Regioselective nucleophilic addition of 3-aryl-5-difluoromethyl-isoxazoles to aldehydes

A series of 5-difluoromethyl-isoxazoles 2 were prepared, and their regioselective nucleophilic addition to aldehydes was investigated. It was found that the nucleophilic difluoromethylation of aldehydes with 5-difluoromethyl-isoxazoles could be efficiently and uniquely achieved in the presence of LDA as a base that provides a large steric hindrance. In contrast, 3,4,5-trisubstituted 5-difluoromethyl isoxazoles were alternatively afforded as the sole product in moderate yields when n-BuLi was used as the base.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 5-Difluoromethyl-isoxazoles were applied as efficient nucleophilic reagents. ► The proper use of base play an important role. ► Aldehydes could be difluoromethylated by treatment of LDA as a base. ► Isoxazoles merit superior atom-economical feature in fluoroalkylation reactions.