Abstract
Sulfur-containing functional groups are present in a myriad of FDA-approved pharmaceuticals, naturally occurring bioactive and agrochemical-relevant molecules. As a result, the expansion of synthetic methodologies for their construction is warranted. In particular, this doctoral study was aimed at developing versatile, safer, scalable, easy-to-operate, and sustainable synthetic protocols of N-acyl carbamothioate and N-acyl urea derivatives. Crucial to this study is the incorporation of sulfur using isothiouronium salts derived from widely available alkyl electrophiles and thiourea, eliminating the need to use free thiols due to their undesirable traits such as foul odour, instability and limited commercial availability. The synthesis of N-acyl carbamothioates (Chapter II) was achieved using N-(acyloxy)-phthalimides derived from carboxylic acids. This comes as an advantage in addition to the utility of isothiouronium, given that carboxylic acids are easily accessible chemical feedstocks. In this Chapter, it was demonstrated that such N-acyl carbamothioates can be accessed at room temperature in one hour without robust purification of the starting materials. Additionally, the synthetic utility of the developed protocol was demonstrated via a two-step, one-pot telescoped process, only requiring solvent evaporation after the formation of N-(acyloxy)-phthalimides. Finally, the utility of acid anhydrides as an alternative to the phthalimides further generalised the developed protocol and improved atom economy. This is in line with the United Nations Sustainable Development Goals (SDG) 12, which supports the design of safer and more sustainable chemical processes with minimal waste (i.e., atom efficiency). In Chapter III, isothiouronium salts in combination with carbamoyl chlorides successfully delivered sulfur-substituted N-acyl urea derivatives under mild reaction conditions (40 °C). Interestingly, it was demonstrated that this transformation could be achieved as a three-component system (alkyl halide, thiourea, and carbamoyl chloride), eliminating the need for prior preparation of isothiouronium salts, as these were generated in situ. Alkyl alcohols, which are also easily accessible chemical feedstocks and can be derived from renewable biomass, were also demonstrated as effective precursors for the replacement of alkyl halides, highlighting the robust nature of this protocol. Furthermore, as part of the mechanistic elucidation, pre-formed salts reacted efficiently, while also providing solutions to the identified limitations of this protocol (the use of long straight-chain alkyl halides such as 1-bromodecane and 1-bromohexadecane). Overall, the general protocols (Chapter II and Chapter III) developed furnished the desired products with up to quantitative yields. Moreover, these protocols were suitable for up-scale synthesis, demonstrating their possible suitability for an industrial setting. The proposed reaction mechanisms highlight the crucial role of the base, which is presumably responsible for the deprotonation of the ...