On the Knorr synthesis of 6-bromo-4-methylquinolin-2(1H)-one

Nicolas Wlodarczyk (1) , Catherine Simenel (2) , Muriel Delepierre (2) , Jean-Christophe Barale (3) , Yves Louis Janin (1)

1 Chimie Organique
2 Résonance Magnétique Nucléaire des Biomolécules
3 Immunologie moléculaire des parasites

In the course of our work on infectious diseases, we were led to prepare 6-bromo-2-chloro-4-methylquinoline as a starting material. Since surprisingly little has been reported in the literature, the two synthetic steps to this compound were investigated. The synthesis involves a condensation between -ketoesters and 4-bromoaniline and the cyclization of the resulting anilides into 6-bromoquinolin-2(1H)-one otherwise known as the Knorr reaction. The 1H NMR monitoring of the first step allowed us to optimize the conditions leading specifically to the anilide without the occurrence of the alternative crotonate. To illustrate the scope of our finding, few additional anilides featuring electron attracting groups were prepared. The study of their cyclization revealed some unsuspected steric effect governing this second step. Aside from rectifying few claims in this chemistry, this study led to a three-step preparation of 6-bromo-2-chloro-4-methylquinoline in a 48 % overall yield from 4-bromoaniline.

Keywords: acylation; cyclization; heterocycles; quinolines; carbocation

Domains: Chemical Sciences; Organic chemistry

Nicolas Wlodarczyk, Catherine Simenel, Muriel Delepierre, Jean-Christophe Barale, Yves Louis Janin. On the Knorr synthesis of 6-bromo-4-methylquinolin-2(1H)-one. Synthesis: Journal of Synthetic Organic Chemistry, 2011, 6, pp.934-942. ⟨10.1055/s-0030-1258440⟩. ⟨pasteur-00584423⟩