New substrates and catalysts for reactivity and sustainability in catalytic sulfination

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This project falls within the EPSRC Synthetic Organic Chemistry research area.Molecules containing the sulfonyl (-SO2-) group, including sulfones, sulfonamides, sulfonate esters and sulfonyl fluorides, have become increasingly important within medicinal and agrochemistry due to the unique physicochemical properties they impart on the molecule. Many methods for their preparation are available, such as oxidation of disulfides or reactions of sulfonyl chlorides. These methods suffer from poor functional group compatibility of oxidation conditions, odorous thiols and disulfides being unfavourable starting materials and instability of sulfonyl chlorides.Modern methods for the synthesis of sulfonyl-containing functional groups focus upon the fixation of sulphur dioxide; an inexpensive feedstock chemical, to generate a sulfinate, a stable and versatile intermediate that can be used to generate a broad variety of sulfonyl-containing functional groups. Issues related to handling the toxic, odorous gas led to the Willis group developing the charge transfer complex DABCO-(SO2)2 (DABSO), which can be used as a sulfur dioxide surrogate. A number of novel methods have been developed utilising DABSO to generate sulfinates, including methods using organometallic reagents, or catalytic methods using aryl halides, however, these too are limited in the diversity of substrates available for use, as both require halides as starting materials, and catalytic methods have only been developed for sulfination of aryl substrates. The focus of this research will be to develop new methods allowing sulfination of a broader variety of substrates, with a particular focus on generating alkyl sulfinates. In our preliminary work, we explored alkyl amines and substrates for sulfination chemistry. Katritzky pyridinium salts can be readily prepared from amines, and have been of interest in recent research due to their ability to generate unstabilised alkyl radicals under mild conditions. In the literature, it had been shown that alkyl radicals can attack SO2 to generate a sulfonyl radical, which could then be trapped by electron-poor alkenes to generate sulfones. We envisaged that using Katritzky salts, we could generate the sulfonyl radical, which would subsequently be reduced under the reaction conditions, thus generating an alkyl sulfinate. We successfully developed conditions for the generation of alkyl sulfinates from secondary alkyl amines via a Katritzky pyridinium salt intermediate, achieving a good yield of 80% for the model substrate. We will optimise conditions to enable the use of primary alkyl amines, and subsequently assess the scope of the reaction. We will also explore the applicability of the reaction conditions for use with sulfinylamine reagents (aza-analogues of SO2) to generate alkyl sulfonimidoyl (-SNO-) derived functional groups.Other substrate classes will also be explored within this project, including carbonyl derivatives such as acyl fluorides, redox-active esters and carboxylic acids in decarbonylative/decarboxylative catalytic regimes, to further diversify the variety of substrates amenable to sulfination, and thus improve the sustainability of and versatility of sulfination processes.In summary, this project will improve the scope of substrates amenable to sulfination, improving access to medicinally and agrochemicially relevant sulfonyl and sulfonimidoyl functional groups.