Japp–Klingemann reaction

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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][5][6] The Reaction is named after the chemists Francis Robert Japp and Felix Klingemann.

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.[7][8]

The Japp-Klingemann reaction used to synthesize indoles

Reaction mechanism[edit]

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[edit]

  1. ^ Francis Robert Japp, Felix Klingemann (1887). "Ueber Benzolazo- und Benzolhydrazofettsäuren". Berichte der deutschen chemischen Gesellschaft 20 (2): 2942–2944. doi:10.1002/cber.188702002165. 
  2. ^ F. R. Japp, F. Klingemann (1887). "Zur Kenntniss der Benzolazo- und Benzolhydrazopropionsäuren (p 3284-3286)". Berichte der deutschen chemischen Gesellschaft 20 (2): 3284–3286. doi:10.1002/cber.188702002234. 
  3. ^ F. R. Japp, F. Klingemann (1887). "Ueber sogenannte »gemischte Azoverbindungen". Berichte der deutschen chemischen Gesellschaft 20 (2): 3398–3401. doi:10.1002/cber.188702002268. 
  4. ^ F. R. Japp, F. Klingemann (1888). "Ueber die Constitution einiger sogenannten gemischten Azoverbindungen". Liebigs Annalen der Chemie 247 (2): 190–225. doi:10.1002/jlac.18882470208. 
  5. ^ Phillips, R. R. Org. React. 1959, 10, 143.
  6. ^ Reynolds, G. A.; VanAllan, J. A. Org. Syn., Coll. Vol. 4, p.633 (1963); Vol. 32, p.84 (1952). (Article)
  7. ^ Bowman, R. E.; Goodburn, T. G.; Reynolds, A. A. (1972). "1,3,4,5-Tetrahydrobenz[cd]indoles and related compounds. Part I. A new synthesis of 3,4-dihydrobenz[cd]indol-5(1H)-one (Uhle's ketone)". J. Chem. Soc. Perkins Trans 1: 1121. doi:10.1039/P19720001121. 
  8. ^ Meyer, M. D.; Kruse, L. I. (1984). "Ergoline synthons: Synthesis of 3,4-dihydro-6-methoxybenz[cd]indol-5(1H)-one (6-methoxy-Uhle's ketone) and 3,4-dihydrobenz[cd]indol-5(1H)-one (Uhle's ketone) via a novel decarboxylation of indole-2-carboxylates". J. Org. Chem. 49 (17): 3195–3199. doi:10.1021/jo00191a028.