Iron-Catalyzed Cyclopropanation with Trifluoroethylamine Hydrochloride and Olefins in Aqueous Media: In Situ Generation of Trifluoromethyl Diazomethane

摘要

Our research group has been interested in the development of novel small-ring modules because of their potential ability to influence the pharmacokinetic properties of candidates in beneficial ways for the drug discovery process. Despite the increasing importance of organofluorine compounds, there are relatively few practical methods available for their ready synthesis in the medicinal chemistry laboratory. Among the various fluorinated groups, the trifluoromethyl group has become increasingly important; indeed, there have been recent advances in the development of chemical methods for the introduction of trifluoromethyl moieties that are note-worthy. It is striking, however, that the use and preparation of trifluoromethyl-substituted cyclopropanes is rare, which is likely correlated to the absence of practical, general methods for their synthesis. Herein, we describe a process that furnishes trifluoromethyl-substituted cyclopropanes from styrenes by a diazotization/carbene generation/cyclopropana-tion sequence [Eq. (1)].