Microwave-Assisted Diastereospecific Skeletal Recasting of the Thiazolo[3,2-a]pyrimidine Scaffold via a Domino Process

Abstract

A microwave-assisted, pyridine-catalyzed domino reaction of 2-arylmethylidenethiazolo[3,2-a]pyrimidines with methanol is reported. This transformation proceeds through an unprecedented mechanism involving pyridine-initiated thiazolidine ring opening followed by stereospecific cyclization, leading to architecturally complex 3,5-diaryl-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylates. The reaction is operationally simple, tolerates a wide range of aromatic substituents (18 examples, 90–97% yield), and affords the products as single diastereomers with complete stereocontrol (2R-,3S-,5S- and 2S-,3R-,5R-), as established by X-ray crystallography and NMR spectroscopy. The synthetic utility is further demonstrated by selective hydrolysis of the C2 ester group, providing previously inaccessible thiazolopyrimidine-2-carboxylic acids (12 examples, 53–70% yield). This work introduces a new skeletal-recasting paradigm for privileged heterocycles, enabling rapid access to stereochemically dense molecular architectures that are otherwise difficult to obtain.