The Development and Application of New Methods for the Synthesis of Organozinc Carbenolds A Thesis Presented by Matthew Edward Popkin 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 WC1H OAJ October 1998 ProQuest Number: U644352 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 U644352 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 "I found this spoon." Monty Python, 1981 Acknowledgements First and foremost, I must thank Professor Willie Motherwell for his friendship, enthusiasm and inspiration over the last three years. I thank all my proof readers for their careful and speedy work. Oliver, Kamal, Mike, Pierre, Ray, Marta, Pierre, Tilly and Yvan. I can't understand myself half the time either. I also thank the technical staff at UCL for all their help. Jill Maxwell and Chris Cooksey for the NMR, John Hill for the GC and mass spectra, Steve Corker for the HPLC and Alan Stones for the microanalysis. I also thank Peter for the sarcasm and Jim for the food. It seems as if the people who have filed in and out of the Motherwell group and the 4th floor are almost to numerous to list, but I'll try and do it all in some sort of order. Distant faces from my first year include Alvin, Tim, Lewis, Richard, Najeeb, Sylvain, Ade, Pete and the unbelievable Jean Marc. Thanks to all for getting me into it. Thanks also to Ellen for getting out of it. Thanks Kamal for doing it all at the same time as me. I thank Pierre for being a monster. I could be see you in France guy. Thanks to Simon and Martin for being special. Thanks to Rodney for showing how a postdoc needs to be handled and to Phil for being a genius. Take it easy. I need to remember Raphael, Erwin, Bruno Manu and Isa B for providing a constant top up of gallic charm in the lab. Isa G I thank most of all for her crepes. The Young Master I acknowledge for his worrying perfection and Greaney for his deeply unlucky devotion to Goodison. Thanks to Oliver for giving me space and Diyan for just being. I acknowledge Cathy for doing ten times as much as any of us and Robyn for doing even more for everyone but herself. Santi thanks for being lucky. I thank Rosa for listening and Letitia for being exceptional every day. How? Marta I thank for poring scorn on all our excesses and being great. Tilly I admire you for the way you live and being lovely. Thank you for your friendship. Yvan you are a great man - sorry about the mess. Thanks and good luck to all of you, especially to Catherine and Rehan. Outside the Lab I thank all the people who worked tirelessly to keep me alive. Chris and Sarah for the home from home - I would have starved - Lucie for everything, Mark, Richie - mates -and Melissa, John, Simon, Wendy, Al, Julie, Lee, Charlotte, Martin, Nick, Nick and Amy. Thanks to wonderful Rob and Cath, lovely Paul and Debbie, George, George, Jim and John. Nice. Thanks to the Beast for being shameless and looking after cows. Thanks Louise. Thanks to Ashley, Melanie and Oakley. Three happy Browns who I love. I thank Sam and Bob who made me feel like a teenager. I can't thank everyone though, but I hope you all know who you are. Most of all I thank my whole family for everything, especially my brothers, the accountant and the one who programmes. I thank my parents for all my education and for being perfect. This is dedicated to them. Abstract This thesis concerns the generation of organozinc carbenoids and their subsequent reactions, particularly with alkenes to generate cyclopropanes. The thesis is divided into three major sections. The first section comprises a review of the current methods available for the direct cyclopropanation of alkenes. The review focuses on the more controlled methods, and in particular on the different classes of precursor suitable for cyclopropanation. The second chapter opens with an overview of the development of the generation of organozinc carbenoid via the reductive deoxygenation of carbonyl compounds. The generation of zinc carbenoids from a range of precursors is subsequently discussed in detail. The results are arranged to allow the reader to observe the chronological development of the chemistry. New observations on the formation of organozinc carbenoids from aldehydes and ketones are discussed first. The generation of organozinc carbenoids from acetals is then studied, and a series of new results presented. The generation of a novel class of a-alkoxyzinc carbenoids from simple orthoformates is then reported. A study into the generation of methylene organozinc carbenoids run concurrently with the aforementioned work is discussed and the chapter finishes with a brief insight into some attempts to generate other organozinc carbenoids and the range of unsuccessful precursors studied so far. A concluding chapter summarises the results of the work described above, and full experimental details together with appropriate references are appended. Contents Abstract 1 Abbreviations 5 1. Introduction: The Controlied Cyclopropanation of Alkenes 1.1. Metal Catalysed Cyclopropanation using Diazocompounds 11 1.2. Cyclopropanation with Ylides 17 1.3. The Use of Transition Metal Carbene Complexes as Cyclopropanating Reagents 25 1.4. Cyclopropanation via Carbenoids Derived from Alkyl Halides 36 1.5. Miscellaneous Cyclopropanating Reagents 49 1.6. Conclusions 55 2. Results and Discussion 2.1. The Development of Methods for the Generation of Organozinc Carbenoids from Carbonyl Compounds 57 2.1.1. The Clemmensen Reduction of Carbonyl Compounds 57 2.1.2. The Controlled Generation of Organozinc Carbenoids from Carbonyl Compounds 61 2.1.2.1. The Generation of Organozinc Carbenoids from Arylaldehydes with Zinc and Boron Trifluoride Diethyletherate 61 2.1.2.2. The Generation of Organozinc Carbenoids from Carbonyl Compounds using Zinc and Chlorotrimethylsilane 63 2.1.2.3. Dicarbonyl Coupling Reactions of Organozinc Carbenoids 65 2.1.2.4. Cyclopropanation with Organozinc Carbenoids Generated using Zinc and Chlorotrimethylsilane 69 2.2. Studies on the Generation of Organozinc Carbenoids from Aldehydes 72 2.2.1. Some Recent Studies on the Cyclopropanation of Acetoxybutadienes 73 2.2.2. The Three Phase Test 78 2.2.2.1. Previous work on the Three Phase Test 79 2.2.2.2. Recent work on the Three Phase Test 81 2.2.2.3. The Three Phase Test with Homogenous Zinc Carbenoids 82 2.2.2.4. The Three Phase Test Employing Benzaldehyde 87 2.2.2.5. Saponification of the Ester Linkage 86 2.2.3.6. The Three Phase Test with Anisaldehyde 87 2.3. The use of Acetals as Organozinc Carbenoid Precursors 90 2.3.1. Observations on the use of Acetals as Organozinc Carbenoid Precursors 92 2.3.2. New Observations on the Generation and Trapping of Organozinc Carbenoids Derived from Acetals 95 2.3.3. Mechanistic Studies on the generation of Organozinc Carbenoids Acetals 97 2.3.4. Observations on the Possible in situ Generation of Aldehydes from Acetalsl 00 2.3.5. Catechol-Acetals as Organozinc Carbenoid Precursors 102 2.3.6. a-Chloroethers as Carbenoid Precursors with Zinc 105 2.4. The Generation of a-Alkoxyzinc Carbenoids from Orthoformates 106 2.4.1. Preliminary Investigation into the Alkoxycyclopropanation of Simple Alkenes 106 2.4.2. Further Studies into the Generation of a-Alkoxyzinc Carbenoids 110 2.4.3 The Alkoxycyclopropanation of Electron Poor Alkenes 118 2.4.4. The Synthesis of Aryloxycyclopropanes from Triarylorthoformates 119 2.4.5. Observations on Alkoxy- and Aryloxycyclopropanation of Diethylallylmalonate 121 2.4.6. Further Optimisation of Reaction Protocol for Alkoxycyclopropanation 122 2.4.7. Chemoselective Alkoxy- and Aryloxycyclopropanation 123 2.4.8. Alkoxy- and Aryloxyzinc Carbenoids derived from Orthoesters 125 2.5. Studies into the Generation of Methylene Organozinc Carbenoids 130 2.5.1. The Generation and Reactivity of Geminal-Haloacetates Derived from Carbonyl Compounds 132 2.5.2. Observations on the Synthesis and Chemistry of Halomethyl Acetates 135 2.5.3. Reactions of Benzoyloxymethylzinc Iodide with Other Alkenes 137 2.5.4. The Use of lodomethyltolylcarbonate as a Methylene Zinc Carbenoid Precursor 140 2.6. Studies into the Generation of Other Organozinc Carbenoids 147 2.6.1. Observations on the Generation of New Carboxymethylzinc Reagents 147 2.6.2. Observations on the Generation of Organozinc Carbenoids from Acid Fluorides153 2.6.2. The Attempted Generation of Organosamarium Carbenoid Species 155 3. Conclusions 157 4. Experimental 4.1 General information 161 4.2 Experimental Information 163 5. References 241 6. Corrigenda 252 Abbreviations Ac acetyl Ar aryl Bn benzyl bpt boiling point br broad /^Bu n-butyl ^Bu tert-butyl cat catalytic A heat d doublet DCM dichloromethane de diastereomeric excess DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide E unspecified electrophile 0 0 enantiomeric excess El electron impact equiv molar equivalents Et ethyl Et2 0 diethyl ether EtOH ethanol EtOAc ethyl acetate FTIR Fourier transform infra r€ g gram(s) CG gas chromatography GCMS gas chromatographyc o l 5 hr hour(s) IR Infra red L unspecified ligand lit.