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

Ilya V Efimov; Marsel Z Shafikov; Nikolai A Beliaev; Natalia N Volkova; Tetyana V Beryozkina; Wim Dehaen; Zhijin Fan; Viktoria V Grishko; Gert Lubec; Pavel A Slepukhin; Vasiliy A Bakulev

doi:10.3762/bjoc.12.233

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

Beilstein J Org Chem. 2016 Nov 15:12:2390-2401. doi: 10.3762/bjoc.12.233. eCollection 2016.

Affiliations

¹ TOS Department, Ural Federal University named after the first President of Russia B.N. Yeltsin, 19 Mira str., 620002 Yekaterinburg, Russia.
² TOS Department, Ural Federal University named after the first President of Russia B.N. Yeltsin, 19 Mira str., 620002 Yekaterinburg, Russia; Chemistry Department, University of York, Heslington, York, YO10 5DD, UK.
³ Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium.
⁴ State Key Laboratory of Elemento-Organic Chemistry Nankai University, Collaborative Innovation Center of Chemical Science and Engineering 300071 Tianjin, China.
⁵ Laboratory of Biologically Active Compounds, Institute of Technical Chemistry Ural Branch of Russian Academy of Sciences, 3 Academician Korolev str., Perm, Russia.
⁶ Medical University of Vienna, Department of Pediatrics, 14 Lazarettgasse, 1090 Vienna, Austria.
⁷ TOS Department, Ural Federal University named after the first President of Russia B.N. Yeltsin, 19 Mira str., 620002 Yekaterinburg, Russia; I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, 20 S. Kovalevskaya str., 620990 Yekaterinburg, Russia.

Abstract

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.

Keywords: [3 + 2]-cycloaddition; isoxazole; isoxazoline; nitrile oxide; β-azolyl enamine.