Japp-Klingemann reaction compounds

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 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. 

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. ... 

The related Japp-Klingemann reaction, which involves addition to an active methinyl compound with subsequent loss of a group, normally leads to hydrazones [23]. 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

The synthesis of this base (131) has been achieved by a series of reactions in which the phenylhydrazone 132 was prepared by a Japp-Klingemann reaction of the appropriate compounds and subsequently subjected to ring closure. Though the subsequent steps present no novel features it is evident that their execution demanded considerable manipulative skill (117). 

It was proposed to synthesize 6-phosphorylated indoles 174 [189] by the Japp-Klingemann reaction. Diazotization of m- di hydroxyphosphoryl)aniline followed by the reaction of the diazo compound with ethylacetoacetic ester gave w-phosphorylphenylhydrazone of ethyl a-ketobutyrate, which was used for the synthesis of the desired compound 174. 

Japp-Klingemann reaction. Formation of hydrazones by coupling of aryldiazonium salts with active methylene compounds in which at least one of the activating groups is acyl or carboxyl. This group usually cleaves during the process. 

The initial intent to cover the subject exhaustively had to be abandoned because of the overwhelming amount of relevant literature. The following reactions are not covered but are briefly discussed, with references to reviews and seminal papers, in the section on Comparison with Other Methods reactions of carbanions and enolates and their surrogates with nitrogen oxides, nitrite and nitrate esters, and nitroso and nitro compounds reactions of enolates with diazonium salts, including the Japp-Klingemann reaction the diazo transfer reaction except as it interferes with the synthesis of azides the animation of boranes and the Neber rearrangement. 

Serotonin has been synthesised by several routes the method shown relies on a Fischer indole synthesis, the requisite aryl-hydrazone being constructed by a process known as the Japp-Klingemann reaction in which the enol of a 1,3-dicarbonyl compound is reacted with an aryl-diazonium salt, with subsequent cleavage of the 1,3-dicarbonyl unit. 

A different synthetic route uses the Japp-Klingemann reaction of ethyl [2-chloro-5-fluoro-6-(4-tolylsulfanyl)nicotinoyl]acetate or, the corresponding 6-chloro compound, with 4-fluo-robenzenediazonium chloride. The resulting hydrazone 3a or 3b is then converted by potassium carbonate in refluxing acetonitrile or by potassium tm-butoxide at room temperature to the 7-(4-tolylsulfanyl)- or 7-chloro-substituted ethyl 6-fluoro-l-(4-fluorophenyl)-4-oxo-l,4-dihy-dropyrido[2,3-c]pyridazinc-3-carboxylatc 4a or 4b, respectively.9,16... 

The phenylhydrazones required for the Fischer synthesis are prepared from carbonyl compounds and phenylhydrazine. Alternatively, they can be obtained by a Japp-Klingemann reaction from CH-acidic compounds (y diketones, y -keto esters, etc.) or from enamines by interaction with aryldia-zonium salts. More complex indoles are thus accessible by a simple route. This is demonstrated by the synthesis of 3-(indol-3-yl)propionic acid 40, the starting material of Woodward s lysergic acid synthesis [52]. 

In addition to direct formation from an arylhydrazine and a carbonyl compound, iV-aryl-hydrazones can be prepared from aryldiazonium ions by coupling with enolates or enamines (Japp-Klingemann reaction). This reaction has most frequently been applied to j -ketoesters. The coupling product undergoes deacylation so that the ultimate product of Fischer cycUzation is an indole-2-carboxylate ester (Scheme 58) <92JMC4823>. 

Sodium acetate Japp-Klingemann reaction with hydroxymethylene compounds Hydrazones from diazonium salts... 

The best known and most significant Fischer indolization variation is that of Japp and Klingemann, described in 1887 [138] and 1888 [139] and reviewed by Phillips in 1959 [140] and Li in 2007 [141], This reaction involves the union of an aryldiazonium salt with a 1,3-dicarbonyl compound to give the requisite arylhydrazone following loss of one of the carbonyl fragments (Scheme 25). Examples of the Japp-Klingemann reaction are combined with the normal Fischer indolization in the AppUcations section. 

It should be mentioned that O-methylation of the ketone in 24 was necessary to avoid competition between the Heck-Matsuda arylation and the nucleophilic addition of the enol to the aryldiazonium salt, a process known as the Japp-Klingemann reaction. Indeed, when 24 was submitted to the standard Heck-Matsuda reacticm conditions, the azo compound 25 was obtained in quantitative yield (Scheme 9). Azo compounds are easily detected due to the formation of highly colored products via this reaction. 

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