Substituent effects in isoxazoles: identification of 4-substituted isoxazoles as Michael acceptors

Abstract

Crystallographic and theoretical studies have been used to investigate substituent effects, which are manifest in electrochemical and yeast-catalysed reactions of 4- and 5-acyl-, alkoxycarbonyl-, cyano- and phenyl-substituted isoxazoles. The results show that isoxazoles substituted at the 4-position with π-electron-withdrawing substituents have enhanced C4–C5 bond polarity and are structurally similar to Michael acceptors. As a consequence there is elongation and weakening of their N–O bonds. By contrast, their 5-substituted regioisomers and isoxazoles substituted at C4 with conjugating, but not π-electron-withdrawing, substituents have diminished C4–C5 bond polarity. This results in the selective electrochemical and yeast-catalysed reduction of 4-substituted isoxazoles, as well as their hydrogenolytic ring cleavage and conjugate reduction with sodium borohydride.