Monosubstituted oxadiazoles were synthesized by the reaction of hydrazides with triethyl orthoformate. Their reactions with benzoyl chloride gave benzoylcarbohydrazides, which under the action of thionyl chloride were cyclized to the respective 2,5-disubstituted oxadiazoles. 3,)-pyrrolidin-2-ones were synthesized from acid hydrazides using carbon disulfide under basic conditions. are important for both chemical and biological purposes. A number of these compounds have demonstrated antibacterial [1], antimicrobial [2], herbicidal [3], and anti-inflammatory [4−6] activities.The present work aims to investigate the synthesis of substituted 1,3,4-oxadiazoles from 1-aryl-5-oxopyrrolidine-3-carbohydrazides and to establish the structure of the products by chemical and spectral methods.Monosubstituted derivatives of oxadiazole can be obtained directly from acid hydrazides and triethoxymethane. 1,3,4-Oxadiazoles 3 were synthesized by refluxing hydrazides 1a,b in an excess of triethyl orthoformate (Scheme). The target compounds crystallized from the reaction mixture after cooling. In their 1 H NMR spectra the signals characteristic for the NHNH 2 fragment of the initial hydrazines are absent, while the proton signal of the CH=N fragment in the oxadiazole moiety is observed in lower field (9.23 ppm). 2,5-Disubstituted oxadiazoles 5 were obtained when the respective benzoyl hydrazydes were dehydrated with thionyl chloride. The products were separated from the reaction mixture by column chromatography.Acyl derivatives of the respective hydrazides 4 were synthesized by stirring acid hydrazides 1a,c−e with benzoyl chloride in pyridine. Hydrazinocarbonyl compounds undergo reaction with carbon disulfide in the presence of potassium hydroxide quite easily. 1-Aryl-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-ones 6c−e were synthesized from acid hydrazides 1c−e according to the method described in the literature [7]. In their 1 H NMR spectra, besides the characteristic proton signals of aromatic and pyrrolidinone ring moieties,
Novel functionalized thiazoles were prepared by the Hantzsch reaction from 3-[(4hydroxyphenyl)carbamothioylamino]-2-methylpropanoic acid and the corresponding α-halocarbonyl compounds in good yields. A series of chemical transformations of the obtained products were carried out, and new functionalized thiazole derivatives with aliphatic, aromatic and heterocyclic substituents were synthesized. 4-Phenyl-substituted N-(4-hydroxyphenyl)-N-carboxyalkylaminothiazoles were used as precursors for the synthesis of bis(thiazol-5-yl)methane derivatives, which then were screened for their antibacterial, antioxidant activities.
A series of 1-aryl substituted dihydro-, 5-methyldihydro- and 6-methyl-dihydro-2,4(1H,3H)pyrimidinediones and their 2-thio analogues were obtained by reaction of the corresponding β-alanines or α-methyl- and β-methyl-β-alanines with urea or potassium thiocyanate. The reaction of N-(2,3- and 3,5-dimethylphenyl)-α-methyl-β-alanines with ethyl acetoacetate gave 1-(2,3- or 3,5-dimethylphenyl)-2,5-dimethyl-1,4,5,6-tetrahydro-4(1H)pyridones. The combined spectral data obtained by 1H-, 13C-, 1H/13C (HETCOR) NMR and IR provided useful information about the structure of the products synthesized in this work.
Interaction of 2-and 4-fluorophenylamines with acrylic and itaconic acids leads to the synthesis of the corresponding N-substituted β-alanines, the cyclization of which leads to derivatives of dihydropyrimidinone, 4-carboxy-2-pyrrolidinone, and tetrahydropyridone. Compounds having benzimidazole, pyrazole, and hydrazine fragments in the molecule have been obtained from 4-carboxy-1-(4-fluorophenyl)-2-pyrrolidinone.While continuing investigations on the chemistry of N-substituted amino acids [1, 2] we have synthesized in the present study fluorine-containing N-aryl-substituted β-amino acids, and have carried out heterocyclization of them into five-and six-membered rings. It is known that the presence of fluorine in a molecule often has a favorable influence on its biological activity.N-(2-and 4-fluorophenyl)-β-alanines 2a,b were obtained by the reaction of the appropriate aromatic amines 1a,b with acrylic acid in 20% acetic acid. On boiling β-alanines 2a,b with urea in glacial acetic acid N-carbamoyl-N-(2-fluorophenyl)-and N-carbamoyl-N-(4-fluorophenyl)-β-alanines 4a,b were synthesized which, without isolation from the reaction mixture, were cyclized by the action of conc. HCl into the corresponding 2,4-(1H,3H)-dihydropyrimidinediones 3a,b.1-(2-and 4-fluorophenyl)-4-(1H,3H)-pyrimidinone-2-thiones 5a,b were synthesized under analogous conditions as for compounds 3a,b only using potassium thiocyanate in place of urea. For purification from N-substituted ureas compounds 3 and 5 were decyclized with 5% sodium hydroxide solution to the corresponding salts of N-aryl-N-carbamoyl(or thiocarbamoyl)-β-alanines 4, 6, insoluble contaminants were filtered off, and salts 4 and 6 in the filtrate were cyclized once again with hydrochloric acid into compounds 3, 5 (Scheme 1).On condensing β-alanine 2b with the ethyl ester of acetoacetic acid 3-ethoxycarbonyl-1-(4-fluorophenyl)-2-methyl-1,4,5,6-tetrahydropyridone 7b was formed, in the 1 H NMR spectrum of which (Table 1) the most characteristic were the singlet signals of the methyl group protons at 1.84 and a triplet and quadruplet for the protons of the ethyl group at 1.20 and 4.09 ppm respectively.On investigating the reactions of aromatic amines 1a,b with itaconic acid the products of intramolecular cyclization of the amino acids, viz. 1-aryl-substituted 4-carboxy-2-pyrrolidinones 8a,b, were isolated from the reaction mixture. We were unable to isolate the free N-substituted β,γ-amino acids. On condensing o-phenylenediamine and 1-aryl-substituted 4-carboxy-2-pyrrolidinones 8a,b in hydrochloric acid (Phillips __________________________________________________________________________________________
The p-aminobenzoic acid was applied for the synthesis of substituted 1-phenyl-5-oxopyrrolidine derivatives containing benzimidazole, azole, oxadiazole, triazole, dihydrazone, and dithiosemicarbazide moieties in the structure. All the obtained compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Bacillus cereus, Listeria monocytogenes, Salmonella enteritidis, Escherichia coli, and Pseudomonas aeruginosa by using MIC and MBC assays. This study showed a good bactericidal activity of γ-amino acid and benzimidazoles derivatives. The antimicrobial activity of the most promising compounds was higher than ampicillin. Furthermore, two benzimidazoles demonstrated good antimicrobial activity against L. monocytogenes (MIC 15.62 µg/mL) that was four times more potent than ampicillin (MIC 65 µg/mL). Further studies are needed to better understand the mechanism of the antimicrobial activity as well as to generate antimicrobial compounds based on the 1-phenyl-5-oxopyrrolidine scaffold.
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