Hydrazones from diazonium salts

JAPP KLINGEMANN Hydrazone Synthesis Synthesis of hydrazones from diazonium salts and an activated methylene group (or enamlne)... 

Hydrazones from diazonium salts a-Ketocarboxylic acid ester phenylhydrazones from /5-ketocarboxylic acid esters s. 2, 462, 813... 

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

Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Elimination of the hydroxyaminomethyl moiety from nitro oxime 15 by treatment with a diazonium salt gave hydrazone 43 (75LA1029) (Scheme 15). The same product was obtained by coupling the diazonium salt with the compound 16. On heating in aniline, oxime 15 was transformed into Schiff base 42. Acylation of the oxime 15 with benzoyl chloride in pyridine led to a mixture of furazan 44 and dinitrile 45. 

Formazans are conveniently produced under phase-transfer catalytic conditions from Af-aryl hydrazones and aryl diazonium salts [24], Yields vary from ca. 50% to 70%, but the procedure is superior to the standard synthesis. 

Hydrazones from a-ketoesters and diazonium salts with the acid of base. 

Few examples of the preparation of hydrazines or hydroxylamines on insoluble supports have been reported (Table 10.17). Hydrazines have been prepared by the reduction of aromatic diazonium salts or /V-nitroso amines (prepared from secondary amines by treatment with tert-butyl nitrite [340]), and by the N-amination of support-bound amines (Entry 3, Table 10.17). The direct reduction of hydrazones with borane to yield hydrazines on solid phase has not been reported, and appears to be difficult because of the ease with which the N-N bond of hydrazines is cleaved by reducing agents [340]. 

Metal-Complex (Formazan) Dyes. The hydrazone from 2-carboxyphenylhydra-zine-4-sulfonic acid and benzaldehyde is suspended in water and then dissolved by adding aqueous sodium hydroxide to obtain pH 6.5 -7.0. This solution is added to the aqueous diazonium salt solution obtained from a typical aqueous diazotiza-tion of 4-(2-sulfooxyethylsulfonyl)-2-aminophenyl-6-sulfonic acid. The mixture is then dripped into an aqueous solution of copper sulfate, while the pH is maintained with soda at 5.5 - 6.5. After complete coupling the pH is adjusted to 1 with concentrated hydrochloric acid. The strongly acidic solution is then neutralized with alkali to pH 5.5. The copper - formazan complex is salted out along with sodium chloride, filtered, washed with dilute aqueous sodium chloride solution, and dried. A dark powder results which gives a dark blue solution in water. It consists of an electrolyte-containing powdered sodium salt of the acid 25 ... 

Fused thiazolopyridazinones such as 96 and 97 were obtained from anilines which were converted to phenyl diazonium salts and reacted with ethyl acetoacetate to prepare phenyl hydrazones 98 (Scheme 23). These compounds participated in a Knoevenagel-type condensation with ethyl cyanoacetate to provide pyridazinones... 

Another type of pyridazine synthesis from pyrones involves coupling of the latter with diazonium salts and rearrangement of the intermediate hydrazones with either aqueous base or acid to pyrid-azinones. Thus, 4-hydroxy 6-methyl-2-pyrone (triacetic lactone) (44)... 

Elimination of carbon dioxide from a carboxylic acid in the presence of a diazonium salt leads to an aryl hydrazone (Japp-Klingemann). Subsequent hydrolysis in the presence of pyruvic acid furnishes the carbonyl Compound, as illustrated by the preparation of 2- -butyrylpyridine (81%). ... 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

Table 9 gives the 13C chemical shifts of the compounds77 (3—40) listed in Table 5. Depending on the nature and orientation of the substituents in the dyes, different conformers, resultant from inner rotation around the C-N bonds, could be identified. The 13C chemical shifts of azobenzene-like compounds and diazonium salts coupling products with heterocycles are reported in Refs. 9, 18, 25, 26, 36, 39, 48, 78-87. The 13C chemical shifts of dyes derived from 3-methyl-l-phenylpyrazol-5-one (of type 78 Table 10),88 pyridone (81),39 and acetoacetanilide (82)65 existing completely in hydrazone forms were assigned.

Biilow and Ganghofer330 obtained dimethyl mesoxalate phenylhydrazone by adding a diazonium salt solution prepared from aniline (12 g), 30% hydrochloric add (36 g), ice + water (150 g), and 98% sodium nitrite (10 g) to a cold solution of dimethyl malonate (20 g) in ethanol (100 g), followed by saturated aqueous sodium acetate solution slowly to incipient turbidity. The hydrazone crystallized during 24 hours storage in a refrigerator and had m.p. 62° after recrystallization from ethanol. 

When the ester (4) is coupled with diazonium salts from p-nitroaniline, 3,4,5-triiodoaniline, or 3,5-diiodo-p-anisidine (NH2 = 1), the unstable azo compounds (5) can be isolated as crystalline intermediates, which, however, pass into the hydrazones if warmed or treated with dilute alkali.333 334 In recent years,335 however, the isolation of various, relatively stable aliphatic arylazo compounds has been reported. 

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