University of Bath PHD Palladium-catalysed C--X bond formations Taylor, Dawn Award date: 2006 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 UNIVERSITY OF BATH Palladium-Catalysed C-XBond Formations Dawn Taylor A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Chemistry 2006 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without the prior written consent of the author. This thesis may not be consulted, photocopied or lent to other libraries without the permission of the author for three years from the date of acceptance of the thesis. 17 bC Mcx.^ UMI Number: U220737 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U220737 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 if! SIT Y OF BATH LIBRARY 3C> 1 6 JUL 2007 f h :? .-........... iIn*wwwwsNweiwwweqwwwweBewwei UNIVERSITY OF BATH This work was carried out in collaboration with Pfizer as part o f a CASE studentship. Supervisors: Dr Michael C. Willis, University of Bath Dr Adam T. Gillmore, Pfizer Abstract Abstract Over the last decade palladium catalysed C-X cross-coupling reactions have been developed successfully as a major tool for the synthetic chemist (Chapter 1) and our contribution to this key area of research will be detailed herein. Chapter 2 describes our successful application of palladium catalysis to the formation of new C-0 bonds in the synthesis of aryl enol ethers. Vinyl triflates can be efficiently converted into the corresponding aryl enol ethers by treatment with a phenol, NaOlBu and a catalyst generated from Pd 2 (dba ) 3 and 2-(di-terJ-butylphosphino)biphenyl 3b. Palladium catalysed vinylic C-0 bond formation is the key-step in efficient preparation of a range of substituted aryl enol ethers . 1 Chapter 3 introduces the protocol we have investigated towards the application of palladium catalysed C-0 bond formations to the synthesis of the benzofuran motif. A catalyst generated from Pd 2 (dba ) 3 and DPEphos effects intramolecular C-0 bond formation between enolates and aryl halides in the conversion of 1 -(2 -haloaryl)ketones directly into the corresponding benzofurans. Both cyclic and acyclic ketones are efficient substrates. Thio-ketones can also be employed, allowing the preparation of the corresponding benzothiophenes . 2 Chapter 4 presents our approach towards a novel cascade O-annulation route to the benzofuran motif, establishing a double palladium catalysed C-0 bond forming cross­ coupling reaction. A catalyst generated from Pd 2 (dba ) 3 and 2-(di -tert- butylphosphino)biphenyl 3b in the presence of sodium trimethylsilanoate, acting as both an oxygen donor and base, effects an unusual tandem C-0 bond formation involving an intermolecular alkenyl C-0 bond formation with subsequent aryl C-0 bond formation. The identical reaction can also be achieved in a competitive yield employing a catalyst generated from Pd 2 (dba ) 3 and HPtBu 3 BF4 in the presence of the mild base CS2 CO3 and 2 -tosylethanol as the oxygen donor. Chapter 5 reports the palladium catalysed intramolecular aryl enol ether synthesis from vinyl triflates. Our established catalyst generated from Pd 2 (dba ) 3 and DPEphos with the mild base CS 2 CO3 successfully executes the intramolecular cyclisation of a phenolic oxygen onto an adjacent vinyl triflate group to give the corresponding benzofuran in excellent yield. The analogous thiol cross-coupling reaction can also be achieved to give the corresponding benzothiophene in excellent yield. Preliminary studies towards the Abstract expansion of our O-enolate cyclisation strategy, mentioned earlier, for the formation of six membered ring aryl enol ethers were successful. Chapter 6 gives overall conclusions and outlines the continuing and future work being carried out in this area. Chapter 7 is a formal account of experimental procedures. References (1) Willis, M. C.; Taylor, D.; Gillmore, A. T. Chem. Commun. 2003, 2222-2223. (2) Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6 ,4755-4757. Contents Contents Abstract i Contents iii Acknowledgements v Abbreviations and Acronyms vi Ligands x Chapter 1 Introduction 1 1.1 Investigation Aims 1 1.2 Desymmetrisation 2 1.3 Resent Results from our Laboratory 2 1.4 Palladium-Catalysis: C-A'Bond Formations 4 1.5 General Catalytic Cycle 6 1.6 Palladium-catalysed Intermolecular C -0 Bond Formations 8 1.7 Palladium-catalysed Intramolecular C -0 Bond Formations 13 1.8 Palladium-catalysed C-S Bond Formations 18 1.9 References 23 Results and Discussion Chapters Chapter 2 Application of Palladium Catalysed C-O Bond Formations to the Synthesis of Enol Ethers 26 2.1 Enol Ethers 26 2.2 Intermolecular Aryl Enol Ethers 32 2.3 Concluding Comments 38 2.4 References 39 Chapter 3 Application of Palladium Catalysed C-O Bond Formations to the Synthesis of the Benzofuran Motif 40 3.1 Synthesis of Benzofuran Motif 40 3.2 Synthesis of Benzothiophene Motif 47 3.3 A Novel OEnolate Cyclisation 49 3.4 Cyclisation and Formation of Benzofurans 56 3.5 Optimisation of Palladium Catalysed a-Arylations 58 3.6 Novel Palladium Catalysed OEnolate Cyclisation 62 3.7 Thio-Ketones to Benzothiophenes 69 3.8 Cyclisation of a-Arylated Cyclopentanone 72 3.9 Indole Strategy 74 3.10 Concluding Observations 76 3.11 References 76 iii Contents Chapter 4 Palladium Catalysed Alkenyl- and Aryl-C-0 Bond Formations: A Cascade O-Annulation Route to the Benzofuran Motif 80 4.1 Proposed Methodology: Tandem Palladium Catalysed C -0 Bond Formations Exploiting an Oxygen Surrogate 80 4.2 Surrogate Chemistry 84 4.3 Discovery of an Oxygen Surrogate Compatible with Palladium Catalysis 91 4.4 Concluding Comments 96 4.5 References 97 Chapter 5 Palladium Catalysed Intramolecular Aryl Enol Ether Synthesis From Vinyl Triflates 99 5.1 Intramolecular Palladium Catalysed Cross-Coupling of Phenols and Vinyl Triflates 99 5.2 Intramolecular Palladium Catalysed Cross-Coupling of Thiols and Vinyl Triflates 105 5.3 Steps Towards an Enantioselective Intramolecular Palladium-Catalysed Synthesis of Aryl Enol Ethers 106 5.4 Extension to O-Enolate Methodology 108 5.5 Concluding Comments 113 5.6 References 113 Chapter 6 Summary and Future Work 115 6.1 Summary 115 6.2 Future Work 115 6.3 References 118 Chapter 7 Experimental 119 7.1 General Experimental 119 7.2 Experimental Analyses 120 Chapter 2 120 Chapter 3 132 Chapter 5 156 7.3 References 179 Appendix 180 Acknowledgements Acknowledgements Many thanks must go first and foremost to my supervisor Mike Willis for all of his advice and guidance throughout the duration of my studies. Also thanks to my industrial supervisor Adam Gillmore for his mentoring both during my placement visit to Pfizer and numerous update meetings. It has been a pleasure working and dining with you both. Thanks to John Lowe, Mark Russell and Chris Chapman (Department of Chemistry, Bath) for their technical NMR and computer support and Inaki Morao, Pfizer, for carrying out the computational studies detailed in this thesis. Pfizer and the EPRSC are also thanked for their financial support. My PhD would never have been the same if it was not for the great people I have met and become friends with including all of the members of the MCW Group both past and present Ai, Ana, Fletch, Gareth, Gary, Helen, Jay, Luke, wee Matt, Phil, Rob, Stav, Steve, Sy and Vincent. A special thanks to Gareth for the useful chemistry discussions and collaboration on the a-arylation chemistry and to Ai, Fletch, Helen, Rob and Sy for proofreading. Also, the then BSc students that had to try to pretend that they were listening to me, Wee Matt and Tim, it was fun! To those doctors/marrieds/wanabes with whom I shared a lab, it has been a pleasure to work with you all especially the girlies Rach, Gan and Ana. And not to forget everyone else in the department, ................your friendship and smiles makes it all worth it. Carly and Belinda, what would I have done without you both? Finally, my family, my surrogate family, my friends and Davy.