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Gold Catalysed Reactions of Propargylic Alcohols

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Gold Catalysed Reactions of Propargylic Alcohols Gold Catalysed Reactions of Propargylic Alcohols A dissertation presented by Matthew N. Pennell In partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY at UNIVERSITY COLLEGE LONDON i Declaration I, Matthew Pennell, confirm that the work presented in this thesis is my own. Where information is derived from other sources, I confirm that it has been indicated and acknowledged. ………………………………………. i Abstract Propargylic alcohols are easily accessed through the reaction of alkynes with aldehydes and ketones. The 1,3-isomerisation of propargylic alcohols to enones is known as the Meyer-Schuster rearrangement. 1 We have demonstrated efficient room temperature reaction conditions for the Au-catalysed Meyer-Schuster rearrangement (>30 examples) of a wide array of secondary and tertiary propargylic alcohols to the corresponding enones in generally excellent yields and with high E-selectivity (A). 2,3 Figure 1: Reactions of Propargylic alcohols Primary propargylic alcohols rearrange to give highly reactive terminal enones, which can undergo conjugate addition reactions with nucleophiles to access β- substituted products through suitable one-pot procedures (B). 2,3 Diethyl acetal substituted propargylic alcohols can be used to access synthetically useful 3- alkoxy furans in the presence of Au in high yield (C). The use of silver as a catalyst promotes substitution of the propargylic alcohol with various oxygen, carbon and nitrogen nucleophiles (D). 3 β-Hydroxyketones can be accessed via a Au-catalysed hydration, employing phenols or acidic alcohols as the reaction additive (E). ii Contents 1. Introduction 1 1.1. Gold catalysts 2 1.2. Homogeneous gold catalysis 5 1.3. Gold activation of alkynes 8 1.4. Gold catalysed reactions of alkynes 11 1.5. Applications in total synthesis 23 1.6. Synthesis of propargylic alcohols 25 1.7. Reactions of propargylic alcohols 28 1.8. The Meyer-Schuster rearrangement and Rupe rearrangement 30 2. Results and discussion 41 2.1. Previous work: Gold catalysed enolate formation from alkynes 41 2.2. Secondary propargylic alcohols: Meyer-Schuster rearrangement 42 and reaction optimisation 2.3. Silver catalysed propargylic alcohol substitution 50 2.4. Terminal propargylic alcohols: Hydration versus Meyer-Schuster 56 rearrangement 2.5. Tertiary propargylic alcohols: Meyer-Schuster rearrangement 57 2.6. Primary propargylic alcohols: One-pot Meyer-Schuster 59 rearrangement and additions 2.7. Influence of the reaction additive: Hydration of propargylic 61 alcohols 2.8. Synthesis and reactions of 3-alkoxyfurans 66 3. Conclusions 75 4. Future Work 77 5. Experimental Section 82 6. References 175 7. Appendix 185 iii Abbreviations AcOH Acetic acid MeCN Acetonitrile Ac Acetyl Bn Benzyl bp Boiling point Bu Butyl Cat. Catalytic X Counter ion Cy Cyclohexyl Et2O Diethyl ether DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EI Electron impact EWG Electron withdrawing group E Electrophile ES Electrospray ionisation ee Enantiomeric excess er Enantiomeric ratio EtOH Ethanol Et Ethyl EtOAc Ethyl acetate iv Eq. or equiv. Equivalents g Grams HRMS High resolution mass spectrometry h Hour(s) IR Infrared spectroscopy n Integer number i Iso LA Lewis acid L Ligand LHMDS Lithium bis(trimethylsilyl)amide LDA Lithium diisopropylamide mp Melting point m- Meta MeOH Methanol Me Methyl mg Miligram mL Millilitre mmol Millimole nm Nanometre NHC N-Heterocylic carbene NMR Nuclear magnetic resonance spectroscopy Nu Nucleophile o- Ortho v p- Para ppm Parts per million Ph Phenyl Pr Propyl Ref. Reference rt Room temperature Temp Temperature t or tert Tertiary TBS tert-Butyl dimethylsilyl TBME tert-Butyl methyl ether THF Tetrahydrofuran TLC Thin layer chromatography PhMe Toluene Et3N Triethylamine UV Ultraviolet UCL University College London υ Wavenumber cm-1 IPR 2,6-bis(disopropylphenyl)imidazol-2-ylidene; vi Acknowledgements First of all I need to thank Tom whose brilliant ideas, infectious enthusiasm and capacity for daytime drinking have made the project so enjoyable throughout my time at UCL. I doubt I will ever, in my working life, have such an excellent boss again. I also need to thank my industrial supervisor Peter who helped make my time at GSK both enjoyable and productive. I have thoroughly enjoyed working in the Sheppard Group and a large proportion of that is down to the company. I would in particular like to thank Osman (the ‘wonderful p’), Lauren, Sam, Fav, Fil and Rhian for making the lab such a welcoming, curiosity driven and entertaining working environment, despite far too many lunchtime crosswords for my liking. Thanks also need to go to Sheppard group members past and present including Laure, Samantha, Emily, and Jarryl who have all been led astray from time to time. In that category I must also include Roomi, Sally, Rosemary, Dan, Liz and the rest of the Baker, Wilden and Caddick groups. A big thank you must also go to Jamie, Jon, Mark and Richard. From day one I was joined by the fabulous Vincent Gray, whose quick wit and ever increasing array of talents continue to astound me and to whom I wish the very best for the future. Rachel, once approved by Vincent, joined us a year later and I am not sure how we ever coped without her. Rachel’s generosity is a constant source of admiration, as are her fabulous dance moves and snail-like drinking pace. Rachel and Vincent have always been their to celebrate, commiserate and savage, when required, and for this and many other things I am truly grateful. My parents unwavering support and encouragement appears limitless despite turning there much loved dining room into my thesis office, which I promise to tidy away in the near future. Also to my friends away from chemistry a big thank you for providing welcome distractions. Finally and by no means least, I would like to thank my girlfriend Eddie, without whom I would never have had the work ethic to embark on my PhD and without her love and support I would never have finished it. vii “Like all young men I set out to be a genius, but mercifully laughter intervened” Lawrence Durrell - Clea (1960) viii 1. Introduction I aim to provide a brief introduction as to what makes Au an effective homogeneous catalyst and discuss its role in activating alkynes towards a variety of nucleophiles for synthesis of substrates and also towards natural products. I will then give a background into the synthesis and reactions of propargylic alcohols. This will build towards discussion of the Meyer-Schuster rearrangement and also the Rupe rearrangement. Following the background discussion of propargylic alcohol reactions and Au catalysis I will go on to talk through the Sheppard group’s previous work in the area of Au catalysis. I will then focus on my own research into the Meyer-Schuster rearrangement of various propargylic alcohols with a commercially available Au catalyst and how the research has developed to include one-pot reactions, propargylic substitution, hydration to β- hydroxyketones and furan synthesis. I will then look to draw some conclusions and make some recommendations for future work. The Hg(II)-catalysed addition of alcohols to alkynes has been known for almost three-quarters of a century (Scheme 1). 4 Given the toxicity of Hg, a range of alternate transition-metal catalysts have been developed. 5 Over the last decade Au has emerged as an important synthetic tool exhibiting mild and chemoselective catalytic activation of alkynes. 6,7,8,9,10,11,12,13,14,15 Au has become the transition metal of choice to replace Hg in reactions such as hydrations, allowing alkynes to be viewed as masked carbonyls under benign conditions in many cases. 16 Importantly Au is employed catalytically in the hydration reaction at significantly lower levels than Hg (see section 1.3. Au activation of alkynes). Scheme 1: Hg hydration of a terminal alkyne 17 Advantages of Au include air stability, due to the high oxidation potential of Au(I) to Au(III) which provides a sufficient barrier to oxidation. Relative non- toxicity and lowered oxophilicity and thus tolerance towards water and alcohols. 1 Plus carbon-Au bonds that favour protodemetallation over beta-hydride elimination. 6,7,8,9,10,11,12,13,14,15 1.1. Gold catalysts Au can exist in three different oxidation states Au(0), Au(I), and Au(III). In aqueous solutions, in the absence of stabilising ligands, Au(I) spontaneously disproportionates to Au(III) and Au(0). 18 Au(I) usually exists as adducts of the form LAuX, where L is a ligand such as a triphenylphosphine or an isocyanide, and X is usually a halide or methyl. The presence of a ligand prevents reduction of Au(I) to metallic Au(0) via dimerisation of the organic residue. Au(I) complexes are 2-coordinate, linear, diamagnetic, 14 electron species, whereas Au(III) complexes are 4 coordinate, square planar, diamagnetic, 16 electron 19 species and tend to exist in the form L3AuX (Figure 1). Figure 1: Main structures of simple Au(I) and Au(III) complexes In general commercially available Au salts and complexes for catalysis range from simple Au(I) and Au(III) halides (1-2) to more elaborate cationic Au complexes employing spectator ligands such as phosphines (3-4) and N- heterocyclic carbenes (5) (Figure 2). In the case of Au(III) when the formal coordination number is less than four, ligands such as chlorine can form a bridging ligand or intramolecular chelation can occur (6, Figure 2). 2 Figure 2: Selection of commercially available Au catalysts Traditionally, a Ag co-catalyst is required to activate Au catalysts that have bonding or intermolecular chelation with halides (Scheme 2). Silver is well known for its high affinity towards halides. The presence of the silver halide had for a long time been considered to have little effect on the reaction with the silver playing a supporting role, although more recently there has been a greater focus on the ‘silver effect’ in Au catalysed reactions, which in some cases has been to shown to help promote the reaction.
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