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Unsaturated Organosulfur Chemistry: Synthesis and Applications

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Unsaturated Organosulfur Chemistry: Synthesis and Applications Unsaturated Organosulfur Chemistry: synthesis and applications A dissertation presented by: Mohima Begum Roomi Chowdhury in partial fulfilment of the requirements for the award of the degree of DOCTOR OF PHILOSOPHY at UNIVERSITY COLLEGE LONDON Christopher Ingold Building University College London 20 Gordon Street London WC1H 0AJ Declaration I, Mohima Begum Roomi Chowdhury, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. ………………………………………. i Abstract The original focus of this thesis was ynol ether synthesis which was successful using simple and easy-to-prepare precursors (chloroacetylenes) but low yielding. Attention was then diverted to the design and synthesis of a range of thioynol ethers (alkynyl sulfides) utilising chloroacetylenes. The reaction of a chloroacetylene with a thiolate salt in the presence of an amine mediator (Me2NH or DMEDA) yielded the alkynyl sulfides in excellent yields. The alkynyl chlorides were easily prepared from the parent alkynes contrasting sharply with the cumbersome synthesis of an alkynyl sulfonamide previously required. As well as chloroacetylenes, bromo- and iodoacetylenes have also been studied and the differences in their reactivity are highlighted. With a successful route to thioynol ethers at hand, brief mechanistic investigations were conducted into their reactivity. Finally, preliminary studies have been carried out on the reactivity of their derivatives. ii Contents Declaration ..................................................................................................................i Abstract ...................................................................................................................... ii Contents .................................................................................................................... iii Abbreviations............................................................................................................. v Acknowledgements .................................................................................................. vii 1. Introduction ......................................................................................................... 1 1.1 Transition metal-free organic synthesis .......................................................... 2 1.2 Transition metal-free reactions involving tert-butoxide ................................... 6 1.3 Ynol ethers .................................................................................................... 17 1.3.1 Introduction to ynol ethers .......................................................................................... 17 1.3.2 Synthetic routes to ynol ethers: β-elimination ............................................................ 19 1.3.3 Synthetic routes to ynol ethers: α-elimination/carbene rearrangement ...................... 28 1.3.4 Synthetic routes to ynol ethers: oxidation of alkynes................................................. 29 1.4 Unsaturated organosulfur chemistry ............................................................. 32 1.4.1 Introduction to organosulfur chemistry ...................................................................... 32 1.4.2 Synthetic routes to thioynol ethers: functionalisation of terminal alkynes ................ 37 1.4.3 Synthetic routes to thioynol ethers: transition metal-catalysed routes ....................... 40 1.4.4 Synthetic routes to thioynol ethers: use of elemental sulfur ...................................... 46 1.4.5 Synthetic routes to thioynol ethers: Umpolung strategies .......................................... 48 1.4.6 Uses of thioynol ethers ............................................................................................... 54 1.5 Previous work in the Wilden group ............................................................... 63 1.5.1 Background ................................................................................................................. 63 1.5.2 Previous work in the Wilden group ............................................................................ 66 2. Results and Discussion .................................................................................... 74 2.1 Aims ............................................................................................................... 74 2.2 New route to ynol ethers from acetylenic halides ......................................... 75 2.2.1 Precursor synthesis and preliminary studies ............................................................... 75 2.2.2 Observations/trends broken down for each haloacetylene ......................................... 78 2.2.3 Summary of the effects of different temperatures ...................................................... 81 2.2.4 Summary of the effects of different amines ............................................................... 81 2.3 New route to thioynol ethers from acetylenic halides ................................... 83 2.4 Probing the mechanism ................................................................................ 91 2.4.1 Background ................................................................................................................. 91 2.4.2 Mechanistic proposal for new transition metal-free synthetic route .......................... 97 2.5 Applications of alkynyl sulfides and their derivatives .................................. 100 2.5.1 Introduction and aims ............................................................................................... 100 2.5.2 Addition on nitrones to alkynyl sulfides and their derivatives................................. 101 2.5.3 Addition of acyl chlorides to alkynyl sulfide derivatives ........................................ 103 3. Conclusions and future work ......................................................................... 106 4. Experimental .................................................................................................. 108 4.1 General Methods ......................................................................................... 108 iii 4.2 Experimental procedures ............................................................................ 109 4.2.1 Synthesis of chloroalkynes ....................................................................................... 109 4.2.2 Synthesis of tert-butyl ynol ether .............................................................................. 116 4.2.3 Synthesis of acetylenic sulfides ................................................................................ 117 4.2.4 Synthesis of addition products .................................................................................. 126 4.2.5 Synthesis of halo(phenylacetylenes) ........................................................................ 128 4.2.6 Addition products from bromo- and iodoalkynes .................................................... 130 4.2.7 Applications of alkynyl sulfides and their derivatives ............................................. 131 5. Appendix ........................................................................................................ 135 Table of Schemes.............................................................................................. 135 Table of Figures ................................................................................................. 140 Publication ......................................................................................................... 141 Data tables from ynol ether study by temperature ............................................ 144 6. References ..................................................................................................... 145 iv Abbreviations Ac Acetyl acac Acetylacetone aq Aqueous Ar Aryl AIBN Azobisisobutyronitrile BINAP 2,2'-bis(Diphenylphosphino)-1,1'-binaphthyl Bn Benzyl Bz Benzoyl Bu Butyl Cy Cyclohexyl d Day DABCO 1,4-Diazabicyclo[2.2.2]octane dba Dibenzylideneacetone DCM Dichloromethane DCE 1,2-Dichloroethane DEAD Diethyl azodicarboxylate DMEDA N,N’-Dimethylethylenediamine DMF N,N-Dimethylformamide DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO Dimethyl sulfoxide E+ Electrophile E Entgegen (against) EBX Ethynyl Benziodoxolone ee Enantiomeric excess EPR Electron paramagentic resonance er Enantiomeric ratio h Hour HAS Homolytic Aromatic Substitution HMDS Hexamethyldisilazide HMPA Hexamethylphosphoramide HRMS High resolution mass spectrometry LRMS Low resolution mass spectrometry m meta MO Molecular orbital v NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NFSI N-Fluorobenzenesulfonamide NMP N-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance NTf bis(Trifluoromethylsulfonyl)imide Nu Nucleophile o ortho OTf Trifluoromethanesulfonate/triflate p para PE Petroleum Ether ppb parts per billion ppm parts per million Py Pyridine r.t. Room temperature sat Saturated SET Single Electron Transfer tert Tertiary TBAB Tetra-n-butylammonium bromide TBAF Tetra-n-butylammonium fluoride TBAI Tetra-n-butylammonium iodide TBDMS Tert-Butyldimethylsilyl TCPOH 2,4,6-Trichlorophenol TEMPO (2,2,6,6-Tetramethyl-piperidin-1-yl)oxyl TFA Trifluoroacetic acid THF Tetrahydrofuran TIPS Triisopropylsilyl TMEDA Tetramethylethylenediamine TMS Trimethylsilyl Tol Tolyl Ts para-Toluenesufonyl/tosyl UV Ultraviolet Z Zusammen (together) vi Acknowledgements Firstly, I’d like to thank my supervisor, Dr. Jon Wilden, who has also been a
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