Modular assembly of arenes, ethylene and heteroarenes for the synthesis of 1,2-arylheteroaryl ethanes

Abstract

The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, to address these limitations, we present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. We disclosed a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C–S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, our approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals. This study highlights the significance of radical polarity matching in designing selective multi-component couplings. De novo syntheses of 1,2-arylheteroaryl ethanes, key scaffolds in drug discovery, are challenging, typically relying on pre-functionalized synthons, harsh conditions and multi-step processes. Now a modular assembly of arenes, ethylene and heteroarenes yields diverse drug-like 1,2-arylheteroaryl ethanes, highlighting the importance of radical polarity matching in selective multi-component couplings.