Conrad-Limpach and Knorr Reactions

Primary arylamines and p-ketoesters react in the presence of strong acid to provide 2-quinolones (Knorr reaction), whereas their thermal reaction yields 4-quinolones (Conrad-Limpach reaction). These reactions present a typical example of kinetic versus thermodynamic control, which has been employed in the synthesis of many quinolone derivatives for more than a century. 

Different reaction mechanisms are postulated for die synthesis of 2-or 4-quinolone derivatives. The Knorr reaction involves a nucleophilic attack of aniline nitrogen on the ester of P-ketoester component, providing anilide, which undergoes Friedel-Crafls cyclization followed by dehydration with sulfuric acid to yield 2-quinolones. On die other hand, a completely different pathway is involved in the case of Conrad-Limpach reaction. Condensation of aniline derivative with P-ketoester provides the corresponding enamino-ester. Enolization was followed by a 67c-electrocyclization reaction to form a 4-quinolone. A postulated alternative reaction padiway invokes the formation of an iminoketene prior to the cyclization step. 

Both reactions are promoted by electron-donating groups on the aromatic ring following the mechanisms described above. 

Some applications of the described reactions include the preparation of chloroquine, an important anti-malarial, which is made by reacting 4,7-dichloroquinoline with 4-diethylamino-l-methylbutylamine at 180 °C. 7-Chloro-4-hydroxyquinoline, a precursor of 4,7-dichloroquinoline, was routinely prepared by heating 3-chloroaniline with the ethyl ester of formylacetic acid, through the Conrad-Limpach quinoline synthesis.  

The same method was also used for the synthesis of the anti-malarial compound mefloquine. Heterocyclization of 2-trifluoromethylaniline with trifluoroacetic acid ethyl ester provides 2,8-6w-(trifluoromethyl)-4-hydroxyquinoline. Bromination with phosphorous tribromide, followed a carbon monoxide introduction, affords 2,7-trifluoromethyl-4-carboxylic acid quinoline. Amide formation and pyridine reduction completes the synthesis providing mefloquine in high yields.  

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The Simonis chromone synthesis and the Pechmann-Duisberg reaction can be considered as O-analogs of the Conrad-Limpach and Knorr reactions for the preparation of quinolines from the corresponding aniline. ... 

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