Parallel Synthesis of Drug-like 5-Amino-Substituted 1,2,4-Thiadiazole Libraries Using Cyclization Reactions of a Carboxamidine Dithiocarbamate Linker

Abstract

A general method has been developed for the solution-phase parallel synthesis of various drug-like 5-amino-substituted 1,2,4-thiadiazole derivatives, which employs initial cyclization reaction of carboxamidine dithiocarbamate 2 with p-toluenesulfonyl chloride. The carboxamidine dithiocarbamate 2 was produced by a three-component nucleophilic substitution reaction between carbon disulfide, benzamidine 1, and benzyl chloride. The key intermediate in this sequence, 5-(benzylsulfanyl)-3-phenyl-1,2,4-thiadiazole (3), is then transformed to the desired 5-amino-substituted 3-phenyl-1,2,4-thiadiazoles 6 in good yields and purities via oxidation of the sulfide group to form the corresponding sulfone followed by substitution reactions with various amines.