Asymmetric Synthesis of Tertiary Thiols by Lithiation of Thiocarbamates A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy In the Faculty of Engineering and Physical Sciences 2010 Paul MacLellan School of Chemistry 2 Contents Abstract 6 Declaration and copyright statement 7 Acknowledgements 8 Abbreviations and conventions 9 Preface 13 Chapter 1: Asymmetric synthesis of tertiary thiols and thioethers 14 1.0.1 Asymmetric synthesis 15 1.0.2 Organosulfur compounds 15 1.0.3 Tertiary thiols 16 1.1 Carbon-sulfur bond formation 17 1.1.1 SN2 displacement of a leaving group 17 1.1.1.1 Sulfonate leaving groups 17 1.1.1.2 Epoxide ring opening 20 1.1.1.3 Mitsunobu reactions 22 1.1.2 Conjugate addition 28 1.2 Carbon-carbon bond formation 34 1.2.1 Electrophilic addition to α-thioenolates 34 1.2.2 Electrophilic addition to α-thioorganolithiums 36 1.2.2.1 Configurational stability in α-thioorganolithiums 37 1.2.2.2 Lithiation of thiocarbamates 41 Chapter 2: Previous work and aims of the project 45 2.1 Discovery of aryl migration in lithiated ureas 45 2.2 Application to carbamates 50 2.3 Aims of the project 52 Chapter 3: Preparation of thiocarbamate precursors 54 3.1 Approach to thiocarbamates 54 3.2 Preparation of thiol 184 55 3.3 Preparation of a series of thioacetates 57 3.4 Addition to isocyanates 59 3 3.5 Addition to carbamoyl chlorides 62 3.6 Addition to carbamoylimidazolium salts 65 3.7 Preparation of chiral benzylic thiocarbamates 67 3.8 Preparation of heteroaromatic benzylic thiocarbamates 69 3.9 Preparation of achiral benzylic thiocarbamates 72 3.10 Preparation of racemic thiocarbamates 72 Chapter 4: Initial studies and optimisation of aryl migration 74 4.1 Initial lithiations of benzylic thiocarbamates 74 4.2 Dithioacetal side-product 76 4.3 Deprotection of rearranged thiocarbamates 79 4.4 Derivatisation of aryl migration products 80 4.5 Screen of conditions with thiocarbamate 180b 83 4.6 Screen of conditions with thiocarbamate 180a 85 4.7 Desulfurisation of thiocarbamate 180d 86 4.8 Study of quenching 87 4.9 Reaction under standard conditions 89 4.10 Variation of temperature 90 4.11 Variation of solvent 91 4.12 Rapid warming of reaction conditions 93 4.13 Variation of base 94 4.14 Mechanistic studies of aryl migration 96 4.14.1 Intramolecular or intermolecular arylation 96 4.14.2 Stereochemical course of rearrangement 97 4.14.3 Deuteration studies 99 4.14.4 Attempted trapping of a dearomatised intermediate 101 Chapter 5: Scope and application of aryl migration 103 5.1 Scope of aryl migration in chiral benzylic thiocarbamates 103 5.1.1 Variation of migrating aryl ring 104 5.1.2 Variation of benzylic aryl ring 108 5.1.3 Variation of benzylic alkyl substitution 110 5.2 Preparation of tertiary thiols 111 5.3 Lithiation of achiral thiocarbamates 113 5.4 Asymmetric alkylation of achiral thiocarbamates 116 5.5 Aryl migration in allylic thiocarbamates 120 4 5.6 Carbolithiation of vinylic thiocarbamates 126 5.7 Aryl migration in alkyl thiocarbamates 129 Chapter 6: Future work 131 6.1 Asymmetric alkylation and aryl migration 131 6.2 Aryl migration in allylic and vinylic thiocarbamates 132 6.3 Carbolithiation of vinylic thiocarbamates 133 6.4 1,2-Shift in rearrangement products and thiocarbamates as protected isocyanates 134 Chapter 7: Experimental 136 7.1 General information 136 7.2 General procedures 137 7.3 Experimental procedures 141 7.4 Deuteration experiments 220 Chapter 8: References 222 Appendix I: X-ray crystal structure data 228 Word count: 48,650 5 Asymmetric Synthesis of Tertiary Thiols by Lithiation of Thiocarbamates University of Manchester Paul MacLellan A submission for the degree of Doctor of Philosophy 2010 Tertiary thiols are a synthetically challenging class of compounds to prepare asymmetrically. The few reported methods for preparing these species require restrictive functionality to be incorporated into the products or are limited to employing simple carbon electrophiles. This thesis details investigations into the lithiation of N-aryl thiocarbamates. A stereoselective intramolecular arylation within lithiated thiocarbamates has been developed allowing the construction of quaternary stereocentres next to sulfur. Simple deprotection allows the isolation of enantiomerically pure tertiary thiols. 2 O R O Li R2 R1 RLi R1 N S R3 N S R3 2 1 2 1 R R NaOEt O R R HS R3 HN S R3 A procedure for aryl migration within benzylic thiocarbamates has been developed and optimised. Rearrangement occurs in good yield and excellent stereoselectivity in a wide range of thiocarbamate substrates. Various substitution patterns are tolerated on the migrating aryl ring, the benzylic aryl ring and on the benzylic carbon centre. Extension of this methodology has incorporated an asymmetric alkylation of achiral benzylic thiocarbamates as a method of preparing aryl migration substrates. This allows the asymmetric synthesis of tertiary thiols in 2 steps from simple achiral precursors. Aryl migration has also been found to occur in lithiated allylic thiocarbamates with high stereospecificity, allowing preparation of a wider range of tertiary thiols. 6 Declaration No portion of the work referred to in this thesis has been submitted in support of an application for another degree or qualification at this or any other university or institute of learning. Copyright Statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns any copyright in it (the “Copyright”) and he has given The University of Manchester the right to use such Copyright for any administrative, promotional, educational and/or teaching purposes. ii. Copies of this thesis, either in full or in extracts, may be made only in accordance with the regulations of John Rylands University Library of Manchester. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. iii. The ownership of any patents, designs, trade marks and any and all other intellectual rights except for the Copyright (the “Intellectual Property Rights”) and reproductions of copyright works, for example, graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and exploitation of this thesis, the Copyright and any Intellectual Property Rights and/or Reproductions described in it may take place is available from the Head of School of Chemistry (or the Vice President). 7 Acknowledgements I would like to thank Prof. Jonathan Clayden for the opportunity to work within his group for these 3 years. I’m also grateful for his invaluable guidance and advice in all aspects of my work. The technical staff at the University of Manchester have made an essential contribution to this project. My thanks go to Dr. Madeleine Helliwell for the crystal structure and Barbara, Roger and Ian for their NMR assistance. Val, Gareth and Rehana in mass spec. have been remarkably helpful, efficient and cheerfully patient with my more stubborn samples, for which I am very thankful. And, in particular, thanks to Rehana for the magic she performs with a tiny spanner and a bit of plastic tubing in front of the most backward HPLC machine this side of Windows 95. This thesis has been proof-read in whole by Dan and in parts by Heloise, Beckii, Sharon, Rob, Julie and Julien. Thanks for the help and for showing me how good proof-reading can be inspirational. I’ve had the good fortune to work alongside many wonderful people during my time in Manchester. Firstly, I’d like to thank Marju Laars for her contribution to the study of allylic thiocarbamates. My thanks go to the residents of the small lab – Heloise, Beckii, Dan, Julie, Steve R and Jemma – for making the first year of this project so enjoyable. Thanks also to Uli, Jordi, Steve, Alex, Alberto, Gilles, Laurent, Morgan, Rob, Abby, Simon, Senior, Olga, Anne, Julien, James, Mike, Nadia, Gaelle, Edmund, Dan F, Simon, Nicole, Nelson, Ole, Thomas, Erik, Alexis, Michele and Jamie. I am a better chemist for working alongside these people; their friendship and help has been invaluable during both good times and Radio 1. I would not have been able to undertake this project without the support of my parents, family, adoptive family (Em, Bek, Michelle and Andy) and friends. I thank God for their love, support and attempts to keep me grounded. Finally, thanks to my wife, Nic, who didn’t laugh when I said I’d like to do a PhD and didn’t blink when I asked if she’d move to Manchester. She is truly half of me. Any accomplishment I have made is as much a result of her dedication as of mine. 8 Abbreviations and conventions °C degrees Celsius Ac acetyl aq. aqueous Ar aryl Bn benzyl Boc tert -butoxycarbonyl Box 1,3-benzooxazole BoxSH 2-sulfanyl-1,3-benzooxazole Btz 1,3-benzothiazole BtzSH 2-sulfanyl-1,3-benzothiazole Bu butyl BuLi butyllithium calc. calculated cat. catalytic CDI carbonyl diimidazole cm 3 millilitres Cy cyclohexyl Cp cyclopentadienyl δ chemical shift (parts per million) d day(s) dba dibenzylideneacetone DBBQ 2,6-di-tert -butyl-1,4-benzoquinone DCM dichloromethane DEAD diethylazodicarboxylate DIAD diisopropylazodicarboxylate DIBAL-H diisobutylaluminium hydride DIPA diisopropylamine DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMPU N,N'-dimethylpropyleneurea DMSO dimethylsulphoxide dr diastereomeric ratio E electrophile er enantiomeric ratio 9 EI electron impact (positive ionisation) equiv.