Radical mediated reactions of dithiocarbamates by Claire McMaster A thesis submitted to The University of Birmingham For a degree of Doctor of Philosophy School of Chemistry University of Birmingham September 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Acknowledgments First of all, I would like to thank Dr. Richard S. Grainger for all his support, advice and guidance throughout my PhD. I am also extremely grateful to Dr. Robert N. Bream, my industrial supervisor for his suggestions and help. Thank you to all the past and present members of the Grainger group. A special thanks to Bene, Bhaven and Tyrone for keeping me entertained from the beginning and also to Marie, Kevin and Carlotta for your proof reading skills and generally making me smile. I would also like to thank everyone who I worked with during my time at GSK. Thanks to the analytical staff at the University of Birmingham for their advice and assistance; Dr. Neil Spencer for NMR and Pete Ashton and Nick May for mass spectrometry. I am eternally grateful to all my friends for keeping me focused and happy and always being there to provide me with everything I need, whether it be support, hugs or bacon. Rob, Mez, JD, Jamie, Dan and the rest of the mazers, I love you all and I couldn’t have done it without you. Finally I would like to thank my family for having faith in me throughout the years. Mum, Dad, Sarah and Skye, you have all helped make this possible. Abstract Acyl radicals are versatile intermediates in organic synthesis. Methods for the generation of acyl radicals, which lead to the prior use of acyl dithiocarbamates within the Grainger group for the synthesis of functionalized 1-oxochroman-4-ones, are reviewed (Chapter 1). This work has been extended to studies which have shown that the 6-exo trig acyl radical cyclisation pathway adopted can be diverted to a formal 7-endo trig pathway through appropriate substitution on the alkene acceptor. Acyl xanthates are shown to behave differently to acyl dithiocarbamates in this respect. Substituted tetrahydrobenzoazepines and tetrahydroquinolines can also be prepared through appropriate nitrogen tethers. Methodology for the reductive removal of the dithiocarbamate group under neutral conditions has been developed (Chapter 2). Hypophosphorus acid and triethylamine in refluxing dioxane has been shown to reduce primary and secondary dithiocarbamates in good yield. Deuterium incorporation occurs using D3PO2. Anomeric dithiocarbamates are reduced with varying amounts of neighbouring O-acyl group migration, depending on conditions. Twisted amides display properties distinct from those of regular amides due to the lack of delocalisation between the nitrogen lone-pair and the carbon-oxygen double bond. A new approach to the synthesis of bridged twisted amides is investigated, based on a transannnular carbamoyl radical cyclisation – dithiocarbamate group transfer reaction (Chapter 3). Stemofoline is a structurally complex, biologically active alkaloid of the Stemona family. Previous routes towards the synthesis of stemofoline and related compounds are reviewed (Chapter 4). Attempted formation of a dithiocarbamate-containing precursor for a tandem 7-endo-trig cyclisation - 5-exo-trig transannular cyclisation - group transfer reaction to give the azatricyclic core of stemofoline is discussed. An alternative route towards an azabicyclic fragment of stemofoline via an intermolecular cyclisation has also been investigated. Abbreviations Å Angstrom Ac acetyl ACCN 1,1'-azobis(cyclohexanecarbonitrile) AIBN 2,2’-azobisisobutyronitrile aq aqueous Bn benzyl Boc t-butoxycarbonyl b.p. boiling point br broad BTEAC benzyltriethylammonium chloride °C degrees Celsius cat. Catalytic cm centimetres d doublet DBU 1,8-diazabicyclo[5.4.0]undecene DCC dicyclohexylcarbodiimide DCE dichloroethane DDQ 2,3-dichloro-5,6-dicyanobenzoquinone DLP dilauroyl peroxide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ee enantiomeric excess EI electron impact equiv. equivalent ESI electrospray ionisation FT-IR fourier transform infrared g gram(s) h hours HMBC heteronuclear multiple bond correlation HRMS high resolution mass spectrometry HSQC heteronculear single quantum coherence Hz Hertz i iso IBX 2-iodoxybenzoic acid In• initiator radical IR infrared J coupling constant (in Hz) kJ kilojoules LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide m multiplet M molar MAP 4-methoxyacetophenone mCPBA meta-chloroperbenzoic acid min minute(s) mL millilitres mol moles MOM methylmethoxy ether mp melting point m/z mass/charge n normal nm nanometre NMR nuclear magnetic resonance P para pet ether petroleum ether (40-60 °C) ppm parts per million Pr propyl q quartet qn quintet quant. quantitative R• radical Rf Retention factor RT room temperature s singlet sat. saturated t tertiary t triplet TBAT tetrabutylammonium triphenydifluorosilicate TBS tert-butyldimethylsilyl TEMPO 2,2,6,6-tetramethylpiperidine-1-oxy Tf trifluoromethanesulfonyl TFA trifluoroacetic acid TIPS triisopropylsilyl THF tetrahydrofuran THP tetrahydropyranyl TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl Tol toluene Ts para-toluenesulfonyl UV ultraviolet W Watt Contents Chapter one: Acyl radicals from dithiocarbamate precursors 1 1.1 Introduction to Radical Chemistry 2 1.2 Introduction to Acyl Radicals 4 1.3 Generation of Acyl Radicals 6 1.4 Acyl Radicals from Xanthates 9 1.5 Generation of Carbamoyl Radicals 14 1.5.1 1-carbamoyl-1-methylcyclohexa-2,5-dienes 15 1.5.2 Oxime Oxalate Amides 17 1.5.3 Cobalt Salophens 19 1.5.4 Selenium Carbamates 20 1.5.5 Dithiocarbamates 21 1.6 Cyclisation of 6-Heptamoyl Radicals 25 1.7 Synthesis of Acyl Dithiocarbamates 28 1.7.1 Intermolecular Reactions of Acyl Dithiocarbamates 30 1.7.2 Intramolecular Reactions of Acyl Dithiocarbamates 30 1.8 Aims and Objectives 34 1.9 Results and Discussion 36 1.9.1 Intramolecular Cyclisations of Acyl Dithiocarbamates 36 1.9.2 Intramolecular Cyclisations to form Nitrogen Containing Heterocycles 44 1.10 Conclusion 51 Chapter two: Radical-mediated reduction of the dithiocarbamate group 53 2.1 Dithiocarbamate Transformations 54 2.1.1 Dithiocarbamate Oxygen Exchange Reactions 54 2.1.2 Elimination of Dithiocarbamates to Alkenes 55 2.2 Previous Reports of Reduction of Dithiocarbamates 56 2.3 Barton-McCombie Reaction 58 2.4 Extensions to Barton-McCombie Type Deoxygenations 64 2.5 Aims and Objectives 70 2.6 Developments of Conditions for Reduction 71 2.6.1 Initiation Using Light Sources 71 2.6.2 Chemical Initiation 74 2.7 Substrate Scope 79 2.8 Deuterium Incorporation 90 2.9 Conclusion 94 Chapter three: Twisted amides 95 3.1 Introduction to Twisted Amides 96 3.2 Bredt’s Rules 97 3.3 Synthesis of 2-quinuclidone 99 3.4 Penicillin 101 3.5 Synthesis of Other Twisted Amides 102 3.6 The Most Twisted Amide 105 3.7 Medium-Bridged Twisted Amides 111 3.8 Wolff-Kishner Reduction of Twisted Amides 121 3.9 Twisted Amides Derived From Trögers Base 123 3.10 Synthesis of Twisted Amides by Transannular Cyclisation 125 3.11 Aims and Objectives 129 3.12 Results and Discussion 130 3.12.1 Synthesis of the Radical Cyclisation Precursor 130 3.12.2 Radical Reactions Towards Twisted Amides 132 3.12.3 Reactions Towards Larger Twisted Amide 138 3.13 Conclusion 141 Chapter four: Stemofoline 143 4.1 Stemona Alkaloids 144 4.2 Stemofoline: General Overview 145 4.3 Synthesis of Stemofoline and Related Alkaloids 146 4.3.1 Kende’s Work Towards Stemofoline 146 4.3.2 Smith’s Synthesis of 2-Substituted Pyrrolidines 151 4.3.3 Gin’s Work Towards Stemofoline Alkaloids 154 4.3.4 Overman’s Synthesis 161 4.3.5 Thomas’ Approaches Towards Stemofoline 167 4.3.6 Martin’s Work Towards Stemofoline 175 4.4 Previous Work in the Grainger Group Towards Stemofoline 180 4.5 Aims and Objectives 187 4.6 Studies Towards the Tricyclic System 188 4.6.1 Horner-Wadsworth-Emmons Approach 188 4.6.2 Cross-Metathesis Approach 191 4.6.3 Sulfur Cross-Metathesis Approach 195 4.6.4 Mannich Reaction Approach 196 4.7 Studies Towards the Bicyclic System 199 4.8 Conclusion 205 Chapter five: Experimental 206 Chapter six: References 306 Chapter one Acyl Radicals from Dithiocarbamate Precursors 1 1.1 Introduction to Radical Chemistry Radicals were first discovered in the early 20th century1 and since the initial work a great deal of interest has been shown in radical chemistry. However it was not until the 1970s that the potential of radicals in synthetic chemistry was appreciated,2 as initially they were thought to be uncontrollable. Radical chemistry is often used to form C-C bonds, making it synthetically interesting. This approach has been used to form cyclic systems as the reaction is energetically favourable; the lower energy π C-C bond (226 kJmol-1) is replaced by a higher energy σ C-C bond (368 kJmol-1). A wide variety of substrates can be cyclised leading to products of anything from 4 to 18 membered rings (Scheme 1).3 Multiple ring systems can also be generated in this fashion. Scheme 1 Radical intramolecular cyclisations Intermolecular C-C bond formation using radical chemistry is also possible and widely used.4 Intramolecular reactions generally proceed at a faster rate than their corresponding intermolecular reactions due to favourable entropy considerations. In general, radical chemistry can be considered advantageous for many reasons.