Diastereoselective and green synthesis of novel Hexahydro Imidazo [1,2-a] pyrimidine, from Azlactones, Brimonidine and Clonidine

An efficient direct domino approach has been developed for the diastereoselective synthesis of novel hexahydroimidazo[1,2-a]pyrimidine-6-yl acetamides. This synthesis involves a domino Michael addition/cyclization reaction of azlactones with brimonidine (used as eye drops for treating open-angle glaucoma) and clonidine (used to treat high blood pressure and attention deficit hyperactivity disorder). The reaction is catalyzed by glacial acetic acid (GAA), which acts as a mild organocatalyst in a metal-free environment, adhering to green chemistry principles by utilizing green solvent (EtOH). Additionally, the transformation proceeds with an atom economy of 100%. The imidazo[1,2-a]pyrimidine moiety plays a crucial role as a benzodiazepine receptor agonist, antiviral, antibacterial, antifungal agent, and calcium channel blocker. This reaction has been performed for the first time, and all synthesized compounds are novel. Their structures were confirmed by single-crystal X-ray crystallography, as well as IR, 1 H NMR, 13 C NMR spectroscopy, and LCMS analysis. Surprisingly, this reaction was diastereoselective, yielding cis -imidazo[1,2-a]pyrimidines 4b–g and trans -imidazo[1,2-a]pyrimidines 6a-g in cyclocondensation reaction of brimonidine 1 or clonidine 2 with azlactones 3a-g , respectively.