V. V. Zalesov

SYNTHESIS, STRUCTURE, AND CHEMICAL PROPERTIES OF N-SUBSTITUTED 2(3)-IMINO- 2,3-DIHYDROFURAN-3(2)-ONES. (REVIEW)

Published data on the synthesis, structure, and chemical properties of N-substituted 2(3)-imino-2,3-dihydrofuran-3(2)-ones to 2002 are reviewed

Synthesis and Intramolecular Cyclization of N-Substituted 2-Amino-4-aryl-4-oxo-2-butenoic Acids

Treating 4-aryl-2,4-dioxobutanoic acids with aromatic amines, 4-aminoantipyrine, and benzophenone hydrazone furnished N-substituted 2-amino-4-aryl-4-oxo-2-butenoic acids that existed in solutions in enaminoketone and iminoketone forms. The acids obtained underwent in the presence of acetic anhydride cyclization into N-substituted 5-aryl-3-imino-3H-furan-2-ones.

Synthesis, Antiinflammatory and Analgesic Activity of 4-Antipyrine Derivatives

Previously [1 – 3], we have reported on the derivatives of 4-aryl-2,4-dioxobutanoic (aroylpyruvic) acids (Ia – Ie, see scheme) possessing analgesic, antiinflammatory, anticonvulsant, and other pharmacological activities. In continuation of these investigations, we have attempted the synthesis of compounds combining the structures of pyruvic acid and 4-aminoantipyrine, the latter representing a base heterocycle in the series of non-narcotic analgesics [4]. Earlier [5], we obtained 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl amides, which exhibit complete enolization in solution and exist in the form of 4-antipyrylamides of 4-aryl2-hydroxy-4-oxo-Z-2-butenoic acids with intramolecular hydrogen bonds (IHBs) of the H-chelate type. It was established that the reactions of acids Ia – Ie with 4-aminoantipyrine (II) do not yield the anticipated salts III. Instead, we obtained 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino)-4-oxo-2acids IVa – IVe (see scheme and Tables 1 and 2). The IR spectra of acids IVa – IVe exhibit either two broadened absorption bands in the regions of 3458 – 3468 and 3415 – 3417 cm – 1 (compounds IVa and IVd) or a “shelf” within 3416 – 3467 cm – 1 (IVb, IVc, IVe) characteristic of the NH group, a band at 1733 – 1735 cm – 1 characteristic of the stretching vibrations of carboxy groups, and a series of bands in the interval from 1587 to 1669 cm – 1 characteristic of a lactam carbonyl in the heterocycle, C=O carbonyl in IHBs, C=N, and C=C (exact assignment being very difficult). The H NMR spectra of acids IVa – IVe contain two sets of signals suggesting the presence of two isomers (A and B): where Ant denotes the antipyrine residue. The existence of such isomers (A and B) was previously reported for structurally close 4-aryl-2-arylamino-4-oxo-2-butenoic acids [6]. The A form is characterized by the presence of a broadened signal due to the protons of COOH groups (13.1 – 13.3 ppm), a singlet due to the protons of NH groups involved in strong IHBs (11.52 – 11.63 ppm), and a singlet due to the protons of CH groups (6.39 – 6.44 ppm). In the spectrum of the B form, the signals from protons of the NH and CH groups are observed in a stronger field (9.56 – 9.71 and 6.08 – 6.39 ppm, respectively), while the signal from COOH groups in this form was not detected (probably because of considerable broadening). According to the relative signal intensity, the content of the B form ranges within 9 – 19%. Similarly to the reactions with acids Ia – Ie, 4-aminoantipyrine can interact with esters If – Ih to form methyl esters of 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino)-4-oxo-2-butenoic acids (Va – Vc). Judging by the H NMR spectra (Table 1), compounds Va – Vc exist in solution in the form of Z and E isomers (the content of the latter form amounting to 9 – 12%). The lower yields of compounds Va – Vc as compared to those of IVa – IVe are related to greater losses in the course of purification. 4-Aminoantipyrine also smoothly reacts with esters Ii – In to form 4-aryl-2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1Hpyrazol-4-ylamino)-4-oxo-2-butenoic acid amides (VIa – VIg). According to the H NMR data (Table 1), compounds VIa – VIg also exist in solution in the form of Z and E isomers. We have established that acids IVa – IVe exhibit cyclization under the action of acetic anhydride, which leads to the formation of 2-aryl-1,5-dimethyl-4-(2-oxo-5-phenyl-2,3-dihydro-3-furanylideneamino)-1,2-dihydropyrazol-4ones (VIIa – VIIe) [7]. The H NMR spectra of compounds VIIa – VIIe exhibit no signals from protons of the NH groups present in the initial compounds (IVd – IVe); the IR spectra display (besides the absorption bands at 1651 – 1654 cm – 1

Synthesis and Antimicrobial Activity of Complexes Based on 4-aryl-2-hydroxy-4-oxo-2-butenoic Acid N-heterylamides

Reaction of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid N-hetarylamides with copper, zinc, and cadmium dichlorides led to the formation of bis[3-aryl-1-(N-hetaryl)carboxamido-1,3-propanedionato]copper,-zinc, and-cadmium, respectively. Compounds with high antimicrobial activity were found among these products.

Iminofuran chemistry: I. Decyclization of N-substituted 5-aryl-3-imino-3H-furan-2-ones by the action of OH-and NH-nucleophiles

In reactions of N-substituted 5-aryl-3-imino-3H-furan-2-ones with OH-and NH-nucleophiles the nucleophilic reagents attack the carbon atom in the position 2 of the furan ring. All reactions involve the destruction of the furan system.

Synthesis and biological activity of substituted 4-aryl-2-methylenehydrazino-4-oxobut-2-enoic acids and their derivatives

Aseries of substituted 2-methylenehydrazino-4-aryl-4-oxobut-2-enoic acids and their anilides and esters were obtained using reactions of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids and their amides and esters with benzophenone hydrazone, benzyl monohydrazone, and triphenylphosphazines. The methyl ester of 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-chlorophenyl)-4-oxobut-2-enoic acid was also synthesized by decyclization of 3-(1,2-diphenyl-2-oxoethylidenehydrazino)-5-(4-chlorophenyl)-3H-furan-2-one using methanol. The synthesized compounds exhibit moderate anti-inflammatory, analgesic, and antimicrobial activity.

Iminofurans chemistry: IV. Synthesis and structure of 2-N-aryl-substituted derivatives of 2-amino-4-aryl-4-oxobut-2-enoic and 2-amino-5,5-dimethyl-4-oxohex-2-enoic acids

Reactions of arylamines with 4-aryl-2-hydroxy-4-oxobut-2-enoic and 2-hydroxy-5,5-dimethyl-4-oxohex-2-enoic acids gave rise to 4-aryl-2-arylamino-4-oxobut-2-enoic and 2-aryl-amino-5,5-dimethyl-4-oxohex-2-enoic acids that existed in solutions as Z- and E-isomers or in a ring form as 3-arylamino-5-tert-butyl-5-hydroxyfuran-2(5H)-ones. The probable cyclization mechanism of these compounds into 5-R-3-arylimino-3H-furan-2-one derivatives was considered.

Chemistry of iminofurans. Wittig reaction of 5-aryl-3-methylidenehydrazono-2,3-dihydrofuran-2-ones

It was shown previously that 5-aryl-2,3-dihydrofuran-2,3-diones react with acylmethylidene(triphenyl)phosphoranes to give 5-aryl-2-acylmethylidene-2,3dihydrofuran-3-ones [1, 2]. Here, among two possible directions of the Wittig reaction (i.e., at the ketone or lactone carbonyl group), its unusual version involving the lactone carbonyl group occurs due to specific electron density distribution in the heteroring [3]. According to the data of [4–6], introduction of a halogen atom (chlorine or bromine) or aroyl or methyl substituent into the 4-position of the furan ring does not change the reaction direction.

Synthesis and Antiinflammatory and Analgesic Activity of the Products of 3-Imino-(3H)-Furan-2-One Recyclization under the Action of Substituted Hydrazines

A series of 6-aryl-4-(1,5-dimetyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-1,4-dihydro-2H-pyridazin-3-ones and 4-[2-aryl-1-(2,4-dinitrophenylamino)-2-oxo-1,2-dihydropyrrol-3-ylidenamino]-1,5-dimetyl-2-phenyl-1,2-dihydropyrazol-3-ones were synthesized via recyclization of 1,5-dimethyl-4-(5-aryl-2-oxo-furan-3-ylidenamino)-2-phenyl-1,2-dihydropyrazol-3-ones under the action of substituted hydrazines. Most compounds exhibit weak antiinflammatory and analgesic activity.

Chemistry of iminofurans: V. Synthesis, structure, and cyclization of 4-R-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene)hydrazino]but-2-enoic acids

Reactions of 1,2-diphenylethane-1,2-dione hydrazone with 4-aryl-2-hydroxy-4-oxobut-2-enoic and 2-hydroxy-5,5-dimethyl-4-oxohex-2-enoic acids provided 4-aryl-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene) hydrazino]but-2-enoic and 5,5-dimethyl-4-oxo-2-[2-(2-oxo-1,2-diphenylethylidene)hydrazino]hex-2-enoic acids. The acids derivatives can exist in solutions as Z- and β-enehydrazino-or β-ketohydrazone forms, and under the treatment with acetic anhydride they undergo cyclization into 5-aryl- and 5-tert-butyl-3-[2-(2-oxo-1,2-diphenylethylidene)hydrazono]-2,3-furandiones.