Lipase-Catalyzed Promiscuous Reaction for the Synthesis of Pyrido[2,3-d]pyrimidine Scaffolds via One Pot Knoevenagel-Michael-Aromatization in Aqueous Ethanol.

Porcine pancreas lipase (PPL) has been used as an efficient green biocatalyst for the multicomponent synthesis of pyrido[2,3-d]pyrimidine derivatives and expanding the biocatalytic promiscuity of lipase in organic synthesis. This robust procedure involves the condensation of various aromatic aldehydes, malononitrile, and 6-amino-1,3-dimethyl uracil in a 1:1:1 molar ratio at 50°C, catalyzed by PPL in an equimolar mixture of water and ethanol (1:1, v/v). The influence of the reaction conditions, including enzyme origin, organic solvents, temperature, and the amount of biocatalyst on the reaction course, was examined. Notably, PPL displayed remarkable catalytic activity, enabling the synthesis of diverse pyrido[2,3-d]pyrimidine derivatives with good to excellent yields (77%-94%). A promiscuous lipase-catalyzed carbon-nitrogen bond formation is presented, accommodating a variety of aromatic aldehydes. This method exhibits several key advantages, including the use of environment-friendly solvents, a nontoxic biocatalyst, mild reaction conditions, straightforward workup procedures, and excellent product yields.