Nikolai Beliaev

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.