Modular and divergent synthesis of 2, N 3-disubstituted 4-quinazolinones facilitated by regioselective N -alkylation

• Published in: Organic & biomolecular chemistry 2024-06, Vol.22 (24), p.4940-4949
• Main Authors: Kim, Kelly E, Comber, Jason R, Pursel, Alexander J, Hobby, Grant C, McCormick, Carter J, Fisher, Matthew F, Marasa, Kyle, Perry, Benjamin
• Format: Article
• Language: English
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/d4ob00564c

The synthesis of a biologically relevant 2-amino- 3-alkylamido 4-quinazolinone has been accomplished in four steps from commercially available materials using design principles from both modular and divergent synthesis. 3-Alkylation of 2-chloro-4(3 )-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 -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 3-alkylamido substituents. These efforts highlight the reciprocal influence of C2 and 3 substitution on functionalization at either position, establish an effective synthetic pathway toward 2, 3-disubstituted 4-quinazolinones, and enable preliminary bioactivity studies while providing an experiential learning opportunity for undergraduate student researchers.