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Suzuki-Miyaura Mediated Biphenyl Synthesis: a Spotlight on the Boronate Coupling Partner

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Suzuki-Miyaura Mediated Biphenyl Synthesis: a Spotlight on the Boronate Coupling Partner Suzuki-Miyaura Mediated Biphenyl Synthesis: A Spotlight on the Boronate Coupling Partner By Christine B. BALTUS [B.Sc. Chemistry; M.Sc. Chemistry] A thesis submitted in partial fulfilment of the requirements of the University of Greenwich for the degree of Doctor of Philosophy October 2011 School of Science University of Greenwich at Medway Chatham Maritime, Kent, ME4 4TB United Kingdom ACKNOWLEDGMENTS First, I would like to thanks Dr. John Spencer, my supervisor, for supervising me during the three years of my Ph.D. I thank him for his availability, his support, his help, his scientific interest, his kindness and cheerfulness which helped stimulate my desire to develop my theoretical knowledge/practical skills and kept me going throughout my Ph.D. I would like to thank Dr. Neil J. Press, my industrial supervisor, for participating in the supervision of my project and for making my three month period stay at Novartis, Horsham, U.K. a very good professional and personal experience and Prof. Babur Z. Chowdhry, my second supervisor, for his support and advice. I would like to thank the pharmaceutical company Novartis U.K. for funding my Ph.D. I would like to thank the School of Science, University of Greenwich at Medway for allowing me to use the equipment I needed for my project, the EPSRC National Mass Spectrometry Service of the University of Wales (Swansea) for carrying out the HRMS analyses and the EPSRC National X-Ray Diffraction Units of the University of Southampton and the University of Newcastle for carrying out X-ray crystallographic measurements. I would like to particularly thank, my work collegues, Dr. Rajendra Prasad Rathnam, Dr. Hiren Patel, Dr. Irina Chuckowree, Dr. Antonino Puglisi and Dr. Jahangir Amin for their advice, their help, their presence, which made my everyday lab-time a very pleasant journey and for their friendship. I also would like to thank the lecturer and technicians, who guided me while using different pieces of equipments, Mrs. Atiya Raza, Mrs. Devyani Amin, Dr. Andy P. Mendham, Mr. Mark Allen and Mr. Ray Cowley. I would like to thank Dr. Aurora Antemir, Mrs. Nazanin Zand, Mrs. Farnoosh Kianfar, Dr. Peter Gunning, Mr. Arun Kumar Kotha and Mr. Charles Whitfield for their support and friendship. Last but not least, I would like to thank my mother Mrs. Mireille Molter and my sisters Misses Nathalie and Nadia Baltus for their support and love. iii ABSTRACT Suzuki-Miyaura Mediated Biphenyl Synthesis: A Spotlight on the Boronate Coupling Partner The biaryl motif is found in many natural and synthetic products that display a wide range of biological activities. This explains why biphenyls are widely encountered in medicinal chemistry as a privileged scaffold. The palladium-catalysed Suzuki-Miyaura (SM) coupling is one of the most important and efficient strategies for the synthesis of symmetrical and unsymmetrical biaryl compounds; the arylboronic acid or ester is a key partner in this coupling reaction. This work presents the synthesis of a library of new molecules containing the biphenyl scaffold; o-, m- and p-(bromomethyl)phenylboronic acid pinacol esters, 2a-c, were selected as coupling partners. Nucleophilic substitution of the bromide was carried out with amine, thiol, alcohol or phenol nucleophiles. Supported reagents and microwave assisted organic synthesis conditions were employed to enhance this chemistry and made it amenable to parallel synthesis. The resulting arylboronates were used in SM coupling reactions in order to obtain a range of biphenyls. The use of Boc-piperazine as a nucleophile in the SN2 reaction, with 2a-c, and 1-bromo-, 2-, 3- or 4-nitrobenzene or 2-bromo-5-nitropyridine as aryl halides in the SM coupling reaction, allowed two other points of functionalisation to be added to the biaryl motif. The conditions for the SM coupling of mercaptomethylphenylboronic esters and ortho - substituted methylphenylboronic esters were optimised in order to broaden the scope of the biaryl library. Phosphines were found to be good nucleophiles in the S N2 reaction with 2a-c. A Wittig reaction was performed with the resulting phosphonium arylboronates in order to synthesise arylboronic esters containing an alkene function prior the reduction of the resulting double bond of the stilbene derivatives and realising a SM coupling to synthesise arylethylbiphenyls. The stilbene derivatives were also synthesised by using the olefin cross-metathesis reaction of 4-vinylphenylboronic acid pinacol ester. A solid state crystallographic study was undertaken on a small library of methylbiphenylamides to compare the crystal structures of isomers or biphenyls with different functional groups. Christine B. BALTUS [B.Sc. Chemistry; M.Sc. Chemistry] iv CONTENTS DECLARATION ii ACKNOWLEDGMENTS iii ABSTRACT iv SCHEMES x FIGURES xiv TABLES xvii ABBREVIATIONS xix OVERVIEW OF THE THESIS xxi Chapter 1: Introduction 1 1.1. Organoboranes 1 1.1.1. Boronic acids 2 1.1.1.1. Introduction 2 1.1.1.2. Synthesis of boronic acids 2 1.1.1.2.1. Electrophilic trapping of organometallic intermediates with borates 2 1.1.1.2.2. Transmetallation of alkenyl and aryl silanes and stannanes 3 1.1.1.2.3. Hydroboration 3 1.1.1.2.4. Metathesis reaction 3 1.1.1.2.5. Hydrolysis of boronic esters 4 1.1.1.2.6. One-pot metal-catalysed synthesis of arylboronic acids 4 1.1.1.3. Applications in organic synthesis 5 1.1.1.3.1. Boron Heck-type coupling with alkenes 5 1.1.1.3.2. Addition on carbonyls, alkenes, alkynes, imines and iminiums 6 1.1.1.3.3. Coupling reactions 7 1.1.1.3.4. Oxidative replacement of boron 8 1.1.1.3.5. Boronic acids as catalysts 8 1.1.1.3.6. Boronic acids as protecting groups for diols and diamines 8 1.1.1.4. Boronic acid in medicinal chemistry 9 1.1.2. Boronic ester 11 1.1.2.1. Introduction 11 1.1.2.2. Synthesis of boronic esters 11 v 1.1.2.2.1. Esterification 11 1.1.2.2.2. Hydroboration 11 1.1.2.2.3. Transmetallation of organosilanes 12 1.1.2.2.4. Metal-catalysed coupling of aryl halides or triflates with diboron reagents 12 1.1.2.2.5. Boronylation by C-H activation 13 1.1.2.3. Applications 13 1.1.2.3.1. Nucleophilic substitutions 14 1.1.2.3.2. Wittig reactions 15 1.1.2.3.3. Triazole and tetrazole aryl boronate synthesis 15 1.1.2.3.4. Asymmetric synthesis 15 1.1.2.3.5. Synthesis of the aryl or heterocyclic moiety 16 1.1.2.4. MIDA boronates 16 1.2. Suzuki-Miyaura coupling reaction 17 1.3. Biphenyls 18 1.3.1. Introduction 18 1.3.2. Biphenyls in medicinal chemistry 19 1.3.3. Synthesis of biphenyls/aryls 20 1.3.3.1. Cross-coupling reactions 20 1.3.3.2. C-H activation 21 1.3.3.3. Other reactions 23 1.4. Microwave-Assisted Organic Synthesis (MAOS) 24 1.5. Presentation of the thesis 25 Chapter 2: Synthesis of a substituted-methylbiaryl library 28 2.1. Introduction 28 2.2. Optimisation of the microwave-mediated S N2 reaction 29 2.3. Microwave-mediated S N2 reactions employing the optimised conditions 31 2.3.1. Bromide displacement by nitrogen nucleophiles 31 2.3.2. Bromide displacement by sulphur nucleophiles 33 2.2.3. Bromide displacement by oxygen nucleophiles 34 2.4. X-Ray diffraction analysis of boronic ester derivatives 36 2.5. Suzuki-Miyaura cross-coupling reaction 37 vi 2.5.1. SM cross coupling reaction catalysed by Pd(OAc) 2 37 2.5.2. SM cross coupling reaction catalysed by Pd(PPh 3)4 39 2.5.3. Synthesis of precursors to valsartan 40 2.6. Conclusion 43 2.7. Experimental Conditions and Analytical Methods 44 2.8. Experimental procedures and data 46 Chapter 3: Synthesis of a (piperazin-1-ylmethyl)biaryl library 67 3.1. Introduction 67 3.2. SM cross-coupling reaction 69 3.3. Cleavage of the Boc group 70 3.4. Piperazine functionalisation 70 3.5. Nitro group reduction 72 3.6. Amino group functionalisation 74 3.7. Conclusion 77 3.8. Experimental procedures and data 78 Chapter 4: Suzuki-Miyaura coupling on S- and ortho -substituted phenylboronic esters 106 4.1. Introduction 106 4.2. SM coupling of S-substituted methylphenylboronic esters 107 4.2.1. Optimisation of conditions for the SM coupling of S-substituted methylphenylboronic esters 107 4.2.2. SM coupling of S-substituted methylphenylboronic esters using the optimised conditions 109 4.2.3. Synthesis of biaryl palladacycles 110 4.3. SM coupling of ortho -substituted methylphenylboronic esters 114 4.3.1. Optimisation of conditions for the SM coupling of ortho -substituted methylphenylboronic esters 114 4.3.2. SM coupling of ortho -substituted methylphenylboronic esters using the optimised conditions 115 4.4. Synthesis of an ortho -substituted (piperazin-1-ylmethyl)biaryl library 117 4.4.1. SM coupling 117 vii 4.4.2. Boc group removal 118 4.4.3. Piperazine functionalisation 118 4.4.4. Nitro group reduction 119 4.4.5. Aniline functionalisation 119 4.5. Conclusion 120 4.6. Experimental procedures and data 121 Chapter 5: Synthesis of an arylethylbiaryl library 139 5.1. Introduction 139 5.2. Bromide displacement by phosphorus nucleophiles 141 5.3. Wittig reaction 143 5.3.1. Introduction to the Wittig reaction 143 5.3.2. Wittig reaction on compounds 5q and 6p -r 144 5.4. Cross-metathesis reaction 150 5.4.1. Background to the cross-metathesis reaction 150 5.4.2. Synthesis of vinyl arylboronates and vinylbiaryls via CM reaction 152 5.4.2.1. Background 152 5.4.2.2.
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