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The Generation and Reactivity of Organozinc Carbenoids

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The Generation and Reactivity of Organozinc Carbenoids The Generation and Reactivity of Organozinc Carbenoids A Thesis Presented by Caroline Joy Nutley In Partial Fulfilment of the Requirements for the Award of the Degree DOCTOR OF PHILOSOPHY of the UNIVERSITY OF LONDON Christopher Ingold Laboratories Department of Chemistry University College London London WCIH OAJ September 1995 ProQuest Number: 10016731 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10016731 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Through doubting we come to questioning and through questioning we come to the truth. Peter Abelard, Paris, 1122 Abstract This thesis concerns an investigation into the generation and reactivity of organozinc carbenoids, from both a practical and mechanistic standpoint, using the reductive deoxygenation of carbonyl compounds with zinc and a silicon electrophile. The first introductory chapter is a review of organozinc carbenoids in synthesis. The second chapter opens with an overview of the development of the reductive deoxygenation of carbonyl compounds with zinc and a silicon electrophile since its inception in 1973. The factors influencing the generation of the zinc carbenoid are then investigated using a control reaction, and discussed. The results from a study to determine whether the carbenoid is homogeneous or heterogeneous are given, and the implications of the results considered. The influence of the electronic nature of the alkene on cyclopropanations is then examined using firstly a series of variously para-substituted alkenes, and then a series of electronically 'extreme' alkenes. In spite of the complexity of this heterogeneous system, a mechanistic rationale is presented to account for all the results. More preparative applications of the reactivity of the carbenoid are then presented. The first report of the cyclopropanation of cyclic enol ethers using the reaction system developed is made. The synthetic scope of a novel intermolecular C-H insertion reaction found in this system is also probed. The implications of preliminary results from a complex intramolecular system are discussed. Attempts to provide a mechanistic appraisal of the results using a specifically labelled system are then presented. Finally, attempts to carry out ylide-rearrangement reactions, and particularly a biomimetic [2,3]-sigmatropic rearrangement of an S-prenyl ylide, derived by trapping the carbenoid formed from prenal onto 3-methyl-l-thiophenyl-but-2-ene, are discussed. These results, and their implications, are drawn together in a concluding chapter, and full experimental details (together with complete spectral data for all compounds synthesised) are appended. Contents A bstract...........................................................................................................................3 Acknowledgements ........................................................................................................7 Abbreviations ................................................................................................................ 8 Chapter 1 The Role of Zinc Carbenoids in Organic Synthesis .............................................11 1.1 Introduction ....................................................................................................................11 1.1.1 Carbenes and Carbenoids ..............................................................................11 1.1.2 Organozinc Reagents and their Carbenoid Connection ........................... 12 1.2 Zinc Carbenoids From Carbonyl Compounds .............................................................. 13 1.2.1 The Clemmensen Reduction .................................................................... 14 1.2.1.1 Mechanistic Studies ..................................................................... 14 1.2.1.1.1 Spectral Studies on Prototypical Zinc Carbenoids ...................................................................17 1.2.1.2 a , P-U nsaturated Ketones in the Clem m ensen Reduction ....................................................................................... 18 1.2.1.3 Diketones in the Clemmensen Reduction .............................. 21 1.2.1.4 Practical Advances in the Clemmensen Reduction ............... 21 1.2.2 Controlled Reductive Deoxygenation of Carbonyl Compounds .............22 1.2.2.1 The Demise of the Proton ........................................................22 1.2.2.2 Direct Deoxygenation of Carbonyl Compounds to Give Alkenes ................................................................................24 1.2.2.3 Dicarbonyl Coupling Reactions .................................................. 26 1.2.2.4 Cyclopropanation Reactions ....................................................... 32 1.3 The Simmons-Smith Reaction and Furukawa Modification .................................... 36 1.3.1 The Simmons-Smith Reaction ................................................................. 36 1.3.2 The Furukawa Modification ........................................................................37 1.3.3 A Synthetic O verview ................................................................................. 37 1.4 Simmons-Smith Reagents from the Reduction of a Zinc (II) Salt with a Diazoalkane ...................................................................................................................55 1.5 Conclusions .....................................................................................................................58 Chapter 2 Results and Discussion ....................................................................................................59 2.1 Background .......................................................................................................................59 2.2 Mechanistic Studies ...................................................................................................... 68 2.2.1 Influence of all Variables on the Course of a Standardised Reaction ......................................................................................................... 68 2.2.1.1 The Standard Reaction ............................................................ 68 2.2.1.2 Zinc Particle Size ......................................................................69 2.2.1.3 Electrophile V ariation ...............................................................72 2.2.1.4 Solvent Variation ........................................................................ 75 2.2.1.5 Zinc Couple V ariation ............................................................. 77 2.2.1.6 Temperature Variation ...............................................................78 2.2.1.7 Lewis Acid Variation ...............................................................79 2.2.2 The Three-Phase T est.................................................................................. 82 2.2.2.1 Choosing the Polymer Bound Alkene ....................................83 2.2.2.2 Two Phase Analogue - Determination of Substrate Suitability ................................................................................... 84 2.2.2.3 Preparation of Polymer Supported A lkene ............................. 86 2.2.2.4 The Three-Phase T est................................................................. 87 2.2.2.5 Saponification of the Ester Linkage on the Polymer ............. 88 2.3 Cyclopropanation Studies .........................................................................................92 2.3.1 Cyclopropanation of para-Substituted Styrenes ..................................... 92 2.3.2 Electronic Influence of the Alkene on Cyclopropanations ....................98 2.3.3 Cyclopropanation of Cyclic Enol Ethers ....................................................102 2.4 C-H Insertion Studies .................................................................................................... 105 2.4.1 Intermolecular C-H Insertion Reactions ................................................ 105 2.4.2 o-Allyloxybenzaldehyde - Attem pts at an Intram olecular Reaction ......................................................................................................... 107 2.4.3 A Heteroatom-Free Intramolecular System ..............................................108 2.4.3.1 Specifically Deuterated System ................................................110 2.5 Attempted Ylide Studies .............................................................................................. 114 2.5.1 Carbonyl Ylides ..............................................................................................114 2.5.2 Sulfur Ylides .................................................................................................115 Chapter 3 Conclusions and Perspectives ................................................................................. 117 Chapter 4 Experimental Procedures ......................................................................................... 121 4.1 General Information .......................................................................................................121
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