A Deoxyfluoroalkylation/Aromatization Strategy to Access Highly Substituted Fluoroalkyl (Hetero)Arenes

Fluorination reactions are essential to pharmaceutical, agrochemical, and material sciences. Specifically, trifluoromethyl arenes/heteroarenes {(Het)Ar–CF₃} are the number one fluorine-containing substructure in agrochemicals and the second most common fluorine-containing substructure in pharmaceuticals. To access (Het)Ar–CF₃, synthetic chemists typically employ Swart’s method, transition-metal catalyzed trifluoromethylation reactions of aryl electrophiles and nucleophiles, radical trifluoromethylation reactions of C­–H-containing arenes, and annulation strategies. However, these methods suffer from several limitations, including harsh conditions that do not tolerate many important functional groups, lack of availability of certain substrates and poor regioselectivity. Combined, these limitations restrict access to highly substituted (Het)Ar–CF₃ compounds, which are valuable substructures in pharmaceutical, agrochemical, and material sectors.

To combat limitations in accessing highly substituted (Het)Ar–CF₃ compounds, innovative strategies to deliver these impactful yet challenging substructures are warranted. To develop such a strategy, we present a deoxyfluoroalkylation-aromatization approach that exploits readily accessible cyclohexanone or piperidone precursors as substrates. In this strategy, substrates are built either by (a) systematic functionalization of cyclohexanone/piperidone to introduce the desired substituents, (b) annulation strategies, or (c) reduction of aromatic ethers. Subsequently, our methodology involves subjecting the cyclohexanone/piperidone precursor to a reliable 1,2-addition reaction with the Ruppert-Prakash reagent (TMSCF₃) followed by various dehydration and aromatization conditions to deliver highly substituted (Het)Ar–CF₃ compounds in a one/two-pot sequence under both thermal and light conditions. This deoxyfluoroalkylation-aromatization strategy enables access to highly substituted (Het)Ar–CF₃ compounds that are difficult, expensive, or impossible to access by current synthetic methods, expanding the scope of valuable (Het)Ar–CF₃ compounds.