New substrates and catalysts for reactivity and sustainability in catalytic sulfination

该项目属于EPSRC合成有机化学研究领域。含有磺酰（- so2 -）基团的分子，包括砜、磺酰胺、磺酸酯和磺酰氟，由于它们赋予分子独特的物理化学性质，在医药和农业化学中变得越来越重要。它们的制备方法有许多，如二硫化物氧化或磺酰氯反应。这些方法存在氧化条件官能团相容性差、有气味的硫醇和二硫化物是不利的起始材料以及磺酰氯的不稳定性等问题。现代合成含磺酰基官能团的方法主要集中在二氧化硫的固定上；一种廉价的原料化学品，用于生成亚硫酸盐，一种稳定和通用的中间体，可用于生成各种含磺基的官能团。与处理有毒、恶臭气体有关的问题促使威利斯集团开发了电荷转移复合物DABCO-(SO2)2 (DABSO)，它可以用作二氧化硫的替代品。已经开发了许多利用DABSO生成亚硫酸盐的新方法，包括使用有机金属试剂的方法，或使用芳基卤化物的催化方法，然而，这些方法在可用底物的多样性方面也受到限制，因为两者都需要卤化物作为起始材料，并且催化方法仅用于芳基底物的亚磺化。这项研究的重点将是开发新的方法，使更广泛种类的底物亚化，特别侧重于生成烷基亚磺酸盐。在我们的初步工作中，我们探索了烷基胺和亚化化学的底物。Katritzky吡啶盐可以很容易地从胺中制备，并且由于它们能够在温和的条件下产生不稳定的烷基自由基而引起了最近的研究兴趣。文献表明，烷基自由基可以攻击SO2生成磺酰自由基，磺酰自由基可以被电子贫乏的烯烃捕获生成砜。我们设想使用Katritzky盐，我们可以生成磺酰自由基，随后在反应条件下被还原，从而生成亚磺酸烷基。我们成功地开发了由仲烷基胺通过Katritzky吡啶盐中间体生成烷基亚磺酸盐的条件，模型底物的产率达到80%。我们将优化条件，使伯烷基胺的使用成为可能，并随后评估反应的范围。我们还将探索与亚砜胺试剂（SO2的偶氮类似物）反应条件的适用性，以生成烷基磺酰酰（- sno -）衍生的官能团。本项目还将探索其他底物类别，包括羰基衍生物，如酰基氟化物、氧化还原活性酯和脱羧/脱羧催化体系中的羧酸，以进一步使适合亚化的底物种类多样化，从而提高亚化过程的可持续性和多功能性。总之，该项目将扩大可进行亚砜化的底物范围，改善获得与医药和农化相关的磺酰基和磺酰基官能团的机会。

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.