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Synthesis 2011(6): 934-942  
DOI: 10.1055/s-0030-1258440
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

On the Knorr Synthesis of 6-Bromo-4-methylquinolin-2(1H)-one

Nicolas Wlodarczyka,b, Catherine Simenelc,d, Muriel Delepierrec,d, Jean-Christophe Baralee,f, Yves L. Janin*a,b
a Institut Pasteur, Laboratoire de chimie médicinale, Département de Biologie Structurale et Chimie, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
Fax: +33(1)45688404; e-Mail: yves.janin@pasteur.fr;
b CNRS, URA 2128, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
c Institut Pasteur, Unité de résonance magnétique nucléaire des biomolécules, Département de Biologie Structurale et Chimie, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
d CNRS, URA 2185, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
e Institut Pasteur, Unité d’immunologie moléculaire des parasites, Département de Parasitologie et de Mycologie, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
f CNRS, URA 2581, 28 rue du Dr. Roux, 75724 Paris cedex 15, France
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Publication History

Received 3 December 2010
Publication Date:
14 February 2011 (online)

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Abstract

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 β-keto esters 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 a few claims in this chemistry, this study led to a three-step preparation of 6-bromo-2-chloro-4-methylquinoline in 48% overall yield from 4-bromoaniline.

Key words

acylation - cyclization - heterocycles - quinolines - carbo­cation