Enantioselective Intermolecular Aminofluorination of Alkenes via I(I)/I(III) Catalysis

The regio- and enantio-selective, intermolecular vicinal fluoroamination of α-trifluoromethyl styrenes has been achieved under the auspices of enantioselective I(I)/I(III) catalysis. Leveraging C2-symmetric resorcinol-based aryl iodide catalysts, it has been possible to intercept the transient iodonium intermediate using simple nitriles, which function as both the solvent and nucleophile. In situ Ritter reaction, via the ephemeral nitrilium species, provides direct access to the corresponding amides (>25 examples, up to 89% yield, e.r. 93:7). This main group catalysis paradigm inverts the intrinsic regioselectivity of the uncatalyzed process, thereby providing facile access to tertiary, benzylic stereocenters bearing both CF3 and F groups. Privileged phenethylamine pharmacophores can be generated in which there is complete local partial charge inversion (CF3δ-/Fδ- versus CH3δ+/Hδ+). Crystallographic analyses of representative β-fluoroamide products reveal conformations that manifest the stereoelectronic gauche effect, leading to highly preorganized modules for next generation drug discovery.