Deoxytrifluoromethylation/aromatization of cyclohexan(en)ones to access highly substituted trifluoromethyl arenes.

Abstract

Trifluoromethyl arenes (Ar-CF₃) are amongst the commonly encountered fluorinated substructures in pharmaceutical, agrochemical, and material sciences. However, predominant methods to access Ar-CF₃ possess several limitations, including harsh conditions, lack of availability of substrates, and poor regioselectivity, which combined restrict access to desirable highly functionalized Ar-CF₃-containing compounds. To expand the scope of accessible Ar-CF₃-based molecules, we present an orthogonal deoxyfluoroalkylation/aromatization approach that exploits readily accessible and programable cyclohexan(en)one substrates, which undergo a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF₃) followed by aromatization to deliver highly functionalized Ar-CF₃ compounds in a one/two-pot sequence. This general strategy enables access to highly substituted Ar-CF₃-containing molecules that are difficult, expensive, and/or impossible to access by current synthetic methods.