Selective Fluorination Strategies
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Durham E-Theses Selective Fluorination Strategies BREEN, JESSICA,RUTH How to cite: BREEN, JESSICA,RUTH (2012) Selective Fluorination Strategies, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/3479/ 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 Abstract There is a great interest in the synthesis of fluorinated aromatic and heterocyclic compounds, which have a range of applications in the pharmaceutical industry. Many common routes to these compounds, however, are low yielding and or/expensive. This thesis is concerned with novel methods for the synthesis of fluoro-aromatics and fluoro- pyrazoles using conventional fluorinating agents, such as Selectfluor™, as well as using elemental fluorine and the flow reactor technology developed in Durham. Firstly, elemental fluorine was used to fluorinate a range of aromatics containing electron-donating substituents, using both batch and flow methods. These methods often afforded the desired compound but with little selectivity and low conversion from the starting materials. Following on from this, ipso fluoro-deboronation techniques using Selectfluor™, were employed to improve the selectivity and yields of the reaction and, in many cases, the desired mono-fluorinated arylfluoride could be accessed in good yield. A range of aryl boronic acid derivatives were explored as the substrate and the results showed that trifluoroborate salts were the most useful substrate. The ipso fluoro- deboronation of heterocyclic boronic acid derivatives was also investigated and showed some promising results. The synthesis of 4-fluoropyrazoles was investigated using three methods. Initially, a two-step process, where the 2-fluoro-1,3-diketone was synthesised and isolated and subsequently reacted with hydrazine, was employed. This allowed a range of 4- fluoropyrazoles to be obtained in high yield and purity. Secondly, a telescoped two-step continuous flow process was employed which did not require isolation of the intermediate 2-fluoro-1,3-diketone. This reaction gave good yields and required less solvent with significantly lower reaction times than the two-step process. Thirdly, C4 mono- and di-fluorination of 3,5-disubstituted pyrazoles was investigated using Selectfluor™ and elemental fluorine. This method gave low conversion from the starting material (50–60 %) but the desired 4-fluoropyrazoles and novel 4,4- difluoropyrazoles could be isolated. Acknowledgements Firstly I would like to thank everyone who has made the last three years so memorable. I would particularly like to thank my academic supervisor, Professor Graham Sandford for his invaluable help and support throughout the course of my Ph.D. I would also like to thank my industrial supervisors, Dr Jonathan Fray and Miss Bhairavi Patel, for their input and enthusiasm and Pfizer for funding. This research would not have been possible without the help of the highly professional technical staff at Durham University, namely: Dr Alan Kenwright, Mr Ian McKeag, Mrs Catherine Heffernan (NMR); Dr Jackie Mosely, Mr Peter Stokes, Mr David Parker (Mass spectrometry); Miss. Judith Magee (Elemental analysis); Dr Dmitrii Yufit (X–ray crystallography); Mr Lenny Lauchlan and Dr Aileen Congreve (Chromatography); Mr Malcom Richardson (Glassblowing) and Mr Dave Hunter (High Pressure Facilities). I would like to give a special mention to the late Mr Peter Coyne (Glassblowing) for showing me a smile every time I saw him. I would like to thank all members of the fluorine group, past and present, particularly Prof. Richard Chambers, Graham Pattison, Ian Wilson, Christopher McPake, Matthew Cargill, Lawrence Hill, Ffion Abraham, Katharine Linton and Peter Harrisson (honorary member). I would also like to thank my family and Peter Harvey for their love and support. ii Memorandum The work described in this thesis was carried out at Durham University between October 2008 and December 2011. This 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 rests with the author. No quotation from it should be published without the prior written consent and information derived from it should be acknowledged. Part of this work has been the subject of the following: J. R. Breen, G. Sandford, D. S. Yufit, J. A. K. Howard, J. Fray, and B. Patel, Beilstein J. Org. Chem, 2011, 7, 1048-1054 This work has been presented, in part, at: 16th European Symposium on Fluorine Chemistry, Ljubljana, Slovenia, July 2010 10th RSC Fluorine Subject Meeting, Durham, UK, September 2010 Departmental Postgraduate Symposium, Durham University, UK, June 2011 ACS National Meetings & Exposition, Denver, Colorado, USA, August 2011 11th RSC Fluorine Subject Meeting, Aberdeen, UK, September 2011 NORSC Green Chemistry Postgraduate Meeting, York, UK, October 2011 iii Nomenclature and Abbreviations Chemical Ac Acetyl Ar Aryl BOC t-butyloxycarbonyl Bu Butyl Cat Catalyst Conc Concentration DABCO 1,4-Diazabicyclo[2.2.2]octane DAST (Diethylamino)sulfur trichloride DCM Dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethylsulfoxide E Electrophile EDG Electron-donating group EI Electron ionisation EWG Electron-withdrawing group ES Electrospray Et Ethyl GC-MS Gas chromatography-mass spectrometry h Hours IR Infra-red J Coupling constant, Hz LC-MS Liquid chromatography-mass spectrometry Me Methyl MeCN Acetonitrile (methyl cyanide) Min Minutes Mol Moles m.p. Melting point MW Microwave iv NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NFSI N-Fluorobenzenesulfonimide NMR Nuclear magnetic resonance PET Positron emission tomography Ph Phenyl Pin Pinacol ester pKa Acid dissociation constant ppm Parts per million Pr Propyl PTFE Polytetrafluoroethylene R Alkyl RT Room temperature SET Single electron transfer THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl Ts Tosyl UV Ultraviolet X Halogen Δ Heat δ Chemical shift/ppm v Table of Contents Abstract .......................................................................................................................................... i Acknowledgements ....................................................................................................................... ii Memorandum ............................................................................................................................... iii Nomenclature and Abbreviations................................................................................................. iv Chapter 1 ..................................................................................................................................... 1 Introduction ................................................................................................................................... 1 1.1 Overview ............................................................................................................................. 1 1.1.1 Fluorine – Isolation and History ....................................................... 1 1.1.2 Properties of the Fluorine Atom ....................................................... 2 1.1.3 Carbon-fluorine Bonds in Organic Synthesis ..................................... 2 1.2 Fluorine in the Pharmaceutical Industry ............................................................................. 3 1.2.1 pKa ................................................................................................ 5 1.2.2 Lipophilicity ................................................................................... 6 1.2.3 Protein Binding Affinity .................................................................. 7 1.2.3.1 Steric Effects ........................................................................ 7 1.2.3.2 Electrostatic Interactions ........................................................ 8 1.3 Fluorination Methods .......................................................................................................... 8 1.3.1 Electrophilic Fluorination Methods .................................................. 9 1.3.1.1 Selectfluor™ ...................................................................... 10 1.3.1.2 Elemental Fluorine .............................................................. 11 1.4 Electrophilic Fluorination Reactions ................................................................................ 12 1.4.1 Fluorination of Aromatic Substrates ............................................... 12 1.4.1.1 Fluorination of Aromatic Substrates Bearing Electron- Withdrawing Substituents Using Fluorine Gas ................................. 13 1.4.1.2 Fluorination of Aromatic Substrates Bearing Electron-donating Substituents ................................................................................... 17 1.5 Synthesis of