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Studies on Enolate Directed Carbometallation Reactions

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Studies on Enolate Directed Carbometallation Reactions Studies on Enolate Directed Carbometallation Reactions A Thesis Presented by Matthew Richard Penny In Partial Fulfilment of The Requirements For The Award of The Degree of Doctor of Philosophy Of University College London University College London Department of Chemistry 20 Gordon Street London WC1H 0AJ 1 Declaration I, Matthew Penny confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract The present thesis is concerned with the concept of an enolate directed carbometallation reaction. The first chapter provides a review of the area of heteroatom directed carbometallation of isolated alkynes and allenes as a powerful method for the formation of double bonds and attempts to rationalise the regio and stereochemistry of such additions. The second chapter begins with the results of a small study on the copper(I) mediated carbometallation reactions of homoallenols. The research into the aforementioned enolate directed carbometallation reaction is then presented and discussed, and especially the efforts made towards efficient formation of a novel “bis-carbanionic” intermediate, possessing both an enolate and a vinyl organometallic reagent. Following on from a preliminary result within the group research was carried out into the carbometallation reactions of enolates derived from carboxylic acids, amides, esters. Whilst amide enolates proved to be problematic, carboxylic acid dianions were found to be suitable substrates for carbometallation and dialkylation of the “bis-carbanion” was successful. After considerable experimentation involving a variety of organometallic reagents and protocols for enolate anion generation, ester enolates were found to be most successful, giving rise to high yields of products and allowing selective reactions of both the vinyl organometallic reagent and the enolate. Finally, very encouraging preliminary results were obtained with an adventurous strategy involving the enolate intermediate obtained from a conjugate addition to an enone. Experiments to probe the reactivity of these novel intermediates, with the aim of selective reaction of only one of the carbanions, are discussed throughout. These results are then summarised and logical conclusions as well as perspectives for future research are drawn. The thesis concludes with a detailed description of the experimental procedures used and characterisation of the compounds prepared. 3 Contents Declaration ................................................................................................................... 2 Abstract ........................................................................................................................ 3 Contents ....................................................................................................................... 4 Abbreviations ............................................................................................................... 6 Acknowledgments ........................................................................................................ 9 Chapter 1: Introduction .............................................................................................. 10 1.1 Principles and Recent Advances in Directed Carbometallation ...................... 10 1.2 Directed carbometallation ................................................................................ 19 1.2.1 Carbocupration and Copper(I) catalysed Grignard additions ................... 29 1.2.2 Transition metal catalysed additions ......................................................... 47 1.2.3 Additions to allenols ................................................................................. 53 1.3 Applications of carbometallation in synthesis ................................................. 60 1.4 Overview .......................................................................................................... 66 Chapter 2: Results and Discussion ............................................................................. 70 2.1 Carbometallation Reactions of homoallenols .................................................. 70 2.2 Enolate anion directed carbometallation: A New Concept .............................. 77 2.2.1 Prior Observations within the Research Group ......................................... 80 2.2.2 Preliminary studies on carboxylic acid dianions and amide enolates ....... 81 2.2.3 Ester enolates ............................................................................................ 91 2.2.4 Alternatives to LDA ................................................................................ 119 4 2.2.5 Enone substrates ...................................................................................... 131 2.3 Summary, Conclusions and Perspectives ....................................................... 142 Chapter 3: Experimental .......................................................................................... 153 General Procedures .......................................................................................... 153 References ................................................................................................................ 218 5 Abbreviations Ac acetyl acac acetylacetonate aq aqueous Ar Aryl BHT Butylated hydroxytoluene b.p. Boiling point Bu Butyl cat. catalytic DCC Dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide dppe 1,2-Bis(diphenylphosphino)ethane dr diastereomeric ratio E Electrophile Et Ethyl Et2O Diethyl ether 6 eq Equivalents HMPA Hexamethylphosphoramide Hex Hexyl IBX 2-Iodoxybenzoic acid LDA Lithium diisopropylamide LiHMDS Lithium hexamethyldisilazide LiTMP Lithium tetramethylpiperidide Me Methyl MeOH methanol min minutes mL millilitre NMM N-methylmorpholine m.p. Melting point Ms Mesyl NMR Nuclear Magnetic Resonance Ph Phenyl ppm Parts per million Rf Retention factor TBAF Tetra-n-butylammonium fluoride TBAT Tetra-n-butylammonium triphenyldifluorosilicate TBS Tert-butyldimethylsilyl 7 THF Tetrahydrofuran Tf Trifluoromethanesulfonyl TLC Thin layer chromatography TMEDA Tetramethylethylenediamine TMS Trimethylsilane 8 Acknowledgments First and foremost, I would like to thank Professor William Motherwell for the opportunity to work in his research group and in this exciting area of chemistry. I will be eternally grateful for the guidance, support and confidence he has given me and for his infectious love of chemistry. Secondly, I would like to thank Dr Robyn Motherwell for her expertise, kindness and willingness to help. Thanks also go to Dr Abil Aliev for help with NMR, John and Lisa in mass spec, Dr Tom Sheppard for helpful advice and Dr Phil Gray for introducing me to carbometallation in the lab. The Motherwell group has been a fantastic place to be so I am grateful to all members, past and present, for making the last 3 years so enjoyable and rewarding. Special thanks go to my „year buddy‟ Josie and Sandy for taking on the challenges of carbometallation. Finally, I would like to thank Mum, Dad and Yumi for their unfailing support and love. 9 Chapter 1: Introduction 1.1 Principles and Recent Advances in Directed Carbometallation Since the present thesis is concerned with novel aspects of directed carbometallation the aim of this introductory chapter is to provide a brief overview and discuss the pertinent literature in the field. Due to the nature of our own area of research, this introduction will focus on the regio- and stereospecific synthesis of olefins. As a result, carbometallation of alkenes will not be covered. Although the emphasis will be on directed carbometallation, some non-directed reactions will also be included for perspective and discussion of principles. The review will accordingly concentrate on the additions of organometallic reagents to isolated alkynes and allenes, and so, conjugate additions will not be covered. Although carbometallation reactions using organo- lithium, zinc and aluminium reagents as well as carboboration reactions have been shown to be successful,1 the majority of directed carbometallation reactions have been carried out with organocopper or Grignard reagents. For this reason and because of the nature of the research carried out, the focus of this chapter will be on the use of these reagents in carbometallation reactions. Even though the alkene unit is commonplace throughout nature and organic chemistry, be it within a target molecule or as a key intermediate required for further elaboration, methods which provide perfect control over the geometrical isomer formed, especially in the cases of tri- and tetrasubstituted alkenes have remained as a formidable problem for many decades. The following Scheme illustrates four of the possible strategies for disconnection of an alkene in a retrosynthetic fashion (Scheme 1).2 10 1 3 1 3 1 3 1 3 R R R R R R R R 4 2 4 2 R R 2 4 2 R R R R R X Type 1: From two fragments Type 3: From a vinyl halide or vinyl metal 1 3 X 3 1 3 R R X R R R 1 4 1 3 R R R R 2 4 2 2 4 R R R R R Type 2: Via elimination Type 4: From an alkyne Scheme 1 Type 1 involves the preparation of the alkene from two separate groups and includes the Wittig reaction by way of example. Alternatively the two components can be connected by a single bond and elimination reactions can then take place to form the double bond (Type 2). Type 3 requires a vinyl
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