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Synthesis and application of thiourea-S,S-dioxide derivatives by James Frederick Shuan-Liang Apps A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry University of Warwick Department of Chemistry February 2008 To my parents ii Table of Contents Abstract .............................................................................................................................. 1 Abbreviations ...................................................................................................................... 2 Chapter 1. Introduction .................................................................................................... 5 1.1 Preface .......................................................................................................................... 5 1.2 Oxidation of sulfur compounds ..................................................................................... 7 1.3 Thiourea oxides in biological systems ........................................................................ 10 1.4 Structure, synthesis and properties of the oxides of thiourea ...................................... 16 1.4.1 Thiourea monoxide .............................................................................................. 16 1.4.2 Thiourea dioxide .................................................................................................. 18 1.4.2.1 X-ray crystallographic studies of thiourea dioxides ................................... 18 1.4.2.2 Computational studies of thiourea dioxides ............................................... 22 1.4.2.3 Synthesis of thiourea dioxides .................................................................... 24 1.4.2.4 Application of thiourea dioxides ................................................................ 28 1.4.2.5 Decomposition of thiourea dioxides ........................................................... 30 1.4.3 Thiourea trioxide .................................................................................................. 32 1.4.3.1 X-ray and computational studies of thiourea trioxides ............................... 32 1.4.3.2 Synthesis of thiourea trioxides .................................................................... 35 1.4.3.3 Reactivity and application of thiourea trioxides ......................................... 39 1.5 Objectives ................................................................................................................... 40 Chapter 2. Synthetic and computational studies of N,N’-disubstituted thiourea dioxide derivatives .......................................................................................................... 42 2.1 Establishing and developing published procedures .................................................... 42 2.1.1 Oxidation of N,N’-dialkylthiourea derivatives ..................................................... 43 2.1.2 Oxidation of N,N’-diphenylthiourea .................................................................... 45 2.1.3 Oxidation of ethylenethiourea derivatives ........................................................... 46 2.2 Computational studies of thiourea dioxide ................................................................. 51 2.3 Computational study and synthesis of novel thiourea dioxides .................................. 53 iii 2.3.1 Dioxide and trioxide of N,N’-diisopropylthiourea ............................................... 54 2.3.2 Dioxide and trioxide of propylenethiourea .......................................................... 61 2.4 N,N’-Diarylthiourea dioxides ...................................................................................... 62 2.5 Future work ................................................................................................................. 69 Chapter 3. Investigation into the application of thiourea dioxide derivatives .......... 70 3.1 Reduction of aldehydes and ketones ........................................................................... 71 3.2 Reduction of nitrogen-containing functional groups .................................................. 75 3.2.1 Removal of tosyl groups from N-tosylaziridines ................................................. 75 3.2.2 Reduction of nitriles to primary amines ............................................................... 76 3.2.3 Deprotection of CBz-amines ................................................................................ 77 3.3 Reduction of disulfides ............................................................................................... 77 3.4 Reduction of alkyl halides .......................................................................................... 79 3.5 Future work ................................................................................................................. 82 Chapter 4. Mechanism of decomposition of disubstituted thiourea dioxides ............ 83 4.1 Reduction of sulfimides with disubstituted thiourea dioxides .................................... 84 4.1.1 Effect of solvent ................................................................................................... 85 4.1.2 Effect of base ....................................................................................................... 87 4.1.3 Nature of the primary decomposition species ...................................................... 90 4.2 Mechanism of reduction of ketones with thiourea dioxide derivatives ...................... 95 4.3 Future Work .............................................................................................................. 100 Chapter 5. Investigation into substituted thiourea dioxides as N-heterocyclic carbene precursors ...................................................................................................................... 101 5.1 Preliminary studies concerning the oxidation of N,N’-dialkylethylenethiourea ....... 104 5.2 Identification of aprotic oxidising agents .................................................................. 108 5.2.1 Dioxiranes .......................................................................................................... 108 5.2.2 Oxaziridines ....................................................................................................... 110 5.3 Oxaziridine-mediated oxidation of ethylenethioureas .............................................. 113 5.3.1 trans-3-(1,1-Dimethylethyl)-3-methyl-2-(phenylsulfonyl)oxaziridine .............. 113 iv 5.3.2 Synthesis of N-sulfonyloxaziridines .................................................................. 114 5.3.3 Synthesis of N-benzyloxaziridine ...................................................................... 116 5.3.4 N-Benzyloxaziridine as an oxidising agent ........................................................ 117 5.3.4 Synthesis and application of N-isopropyloxaziridine ........................................ 120 5.4 Preparation of substituted ethylenethiourea dioxide from carbenes ......................... 122 5.4.1 N,N’-Di-tert-butylethylenethiourea dioxide ....................................................... 122 5.4.2 New adducts via Denk’s methodology .............................................................. 125 5.5 Investigation into the preparation of Pd(0)carbene complexes ................................. 127 5.6 Future Work .............................................................................................................. 129 5.7 Overall conclusions ................................................................................................... 130 Experimental ................................................................................................................. 132 Chapter 2 experimental ................................................................................................... 134 Chapter 3 experimental ................................................................................................... 150 Chapter 4 experimental ................................................................................................... 161 Chapter 5 experimental ................................................................................................... 180 References ...................................................................................................................... 223 Appendix ........................................................................................................................ 233 X-ray crystallographic data for N,N’-diisopropylthiourea dioxide ............................. 233 Near-IR spectrum, monitoring the oxidation of trans-4,5-tetramethyleneimidazolidin- 2-thione ....................................................................................................................... 236 Density Functional Theory DFT data ......................................................................... 237 A. Basis set investigations of thiourea dioxide ..........................................................