Ilya V. Efimov

Novel method for the synthesis of 4-(azol-5-yl)isoxazoles

In contrast to monocyclic and condensed isoxazoles, which are widely represented in the scientific and patent literature, bicyclic assemblies of isoxazoles with other azoles are poorly studied [1, 2]. In particular, isoxazoles linked to 1,2,3-thiadiazole and isothiazole rings have not been reported in the literature. Current methods for the preparation of 4-(azol-5-yl)isoxazoles are not numerous and include the construction of either an azole or an isoxazole ring. The formation of an isoxazole ring through reactions of various derivatives of 1,3-dicarbonyl compounds, -ketoesters, -ketonitriles, and malononitrile derivatives with hydroxylamine has been used for the preparation of 4-(azol-5-yl)isoxazoles [1]. The cycloaddition reaction of azolylacetylenes to nitrile oxides [1, 3] represents an alternative way of preparing this type of compound. Despite the good yields, for the majority of reactions these methods are limited by the poor availability of the starting compounds. The Suzuki cross-coupling reaction is complex in experimental settings and hence has a limited use for the synthesis of 4-(azol-5-yl)isoxazoles [4].

Rh(II)-mediated domino [4 + 1]-annulation of α-cyanothioacetamides using diazoesters: A new entry for the synthesis of multisubstituted thiophenes

A new approach towards the synthesis of multisubstituted thiophenes is elaborated based on Rh(II)-catalyzed domino reactions of acyclic diazoesters with α-cyanothioacetamides. It provides a way for the preparation of 5-amino-3-(alkoxycarbonylamino)thiophene-2-carboxylates, 2-(5-amino-2-methoxycarbonylthiophene-3-yl)aminomalonates and (2-cyano-5-aminothiophene-3-yl)carbamates with the preparative yields of up to 67%. It was also shown that α-cyanothioacetamides easily interact with dirhodium carboxylates to give rather stable 2:1 complexes, resulting in an evident decrease in the efficiency of the catalytic process at moderate temperatures (20–30 °C).

Synthesis of Assemblies of Isoxazole and Azoles Based on 1,3-Dipolar Cycloaddition Reaction of Enamines with Nitrile Oxides

2-(1,2,3-Thiadiazol-5-yl)enamines and 3-(1,2,3-triazol-4-yl)enaminones react with arylhydroxamoyl chlorides at room temperature with the exclusive formation of 3-aryl-4-(1,2,3-thiadiazol-5-yl)- and [4-(1,2,3-triazol-4-yl)carbonyl]isoxazoles in high yields. The proposed mechanism includes in situ generation of nitrile oxides, which participate in the (3+2)-dipolar cycloaddition reactions leading to the formation of the isoxazole ring.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

Reactions of β-azolyl enamines and nitrile oxides were studied by both experimental and theoretical methods. (E)-β-(4-Nitroimidazol-5-yl), (5-nitroimidazol-4-yl) and isoxazol-5-yl enamines smoothly react regioselectively at room temperature in dioxane solution with aryl, pyridyl, and cyclohexylhydroxamoyl chlorides without a catalyst or a base to form 4-azolylisoxazoles as the only products in good yields. The intermediate 4,5-dihydroisoxazolines were isolated as trans isomers during the reaction of (E)-β-imidazol-4-yl enamines with aryl and cyclohexylhydroxamoyl chlorides. Stepwise and concerted pathways for the reaction of β-azolyl enamines with hydroxamoyl chlorides were considered and studied at the B3LYP/Def2-TZVP level of theory combined with D3BJ dispersion correction. The reactions of benzonitrile oxide with both E- and Z-imidazolyl enamines have been shown to proceed stereoselectively to form trans- and cis-isoxazolines, respectively. The preference of E-isomers over Z-isomers, driven by the higher stability of the former, apparently controls the stereoselectivity of the investigated cycloaddition reaction with benzonitrilе oxide. Based on the reactivity of azolyl enamines towards hydroxamoyl chlorides, a novel, effective catalyst-free method was elaborated to prepare 4-azolyl-5-substituted isoxazoles that are otherwise difficult to obtain.

Design and synthesis of imidazoles linearly connected to carbocyclic and heterocyclic rings via a 1,2,3-triazole linker. Reactivity of β-azolyl enamines towards heteroaromatic azides

Herein we report an investigation on the 1,3-dipolar cycloaddition of 5-azido-4-nitroimidazoles to β-azolylenamines and the subsequent transformations of the intermediate 1,2,3-triazolines. 5-Azido-1-methyl-4-nitroimidazoles were combined with β-azolylenamines to form novel imidazoles linearly connected via a 1,2,3-triazole to 1,2,3-thiadiazole and isoxazole rings. On the other hand, in the reaction of β-(imidazol-4-yl)enamine with 1-methyl-4-nitro-5-azidoimidazole, the N,N-dimethyl-N′-(1-methyl-4-nitro-1H-imidazol-5-yl)formimidamide was isolated as a single product. A third type of product, active methylenes containing N-imidazol-5-yl-amidines were obtained in a similar reaction of β-phenylenamine. The factors which govern the outcome of the reactions of these heterocyclic enamines with highly electrophilic imidazolylazides were carefully studied on the basis of DFT calculations with a mPW1K density functional. The formation of various products in the reaction of imidazolyl azides with enamines was rationalized by different transformation pathways of a common 1,2,3-triazoline intermediate. According to the calculations, the two transformation paths, that are different from the path leading to aromatic 1,2,3-triazoles, occur by a stepwise mechanism involving a diazo compound formed by ring-opening of the intermediate 1,2,3-triazolines. Based on literature analysis and theoretical investigations, it is proposed that elimination of an amine from the intermediate 1,2,3-triazolines leading to 1,2,3-triazoles is a base-catalyzed process which takes place via an E1cb mechanism.

Synthesis of 1,2,3-triazoles linked into chains with other carbo- and heterocycles by a reaction between β-azolyl enamines and azides

The reactions of β-azolyl enamines with azides proceeded under solvent-free conditions in the absence of base at 110°С by one of the possible routes, selectively forming 1,4-disubstituted 1,2,3-triazoles. The proposed reaction mechanism includes cycloaddition of the starting reagents, leading to 1,2,3-triazoline intermediates, followed by elimination of dimethylamine and the formation of aromatic triazole ring.

Crystal structure of ethyl 3-(4-chloro-phen-yl)-5-[(E)-2-(di-methyl-amino)-ethen-yl]-1,2-oxazole-4-carboxyl-ate.

In the title compound, C16H17ClN2O3, two molecules, A and B, with different conformations, comprise the asymmetric unit. In molecule A, the C=O group of the ester points away from the benzene ring [C—C—C=O = −170.8 (3)°], whereas in molecule B, it points back towards the benzene ring [C—C—C=O = 17.9 (4)°]. The dihedral angles betweeen the oxazole and benzene rings also differ somewhat [46.26 (13) for molecule A and 41.59 (13) for molecule B]. Each molecule features an intramolecular C—H⋯O interaction, which closes an S(6) ring. In the crystal, the B molecules are linked into [001] C(12) chains by weak C—H⋯Cl interactions.