Synthesis, characterization, and DFT study of a novel pyrido[2',3':4,5]pyrimido[2,1-b][1,3]thiazines via Michael addition and intramolecular cyclization

Two novel series of pyrido[2',3':4,5]pyrimido[2,1-b][1,3]thiazine-3-carbonitriles and ethyl pyrido[2',3':4,5]pyrimido[2,1-b][1,3]thiazine-3-carboxylates were synthesized from a key intermediate 2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one via its reactions with arylidene malononitriles and ethyl 2-cyano-3-arylacrylates, respectively. The target compounds were synthesized through Michael addition followed by intramolecular cyclization, and their structures were confirmed by IR, NMR, MS, and elemental analyses. Density Functional Theory calculations using the B3LYP functional were employed to evaluate Frontier Molecular Orbitals and conceptual DFT reactivity descriptors for selected reactants and products, enabling assessment of stability/reactivity trends and providing a rationale for the observed regioselectivity. Comparisons of nucleophilicity/electrophilicity, global hardness/softness, and total energies supported the preferential formation of the linear pyridopyrimidothiazine frameworks over the corresponding annular isomers, in agreement with the experimental outcomes.