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Japp–Klingemann reaction

Chemical reaction

Felix Klingemann 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.

:[[File:Japp-Klingemann Reaction Scheme.png|500px|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.

:[[File:Japp-Klingemann Fischer Indole Combination.png|550px|The Japp-Klingemann reaction used to synthesize indoles]]

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 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.

Applications

Indole synthesis: Hydrazones formed in this reaction undergo Fischer Indole synthesis.

Pyrazole synthesis: On cyclization, Hydrazones yield Pyrazoles.

Preparation of Azo Derivatives.

Widely used in Medicinal Chemistry for Heterocyclic frameworks.

References

[[Francis Robert Japp]], [[Felix Klingemann]]. (1887). "Ueber Benzolazo- und Benzolhydrazofettsäuren". [[Berichte der deutschen chemischen Gesellschaft]].
(1887). "Zur Kenntniss der Benzolazo- und Benzolhydrazopropionsäuren (p 3284-3286)". Berichte der Deutschen Chemischen Gesellschaft.
(1887). "Ueber sogenannte »gemischte Azoverbindungen". [[Berichte der deutschen chemischen Gesellschaft]].
(1888). "Ueber die Constitution einiger sogenannten gemischten Azoverbindungen". [[Liebigs Annalen der Chemie]].
Phillips, R. R. ''Org. React.'' '''1959''', ''10'', 143.
link. (2012-07-16))
(1972). "1,3,4,5-Tetrahydrobenz[''cd'']indoles and related compounds. Part I. A new synthesis of 3,4-dihydrobenz[''cd'']indol-5(1''H'')-one (Uhle's ketone)". J. Chem. Soc. Perkin Trans. 1.
(1984). "Ergoline synthons: Synthesis of 3,4-dihydro-6-methoxybenz[''cd'']indol-5(1''H'')-one (6-methoxy-Uhle's ketone) and 3,4-dihydrobenz[''cd'']indol-5(1''H)''-one (Uhle's ketone) via a novel decarboxylation of indole-2-carboxylates". [[J. Org. Chem.]].
Lamberth, Clemens. (2002). "An improved procedure for the preparation of 1-aryl-4-hydroxy-1''H''-pyrazoles". Organic Preprarations and Procedures International.

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