Highly regioselective synthesis of 7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-5-carboxylate derivatives under mild conditions

7-Oxo-7H-1,3,4]thiadiazolo3,2-a]pyrimidine-5-carboxylate derivatives are biologically and pharmacologically useful heterocycles. An efficient synthetic methodology for this class of compounds was developed through catalyst-free, one-pot reactions between 2-aminothiadiazoles and dimethyl acetylenedicarboxylate (DMAD) in THF with the aid of ultrasound irradiation. The reactions show applicability to a wide range of substrates and high regioselectivity for the “7-one” products over their “5-one” isomers. Detailed reaction mechanisms were mapped out by theoretical modeling analysis based on density functional theory (DFT) calculations. Mechanistic studies indicate that the favored reaction pathway involves a sequence of hydrogen-bond directed Michael addition, synergistic proton transfer/five-membered ring opening, and intramolecular cyano hetero-Diels-Alder reactions.