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New Catalysts for Amine Alkylation Reactions Promoted by Hydrogen Borrowing

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New Catalysts for Amine Alkylation Reactions Promoted by Hydrogen Borrowing New catalysts for amine alkylation reactions promoted by hydrogen borrowing Roberta Lanaro Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Chemistry June 2015 The candidate confirms that the work submitted is his/her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Roberta Lanaro to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2015 The University of Leeds and Roberta Lanaro ii Acknowledgements First, I would like to thank Steve for his invaluable guidance, for all the ideas and advice throughout the entire project and for his support over the past three and a half years. I must also thank my co-supervisors: Paddy McGowan and John Blacker for their ideas and advice, particularly in the organometallic and kinetic fields. I would like to thank my industrial supervisor, Lianne Frodsham, for her support and help throughout the project and for her supervision during my CASE placement in AstraZeneca. I would like to thank the University of Leeds, Kocienski Bequest and AstraZeneca for funding. I must thank the technical staff in the University of Leeds, particularly Ian Blakeley and Tanja Marinko-Covell for the elemental analyses and Helena Shepherd and Chris Pask who recorded all the X-ray crystal structures of my complexes. I would particularly thank Chris for his help in the elucidation of the structures. I must also thank the MChem student Ashley Thompson for all of her hard work. I would like to thank all the present and past members of the Marsden’s group who made amazing these three and a half years here in Leeds. First, I would like to thank the original members: David, John Li, Mary, James, Nic and Dan for their invaluable help and advice, for the tea breaks and the (often random) discussions. I would like to thank the amazing post-doc team: Tarn, Mark, Tony, Andrea, Ignacio and James for all of the suggestions and proofreading of reports and thesis. Thank you to the new PhD members, Seb and Gayle. I’ll miss you all! I would also like to thank the “additional” members Chris for the good laugh at the pub and at the Christmas meals and Carlo for sharing our AZ meetings and placement. I would like to thank my family for all of the support and encouragement throughout this time, despite not being particularly happy of me living abroad. Finally, thank you to Gabri to be always present and supporting over these three and a half years and to share with me sorrows and joys of the PhD. iii Abstract N-Alkylation of amines with alcohols mediated by borrowing hydrogen is a useful synthetic tool for the preparation of functionalised amines. Specifically, alcohols can be temporarily converted into carbonyl compounds by the metal-catalysed removal of hydrogen. The carbonyl compounds are more reactive than the precursor alcohols and can react in situ with amines to give imines. The metal catalyst returns the borrowed hydrogen to the imines, giving the alkylated amines. Chapter 1 outlines the potential for the atom-efficient hydrogen borrowing processes, giving an overview of the main transformations that can be carried out using this interesting methodology. A preliminary investigation of the reaction mechanism gave us useful information for the synthesis of more robust catalysts for these processes. As a result, a new family of rhodium and iridium complexes was synthesised, which contained a modified Cp* ligand bearing an amine on the tethered chain. Two iridium catalysts were found to be the most active among our family of monomeric complexes. More than 20 substrates containing aryl, heteroaryl and alkyl groups were prepared in 62-99% yields; among them, primary and secondary alcohols and primary and secondary amines have been used. Furthermore, a broad range of functional groups were tolerated, such as halides, nitriles, ethers, esters, amides, sulphonamides and carbamates. Furthermore, the development of a recyclable rhodium complex and a chiral iridium catalyst were attempted. To conclude, Chapter 5 describes the catalytic activities of three dicationic monomers. The N-alkylation of amines on water was explored. The procedure works well for a range of substituted alcohols and amines; in total, 10 compounds have been isolated in good to excellent yield (> 69%). iv Contents Acknowledgements .......................................................................................................... iii Abstract ............................................................................................................................ iv Contents ............................................................................................................................ v Abbreviations ................................................................................................................. viii Chapter 1. Introduction ..................................................................................................... 1 1.1 Alkylation of Amines with Alcohols promoted by Hydrogen Borrowing .............. 1 1.2 History ..................................................................................................................... 5 1.3 Ruthenium-catalysed N-Alkylation with Alcohols ................................................. 6 1.4 Iridium-catalysed N-Alkylation with Alcohols ....................................................... 8 1.5 Mechanistic studies for the alkylation of amines catalysed by [Cp*IrCl2]2.......... 13 1.6 N-Alkylation by Alcohols Catalysed by other Metal Complexes ......................... 19 1.7 Formation of N-Heterocycles ................................................................................ 22 1.8 N-Alkylation of Amides, Carbamates and Sufonamides with Alcohols............... 26 1.9 N-Alkylation of Amines with Alcohols affording Chiral Compounds ................. 28 1.10 Project Aims ........................................................................................................ 31 Chapter 2. Initial Attempts to Study the Reaction Mechanism ....................................... 33 2.1 Evaluation of the Active Iridium Catalyst: Amine-Coordination or Carbonate-Coordination .............................................................................................. 33 2.2 Determination of the Reaction Order: Amine ....................................................... 37 2.3 Determination of the Reaction Order: Alcohol ..................................................... 38 2.4 Determination of the Reaction Order: Catalyst ..................................................... 40 2.5 Conclusions ........................................................................................................... 41 Chapter 3. Synthesis of New Complexes ........................................................................ 42 3.1 Introduction ........................................................................................................... 42 3.2 Synthesis of New Monomeric Rhodium(III) Catalysts ......................................... 44 3.3 Modification of Rhodium(III) Complex 67: Secondary Amine ........................... 50 v 3.4 Modification of Rhodium(III) Complex 67: Tertiary Amine ............................... 54 3.5 Modification of Rhodium(III) Complex 67: Iodide as Halide ligand ................... 61 3.6 Modification of Rhodium(III) Complex 67: Dicationic Rhodium Monomer ....... 61 3.7 Modification of Rhodium(III) Complex 67: Synthesis of Monomer containing a Fluorous Tag ............................................................................................................... 63 3.8 Synthesis of New Monomeric Iridium(III) Complexes ........................................ 67 3.9 Modification of Iridium(III) Complex 102: Secondary Amine ............................ 70 3.10 Modification of Iridium(III) Complex 102: Tertiary Amine .............................. 72 3.11 Modification of Iridium(III) Complexes 102 and 105: Iodide as Halide Ligand 74 3.12 Modification of Iridium(III) Complex 102: Chiral Iridium Complexes ............. 75 3.13 Modification of Iridium(III) Complex 102: Dicationic Iridium Complexes ...... 79 3.14 Conclusions ......................................................................................................... 84 Chapter 4. Catalytic Activity of Rhodium and Iridium Complexes ............................... 85 4.1 Activity of Rhodium Complexes with Respect to Length of Side Chain ............. 85 4.2 Activity of Rhodium Complexes with Respect to the Substitution on Tethered Amine .......................................................................................................................... 86 4.3 Activity of Rhodium Complexes with Respect to the Halide Ligands ................. 88 4.4 Solvent Tolerance and Catalyst Loading using Catalyst 67 ................................. 89 4.5 Activity of Iridium Complexes with Respect to the Substitution on Tethered Amine and with Respect to the Halide Ligands .......................................................... 91 4.6 Comparison between Catalysts 67 and 102 .......................................................... 93 4.7 Solvent Tolerance and Catalyst Loading using Catalyst 102 ..............................
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