd2dba3 (2.5 mol%) L15 (7.5 mol%)

L15 O

CO2Me 47

Scheme 11.15 et al. [33].

O

R3

R2

R1

N

R3

X N H 46, 82–95% 72–96% ee

or

45, 90–96% 90–98% ee

n

CO2Me

R3:

NH HN

CO2Me

R2

CO2Me

PPh2 Ph2P

Asymmetric ring-opening of VCP with indoles. Source: Modified from Trost

In 2011, the groups of Krische and Johnson jointly developed an asymmetric reductive C─C coupling of VCP with aldehydes or in situ-generated aldehydes by dehydrogenation of alcohols (Scheme 11.16) [4]. In the presence of chiral cyclometalated iridium catalyst 16, diester-substituted cyclopropane 44 underwent ring-opening to form a nucleophilic π-allyl-iridium intermediate 49. Subsequent reductive coupling with aldehydes produced homoallylic products 48. Here, the polarity at the donor site of VCP was inversed, and 44 served as a 1,3-bisnucleophilic synthon.

O CO2Me CO2Me + 44 (1.5 equiv.)

R or OH

cat 16 (5 mol%) K3PO4 (5 mol%) H2O, THF, 60 °C 6 : 1->20 : 1 d.r. O

R

OR IrLn

O 49

OR

MeO2C

Ph2 P Ir P Ph2

CO2Me

R HO 48, 63–89% 91–98% ee

cat 16

NC

O

NO2

O

11.3 CCiral oed-alent ransition

11.3.2

etal romotei eactions of -inyl Cyclopropanes

[3 + n] Annulations

An asymmetric [3+2] annulation of VCP with alkylidene azlactones was disclosed to construct spiro-annulated vinyl cyclopentanes 51. The π-allyl-palladium complex generated from the ring-opening of the bis(2,2,2-trifluoroethyl)malonate VCP 50 engaged in Michael addition with alkylidene azlactone acceptors, and further followed by ring closure to give 51 (Scheme 11.17a) [5]. Later, the same group extended the scope to Meldrum’s acid-substituted VCP and alkylidenes. Enantioenriched spiro-cyclopentanes 53 were produced with an excellent level of stereoselectivity (Scheme 11.17b) [34]. The remote stereoinduction was ascribed to the reversible conjugate addition of the π-allyl-palladium intermediate to Michael acceptors. A palladium(0)-catalyzed [3 + 2] annulation of VCPs proceeding via conjugate addition of acceptor-stabilized π-allyl-palladium intermediate was then extended to other Michael acceptors. Utilizing chiral imidazoline–phosphine ligand L17 and Pd(0) catalyst, Shi and coworkers described an enantioselective [3 + 2] annulation with β,γ-unsaturated α-keto esters and α,β-unsaturated N-acyl pyrrole, providing optically active cyclopentanes 55 containing multiple stereocenters in good diastereo- and enantioselectivity (Scheme 11.17c) [35]. The use of

O

CO2R1 CO2R1 +

(a)

50 R1: CF3CH2

+

R1

(c)

+

O

O

OR

CO2R1 + 56

O

O O

O

toluene, rt 6 : 1–17 : 1 d.r.

O

O

O 53, 32–78% 85–96% ee

CO2R2 Pd2dba3 (5 mol%) L17 (10 mol%) O toluene, rt 10 : 1->20 : 1 d.r.

R 54 (1.5 equiv.) R1: CO2Me, CN CO2R1

(d)

R

52

R1

Ph

N

R1O2C R1O2C

Pd2dba3 (2 mol%) L15 (6 mol%)

O

R

(b)

O

51, 51–87% 63–98% ee

O

O

toluene, rt 3 : 1->19 : 1 d.r..

R

O

O

O

Ph

N

O

Pd2dba3 (2 mol%) L15 (6 mol%)

O

CO2Et N N

R R1 R1

O

O CO2R2

N PPh2

55, 52–96% 82–98% ee R2 N

X R (1.5 equiv.) X: N, CH

Pd2(dba)3 (5 mol%) L15 (10 mol%) CH2Cl2, 30 °C 0.6 : 1–3.6 : 1 d.r.

L17 R2

N R

N

CO2R1 N

X

CO2Et

CO2R'

57, 30–99% 45–92% ee

Scheme 11.17 Asymmetric [3 + 2] annulation of VCPs with Michael acceptors.

Ph

345

346

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

α-nucleobase-substituted acrylates as dipolarophiles for an asymmetric [3 + 2] annulation with VCPs was also shown by Guo and coworkers (Scheme 12.17d). Various purine-, pyrimidine-, as well as α-heteroaryl-substituted acrylates engaged in such transformation to give enantioenriched carbocyclic nucleoside analogs 57 in good-to-high enantioselectivities and yields, albeit with low distereoselectivities [36]. In 2015, Liu and coworkers described a chiral MeObiphep ligand L18/Pd(0)catalyzed [3 + 2] annulation of nitroolefins with VCP, allowing the synthesis of chiral nitrocyclopentane derivatives 58 with three consecutive stereocenters in moderate enantioselectivities but with low diastereoselectivities (Scheme 11.18a) [37a]. A higher level of diastereocontrol was observed when indane-1,3-dione-derived vinyl cyclopropane was employed [37b]. An enantioselective dearomative [3+2] annulation occurred by using 3-nitroindoles as the Michael acceptors (Scheme 11.18b). While the transformation tolerated different substituted 3-nitroindoles, only the dicyano VCP 54 was investigated in the transformation [38]. Enantioenriched spirocyclopentane-1,3′-indolenines 60 were accessed by a palladium(0)-catalyzed [3 + 2] annulation with aryl sulfonyl indoles, as reported by Liu and coworkers (Scheme 11.18c). A zwitterionic π-allyl palladium complex intermediate was proposed to act as both a base to generate α,β-unsaturated imines 61

+ R

CN

(a)

CN +

N R1 (3 equiv.)

54

CO2Me CO2Me +

PhO2S

N H R: Ar, furyl

44 (3.0 equiv.)

4 Å MS THF, 10 °C >20 : 1 d.r.

PPh2 PPh2

L18

Ph

R O2N

MeCN, – 15 °C 1.4 : 1–7.3 : 1 d.r.

CN CN

O O

N H R1 59, 42–80% 70–97% ee

MeO2C

Ph L19

CO2Me

Ph

R

R 61 R1

P N

O O

N

N

P N

L20

Ph

60, 39–76% 64–97% ee

(c) R' R'

(d)

MeO MeO

CN CN 58, 0–97% 17–92% ee

R Pd(dba)2 (5 mol%) L20 (10 mol%)

R1

R

toluene, rt 0.9 : 1–1.6 : 1 d.r.

NO2 Pd(dba)2 (2.5 mol%) L19 (5 mol%)

R

CN

(b)

NO2

(1.1 equiv.)

54

O2N

Pd(dba)2 (5 mol%) L18 (10 mol%)

CN

TsN +

62

Scheme 11.18

R

O

R1

Pd2dba3 (2.5 mol%) L21 (5 mol%) toluene, rt 2.5 : 1–6 : 1 d.r.

TsN

R

R1

R' R'

O O

O

O

PPh2 PPh2

63, 64–91% 88–99% ee

O

L21

Asymmetric [3 + 2] annulation of VCPs with Michael acceptors.

11.3 CCiral oed-alent ransition

etal romotei eactions of -inyl Cyclopropanes

from sulfonyl indoles and as a reaction partner [39]. Cyclic 1-azadienes was also applied to a similar transformation afterward, leading to [5] spirocyclic carbocycles 63 (Scheme 12.18d) [40, 41]. Meldrum’s acid-, indane-1,3-dione-, dicyano-, as well as barbituric acid-derived VCPs, reacted smoothly to give annulated products in excellent regio- and enantioselectivities. A Pd(0)-catalyzed [3+2] annulation of para-quinone methides with VCPs was uncovered by Zhao et al. Optically active spiro[4.5]decanes 64 were harvested via a 1,6-conjugate addition/annulation process. Different ester groups on the VCPs were well-tolerated (Scheme 11.19a) [42]. Enantioenriched cyclopentenes 65 could also be synthesized by using ketoesters- or 1,2-diones-activated alkynes as Michael acceptors. Here, the introduction of an additional carbonyl group at the α-position O

CO2R1 CO2

R1

tBu

+

56 (1.2 equiv.)

54 (2.5 equiv.)

Scheme 11.19

toluene, 23 °C 3 : 1->20 : 1 d.r.

R1O2C

+

tBu

R

R1O2C

R2 R1 R1: Ar, alkyl, silyl R2: CO2R', COAr

Pd(dba)2 (5 mol%) L21 (10 mol%) CH2Cl2/DME 10 °C

L22 PAr2

O

PAr2

t

Bu

64, 47–98% 51->99% ee

O

CN CN

Pd(dba)2 (1 mol%) L22 (2.5 mol%)

R R: Ar, Me

(a)

(b)

tBu

R1

R2

Ar = 3,5-(CH3)2C6H3

O

NC NC 65, 32–89% 52–89% ee

Asymmetric [3 + 2] annulation of VCPs with Michael acceptors

of alkynyl esters was essential to activate the C─C triple bond to engage in the transformation (Scheme 11.19b) [43]. This type of annulation was successfully extended to heteroatom-containing dipolarophiles. Chiral tetrahydrofuran derivatives 66 were yielded via the reaction of VCP with isatin dipolarophiles (Scheme 11.20a). The diastereoselectivity could be improved by using a LiCl additive [44]. As heteroanalogous carbonyl systems, aldimines or isatin-derived ketimines underwent [3 + 2] annulation with cyclopropanes, allowing for the formation of tetrahydropyrrole derivatives 67. Chiral phosphoramidite ligand L24/Pd2(dba)3 catalyst promoted the reaction of various isatin partners and different diester-substituted VCPs efficiently (Scheme 11.20b) [45]. Other dipolarophiles, such as 3-diazooxindoles, engaged in the palladium-catalyzed ­ [3 + 2] annulation with VCPs, resulting in 1,3-indanedione- and oxindole-fused spiropyrazolidines 69 in high yields and good enantioselectivities (Scheme 11.20c) [46]. Besides extensive studies in [3 + 2] annulation, VCPs also participated in [4 + 3] annulation to construct seven-membered rings. You and coworkers investigated a

347

348

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes O

CO2R1 CO2R1

+ R

56 (1.2 equiv.)

N R2 (1.5 equiv.)

O

R1O2C R1O2C

Pd2(dba)3 (7.5 mol%) L23 (15 mol%)

O

LiCl (2.5 equiv.) THF, rt 3.3 : 1–15.7 : 1 d.r.

NBoc Pd(dba)2 (10 mol%) L24 (10 mol%) O THF, 25 °C N 2 : 1–5 : 1 d.r. R1

CO2Me + R 44 (1.2 equiv.)

MeO2C MeO2C

O O

N2 + N R R1 (1.5 equiv.)

O 68

Scheme 11.20

CO2R1 CO2R1 56 (2.0 equiv.)

O P N O 1-naphthyl L24

67, 81–94% 81–96/49–87% ee

(b)

(c)

Ph

NBoc O N R1

R

O

O

Toluene, 0 °C

N N

O 69, 39–99% 48–84% ee

R1

R

R2 N

Ph

N

Ph

PAr2 L25 R2: Naphthalen-2-ylsulfonyl Ar: 3,5-(MeO)2C6H3

Asymmetric [3 + 2] annulations of VCPs with dipolarophiles.

R +

Pd2dba3 (5 mol%) L25 (10 mol%)

N

Ph

N Ph PnBu2 L23

N R R2 66, 28–98% 8–96% ee

(a) CO2Me

Ts N

O

N

O

[Pd(h-C3H5)Cl]2 (5 mol%) L26 (15 mol%) Et3B (0.5 equiv.) Cs2CO3 (1.0 equiv.) tBuOMe, 50 °C

R O

CO2R1 CO2R1

N 70, 43–82% 83–98% ee

O N PPh2

Ph

L26

Scheme 11.21 Asymmetric [4 + 3] annulation of VCPs with anthranils. Source: Modified from You et al. [47].

Pd(II)-catalyzed dearomative [4 + 3] annulations with anthranils. With PHOX ligand 26 and triethyl borane, enantioenriched bridged cyclic compounds 70 could be harvested in excellent enantioselectivity. The use of borane was an activator for the anthranils to engage in this transformation (Scheme 11.21) [47]. Based on the synergistic merging of iminum/enamine organocatalysis with palladium(0) catalysis, Vitale and coworkers disclosed an asymmetric [3 + 2] annulation between VCPs and enals. In this reaction, highly activated α,β-unsaturated iminium ion dipolarophile 72 was generated in the presence of Hayashi−Jørgensen catalyst 27 and Brønsted acid additive, which further reacted with zwitterionic π-allyl-palladium species 51, in a stereoselective manner, to give cyclopentane products 71. Various VCPs and aromatic enals were successful partners for the transformation (Scheme 11.22) [48]. This dual-activation strategy was also extended to indane-1,3-dione-, azlactone-, dicyano-, and cyanoester-substituted VCPs [49].

11.4 CCiral rranocatalytic eactions of D–A Cyclopropanes ani R1 R1

+ Ar (1.5 equiv.)

56

Pd2(dba)3 (5 mol%) dppe (10 mol%)

CHO

p-NO2C6H4CO2H (20 mol%) cat 27 (20 mol%), PhCF3, rt 62 : 25 : 13–91 : 4.5 : 4.5 d.r.

N 72

CHO

Ar

Ar Ph Ph TMSO

N H

N H (cat 27)

R1 Ar R1

Ar 71

OHC Ar R1 R1 71, 29–98% 98->99% ee

N [Pd]

R1

N

R1

[Pd]

iscellaneoos

[Pd] 51

[Pd0]

R1 R1

56

11.4 Chiral Organocatalytic Reactions of D–A Cyclopropanes and Miscellaneous Chiral organocatalysts, bearing acidic or basic functionalities, could activate D–A cyclopropanes through catalyst–substrate interactions, such as nucleophilic/ electrophilic activation, hydrogen bonding, and ion pairing. The activation mode highly depended on the structure of cyclopropanes. Upon activation, the ring-cleavage of cyclopropane resulted in reactive intermediates, which reacted with a nucleophile, an electrophile, or a radical acceptor to deliver functionalized molecules.

11.4.1

Enamine/Iminium Catalysis Activation

Utilizing the HOMO-raising approach, cyclopropyl-substituted aldehydes were activated by chiral secondary aminocatalyst through the formation of covalently bonded reactive intermediates. Jørgensen and coworkers developed a stereoselective [2 + 2] annulation between cyclopropyl monoacetaldehydes 73 and 3-olefinic oxindoles or benzofuranone for the synthesis of chiral cyclobutanes 74 (Scheme 11.23a). Chiral aminocatalyst 27 activated 73 to form an enamine intermediate 76, which underwent a ring-opening and protonation process to generate an electrophilic α,βunsaturated iminium ion 77 in the presence of Brønsted acid. Subsequent deprotonation led to nucleophilic dienamine intermediate 78, which further reacted with 3-olefinic oxindoles or benzofuranones to give 74 [50]. Utilizing electrophilic intermediate 77, Vicario and coworkers described a domino cyclopropane ringopening/aza-Michael/aldol condensation sequence with o-aminobenzaldehydes (Scheme 11.23b). The obtained chiral dihydroquinolines 75 could be converted into pyrroloquinolines in one pot by acid-promoted lactamization [51].

349

350

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

CHO

R3 +

CO2R1

O

X

CO2R1

(a)

1) cat 27 (10 mol%) PhCO2H (10 mol%) CHCl3, –20 °C

R2

73 (2.0 equiv.)

X: NBoc, O

CHO

CO2R1

R2

2) Ph3PCHCO2Et CHCl3, rt 5.1 : 1–13.9 : 1 d.r.

CHO

4-NO2C6H4CO2H (20 mol%)

NH2

cat 27 (20 mol%) CHCl3, rt

CO2R1 +

R1O2C 2 R R

CO2Et

O

X

74, 55–86% 75–97% ee CHO R2

N H R1O2C

73 (1.0 equiv.)

N

CO2R1

3

CO2R1

75, 64–99% 79–97% ee

Ph Ph OTMS

N H

Ph Ph OTMS

N

Ph Ph OTMS

–H

CO2R1 CO2R1 76

R1O2C

CO2R1 77

R1O2C

CO2R1

78

(b)

Scheme 11.23

Asymmetric cascade reactions of cyclopropyl monoacetaldehydes.

Gilmour and coworker developed a formal 1,3-addition of Cl2 to meso-cyclopropane carbaldehydes 79 through a merged iminium–enamine activation by using MacMillantype imidazolidinone catalyst 28. Nucleophilic ring-opening of amine catalystactivated cyclopropyl iminium species with collidine hydrochloride gave enamine 80, which further reacted with electrophilic “Cl+” reagent perchlorinated quinone to form 1,3-dichlorinated 81 (Scheme 11.24a) [52]. Utilizing a similar strategy, Werz and coworkers reported an asymmetric 1,3-chlorochalcogenation using sulfenyl or selenyl chlorides as 1,3-difunctionalization reagents (Scheme 11.24b) [53]. The nucleophilic ring-opening of secondary amine-activated cyclopropyl carbaldehydes with carboxylic acid was also reported by Vicario and coworkers (Scheme 11.24c) [54]. Enantioenriched γ-acyloxy-substituted aldehydes 83 were provided in good yields and enantioselectivities with benzoic or aliphatic carboxylic acids.

11.4.2

Brønsted Base Catalyst Activation

Based on hydrogen bonding/nucleophilic activation, in 2009, Jørgensen and coworkers described an enantioselective fragmentation of meso-cyclopropane using a bifunctional urea−amine catalyst 31. The meso-cyclopropane 84 was activated by the basic quinidine moiety of catalyst 31, whereas the acidity of the α-H was increased through hydrogen bonding between the carbonyl and the thiourea (Scheme 11.25a) [55]. Employing urea−amine catalyst 32, the same group also developed an organocatalytic asymmetric [3 + 2] annulation of dicyano-substituted cyclopropylpropan2-one 86 with nitroolefins to synthesize cyclopentanes 87. Here, the deprotonation

11.4 CCiral rranocatalytic eactions of D–A Cyclopropanes ani

CHO R

N

79 R = alkyl, Ph Bn

(a) CHO

+

R

(b)

R

79 R = alkyl, Ph

1) Cat 29•DCA (20 mol%) EtOAc, –4 °C

PhSeCl

2) NaBH4, EtOH

R

R 79

(c)

Cl

CH2OH R 82, 42–84% 0–80% ee

O

N

Bn

R1

CHCl3, 50 °C or m-xylene, 80 °C

O

CHO

H

N 1-naphthyl H cat 29

R

Cat 30 (20 mol%)

(1.5–3.0 equiv.)

Cl

CHO R 81, 67–72% 72–92% ee

SR1(SePh)

R

1 : 1–15 : 1 d.r.

(1.2 equiv.)

R1CO2H

R Cl

80

R1SCl or

CHO +

6 : 1->19 : 1 d.r.

R

N H •TFA cat 28 (20 mol%)

Cl

Cl

NR'2

Cl

O

Cl Cl

Cl

R

N H

R

O

Cl

Cl

iscellaneoos

Ar Ar

N H

OSiPh2Me Ar: 3,5-(F3C)2C6H3 cat 30

O R 83, 26–88% 66–95% ee

Scheme 11.24 Asymmetric ring-opening of cyclopropane carbaldehydes with electrophiles and nucleophiles.

of the cyclopropyl ketone by the basic pyrrolidine in 32 led to a reactive D–A cyclopropane, which reacted with nitroolefins to give chiral annulated products (Scheme 11.25b) [56]. O

O

cat 31 (10 mol%) CH2Cl2, 40 °C

EtO2C

CO2Et 84

(a)

O

CN CN +

R 86 R = alkyl, aryl

R

R2

CO2Et EtO2C 85, 84% 96% ee

Ar

11.4.3

H N

H

O

N

cat 31

NO2

cat 32 (20 mol%) CH2Cl2, –25 °C >20 : 1 d.r.

(1.5 equiv.)

S

HN H

S

(b)

Scheme 11.25

H N

EtO2C

N COR

R3 1

Ar HN

Ar: (F3C)2C6H3

NO2 R3 NC R2 NC R1 87, 56–98% 66–91% ee

NR' CO2Et R''

S Ar

N H

N H

N

cat 32 Ar = 4-NO2C6H4

Brønsted base-facilitated transformations of cyclopropanes.

Nucleophilic Catalyst Activation

Troxler and Scheffold developed a vitamin B12-catalyzed enantioselective desymmetrization rearrangement of meso-cyclopropanes 88. The Cob(I)alamin catalyst, served as the nucleophile, and engaged in the ring-opening of spiroactivated cyclopropanes. The resulting Co(III) intermediate 89 underwent reductive elimination to form cycloalk-2-enyls 90 (Scheme 11.26) [1].

351

352

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes

O

Cob(I)alamin (2 mol%)

O

O

O

O O

THF/H2O, rt

O

O

O

O

O

O

Co(III) n n = 1,2 88

n 90, 92–99% 77–86% ee

n 89

Scheme 11.26 Asymmetric desymmetrization-fragmentation of meso-cyclopropanes. Source: Modified from Troxler et al. [1].

11.4.4

Brønsted Acid Catalyst Activation

Ring enlargements of D–A cyclopropanes represent an expedient method to generate more stable cyclic chemical frameworks in an atom-economical manner. An enantioselective Brønsted acid-catalyzed Cloke–Wilson rearrangement was reported by Vicario and coworkers. Brønsted acid protonated the ketones 91 to form transient carbocationic intermediates, which underwent cyclization to give dihydrofurans 92 through a DYKAT (Scheme 11.27a) [57]. O

R

cat 33 (10 mol%) R1

91

(a)

R2

m-xylene/Cl(CH2)2Cl –30 or –40 °C

R: electron-rich aryl, heteroaryl R1: aryl, alkyl, ester R2: ester, H

MeO2C

CO2Me

O

Ar

+

Ar1

H N

Ar R1

Ln

O

R

CO2Me

O H

N R Ar1

O

R2

O

92, 48–94% 56–94% ee

Ar III

O P OH

cat 33 Ar

Ar = 1-naphthyl O

Ar

Ar CO2Me

CHCl3, –10 °C to rt 2.2 : 1->20 : 1 d.r. R

MeO

(b)

O

cat 34 (0.24–1.3 mol%) Ln(OTf)3 (0.2–1 mol%)

93

O O *O P NTf

R

N Ar1

CO2Me

Ar

94, 71–95% 62–98% ee H

O O *O P NTf

N

cat 34 O O P NHTf O

Ar = 2,4,6-iPr3C6H4

Ar1

Ar

MeO2C MeO

O

O Ln IV

Scheme 11.27 Brønsted acid-facilitated transformations of D–A cyclopropanes.

An achiral rare-earth metal Lewis acid and chiral Brønsted acid cooperatively catalyzed-cascade ring-opening/aza-Piancatelli rearrangement of furyl-substituted D–A cyclopropanes 93 with anilines or N-alkyl anilines has been reported by Tang and Cai (Scheme 11.27b) [58]. The authors proposed that a chiral anion-stabilized oxocarbenium enolate−Ln(III) intermediate III was generated via Ln(III)-facilitated

11.4 CCiral rranocatalytic eactions of D–A Cyclopropanes ani

iscellaneoos

ring-opening of the cyclopropane. Subsequent N-triflylphosphoramide anion promoted nucleophilic attack by the amine and further Ln(III)-assisted ring-opening of the furan led to a pentadienyl carbocation intermediate IV. Stereoselective 4π-electrocyclization resulted in functionalized aminocyclopentenone 94 bearing an α-quaternary carbon stereocenter in good enantioselectivity.

11.4.5

Radical Pathway

Besides the ionic pathway, the enantioselective radical reactions of D–A cyclopropanes also provide efficient access to enantioenriched molecules. In 2014, Maruoka and coworkers designed a stereoselective [3 + 2] annulation of VCPs with electron-rich alkenes by using thiyl radical precatalyst 35 (Scheme 11.28) [59]. The thiyl radical generated by oxidation was added to VCPs, resulting in carboncentered radical 97, which then reacted with alkenes to form radical 98. Subsequent cyclization gave cyclopentanes 96, and the thiyl radical was released. COR1 COR2 95

+

hv, toluene, 0 °C R3 R4 1.1 : 1->19 : 1 d.r. 3 R : OR′, NHR' (2.0 equiv.)

96 ArS 98

cat 35 (3 mol%) BPO (6 mol%)

R3 R4

ArS

CO2R1 COR2

R3

R4 96, 73–99% 12–93% ee CO2R1 COR2 95

R

COR1 COR2

HS OH

R

Ar Ar Si tBu

cat 35 Ar: 4-F3CC6H4 R: 10-Bu-9-anthryl BPO: dibenzoyl peroxide

CO2R1

ArS

COR2 97 R3

R4

Scheme 11.28 Asymmetric [3 + 2] annulation of VCPs with alkenes. Source: Modified from Maruoka et al. [59].

The combination of a chiral Gd(III)/pybox and [Ru(bpy)3](PF6)2 photoredox catalyst system was developed to facilitate a [3 + 2] photocycloaddition between aryl cyclopropyl ketones and alkenes (Scheme 11.29a). Photoredox catalyst 36 promoted the one-electron reduction of Lewis acid-activated aryl cyclopropyl ketone to form a ketyl radical. The latter underwent fragmentation and stereocontrolled radical cyclization to give a chiral acyl-substituted cyclopentane derivative 100 [60]. Meggers and coworkers also described a rhodium catalyst Δ-RhS 37-catalyzed [3 + 2] cycloaddition of cyclopropyl imidazolyl ketones with alkenes (Scheme 11.29b). Here, the rhodium catalyst acted as both a Lewis acid catalyst and a photoredox catalyst. The direct photoexcitation of cyclopropane/catalyst complex 103 generated a strong photooxidant 103*, which could be reduced to provide a ketyl radical 104. The followed fragmentation and enantioselective radical addition delivered optically active cyclopentanes [61].

353

354

11 Asymmetric Catalytic Activation of Donor–Acceptor Cyclopropanes Gd(OTf)3 (10 mol%) L36 (20 mol%)

O R1

Ar

+

O

NMe2

Ar

Ru(bpy)3(PF6)2 (2.5 mol%) MeCN, 23 W CFL, rt (2.5 equiv.) 2 : 1->20 : 1 d.r. R2

99

O R1 100, 47–95% 50–99% ee

(a) O

R1 R2

N N

R2

+

Ph

R3

R4

[Rh] O

102 + e

N

101 [Rh]

O

R3

N

N

R3

N

blue LED, acetone, rt 1.3 : 1->20 : 1 d.r.

(2.5 equiv.) R3: EWG, Ar

101 (1.0 equiv.) R1, R2: alkyl, aryl

O

Δ-RhS 37 (2–4 mol%) DIPEA (50–200 mol%)

N

Ph

R2 102, 63–99% 88->99% ee

R1 R2

tBu

R4

[Rh]

106

Ph

R2

N

R1

[Rh]

R3

[Rh]

O R1

N

R4

N

(b)

Scheme 11.29

Ph

N

105

N N N

Me

Rh N S Δ-RhS 37

*

O

R1 R2

Ph

103* e

O

1

R R2

N

R2

tBu

S

Me

hv

Ph 103

N

tBu

R1

N N

L36

tBu

R4

O

N N

Ph

104

Asymmetric [3 + 2] annulation of cyclopropyl ketones with alkenes.

Utilizing a radical redox relay strategy, a stereoselective [3 + 2] annulation of cyclopropyl ketones with radical acceptor alkenes was developed by Lin and coworkers (Scheme 11.30). A chiral TiIV(salen) complex was reduced by Mn to TiIII(salen), which coordinated with cyclopropyl ketone to form redox-active species. The followed single-electron transfer/ring cleavage/radical cyclization process gave annulated cyclopentanes 108. Such TiIV/TiIII redox catalytic system was quite efficient for styrene, and a high level of enantiocontrol was obtained. However, lower enantioselectivity was observed by using electron-deficient alkenes [62].

R1 O Me Me 107 R1: Ar, Me

+

cat 38 (10 mol%) Mn (1.5 equiv.) R2

Et3N•HCl EtOAc, 22 °C (1.2 equiv.) 2 : 1->19 : 1 d.r. R2: Ar, EWG

R2 Me Me

cat 38

Ph

N Cl N Ti O Cl O

COR1

108, 53–98% 13–98% ee

Ph

Ad

Ad

eferences

11.5 Conclusion Over these past two decades, catalytic asymmetric transformations of D–A cyclopropanes have benefited greatly from the rapid development of organic synthesis methodology. A number of chiral Lewis/Brønsted acids, Brønsted bases, organocatalysts, as well as radical-involved catalysts have been successfully used to render transformations enantioselectively, providing efficient approaches to optically active acyclic and cyclic compounds. Their applications have also been demonstrated by the synthesis of biologically active and related products. However, there are still some limitations and unresolved problems. The activation mode between cyclopropanes and chiral catalysts is highly dependent on the structure of the cyclopropanes. The catalytic asymmetric transformations of D–A cyclopropanes are still dominated by chiral Lewis acid catalysts. Furthermore, the donor group of cyclopropanes is mostly confined to aryl/vinyl/heteroatom substituents, and less reactive D–A cyclopropanes, such as an alkyl donor, remain elusive. Enantioselective radical transformations of D–A cyclopropanes are still largely undeveloped. Thus, the design of novel activation model, new catalyst systems, as well as their applications in organic synthesis are still highly demanding.

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12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products Amrita Saha, Karuna Mahato, Satysen Yadav, and Manas K. Ghorai Indian Institute of Technology Kanpur, Department of Chemistry, Kanpur, Uttar Pradesh, 208016, India

CHAPTER MENU 12.1 Introduction, 359 12.2 Synthesis of Alkaloids, 360 12.3 Synthesis of Terpene/Terpenoids, 379 12.4 Synthesis of Miscellaneous Natural Products, 403 12.5 Conclusion, 427 Acknowledgment, 427 References, 427

12.1 Introduction Cyclopropanes are an important class of compounds in organic chemistry. Despite high strain (~115 kJ/mol), cyclopropane does not lose its cyclic structure, and its C—C bond also remains kinetically inert. Enhancement of the reactivity of these strained three‐membered rings could be possible by introducing electron‐donating and electron‐withdrawing groups in the vicinal carbons of the rings, and these reactive cyclopropanes are well known as donor–acceptor (DA) cyclopropanes [1, 2]. The developed potential general methods for preparation as well as high reactivity make DA‐cyclopropane a very popular and very useful synthetic building block for the construction of various important structural cores and also in the total synthesis of many natural products. Cyclopropanation followed by ring opening, or cycloaddition and cyclopropanation‐ring opening‐cyclization are popular strategies widely used in the total synthesis of complex natural products. Over the years, DA‐cyclopropanes have been utilized as a reactive subunit for the synthesis of many alkaloids, terpenes/terpenoids, and also many other natural products. However, here we demonstrate the importance of DA‐cyclopropanes in the total synthesis of bioactive natural products from 2001 to 2021. Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

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12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

12.2 Synthesis of Alkaloids Alkaloids are pharmacologically valuable natural products that mostly contain basic nitrogen atoms. To date, more than 20 000 alkaloids have been documented in the literature. Although the major sources of alkaloids are plants, apart from plants, alkaloids can also be produced by bacteria, fungi, insects, and animals. In this chapter, first, we highlight and summarize the recent advancements in the total synthesis of various alkaloids of different families utilizing DA‐cyclopropane chemistry. The simplest naturally occurring alkaloid, (±)-horsfiline (4), is isolated from the leaves of Horsfieldia superba, a tree native to Malaysia [3]. The Carreira group developed a versatile route to the alkaloid (±)‐horsfiline from commercially available isatin 1 in 41% overall yield. The synthesis involves the MgI2‐catalyzed cyclopropane ring expansion of 3 leading to the formation of the spiro[pyrrolidine‐3,3’‐oxindole] scaffold, as shown in Scheme 12.1 [4]. O

MeO

1. NaH, BnBr, 74% O 1

N H

MeO

Br O

2. N2H4·H2O, 91% 2 N

N Bn

N N

MeO O N Bn 3

Scheme 12.1

Br

NaH, 81%

1. MgI2 (5.5 mol%), 83%

NMe MeO O N Bn

2. Na, NH3, 91%

(±)-Horsfiline (4)

Total synthesis of (±)–Horsfiline.

The Carreira group modified their earlier [5a] report for the total synthesis of the anticancer alkaloid (±)‐strychnofoline (12) [5b], isolated from the leaves of Strychnos usambarensis [6]. The synthesis involved the ring expansion of spiro[cyclopropan‐1,3′‐ oxindole] 8 with a cyclic disubstituted aldimine 10 in the presence of MgI2 to provide the corresponding ring‐expansion product 11 in 55% yield as a single diastereomer. The ring‐expansion product 11 possessed the same stereochemical pattern as that of the (±)‐strychnofoline, and it was converted to the targeted natural product (±)‐strychnofoline (12) in eight additional linear steps (Scheme 12.2). In 1996, Osada and co‐workers discovered the bioactive indole alkaloid spirotryprostatin B (17) from the fermentation broth of Aspergillus fumigatus BM939 [7]. The synthesis of spirotryprostatin B was performed by the MgI2‐catalyzed annulation reaction of a spiro[oxindole‐3,1′‐vinylcyclopropane] and an alkynyl imine, as shown in Scheme 12.3 [8]. The synthesis began with a known diazoketone 13, prepared in two steps from readily available isatin. Rhodium‐catalyzed cyclopropanation of diazoketone 13 with piperylene resulted in the formation of spiro[cyclopropane‐1,3′‐ oxindole] 14 in 71% yield as an inseparable mixture of diastereomers. The reaction of cyclopropane 14 with imine 15 in the presence of MgI2 afforded 16 in a combined

12.2 Synthesis of Allaloids NH2 Dibromoethane, DMF, NaH, 0 °C

O N Bn

TBSO 5 OMe

then MeOH, –78 to 25 °C 86% yield

6 O

BnBr, NaH

O

DMF, 0 °C 87% yield

N Bn

BnO 8

N

N Bn

BnO

OTBDPS

H

N Bn

8 MgI2 THF, 80 °C 55% yield

10

9 N

OTBDPS

H

7

OMe N

O HO

H N H

HO

O

11

O MeN

H N H

(±)-Strychnofoline (12)

Scheme 12.2 Total synthesis of (±)-Strychnofoline. N

Me {Rh(OAc)2}2 (1 mol%), benzene

N2

15 O

O N H 13

DCM

Me

Pd(PPh3)4, 6 mol% NDMBA,DCM

O O

O NH

HN

N H 14

Me

TIPS

MgI2, THF

HN

H O Me

16

TIPS

Me Spirotryprostatin B (17)

Scheme 12.3 Total synthesis of Spirotryprostatin B.

68% yield, as a mixture of diastereomers (dr 6:1). It was further converted to spirotryprostatin B (17) after a number of steps. (+)‐Phyllantidine (22) is a securinega alkaloid, and it was isolated from Phyllanthus discoides and Seurinega suffruticosa [9]. Kerr group reported the total synthesis of (+)‐ phyllantidine (22) alkaloid, where the first step involved the three‐component coupling of vinyl cyclopropane 18, aldehyde 19, and hydroxylamine 20 in the presence of ytterbium triflate hydrate as the Lewis acid to produce tetrahydo‐1,2‐oxazine 21 as a mixture of diastereomers (dr 12:1) in 86% yield. The compound 21 was subsequently converted in several steps into (+)‐phyllantidine (22) (Scheme 12.4) [10]. The marine alkaloid (+)‐nakadomarin A (27) was isolated from an Okinawan sea sponge and shows anticancer, antifungal, and antibacterial activities [11]. The Kerr

361

362

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products CHO

PMBO 19

Yb(OTf)3·H2O (5 mol%)

+ CO2Me

MeO2C

18

NHOH MeO

20 H

H

PMB O N H

4 Å MS, toluene, reflux 86% yield

CO2Me

O N H

OPMB

O O

CO2Me

(+)-Phyllantidine (22)

cis/trans=12 : 1 21

Scheme 12.4 Total synthesis of (+)-Phyllantidine.

group next reported the total synthesis of (+)‐nakadomarin A (27) involving a three‐ component cycloaddition of cyclopropane 23, aldehyde 24, and hydroxylamine 25 to generate highly functionalized tetrahydro‐1,2‐oxazine 26 as a single diastereomer. The chirality of cyclopropane 23 dictated the absolute configuration of the resulting oxazine 26, from which (+)‐nakadomarin A (27) was synthesized in 22 linear steps (Scheme 12.5) [12]. OBn CO2Me CO2Me 23 OTBDPS

+

NHOH MeO 25

Yb(OTf)3, 4Å MS 100 °C 87% yield

O CHO Br 24 PMBN O Br OTBDPS

O

OBn

CO2Me CO2Me

H

N

H N

O

26 (+)-Nakadomarin A (27)

Scheme 12.5

Total synthesis of (+)-Nakadomarin A.

The Qin group developed the first total synthesis of (±)‐communesin F (33) that can act as an insecticide [13]. The synthesis commenced with the condensation of indole 28 and acid 29 followed by ketone‐to‐diazo functional transformation to produce 30. Next, CuOTf‐mediated intramolecular cyclopropanation led to the formation of the stable cyclopropane intermediate 31 as diastereomeric mixtures (dr 1.6:1).

12.2 Synthesis of Allaloids

Treatment of 31 with PBu3 in aqueous THF led to cascade ring opening and ring‐ closing reactions of cyclopropane with in‐situ generated aniline to furnish the pentacyclic compound 32 in diastereomerically pure form. (±)‐Communesin F (33) was synthesized from 32 in several steps with about 3% overall yield (Scheme 12.6) [14]. OH Br Et3N, CH2Cl2 TsNHNH2, TsOH CHCl3, reflux, 5 h 85% yield

0 °C, 5 h 95% yield

N Me

28 + O HO

SOCl2, 60 °C, 2 h

DBU, CH2Cl2, 12 h 85% yield

O N3 29 O

Br

N Me

N3

O

O

Br

O

CuOTf, CH2Cl2

N2

rt, 1 h 88% yield

30

N N3 Me 31 PBu3, aq. THF 0 °C, 0.5 h 83% yield

2'' Me

O H

N

N Me

H

N

H

N H

s-trans rotamer (minor) of (±)-communesin F (33b)

H

Me 2'' O H N N

N Me

N H

Br

O

N Me

O H H N H

32

s-cis rotamer (major) of (±)-communesin F (33a)

Scheme 12.6 Total synthesis of (±)-Communesin F.

The Kerr group also demonstrated the total synthesis of Securinega alkaloid (−)‐ allosecurinine (42) that was isolated from the plants of the Euphorbiaceae family [15]. Enantiopure cyclopropane 37 was the crucial substrate for this synthesis. Homoallylic alcohol 35 upon protection as p‐methoxyphenyl ether via Mitsunobu reaction followed by asymmetric dihydroxylation and dimesylation provided the compound 36. A double displacement reaction of 36 with dimethyl malonate produced cyclopropane 37, which upon deprotection followed by tosylation and displacement with N‐hydroxyphthalimide furnished the cyclopropane 38. Deprotection of 38 with ethanolic hydrazine formed the free cyclopropane 39, which underwent Yb(OTf)3‐catalyzed cyclization reaction with protected aldehyde 40 to provide the substrate 41. (−)‐Allosecurinine (42) was obtained from 41 in 13 steps with a 5% overall yield (Scheme 12.7). Pagenkopf and coworkers developed the shortest total synthesis of indole alkaloid (±)‐goniomitine (47) that was isolated from the root bark of Gonioma malagasy. The synthesis began with commercially available δ‐valerolactum, which upon

363

364

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products OH O

34

OMs

+ HO

36

35

Dimethylmalonate, NaH, THF, 0 °C then bismesylate reflux 45% yield

(i) CAN, 4 : 1 AcCN/H2O 93% yield MeO2C CO2Me (ii) TsCl, DABCO, H CH2Cl2, 0 °C to rt PMPO

(iii) N-hydroxyphthalimide, DBU, DMF 69% yield (2 steps)

37

MeO2C O N O

O ee ≥99% 38 Hydrazine hydrate, 3 : 1 EtOH/CH2Cl2

Yb(OTf)3·H2O (5 mol%) O

N O

MeO2C MeO2C

O (–)-Allosecurinine (42)

CO2Me

H

PMPO

N H

OMs

PMPO

CH2Cl2, 30 min, then H2N O O OPMP 40 88% yield

41

H

CO2Me CO2Me

39

Scheme 12.7 Total synthesis of (−)-Allosecurinine.

several steps formed the highly functionalized nitrile 44. [3+2] Cycloaddition of 44 with DA‐cyclopropane 45 afforded the substrate 46 from which (±)‐goniomitine (47) was synthesized in 10 steps with a 5.2% overall yield (Scheme 12.8). This is the first reported application for the [3+2] cycloaddition of DA‐cyclopropane with a nitrile moiety in the total synthesis of natural products [16]. The same group also accomplished the total synthesis of indole alkaloid (±)‐quebrachamine (48), starting from the same substrate δ‐valerolactum (43) [17]. (±)‐ Quebrachamine is a tetracyclic indole alkaloid and is isolated from Aspidosperma quebracho tree bark. Once again, the key step was the cycloaddition of DA‐cyclopropane OMe CO2Et NC

O NBn

O

TMSOTf, EtNO2 NBn

Et

43

45 74% yield

44 OH O CO2Et Et N H

46

NBn N H HN (±)-Goniomitine (47)

Scheme 12.8 Total synthesis of (±)-Goniomitine.

12.2 Synthesis of Allaloids

45 with functionalized nitrile moiety 44 to furnish the compound 46, as shown in Scheme 12.9. Another crucial step involved in the synthesis was the formation of the nine‐membered ring by photo‐induced cyclization strategy. Starting from δ‐valerolactum (43), (±)‐quebrachamine (48) was obtained with an overall yield of 17.8% over 13 steps (Scheme 12.9). O NC

OMe NBn

Me3SiOTf

+

EtNO2 74% yield

CO2Et 45

44 CO2Et

O

N H

N NBn

N H Quebrachamine (48)

46

Scheme 12.9 Total synthesis of (±)-Quebrachamine.

The Qin group also demonstrated the total synthesis of anti‐multi‐drug‐resistant indole alkaloid (−)‐ardeemin (55), that was isolated from the fermentation of a strain of Aspergillus fischeri [18]. The key step in the synthetic route involved a three‐step, one‐pot cascade reaction of 50 with diazoester 51 to construct the nonracemic 3‐substituted hexahydropyrrolo[2,3‐b]indole 54 via intermolecular cyclopropanation, ring opening, and ring closure. The total synthesis has been completed in 20 steps with an overall yield of about 2% (Scheme 12.10) [19]. O

O N H

L-trytophan 49

N Me 50

O

51

OEt

N

O

N Me N O H (–)-Ardeemin (55)

H O EtOC

Cu(OTf)-toluene toluene, 25 °C, 6 h 45% yield

COOEt

N

Scheme 12.10

N2

N N Me major 54

O O

Cascade

O O

N H N Me 52

O EtOC

O N H

O

N Me 53

Total synthesis of (−)-Ardeemin.

Spino and coworkers reported for the first time the total synthesis of optically active (+)‐aspidofractinine (62) that was isolated from the leaves of Pleiocarpa tubicana and Aspidosperma refractum [20]. Cu(I)‐catalyzed chemoselective cyclopropanation of 58 was employed as one of the key steps, and then 6‐exo trig radical

365

366

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

cyclization of 59b afforded the compound 60. Treatment of 60 with sodium anthracene radical anion resulted in the removal of the N‐protecting group, followed by ring‐opening of cyclopropane to synthesize the imine 61, which in some additional steps produced (+)‐aspidofractinine (62). Total synthesis of (+)‐aspidofractinine (62) has been accomplished from cheap indole moiety 56 in 21 steps with a 2.1% overall yield (Scheme 12.11). O O N H

N2

H

+ H

56

N PhO2S

57

Cu(OTf) (20 mol%)

N

Cl DCM 76% yield 58

O

O N X

N PhO2S

Bu3SnH, reflux

59a: X = Cl

NaI acetone

N

AIBN, PhH 92% yield for 2 steps

N PhO2S 60 Anthracene Na

59b: X = I

DME, –70 °C 96% yield O

N

N H (+)-Aspidofractinine (62)

Scheme 12.11

N

N 61

Total synthesis of (+)-Aspidofractinine.

The Kerr group also contributed to the total synthesis of FR901483 (71) and completed the synthesis in 18 linear steps [21]. FR901483 (71) is an immunosuppressive alkaloid isolated from the fermentation broth of Cladobotryum sp. [22]. The key step involved an intramolecular cyclization reaction of suitably disposed DA‐cyclopropane and an in situ‐generated imine in 69. Desymmetrization of prochiral spirofused cyclopropane and triethylborane promoted coupling of chiral α‐aminoaldehyde 66 and α‐iodocyclohexanone derivative 65, which were also the other important steps in the reaction sequence (Scheme 12.12). Jung et al. accomplished the total synthesis of (+)‐fawcettimine (82) which is a tetracyclic alkaloid of Lycopodium class [23]. The synthesis relied on the stepwise Mukaiyama–Michael addition of silyl enol ether of an acetylcyclopropane‐1,1‐ dicarboxylate 76 to the enone 78 followed by Wittig olefination, and then Sc(OTf)3 promoted intramolecular ring‐opening cyclization of cyclopropane 80 to afford hydrindanone 81 as a single diastereomer in good yield. From 81, (+)‐fawcettimine (82) could be synthesized following an additional nine steps (Scheme 12.13). Moreover, they have also established that the reaction follows an “SN2‐type” mechanism and is a diastereospecific reaction proceeding with complete retention of stereochemistry at the cyclopropyl center.

12.2 Synthesis of Allaloids OTMS

O Ph

N Ph H ·HCl

NIS, THF, –78 °C

n-BuLi,

THF TMSCl, –95 °C 98% yield, 82% ee

CO2Me CO2Me 63

97% yield, 5 : 2 dr

CO2Me CO2Me 64

NHBoc O

PMB (S) CHO

I

66

O

H

OH

BEt3, toluene, 0 °C-rt

CO2Me CO2Me 65

NHBoc

67% yield, contains 17% minor diastereomeric byproducts

CO2Me

OMe

CO2Me 67 1. NaBH(OAc)3, AcOH CH3CN, 0 °C 2. BnBr, Ag2O, Bu4NI 60 °C 53% yield (2 steps)

BnO Yb(OTf)3, (CH2O)n

H

OBn

BnO

H

OBn

TFA, 0 °C

4 Å MS Dichloroethane, 70 °C 67% yield

NH2

CO2Me

OMe

87% yield

CO2Me

OMe

CO2Me 69

O HO P HO O

NHBoc

CO2Me 68

BnO OMe

OMe HO

N

BnO

·2HCl MeHN

MeO2C CO Me 2

FR901483 (71)

Scheme 12.12

N

70

Total synthesis of FR901483.

The Shair group completed the total synthesis of Lycopodium alkaloid (+)‐fastigiatine (87) in 15 steps from cyclopropane 83 with an overall yield of 30% [24a]. (+)‐ Fastigiatine belongs to the lycodine structural class and was isolated from the alpine club moss Lycopodium fastigatum [24b]. The synthesis commenced with cyclopropane 83, which was prepared from (S)‐epichlorohydrin in four steps. 83 was then transformed to cyclopropane 84 in 83% yield upon transesterification with 2‐(trimethylsilyl)ethanol followed by treatment with Boc‐anhydride. Cyclopropane 84 underwent regioselective ring opening with mixed cuprate 85 to afford the key synthetic intermediate 86 in 93% yield (Scheme 12.14). Other important key steps involved in this total synthesis were diastereoselctive [3+3] cycloaddition and the transannular Mannich reaction to build the core of (+)‐fastigiatine (87). The Fukuyama group accomplished the first total synthesis of gelsemium ­alkaloid gelsemoxonine (100), which was isolated from the leaves of Gelsemium elegans [25]. The embedded spiro quaternary carbon center connected to bicyclic seven‐membered core 99 in this natural product was constructed via divinylcyclopropane‐cycloheptadiene rearrangement of highly functionalized substrate 97 (Scheme 12.15).

367

368

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

Me

1) NaHMDS MeO2CCl 2) NaHMDS

O

Me MeO2C

N O

PhSeBr Ph 3) H2O2 72 77% yield

H2SO4 MeOH

CO2Me

(S)

Me

O

S O

O

H

76 Tf2NH CH2Cl2

Me

DMF –40 °C to 50 °C 51% yield

77

Me

76

DBU Acrylonitrile

Ph

O

CO2Me CO2Me

TBSO NC 79

H

Me Ph3P CH2

(S)

–78 °C 85% yield

CN

78

O H

CO2Me CO2Me

75

Me

74

OTBS (S)

CH2 H

(R)

75% brsm TBSO NC

80

CO2Me CO2Me Sc(OTf)3 CH2Cl2 25 °C 77% yield

H

Me

H

Me O

HO

CH2 (S)

N

O

CO2Me

CN CO2Me (+)-Fawcettimine (82)

Scheme 12.13

81

Total synthesis of (+)-Fawcettimine. Me

O 1. cat. KH TMSEOH

O

O

NH

EtO

2. Boc2O 83% yield (2 steps)

83

TMSE O

Me

O

85 NH

TMSEO 84 Me

O

O

Me N

NBoc O

O

O

Me N

O 86

Scheme 12.14

O

(+)-Fastigiatine (87)

Total synthesis of (+)-Fastigiatine.

O

N

Ph

73

CH2Cl2 97% yield

CO2Me

MeO2C

71% yield

TBSOTf DIPEA

O

reflux 78% yield

N O

H Me

O H2C SMe2

O

CuLi·LiI

tBu

THF, –78 → 0 °C 93% yield

Ph

Br O

OH O

EtO2C

O OAc 89 74% ee

88

O H

CO2Et 90

DBU, THF, 0 °C 78% yield

O R H CO2Et

EtO2C

HO H

NaBH4, MeOH (slow addition) THF, reflux, AcOH, 0 °C 84% yield

HO 93

91: R = OAc TMSOTf, Et3SiH

lipase CR n-BuOH/n-hexane rt, 65% yield

H OH

1. Piv2O, pyridine, DMAP CH2Cl2, reflux 86% yield

MeCN, 0 °C to rt 82% yield 92: R = H

>99% ee

O

2. IBX, DMSO, 50 °C 93% yield

TMSO H O

H

Toluene, 70 °C, 30 min

O PivO SiMe3 O

N

OMe

PivO

TBAF, AcOH, rt 89% yield (2 steps)

O

98

O

O

N OMe

HO

O PivO

O 99

O

N H

O H

O

LHMDS, –78 °C

N MeO 97

N OMe O

Gelsemoxonine (100)

Scheme 12.15 Total synthesis of Gelsemoxonine.

1. n-Bu2BOTf, i-Pr2NEt H

TMSCl, THF PivO O

N MeO 96

O H

O CH2Cl2, –78 °C 2. MsCl, TMEDA CHCl2, –78 °C 88% yield (2 steps)

O H CHO

PivO 94 O N MeO 95

370

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

In 2011, the Stoltz group reported an efficient approach for the synthesis of melodinus alkaloids. These alkaloids belong to the dihydroquinolinone family of natural products and were isolated from Melodinus scandens Forst. They performed palladium‐catalyzed [3+2] cycloaddition reaction of β‐nitrostyrene 101 with vinylcycloprpane 102 to construct the cyclopentane core 103 of melodinus alkaloids (104) (Scheme 12.16). Following this strategy, the synthesis of the tetracyclic ABCD ring system of this natural product family could be easily accomplished in six steps from commercial sources [26]. NO2 Pd2(dba)3, dppe

+ MeO2C

NO2 101

THF, 40 °C, 14 h 60% yield

CO2Me

102 O

O2N NO2

H

H H

MeO2C

H

CO2Me

N O H ABCD ring systems of Melodinus alkaloids (104)

103

Scheme 12.16

Synthesis of ABCD ring systems of Melodinus alkaloids.

The Harrity group described an enantiospecific and diastereocontrolled approach to the total synthesis [27] of quinolizidine alkaloid (−)‐217A (109) which was isolated from the Madagascan frog Mantellabaroni. One of the key steps in this total synthesis was the piperidine 2,3‐cyclopropanation‐ring‐opening reaction. Cyclopropanation of enamide 106 produced the corresponding cyclopropane 107 in excellent yield, and 107 underwent ring opening to afford aminal 108, from which quinolizidine (−)‐217A (109) could be obtained in several steps (Scheme 12.17) [28]. NH3Cl MeO2C

CH2I2, Et2Zn, toluene N Ts OTBDPS

CO2Me 105

NIS MeOH

85% yield, >95 : 5 dr

106

I N OMe Ts OTBDPS 108

N Ts OTBDPS 107

Me H N

Quinolizidine (–)-217A (109)

Scheme 12.17 Total synthesis of Quinolizidine (−)-217A.

The Curran group demonstrated the first stereoselective synthesis of Melodinus alkaloids (±)‐meloscine (120) and (±)‐epimeloscine (119). The strategy commenced with Rh(I)‐catalyzed cyclopropanation of bisbenzyl ether 110 to yield the trisubstituted

12.2 Synthesis of Allaloids

cyclopropane 111. One key chemical step in the reaction sequence was the stereoselective cascade radical annulation of divinylcyclopropane 116 for the generation of two rings in compound 117. The total synthesis of (±)‐epimeloscine (119) has been completed with an overall yield of 6%, and (±)‐meloscine (120) was synthesized from (±)‐ epimeloscine (119) by epimerization (Scheme 12.18) [29].

BnO

BnO

N2CHCO2Et

OBn

Rh(OAc)2 66% yield

110

O

1. Pd(OH)2, H2 O

2. TEMPO, PhI(OAc)2 86% yield

O

O OEt 112

OBn OEt 111

1. Ph3P CH2 2. LiOH 60% yield

NBoc

NH2 H

N

O

115

O

Pyridine, DMAP NBoc

O

77% yield

116 Z-rotamer favored O

O

H Bu3SnH

HN

1. TFA

38% yield

2. allyl bromide 73% yield

NBoc

Cl 114

H

HN

OH 113 Ghosez reagent Me2C C(Cl)NMe2

NBoc

118

117

RCM 89% yield O

O

H

HN

KOtBu 83% yield

N Epimeloscine (119)

Scheme 12.18

H

HN N Meloscine (120)

Total synthesis of (±)-Epimeloscine and (±)-Meloscine.

The France group completed a diastereoselective synthesis of (±)‐deethyleburnamonine (127) in six steps with about 18% overall yield. (±)‐Deethyleburnamonine represents the simplest example of both eburnan and tacaman classes of alkaloids (no ethyl group present), which exhibit interesting pharmacological properties. Generation of ABDE portion of the target 126 via tandem ring‐opening/Friedel– Crafts alkylation of donor–acceptor–acceptor amino cyclopropane 125 under the influence of an indium(III) catalyst served as the key step for the synthesis (Scheme 12.19). Apart from that, this total synthesis exploited the following key reactions: (i) Generation of C ring via TFA‐mediated N‐Boc deprotection/N‐alkylation and (ii) a Krapcho decarboxylation to produce the target compound [30].

371

372

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products Br BocN

N H 121

O

O

Cl

124

OMe

N

+ O

O Rh2esp2

N2

Br OMe

DCM, rt 49% yield

123

122 O

O OMe

N Br

DCM, rt 71% yield

BocN

O

In(OTf)3 (30 mol%)

H

N Br

125

O H

OMe

H BocN 126 dr 3 : 1

O N H

H N

(±)-Deethyleburnamonine (127)

Scheme 12.19

Total synthesis of (±)-Deethyleburnamonine.

The Jiang group reported a Lewis acid‐copper (I) binary catalyst‐mediated reaction between cyclopropyl aldehydes and nitriles to synthesize fused indolizinones via Lewis acid‐induced ring‐opening of cyclopropyl aldehydes with nitriles followed by copper(I)‐catalyzed Ritter reaction and acid‐promoted N‐acyliminium ion cyclization sequence. This unique process has been applied to the total synthesis of bioactive crispine A (130) [31]. Indolizidine alkaloid cripsine A was isolated from Carduus crispus and possesses antitumor activity against SKOV3, KB, and HeLa human cancer lines [32]. Treatment of cyclopropane carbaldehyde 128 with benzylamine resulted in the formation of aldimine, which, when reacted with 129 under standard indolizinone formation reaction conditions led to 3,4‐dimethoxyphenyl indolizinone. It underwent lithium aluminum hydride‐induced reduction to produce crispine A (130) (Scheme 12.20). 1. BnNH2, TsOH, 4 Å MS, toluene; then O O CHO

CN 129

CuBr, PBu3 BF3·Et 2O, H2O

128

MeNO2, 90 °C, 18 h 2. LiAlH4-Et3NHCl, THF

Scheme 12.20

Synthesis of Crispine A.

O

N

O Crispine A (130)

12.2 Synthesis of Allaloids

The Waser group accomplished the first total synthesis of Aspidosperma indole alkaloid (±)‐jeratinine E (136), which was isolated from a leaf extract of the Malayan plant Tabernaemontanan corymbosa and was found to exhibit cytotoxic activity against human KB cells. δ‐Valerolactum served as the starting material for the synthesis. The key synthetic step was the selective formal homo‐Nazarov cyclization of aminocyclopropane to form four of the five rings contained in the final product. The synthesis commenced with the preparation of Weinreb amide 132 from δ‐valerolactum 131 in seven steps, followed by treatment of 132 with the organolithium reagent generated from N‐carboxy indole 133 to afford the aminocyclopropane 134, which underwent homo‐Nazarov cyclization to produce cis‐diastereomer of 135. Other key reactions involved in the reaction sequence were the installation of an ester group onto the core and a late‐stage selective demethylation. Utilizing this protocol (±)‐jeratinine E (136) was obtained in 16% overall yield over 17 steps starting from δ‐valerolactum 131 (Scheme 12.21) [33]. CO2H N

MeO O

H N

O

Et

MeO

Me O N H Me

131

O HN

133

Et

H

N Cbz

tBuLi,

LiCl, THF –78 to –20 °C

N Cbz

MeO

132

134

OMe

20 mol% Cu(OTf)2 CH3CN H N

CO2Me Et

MeO HO

N

Jerantinine E (136)

Scheme 12.21

O

H N

Et MeO MeO

CbzN 135

Total synthesis of (±)-Jerantinine E.

Ivanov et al. developed a new method for SN2‐type ring‐opening of various DA cyclopropanes with azide ions, and the reaction proceeds in a highly regioselective and stereoselective manner where the nucleophilic attack takes place at the more substituted C2 atom of the cyclopropane with complete inversion of configuration at C2. This developed methodology was successfully applied to the synthesis of natural products and medicines like (−)‐nicotine (139) and atorvastatin (Lipitor) (142). (−)‐Nicotine belongs to the tobacco alkaloid family and is well known for its effect on the central nervous system. It may also be used as an insecticide. The synthesis began with the ring opening of optically active 3‐pyridyl‐derived cyclopropane (R)‐137 with azide ions under the standard conditions to afford the ring‐opening product (S)‐138. Krapcho dealkoxycarbonylation of the ring‐opening product (S)‐138 followed by treatment with Ph3P furnished the corresponding lactum, which

373

374

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

upon reduction with LiAlH4 and then reductive methylation produced (−)‐nicotine (139) (Scheme 12.22). N

CO2Me CO2Me N

NaN3, Et3N·HCl N3

137

Scheme 12.22

N

CO2Me

DMF, 100 °C

N

CO2Me 138

(–)-Nicotine (139)

Total synthesis of (−)-Nicotine.

This methodology was further used for the preparation of synthetic drug ­ atorvastatin (142), the calcium salt of which is being used as the cholesterol‐ lowering medication Lipitor. The synthesis commenced with ring opening of 4‐F‐phenylcyclopropane‐1,1‐diester 140 with azide ion under the developed reaction condition to form the ring‐opening product 141, which underwent Staudinger/ aza‐Wittig reaction, dehydrogenation, bromination, and Suzuki cross‐coupling to produce tetrasubstituted pyrrole intermediate from which atorvastatin (142) could be synthesized following literature reports (Scheme 12.23) [34]. Ph CO2Et CO2iPr

NaN3, Et3N·HCl DMF, Δ

F

140

Scheme 12.23

CONHPh

F CO2Et N3

N

F OH

O

141

O

HO2C

OH

Atorvastatin (142)

Synthesis of Atorvastatin.

The Gelsemium alkaloids enjoy a special stardom in natural product chemistry. The flowering plants belonging to the family Gelsemiaceae that produce these toxic alkaloids have been well documented in the literature. They find application in traditional Asian medicine for the treatment of various ailments [35]. Ferreira and co‐workers have reported the first total synthesis of (±)‐gelsenicine featuring cyclopropanation in an important step. From the known aldehyde 143, the diyne precursor EE‐144 was synthesized in three steps. Au‐catalyzed cycloisomerization/Cope rearrangement of EE‐144 gave bicycle 146 via the formation of the cyclopropane intermediate E‐145. This compound 146 after a series of transformations converted to (±)‐gelsenicine (147) in 66% yield (Scheme 12.24) [36]. The steroidal alkaloid (−)‐batrachotoxin (153) is a lethal component of the Colombian poison dart frogs and acts as a powerful agonist of voltage‐gated sodium channels (NaVs). In 1963, the toxin (−)‐batrachotoxin was first isolated by Witkop and co‐workers from the membrane extracts of Phyllobates bicolor [37]. Thus, on account of its compelling biological activity and exhilarating chemical structure, Du Bois and co‐workers accomplished the total synthesis of both (−)‐batrachotoxin and its enantiomer in 2016, as shown in Scheme 12.25 [38]. Ketalization and enol ether

12.2 Synthesis of Allaloids t-Bu t-Bu PH -Au NCHCH3

Ph O

O

3 steps

CHO

CO2Me

SbF6

(cat.) 93%

H

Me

143

(E,E)-144 O

H O

CO2Me

MeOH 60 °C

H Ph

NOMe

CO2Me

75%

Me

N O

Et

146

Geisenicine (147)

Total synthesis of (±)-Gelsenicine. 1. HO

OH HCl H2, Pd/C

Me O

148 Hajos-Parrish ketone

O Me

Me OTES tBuOK

O

2. TESOTf/ Et3N 78% (2 steps)

O

O

CHBr3 53%

H

O

HO Me

O

O NH Me

O H

Me

HO Me

N H 152

Et3N, Δ 79%

(–)-Batrachotoxin (153)

Scheme 12.25

Me N Me

Me

EtO2CO

O

H 150

O

Me Me N Me

Br

O

149

HO

H

H

Me (E)-145

Scheme 12.24

O

Ph

OH

O

O HO

H

Batrachotoxinin A (151)

Total synthesis of (−)-Batrachotoxin.

formation of Hajos–Parrish ketone 148 gave 149, which was reacted with in situ‐ generated dibromocarbene, followed by ring expansion to afford the vinyl bromide 150. After a series of reactions 150 furnished batrachotoxinin A (151) which on esterification at the C‐20 position furnished (−)‐batrachotoxin (153). The kainoid amino acids have stimulated great attention on account of their numerous biological properties, such as neuroexcitatory and excitotoxic activities [39]. β‐Allokainic acid (158) belongs to such kainoid alkaloid family. Kerr and coworkers have developed a simple route to substituted 2,5‐dihydrooxepine rings 157 through a vinylogous Cloke–Wilson rearrangement [40] of DA cyclopropane 156. The compound 157 was converted to (±)‐β‐allokainic acid (158) after a few steps (Scheme 12.26) [41]. GB alkaloids are found in the bark of Galbulimima belgraveana and G. baccata native to Papua New Guinea, Malaysia, and Northern Australia. It leads to

375

376

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products O +

O

O

H

OEt

H

Rh2(eps)2

OEt

N2

O

155

154

156

O EtO CO2H HN

O

(±) β-Allokainic acid (158)

157

Scheme 12.26

CO2H

Total synthesis of (±)-β-Allokainic acid.

psychedelic effects when the barks are munched, and in addition, it also finds application in traditional medicine [42]. In 2019, Shenvi and co‐workers accomplished the synthesis of GB22 (164) via Ir/Ni dual‐catalytic siloxycyclopropane C─C bond cleavage/arylation, as shown in Scheme 12.27 [43]. The synthesis started with the commercially available ketone 159, which was first converted into the silyl‐enol ether, and subsequent Simmons–Smith cyclopropanation led to siloxycyclopropane 160. Iridium photocatalysis followed by nickel‐catalyzed cross‐coupling of siloxycyclopropane 160 with bromoarene 161 afforded 162. Next, a Friedel–Crafts alkylation reaction was carried out using Et2AlCl in HFIP to furnish 163. After diastereoselective hydrogenation of the pyridine ring of 163 from the convex face, followed by reductive amination with formaldehyde afforded (±)‐GB22 (164) in 64% yield. O

Me

1. TMSOTf, Et3N 2. Et2Zn, TFA, CH2I2 (65% , 2 steps)

N 159

Br

O OBn

TMSO

161 Me

Me

N 160

N OBn

[Ir dF(CF3)ppy 2 (dtbbpy)]PF6 NiCl2•glyme, dtbbpy, KH2PO4, DMSO, blue LED 48%

162 Et2AlCl, HFIP 52%

Me Me

Me N H

HO

N

1. Rh/Al2O3, H2 2. CH2O, NaBH3CN 64%

OH GB22 (164)

Scheme 12.27 Total synthesis of GB22.

H HO

OH 163

12.2 Synthesis of Allaloids

The indole alkaloid Melokhanine E (171) was isolated in 2016 from Melodinus khasianus, a subtropical plant used in traditional Chinese medicine for the treatment of rheumatic heart disease and meningitis [44]. Recently, the Pierce group unveiled a 12‐step convergent synthesis of (±)‐melokhanine E (171) with an 11% overall yield, as shown in Scheme 12.28 [45]. The approach employed the application of two cyclopropane moieties 166 and 169 as reactive precursors to a 1,3‐dipole and imine species to assist stereoselective creation of the core scaffold through MgI2‐mediated formal [3+2] cycloaddition. Piperidine derivative 169 and spirocyclic cyclopropane 166 were prepared by the reported literature procedure from anthranilic acid 167 and delta‐valerolactam 165 in 6 and 4 steps, respectively. MgI2 promoted ring‐opening/cyclization of coupled biscyclopropane 170 under microwave conditions, resulting in the spirocycle opening and the thermolysis of the Boc‐ carbamate to form the reactive imine intermediate, which subsequently underwent the formal [3 + 2] cycloaddition, affording the (±)‐melokhanine (171) in 88% yield as a single diastereomer. O

O

O

4 steps

NH

N H 166

165

Collidine triphosgene

OH

O OH + NH2

6 steps

O O

167

O

H N

Boc

N H

O

N

CH2Cl2 40 °C, 45%

170

Br 168

Boc

MgI2, Microwave, toluene, 200 °C

169

O N N

H

O (±)-Melokhanine E (171)

Scheme 12.28

Racemic total synthesis of (±)-Melokhanine E.

The Daphniphyllum alkaloids show a wide range of biological activities spanning from anticancer, anti‐HIV, and antioxidation, to vasorelaxant activities [46]. Qiu and coworkers developed an efficient general strategy for the synthesis of the total synthesis of (−)‐daphenylline (177) and (−)‐himalensine A (179) (Scheme 12.29) [47]. The amide atropisomers 173 were generated in several steps from (S)‐carvone 172. The addition of diazo acetoacetamide into a solution of [Cu(tbs)2] in toluene afforded cyclopropyllactone 174, which underwent a formal Cope rearrangement in the presence of tri‐tert‐butylphosphine to afford cycloheptenone 175 in an 82% yield [48]. Next, the diene 176 was generated from 175 in an overall 81% yield. The diene 176 acted as a common intermediate for the synthesis of calyciphylline A‐type alkaloids, i.e. (–)‐daphenylline (177) and (–)‐himalensine A (179).

377

378

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

6 steps

1. DBU, p-ABSA CH3CN

O N

2. Cu(tbs)2, toluene 55%

O

(S)-carvone 172

N

O

O

O

173

174 tBu P 3 PhCl, 82%

N

H

H

Daphenylline (177)

SO2Ph 1. PhO2S toluene, DBU 77%

4 steps

2. Lawesson reag. 3. Raney Ni 74%

H

N O

H

H

N O

H

O

175

176 1. m-CPBA, CH2Cl2 2. K2CO3 /MeOH, 72% 3. DMP,CH2Cl2 4. NaOMe, MeOH 77%

O O H

2. NaBH(OAc)3 CH3COOH CH2Cl2, 24%

N H Himalensine A (179)

Scheme 12.29

O O H

1. [Ir(CO)(PPh3)2Cl] TMDS,CH2Cl2 N O

H 178

Total synthesis of (−)-Daphenylline and (−)-Himalensine A.

Lyconesidines A and B were first isolated from the club moss, Lycopodium chinense, by Kobayashi and co‐workers in 2002 [49]. In 2021, Takemoto et al. reported the synthesis of Lyconesidine B (183) in overall 30 steps, as shown in Scheme 12.30, involving domino cyclopropanation and ring‐opening [50]. The synthesis began with triflate 180 prepared from δ‐valerolactam and it was converted to the diazo compound 181 after several steps. The diazo compound 181 on treatment with a combination of CN

OTBS (NHCOtBu)

Rh2 4 (0.4 mol%, CH2Cl2

N2 N OTf Boc 180

N Boc

CN O 181

NaBH(O2CCF3)3 THF, 72%

O NC OTBS N

Boc

181a Domino cyclopropanation and ring-opening

Scheme 12.30

Total synthesis of Lyconesidine B.

H

N

Boc 182

O OTBS

OH HO

OH H

N Lyconesidine B (183)

12.3 Synthesis of TerpeneeTerpenoids

Rh2(NHCOtBu)4 and NaBH(O2CCF3)3, prepared from NaBH4 and TFA (1:3), gave 182 in 72% yield as the single product. The reaction advanced through cyclopropanation, ring‐opening of the unstable intermediate (181a), followed by the reduction of an iminium ion to generate decahydroquinoline 182. Lyconesidine B (183) was obtained from 182 after several steps with a 0.52% overall yield.

12.3

Synthesis of Terpene/Terpenoids

Terpene or terpenoids are a prominent class of natural products found in various fungi, algae, plants, and sponges. They have achieved significant pharmaceutical value because of their broad spectrum of medical applications. Apart from that, they also provided humans with hormones, flavors, fragrances, and commercial products. This section of this chapter highlights the recent total syntheses of terpenes/terpenoids employing DA‐cyclopropane chemistry. The sesquiterpenes (+)‐(R, S)‐isoclavukerin (188) and (−)‐(S, S)‐clavukerin A (189) were isolated from the Okinawan soft coral Clavularia koellikeri [51]. Alexakis et al. reported a tandem asymmetric formal total synthesis of (+)‐(R, S)‐isoclavukerin (188) and (−)‐(S, S)‐clavukerin A (189), as shown in Scheme 12.31 [52]. Silylation of the conjugated adduct zinc enolate 185 of 184 was carried out with TMSOTf at room temperature. This silyl enol ether was then subjected to cyclopropanation employing diiodomethane to furnish the cyclopropanol 186 with excellent yield (95%) and enantiomeric excess (98%). FeCl3 promoted radical cleavage of the cyclopropane ring followed by the elimination of the corresponding α‐chloro ketone to give the γ‐methylenone 187 in an excellent yield (90%). 187 acted as an intermediate for the synthesis of (+)‐(R, S)‐isoclavukerin (188) and (−)‐(S, S)‐clavukerin A (189). The Narasaka group reported for the first time the total synthesis of (−)‐sordarin (198). It is a potent antifungal agent, and its structure contains a diterpene aglycon. One of the key steps in this synthesis involves oxidative radical cyclization of O

3 Me2Zn, 1 mol% CuX, 2 mol% L* Ph

184 L* =

O O

OZnMe

1. 1.5 equiv. TMSOTf 2. 2 equiv. CH2I2 3. NH4Cl sat.

Me 185

TMSO

n Me 186 1. FeCl3 2. NaOAc 90%, 90% ee

Ph

O H (+)-(R,S)- Isoclavukerin (188) n 187

Me

H (–)-(S,S)-Clavukerin A (189)

Scheme 12.31

Total synthesis of (−)-(S, S)-Clavukerin A and (+)-(R, S)-Isoclavukerin.

379

380

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

cyclopropanol derivative 192 in the presence of an Ag(I) catalyst. The reaction of 192 with AgNO3‐(NH4)2S2O8‐pyridine system in the presence of 1,4‐cyclohexadiene in DMF leads to the stereoselective formation of optically active bicyclo[5.3.0]decan‐3‐ one skeleton 194 via cyclization of β‐keto radical intermediate 193. Bicyclic compound 194 was further converted to (−)‐sordarin (198) in several steps (Scheme 12.32) [53]. O

OTMS

MgBr cat. CuBr·SMe2 TMSCl, HMPA THF, –78 °C, 1 h 91% yield

OTBS 190

OTBS 191 Cat. AgNO3 (NH4)2S2O8 1,4-cyclohexadiene

OH (i) Et2Zn, CH2I2, Et2O, reflux, 13 h (ii) K2CO3, MeOH, rt, 1 h 82% yield

O

pyridine, DMF H

20–25 °C, 4 h 85% yield

OTBS 192

H

193

H

OH

H OHC CO2Et 195

MeO

OH OH

HO HO

O

Me OPMB F O

O

OH

OTBS 194

O

OH Me O OMe OH

H OHC CO2H

196 OMe 197

Scheme 12.32

O

H

H 195

OTBS

(–)-Sordarin (198)

Total synthesis of (–)-Sordarin.

Reiser group devised the first enantioselective synthesis of guaianolide (+)‐arglabin (208) [54]. This natural product was isolated from Artemisia glabella and exhibits antitumor activity against different tumor cell lines. The first step involved the copper(I)‐catalyzed synthesis of cyclopropanealdehyde 201 in diastereo and enantiomerically pure form followed by borontrifluoride‐mediated Sakurai alkylation and then cascade retroaldol/lactonization reaction to generate compound 207. A second Sakurai alkylation on 207 followed by ring‐closing metathesis produced the targeted natural product (+)‐arglabin (208) (Scheme 12.33). Pseudolaric acid B (215) is a bioactive diterpene acid and is isolated from the extract of the root bark of Pseudolarix kaempferi Gordon (pinaceae). This natural product is also found to exhibit potent cytotoxic, antifertility, and antifungal activities. Trost and coworkers reported the asymmetric synthesis of pseudolaric acid B

12.3 Synthesis of TerpeneeTerpenoids

O

1. Ethyldiazoacetate Cu(OTf)2, (R,R)-iPr-box PhNHNH2, CH2Cl2 85–90% ee

CO2Me

2. Recrystallization (pentane) >99% ee, 38% yield

199

H EtO2C H

CO2Me

O 200

MeO2C(O)CO

1. O3, CH2Cl2, –78 °C

OHC

2. Dimethylsulfide, 94% yield

CO2Et

H 201

O

OSiMe3 CH3MgCl, TMSCl, CuI LiCl, THF, –78 °C, 4 h

OPMB 202

OPMB

90% yield

203 CH3 OPMB SiMe3

TMSCH2MgCl, [Ni(acac)2] Et2O, reflux, 16 h

201 BF3

Me3Si

72% yield

H OPMB

–EtOH 62% yield

H

H

H R=

OH

OH

H

O

H

(+)-Arglabin (208)

Scheme 12.33

C(O)CO2Me 201

OH H CO2Et OR 205

H CHO H

O

O H

H

H

206 H

H CO2Et OR

CH3 OPMB

CO2Et OH

H

BF3

O

H

204

CH3 OPMB

204

H

O

O H H 3C

OPMB

207

Total synthesis of (+)-Arglabin.

starting from two simple precursors, 2‐acetylbutyrolactone 209 and cis‐butenediol 211 [55]. Cyclopropanaldehyde 212 was synthesized via Charette cyclopropanation from 211, and subsequent reactions furnished the vinylcyclopropane 213 with 10:1 E/Z selectivity. The key step involved the Ru‐catalyzed [5+2] cycloaddition reaction in 213 to give polyhydroazulene core 214 with 15:1 diastereosectivity (Scheme 12.34). Other key steps involved alkoxycarbonyl radical cyclization and selective cerium acetylide addition to form the tricyclic core of pseudolaric acid B (215) stereoselectively.

381

O

OTBS

O

Me

I

Me

O

210 209

(i) TBDPSCl, imidazole, THF 92% yield HO

OH 211

(ii) Et2Zn, DME, CH2I2 Charette's auxillary CH2Cl2, –10→23 °C 91% yield, >90% ee (iii) (COCl)2, DMSO, NEt3 CH2Cl2, quant

TMS

O

OTBDPS

(i) MePh3P+Br–, PhLi/LiBr, THF (ii) 210, 0 °C, then PhLi/LiBr (iii) 212, –78 °C, then PhLi/LiBr, 23 °C (iv) HCl, –78 °C, then KOtBu, 23 °C

212

TBDPSO K2CO3, MeOH 58% yield over two steps (53% (E)-213)

TBSO Me

H

213

[CpRu(CH3CN)3]+PF6– acetone O O

HO2C Me

Me H

O

H Me TBSO

O CO2Me

Pseudolaric acid B (215)

Scheme 12.34 Total synthesis of Pseudolaric acid B.

Me

H dr = 15 : 1 214

OTBDPS

12.3 Synthesis of TerpeneeTerpenoids

Yu and coworkers demonstrated a general method to build up triquinane skeleton via tandem Rh(I)‐catalyzed two‐component [(5+2)+1] cycloaddition/aldol condensation strategy [56]. This devised method was employed for the racemic synthesis of two representative linear triquinanes, (±)‐Hirsutene (220) and (±)‐1‐Desoxyhypnophilin (221), which are a subset of polyquinanes representing an important class of sesquiterpenoids. The syntheses commenced with Horner–Wadsworth–Emmons olefination of dimethylhexenal 216, followed by treatment with TBSOTf and Et3N to form silylenol ether 217. Chemoselective cyclopropanation of 217 provided pure (Z)‐ene‐vinylcycloprpane 218, which underwent [(5+2)+1] cycloaddition to afford the desired tricyclic ketone 219 in diastereomerically pure form. This was the common key intermediate for the synthesis of two targeted natural products: (±)‐hirsutene (220) and (±)‐1‐desoxyhypnophilin (221). From 219, these two natural products were synthesized following some additional steps (Scheme 12.35). CH2I2 CHO

Et2Zn 86% yield

OTBS

216

OTBS

217

1. 0.2 atm CO + 0.8 atm N2 cat. [Rh(CO)2Cl2], dioxane 80 °C, 48 h

218 OH

H

2. HCl-H2O, rt, 1 h 60–62% yield

H

H

H

H

O

219

Hirsutene (220)

O

H

O H 1-Desoxyhypnophilin (221)

Scheme 12.35

Total synthesis of Hirsutene and 1-Desoxyhypnophilin.

The Yu group further synthesized another two important terpenoids, (±)‐asterisca‐3(15),6‐diene and (±)‐pentalenene, following the Rh‐catalyzed [(5+2)+1] cycloaddition strategy. Compound 224 was prepared from commercially available aldehyde 222 in two steps, and 224 was then converted to bicyclic cyclooctenone 225 under Rh‐catalyzed [(5+2)+1] cycloaddition reaction. 225 was the common intermediate for the synthesis of two natural products: (±)‐asterisca‐3(15),6‐diene (226) [57] and (±)‐pentalenene (227) (Scheme 12.36) [58]. The same analogy, tandem Rh(I)‐catalyzed [(5+2)+1] cycloaddition/aldol condensation had been again used by the Yu group to synthesize linear triquinane natural product (±)‐hirsutic acid C (232) [59], which belongs to the tricyclic sesquiterpene class [60]. The β‐ene‐vinylcyclopropane substrate 230 was prepared first starting from ester 228 and then 230 was subjected to the tandem [(5+2)+1]/aldol reaction conditions. This reaction showed poor diastereoselectivity, and two inseparable

383

384

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products H 1. MeOCH2PPh3Br KOtBu, THF, 0–20 °C

222

H

CHO

2. H2SO4, THF-H2O, rt 68% yield

CHO

(±)-Asterisca-3(15),6-diene (226) 216 Balloon pressured mixed gas (0.2 atm CO + 0.8 atm N2)

CH2PPh3Br

5 mol% [Rh(CO)2Cl]2, dioxane 0.05 M, 90 °C

223

O

H

65% yield

nBuLi, THF, 0 °C 90% yield

H

224

225

H

(±)-Pentalenene (227)

Scheme 12.36

Total synthesis of (±)-Asterisca-3(15),6-diene and (±)-Pentalenene.

cycloadducts 231 and 231´ were produced in a 1:1.5 ratio where the minor diastereomer 231 was the desired product. Then the mixture of 231 and 231′ was subjected to some sequential reactions to complete the total synthesis of (±)‐hirsutic acid C (232) (Scheme 12.37).

MeO2C Me

MeO2C Me

Me

CO2Me 228

229 H

1. 0.2 atm CO [Rh(CO)2Cl]2 dioxane, 80 °C

MeO2C Me

2. HCl-H2O, rt [(5+2)+1]/aldol reaction MeO2C Me

H 231

H 231'

Me

CH2Cl2, 25 °C 54% yield OTBS

Me

230

OTBS

OH

H

O

+ H

MeO2C

CH2I2, Et2Zn

O

MeO2C OH

H

OH

(±)-Hirsutic acid C (232) O

52% combined yield (231:231' = 1 : 1.5)

Scheme 12.37 Total synthesis of (±)-Hirsutic acid C.

The Yu group further developed a new strategy for the synthesis of bicyclic cyclohexenones and cyclohexanones by Rh(I)‐catalyzed [(3+2)+1] cycloaddition reaction of 1‐yne/ene‐vinylcyclopropanes and CO [61]. This reaction can be considered as a homologous Pauson–Khand reaction. This analogy has been used for the

12.3 Synthesis of TerpeneeTerpenoids

synthesis of (±)‐α‐agarofuran, a furanoid sesquitepenoid natural product. The key step for the synthesis was [(3+2)+1] reaction of 1‐yne‐VCP 238 and CO to furnish bicyclic skeleton 239. The targeted natural product (±)‐α‐agarofuran (240) was synthesized from 239 following some additional steps (Scheme 12.38). CO2Et

CO2Et

MgBr CuCN BF3·OEt 2

233

234

66% yield MeO2C I

1. DIBAL-H 2. I2, PPh3 imidazole 73% yield (2 steps) O

236 CO Me 2

Me

NaH 69% yield

235

MeO2C

CO, [Rh(CO)2Cl]2

MeO2C

Me

[(3+2)+1] cycloaddition 86% yield, dr 15 : 1

Me (±)-α-Agarofuran (240)

Scheme 12.38

O

Me

237 LiCl, DMF 88% yield

Me

Me

MeO2C MeO2C

239

238

Total synthesis of (±)-α-Agarofuran.

The Wang group first time reported the construction of bridged oxa‐ and aza‐ [n.2.1] (n = 2, 3, 4) skeletons via Lewis acid‐catalyzed type II intramolecular [3+2] cycloaddition reaction of cyclopropane‐1,1‐diester with carbonyls and imines. The devised analogy was further employed for the total synthesis of platensimycin (246) [62], a promising antibacterial agent [63]. The synthesis commenced with the preparation of cyclopropane‐1,1‐diester 243 from 241. The key step was Sc(OTf)3‐ catalyzed [3+2] intramolecular cycloaddition of 244 to afford compound 245, which, following some additional steps [64, 65] produced platensimycin (246) (Scheme 12.39). Br

Me3SOI, NaH, DMSO 90%)

CO2Me

O O

CO2Me

OMe

CO2Me OMe

OMe 242

241

CO2Me

243 OsO4, NaIO4, THF/H2O = 2 : 1 91%

OH O HO2C OH

O

N H

CO2Me CO2Me O

Scheme 12.39

CO2Me CO2Me

87% yield

O Platensimycin (246)

O

Sc(OTf)3 (20 mol%), DCE

OMe 245

Total synthesis of platensimycin.

OMe 244

385

386

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

Davies and Sarpong groups synthesized [66] two important diterpenes, (+)‐barekoxide (250) and (−)‐barekol (251) that were isolated from the Kenyan sponge Raspailia sp. [67]. The synthesis was based on dirhodium catalyst Rh2(R‐PTAD)4‐ catalyzed tandem cyclopropanation/Cope rearrangement of bicyclic diene 247 and siloxyvinyldiazoacetate 248 to furnish the tricyclic compounds 249 and 249′ with a 6:1 diastereomeric ratio from which 249 could be separated in pure form with a 47% yield via recrystallization. Here, the diastereoselectivity was completely controlled by the chiral catalyst. The reaction proceeded by cyclopropanation, followed by cope rearrangement of the resulting divinylcyclopropane. From 249, (+)‐barekoxide was synthesized in six steps. Now (+)‐barekoxide (250) was converted to (−)‐barekol (251) via acid‐catalyzed isomerization reaction (Scheme 12.40) [68]. N2 +

H

CO2Me

Rh2(R-PTAD)4 hexanes, reflux

OTBS

CO2Me 65% combined yield OTBS (Isolated yield of 249 47%) 248

247

CO2Me OTBS

+ H

H 249

249′ dr(249 : 249′) 6 : 1

CO2Me

O

OTBS H

H 249

Scheme 12.40

OH

HClO4, DMF H

73% yield

(+)-Barekoxide (250)

H

H (+)-Barekol (251)

Total synthesis of (+)-Barekoxide and (+)-Barekol.

Banwell and coworkers accomplished the first total synthesis of hirsutene‐type sesquiterpenoid (+)‐connatusin B (261), which was isolated from the culture broth of the fungus Lentinus connatus [69]. One of the key steps for this synthesis was the oxa‐di‐π‐methane rearrangement of 254 to generate cyclopropane ring‐fused linear triquinane 255. The cleavage of a three‐membered ring in 259 upon treatment with tri‐n‐bytyltin hydride and AIBN to construct the linear triquinane 260 was another important step in the way of (+)-connatusin B (261) synthesis. From 260, connatusin B (261) was synthesized in several steps (Scheme 12.41). Next, the Banwell group synthesized another hirsutane‐type sesquiterpene (−)‐ connatusin A (268), which was isolated from the fungus Lentinus connatus BCC8996 [48]. The reaction commenced with enantiomerically pure cis‐1,2‐dihydrocatechol 262. Noteworthy transformations of this total synthesis include a Diels– Alder cycloaddition reaction between cyclopentenone 252 and acetonide 253, oxa‐di‐π‐methane rearrangement of bicyclo[2.2.2]octenone 263 to synthesize the cyclopropannulated triquinane 264, SmI2‐mediated reduction of 264 to generate 265, treatment of 265 with LiHMDS followed by trapping of kinetic enolate with MeI to afford 266, and nBu3SnH‐AIBN‐induced reduction of cyclopropane ring‐ fused triquinane 266 leading to the cleavage of three‐membered ring and formation of compound 267. Finally, 267 was transformed to (−)‐connatusin A (268) in five additional steps (Scheme 12.42).

12.3 Synthesis of TerpeneeTerpenoids

O

252 + O

AcO

254

O

OBz

Acetophenone O acetone Photolysis 18 °C, 3.5 h

253 H

H

H

Eschenmoser’s O salt, –78 –18 °C 16 h

H

AcO

LiHMDS THF, –78 °C 1 h then

H

AcO

X 255a: X = OBz SmI2 THF/MeOH –78 °C, 0.16 h 255b: X = H

256

H

MeI Et2O/CH2Cl2 18 °C, 16 h then

H

O Al2O3 (basic) CH2Cl2 NMe2 18 °C, 0.5 h

AcO

H

H

O

257

AD-Mix-α K2OsO4·2H 2O tBuOH/H2O MeSO2NH2 0 °C, 16 h H

n-Bu3SnH, AIBN (cat) C6H6, 80 °C, 6 h

AcO

H

H

H

O

O

THF, 0 – 18 °C, 18 h

O 259

HO

H HO HO

AcO

O

H HO HO

O

H

H

O

O O

(+)-Connatusin B (261)

Scheme 12.41

AcO

258 H

H

H

(MeO)2CMe2 p-TsOH·H2O (cat)

260

Total synthesis of (+)-Connatusin B.

After successful synthesis of (±)‐asterisca‐3(15),6‐diene and (±)‐pentalenene terpenoids utilizing Rh‐catalyzed [(5+2)+1] cycloaddition strategy, the Yu group further explored this reaction in the enantioselective total synthesis of sesquiterpenoid (+)‐ asteriscanolide (275) [70]. The synthesis proceeded by the formation of chiral ene‐ vinylcyclopropane substrate utilizing catalytic asymmetric alkynylation of aldehyde. Again, the construction of [6.3.0] carbocyclic core 274 via a chiral substrate‐induced Rh(I)‐catalyzed [(5+2)+1] cycloaddition was the key step for this synthesis (Scheme 12.43). The total synthesis was completed in 19 steps, with an overall yield of 3.8%. Xiao et al. accomplished the diastereoselective total synthesis of nortriterpenoid (±)‐schindilactone A (281) [71]. This natural product was isolated from the plants of Schisandraceae and has been used for rheumatic lumbago and related disease treatment. Key step associated with the synthesis includes an intermolecular Diels–Alder reaction of diene 276 and dienophile 277 and cyclopropanation with dibromocarbene of vinyl silyl ether 278 derived from the initial adduct, followed by AgClO4‐ mediated rearrangement of cyclopropane 279 to afford vinyl bromide 280, which

387

388

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products OH

2,2-DMP, p-TsOH·H 2O 18 °C, 1 h

OH 262 O

H

252 +

O

AcO

O

hν, 18 °C, 24 h

H

AcO

OBz

O

H

Acetophenone, acetone

263

SmI2, MeOH, THF –78 °C, 0.25 h

253

O X 264: X= OBz 265: X = H

LiHMDS, THF, –78 °C, 1 h then MeI, 18 °C, 16 h H

HO

OH

H

H

AcO

OH

H

H

Bu3SnH, AIBN, C6H6 80 °C, 10 h

O

AcO

267

(–)-Connatusin A (268)

Scheme 12.42

H

H

O

H

O

266

Total synthesis of (−)-Connatusin A. O H

+ OH

269

270

OTBS N

O2 N

HO

Zn(OTf)2

Red-Al, THF, 40 °C

Et3N, toluene, 55 °C 90% yield, 94% ee

92% yield 271

272 TBSCl, imidazole DMAP, DMF, 40 °C 96% yield

O H

OH

H O

HO

H

TBSO

H

H

(+)-Asteriscanolide (275)

Scheme 12.43

H

274

0.2 atm CO + 0.8 atm N2 [Rh(CO)2Cl]2 O

TBSO

toluene, 90 °C 70% yield 273

Total synthesis of (+)-Asteriscanolide.

upon subsequent reactions generated the desired natural product (Scheme 12.44). This is the first reported total synthesis of (±)‐schindilactone A (281). The Reiser group also completed the total synthesis of monoterpene (−)‐paeonilide (288) in 2012 [72]. Furan‐3‐carboxylic acid 282 served as the starting material for the reaction. The reaction proceeded by the asymmetric cyclopropanation of 283 to generate 284 followed by selective hydrolysis to synthesize 285, which was selectively

12.3 Synthesis of TerpeneeTerpenoids

OTBS

O

276 +

O Me Me

O Me

OTES

COOMe

OTBS KOtBu, CHBr , petroleum ether 3 –20 °C, 30 min

H

O O Me Me

OTES OTBS Br Br H 279

278 AgClO4·H2O, acetone 30 °C, 10 h 82% yield for 2 steps

277

O O

HO O Me Me

O

Me

Me H H O H O O H Me

O O

H

O O Me Me

OTES O Br H 280

(±)-Schindilactone A (281)

Scheme 12.44

Total synthesis of (±)-Schindilactone A.

transformed to 286 in which the carboxylic acid group was placed in the concave face of the bicycle 286. Acid‐induced cyclopropane ring‐opening/lactonization converted 286 to 287 from which (−)‐paeonilide (288) was obtained in seven steps with a 4.4% overall yield (Scheme 12.45). O Cu(OTf)2 O N

MeO2C 283

N

iPr

iPr

PhNHNH2 N2

82% yield

HO2C 282

O

O

H2SO4, MeOH

CO2tBu

38% yield (53% brsm) 83% ee

O MeO2C

H

O

LiOH CO2tBu

85% yield

H 284

H CO2tBu

HO2C

H 285 Pd/C, H2 quant.

O O BzO

H

O O O

(–)-Paeonilide (288)

Scheme 12.45

H

HO2C

O

H 287

O

HCl O

HO2C

H CO2tBu H 286

Total synthesis of (−)-Paeonilide.

Further, the Reiser group accomplished the first enantioselective total synthesis of (+)‐ and (−)‐arteludovicinolide A (293) [73]. The sesquiterpene lactone (+)‐arteludovicinolide A (293) was discovered in the aerial parts of Artemisia ludoviciana and was found to have anti‐inflammatory activity (NO inhibition via iNOS pathway). Moreover, (+)‐arteludovicinolide A (293) has 15 times higher anti‐ inflammatory activity at noncyctotoxic concentrations (≤10 μM) than previously

389

390

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

reported for concentrations of ≥45 μM. The synthesis commenced with the preparation of cyclopropanecarbaldehyde 201 (90% ee) as a single diastereomer in two steps from methyl 2‐furoate. BF3‐mediated allylation of 201 to afford 290, followed by protection of the hydroxyl group with TIPS, gave rise to 291 and the hydrolysis of oxalic ester in 291 resulted in acyclic aldehyde 292. From 292, (+)‐arteludovicinolide A (293) was synthesized following some additional steps (Scheme 12.46). (−)‐Arteludovicinolide A (293) was synthesized in a similar way starting from enantiopure ent‐201. Using this protocol, either enantiomer of arteludovicinolide A (293) could be obtained with an overall yield of 4.8% over nine steps starting from methyl 2‐furoate. MeO2C

1. O3, DCM, –78 °C

H

O

OHC

CO2Et 2. Me2S

H 289

OC(O)CO2Me

H CO2Et

BF3·OEt 2 allylTMS

OR Allyl

H CO2Et 290:R = H (dr = 94 : 6)

DCM, –78 °C

201

OC(O)CO2Me

TIPSOTf 2, 6-lutidine DCM

291:R = TIPS Ba(OH)2·8H2O MeOH, 0 °C 82% yield (3 steps)

H

OH O OTIPS

O

CO2Et CHO (anti/syn = 90 : 10) 292

Allyl

O O (+)-Arteludovicinolide A (293)

Scheme 12.46

Total synthesis of (+)-Arteludovicinolide A.

The Reiser group next performed the enantioselective total synthesis of another sesquiterpene lactone xanthatin (295), which belongs to the Xanthium family and displays anticarcinogenic, antibacterial, and antimytic properties along with low toxicity [74]. The synthesis began with the preparation of γ‐butyrolactone 294 from 201, which underwent allylation/retroaldol/lactonization cascade process to furnish γ‐butyrolactone 294 with high diastereo‐ (trans/cis 98:2) and enantioselectivity (>99% ee). From 294 xanthatin was obtained following some additional steps (Scheme 12.47). 6‐epi‐Ophiobolin N belongs to the family of ophiobolin sesterterpene, having a 5‐8‐5 fused ring system with multiple stereogenic centers. These sesterterpenes are O OHC

O CO2Et 201

SiMe3

1. CO2Me

2. MeOH/NEt3 45% yield

H

CHO

BF3

O O

O

294 99% ee 98 : 2 d.r. (trans/cis)

Scheme 12.47 Total synthesis of Xanthatin.

O O

H Xanthatin (295)

Ph

12.3 Synthesis of TerpeneeTerpenoids

reported to exhibit significant bioactivities [75], including cytotoxicity against various cancer cell lines [76]. Their gifted biological potential and synthetically exciting chemical skeleton have drawn synthetic attention [77]. In 2016, Maimone et al. reported a nine‐step, asymmetric synthesis of (–)-6‐epi‐Ophiobolin N (303), featuring cyclopropanation (Scheme 12.48) [78]. Inexpensive (−)‐linalool was used as a chiral pool building block for the synthesis of 298. In a separate sequence, trans, trans farnesol 296 when subjected to Charette’s asymmetric cyclopropanation followed by an Appel‐type reaction led to the formation of iodide 297. For the crucial C─C bond‐forming step, iodide 297 was treated with tert‐butyllithium to induce anionic cyclopropane ring opening. Next, this presumed lithiated intermediate on reaction with copper iodide, enone 298, and trichloroacetyl chloride furnished 299 in 60% yield (dr = 3:1) via a 1,4‐addition/trapping sequence. Further synthetic manipulation, as shown in Scheme 12.48, afforded (−)‐6‐epi‐ophiobolin N (303). Marine cembranoids are a group of macrocycle‐derived diterpenes produced by several species of coral [79]. The soft coral Sinularia pavida produces (−)‐pavidolide B (313), a tetracyclic 7,5,5,6‐fused cembranoid that displays inhibitory activity against various human promyelocytic leukemia cell lines [80]. In 2017, Gong and coworkers developed a novel route to (−)‐pavidolide B based on a radical cascade employing a vinyl cyclopropane cleavage/formal annulation process [81]. Domino Michael’s addition/alkylation of dimethyl bromomalonate 304 and dieneal 305 in the presence of proline‐derived catalyst gave the key enantioenriched cyclopropane fragment 306 (Scheme 12.49) [82]. Acetal formation and subsequent mild ester monohydrolysis of the aldehyde group of cyclopropane 306 gave carboxylic acid 307 an inseparable pair of diastereomers. Hydrogenation of the isopropenyl group in 309 employing Wilkinson’s catalyst afforded the alcohol 310. The amalgamation of acid 307 and alcohol 310 obtained from (+) carvone under Mitsunobu conditions gave an intermediate 311 in high yield. 311 underwent radical cascade reaction in the presence of visible light, Ir(III) complex, p‐toluidine, and thiophenol via the formation of phenylthiyl radical, and the concurrent cyclopropane fragmentation furnished the annulated product 312 as a single diastereomer in 50% yield [83–85]. 312 was transformed to (−)‐pavidolide B (313) after several steps. Yu and co‐workers reported the asymmetric total synthesis of the clovane‐type sesquiterpenes (–)-clovan‐2,9‐dione (324) with a [6.3.1.01, 5]dodecane skeleton. The synthesis involves an Rh (I)‐catalyzed [3+2+1] cycloaddition of 1‐yne‐vinylcyclopropane (1‐yne‐VCP) 322 with CO to obtain the framework of the target natural product, as shown in Scheme 12.50 [86a]. The aldehyde 314 [86b] and ester 315 [86c] were prepared from the known starting materials. The intermolecular aldol reaction of 314 with 315 followed by LAH reduction and subsequent selective oxidation of the primary hydroxyl gave the aldehyde (±)‐317 in the presence of TEMPO, NCS, and TBAC. (±)‐317 was converted to 322 after several steps, as shown in Scheme 12.50. Rh(I)‐catalyzed [3+2+1] cycloaddition of (+)‐322 with CO under a 0.2 atm CO atmosphere afforded the desired product (−)‐trans‐323 and (−)‐cis‐323 in 83% total combined yield with a 3:1 diastereomeric ratio. These two diastereomers were separated by column chromatography. (−)‐trans‐323 was transformed into the sesquiterpenes (–)-Clovan‐2,9‐dione (324) after several reaction steps.

391

BuLi, CuI.DMS Me

Me OH

Me

I

1. Et3Zn, CH2I2

Me Me

296

2. I2, PPh3 58% CONMe2 O Bu B O CONMe2

LiO

H

H

Me

HO H O

Cl3CCOCl 60%, 3 : 1 dr

Me

Me

O H

HO

Me Li-napthalenide

H

H H

Me H

Me

Me Me

(COCl)2 DMSO, Et3N 78% TsOH, Δ 72% (BRSM)

302

Scheme 12.48

Me

Ar

Me Me

H

Me 300

OH

H

OH Ar

77%

H

TBSO Me

SH

Me

H TBSO Me

Ar

Me

Cl Cl

301

HO

Me

Ar

Et3B (1 equiv.) (TMS)3SiH (1 equiv.) cyclopentane/air –10 °C

Me

H

Me

Me 299

Me S

Me

H

Me

297

Me

CCl3 Me

OTBSO Me

DIBAL/-nBuLi then H+

Me

OLi Li H

TBSO Me

OTBS

O 298

Total synthesis of (–)-6-epi-Ophiobolin N.

O

O

H H

H Me

H

Me

Me H

(–)-6-epi-Ophiobolin N (303)

Me Me

Ar= S

CO2Me Br

CO2Me

CHO

+ Me

304

Ph N Ph H OTMS (20 mol%) Et3N, CHCl3 ,0 °C

305

306 O

Cu-Al Ox, air tBuOK, EtOH

Me

42%

Me 308 (+)-carvone

95% OH Me 309

OEt Me 307

H

O H

O Me H

H

O

H

EtO

OH Me 310

Me Me

O (–)-Pavidolide B (313)

Total synthesis of (−)-pavidolide B.

EtO

H

H R

O O

Me Me

O Me

312

Me Me

PhSH, 0.5 mol% [Ir] p-toluidine

OEt

310, PPh3 DEAD 74% dr = 1.5 : 1

Me

Me

Me

CO2H

MeO2C

CH(OEt)3, PTSA

Me4NOH, aq. i-PrOH 80% (2 steps) dr = 1.5 : 1 O cat. RhCl(PPh3)3 Me H2, toluene

CHO

Me

O Me

Scheme 12.49

CO2Me

MeO2C

79%, 95% ee, dr = 11 : 1

O Me

Me EtO blue LED R 50% OEt O lr(dF(CF3)-ppy)2(dtbbpy)PF6 R= CO2Me 311

tBuLi,

t O Bu

+

O

CHO

THF, –78 °C, 1.5 h

Me

then LiALH4 60 °C, 3h, 66%

tBu

314

TEMPO, TBAC, NCS OH

HO

DCM, buffer, rt, 3 h, 88%

O

HO 317

O CO2Et P OEt NaH, THF 0 °C, 40 min, 90%

316

315

EtO

PDC, 4 A MS, DCM O

1. DIBAL, DCM, –78 °C, 1.5 h

rt, 2 h, 81%

OTBS

2. TBSCl, imidazole, DCM, rt OTBS 1 h, 92% (2 steps)

HO

320

319

HO 318

CO2Et

(S)-CBS, BH3.SMe2, PhMe –30 °C, 4 h, 87%, ee = 96% [Rh(CO)2Cl]2 (5 mol%) CO (0.2 atm)

BnBr, TBAI, NaH, DMF HO

OTBS

0 °C to rt, 19 h, 87%

BnO

OTBS

321

322 O

H

OTBS

Scheme 12.50

O

O

(–)-Clovan-2,9-dione (324)

Total synthesis of (−)-Clovan-2,9-dione.

+ BnO

BnO OTBS trans-323

OTBS cis-323

Separated by column chromatography

BnO

trans-323

PhMe, 100 °C, 1 h 83%(combined yield) dr = 3 : 1

O

O

12.3 Synthesis of TerpeneeTerpenoids O

O

O

+ EtO N2

H (R)-Carvone 308

Rh2(esp)2

OEt

O

O

O OEt

O

O

O

KHMDS

EtO

89% (1 : 0.6 dr) EtO

H

325

H

326

327 Acrolein Et 3N 2 steps 63% (2 : 1 dr)

OTBS O

O

O

TBSOTf 2,6-lutidine

OH O

O

O

Fe(acac)3 PhSiH3

EtO

EtO

i-PrOH

330a/330b

OTBS O

EtO H 331

Scheme 12.51

DABCO 2 steps 86% from 331a 85% from 332b

OTBS O

O

O

H

329a/329b (separated) (3R, 4S)-329a: 35% (3S, 4R)-329b: 19%

Pd(OH)2/C EtOH, H2

O

O

EtO

H

H

O O

O

H 332

328

OH SmI2 THF/H2O 10/1(v/v) then HF/Et3N 10/1 (v/v) 76%

O

HO

H rumphellclovane E (333)

Total synthesis of Rumphellclovane E.

Rumphellclovanes E (333) is isolated from the gorgonian coral Rumphella antipathies. It belongs to the family of clovane‐type sesquiterpenoids [87]. In 2021, Liu reported the synthesis of Rumphellclovane E (333), starting from (R)‐carvone, as shown in Scheme 12.51 [88]. Rh‐catalyzed cyclopropanation of (R)‐carvone 308 with diazo compound 325 gave the corresponding DA cyclopropane 326. Intramolecular acylation of 326 in the presence of KHMDS afforded 327, which on treatment with acrolein and NEt3 in acetonitrile gave compound 328 as a mixture of inseparable diastereomers (2:1 dr). Treatment of 328 with Fe(acac)3 catalyst, delivered 329a and 329b in 35% and 19% isolated yield, respectively. The TBS ether 330a upon hydrogenolysis, hydrolysis, and decarboxylation produced the compound 332 with an 86% yield over two steps via the intermediate 331. Likewise, 330b was also transformed to 332 with an 85% overall yield. 332 on treatment with SmI2 in THF/H2O and subsequent treatment with HF·Et3N furnished rumphellclovane E (333) in 86% yield. The chromodorolides are diterpenoid natural products isolated from nudibranchs in the genus Chromodoris [89]. In 2018, Overman and co‐workers reported the synthesis of Chromodorolide B (337), as shown in Scheme 12.51 [90]. The synthesis began with enantioenriched enedione 334; a five‐step sequence of reactions was used to obtain the trans‐hydrindanone cyclopropane 335. Employing Simmons–Smith cyclopropanation as the key step, reductive cleavage of the strained cyclopropane 335 was carried out via hydrogenation with Adam’s catalyst, followed by PCC oxidation, giving the ketone 336, which was further transformed to (−)‐chromodorolide B (337).

395

396

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products 1. (HOCH2)2, H+ 2. LiAlH4

Me O

3. MeOCOCl DMAP 4. Pd(acaa)2, Bu3P HCO2H 5. Et2Zn, ClCH2I then HCl, MeOH 67% (5steps)

O Me (S)- 334

Me O

Me O

1. H2, PtO2, HOAc 2. PCC 88% (2 steps)

H Me

Me MeH

335

336 O H

AcO AcO Me H

O O

H H OAc

Me MeH (–)-Chomodorolide B (337)

Scheme 12.52

Total synthesis of (–)-Chromodorolide B.

JBIR‐03 is an indole diterpene found in Dichotomomyces cejpii var. cejpii NBRC 103559, a marine‐derived strain of Aspergillus oryzae [91] and of D. cejpii [92]. In 2018, Kuwahara and co‐workers reported the enantioselective total synthesis of JBIR‐03 (343) and asporyzin C (342), as shown in Scheme 12.53 [93]. The synthesis started with optically enriched (+)‐Wieland–Miescher ketone 338, which gave H

10 steps

HO

O

H

O

OTBS

338

339 H

1. CH2I2, Et2Zn 0 °C, 63%

O

2. DMSO, SO3•Py, Et3N CH2Cl2, 0 °C to rt 92%

H OTBS 340 Na (C10H8), tBuOH, THF –78 °C, 1 h then Comins’ reagent THF/HMPA, –78 °C, 50% H

H TfO H N OH H asporyzin C (342)

H OH

OTBS 341

H

N H

(MeCN)2-PdCl2, THF

H

H JBIR-03 (343)

Scheme 12.53

O

0 °C, 70%

Total synthesis of JBIR-03 and asporyzin C.

12.3 Synthesis of TerpeneeTerpenoids

access to allylic alcohol 339 after several steps. The hydroxy‐directed Simmons– Smith cyclopropanation of 339 resulted in the formation of its corresponding cyclopropyl alcohol, which underwent subsequent Parikh–Doering oxidation to furnish the cyclopropyl ketone 340 in diastereomerically pure form. The reaction of sodium naphthalenide in the presence of tBuOH acting as a proton source led to reductive cleavage of the cyclopropane ring of 340, generating an enolate intermediate, which was then trapped with Comin’s reagent to accomplish the synthesis of enol triflate 341 with the anti‐stereochemistry between the contiguous C3/C4 quaternary stereocenters. The compound 341 acted as an intermediate for the synthesis of asporyzin C (342) and JBIR‐03 (343) in an absolutely diastereoselective manner [94]. The asteraceae plant Dichrocephala benthamii is an annual herb found in China and India. Traditionally, in folk medicine, the whole plant is used for the treatment of cold and fever in children, indigestion, hepatitis, and pneumonia [95]. A detailed investigation of D. benthamii led to the isolation of two new modhephane sesquiterpenoids analogs dichrocephones A and B (350–351) [96]. In 2018, the Christmann group reported an enantioselective synthesis of dichrocephones A and B (350–351), as shown in Scheme 12.54 [97]. Alkyne 344 was synthesized from commercially available cyclopentane‐1,3‐dione. 344 afforded pseudosymmetric dienone 345 after a few steps. The spirocycle 346 was synthesized in 63% yield by the monocyclopropanation of 345 at the sterically less hindered alkene. Hydroxy‐directed epoxidation of the NaH, Me3SOI DMSO, THF

O O O 344

Me

Me Me HO Me

O

25 °C, 5 h

Me

OH 345

Me Me

HCO2H Me

349

0 °C, 18 h

HO Me OH 348

O

1. LiAlH4 Et2O, 0 to 25 °C, 18 h 2. PtO2, NaOAc, H2 AcOH, 25 °C, 70 min 3. py.SO3, Et3N, DMSO DCM, 25 °C, 12 h

HO Me

Me Me

BF3.OEt2 O

Me Dichrocephone A (350)

DCM, 0 °C, 3 h 88%

Me

O Me

O

Dichrocephone B (351)

aq. HCl, DCM 25 °C, 1 h

Scheme 12.54

TFAA, H2O2 Na2HPO4 DCM, –40 to 0 °C 4h

O Me

OH 347

THF, 25 °C, 18 h

HO

OH 346

PhSiH3, O2 Co(acac)2 (30 mol%)

Me Me

O Me

Total synthesis of Dichrocephones A and B.

O

397

398

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

enone with trifluoroperacetic acid gave access to the crucial bis‐spirocyclic intermediate 347. Next, the simultaneous ketone reduction and epoxide opening using LiAlH4 followed by regioselective hydrogenolytic cyclopropane opening with Adams Q catalyst in acetic acid generated geminal dimethyl group in 348. 348 on simple synthetic manipulation was converted to Dichrocephones A and B (350–351). Englerin A is a guaiane sesquiterpene isolated from the bark of Euphorbiaceae Phyllanthus engleri by Beutler and coworkers in 2009. This compound has a unique oxygen‐bridged hydroazulene skeleton with seven stereogenic centers, and it exhibits substantial anti‐cancer activity against renal cell carcinoma. Due to its extraordinary structure and biological properties, Englerin A has been a synthetic target in many research laboratories around the world [98]. Wang et al. reported the synthesis of (−)‐Englerin A from the commercially available (R)‐(+)‐limonene, as shown in Scheme 12.55 [99]. In addition, (−)‐Englerin B, (+)‐Orientalol E/F, and (−)‐ Oxyphyllol were also synthesized. The protocol involved a crucial hydroxyl‐directing stereoselective and regioselective intramolecular cyclopropanation and stereoselective formal intramolecular [3+2] cross cycloaddition ([3+2]‐IMCC) of a carbonyl with a cyclopropane 1,1‐diester. The hydroxyl group directed intramolecular cyclopropanation of 352 afforded the lactone 353 in 58% overall yield via a three‐step ­isolation‐free sequence comprising of Mukaiyama esterification, a Regitz diazotization, and a chemoselective intramolecular cyclopropanation of double bond. Lactone 353 on the treatment of with sodium methoxide gave transesterification product 354 in a 87% yield. Subsequent protection of the hydroxyl group in 354 with chloroacetyl chloride, followed by the ozonolysis of the double bond, afforded the formal [3+2]‐ IMCC precursor 356 in 75% yield over two steps. Next, Sc(OTf)3‐catalyzed cycloadduct formation took place, giving 357 in 79% yield. The aldehyde 358 was obtained from 357 after several reaction steps, which paved the way toward the synthesis of (−)‐Englerin A (359), (−)‐Englerin B (360), (+)‐Orientalol F (361), Oxyphyllol (362), and Orientalol E (363), after multistep synthetic transformation [100]. The ent‐kaurene diterpenoid, maoecrystal P (370) has drawn the attention of the scientific community on account of its promising cytotoxicity against human tumor cells [101]. In 2018, the Luo group completed the total synthesis of the racemic maoecrystal P (370), as shown in Scheme 12.56 [102]. Intermolecular Diels–Alder cycloaddition between the enone‐aldehyde 364 and the diene 365 mediated by BF3. OEt2 furnished tetracyclic compound 366, which has a cyclopropane ring. Next, on concurrent reduction with NaBH4, acetyl protection, and allylic oxidation gave the desired enone 368, which on Pd‐catalyzed hydrogenolysis of the cyclopropane ring gave a pair of diastereoisomers 369 at C‐16. The synthesized compound 369, after a series of reactions, afforded Maoecrystal P (370). The triterpenoid natural product botryococcene (378b) was isolated from Botryococcus braunii, an ancient microalga. In 2018, Marek and co‐workers reported an elegant strategy for the synthesis of botryococcene, as shown in Scheme 12.57 [103]. The synthesis involves rhodium‐catalyzed (2+1) cycloaddition reaction of alkyne 372 with diazo ethylacetate to generate cyclopropene 373. The latter underwent a one‐pot copper‐catalyzed carbometallation, transmetallation, and palladium‐ catalyzed crosscoupling with alkenyl iodide 374 to produce alkenylcyclopropane ester. It was reduced in situ to alcohol, and subsequent phosphonation afforded the

1. Monomethyl malonate Et3N, DMAP, CMPI DCM, 25 °C

OH

O

2. TsN3, K2CO3, MeCN 25 °C 3. Rh2(OAc)4, DCM, 25 °C 58% in 3 steps

352

H

OH

Na, MeOH then 14, 0 °C

O

87%

H

CO2Me

CO2Me

CO2Me

353

354 ClCH2COCl Py, DCM, 0 °C 89%

O

Cl Sc(OTf)3 (0.05 equiv.) DCE, 50 °C, 2 h, Ar CO2Me

O

79%

H

O

H

O

92%

OH

O (–)-Englerins A (359)

358 OH

1. Rh(PPh3)3Cl, toluene 120 °C, 95% (brsm)

O H (+)-Orientalols F (361)

Ph

O K2CO3 MeOH/ H2O/ THF 0 °C O

H2, 11.5 MPa Pd/C, EtOH, 25 °C 65%, dr = 4 : 1

CO2Me CO2Me 355

O

CHO

H

2. NaBH4, CeCl3.7H2O MeOH, 0 °C, 84%

H

Ph

O

Cl

O

CO2Me 356

357

358

O3, DCM/MeOH, –78 °C then Me2S, 25 °C, 84% O CO2Me

H

CO2Me

O

O

Cl

O

H

O O

H

OH

(–)-Englerins B (360)

H

OH O

H (–)-Oxyphyllol (362)

1. Ac2O, DMAP Et3N, DCM 25 °C, 100% 2. CrO3, n-Bu4NIO4 MeCN/DCM –30 °C, 48% 3. K2CO3, MeOH 40 °C, 99%

Scheme 12.55 Total synthesis of Englerin A-B, (+)-Orientalol F, (−)-Oxyphyllol, and (+)-Orientalol E.

HO

H

OH O

H (+)-Orientalols E (363)

400

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products O

H

CHO

CO2iPr

+ H

Me Me 364 O

CN

BF3•Et 2O –30 °C 90%

365 H

O

CO2iPr CN

H H

OH

H

NaBH4 78%

Me MeH

H

OH

CO2iPr CN

H Me MeH 367

366

1. Ac2O, p-TsOH 2. NBS, AIBN, CCl4 then AgBr4, DMSO 74%

O

H 16 steps

O Me Me OH

O

AcO

CO2iPr

OAc H

O

Pd2(dba)3 HCOOH

AcO

H

OAc

Me MeH O 369

CO2iPr CN

H H

86%

maoecrystal P (370)

Scheme 12.56

CN

Me MeH O 368

Total synthesis of Maoecrystal P.

cyclopropane 375. Diastereoselective 1,6‐nucleophilic ring fragmentation of 375 mediated by Me3Al afforded epi‐botryococcene (378a) in 66% yield with dr 3:1. Likewise, for the synthesis of botryococcene, the cyclopropene 376 (er 91:9) underwent sequential copper‐catalyzed carbometallation, transmetallation, and palladium‐ catalyzed cross‐coupling with 374 to give cyclopropane ester, which on reduction and phosphonation gave cyclopropane 377. Diastereoselective 1,6‐nucleophilic ring fragmentation of 377 furnished botryococcene (378b) in 80% yield with dr 3:1. The synthesis of botryococcene (378b) was accomplished in 5 steps with a 24% overall yield from 376. The terpenoid Vibralactone was first isolated from basidiomycete fungus Boreostereum vibrans by Liu et al. in 2006 [104]. It consists of a β‐lactone fused bicyclic structure and exhibits numerous biological activities. Nelson and co‐workers reported a short PGF synthesis of vibralactone (383) via photochemical valence isomerization of 3‐prenyl‐pyran‐2‐one 379 in the presence of 300 nm light, providing oxabicyclo[2.2.0]hexenone 380, followed by Rh catalyzed metal carbene transfer reaction to generate the anticipated cyclopropane 381 in 22% yield. Additionally, a mild base DBU‐mediated ring expansion occurred, furnishing the single allyl isomer 382 with a 69% yield. The latter, on DIBAL‐H reduction, furnished racemic vibralactone (383). This four‐step synthesis was accomplished with a 4.3% overall yield (Scheme 12.58) [105].

O

Br Br

Rh2(OAc)4

371

OEt

N2CHCO2Et

Mg, HgCl2 72%

35%

372

373 1. MeMgBr, CuI, THF, –40 °C 1 h, ZnBr2 then374, Pd(PPh3)4 (10 mol%), THF –40 °C to 40 °C, 17 h 2. DIBAL-H, THF, 0 °C to rt, 3 h, 13%, 2 steps 3. CIPO(OEt)2, Et3N, DMAP, CH2Cl2, 0 °C 4 h, 51%

I 374

OPO(OEt)2

Me3Al, pentane, –40 °C 66%, dr 3 : 1 epi-botryococcene (378a)

O OEt 376

375

OPO(OEt)2

1. CuI, THF, –40 °C, 1 h, ZnBr2, then 374, Pd(PPh3)4 (10 mol%), THF, –40 °C to 40 °C, 17 h 2. DIBAL-H, THF,0 °C to rt, 3 h, 38%, 2 steps 3. CIPO(OEt)2, Et3N, DMAP, CH2Cl2, 0 °C, 4 h, 51% dr >98 : 2 : ;0 : 0 er 91 : 9

377

Me3Al, pentane, –40 °C 80%, dr 3 : 1, er 91 : 9

Botryococcene (378b)

Scheme 12.57 Total synthesis of Botryococcene.

402

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

O 300 nm hv

O

N2

O

H

379

O H

3 mol% Rh2(esp)2

O

PhH, 83%

O

CO2Et

H

H

PhH/ DCE, 22%

O

380

OEt 381 DBU, PhH 18 h, 75 °C, 69%

O

O

O

O

DIBAL-H

H

H

THF/ PhH, 1.5 h –40 °C–0 °C, 34% OH

O

Vibralactone (383)

Scheme 12.58

O

(7 steps)

O O

382

Total synthesis of (±) Vibralactone.

O

OH

OEt

OEt OMe Me

1. TsN3, Et3N MeCN, 30 °C OTIPS 2. Cu(tbs)2, PhMe 87% (2 steps)

Me

O

O

Me O HO

Me

Me

Me

Me

H

H 386 TMSOTf (CH2OTMS)2 70%

H Me

OH

HO

H

OMe OTIPS

385

384

OEt

OH O

HO

OH O H

Me

Rhodomolleins XX (388)

OEt OMe

OTIPS

Me 387

Me O HO

H Me

OH Me

Me

H

OH HO

Rhodomolleins XXII (389)

Scheme 12.59

Total synthesis of (–)-rhodomolleins XX and XXII.

Ding and coworkers reported the first total syntheses of rhodomolleins XX and XXII (388–389) belonging to grayanoid family, as shown in Scheme 12.59 [106]. The strategy started with the 7‐step synthesis of β‐ketoester 385 from known 3‐hydroxy‐2‐ methoxybenzaldehyde 384. The compound 385 on Regitz diazo transfer delivered an a‐diazo‐β‐ketoester, followed by the treatment with Cu(II) salen complex, which generated the cyclopropane 386. Treatment of 386 with TMSOTf and (TMSOCH2)2 resulted in the protection of the C‐2 ketone as well as simultaneous ring opening of the cyclopropane furnishing the styrene 387, which could be converted to (−)‐rhodomollein XX (388) and (−)‐rhodomollein XXII (389) after multistep conversation.

12.4 Synthesis of iscellaneous Natural Products

O

O

O

O

Me

O

Me

Me

TMSO 391

390

O

Me

OHMe H

H

OH

Me

Me

Me H O OH H

O

Me H O

Me

Me

Me

H

H O

O

Me

O

HO

HO 392

O Me

O hν (254 nm)

Me AcOH, 18 °C 56%

H

(–)-Rhodomollanol A (395)

Scheme 12.60

O

H

Me

O

O

O

O

Me

O

394

Me HO

O

393

Total synthesis of (−)-Rhodomollanol A.

(−)‐Rhodomollanol A (395) is an oxygenated grayanane‐type diterpenoid with an uncommon [3,5,7,5,5,5] hexacyclic framework and displays a moderate PTP1B inhibitory activity. Ding and co‐workers recently reported the first total synthesis of (−)‐rhodomollanol A, characterized by a series of synchronized domino reactions and skeletal rearrangements, as shown in Scheme 12.60 [106, 107]. The divinyl ketone 391, obtained from bicyclic enone 390, was subjected to Photo‐Nazarov cyclization to generate allylic carbocation 392, which triggered the ring expansion of the central cyclohexane ring to afford 393 having a cyclopropane ring via 1,4‐alkyl migration. Under acidic conditions (AcOH), the trimethylsilyl group was removed, and intramolecular ring‐opening of the cyclopropane by the tethered hydroxyl group afforded 394 in a 56% yield. The latter was transformed to (−)‐rhodomollanol A (395) in 12 steps.

12.4 Synthesis of Miscellaneous Natural Products Apart from alkaloids and terpenes/terpenoids, the total synthesis of many other natural products involved DA‐cyclopropane synthesis followed by its synthetic transformations. This part of the chapter highlights the syntheses of different other natural products where a few key steps involve the DA‐cyclopropane reagent. (−)‐Doliculide (401) is a unique 16‐membered depsipeptide obtained from the Japanese sea hare Dolabella auricularia (Aplysiidae) [108]. Doliculide (401) is known to show potent cytotoxicity against HeLa‐S3 cells. In 2001, Ghosh et al. reported the synthesis of (−)‐Doliculide (401), as shown in Scheme 12.61 [109]. The synthesis began with the Charette asymmetric cyclopropanation of allyl alcohol 396 using the amphoteric chiral dioxaborolane ligand and Zn(CH2I)2∙DME complex to furnish the cyclopropane derivative 397 in quantitative yield and with high diastereoselectivity (91% de). Selective ring opening of the cyclopropane 397 with PPh3,

403

404

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products CONMe2

Me2NOC HO O

BnO

HO O B Bu

Zn(CH2I)2•DMF CH2Cl2, –15 °C 99% condition A

Me 396

BnO

2. n-BuLi, TMEDA, Et2O molecular sieves, –78 °C 72%

Me 397

HO

O

N H

1. I2, PPh3, imidazole CH2Cl2 2. n-BuLi, TMEDA Et2O, –78 °C

BnO Me

(–)-Doliculide (401)

Scheme 12.61

Me

Me

O

H N Me

Me 398

HO Me

Me

O

BnO

1. 9-BBN, THF, H2O2, OH–, 0 °C 2. Swern oxidation 3. NaH, (EtO)2P(O)CH2CO2Et THF, 0 to 23 °C 4. DIBAL-H, CH2Cl2 5. Condition A

OH I

Me

1. I2, PPh3, imidazole, CH2Cl2

Me 400

Me BnO Me 399

Total synthesis of (–)-Doliculide.

iodine, and imidazole provided the iodide, followed by the treatment with n‐BuLi in the presence of TMEDA and molecular sieves, which afforded the alkene 398 in 72% yield over two steps [110]. Hydroboration of alkene 398 with 9‐BBN, followed by Swern oxidation, delivered the analogous aldehyde. Next, Horner–Emmons homologation of the aldehyde, DIBAL‐H reduction, followed by Charette asymmetric cyclopropanation of the subsequent allylic alcohol, furnished the cyclopropane 399 in 55% overall yield starting from 398. Cyclopropane derivative 399 was transformed to olefin 400 in 72% yield. This olefin 400 was transformed to (−)‐Doliculide (401) after several steps. (−)‐Roccellaric acid (404) and (−)‐Nephrosteranic acid (406) are trisubstituted γ‐ butyrolactones belonging to the family of paraconic acids, a class of γ‐butyrolactone natural products isolated from various species of lichens, mosses, and fungus. They possess antifungal, antibiotic, antitumor, and antibacterial properties [111]. Because of their pharmacological profile, they have attracted considerable interest from organic chemists. The total synthesis of four paraconic acids, i.e. (−)‐roccellaric acid (404), (−)‐protolichesterinic acid (405), (−)‐nephrosteranic acid (406), and (−)‐protopraesorediosic acid (407), was carried out by Reiser et al. by taking the advantage of a retro‐aldol/lactonization sequence as vital steps (Scheme 12.62) [112]. Enantioselective cyclopropanation of methyl ester of furan‐2‐carboxylic acid (199) gave the DA cyclopropane 200a, which underwent furan ring cleavage by ozonolysis to furnish the cyclopropane 201. The strategic intermediate 201 was subjected to allylation in the presence of BF3∙OEt2 followed by the reaction with base affording the lactone 402 via a retro‐aldol/lactonization sequence. The lactone 403 was used in a divergent approach to synthesize various paraconic acids (404–407).

12.4 Synthesis of iscellaneous Natural Products O Cu(OTf)2/ L PhNHNH2

O

MeO2C

N2 199

O N

N L

tBu

H

O

CO2Et, 63% O

H

MeO2C

H 200a

O

O3 CO2Et DMS, 94%

OHC H

CO2Me

CO2Et 201

H tBu

424

SiMe3 BF3. Et2O 72%

O COOH O

CHO

CH3

O

12

O

CO2H O

O

CH3

12 (–)-Protolichesterinic acid (405)

Scheme 12.62

64–72%

O 403

(–)-Roccellaric acid (404)

HO

OH

H

O

CO2Et

CO2Me

402 95 : 5 (trans:cis) CO2H

CO2H O

O

CH3

O

O

CO2H 14

10 (–)-Nephrosteranic acid (406) (–)-Protopraesorediosic acid (407)

Total synthesis of Paraconic Acids.

Borschberg reported the discovery of β‐araneosene, a metabolite of the mold Sordaria araneosa [113]. Corey and co‐workers reported the synthesis of isoedunol (411) and β‐araneosene (412), as shown in Scheme 12.63 [114]. Treatment of 408 with EtMgBr, ClTi(OiPr)3 furnished cyclopropyl carbinol 409, which when reacted with Me3Al furnished cyclobutanone 410 in 90% yield. 410 was converted to isoedunol (411) after several steps. The reaction of chloromethyl methylether in the presence of iPr2NEt, TBAI gave methoxymethyl (MOM) ether of isoedunol, which on dissolving metal reduction with excess Li in NH3 afforded β‐araneosene (412). Apart from the terpenoids, the Reiser group also synthesized (S)‐vigabatrin (418), starting from the inexpensive pyrrole moiety 413 [115]. (S)‐Vigabatrin is an irreversible inhibitor of GABA‐T and is being used for adjunctive therapy in patients suffering from epilepsy. First, 3,4‐didehydropyrohomoglutamate 417 was successfully synthesized with 91% ee from pyrrole moiety 413 via cyclopropanation followed by radical ring opening, and then 417 was further converted to (S)‐vigabatrin (418) following several additional steps (Scheme 12.64). The Inaba group describes the synthesis of protein kinase C‐β (PKCβ)‐selective inhibitor JTT‐010 (423) [116]. Synthesis of five‐membered heteroaromatic fused pyrrolidine 421 via ring opening of cyclopropane 420 with five‐membered heteroaromatic 419 with a leaving group in C(2) position served as the foundation for the synthesis. Compound 421 was synthesized with a 76% yield in optically pure form, and it had all the necessary components, including the absolute configuration needed to be the precursor for JTT‐010 (423). Compound 422 was also found to be optically active, indicating that ring opening of cyclopropane and consequent decarboxylation proceeded with retention of configuration. Further JTT‐010 (423) was synthesized from 422 following some sequential additional steps (Scheme 12.65).

405

406

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products O OMe EtMgBr, ClTi(Oi-Pr)3

OMTM

Me

THF, 0 to 23 °C

O Me

Me

Me

O Me 408

O

HO Me3Al, toluene

OMTM

Me Me

Me

O

Me

409

410

MOMCl, iPr2NEt, TBAl THF, 67 °C

Me

Me

Li, NH3, THF –60 °C 92%, 2 steps

H

H

β-Araneosene (412)

Scheme 12.63

O Me

Me

Me

O

Me

Me

CH2Cl2, 4 °C

O Me

OH

Isoedunol (411)

Total synthesis of Isoedunol and β-Araneosene. H MeO2C 75 g CO2Me MeO2C

N2

N Boc 413

H

Cu(OTf)2 PhNHNH2 45% yield

160 g H 414

H

47% yield 98.3% ee

415

SMB

N Boc

H 73 g 46% yield 99.8% ee

MeO2C H 415ʹ

H

1) NBS, H2O, CH3CN 5 °C, 5 min

MeO2C

2) CrO3, H2SO4 N acetone, rt, 2 h Boc > 99% ee 62% yield 415ʹ H

H MeO2C

N Boc

Br Bu3SnH, AIBN

H

N Boc

O benzene, Δ, 5 min N 94% yield, 91% ee Boc 416

MeO2C

O N Boc 417

CO2 NH3 (S)-Vigabatrin (418)

Scheme 12.64

Total synthesis of (S)-Vigabatrin.

The Johnson group utilized their developed [3+2] cyclopropane‐aldehyde cycloaddition strategy for the synthesis of natural product (+)‐virgatusin (431), which is identified as a potent antibacterial and antifungal agent [117]. The synthesis commenced with the preparation of enantioenriched cyclopropane 427, which

12.4 Synthesis of iscellaneous Natural Products CO2Me OTs

CO2Et +

N H 419

O

O

K2CO3 N

76% yield

420

421 O

NaOH then HCl

CO2Me CO2Et O

H N

O

O

HN

N OH 422

N NH2·CH3SO3H JTT-010 (423)

Scheme 12.65

Total synthesis of JTT-010.

underwent AlCl3‐catalyzed formal [3+2] cycloaddition with piperonal 428 to afford tetrahydrofuran moiety 429 as a single diastereomer. Compound 429 was further converted to (+)‐virgatusin core 430 with >20:1 diastereoselectivity via benzyl ester hydrogenolysis followed by decarboxylation. Finally, 430 upon LiAlH4 reduction and methylation afforded the targeted natural product (+)‐virgatusin (431) (Scheme 12.66). The Johnson group also accomplished the total synthesis of (+)‐Polyanthellin A (437), a reported antimalarial agent [118]. The synthesis relied on the MADNTf2‐ catalyzed [3+2] cycloaddition of DA‐cyclopropane 434 and β‐silyloxy aldehyde 435 to afford 436 in 76% yield with good diastereoselectivity. (+)‐Polyanthellin A (437) was synthesized from 436 following some additional steps (Scheme 12.67). The Wang group also completed the total synthesis of the natural product (±)‐ bruguierol A (443) from commercially available 3‐bromoanisole 438 [119]. (±)‐ Bruguierol A (443) was isolated from the stem of Bruguiera gymnorrhiza tree and exhibits potent biological activity. The key strategy for the synthesis was Sc(OTf)3‐ catalyzed intramolecular [3+2] cycloaddition of cyclopropane 441 to construct 8‐ oxabicyclo[3.2.1]octane skeleton 442 (Scheme 12.68). The total synthesis has been completed in 10 steps from 3‐bromoanisole 438 with a 16.8% overall yield. The Kerr group also synthesized (+)‐isatisine A (447), a natural product present in Isatis indigotica Fort plant species [120]. The first step of the synthesis followed Johnson tetrahydrofuran synthesis from (S)‐vinylcyclopropane diester 445 and indole‐2‐carboxaldehyde 444 in the presence of Sn(OTf)2 catalyst to afford 446 in 89% yield as a mixture of diastereomers. The diastereomeric ratio between 2,5‐cis:2,5‐ trans (furan numbering) isomers of 446 was found to be 11:1 (Scheme 12.69). The total synthesis was completed in 14 steps with a 5.8% overall yield. The Nakada group reported an enantioselective approach to the natural product (−)‐platencin (453), which contains a tricyclic framework of only carbon atoms [121]. It was isolated from Streptomyces platensis MA 7339 and acts as a moderate inhibitor of both FabF and FabH, an enzyme required for catalyzing the initial condensation in the synthesis of bacterial fatty acid. The reaction proceeded by preparation of tricycle[4.4.0.0]decene derivative 450 via enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) followed by conversion of 450 to chiral intermediate 451 containing α,β‐unsaturated sulfone functionality, which can act as

407

408

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

H + 424

Br

CO2Me

HN

2,6-lutidine EtOH

CO2Me 425

OMe

Ph

TMSO Ph 30 mol%

O

OMe OHC

CO2Me CO2Me

MeO

BnO2C

1. NaClO2, H2O2

CO2Me

H2O/MeCN 2. BnBr, Et3N THF 43% yield (3 steps)

OMe 426

CO2Me

KH2PO4

MeO

OMe 427 (2R,3S)

O AlCl3 (15 mol%), CH2Cl2

H

80% yield O 428 O BnO2C

CO2Me O

MeO

O

MeO

O

430

2. KOAc DMSO/H2O 100 °C 72% yield

O

MeO

429

O

Diastereoselection >20 : 1

MeO

OMe

1. LAH, THF 99% yield

O O

MeO

O

MeO

Diastereoselection >20 : 1

MeO

CO2Me CO2Me

BnO2C

1. Pd/C, H2 99% yield

O

2. NaH, CH3I THF, 35 °C 75% yield

(+)-Virgatusin (431)

Scheme 12.66

Total synthesis of (+)-Virgatusin.

a potential radical acceptor. 451 could be successfully transformed in four steps to Nicolaou’s intermediate [122] 452 for his total synthesis of (−)‐platencin (453) (Scheme 12.70). The Gharpure group reported the enantioselective and diastereoselective total synthesis of cis isomers of (+)‐Hagen’s gland lactones (460) in 2011 [123]. Hagen’s glands are located near the abdominal tips of braconid wasps, Diachasmimorpha lingicaudata (Ashmead), Diachasmimorpha tryoni (Cameron), and Fopius arisanus (Bioesters), and contain fragrance‐rich lactones [124, 125]. The total synthesis proceeded by intramolecular cyclopropanation of vinylogous carbonates 455a–b in a regio‐ and stereoselective manner in presence of Cu(acac)2 to furnish the DA‐ substituted cyclopropanes 456a–b and then regioselective radical ring opening of cyclopropanes 458a–b using nBu3SnH and AIBN (Scheme 12.71). The total synthesis was completed in 12 steps from readily available aldehydes 454a–b. The Snapper group reported the total synthesis of marine natural product norrisolide (467), which was first isolated from the nudibranch mollusc Chromodoris

12.4 Synthesis of iscellaneous Natural Products H

O CO2Me

CHO 432

H

1. p-AcHNC6H4SO2N3 Et3N, MeCN 2.

433

O

OHC

tBu N

Cu O2 (4 mol%) C6H6, reflux slow addition of diazo over 20 h 71% yield

Me OTMS

O

435

CO2Me

Me OTMS R O

tBu

H

H

O AlMe

434

2

Me

R = CO2Me 436 Diastereoselection 11 : 1 : 0.6 (5:epi-C7:C2/C9 trans)

tBu (15 mol%)

HNTf2 (10 mol%) CH2Cl2, –30 °C 76% yield

Me

AcO MeH H

O O HH Me (+)-Polyanthellin A (437)

Scheme 12.67 Total synthesis of (+)-Polyanthellin A.

O MeO

O

N2 C(CO2Me)2 Rh2(esp)2

O

O

77% yield

Br

MeO

438

MeO

439

CO2Me CO2Me

440 1 M HCl, THF, rt 95% yield

O

O

HO

O

Sc(OTf)3, DCE

CO2Me

98% yield

MeO

(±)-Bruguierol A (443)

Scheme 12.68

CO2Me CO2Me

CO2Me

MeO 442

441

Total synthesis of (±)-Bruguierol A.

norrisi [126]. It has also been found in sponges from the same area in minor amounts. They divided the synthesis into two parts. The first part involved the synthesis of hydrindane portion 465 of the molecule, and the second part involved the preparation of side chain 464. The enantioselective cyclopropanation of furan‐2‐one 461 synthesized 462, followed by rearrangement of 462 generated 463, which furnished side chain 464 in four sequential steps. The coupling of two parts 464 and 465

409

410

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products O N Ts

H

+

CO2Me CO2Bn

444

Sn(OTf)2, CH2Cl2 89% yield

445

11 : 1 cis:trans O N Ts MeO2C CO2Bn

O N

446

OH OH

O

≈ 3.5 : 1 epimeric mixture (ultimately inconsequential)

Scheme 12.69

H N

O

OH

(+)-Isatisine A (447)

Total synthesis of (+)-Isatisine A. O

O N

(CH2)2OTBDPS

CO2H O N2 448

(15 mol%) [CuOTf]2PhMe (5 mol%)

SO2Ph 449

Toluene 72% yield, 95% ee

1) PhSLi, THF, reflux 96% yield 2) NaBH4, MeOH, THF, 0 °C 100% yield

(CH2)2OTBDPS O H H PhO2S 450

3) MsCl, Et3N, (CH2Cl)2, 50 °C 98% yield 4) t-BuOK, THF, –78 °C 92% yield OH O

HO2C OH

N

O

(CH2)2OTBDPS

PhO2S

H

SPh 451

O

N H 452

(–)-platencin (453)

Scheme 12.70

Total synthesis of (−)-Platencin.

followed by several reactions produced the natural product norrisolide (467) in 1.7% overall yield (Scheme 12.72). The Nakada group also accomplished the stereoselective total synthesis of nemorosone (472), which belongs to polycyclic polyprenylated acylphloroglucinols (PPAPs) and exhibits anti‐HIV and antitumor activities [127]. In the way, of this natural product synthesis, the authors developed a new approach for the synthesis of bicyclo[3.3.1]nonane‐2,4,9‐trione core via intramolecular cyclopropanation of 469 to generate 470, which underwent stereoselective alkylation followed by regioselective ring opening of cyclopropane to form diketone 471 as a single isomer. 471 produced the targeted natural product nemorosone (472) following some additional steps (Scheme 12.73).

12.4 Synthesis of iscellaneous Natural Products O R

R

454

80% yield for a 60% yield for b

455a: R = n-C4H9 455b: R = n-C6H13

H CO2Et

R

CO2Et

O 455

454a: R = n-C4H9 454b: R = n-C6H13

O

Cu(acac)2, CH2Cl2 reflux, 2 h

N2

CHO

O

H 456 456a: R = n-C4H9 456b: R = n-C6H13

LiAlH4, THF –78 °C, 20 min

HO

88% yield for 457a

R

83% yield for 457b

H CO2Et O

H 457 457a: R = n-C4H9 457b: R = n-C6H13 PPh3, CBr4 pyridine, CH2Cl2 rt, 36 h 80% yield for 458a 78% yield for 458b

H

Br

1. nBu3SnH, AIBN, benzene, reflux, 2 h 2. LiOH, EtOH/H2O, rt, overnight 81% yield for 459a, 99% yield for 459b

R

CO2Et O

H

458 458a: R = n-C4H9 458b: R = n-C6H13 H R

O

O R

H

O

H 460

CO2H H

O

H 459

460a: R = n-C4H9 460b: R = n-C6H13

459a: R = n-C4H9 459b: R = n-C6H13

(+)-Hagen’s Gland Lactones (460)

Scheme 12.71

Total synthesis of (+)-Hagen’s Gland Lactones.

Perali and Kalapati performed the first enantioselective total synthesis of (S)‐ longianone (477) [128]. Starting from 3,4,6‐tri‐O‐acetyl‐d‐glucal 473 the targeted molecule was obtained in 14 steps with 8% overall yield. The reaction proceeded via Rh‐catalyzed stereoselective cyclopropanation of glycal 474 to afford enantiomerically pure 1,2‐cyclopropanecarboxylate 475, which upon treatment with N‐bromosuccinimide resulted in bromonium ion‐induced electrophilic ring opening and produced bromohydrin 476 (Scheme 12.74). Other notable transformations in this total synthesis included one‐pot dehydrohalogenation, stereoselective intramolecular hetero‐Michael addition, and ester hydrolysis to furnish the final product. In 2013, the Kerr group reported that cyclopropane hemimalonates could be readily converted to γ‐substituted butanolides in the presence of inorganic salts under microwave irradiations with retention of stereochemistry [129]. This reaction was successfully applied to the synthesis of a small natural product (R)‐(+)‐dodecan‐4‐ olide (482). (R)‐(+)‐Dodecan‐4‐olide (482) is a naturally occurring butanolide, and it was isolated from various natural sources like the pyridial glands of rove beetles,

411

412

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products tBu

O Rh

O O Rh O 4

MeO2C

Müller’s catalyst

O O

O

Dimethyl 2-diazomalonate PhF 70% yield, 60–70% ee

461

O

Benzene, 185 °C

MeO2C

462 O

O

O

MeO

O

MeO

82% yield

O

OTBS

O

MeO2C

N Me MeO 464

463

MeO Me O

1. 2,4,6-Triisopropylphenylsulfonyl hydrazide HBF4, CH3CN, rt, 12 h, 72% yield

O

O Me

O

2. n-BuLi, THF, 2 h, –78 °C to 0 °C;

H Me Me 465

464, THF, –78 °C to 30 °C, 12 h, 92% yield

H Me Me

AcO O Me

O

O H Me Me Norrisolide (467)

Scheme 12.72

Total synthesis of Norrisolide. OMe OTIPS

OMe CO2Me OMe

O MeO

468

[CuOTf]2·PhMe (2 mol%)

N2

469

O

O N N (4 mol%)

Toluene, rt OMe OTIPS

MeI, tBuOK, THF –78 °C to rt

O OMe 470

O OTIPS

MeO

then 2 N HCl THF, rt 58% yield (2 steps)

471 O

O Ph O HO

O

H

Nemorosone (472)

Scheme 12.73

Total synthesis of Nemorosone.

OTBS 466

12.4 Synthesis of iscellaneous Natural Products O

O

OAc OAc

OAc

OBn 474

473

O

Rh2(OAc)4 MDA, CH2Cl2 60% yield

COOMe

OBn 475 O

O

O

OH

NBS

COOMe

H2O:dioxane 66% yield

O

O

OBn Br (S)-Longianone (477)

476

Scheme 12.74

Total synthesis of (S)-Longianone.

butterfat, fruits, and territorial marking fluid of the Bengal tiger. Grubbs second‐ generation ruthenium catalyst mediated the cross‐metathesis of dimethyl ester vinyl cyclopropane 478 and oct‐1‐ene 479, followed by monosaponification generating cyclopropane hemimalonate 480, which under standard butanolide synthesis conditions produced alkenyl butanolide 481. Finally, reduction of 481 with tosylhydrazide afforded (R)‐(+)‐Dodecan‐4‐olide (482) in 67% overall yield with 94% ee (Scheme 12.75). HO2C MeO2C MeO2C

1. Grubbs (II) DCM, reflux

CO2Me +

2. NaOH, MeOH 87% yield overall 7 : 1 E to Z

95% ee 478

479

480 O

O O

O LiCl, Me3N·HCl DMF, 150 °C, mW

TsNHNH2

78% yield overall

THF 98% yield

NaOAc, H2O

7 : 1 E to Z

481 (R)-(+)-Dodecan-4-olide (482) 94% ee

Scheme 12.75

Total synthesis of (R)-(+)-dodecan-4-olide.

In 2014, Gharpure et al. accomplished the enantiospecific collective total synthesis of butanolide and butenolide natural products utilizing oxygen‐substituted DA cyclopropane as a common precursor [130]. The authors performed the first total synthesis of (+)‐juruenolide D (487b), butanolide (489a‐b), butenolide (490), (+)‐ hydroxyancepenolide (492a), (+)‐hydroxyancepenolide acetate (492b), and also did the total synthesis of (+)‐juruenolide C (487a), (+)‐blastmycinone (488a), (+)‐antimycinone (488b), and (+)‐ancepsenolide (491). Among these natural products,

413

414

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

(+)‐juruenolide C and D (478a–478b) were isolated from Virola surinamensis, and butanolide (489a) was found in Iryanthera sp. (+)‐Blastmycinone (488a) and (+)‐antimycinone (488b) were isolated from Streptomyces sp. and were found to possess antitumor and antifungal activities. Marine natural product butanolide (489b) and its dehydration product butenolide (490), (+)‐ancepsenolide (491), and (+)‐hydroxyancepenolide (492), were isolated from Caribbean gorgonian Pterogorgia ancepsand displays the defensive mechanism of the species. (+)‐Hydroxyancepenolide acetate (492b) was isolated from only Pterogorgia citrima but (+)‐ancepsenolide (491) and (+)‐hydroxyancepenolide (492a) were isolated from both Pterogorgia citrima and Pterogorgia guadalupensis. (+)‐Ancepsenolide (491) exhibits pesticidal activities as well as antitumoral, immunosuppressive, and antimalarial properties. The synthesis commenced with the conversion of DA cyclopropane 483 to lactol 486, which acted as the common intermediate for the synthesis of all butanolide and butenolide‐based natural products (487–492). LiAlH4‐induced chemo‐ and ­stereoselective reduction of ketone moiety in 483 generated alcohol 484, which upon treatment with cat. amount H2SO4 in MeOH furnished lactone 485 via tandem regioselective cyclopropane ring‐opening/trapping of oxonium ion by MeOH/ intramolecular lactonization sequence. Lactone 485 underwent reduction with DIBAL‐H to afford the desired lactol 486. All the aforementioned natural products were successfully synthesized from 486 (Scheme 12.76). The Nakada group previously reported an enantioselective approach to the synthesis of (−)‐platencin using CAIMCP strategy in 2010. The authors again in 2012 reported the stereoselective total synthesis of PPAP nemorosone. In 2015 they further proposed the enantioselective approach to another four polycyclic PPAPs viz., nemorosone (496), hyperfoin (497), clusianone (499) and garsubellin A (498) [131a]. These PPAPs exhibit immense biological activities, e.g. nemorosone displays antitumor and anti‐HIV activities, hyperfoin has antitumor and antidepressant activities, clusianone shows antiviral activity against both Epstein–Barr and HIV virus in addition to antitumor activity, and garsubellin A possesses anti‐Alzheimer activity. The synthesis commenced with the conversion of aldehyde 493 to α‐diazo β‐keto sulfone 494, and CAIMCP of 494 produced compound 495 in 79% yield with 84% ee. Interestingly, it was found that compound 495 was not cyclopropane rather 495 was obtained via ring opening of cyclopropane followed by skeletal rearrangement during the course of CAIMCP. Now, all these four PPAPs were possible to synthesize from the common intermediate 495 (Scheme 12.77) [131b, e]. Magauer and co‐workers reported the synthesis of the anticancer natural product chartarin (506) from commercially available indanones, as shown in Scheme 12.78. The protocol proceeded through a two‐step process involving the thermally induced fragmentation of a cyclopropane indanone with a simultaneous 1,2‐chloride shift [132]. The synthesis began with the coupling of Indanon 500 obtained from commercially available 7‐methoxy‐1‐indanone with para‐quinone 501 in the presence of catalytic amounts of hydroquinidine and subsequent decarboxylation of the tertbutyl ester in the presence of trifluoroacetic acid to afford the 2‐arylated indanone 502 in good overall yield on gram scale [133]. Next, 502 was oxidized employing StahlÏs palladium‐catalyzed aerobic dehydrogenation conditions [134] and subsequent treatment with KHMDS in the presence of 18‐crown‐6

O O O

n O O OH Me 487a: (+)-Juruenolide-C, n = 5 487b: (+)-Juruenolide-D, n = 7

O Me

H

O

CO2Et H 483

LiAlH4

HO

THF –78 °C

Me

H

O

H

conc. H2SO4 MeOH 0 °C - rt

H

H

O

PhMe –78 °C

OMe O 485

Me 488a: (+)-Blastmycinone, n = 2 488b: (+)-Antimycinone, n = 4

O

10

O

Me 489a: n = 7, R = Ph 489b: n = 13, R = Me Butanolide

OMe O 486

O

O

O

O Me

O

O 10

O

OH

Me 492a: (+)-Hydroxyancepsenolide

Scheme 12.76 Total synthesis of Butanolide and Butenolide natural products.

O Me

R

OH

H

OAc

Me 492b: (+)-Hydroxyancepsenolide acetate O

n

O

H Me

Me

O

O

O Me

DIBAL-H

O Me

484 dr = 10 : 1

Me

O

OH

O CO2Et

Me n

O

O 10

O

Me 491: (+)-Ancepsenolide

Me 14

Me 490: Butenolide

O Ph HO

O

O

O

HO

O

H

Nemorosone (496)

O

H

Hyperforin (497)

Bn Bn 1. NaClO2, NaH2PO4 OMe OTIPS CHO OMe 493

2-methyl-2-butene, 79% yield

OMe OTIPS

2. Me2SO4, K2CO3, 96% yield 3. MeSO2Ph, nBuLi 4. TsN3, K2CO3, CH3CN 87% yield (2 steps)

O MeO

N2 SO2Ph 494

iPr

(15 mol%)

O

iPr

MeO

Cu(CH3CN)4PF6 (10 mol%) H2O (10 equiv)

OTIPS

PhO2S 495 O

toluene, 80 °C, 12 h 79% yield, 84% ee

O

O

O

O HO

O

H

Ph O

OH Garsubellin A (498)

Scheme 12.77 Total synthesis of Nemorosone, Hyperfoin, Clusianone, and Garsubellin A.

O

H

Clusianone (499)

12.4 Synthesis of iscellaneous Natural Products O

OMe O

MeO2C

1. HQ; PivCl

CO2tBu +

2. TFA O 501

500

OPiv MeO2C OMe O

OPiv

OMe O

Pd(TFA)2, O2 OPiv

KHMDS, MDCA OPiv 18-crown-6

MeO2C

Cl O

502

OMe 503 K2CO3, MeOH Tf2O, NEt3

TfO MeO2C

OTf MeO2C OMe O

OMe OH OPiv OMe

Sulfolane

O

Cl

OPiv

200 °C, 15 min

Cl O

505

OMe 504

O

Me 1. Pd(dppf)Cl2, Me2Zn 2. NaOH, p-TsOH.H2O

OH O

3. Pd(CH3CN)2Cl2 SPhos, KB(OMe)4 4. pyridine.HCl

OH O Chartarin (506)

Scheme 12.78

Total synthesis of chartarin.

to give the cyclopropane 503 in 75% yield. The sequential reaction of 503 with methanolic potassium carbonate and then triflic anhydride provided cyclopropane 504. The ring‐opening reaction of the cyclopropane 504 was carried out by heating its solution in sulfolane to generate the biaryl intermediate 505 in 75% yield. Next 505 on heating with dimethyl zinc in the presence of Pd(dppf)Cl2 and subsequent treatment with NaOH/p‐TsOH·H2O, followed by the treatment with potassium tetramethoxyborate, bis(acetonitrile)dichloropalladium(II), SPhos, pyridine hydrochloride gave chartarin (506). Piperarborenine B (512) is a cyclobutane‐containing natural product isolated from Piper arborescens [135]. It exhibits activity against P‐388, A‐549, and HT‐29 cancer cell lines. Fox and co‐workers reported a highly efficient, enantioselective total synthesis (8% overall yield) of the natural product, piperarborenine B (512), as shown in Scheme 12.79 [136]. The strategy involves the synthesis of diazoester 508 from commercially available veratraldehyde 507 using a Tsuji–Trost allylation, followed by treatment with p‐ABSA and NaOH in a mixture of acetonitrile/H2O in 47% yield over three steps. The diazoester 508 on reaction with Rh2(SNTTL)3(dCPA) followed by

417

MeO

CHO

1. vinylMgBr 2. Pd(OAc)2, AdCO2H PPh3, H2O 110 °C, 30 min

CO2tBu

N2

,

1. Rh2(S-NTTL)3(dCPA) (0.1 mol%), PhMe, –78 °C 2. CuBr.SMe2 (0.5 equiv.) PPh3, THF, rt, 30 min

OMe MeO

OMe

MeO

507

CO2tBu 3. p-ABSA, NaOH H2O, ACN, 0 °C

508

O MeO

OMe

3. BHT, –78 °C to –10 °C

511 BHT

47% yield, 3 steps

H-OAr CO2tBu Ar

R Ar

509

Scheme 12.79 Total synthesis of Piperarborenine B.

OMe

N O

MgBr MeO

N

CO2tBu

O

MeO

O

O

,

OtBu O 510

OMe

Piperarborenine B (512)

12.4 Synthesis of iscellaneous Natural Products

cuprate addition using CuBr·SMe2, PPh3, and 2‐methyl‐1‐propenylmagnesium ­bromide provided the desired trisubstituted cyclobutane 510 via the formation of bi‐ cyclo‐propane 509 in 69% yield, 92% ee, and 4:1 dr after kinetic protonation with BHT. This cyclobutane 511 furnishes piperarborenine B (512) after several steps. Diarylheptanoids are a class of secondary plant metabolites belonging to diarylheptanoid natural products. It was isolated in 2003 from the rhizomes of Dioscorea spongiosa and is reported to have anti‐osteoporotic activity [137]. Gharpure and co‐workers reported the synthesis of diospongins B (517) via the cleavage of the DA‐substituted cyclopropapyranones 515, which was harvested by stereoselective intramolecular cyclopropanation of vinylogous carbonates 514 with carbenes using a copper catalyst, as shown in Scheme 12.80. Regioselective ring‐opening reaction of 515 under radical conditions provided by nBu3SnH and AIBN in refluxing benzene afforded the pyranone 516, which led to the rac‐diospongin B (517) in 68% yield [138]. O

O

CuI/Cu Powder (10 mol%)

N2

OH O

OH

CO2Et

H

515

O O

CO2Et

516

Scheme 12.80

O

OH

O n-Bu3SnH AIBN, C6H6 reflux, 60 °C

CO2Et

CH2Cl2, reflux

514

513

H

O Diospongin B (517)

Total synthesis of rac-diospongin B.

In 2018, Lee et al. reported the total syntheses of basiliolide A1 (525), basiliolide A2 (526), and basiliolide C (527), as shown in Scheme 12.81 [139]. The synthesis of basiliolides A1 and A2 (525–526) began with an intramolecular cyclopropanation of (E)‐518 and (Z)‐518 (prepared from geraniol and nerol, respectively, in three steps) to obtain (±)‐519a and (±)‐519b, respectively. The ketone moiety was reduced with NaBH4 to afford β‐hydroxy esters (±)‐520 as single diastereoisomers, where the attack took place from the less hindered α face to escape a steric interaction with the γ‐lactone moiety. Subsequent hydrolysis of the γ‐lactones under basic conditions, followed by a reaction with allyl bromide, generated the allyl esters. The free ­alcohols were transformed into iodides (±)‐521 using PPh3/I2/imidazole. Lithium‐ iodine interchange took place with nBuLi leading to the ring‐opening of the cyclopropane furnishing esters (±)‐522 as single diastereoisomers. (±)‐522 on treatment with VO(acac)2/TBHP and Ag2O/MeI gave (±)‐523, which was transformed to (±)‐524 after several steps. (±)‐523 gave rise to seco acid derivatives (±)‐transtaganolides E and F 524 after a few steps. O‐acylation of (±)‐524 with Tf2O in toluene to led (±)‐basiliolides A1 (525) and A2 (526). Likewise, (±)‐524 was also converted to (±)‐basiliolide C (527).

419

O

O

O

O

Cu(TBS)2 (10 mol%) 80 °C, 15h

O

O

OH O

O O

O

1. KOH, then allyl bromide (95–98%)

518

OH O O

OAllyl I

2. PPh3, imid, I2 (85–88%)

75–77%

74–75%

N2

O

NaBH4, MeOH –78 to –20 °C

(±)-519a: C8-α-methyl (±)-519b: C8-β-methyl

(±)-521a: C8-α-methyl (±)-521b: C8-β-methyl

(±)-520a: C8-α-methyl (±)-520b: C8-β-methyl

nBuLi,

< –80 °C

97–98%, MeO

O O

OMe

O O

MeO

O

O

O

CO2H

OH O O OAllyl

O

O

AcO (±)-transtaganolide E (524a): C8-α-methyl (±)-transtaganolide F (524b): C8-β-methyl

(±)-basiliolide C (527)

–78 to –20 °C

MeO

O O

(±)-523a: C8-α-methyl (±)-523b: C8-β-methyl

Tf2O, Et3N toluene

MeO O

O (±)-BasiliolideA1 (525)

O O

O

O (±)-BasiliolideA 2 (526)

Scheme 12.81 Total syntheses of basiliolides A1, A2, their seco acid derivatives transtaganolides E and F and basiliolide C.

1. VO(acac)2, TBHP 95–96%

O

OAllyl

2. Ag2O, MeI (92–95%) (±)-522a: C8-α-methyl (±)-522b: C8-β-methyl

12.4 Synthesis of iscellaneous Natural Products

From the stem bark of lophira lanceolate, Bodo and Martin et al. first isolated Lophirone F a hexaphenolic biflavonoid natural product [140]. Lophirone F shows inhibitory activities against Epstein–Barr virus (EBV) and early antigen (EA) induction by a tumor promoter, teleocidin B‐4 [141]. In 2019, Do and coworkers reported the total synthesis of Lophirone F hexamethyl ether (531), as shown in Scheme 12.82 [142]. Corey–Chaykovsky cyclopropanation of benzylidene 528 with the dimethylsulfonium bromide salt led to trans‐cyclopropane (±)‐529 (80% yield, >20:1 dr). Next, aluminum trichloride‐catalyzed formal [3+2] cycloaddition of the cyclopropane 529 with 4‐methoxybenzaldehyde resulted in the formation of tetrahydrofuran 530 in very good yield and excellent diastereoselectivity (80% yield, >20:1 dr). The tert‐butyl ester 530 transformed to lophirone F hexamethyl ether (531) in an excellent dr (>20:1 dr). Me S

MeO

CO2Me CO2Me 528

Br

CO2tBu (1.3 equiv.)

O MeO

CO2Me CO2Me

DBU/DCM rt, 18 h (80%,(>20 : 1 dr)

CO2tBu 529

MeO (2 equiv.) AlCl3 (15 mol%) DCM, rt, 5 min 80%

MeO

tBuO

MeO O

MeO2C CO2Me 2C

MeO

OMe

O O MeO 530

Scheme 12.82

OMe

O

OMe

MeO Lophirone F hexamethyl ether (531)

Total synthesis of Lophirone F hexamethyl ether.

Spirochensilide A (539) was isolated from an endemic Chinese plant, Abies chensiensis, in 2015 by Gao and co‐workers [143]. Spirochensilide A (539) might be a useful probe for studying inflammatory diseases as it inhibits NO production, with 30% inhibition at a concentration of 12.5 μg/ml. In 2020, Yang et al. reported an asymmetric total synthesis of Spirochensilide A (539) in 22 steps with a total yield of up to 2.2% via a tungsten‐mediated cyclopropene‐based PK reaction, as shown in Scheme 12.83 [144]. The synthesized compound 532 was alkylated with lithium reagent 533 in the presence of CeCl3, and the resultant secondary alcohol was protected with TES to furnish cyclopropene 534 in 98% overall yield. 534 was converted to 535b along with its diastereoisomer 535a. The cyclopropane 535b upon treatment with tBuOK gave 536; regioselective hydrogenation of 536 using Pd/C followed by subsequent reductive ring‐opening reaction of the product 537 with Li/NH3 gave 538 in 76% yield over three steps. The compound 538 was then transformed into the natural product Spirochensilide A (539) after several steps. In 2003, Ohta isolated Ikegami Exigurin (547) from the marine sponge Geodia exigua found on Oshima Island [145]. Ichikawa accomplished the first total

421

422

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products

TBSO

TMS

Li

533

TMS

TESOTf, Et 3N then MeOH, K 2CO3 (98%)

H Me Me 532

TMS

OTESO H Me

CeCl3

Me CHO

TBSO

H

H Me Me 534

W(CO)3(MeCN)3 EtOH, HMPA, CO (61%, 535a : 535b = 1 : 1) or Ni(COD)2/bipy, CO (84%,535a : 535b = 4 : 1) or Mo(CO)3(DMF)3 (70%, 535a : 535b = 2 : 1)

H OTESO Me TBSO Me MeH

H OTESO

TMS O

+

TMS

Me TBSO Me MeH

O

535a

535b tBuOK, tBuOH

95% H OTESO

Li-NH3 then, DCE (80% in 2 steps)

Pd/C H 2 (balloon pressure) EtOH, EtOAc

Me TBSO Me MeH

H

O

H OTESO Me TBSO Me MeH 536

537 Me Me O

Me

O O

H

Me HO

O

H OTESO

Me

Me TBSO Me MeH

H Me Me Spirochensilide A (539)

Scheme 12.83

O

Me

H

O

538

Total synthesis of Spirochensilide.

synthesis of a marine natural product, exigurin (547), in 13 steps starting from (+)‐ menthone, as shown in Scheme 12.84 [146]. α‐Diazo‐β‐keto sulfone 541, obtained from (+)‐menthone, was treated with copper(II) N‐(tert‐butyl)salicylaldimine to furnish cyclopropyl ketone 542 as a single diastereomer in 75% yield. The ring‐ opening reaction of the cyclopropane 542 with the azide anion (NaN3) using a combination of magnesium perchlorate and the phase transfer catalyst (nBu4N·HSO4) gave 543 in 66% yield. 543 was converted into 544 involving the triflation of ketosulfone with triflic anhydride and sodium hydride, followed by the palladium‐catalyzed Suzuki–Miyaura coupling employing trimethylboroxine. The sulfonyl group of 544 was removed by using samarium diiodide, and simultaneous azide reduction ­generated the corresponding amine, which underwent formylation with acetic formic anhydride to give exiguamide 545. Dehydration of 545 with triphosgene in the presence of triethylamine gave rise to (−)‐10‐epi‐axisonitrile‐3 546 in 88% yield. Finally, a bioinspired Ugi five‐centre four‐component reaction (U‐5C‐4CR) using a solution of formaldehyde and sarcosine methanol with (−)‐10‐epi‐axisonitrile‐3 546 gave exigurin (547) in 53% yield.

12.4 Synthesis of iscellaneous Natural Products

O

N2

O

SO2Ph 540

541

tBu

O

PhO2S

NaN3 4NHSO4 Mg(ClO4)2

Cu N O tBu

O

nBu

O SO2Ph

PhMe, 80 °C, 75%

DMF, 100 °C 66%

N3

542

543 1. NaH, Tf2O, DME, 92% 2. MeB3O3, Pd(PPh3)4 K 2CO3, dioxane, 96% PhO2S

Triphosgene Et 3N

SmI2, HMPA EtOH, THF, 50% NHCHO

CH2Cl2, 88%

AcOCHO AcOEt, 68%

N3

545

544 Me

O N H

Me N CO2Me

CO2H N H HCHO, MeOH

Exgurin (547)

Scheme 12.84

N

53%

C

546

Total synthesis of exigurin.

Cotylenin A (553) was initially isolated as a plant growth regulator; however, biological studies later showed that it leads to the differentiation of murine and human myeloid leukemia cells and the apoptosis of a broad [147] range of human cancer cell lines by combined treatment with interferon‐α. Cotylenin A (553) has attracted considerable attention from the scientific community in the past decades on account of its anti‐cancer activity. In 2020, Nakada et al. described a convergent enantioselective total synthesis of cotylenin A (553), as shown in Scheme 12.85 [148]. The synthesized compound 548, when subjected to the CAIMCP afforded the cyclopropane 549 in 86% yield with 86% ee. 549 underwent ring opening with sodium cyanide to give 550, which was transformed into 551 after several steps. Finally, 551 reacted with TBAF to afford cotylenol (552). 551 was also converted to cotylenin A (553). Haliclonin A (559), isolated from the marine sponge Haliclona sp. collected from Korean waters, is a macrocyclic diamide of a novel skeletal class. Recently, Yokoshima accomplished the total synthesis of haliclonin A (559), starting from 3,5‐dimethoxybenzoic acid (554), as shown in Scheme 12.86 [149]. The symmetric compound 555, obtained from 3,5‐dimethoxybenzoic acid 554 underwent cyclopropanation with a

423

424

12 Application of Donor–Acceptor Cyclopropanes in Total Synthesis of Natural Products Bn Bn O O N N H

CuPF6(CH3CN)4 (3.0 mol%) O

SO2Mes

N2

PhMe, 60 °C 86%, 86% ee

SO2Mes

O

548

549 OH

HO H NaCN, DMSO

CN

80 °C, 77%

H

SO2Mes

O

OMe

TMSO

550 99% ee

T

, HF

,T

F BA

551

rt

93%

OH

HO

O HO

H

O

O

O

HO

OMe

HO

O

O

OMe

H

Cotylenol (552)

OMe

TMSO

Cotylenin A (553)

Scheme 12.85

Total synthesis of Cotylenin A.

O CO2H

MeO

N2

O

O

MeO N Ts 555

OMe 554

OMe

N Cu N

O

Toluene, 75 °C ~65%

O

MeO N Ts

H

OMe

556 1. aq. NaOH, MeOH 2. THF, 0 °C to rt

HO

O N

O N CHO Haliclonin A (559)

Scheme 12.86

O

O CSA (0.1 equiv.)

H MeO N Ts 558

Total synthesis of Haliclonin A.

O

DCM, rt 92%

H HO2C MeO N Ts 557

OH OMe

12.4 Synthesis of iscellaneous Natural Products

chiral copper catalyst to afford enantioenriched cyclopropane 556. The reaction of 556 with sodium hydroxide gave carboxylic acid 557, which when treated with 10‐camphorsulfonic acid (CSA) in dichloromethane, resulted in the formation of 558 in 92% yield over two steps. The compound 558 finally gave rise to haliclonin A (559) in twenty five further steps. Dictyopterenes C’ (567) is found in sexually mature thalli of the Japanese brown algae Scytosiphon lomentaria [150]. Ryu and coworkers accomplished an effective strategy for enantioselective synthesis of (−)‐dictyopterene C’ (567) on the basis of chiral oxazaborolidinium ion (COBI)‐catalyzed enantioselective cyclopropanation and subsequent divinylcyclopropane‐cycloheptadiene rearrangement [151]. Enantioselective cyclopropanation of α,β‐unsaturated aldehyde 560 and diazoacetate 561 in the presence of COBI catalyst gave the cyclopropane 562. Highly trans‐ selective Julia–Kocienski olefination with 1‐phenyl‐1H‐tetrazole and potassium bis(trimethylsilyl)amide (KHMDS) furnished the alkene 563 in high yield. After the DIBAL‐H reduction of tert‐butyl ester group to aldehyde and simultaneous Wittig reaction with a methylphosphonium salt using n‐butyllithium produced divinylcyclopropane products 564. 564 was converted to 1,4‐cycloheptadienes 566 through the DVCPR endo‐boat‐like transition‐state 565. Finally, palladium‐catalyzed reduction of vinyl bromide 566 afforded desired (−)‐dictyopterene C’ (567) in five steps and 42% yield, as shown in Scheme 12.87. Ar1 HN

Ar1

B O Ar 2 COBI catalyst

N N N N

OTf Br

CHO

N2 +

H

tBuO

CO2tBu EtCN, –78 °C

2C

H

561

560

nBu

PdCl2(PPh3)2, NaBH4 TMEDA,THF reflux, 3 h, 80%

(–)-Dictyopterene C’ (567)

KHMDS, DME

Br

–78 °C, 30 min

nBu

tBuO C 2

H

Br 563

562

Ar1 = 3,5-dimethylphenyl, Ar2 = 2- ethylphenyl

Br

CHO

1. DIBAL-H (1.0 M in toluene), toluene, –78 °C, 10 min 2. MePPh3Br, n-BuLi (2.5 M in n-hexane), Et2O, 0 °C, 24 h

Br

nBu

H nBu

nBu

H Br

566

565

H

Br 564

Scheme 12.87 Total synthesis of Dictyopterenes C’.

The high natural abundance and varied biological activities of α‐alkylidene‐γ‐ butyrolactones have stimulated the scientific community to dense efficient methods for their synthesis [152a]. Unsworth and co‐workers reported the total syntheses of three natural products, (±)‐savinin (573), (±)‐gadain (574), and (±)‐peperomin E (579) in 2016 as shown in Scheme 12.88 [152b]. α‐Diazo‐α‐(diethoxyphosphoryl) acetate 570 was derived from allylic alcohol 568. The compound 570 on treatment

425

O

O PO(OEt)2

O

OH HO2C

O

H

PO(OEt)2

T3P, EtN(i-Pr)2, PhMe

O

N2

p-ABSA, LHMD, THF or

O

H

PO(OEt)2

O

O

H

DBSA, DBU, CH2Cl2

O

O 570

569

568

Rh2(oct)4 O

O

O

O O

KO tBu piperonal

O O (±)-savinin (573) and (±)-gadain (574) (1.9 : 1, 8 : 9)

O SmI2

THF, heat 53%

O

CH2Cl2, 45 °C, 20 h

O P OEt OEt

PO(OEt)2

O

O

THF

O

H H

O

O

571

572 O PO(OEt)2

O N2

O O

O

O

O

O

O

OMe

OMe

575

O Rh(II) cat. (2 mol%)

O

PO(OEt)2

O

O H

CH2Cl2, 45 °C 20 h, 41%

OMe

OMe OMe O

576

O 577 SmI2, THF –78 °C, 55%

O

O

O

O

O

O O

O

OMe O

PO(OEt)2

KOtBu, (CH2O)n THF, 0 °C to rt 87%

OMe Peperomin (579)

Scheme 12.88 Total synthesis of (±)-savinin, (±)-gadain, and (±)-peperomin E.

O O

OMe O

OMe 578

References

with 2 mol% rhodium(II) octanoate in CH2Cl2 under refluxing conditions, led to the efficient formation of cyclopropane 571, which was reacted with samarium(II) to give the lactone 572 in 38% yield, as a single diastereoisomer, which on reaction with KOtBu and piperonal, led to a 1.9:1 mixture of α‐methylene‐γ‐butyrolactones (±)‐ savinin 573, (±)‐gadain 574 in 53% overall yield. These isomers were separated by column chromatography, and the spectral data for both compounds were in full agreement with the reported literature. Next, for the synthesis of (±)‐peperomin E (579), it began with the conversion of commercially available aldehyde 575 to the key cyclopropanation precursor 576. The rhodium‐catalyzed cyclopropanation of α‐diazo‐α‐(diethoxyphosphoryl)acetate 576 led to the formation of 577, which underwent ring‐opening with samarium(II) iodide to form the lactone 578. Finally, Horner‐Wadsworth‐Emmons olefination of 578 afforded peperomin E (579).

12.5 Conclusion The total synthesis of natural products has always been considered as one of the most exciting and dynamic fields in organic chemistry. This chapter summarizes the application of DA‐cyclopropanes in the total synthesis of various alkaloids, terpenes/terpenoids, and other natural products of diverse biological activities. As discussed, cyclopropanation followed by synthetic transformations of the corresponding cyclopropanes were considered as some of the important key steps in each of the above total syntheses. More interestingly, in some cases, the reactions were also able to show high selectivity. Hence, good diastereocontrol as well as enantiocontrol even led to the total synthesis of natural products in an enantioselective manner. Since DA‐cyclopropane chemistry is in constant growth, the syntheses described above are only some limited examples of the expanding literature on the application of DA‐cyclopropanes in the total synthesis of natural products.

­Acknowledgments M.K.G. is grateful to IIT Kanpur and SERB (DST), India, for financial support. A. S. and K. M. thank IIT‐Kanpur for Institute Research Fellowships and S.Y. thanks UGC for a Junior Research Fellowship.

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433

Index a

Abies chensiensis 421 acceptor indolyl olefins 85 3-acetonyl-2,3-dehydropiperidines 193 2-acetylcyclopropanecarbaldehydes 154 acetylenedicarboxylate 51 activated acyclic dienol-type Breslow intermediate 155 activated cyclopropanes 17–19, 21, 22, 37, 40, 41, 47, 48, 51, 54, 59, 63, 66, 67, 69, 83, 162, 270, 339, 351 activated vinyl cyclopropane 18 activation barriers 21, 24–26, 32 acyclic azadienes 68 acyclic diene systems 45 acyclic zwitterionic intermediate 149 1-acyl-2-arylcyclopropanes 205 1-acyl-2,2-bis(phenylsulfanyl) cyclopropanes 193 2-acylcyclopropanecarbaldehydes 154, 157 γ-acyloxy-substituted aldehydes 147, 350 3-acyl-2-styrylcyclopropane-1, 1-diesters 196 α-agarofuran 385 AgNO3-(NH4)2S2O8-pyridine system 380 alkaloids (–)-allosecurinine 363–364 (±)-β-allokainic acid 375–376

(–)-ardeemin 365 (+)-aspidofractinine 366 Atorvastatin 374 (–)-batrachotoxin 374–375 (±)-Communesin F 363 crispine A 372 (–)-daphenylline 378 (±)-deethyleburnamonine 371–372 (±)-epimeloscine and (±)-meloscine 371 (+)-fastigiatine 368 (+)-fawcettimine 366, 368 FR901483 366–367 GB22 376 gelsemoxonine 369 (±)-gelsenicine 374–375 (±)-goniomitine 364 (–)-himalensine A 377–378 horsfiline 360 (±)-jerantinine E 373 Lyconesidine B 378 melodinus alkaloids 370 (±)-melokhanine E 377 (+)-nakadomarin A 362 (–)-nicotine 374 (+)-phyllantidine 361, 362 (±)-quebrachamine 365 quinolizidine (–)-217A 370 spirotryprostatin B 360–361 (±)-strychnofoline 360

Donor–Acceptor Cyclopropanes in Organic Synthesis, First Edition. Edited by Prabal Banerjee and Akkattu T. Biju. © 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.

434

Index

1-alkenyl-2-alkoxycyclopropanecarboxylates 201 2-alkenyl-1-arylcyclopropanecarboxylates 216 2-alkenyl-2-arylcyclopropane-1,1diesters 215 1-alkenylcyclopropanecarboxylates 201 2-alkenylcyclopropane-1,1-dicarboxylates 194, 195 alkenylcyclopropanes 199, 200, 202, 207, 208, 215 alkenyl cyclopropyl ketones 214 2-alkenylcyclopropyl ketones 216 7-alkenyl-2-oxobicyclo[4.1.0]heptanes 200 2-alkenyl-2-siloxy-2,3-dihydrofurans 217 2-alkenyl-2-(t-butyldimethylsiloxy) cyclopropylmethanols 217 alkoxy cyclopropanecarboxylates 52, 54 2-alkoxycyclopropanecarboxylates 192 alkoxycyclopropane monocarboxylates 42 alkoxytetrahydrothiophenes 78 2-(1-alkyl-2-(het)arylvinyl) cyclopropylmalonates 201 alkylidenebenzofuranones 142 alkylidenemalonates 194, 195 alkylideneoxindoles 142, 153, 156, 318 2-alkynylcyclopropylcarbaldehydes 218 allenylsilanes 73, 87 β-allokainic acid 375–376 (–)-allosecurinine 363–364 allylsilanes 41, 42, 87 amino-3-aminomethylation of D–A cyclopropanes 173 1,3-aminobromination of D–A cyclopropanes 175 1,3-aminochalcogenation of donor-acceptor cyclopropanes 178, 179 aminocyclopropane 339 dicarboxylates 44 monoesters 54 2-amino cyclopropane dicarboxylates 44 1,3-aminofunctionalization of D-A cyclopropanes 187

1,3-aminothiolation of D-A cyclopropanes using sulfenamides 180–182 2-aminoxyethyl-substituted cyclopropane 218 annulated β-lactams 219 [3+n] annulations 337, 341 [BnNEt3]2MoS4 324 (3+2) annulation 282 (3+3) annulation 282–285 (9-anthracenyl) cyclopropanedicarboxylate 103 anthranils 99, 100, 348 anthranyl aldehydes 102 β-araneosene 404–405 (–)-ardeemin 365 (+)-arglabin 380–381 aromatic aldehydes 61, 63, 108, 109, 286, 287, 339 1-aroy-2-arylcyclopropanes 210 1-aroyl-2-arylcyclopropanecarboxylates 211 aroyl-substituted D-A cyclopropanes AlCl3 or SnCl4-mediated ring-opening reactions 276 (3+2) annulation 280–282 (3+3w) annulation 282–285 conversion 285–286 ring-opening reactions with hydrazines 278–280 synthesis 274–276 TiCl4-mediated ring-opening reactions 278 (+)-arteludovicinolide A 390 5-aryl-3-(2-aryl-2-nitrovinyl)isooxazoline N-oxides 209 aryl 2-[4,4-bis(methylthio) butadienyl]cyclopropyl ketones 200 arylcyclopropanedicarboxylates 58 4-arylcyclopentenes 216 2-arylcyclopropane-1,1-diesters | 194, 215 2-aryl-cyclopropane-1,1-diketones 89 2-aryl D–A cyclopropanes 122–123 2-aryl-2,3-dihydrofuran-4-carboxylates 204

Index

2-aryl-2,3-dihydrofurans 205 2-arylethylidenemalonates 194, 195 4-aryl-4-hydroxybutyrophenones 210 5-aryl-2-methyl-3-R-4,5-dihydrofuran-3carboxylates 203 2-aryl-1-nitro-1-(1-nitro-2-arylvinyl) cyclopropane 209 (3-aryl-1-oxoindan-2-yl)malonates 215 3-aryl-2-styrylcyclopropane-1,1dicarboxylates 196 arylsulfenyl chlorides 146 2-aryl-1-(tri-or difluoroacetyl) cyclopropanecarboxylates 206 Aspergillus fischeri 365 Aspergillus fumigatus 360 (+)-aspidofractinine 366 Aspidosperma quebracho 364 (+)-asteriscanolide 387–388 a-substituted dialkylbromomalonates 155 Atorvastatin 323, 373, 374 8-aza-and 8-oxabicyclo[3.2.1]octane derivatives 193 azeto[2,3-d]isoxazolidine skeleton 219 aziridines 82, 93, 94, 106, 120, 121, 255 azodicarboxylate 79, 296

b

Baeyer strain 16 (+)-barekoxide and (+)-barekol 386 (–)-batrachotoxin 374, 375 benzenothiols 145 benzo[b]thiepines 145 benzo[c]thiophene derivative 212 benzocycloheptenes 216 benzodithioloneimines 100 benzofuran-based azadienes 45 (benzofuran-2-yl)acetate 194 (benzofuran-3-yl)acetic acid 194 2-(benzofuran-3-yl)cyclopropane-1, 1-dicarbonitrile 198 benzoisothiazolo[2,3-a]pyridin-7-one 5,5-dioxides 154 benzoquinone 121 1-benzoyl-2-hydroxyphenyl-3,3dimethylcyclopropane 219

benzyloxyureas 118 bezimidazolium precatalyst 152 BF3·Et2O promoted [3+2] cyclodimerization 309 bicyclic alkenylcyclopropanes 199 bicyclo[4.1.0]heptanes 199, 200, 212 bicyclo[2.2.2]octane system 88 2-(biphenyl-2-yl) cyclopropane-1,1-diester 218 3,4-bis(acylmethyl)furans and-pyrroles 204 1,3-bisarylation of D-A cyclopropanes 181–183 1,3-bisfunctionalization of D-A cyclopropanes with arenes and nitrosoarenes 172 bisfunctionalization of donor-acceptor containing cyclopropyl boronic ester 178 bishemiaminals 204 2,2-bis(β-methylstyryl)-substituted cyclopropane 215 bis-polysubstituted pyrroles 127 botryococcene 398–401 β-branched α,γ-dichlorinated aliphatic aldehydes 146 Breslow intermediates 140, 148–157 Brønsted acid catalyst activation 352–353 (±)-bruguierol A 409 (butadienyl)cyclopropanes 199 butanolide and butenolide natural products 415 but-3-enylidenemalonates 196 γ-butyrolactone 75, 80, 100, 285–287, 289

c

10-camphorsulfonic acid (CSA) 425 carbanion-carbonium ion intermediates 9 carbodimides 75, 76 carbonyl groups 8, 18, 52, 66, 74–75, 102, 127–128, 210, 238, 255–258, 263, 267, 302, 314, 347 1,3-carbothiolation of D–A cyclopropanes 183–184

435

436

Index

Carreira’s cycloaddition 67 catalyst free activation of D–A cyclopropanes 319–327 catalyst free ring-opening of D–A cyclopropanes with sodium azide 323 with cyanate ion 324 cyclopropane hemimalonates 319 cyclopropane-1,1-hemimalonate with sodium azide 320–321 formal [4+1] cycloaddition via photopromoted siloxycarbene 327 1-nitro-1-cyclopropyl ketones 322 non-catalytic reaction of cyclopropane hemimalonate with indole 320 with phenoxyanions 322 reorganization/dealkoxycarbonylation reaction of 322 ring-enlargement of donor-substituted nitrocyclopropanes 327 ring-opening decarboxylation of cyclopropane hemiaminoglycate with sodium azide 320–321 spontaneous ring-enlargement of 326 THF unit 325 with thiophenolates 324–325 catalytic asymmetric intramolecular cyclopropanation (CAIMCP) 409, 414, 423 C≡Ctriple bond 50 Charette asymmetric cyclopropanation of allyl alcohol 403 Charette cyclopropanation 381 chartarin 414, 417 chiral cyclopropanes 150, 333 chiral imidazolidinone catalyst 146 chiral Lewis acid catalyzed reactions of donor-acceptor (D-A) cyclopropanes 2-substituted cyclopropane-1, 1-diketones 341–343 2-substituted cyclopropyl diesters [3+n] annulations 337–341 ring-opening reactions 334–337

chiral organocatalytic reactions of DA cyclopropanes Brønsted acid catalyst activation 352–353 Brønsted base catalyst activation 350–351 nucleophilic catalyst activation 351–352 radical pathway 353–354 chiral pyrrolidines 68 chloride-initiated asymmetric cyclopropane ring opening reaction 147 chlorochalcogenation of cyclopropyl carbaldehydes 170–171, 174 chloromethyl allylsilanes 87 Chromodoris norrisi 410 Chromodorolide B 395, 396 chrysantemal 203 cis-1-acyl-2-arylcyclopropanecarboxylates 204–205 cis-configured cyclopropane substrates 143 cis-substituted D-A cyclopropane 26 cis-2-vinylcyclopropanecarbaldehyde 217 (–)-(S, S)-clavukerin A 379 Clavularia koellikeri 379 Cloke–Wilson rearrangement and related processes affording pyrrole derivatives 208–209 rearrangement of acyl-substituted cyclopropanes to 3-dihydrofurans 202–208 related rearrangements affording other heterocycles 209–210 Cloke–Wilson-type rearrangement 160 (–)-clovan-2,9-dione 391, 394 clusianone 414, 416 (±)-communesin F 363 (–)-connatusin A 386, 388 (+)-connatusin B 386–387 conversion of D–A cyclopropanes to β-hydroxy ketones 182–184 Cope rearrangement and related isomerizations 215–218

Index

copper-catalyzed cyclopropanation 231 Corey–Chaykovsky cyclopropanation of benzylidene 421 Corey–Chaykovsky reaction 231, 260 cotylenin A 423, 424 coumarin-2-ones 150 covalent organocatalysis 139 activation of cyclopropanes 140 Breslow intermediates 148–157 phosphine/tertiary amine catalysis 157–161 secondary amine catalysis enamine activation 141–144 iminium ion activation 144–148 crispine A 372 cyclic annulated nitronates 122 cyclic 1-azadienes 347 cyclic dithioacetals 49 cyclic nitronates 93, 122, 327 cyclization reactions of 1,1-dicyano cyclopropanes 125–126 cyclizations of cyclopropanes containing carbonyl group 127–128 cyclizations with phenols and nitrogencontaining heterocycles 124–125 cyclizations with sulfur reagents 126–127 (3+n)-cycloaddition 11 [3+2] cycloaddition reaction of di-cyano cyclopropylketones with nitroolefins 315 cyclodimerization reactions of D–A cyclopropanes 38, 112–117 cyclohepenones 160 cyclohepta[cd]indoles 216 cycloheptadienes 143, 215 cycloheptenones 216 cyclohexadienedithiones 100 cyclohexane derivatives 114 cyclopenta[b[benzofuran 198 cyclopenta[c]chromene skeleton 53 cyclopentachromenes 128 cyclopentaindolines 54 cyclopentanaphthalenes 56 cyclopentanes 41, 43, 73, 112, 113, 303, 315, 339, 345, 350, 353, 354

cyclopropa[b]benzofurans 194 cyclopropa[b]thiophene 192 cyclopropanecarbaldehyde products 144 cyclopropanecarbaldehydes 145, 150–151, 153, 157, 261 cyclopropane dicarboxylates 40, 42–44, 49, 54, 56, 61–63, 68, 69, 84, 90, 93, 102, 116, 117, 119–123 1,1-cyclopropane dicarboxylates 40, 41 cyclopropane diesters 44, 255, 256, 258 cyclopropanedinitriles 105 cyclopropenones 65 cyclopropylacetaldehyde dicarboxylates 142 cyclopropylacetaldehydes 142, 156 cyclopropyl acrylaldehydes 158 cyclopropylketone moiety 53 cyclopropyl ketones 3, 39, 42, 51, 52, 54, 59, 67, 112–113, 200, 202, 205, 210, 211, 214, 216, 257, 259, 267, 306, 314–316, 322, 342, 353, 354 cyclopropylmethylenaminol Breslow intermediate 157 1-cyclopropyl-2-methylisoquinolinum salt 208 cyclopropyl monocarbonyls applications 270 heterocyclic synthesis 264–270 metal catalyzed annulation reactions 264–267 ring expansion and ring opening reactions 267–270

d

DABCO catalyzed Cloke–Wislon rearrangement of electrophilic cyclopropanes 159–160 DABCO-catalyzed cyclopropane ring-opening/Michael/cyclization cascade reaction 159–160 (–)-daphenylline 377–378 Daphniphyllum alkaloids 377 (±)-deethyleburnamonine 214, 371–372 2,3-dehydropiperidines 193 (±)-1-desoxyhypnophilin 383

437

438

Index

densely functionalized cyclobutanes 142 Diachasmimorpha lingicaudata 409 Diachasmimorpha tryoni (Cameron) 409 1,1-diacyl-2-aryl/ alkenylcyclopropanes 207 1,1-diacyl-2-vinylcyclopropanes 206–207 2,5-diarylcyclopent-3-ene-1,1dicarboxylates 196 diarylethenes 43 diarylprolinol 147, 164 diastereomerically pure cyclopropanes 198 4,5-diazaspiro[2.4]hept-4-enes 176 1,3-diazepines 101 diaziridines 82, 93, 94 diazocarbonyl compounds 95, 96 dibenzacridins 128 1,3-dichlorinated products 22 3,3-dichlorocyclopentene 197 1,1-dichloropenta-1,3-and 1,4-dienes 197 1,1-dichloro-2-vinylcyclopropane 197 Dichrocephala benthamii 397 dichrocephones A and B 397, 398 dicobalt cluster 68 Dictyopterenes C 425 dienes as traps for 1,3-zwitterions 97–99 dihydrobenzodithiepine derivatives 101 dihydrobenzofurans 219, 220 2,3-dihydrobenzofurans 219, 220 2,3-dihydrofuran 192, 202–208, 217, 269 dihydrofurane products 158, 160 3,4-dihydro-2H-pyrrole derivatives 80 dihydroindolizine derivatives 70, 208 dihydroisoquibnolines 143 4,5-dihydroisoxazoline 209 dihydronaphthalene 110, 211 2,3-dihydropyrroles 192, 202, 342, 343 dihydroquinolines 142, 349 dimethoxycyclopropane 40, 51, 67, 79 2,2-dimethoxy cyclopropanecarboxylate 73, 74 6,7-dimethoxy-1-(2-phenylcyclopropyl)-3, 4-dihydroisoquinoline 208 2,5-dimethylfuran 55, 120

2,4-dinitrophenylcyclopropyl carbaldehyde 150 1,4,2-dioxazoles 70 1,3-dipolar synthons 11, 229 disfavored 5-endo-trig cyclization 161 2,3-disubstituted cyclopent-3-ene-1, 1-dicarboxylates 201 disubstituted cyclopropane dicarboxylates 90 γ,γ-disubstituted N-arylated α-amino esters 172 α,β-disubstituted δ-oxoamides 150 divinylcyclopropane-cycloheptadiene reaction 17 (R)-(+)-dodecan-4-olide 413 Dolabella auricularia 403 (–)-Doliculide 403–404 donor-acceptor cyclopropanes (DACs) 19 computational and kinetic investigations 22–32 1,3-dipolar cycloadditions 3 1-ethoxy-1-(trimethylsiloxy) cyclopropane 5 hand-drawn scheme 4 isomerizations to alkenes 192–197 number of publications 2 organic synthesis 2 principles of 6–10 siloxy-substituted cyclopropanecarboxylates 4–6 terminology 10–12 donor-acceptor cyclopropyl carbonyls cyclopropane mono-carbonyls 259 diastereomers and controlled reactivity 257–258 not merely a three-carbon synthon 258 reduced reactivity 256–257 two nucleophilic and two electrophilic sites 258–259 donor-acceptor cyclopropyl monocarbonyls preparation methods 260–263 from arylthio cyclopropyl carbaldehydes 262

Index

from diazo compounds 262–263 from 1,2-dicarbonyl compounds 263 from homoaldol adducts 261 from olefins 260–261 donor-acceptor (DA) aminocyclopropanes 228 classification and reactivity 228 formal cycloaddition 244–249 ring-opening reactions 235–244 intermolecular 240–244 intramolecular 236–240 synthesis 229 acrylates 233 cyclopropene 233 cyclopropylamines 234–235 β-dehydroamino acids 231 enamines 231–232 2-haloethylidene malonates 233–234 donor-acceptor (D–A) cyclopropanes amino-3-aminomethylation of 173 1,3-aminobromination of 175 1,3-aminochalcogenation of 178 1,3-aminofunctionalization of D-A cyclopropanes 187 1,3-aminothiolation using sulfenamides 180–181 1,3-bisarylation of 181–182 1,3-bisfunctionalization of D–A cyclopropanes with arenes and nitrosoarenes 172 bisfunctionalization of donor-acceptor containing cyclopropyl boronic ester 178 1,3-carbothiolation of 183–184 catalyst free activation of [BnNEt3]2MoS4 324 catalyst free ring-opening of D–A cyclopropanes with sodium azide 323 with cyanate ion 323–324 cyclopropane hemimalonates 319 cyclopropane-1,1-hemimalonate with sodium azide 320–321

formal [4+1] cycloaddition via photopromoted siloxycarbene 327 1-nitro-1-cyclopropyl ketones 322 non-catalytic reaction of cyclopropane hemimalonate with indole 320 with phenoxyanions 322 reorganization/ dealkoxycarbonylation reaction of 320, 322 ring-enlargement of donorsubstituted nitrocyclopropanes 327 ring-opening decarboxylation of cyclopropane hemiaminoglycate with sodium azide 320–321 spontaneous ringenlargement of 326 THF unit 325 with thiophenolates 324–325 chiral Lewis acid catalyzed reactions of 334 chiral organocatalytic reactions of 349–354 chlorochalcogenation of cyclopropyl carbaldehydes 170–171, 174 conversion to β-hydroxy ketones 182 with 4,5-diazaspiro[2.4]hept-4enes 176 electricity driven 1,3-oxohydroxylation of 328 electrochemical promoted ring opening 329 enantioselective 1,3-dichlorination of formyl group-containing cyclopropanes 168 four component coupling of 177–178 halochalcogenation of 174, 243 halogenation-peroxidation of 178–181 1,3-haloamination of 184–185 low-valent transition metal complexes, VCPs 343

439

440

Index

metal-free electrophilic activation of with alkynes and alkynylnitriles 304 BF3·Et2O promoted [3+2] cyclodimerization 309 1,3-bisfunctionalization products 313 [3+2] dehydration cycloaddition 303 1,3-dichlorides 312 Homo–Nazarov cyclization 306–307 iminium–enamine activation 302 iminium–enamine activation of 312 in-situ formed boron species promoted ring-opening of 309–310 protic ionic liquid (PIL) 306 TfOH catalyzed nucleophilic ring 302–303 TsOH promoted [3+2] annulation of 305 vinylcyclopropanes 309 metal-free nucleophilic activation of Brønsted base activation for carbonyl substituted 317 Brønsted base activation of 315 [3+2] cycloaddition reaction of di-cyano cyclopropylketones with nitroolefins 315 enamine-activation of cyclopropanes 317 enantioselective formal [2+2] cycloaddition reactions of 318 formal [8+3] cycloaddition of di-cyano cyclopropylketones with tropone 316 N-heterocyclic carbene promoted nucleophilic activation of 318–319 pyrrolo[1,2-a]quinolones 318–319 quinidine-derived thiourea catalyzed ring opening 315 natural products 403

nitrogen-containing synthetic bioactive compounds and natural products 228 radical 1,3-dichlorination reaction, with iodobenzene dichloride 327 ring-opening 1,3-carbocarbonation of 185–186 ring-opening 1,3-dichlorination of D-A cyclopropanes 169–170 subclass 227 synthesis of alkaloids 360–379 terpene/Terpenoids 379–403 donor cyclopropanes 17 dysprosium triflate 70

e

electrophilic cyclopropane reagent 159 electrophilic vinylcyclopropanes 160, 161 enamine activaion 141–144 enamine containing cyclopropanedicarboxylate 141 enamines with carbonyl substituents 45 enantio-enriched spiro-cyclopentanes 345 enantiomerically pure cyclopropane 206 enantiomerically pure tetrahydrofuran derivatives 61 enantioselective 1,3-dichlorination of formyl group-containing cyclopropanes 168 Englerin A-B, (+)-Orientalol F, (–)-Oxyphyllol and (+)-Orientalol E 399 enol silyl ethers 42, 48, 341 (±)-epimeloscine and (±)-meloscine 371 6-epi-Ophiobolin N 391–392 Epstein–Barr virus (EBV) 421 1-ethoxy-1-(trimethylsiloxy) cyclopropane 5 ethyl 2,2-dimethoxycyclopropanecarboxylate 40, 51 ethyl 2,2-dimethyl-1nitrocyclopropanecarboxylate 209

Index

f

(+)-fastigiatine 367–368 (+)-fawcettimine 368 five-membered carbocycles 39, 40, 197, 338 five-membered ketenimines 128 4-fluorobenzaldehyde 27, 29 Fopius arisanus (Bioesters) 409 formal [3+1]-and [3+1+1]cycloadditions 105–106 formal [3+2]-cycloaddition annulation with aromatic C=C bond 53–57 with C=C double bond 40–50 C≡C triple bond 50 with C=N double bond 66–73 with C≡N triple bonds in nitriles 80 with C=O double bond 59–66 with C=S and C=Se double bonds 77–78 with cumulenes and heterocumulenes 73–76 general aspects 39–40 involving aryl/heteroaryl donor substituent 57–58 with N=O and N=N double bonds 78–80 with SCN and SeCN 76–77 with three-membered heterocycles 80–82 formal [3+3]-cycloaddition and annulation reactions with allenes, allyl and propargyl derivatives 87–88 with aromatic substrates as 1,3-synthons 84–87 with azides and diazo compounds 94–96 with dinitrogen substrates 93–94 general aspects 83 with mercaptoacetaldehyde 88–89 with nitrones and nitronates 89–93 formal [4+3]-cycloaddition and annulation

dienes as traps for 1,3-zwitterions 97–99 with heterodiene systems and their analogs 99–102 formal [8+3]-cycloaddition reactions 102–103 formal stepwise high-order cycloaddition/ annulation reactions 103–105 formylcyclopropanes 144–150, 152–156, 318 four component coupling of D-A cyclopropanes 177–178 FR901483 72, 366, 367 Friedel–Crafts alkylation reaction 242, 336, 376 functionalized o-mercaptosalicylaldehydes 145 furopyrimidine 205 furo[2,3-d]pyrimidines 205 furopyrrole derivatives 120 furyl-2-carbaldehydes 120

g

GaCl3-mediated cycloaddition/annulation reactions 109–122 Galbulimima belgraveana 375 garsubellin A 414, 416 GB22 376 gelsemoxonine 367, 369 (±)-gelsenicine 374–375 Geodia exigua 421 (±)-goniomitine 213, 364 (±)-goniomycin 80

h

(+)-Hagen’s gland lactones 409, 411 haliclonin A 423–425 halochalcogenation of D–A cyclopropanes 174 halogenation-peroxidation of D–A cyclopropanes 178–180 1,3-haloamination of D-A cyclopropanes 184–186 Hammett plot 28, 30 2H-azirines 82

441

442

Index

1-(hetarylcarbonyl) cyclopropanecarboxylates 211 1-heteroaroyl-2-silylmethylcyclopropanes 211 hexahydro-3,5-methanocyclopenta[c] isochromene 120 hexahydro-3H-5,8-methanocyclopenta[a] azulene 120 hexahydropyridazines 118 hexahydropyrroloquinoline derivatives 72 (9H-fluoren-9-yl)methyl malonates 218 highly electrophilic alkylideneoxindole/ benzofuranone reagent 142 (–)-himalensine A 377, 378 (±)-hirsutene 383 (±)-hirsutic acid C 384 homoenolate-type enol species 157 homo-Michael type adduct 145 homo-Nazarov cyclization of 211–215, 306, 307 Horner–Emmons homologation of the aldehyde 403 Horner–Wadsworth–Emmons olefination of dimethylhexenal 383 horsfiline 360 2-H-3-substituted indoles 194 hydrazoyl chlorides 93 hydroformylation of cyclopropenes 261 hydropyrrolobenzazoles 338 hydrotris(3,4,5-tribromopyrazolyl) borate 193 2-(2-hydroxyaryl) cyclopropane-1,1-diesters 219 2-hydroxyaryl-substituted cyclopropanes 219 7-hydroxybenzothiophene 212 γ-hydroxybutyric acid (GHB) derivatives 336 1-hydroxy-3,4-dihydronaphthalene derivatives 211 9-hydroxy-4H-cyclopenta[b]naphthalen4-one derivatives 121 basiliolides A1, A2 419–420

β-hydroxy ketones 182–184, 328 hyperfoin 414, 415

i

imidalodidinone catalyst 146 imidazolium derived catalyst 150 imidazolium precatalyst 152 imine oxindoles 68 iminium–enamine activation 302, 311, 350 iminium ion activation 144–148, 259 iminum/enamine organocatalysis with palladium(0) catalysis 348 1,3-indanedione-and oxindole-fused spiropyrazolidines 347 indanes 57, 113 indole spiro derivatives 67 2-indolinecarbaldehydes 151 3-indolinecarbaldehydes 152 indolo[2,1-h]quinoline derivative 213 indolo[2,1-h]quinolines 213 indolo[2,3-h]quinoline derivatives 212 (indol-2-yl)acetic acid 194 3-indolylacetic acids 193–194 indolyl acetylenes 84 (indol-1-yl)-and (pyrrol-1-yl) carbonylcyclopropanes 214 1-(indol-2-ylcarbonyl)-2amidocyclopropane 213 (3-indolyl)cyclopropylketones 113 7-(indol-2-ylcarbonyl)-1-azabicyclo[4.1.0] heptanes 212 inorganic thiocyanates (thiocyanates) 77 interferon-α Cotylenin A 423 intermolecular ring-opening 240–244 internal alkynes 51, 58 intramolecular nucleophilic ring opening–ring closure (INRORC) processes 192, 218–220 intramolecular ring-opening 236–240 iridium photocatalysis 376 isatin derivatives 124 isatin electrophile 157 Isatis indigotica 408 (+)-isatisine A 408, 409

Index

isobenzofuran 30, 31, 97, 98, 220 isocyanates 75, 76 isoedunol 404, 405 isomeric cyclopent-2-ene-1, 1-diesters 201 isooxazoline N-oxides 209 isoquinolines 122, 247 isothiocyanates 4, 75, 76, 287–289 isoxalidines 79

j

JBIR-03 and asporyzin C 396 jerantinine E 213, 238, 373 (±)-jerantinine E 373 Johnson’s reaction 59 Jorgensen-Hayashi catalyst 142 JTT-010 406

k

ketene dithioacetals 193 ketenimines 75, 128 Knoevenagel adducts 47, 84, 103 Knoevenagel condensation products

47

l

γ-lactam 159 (S)-Longianone 413 lophira lanceolate 421 lophirone F hexamethyl ether 421 lowest unoccupied molecular orbitals (LUMOs) 17 Lyconesidines A and B 378 Lycopodium chinense 378

m

malonodinitriles 120, 121 maoecrystal P 398, 400 (±)-martinellic acid 18–19 melodinus alkaloids 370 Melodinus scandens 370 (±)-melokhanine E 377 mercaptoacetaldehyde 88–89, 282–285, 293–295, 342 meso-diaminocyclopropanes 336 meso-2,3-disubstituted formylcyclopropanes 146

meso-formylcyclopropanes 146, 147 metal-free electrophilic activation of D–A cyclopropanes alkynes and alkynylnitriles 304 BF3·Et2O promoted [3+2] cyclodimerization 309 1,3-bisfunctionalization products 313 [3+2] dehydration cycloaddition 303 1,3-dichlorides 312 homo-Nazarov cyclization 307 iminium–enamine activation 302, 311–312 in-situ formed boron species promoted ring-opening of 310 protic ionic liquid (PIL) 306 TfOH catalyzed nucleophilic ring 302–303 TsOH promoted [3+2] annulation of 305 vinylcyclopropanes 309 metal-free nucleophilic activation of D–A cyclopropanes Brønsted base activation for carbonyl substituted 317 Brønsted base activation of 314–315 [3+2] cycloaddition reaction of di-cyano cyclopropylketones with nitroolefins 315 enamine-activation of cyclopropane 317 enantioselective formal [2+2] cycloaddition reactions of 318 formal [8+3] cycloaddition of di-cyano cyclopropylketones with tropone 316 N-heterocyclic carbene promoted nucleophilic activation of 318–319 of pyrrolo[1,2-a]quinolones 318–319 quinidine-derived thiourea catalyzed ring opening 314–315 methoxycyclopropane dicarboxylates 41 7-methoxy-1-indanone with para-quinone 414

443

444

Index

2-(4-methoxyphenyl)-1-acetyl-3-Rcyclopropanecarboxylates 203 4-methoxyphenyl derivative 211 methylenecyclopropanes 70 methylenetetrahydropyrans 88 (5-methyl-2-furyl) cyclopropanedicarboxylate 120 5-methyliden-3-methoxycarbonyl3-phenyltetrahydropyran2-one 105 Michael acceptors 17, 41, 43, 47, 49, 123, 184, 187, 343, 345–347 Michael initiated ring closure (MIRC) methodology 274, 289

n

(+)-nakadomarin A 362 2-naphthols 56, 242, 303–305, 342 1-naphthylamines 128, 280 N-acetylcyclopropa[b]indole 193 naphthoquinone 121 N-arylmethaneimine 101 natural bond orbital (NBO) analyses 24 natural products (±)-bruguierol A 408–409 butanolide and butenolide 414–415 chartarin 417 cotylenin A 424 dictyopterenes C 425 (–)-Doliculide 403 exigurin 423 (+)-Hagen’s Gland Lactones 411 haliclonin A 423–424 (+)-isatisine A 409 isoedunol and β-araneosene 404–405 JTT-010 406 lophirone F hexamethyl ether 421 with mercaptoacetaldehyde 282–285 nemorosone 410, 412 with nitriles 280–282 norrisolide 410, 412 paraconic acids 404–405 piperarborenine B 417–418 (–)-platencin 409–410 (+)-polyanthellin A 408

rac-diospongin B 419 (R)-(+)-dodecan-4-olide 413 (±)-savinin, (±)-gadain and (±)-peperomin E 425–426 (S)-longianone 411, 413 Spirochensilide 421–422 (S)-vigabatrin 406 (+)-virgatusin 407 Nazarov reaction and its homo-version 210–215 N-benzylic sulfonamides 108 2,N-diaryl-1-carbamoylcyclopropanecarboxylates 220 nemorosone 410, 412, 414, 416 N-heterocyclic carbenes (NHCs) 140, 150, 199 catalysis 148 Nicolaou’s intermediate 409 (–)-nicotine 323, 374 2-nitrobenzofurans 55 2-nitrocyclopropyl carbaldehehyde 150 1-nitro-1-cyclopropyl ketones 322 nitrones, synthesis of 70 1-nitro-2-phenylcyclopropane 209 nitrosoarenes 79, 86, 87, 92, 172 nitro-substituted D–A cyclopropanes BF3-mediated ring-opening reactions 291–292 reactions with activated aromatics 293 with 2-aminopyridines 294–295 with mercaptoacetaldehyde dimer 293–294 with nitriles 292–293 synthesis 289–290 nitro-substituted enines 45 norrisolide 410, 412 N-substituted 3-phenyl-1, 2-oxaziridines 106 N-sulfinylamines 76, 78 N-sulfoxy-substituted 1,3-azadienes 45 Nucleophilic Catalyst Activation 351–352 nucleophilic ring-opening of acceptor cyclopropanes 17

Index

nucleophilic ring-opening reactions 21, 278, 313

7,

o

o-aminobenzaldehydes 142, 349 octahydroindolo[2,3-h]quinolines 212 3-aroyl-2-arylcyclopropane-1, 1-dicarboxylates 215 Olsson’s cycloaddition 67 optically active 2-aryl-2, 3-dihydrofurans 205 optically active cyclopropanes 211, 340 optically active dihydrofurans 204–205 optically active pyrrolidines 70 ortho-bromo cyclopropanes 122 ortho-ethynylbenzaldehydes 48 ortho-nitro arylalkines 92 ortho-OH substituted cyclopropanes 122 8-oxabicyclo[3.2.1]octadiene 215 2-oxabicyclo[3.3.0]octane derivatives 116 2-oxabocyclo[3.2.1]octa-3,6-diene 217 oxindole 49, 50, 68, 89, 91, 318, 340, 347, 349 2-oxo-6-vinylbicyclo[3.1.0] hexane-1-carboxylate 199 ozonolysis of vinyl cyclopropanes 261

p

(–)-paeonilide 389 palladium(0)-catalyzed [3+2] annulation 346 of VCPs 345 paraconic acids 403–405 para-substituted D-A cyclopropanes 28, 30 (–)-pavidolide B 391, 393 Pd(II)-catalyzed dearomative [4+3] annulations with anthranils 347 perchlorinated quinone 146, 269, 350 2’-phenylbicyclopropyl-1,1-dicarboxylate 196–197 2-phenylcyclopropylmethylenmalonate 195

1-phenyl-2,2-divinylcyclopropanecarboxylic acid 198 3-phenyl-2H-azirine 70 phenylisocyanate 74 phenyltriazolinedione 79 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) 79, 103, 104 2-phenyl-2-vinylcyclopropanecaroxaldehyde 217 phosphine/tertiary amine catalysis 157–161 phthalazinium dicyanomethanides 94, 95 Phyllanthus discoides 361 (+)-phyllantidine 361–362 Phyllobates bicolor 374 (±)-picropodophyllone 210 (±)-picropodophyllone:cycloprop ane 210 piperarborenine B 417–419 Pitzer strain 16 (–)-platencin 409–410 platensimycin 385 p-nitrocinnamaldehyde 144 (+)-polyanthellin-A 65, 408 polycyclic polyprenylated acylphloroglucinols (PPAPs) 410, 414 polycyclic spiro derivatives 49, 50 polyfunctional cyclopentanecarboxylate 40 polyfunctionalized cyclopentane derivatives 45 polysubstituted alkenes 57 polysubstituted D–A cyclopropanes 91, 105 polysubstituted pyrroles 125, 127 (S)-proline 145 propargyl alcohols 88 protic ionic liquid (PIL) 306 pseudolaric acid B 380–382 Pseudolarix kaempferi Gordon (pinaceae) 380 pyranoindolones 153 pyranones 153

445

446

Index

pyridazinones 118, 280 1-(2-pyridyl)-2-styrylcyclopropanecarboxylates 208 pyrimidoazepinetriones 118 pyrrolidines 68, 70, 71, 82, 91, 204, 280, 282, 283, 337 pyrrolo[1,2-a]indol-3-ones 151 pyrrolo[1,2-b]isoxazole derivatives 218 pyrroloisoquinolines 143 pyrroloisoquinolinium salt 208 (pyrrol-1-yl)carbonylcyclopropanes 213, 214

q

(±)-quebrachamine 365 quinolizidine (-)-217A 370

r

rac-diospongin B 419 radical pathway 185, 244, 353–354 reaction enthalpies 25, 26 red-colored acyclic titanium enolate 6 regioisomeric cyclopentenones 120 relaxed force constant (RFC) 27, 29 (–)-rhodomollanol A 401, 403 rhodomolleins XX and XXII 196, 400, 402 ring-opening 1,3-carbocarbonation of D-A cyclopropanes 185–186 ring-opening 1,3-dichlorination of 169–170 ring-opening reactions 235 with 2-aminopyridines 294–295 with hydrazines 278–280 intermolecular 240–244 intramolecular 236–240 with 1-naphthylamines 280 Rumphellclovane E 395, 396

s

salicilicaldehydes 150 salicylic aldehydes 101 (±)-savinin, (±)-gadain and (±)-peperomin E 425–426 Scheffold and Troxler’s desymmetrizationfragmentation 333

(±)-schindilactone A 388–389 secondary amine catalysis enamine activation 141–144 iminium ion activation 144–148 selenocyanates 76, 77 sesquiterpenes (+)-(R, S)isoclavukerin 379 Seurinega suffruticosa 361 siloxycyclopropane 5, 192, 193, 376 2-siloxycyclopropanecarboxylates 192, 193 siloxy-substituted cyclopropanecarboxylates 1, 4–6 silylcyclopropanes 51 silyl substituted methylidene cyclopentanes 73 Simmons-Smith cyclopropanation 376, 396, 397 Sordaria araneosa 404 (–)-sordarin 379, 380 speciosin H 148, 149 (–)-speciosin H 149 spiroactivated vinylcyclopropanes 18 spiroanthracenoxazolidine 71 spirochensilide A 421, 422 spiro[cyclopropane-1,2’-cyclohexane-1, 3-diones] 203 spirocyclopropaninedenones 118 spiro[indoline-3,2’-pyrrolidin]-2-one derivatives 68 spiro-linked tetrahydrofurans 65 spirotryprostatin B 72, 360, 361 (–)-spirotryprostatin-B 72 stable dimer (1,4-dithiane-2,5-diol) 88 stepwise cyclization 118–128 strain model 15 Streptomyces platensis 409 (±)-strychnofoline 360–361 Strychnos usambarensis 360 2-styrylcyclopropane-1, 1-dicarboxylates 195, 196, 200 styrylmalonates 107–109, 194, 195, 200 β-styrylmalonates 38, 57, 106–109, 113, 117, 120 (E)-styrylmalonates 194

Index

substituted cyclopentanols 82 1, 2-substituted cyclopropane dicarboxylates 42 2-substituted 1,1-cyclopropane dicarboxylates 40 2-substituted cyclopropane-1, 1-dicarboxylates 59 2-substituted formylcyclopropanes 145 substituted methylenecyclohexanes 87 substituted 1-naphthylamines 128 substituted tetrahydrofurans 59, 82, 337 substituted tetrahydropyrimidinones 118 substituted 1,3,5-triazines 71 2-substituted tropones 102 γ-substituted-α,β-unsaturated esters 155 sulfonylketenimines 128 sulfur-containing spiro derivatives 49 sulfur diimide derivatives 76, 78 syn-bicyclo[3.1.0]hex-2-ene-6carbaldehyde 217

t

terpene/terpenoids (±)-α-agarofuran 385 (+)-arglabin 380–381 (+)-arteludovicinolide A 390 (+)-asteriscanolide 388 (±)-asterisca-3(15),6-diene and (±)-pentalenene 384 (+)-barekoxide and (+)-barekol 386 botryococcene 398, 401 chromodorolide B 391, 395 (–)-clovan-2,9-dione 391, 394 (–)-connatusin A 386, 388 (+)-connatusin B 386–387 dichrocephones A and B 397 of Englerin A-B, (+)-Orientalol F, (–)-Oxyphyllol and (+)-Orientalol E 398–399 6-epi-ophiobolin N 391–392 hirsutene and 1-desoxyhypnophilin 383 (±)-hirsutic acid C 384 JBIR-03 and asporyzin C 396

maoecrystal P 398, 400 (–)-paeonilide 389 (–)-pavidolide B 391, 393 platensimycin 385 pseudolaric acid B 381–382 (–)-rhodomollanol A 401, 403 rhodomolleins XX and XXII 400, 402 rumphellclovane E 395 (±)-schindilactone A 388–389 (–)-sordarin 380 (–)-(S, S)-clavukerin A and (+)-(R, S)isoclavukerin 379 (±)-vibralactone 400, 402 xanthatin 390 tert-butyl azadicarboxylate 121 tetracyanoethylene 40, 48 tetracyclic cyclopenta-fused spiroindolines 54 tetracyclic 1,2,3,4-tetrahydrocyclohepta[de]anthracene skeleton 103 tetrahydrobenzofuran-2-ones 204 2,3,6,7-tetrahydrobenzofuran-4(5H)ones 203 tetrahydro-1H-furo[3,4-c]pyrrol1-ones 80 tetrahydro-1,2-oxazines 333, 339, 340 tetrahydrofuran 4, 27, 55, 59–61, 63, 65, 127, 201, 325, 347, 407–408, 421 tetrahydroindenopyridazinones 118 tetrahydrooxazine heterocycles 90 tetrahydrooxazines 90, 91 tetrahydropyran 88, 201 tetrahydropyran derivatives 88 tetrahydropyridazine derivatives 93 tetrahydropyridazines 70, 93–95, 264 tetrahydroquinoline derivatives 86 tetrahydroquinolines 86, 100 tetrahydrothiepins 100 tetrahydrothiopyran 88, 284, 342 tetralin derivatives 86, 110 tetrasubstituted activated cyclopropanes 47 TfOH catalyzed nucleophilic ring 302–303

447

448

Index

thiazepines 128 thiochalcones 100 thiocyclopentenes 49 thioisocyanate 74 tin(IV) chloride-induced rearrangement of cyclopropanes 200 TMSOTf catalyzed isomerization of 2-arylcyclopropane-1, 1-dicarboxylates 307 torsional strain 16 trans-1-acyl-2-arylcyclopropanecarboxylates 206 trans-fused γ-lactones 18 1,3,5-triazines 71 tricyclic bisacetals 204 tricyclic indole derivatives 54 trifluoroethylcarboxylate substituents 70 2,4,6-trimethylphenyl-derived cyclopropane 194 2,4,6-trimethylphenyl-substituted analogue 194

2-vinyl cyclopropane dicarboxylates 62 vinylcyclopropane–cyclopentene rearrangement (VCR) 17, 197–202, 216 vinyl cyclopropanes (VCPs), 41, 43, 63 [3+n] annulations 345–349 ring-opening reactions 344 vinylcyclopropane-to-cyclopentene isomerization 191–192 5-vinyl-4,5-dihydrofurans 207 vinylpyrrolidone 18 2-vinylspiro[cyclopropane-1,3’-oxindoles] 216 (+)-virgatusin 65, 407

u

xanthatin

α,β-unsaturated aromatic ketones 86 α,β-unsaturated aryl ketones 86–87 α,β-and β,γ-unsaturated compounds 123 unsubstituted indolylacetylenes 84 unsubstituted tropone 103

v

(±) vibralactone 400, 402 vicinally substituted donor-acceptor cyclopropanes 19 (S)-vigabatrin 406 vinilogous (2-phenylcyclopropyl) methylenemalonate 195 vinyl azides 46

w

Walsh model 16 Walsh orbitals of cyclopropane Wiberg bond index (WBI) 24

x y

ynamides

z

16

390

52, 246, 247

Z-alkylidenetetrahydrofurans 309, 311 1,3-zwitterinic synthones 38 zwitterionic π-allyl palladium complex 346 1,3-zwitterionic building blocks 11 zwitterionic mesomeric formula 7, 10 1,3-zwitterionic synthones 37, 38 1,3-zwitterions 42, 49, 54, 83, 86, 97–99, 308, 334