One‐Pot, Solvent‐Free Construction of Polysubstituted Pyrrol‐2‐ones via α‐Keto Acid‐Arylamine‐DMAD Cascade C─C Coupling and Insights into LSD1 Enzyme Binding

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.