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Development of Novel Metal-Catalysed Methods for the Transformation of Ynamides Thesis Submitted in Accordance with the Requirements of The University of Edinburgh for the Degree of Doctor of Philosophy By Donna L. Smith Supervised by Dr. Hon Wai Lam School of Chemistry College of Science and Engineering 2013 Declaration I hereby declare that, except where specific reference is made to other sources, the work contained within this thesis is the original work of my own research since the registration of the PhD degree in September 2009, and any collaboration is clearly indicated. This thesis has been composed by myself and has not been submitted, in whole or part, for any other degree, diploma or other qualification. Donna L. Smith 2 Abstract I. Rhodium-Catalysed Carbometalation of Ynamides using Organoboron Reagents As an expansion of existing procedures for the carbometalation of ynamides, it was discovered that [Rh(cod)(MeCN)2]BF4 successfully promotes the carbometalation of ynamides with organoboron reagents. A variety of organoboron reagents were found to be suitable for this reaction, but mostly the use of arylboronic acids was explored. The developed methodology provides β,β-disubstituted enamide products in a regio- and stereocontrolled manner. II. Palladium-Catalysed Hydroacyloxylation of Ynamides In the presence of palladium(II) acetate, ynamides successfully underwent a hydroacyloxylation reaction with a variety of carboxylic acids. This carboxylic acid addition occurred highly regio- and stereoselectively to provide α-acyloxyenamides. Applications of the α-acyloxyenamide products were also investigated. III. Rhodium-Catalysed [2+2] Cycloaddition of Ynamides with Nitroalkenes A novel rhodium catalyst system has been developed in order to promote the [2+2] cycloaddition reaction between ynamides and nitroalkenes. The reaction provides cyclobutenamide products and was diastereoselective in favour of the trans 3 cyclobutenamide. Both the ynamide scope and the nitroalkene scope of the reaction have been explored. 4 Contents Acknowledgements ..........................................................7 Abbreviations ..........................................................8 1. Introduction ........................................................12 1.1 An Introduction to Ynamides ........................................................12 1.2 The Synthesis of Ynamides ........................................................14 1.3 The Reactivity of Ynamides ........................................................19 1.4 Conclusions ........................................................2 8 1.5 Overall Aims of Forthcoming Chapters ........................................................2 9 2. Rhodium-Catalysed Carbometalation of Ynamides with Organoboron Reagents ..........................................................30 2.1 Introduction .........................................31 2.1.1 Introduction to Enamides .........................................31 2.1.2 Reactions of Enamides .........................................32 2.1.3 Synthesis of Enamides .........................................34 2.1.4 Carbometalation of Ynamides .........................................38 2.1.5 Addition of Organoboron Reagents to Alkynes .. .......................................42 2.2 Results and Discussion .........................................47 2.2.1 Preparation of Ynamides .........................................47 2.2.2 Optimisation of the Carbometalation Reaction .........................................51 2.2.3 Carbometalation of Ynamides Using Boronic Acids .................................. 53 2.2.4 Carbometalation of Ynamides Using Other Organoboron Reagents ........58 2.2.5 Regio- and Stereochemical Determinations .........................................59 2.3 Mechanism .........................................60 2.4 Conclusions .........................................62 3. Palladium-Catalysed Hydroacyloxylation of Ynamides ........................64 3.1 Introduction ...........................................65 3.1.1 Hydroacyloxylation of Alkynes ...........................................65 5 3.1.2 Reactions of Enol Esters ...........................................71 3.2 Results and Discussion ...........................................76 3.2.1 Screening and Optimisation ...........................................76 3.2.2 Exploration of the Carboxylic Acid Scope ...........................................79 3.2.3 Hydroacyloxylation of Aryl-Substituted Ynamides ..................................83 3.2.4 Hydroacyloxylation of Aliphatic-Substituted Ynamides ...........................87 3.2.5 Regio- and Stereochemical Determinations ...........................................89 3.3 Mechanism ...........................................90 3.4 Product Manipulations ...........................................93 3.5 Conclusions ...........................................97 4. Rhodium-Catalysed [2+2] Cycloaddition of Ynamides with Nitroalkenes ........................................................99 4.1 Introduction .........................................100 4.1.1 [2+2] Cycloaddition Reactions of Ynamides .........................................100 4.2 Results and Discussion .........................................107 4.2.1 Reaction Optimisation .........................................108 4.2.2 Exploration of the Ynamide Scope .........................................112 4.2.3 Exploration of the Nitroalkene Scope .........................................116 4.2.4 Structural Determinations .........................................120 4.3 Mechanism .........................................121 4.4 Alternative Substrates .........................................127 4.5 Conclusions .........................................128 5. Experimental ..................................................................130 5.1 Preparation of Ynamides ......................................................1 31 5.2 Chapter 2 Experimental ......................................................139 5.3 Chapter 3 Experimental ......................................................14 8 5.4 Chapter 4 Experimental ......................................................167 6. References ......................................................188 7. Appendix ...................................................... 197 6 Acknowledgements Many thanks to Dr Hon Wai Lam for giving me the opportunity to work in his group, providing me with such an interesting project to work on and for all your help and support. I am grateful to have had you as a supervisor and have learnt a lot. Thank you to AstraZeneca, the EPSRC and The University of Edinburgh for providing funding and facilities for my PhD research. Thank you to Dr William Goundry for being my CASE supervisor and to everyone who made me feel welcome during my industrial placement at Macclesfield. Thank you to everyone in the Lam group past and present for making my time at Edinburgh very enjoyable. The group is now far too big to mention everyone individually, but all the lunchtime and coffee break chats always brightened up my day. You have been a great bunch to work and socialise with. Thanks especially to Benoit for showing me the ropes of the lab when I first started and sharing his tips on ynamide chemistry. Thank you to Graham and Sam for listening to all my comments, complaints and questions, and joining me on all the nights out. Thank you to Dan and Alan for providing advice during my thesis writing (your input definitely helped), and to Martin for some proof reading. Good luck with the rest of your research everyone. Thank you to my family, for always supporting me and for putting up with all the time I have spent talking about and working on this thesis. 7 Abbreviations Ac acetyl acac acetylacetonate AIBN azobisisobutyronitrile AD asymmetric dihydroxylation aq aqueous Ar aryl BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene bipy 2,2’-bipyridyl Bn benzyl Boc t-butyloxycarbonyl box bisoxazoline Bu butyl Bz benzoyl cat. catalyst Cbz carboxybenzyl cod 1,5-cyclooctadiene conv conversion Cp* 1,2,3,4,5-pentamethylcyclopentadienyl CPBA chloroperbenzoic acid Cy cyclohexyl d doublet dba dibenzylideneacetone DIBAL di-iso-butylaluminium 8 DMAP 4-(dimethylamino)pyridine DME dimethoxyethane DMEDA dimethylethylenediamine DMF N,N-dimethylformamide DMM di(propylene glycol) dimethyl ether dppb 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio E electrophile ee enantiomeric excess equiv equivalents Et ethyl EWG electron-withdrawing group Fur furanyl g gram(s) h hour(s) Hex hexyl HMDS hexamethyldisilazane i iso IMes 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene