A Three-Component Path to Amino Thiadiazoles and Amino Oxadiazoles via a Nitrilium Ylide

A novel multicomponent reaction to 2-amino-1,3,4-thiadiazoles has been developed using 5-substituted-1<i>H</i>-tetrazoles, amines, and TCDI as the key C═S donor. This modular process, inspired by the Huisgen reaction to obtain 1,3,4-oxadiazoles from acylated tetrazoles, proceeds via a key nitrilium ylide generated from tetrazole cycloreversion/nitrogen extrusion. This strategy allows for the rapid, facile, and scalable assembly of numerous 2-amino-1,3,4-thiadiazoles and 2-amino-1,3,4-oxadiazoles using CDI as a C═O donor, without the requirement for cross-coupling methodologies. The limitations to the amine scope were explored, and the developed reaction was showcased by the strategic modification of a nonsteroidal anti-inflammatory drug (NSAID), crisaborole.