Alkylation of 2- and 3-alkoxycarbonyl-4-quinolinones. DFT study on the regioselectivity

Abstract The reaction of 2-alkoxycarbonyl-4-quinolinones ( 1 ) with a variety of alkylating reagents under different conditions, lead to the corresponding O -alkylated products. The behavior in basic medium of compounds 1 differs from the 3-alkoxycarbonyl-4-quinolinones ( 4 ) isomers suggesting that the position of the carboxylate group determines the regioselectivity of the reaction. DFT calculations allow us to conclude that for 3-alkoxycarbonyl-4-quinolinones, the N- alkylation would be thermodynamically and kinetically favored. But for 2-alkoxycarbonyl-4-quinolinones the side chain in the 2-position of the ring prevents the planar approximation to the contiguous heteroatom leading to a more favorable O - alkylation transition state. Crystal structure of an O -alkylated product is determined by single crystal X-ray diffractometry.