Durham E-Theses Functionalised Pyridyl- and Pyrimidyl- Boronic acids and derived new Biheteroaryls Smith, Amy Elizabeth How to cite: Smith, Amy Elizabeth (2005) Functionalised Pyridyl- and Pyrimidyl- Boronic acids and derived new Biheteroaryls, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/2751/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 University of Durham A Thesis Entitled Functionalised Pyridyl- and Pyrimidyl- Boronic Acids and Derived New Biheteroaryls Submitted by Amy Elizabeth Smith, B.Sc. (Hons) (Ustinov College) Department of Chemistry A Candidate for the Degree of Doctor of Philosophy 2005 The copyright of this thesis rests wnh the author or the university to which к was submitted. No quotation from It, or Information derived from It may be published wHhout the prior written consent of the author or university, and any Information derived from ท should be acknowledged. 2 Ց NOV 2008 ACKNOWLEDGEMENTS I would like to thank my academic supervisor Prof. M. R. Bryce and my industrial supervisor Mr. B. Tarbit for their invaluable help and support throughout this project. Thanks also go to the EPSRC and Seal Sands Chemicals for funding, and to the members of the Bryce research group past and present for making me feel part of the team. This research would not have been possible without the help of the technical staff, namely: Dr Alan Kenwright, Mr Ian McKeag and Mrs Catherine Heffernan (NMR); Dr Mike Jones and Miss Lara Turner (mass spectrometry); Mrs Jarika Dostal (elemental analysis); Dr Andrei Batsanov (X-ray crystallography), Mr Malcolm Richardson and Mr Peter Coyne (glassblowing); Mr Tony Baxter and Mrs Elizabeth Wood (stores) and all the other people who I have worked and studied with เท the chemistry department and at Seal Sands Chemicals. 1 would also like to thank all the friends I made during my time at Durham, in particular David Haigh, Rachel Roberts, Rachel Slater, and Lucy Wheatley for their support which came in every form fr이ฑ study nights to pub nights. Finally I would like to thank my family, especially my mam and dad for their continuing love, patience and support throughout my time at university, and Ian for making Durham a very special place filled with the best memories. Іі MEMORANDUM The work presented within this thesis was carried out at the University of Durham between October 2002 and September 2005. The thesis is the work of the author, except where acknowledged by reference and has not been submitted for any other degree. The copyright of this thesis lies solely with the author and no quotation from it should be published without prior written consent and information derived from it should be acknowledged. Part of this work has been the subject of the following publications: • A. E. Thompson, G. Hughes, A. ร. Batsanov, M. R. Bryce, p. R. Parry, and B. Tarbit; J. Org. Chem. 2005, 70, 388. • A. E. Thompson, A. ร. Batsanov, M. R. Bryce, N. Saygili, p. R. Parry, and B. Tarbit, Telrahedroท, 2005, Ճ7, 5131, and has been presented at: • Seal Sands Chemistry Day, Ramside Hall 2004 • Durham University Chemistry Department Final Year Postgraduate Symposium, Durham 2005 • Seal Sands Chemistry Day, Wynyard 2006 III ABBREVIATIONS DMF Dimethylformamide THF Tetrahydrofuran NMR Nuclear Magnetic Resonance TMEDA MA^,jV',^'-Tetramethyl-l,2-ethylenediamine DMSO Dimethylsulfoxide HPLC High Pressure Liquid Chromatography nOe nuclear Overhauser effect DCM Dichloromethane DPA Diisopropylamine LDA Lithium Diisopropylamide TLC Thin Layer Chromatography dba dibenzylideneacetone dppf diphenylphospliinoferrocene Су cyclohexyl ТРВ Triisopropylborate TMB Trimethylborate TBB Tributylborate /7-BLILİ DoM directed (ฬ/?o-metallation DMGs directing metallating groups LTMP Lithium 2,2,6,6-tetramethylpiperidide DME dimethylether ROESY Rotating frame Overhauser Enhancement Spectroscopy COSY Correlation Spectroscopy IV HSQC Heteronuclear Single Quantum Coherence HMBC Heteronuclear Multiple Bond Correlation EtOAc Ethyl acetate STATEMENT OF COPYRIGHT No part of this thesis may be reproduced by any means, nor transmitted, nor translated into any machine language without the written permission of the author. V ABSTRACT The novel substituted pyridylboronic acids 2-ethoxy-3-pyridylboronic acid 103, 2,6- dimethoxy-3-pyridylboronic acid 146, 2,3-dimethoxy-4-pyridylboronic acid 158, 2,6- difluoro-3-pyridylboronic acid 225, 2,6-dichloro-3-pyridylboronic acid 230 and 2,3- dichloro-4-pyridylboronic acid 238 have been synthesised, and the synthesis of existing alkoxy pyridylboronic acids 2-methoxy-5-pyridylboronic acid 40 and 2-methoxy-3- pyridylboronic acid 43 has been optimized and scaled up. The novel substituted pyrimidylboronic acids 2-chloro-5-pyrimidylboronic acid 244 and 2-amino-5- pyrimidylboronic acid 221 have been syntliesised. All of the above mentioned boronic acids were shown to undergo palladium-catalysed Suzuki cross-coupling reactions with a variety of heteroaryl halides to yield novel heteroarylpyridine derivatives. B(0H)2 B(0H)2 B(0H)2 ,OMe B(0H)2 ՝N OEt MeO N OMe N OMe 103 146 B(0H)2 N СІ 230 B(0H)2 B(0H)2 В(0Н)2 N リ CI^՝N 43 244 221 A range of halogenated aromatics and heteroaromatics bearing primary amine groups have been shown to be suitable substrates for Suziiki-Miyaura cross-coupling reactions with arylboronic acids and pyridylboronic acids under standard conditions, without the need for protection/deprotection steps. New amino-SLibstituted arylpyridines, bipyridines, pyrazinopyridines, indolinopyridines, carbazolopyridines and indolopyridines have thereby been obtained. One derivative was further functionalised via diazotisation. VI PAGE NUMBER Acknowledgements 11 Memorandum ІІІ Abbreviations IV Abstract VI Contents VII 1.0 Introduction 1.1 Synthesis of Aryl and Heteroarylboronic Acids 1.2 Application of Boronic Acids 22 1.3 Conclusion 37 2.0 Alkoxyboronic acids: Scale-up of existing preparations and the synthesis of new examples 2.1 Introduction 44 2.2 Large-scale Syntheses of Previously Published Alkoxy-substituted Pyridylboronic Acids 44 2.3 Novel Alkoxypyridylboronic Acids 46 2.3.1 2-Ethoxy"3-pyridylboronic Acid 46 2.3.2 2,6-Dimethoxy֊3-pyridylboronic Acid 56 2.3.3 2，3-D^^ Acid 59 2.4 Conclusion 60 3,0 Amine Substituted Couplings and Amine Substituted Boronic acid 3.1 Introduction 63 3.2 รนzLiki-Miyaura Cross-Couplings with a Partner Bearing a Primary Amine Group 64 3.3 Transformation of 184 via Diazotization 81 3.4 2-Amino-5-pyrimidylboronic Acid 82 3.5 Conclusion 86 VII 4.0 Synthesis and Application of Novel Halopyridylboronic Acids 4.1 Introduction 89 4.2 2,6֊Ditไนoro֊3-pyridylboronic Acid 89 4.3 2,6-Dichloro-3֊pyridylboronic Acid 92 4.4 2,3-Dichloro֊4-pyridylboronic Acid 100 4.5 2-Chloro-5-pyrimidylboronic Acid 103 4.6 Conclusion 107 5.0 Experimental Procedures 5.1 General Methods 108 5.1.1 General Procedure for all the Cross-Coupling Reactions 109 5.2 Experimental Procedures of Chapter 2 109 5.3 Experimental Procedures of Chapter 3 120 5.4 Experimental Procedures of Chapter 4 138 Chapter 1 Introduction Introduction to Application of Boronic Acids 1.0 Introduction Functionalised aryl and heteroaryl systems are important synthetic templates for industries such as agrochemicals, fine chemicals and pharmaceuticals. Small multi- substituted ring systems may be incorporated into larger systems by utilising substituted boronic acid moieties in Suzuki-Miyaura cross-coupling reactions. It is therefore imperative that newly functionalised boronic acid ring systems are developed. These systems must also cross-couple successfully with a range of halogenated partners in order to satisfy the need for building blocks for the next generation of industrial products. In this first chapter the literature methods used to synthesise heteroaryl boronic acids are discussed in detail. In addition to this, the palladium catalysed Suzuki- Miyaura cross-coupling reactions of these boron containing species are also reviewed. The following chapters encompass the syntheses of heteroaryl boronic acids containing alkoxy, amine and halogen substituents, respectively. Furthermore, the successful large-scale (ca. 100 g) syntheses of several alkoxy-substituted heteroaryl boronic acids are also reported. The later part of each chapter explores the Suzuki- Miyaura reactions of each novel class of boronic acids with various cross-coupling partners. Chapter 3 examines in detail the Suzuki-Miyaura cross-coupling reactions of a range of heteroaryl and aryl halides bearing amine groups with a range of aryl and heteroaryl boronic acids. 1.1 Synthesis of Aryl and Heteroatylboronic Acids The main method used in the syntheses of boronic acids is the reaction of an organometallic reagent with an electrophile, in this case a trialkylborate such as triisopropylborate (TPB).* This route is also useful for the syntheses of boronate