Knorr 2-quinolone

Quinolones are obtained in the Conrad-Limpach-Knorr synthesis, which is subject to either kinetic or thermodynamic control, when aniline is reacted with a 3-keto ester (Scheme 3.11a). At room temperature the more reactive keto group combines with the aniline nitrogen atom, leading to an enamino ester the kinetic product. Cyclization of this product to a 4-quinolone requires heating at 250 C. 

C.S. Cooper and co-workers synthesized several quinolones containing five- and six-membered heterocyclic substituents at the 7-position and tested their antibacterial activities. The 1,4-diketone substrate was prepared via the oxidative coupling of isopropenyl acetate and an acetophenone derivative. The Paai-Knorr furan synthesis was conducted in the presence of p-TsOH. 

Primary arylamines and p-keto esters condense in the presence of strong acids to form 2-quinolones Knorr synthesis) via P-keto anilides (e.g. 78). A thermal reaction involving p-anilinoacrylic esters (e.g. 79) yields 4-quinolones (Konrad-Limpach synthesis). ... 

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. 

When P-ketoesters are reacted with primary aromatic amines, product formation is dependent on the reaction conditions. In the presence of strong acids, P-ketoaniUdes 98 are formed, which undergo cyclization to 2-quinolones (Knorr synthesis). When the reaction is carried out thermally, P-aminoacrylates 99 are the primary products, which cyclize to give 4-quinolones (Konrad-Limpach synthesis) ... 

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