Modular and divergent synthesis of 2,N3-disubstituted 4-quinazolinones facilitated by regioselective N-alkylation†

Abstract

The synthesis of a biologically relevant 2-amino-N3-alkylamido 4-quinazolinone has been accomplished in four steps from commercially available materials using design principles from both modular and divergent synthesis. N3-Alkylation of 2-chloro-4(3H)-quinazolinone using methyl bromoacetate, followed by C2-amination produced a suitable scaffold for introducing molecular diversity. Optimization of alkylation conditions afforded full regioselectivity, enabling exclusive access to the N-alkylated isomer. Subsequent C2-amination using piperidine, pyrrolidine, or diethylamine, followed by amide bond formation using variously substituted phenethylamines, generated fifteen unique 4-quinazolinones bearing C2-amino and N3-alkylamido substituents. These efforts highlight the reciprocal influence of C2 and N3 substitution on functionalization at either position, establish an effective synthetic pathway toward 2,N3-disubstituted 4-quinazolinones, and enable preliminary bioactivity studies while providing an experiential learning opportunity for undergraduate student researchers.