Solid-Phase Synthesis of 1,3,4-Thiadiazole Derivatives via Desulfurative Cyclization of Thiosemicarbazide Intermediate Resin

Abstract

A 1,3,4-thiadiazole library was constructed by solid phase organic synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amido-5-amino-1,3,4-thiadiazole resin by the cyclization of thiosemicarbazide resin using p-TsC1 as the desulfurative agent, followed by the functionalization of the resin by alkylation, acylation, alkylation/acylation, and Suzuki coupling reactions. Both the alkylation and acylation reactions chemoselectively occurred at the 2-amide position of 2-amido-5-amino-1,3,4-thiadiazole resin and the 5-amine position of 2-amido5-amino-1,3,4-thiadiazole resin, respectively. Finally, these functionalized 1,3,4-thiadiazole resins were treated with trifluoroacetic acid in dichloromethane, affording diverse 1,3,4-thiadiazole analogs in high yields and purifies. The 1,3,4-thiadiazole analogs show a different distribution of physicochemical and biological properties compared with our previously constructed 1,3,4-oxadiazole and 1,3,4-thiadiazole libraries in a range of orally available drug properties.