On the mechanism of the alkylation of quinoline and naphthyridine derivatives

Abstract

Ethylation studies on substituted 3-ethoxycarbonyl-4-oxo-quinolines and -naphthyridines as well as of the potassium salts of their enolates has revealed that the pathway suggested by Frank et al. for the alkylation of 4-quinolone with (Et₃O)PO, i.e., thermal rearrangement of an O- to N-alkyl product cannot be extended to this class of compound since no O-alkylated intermediates could be detected. The mechanism of the alkylation was revised and the site of attack was rationalised using Klopman's theorem and Pearson's HSAB (hard–soft acid–base) theory based on AM1 level semiempirical calculations. Our results suggest a nucleophile enolate intermediate, the alkylation of which can only lead to the N-alkylated product. In accordance with our calculations, the reactive enolates of the title compounds could be selectively transformed into the corresponding N-alkylated products. The selective formation of the N-alkylated product was explained by an analysis of the total charge distribution and frontier orbitals. The conclusions can be generalised for other alkylations.