Doebner quinoline synthesis

The Doebner reaction is a three component coupling of an aniline (1), pyruvic acid (2), and an aldehyde (3) to provide a 4-carboxyl quinoline (4). That product can be decarboxylated to furnish quinoline 5. 

In 1883, Bottinger described the reaction of aniline and pyruvic acid to yield a methylquinolinecarboxylic acid. He found that the compound decarboxylated and resulted in a methylquinoline, but made no effort to determine the position of either the carboxylic acid or methyl group. Four years later, Doebner established the first product as 2-methylquinoline-4-carboxylic acid (8) and the second product as 2- methylquinoline (9). Under the reaction conditions (refluxing ethanol), pyruvic acid partially decarboxylates to provide the required acetaldehyde in situ. By adding other aldehydes at the beginning of the reaction, Doebner found he was able to synthesize a variety of 2-substituted quinolines. While the Doebner reaction is most commonly associated with the preparation of 2-aryl quinolines, in this primary communication Doebner reported the successful use of several alkyl aldehydes in the quinoline synthesis. 

Doebner also found that under certain conditions (specifically cold ether), the result of the three-component coupling was not the quinoline but diketopyrrolidine 10.  

A possible mechanism is shown. Condensation of 6 and 3 provides 11, which can be attacked by the enol of 2 (12) to provide 13. Intramolecular condensation yields 16, which is then oxidized to 17. A common variant of the Doebner reaction involves first 

Alternatively, the pyruvic acid can first condense with the aldehyde. Addition of the aniline to the P-position of 18 provides the same intermediate (13), as above. The mechanism could be substrate dependent. 

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Pfium, D. A. Doebner Quinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 407—410. (Review). 

Unsaluraled aldehydes or ketones also condense with the amines in an acidic [2569, 2364, 3012] or basic [2361] medium some of these reactions are known by the names of their discoverers, for example, the Doebner-Miller synthesis [2364) or the Doebner quinoline synthesis [3214]. The latter needs neither acid nor base. 

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