Reaction Japp-Klingemann

Arylhydrazones from reaction of /3-dicarbonyl compounds with arenediazonium salts 

The coupling of arenediazonium compounds 1 to 1,3-dicarbonyl substrates 2 (Z = COR) is known as the Japp-Klingemann reaction As suitable substrates, /3-ketoacids (Z = COOH) and /3-ketoesters (Z = COOR) can be employed. As reaction product an arylhydrazone 4 is obtained. 

In general the reaction is conducted in aqueous solution under basic conditions—e.g. in the presence of KOH. The 1,3-dicarbonyl substrate is deprotonated to give the corresponding anion 5, which then couples to the arenediazonium species 1, to give the diazo compound 3  

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

Such diazo compounds 3 however, that contain two electron-withdrawing substituents, are unstable under these reaction conditions. They further react by hydrolytic cleavage of one carbonyl substituent to give an anionic species 6, that is stabilized by resonance, and which yields the hydrazone 4 upon acidic workup  

R = alkyl, aryl R = H, alkyl, aryl, acyl, CN, Cl, Br R = O-alkyl, O-aryl, OH R = electron-withdrawing or electron-donating groups 

The Japp-Klingemann reaction was the key step during the first synthesis of the pentacyclic pyridoacridine marine cytotoxic alkaloid amoamine A by E. Delfoume et a P The diazonium salt was added to a vigorously stirred solution of ethyl-2-methyl-3-oxobutyrate in ethanol containing KOH, NaOAc and water. The resulting hydrazone was exposed to polyphosphoric acid to form the indole ring. 

A new heterocyclic ring system, 5/-/,12/-/-[1]Benzoxepino[4,3-b]indol-6-one, was prepared by the Fischer indole cyciization of a substituted benzoxepin-5b-one phenylhydrazone by G. Primofiore and co-workers. The phenylhydrazone precursor was prepared via the Japp-Klingemann reaction of the corresponding 3,4-dihydro-4-hydroxymethylene[1]benzoxepin-5(2H)-one. 

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If, instead of an ester, the Japp-Klingemann reaction is done with a salt of a P-ketoadd, decarboxylation occurs and the eventual product is a 2-acyl-indole. 

In addition to formation from a ketone, the hydra2ones can be obtained from dicarbonyl compounds by a Japp-Klingemann reaction. This is especially useful for P-ketoesters and P-ketoacids, which undergo either deacylation or decarboxylation. 

The diazo coupling with C—H acidic aliphatic substrates is a feature of the Japp-Klingemann reaction. 

Another route to suitable arylhydrazones is offered by the Japp-Klingemann reaction. 

The Japp-Klingemann reaction is a special case of the aliphatic diazo coupling. For a successful reaction, the dicarbonyl substrate 2 should bear a sufficiently CH-acidic hydrogen. 

SO the product in this case is also the hydrazone, and not the azo compound. In fact, compounds of the type 16 are seldom isolable from the reaction, though this has been accomplished. The cleavage step shown is an example of 12-41 and, when a carboxyl group cleaves, of 12-38. The overall process in this case is called the Japp-Klingemann reaction and involves conversion of a ketone (17) or a carboxylic... 

As in the Japp-Klingemann reaction, when Z is an acyl or carboxyl group (in the case of R2CH—Z), it can be cleaved. Since oximes and nitroso compounds can be reduced to primary amines, this reaction often provides a route to amino acids. As in the case of 12-4, the silyl enol ether of a ketone can be used instead of the ketone itself. Good yields of a-oximinoketones (20) can be obtained by treating ketones with fert-butyl thionitrate. ... 

Alternatively to the Japp-Klingemann reaction phenylpyruvic acid or ethyl phenylpyruvatc can be condensed with 4-chlorophenylhydrazine.J... 

A large rtumber of carbazole syntheses involve the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles. They are usually prepared by either the Fischer-Borsche synthesis or the Japp-Klingemann reaction. The most commonly used dehydrogenating agents are palladium on charcoal or chloranil (495,496). 

The preparation of the hydrazone required in the Borsche method was accomplished very conveniently using the Japp-Klingemann reaction (499,500). The reaction uses formylcyclohexanone (515) and a diazotized aromatic amine (516) for the synthesis... 

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