University of Huddersfield Repository Walton, Scarlett Maria Catalytic Functionalisation of sp3 Bonds Original Citation Walton, Scarlett Maria (2017) Catalytic Functionalisation of sp3 Bonds. Doctoral thesis, University of Huddersfield. This version is available at http://eprints.hud.ac.uk/id/eprint/34344/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. Users may access full items free of charge; copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational or not-for-profit purposes without prior permission or charge, provided: • The authors, title and full bibliographic details is credited in any copy; • A hyperlink and/or URL is included for the original metadata page; and • The content is not changed in any way. For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ CATALYTIC FUNCTIONALISATION OF SP3 BONDS Scarlett Maria Walton A thesis submitted to the University of Huddersfield in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Huddersfield September 2017 Word Count: 33061 Copyright statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns any copyright in it (the “Copyright”) and s/he has given The University of Huddersfield the right to use such copyright for any administrative, promotional, educational and/or teaching purposes. ii. Copies of this thesis, either in full or in extracts, may be made only in accordance with the regulations of the University Library. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. iii. The ownership of any patents, designs, trademarks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions 2 In Loving Memory of my Dear Uncle Peter ‘There Is A Light That Never Goes Out’ 3 List of Publications: This following publication(s) is/are based on work presented in this thesis: i: Catalytic sp3-sp3 Functionalisation of Sulfonamides: Late-Stage Functionalisation of Drug-Like Molecules Othman Abdulla.; Adam D. Clayton.; Robert A. Faulkner.; Duncan M. Gill.; Craig R. Rice.; Scarlett M. Walton.; Joseph B. Sweeney. Chem. Eur. J. 2017, 23, 14941497. ii: Simple -functionalisation of sulfonamides Adam D. Clayton.; Philippa A. Lawrence.; Scarlett M. Walton.; Joseph B. Sweeney. Manuscript in press. iii: Electrospray source-induced rearrangement of -aryl tertiary sulfonamides via sulfur dioxide extrusion Othman Abdulla.; Adam. D Clayton.; Millicent A. Obeng.; Megan R. Scott.; Scarlett M. Walton.; Joseph B. Sweeney.; Jack V. Blackburn. Manuscript in press. 4 ACKNOWLEDGEMENTS Firstly, I would like to express my deepest gratitude to my supervisor Prof Joe Sweeney, for his continuous support and encouragement throughout my PhD. Also, for the opportunity to not only to work on an interesting thesis project, but for pushing my ability to work on several projects, to mentor placement and project students, and to be involved in various outreach activities. These opportunities have added to my PhD experience and enabled me to develop the skills to become a confident and versatile chemist, for that I am truly grateful. Secondly, I would like to thank my co-supervisor Dr Duncan Gill, for his insightful comments and encouragement, not only in my research, but throughout three years of RSC-SCI National Retrosynthesis competitions. His motivation, passion of science and belief in our team empowered us to be finalists in 2015 and 2017. I would like to acknowledge the Faculty of Applied Sciences staff at the University of Huddersfield, in particular the support from Dr Jack Blackburn (Mass Spectrometry), Dr Neil McLay (NMR), and Hayley Markham. I thank my fellow Sweeney/Gill group members (both past and present) and all the lovely people working in X1/20, for the stimulating scientific discussion, the laughs, and our mutual love of cake. A special mention must go to: Dr Julien Doulcet, for proof-reading this thesis and offering helpful advice, Dr Ian Pocock, for his support and teaching- you really are a walking Wikipedia! Also, to Catherine, my bestie, for her ability to always put a smile on my face every day. I would like to express my profound gratitude to my lovely friends and family, for their unfailing support, enthusiasm and unlimited supply of tea and prosecco. A special mention must go to Gareth, for his love, confidence in my ability, and support over the past nine years. To my sister Shannon, for her positive vibes, craziness and most enjoyable sissy nights, even when living across the pond. Finally, to my amazing parents, Mama and Papa G, who are my inspiration and my rock- I love and thank you both. 5 ABSTRACT Reported herein is an investigation into palladium-catalysed -allylation employing sulfonamide nucleophiles. Anions of benzylsulfonamides have been shown to react with a series of allyl acetates in the presence of Pd0 catalysts, phosphine ligands and base at room temperature, enabling the synthesis of sp3-functionalised sulfonamides. The developed methodology has allowed access to a library of novel allylated sulfonamides, varying both amine substituent and allylic functionality. In addition, we have applied our methodology to a series of known sulfonamide drug targets, to demonstrate our reaction as a useful late-stage functionalisation tool, whilst populating chemical space. The performed mechanistic study using a stereospecific electrophile confirms benzylsulfonamides behave as soft carbon nucleophiles in the Tsuji-Trost reaction, as a ‘net retention’ of stereochemistry is observed (confirmed by X-ray crystallography). Moreover, the asymmetric synthesis of allylated sulfonamides is probed, although obtaining enantioselectivity - to SO bonds is naturally difficult, due to the conformational preferences of sulfonamide carbanions. Traditional methods for direct -alkylation of sulfonamides require strong bases, reactive electrophiles, low temperatures and use of stoichiometric amounts of additives. Therefore, in addition to a catalytic method, we report an alternative method reacting benzylsulfonamides with allyl bromide electrophiles via a nucleophilic substitution reaction, using mild conditions (LDA, THF at –20 °C). 6 Table of Contents Acknowledgements ............................................................................................................................................ 5 Abstract .............................................................................................................................................................. 6 Abbreviations ..................................................................................................................................................... 9 Chapter 1 Introduction ..................................................................................................................................... 11 1.1 Palladium-Catalysed Cross-Coupling Overview ................................................................................... 11 1.2 Asymmetric Allylic Alkylation ................................................................................................................. 16 1.2.1 Overview ......................................................................................................................................... 16 1.2.2 The Tsuji-Trost Reaction ................................................................................................................ 16 1.2.3 Electrophiles ................................................................................................................................... 17 1.2.4 Mechanism ..................................................................................................................................... 18 1.2.5 Mechanistic Study ........................................................................................................................... 19 1.3 Soft Nucleophiles .................................................................................................................................. 21 1.3.1 Carbon Nucleophiles ...................................................................................................................... 21 1.3.2 Nitrogen Nucleophiles..................................................................................................................... 24 1.3.3 Oxygen and Sulfur Nucleophiles .................................................................................................... 25 1.4 Hard Nucleophiles ................................................................................................................................. 26 1.4.1 Reactions with Hard Nucleophiles .................................................................................................