In this study, we report a novel and efficient synthetic strategy for the construction of a fused bicyclic heterocyclic system with promising potential in medicinal chemistry. The synthesis begins with the reaction of ethyl bis(methylthio)methylene malononitrile with guanidine nitrate in the presence of potassium carbonate as a base, using dimethylformamide (DMF) as the solvent under reflux conditions. This reaction furnishes 2-amino-1,6-dihydro-6-imino-4-(methylthio)pyrimidine-5-carbonitrile as a key intermediate. Subsequent treatment of this intermediate with acetylacetone under acidic conditions initiates a Michael addition followed by a Robinson annulation, leading to intramolecular cyclization. This tandem sequence proceeds smoothly to afford the target compound, 4-imino-6,8-dimethyl-2-(methylthio)-4H-pyrimido1,2-apyrimidine-3-carbonitrile in excellent yield. The synthesized compound was characterized by various spectroscopic techniques including IR, NMR, and mass spectrometry confirming its proposed structure. Notably, the target molecule contains a replaceable methylthio (-SCH₃) group at the 2-position making it a versatile precursor for further functionalization. The reactivity of this compound was explored through its reactions with different nucleophiles, such as substituted aromatic amines, aromatic phenols, heterocyclic amines, and active methylene compounds to afford a series of novel derivatives in good to excellent yields. Overall, this synthetic approach offers a convenient, efficient, and versatile route to access pyrimido1,2-apyrimidine scaffolds which are of significant interest for the development of bioactive and pharmacologically relevant molecules.
Jadhav et al. (Sat,) studied this question.