Study of the acylation reaction of 2,6-dimethyl-3,5-pyridinedicarboxylic acid hydrazides

Abstract

Keywords: aromatic acid halides, hydrazide, hydrazine hydrate, hydrazinolysis, X-ray analysis.The studies [1,2] demonstrated the possibility of a stepwise hydrazinolysis of the ester groups in diethyl 2,6-dimethyl-3,5-pyridinedicarboxylate with subsequent formation of 3-ethoxycarbonyl-2,6-dimethyl-5-pyridine-carboxylic acid hydrazide (1) and 2,6-dimethyl-3,5-dipyridinedicarboxylic acid dihydrazide (2) and then the corresponding hydrazones using aromatic aldehydes. It was found that the free ester group in the case of the hydrazones obtained from the monohydrazide 1 does not participate in the hydrazinolysis reaction.With the aim of investigating the chemical properties of the hydrazides 1 and 2 we have studied their acylation reaction with the aromatic acid halides 3a-h. This reaction occurs under base catalysis conditions using dry, refluxing acetonitrile. The choice of solvent and the temperature conditions are limited by the solubility of the hydrazides 1, 2 in organic solvents.The 3,5-pyridinedicarboxylic acid N-aroyl hydrazides 4, 5a-h formed in the reaction are neutralized using aqueous alcoholic sodium bicarbonate solution to give the corresponding bases 6, 7a-h (Tables 1-3). As is evident from the Table the most difficulty occurs in the reaction with 2-methoxybenzoyl chloride and this is evidently linked both with the lower electrophilicity of the reagent and with the steric hindrance generated by the ortho-methoxy group.The N-aroyl hydrazides 6, 7a-h are quite stable to acid and base hydrolysis but this occurs to give 2,6-dimethyl-3,5-pyridinedicarboxylic acid by refluxing for 6-10 h in 15% hydrochloric acid, virtually the same time being needed for the complete hydrolysis using a 2N aqueous alcohol solution of potassium hydroxide under reflux.The ester group of the monohydrazide 1 readily takes part in a hydrazinolysis reaction to give the dihydrazide 2 [1]. We were interested in the possible hydrazinolysis of the ester group in the obtained N-aroyl hydrazides 6a-h. It was found that prolonged reflux of both the bases 6a,b,e,f,h and the hydrochlorides __________________________________________________________________________________________

Synthesis of Some N, N′‐Diacylhydrazine Derivatives with Radical‐Scavenging and Antifungal Activity

“…All the intermediate‐substituted acylhydrazines were synthesized according references, and the m.p. of these intermediates accorded with references (27–37).…”

Synthesis and hydrazinolysis of β-(1,3,4-oxadiazol-2-yl)pyridines

“…In the IR spectra of the synthesized (1,3,4-oxadiazol-2-yl)pyridines 5b-i (Table 2) there are intense valence bands of the C=N bond in the 1610-1620 cm -1 range, which corresponds to previous date [4]. The stretching bands of the ester groups (Table 2) undergo a high frequency shift in comparison with the starting diacylhydrazines (from the 1710-1720 range for compounds 3c,d,g,i [8] to the range 1735-1740 cm -1 for the corresponding oxadiazoles 5c,d,g,i), which may indicate the greater electron acceptor influence of the 1,3,4-oxadiazole unit. The excluded compounds 3b and 5b contain the 4-tert-butylphenyl substituent.…”

“…Preparation of 1,3,4-oxadiazoles containing pyridine units is coupled with a number of difficulties, linked with their chemical instability and the complexity of isolating them from the reaction media [7].Previously [8] we studied the reactivity of hydrazides of 3,5-pyridinedicarboxylic acid 1, 2 in acylation reaction with aromatic acids chlorides which proceeded with formation of the hydrochlorides of the corresponding mono-and bis-1,2-diacylhydrazine-2,6-dimethylpyridines 3, 4b-d, g, isolated in the form of the bases.With the objective of preparing the (1,3,4-oxadiazol-2-yl)pyridines 5 and 6 we have investigated the reaction of the heterocycles 3 and 4 with various dehydrating agents (phosphorus oxychloride, thionyl chloride, oleum, and polyphosphoric acid). The most effective cyclizing agent is phosphorus oxychloride.…”

“…Previously [8] we studied the reactivity of hydrazides of 3,5-pyridinedicarboxylic acid 1, 2 in acylation reaction with aromatic acids chlorides which proceeded with formation of the hydrochlorides of the corresponding mono-and bis-1,2-diacylhydrazine-2,6-dimethylpyridines 3, 4b-d, g, isolated in the form of the bases.…”

“…Comparative analysis of the 1 H NMR spectra shows that in going from the 1,2-diacylhydrazines 3b-d,g,i [8] to the corresponding (1,3,4-oxadiazol-2-yl)pyridines 5b-d,g,i ( Table 3) the signal of the pyridine proton underwent a weak field shift from 7.9-8.2 to 8.7-8.8 ppm, while the introduction of a second oxadiazole ring in the case of compound 6c, which contains a 2-fluorophenyl substituent, led to an additional shift of ~0.2 ppm to weak field. As a result of a comparative analysis of the spectra of (1,3,4-oxadiazol-2-yl)pyridines 5a-i with the spectra of the products of their hydrazinolysis 7a-f,i a shift of the signal of the gamma-proton by 0.3-1.1 ppm to strong field was observed, which is explained by the electron donor characteristic of the hydrazine unit in comparison with the ester group.…”