Gould–Jacobs reaction

Specifically, 4-quinolinol can be synthesized. In this reaction aniline or an aniline derivative first reacts with malonic acid derivative ethyl ethoxymethylenemalonate with substitution of the ethoxy group by nitrogen. A benzannulation takes place by application of heat to a quinoline. The ester group is hydrolysed by sodium hydroxide to the carboxylic acid and decarboxylation again by application of heat to 4-hydroxyquinoline.

Extension of the Gould-Jacobs approach can prepare unsubstituted parent heterocycles with fused pyridine ring of Skraup type (see Skraup reaction).

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Mechanism

The mechanism for the Gould–Jacobs reaction begins with a nucleophilic attack from the amine nitrogen follows by the loss of ethanol to form the condensation product. A 6 electron cyclization reaction with the loss of another ethanol molecule forms a quinoline (ethyl 4-oxo-4,4a-dihydroquinoline-3-carboxylate). The enol form can be represented from the keto form through keto-enol tautomerism. Protonation of the nitrogen forms ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate.