Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives

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Murphy, Chloe C.
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University College Cork
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Highly functionalised a-thio-b-chloroenones are extremely useful synthetic intermediates. Their formation through a N-chlorosuccinimide (NCS) mediated chlorination cascade is a powerful synthetic methodology which transforms an unreactive sp3 b-carbon into a highly reactive sp2 b-carbon.a-Thio-b-chloroenones have the potential to act as Michael acceptors, dienophiles, and dipolarophiles, and can undergo Stille coupling making them highly versatile synthetic intermediates. They can also undergo sulfur oxidation enabling further functionalisation. The first chapter is a literature review of Stille coupling involving b-haloenone systems, including where this is embedded as a substructure, e.g. in aromatic systems, from 1996 onwards. The diversity of examples of the use of this transformation in the construction of complex natural products and other materials, including polymers, highlights the synthetic utility of this C–C bond forming reaction, and its robustness across a wide range of substrates. The results of the work carried out in this project are discussed in detail in chapter two. This includes the synthesis of novel a-thio-b-chloropropenones which, for the first time, incorporate substitution on the thiobenzyl ring. The b-chloropropenones form as a mixture of E and Z isomers, with the Z isomer predominating. This work was the first time that the E and Z isomers were separated and individually characterised. The scope of the chlorination cascade was also expanded to include a longer alkyl chain, thereby forming a library of novel a-thio-b-chlorobutenones and pentenones which contain a methyl or ethyl group in the b-position rather than hydrogen. While the b-chlorobutenones and pentenones also form as a mixture of E and Z isomers, a decrease in stereoselectivity is observed with the extended chain length, and the E isomer predominates. Chemoselective oxidation of the a-thio-b-chloropropenones, butenones and pentenones to the sulfoxide level was achieved using Oxone®. While all of the b-chloroenones formed both E and Z sulfoxide isomers, equilibration to the thermodynamically favoured E sulfoxide was observed for the chloropropenones. The reactivity of the b-chloroenones in nucleophilic addition/elimination reactions with nitrogen, oxygen, and sulfur nucleophiles, at both the sulfide and sulfoxide level, is described. Overall, reaction at the sulfoxide level was seen to be more efficient; furthermore the efficiency of nucleophilic addition decreased as the length of the alkyl chain increased. At the sulfide level of oxidation, it was noted that the Z isomer reacted faster than the E isomer. Of particular significance in this work is the synthesis of a series of novel chalcone derivatives which were prepared using Stille coupling. Six a-thiochalcones and five a-sulfinylchalcones synthesised in this work were accepted by the National Cancer Institute (NCI) for testing and were found to be extremely potent growth inhibitors. The third chapter details the experimental procedures used in this work and describes the spectroscopic details of all of the compounds synthesised in this body of work including full characterisation of all novel compounds.
a-thio-b-chloroenones , Stille coupling , Chalcones , Nucleophilic addition , Sulfur oxidation , Organosulfur chemistry
Murphy, C. C. 2020. Novel synthetic methodology employing organosulfur chemistry in the synthesis of chalcone derivatives. PhD Thesis, University College Cork.