Reactivity of Diazo Carbonyl Compounds with Thioethers under Visible Light and Metal Catalysis to Access Bioactive Scaffolds: Application to Photoflow and Mechanochemistry

Abstract

Diazo compounds are highly valued in synthetic organic chemistry due to their broad reactivity and wide-ranging applications. They exhibit distinct reactivity towards metals as well as visible light. It is well known that diazo compounds form metal carbene intermediates with various transition metal catalysts. Over the years, we have explored the reactivity of donor-acceptor as well as acceptor-acceptor diazo compounds, focusing on the synthesis of structurally diverse diazo arylidene succinimides (DAS) and diazo pyrazolones (DIPOLs), as well as their tunable reactivity under different reaction conditions. We have systematically investigated diazo transformations under both metal and visible-light catalysis to synthesize useful bioactive scaffolds. Recognizing the challenges and significance of these compounds, we designed and developed biologically important maleimide-S linkages via a 1,3-H transfer followed by [2,3]-sigmatropic rearrangements. These processes involved the formation of sulfonium ylides as key intermediates, enabling the access of biologically relevant compounds. This work highlights the novel umpolung reactivity of DAS for distal C-H functionalization of thiocarbonyl compounds with controlled reactivity and selectivity. Additionally, we have demonstrated the mechanochemical Doyle-Kirmse reaction to access the corresponding allenes and demonstrated that the solid state reaction is safer in case these diazo compounds and they worked more efficiently than that of conventional homogeneous reaction conditions. On the other hand, diazo compounds derived from pyrazolones have been rarely reported in the literature under metal catalysis. In this study, we developed a novel protocol for the Stevens rearrangement of DIPOLs with thiocarbonyl compounds via ruthenium catalysis. This approach successfully demonstrated the unique reactivity of cyclic acceptor-acceptor DIPOLs, providing access to biologically important alkoxy pyrazoles and novel sulfonium ylides through the in-situ generation of sulfur ylides. Furthermore, for the first time we explored the photochemical Doyle-Kirmse reaction of acceptor-acceptor pyrazolones. Also, we have successfully demonstrated this reaction to synthesize homoallyl, bis-homoallyl, and pesticidal analogs. As an application, we have also performed a gram-scale reaction under photo-flow conditions.