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.^[1][2][3][4]

The Japp-Klingemann reaction

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.^[5][6]

The Japp-Klingemann reaction used to synthesize indoles

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.

The Japp-Klingemann reaction mechanism

References

1. ^  Japp, F. R.;Klingemann, F. Ber. 1887 20, 2942, 3284, 3398.
2. ^  Japp, F. R.;Klingemann, F. Ann. 1888, 247, 190.
3. ^  Phillips, R. R. Org. React. 1959, 10, 143.
4. ^  Reynolds, G. A.; VanAllan, J. A. Org. Syn., Coll. Vol. 4, p.633 (1963); Vol. 32, p.84 (1952). (Article)
5. ^  Bowman, R. E.; Goodburn, T. G.; Reynolds, A. A. J. Chem. Soc. Perkins Trans 1 1972, 1121. (doi:10.1039/P19720001121)
6. ^  Meyer, M. D.; Kruse, L. I. J. Org. Chem. 1984, 49, 3195-3199. (doi:10.1021/jo00191a028)de:Japp-Klingemann-Reaktion