The metal-free synthesis of poly-substituted pyrrole-2-ones under solvent-free conditions is employed. This green protocol proceeds in the presence of an additive, generating CO2 as a by-product. Further molecular docking studies are carried out against LSDI, exhibiting strong critical interactions for therapeutic studies.

Abstract

A catalyst-free, solvent-free, one-pot synthesis of polysubstituted pyrrol-2-ones has been developed via the decarboxylative coupling of α-keto acids, arylamines, and dimethyl acetylenedicarboxylate (DMAD). This green protocol proceeds under mild conditions (80 °C, air) with oxalic acid as an additive, affording products in excellent yields (up to 94%) and broad substrate scope, including electron-rich and electron-deficient phenyl glyoxylic acids and anilines. Mechanistic studies reveal a cascade involving imine formation, enamine intermediate generation, and intramolecular cyclization, supported by isolation of key intermediates (e.g., dimethyl 2-(phenylamino) fumarate). The synthetic utility was further highlighted by molecular docking studies against LSD1 (lysine-specific demethylase 1), a target in epigenetic cancer therapy. Among 20 derivatives, compounds 4b, 4l, 4n, 4p, and 4s exhibited strong binding affinities (−8.14 to − 9.56 kcal/mol), forming critical interactions with active-site residues (e.g., His564, Glu559, and Phe538). ADMET predictions confirmed favorable drug-likeness for top candidates, despite minor Lipinski's rule violations due to higher molecular weights. This work presents an eco-compatible route to bioactive pyrrol-2-ones and identifies promising scaffolds for LSD1 inhibition, bridging synthetic efficiency and therapeutic potential.