A. E. Rubtsov

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

Iminofuran chemistry: VII. Intramolecular cyclization of 2-N-aryl-substituted derivatives of 2-amino-4-aryl-4-oxobut-2-enoic and 2-amino-5,5-dimethyl4-oxohex-2-enoic acids

The cyclization at the treatment of acetic anhydride of 4-aryl-2-arylamino-4-oxobut-2-enoic and 2-arylamino-5,5-dimethyl-4-oxohex-2-enoic acids was investigated furnishing derivatives of 5-aryl-3-aryl-imino-3H-furan-2-ones and 4-arylamino-2-tert-butyl-2,5-dihydro-5-oxofuran-2-yl acetate respectively. 2-N2-Methylenesubstituted 4-aryl-2-hydrazino-4-oxobut-2-enoic and 5,5-dimethyl-2-hydrazino-4-oxohex-2-enoic acids cleanly underwent cyclization under the effect of acetic anhydride into 5-aryl-3-hydrazono-3H-furan-2-ones and 5-tert-butyl-3-hydrazono-3H-furan-2-ones.

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.

Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (−)‐Elisabethadione

A new, highly efficient Lewis base catalyst for a practical enantio- and diastereoselective crotylation of unsaturated aldehydes with E- and Z-crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (-)-elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy-Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.

Chemistry of iminofuran: VIII. Recyclization of 5-aryl-3-arylimino-3H-furan-2-ones effected by cyanoacetic acid derivatives

The recyclization of 5-aryl-3-arylimino-3H-furan-2-ones under the action of esters, nitriles, and amides of cycnoacetic acids resulted in the corresponding esters, nitriles, and amides of (5E)-2-amino-1-aryl-4-oxo-5-(2-oxoethylidene)-1H-4,5-dihydropyrrole-3-carboxylic acids.

Synthesis And Analgesic Activity Of 4-Aryl-2-Arylamino-4-OXO-2-Butenoic Acid Hetarylamides

4-Aryl-2-arylamino-4-oxo-2-butenoic acid hetarylamides were synthesized by the reaction of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid hetarylamides with aromatic amines and also by ring opening of 5-aryl-3-arylamino-3H-furan-2-ones by heterocyclic amines. Their analgesic activity was studied. Compounds with activity comparable to and exceeding that of the reference drugs and with low toxicity were found.

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.

Chemistry of iminofurans: IX. Synthesis and cyclization of (2Z)-2-{(2Z)-2-[2-(3-R-adamantan-1-yl)-2-oxoethylidene]hydrazinyl}-4-(het)aryl-4-oxobut-2-enoic acids

Abstract1-(3-R-adamantan-1-yl)-2-[(triphenyl-λ5-phosphanylidene)hydrazinylidene]ethanone reacted with 4-aryl(hetaryl)-2,4-dioxobutanoic acids to give 2-{2-[2-(3-R-adamantan-1-yl)-2-oxoethylidene]hydrazinyl}-4-aryl(hetaryl)-4-oxobut-2-enoic acids which were shown to exist in solution as mixtures of Z- and E-isomeric enehydrazine tautomers. The products underwent cyclization to 3-{[2-(3-R-adamantan-1-yl)-2-oxoethylidene]- hydrazinylidene}-5-aryl(hetaryl)furan-2(3H)-ones.