Japp–Klingemann reaction

The Japp–Klingemann reaction is a chemical reaction used to synthesize hydrazones from β-keto-acids (or β-keto-esters) and aryl diazonium salts. The reaction is named after the chemists Francis Robert Japp and Felix Klingemann.


 * Japp-Klingemann Reaction Scheme.png

The hydrazone products of the Japp–Klingemann reaction are most often used as intermediates in syntheses of more complex organic molecules. For example, a phenylhydrazone product can be heated in the presence of strong acid to produce an indole via the Fischer indole synthesis.


 * Japp-Klingemann Fischer Indole Combination.png

If there is a leaving group elsewhere in the Japp–Klingemann product, the hydrazone instead can cyclize at that site via a substitution reaction to give a pyrazole. This process is a key part of the synthesis of pyraclofos and related compounds:



Reaction mechanism
To illustrate the mechanism, the Japp-Klingemann ester variation will be considered. The first step is the deprotonation of the β-keto-ester. The nucleophilic addition of the enolate anion 2 to the diazonium salt produces the azo compound 3. Intermediate 3 has been isolated in rare cases. However, in most cases, the hydrolysis of intermediate 3 produces a tetrahedral intermediate 4, which quickly decomposes to release the carboxylic acid 6. After hydrogen exchange, the final hydrazone 7 is produced.