The goal of this research proposal is to develop catalyst-controlled regioselective methodologies for the addition of radicals into pharmaceutically relevant aromatic scaffolds. Particularly, we are interested in directing electrophilic perfluoroalkyl radicals (i.e. CF3) into aromatics and heterocycles. We propose to use a Lewis basic catalyst (LBC) approach to control the regioselectivity of electrophilic radical additions through a mechanism that is analogous to electrophilic aromatic substitution (SEAr). Bifunctional catalysts that contain Lewis bases and a H-bonding handle have been shown to form non-covalent interactions with the substrate via hydrogen bonding, allowing for the directed activation of the electrophile and subsequent coordination to the substrate. Preliminary data suggests that different LBCs can yield different constitutional isomers. Mechanistic studies for this project will be able to reveal key features of the innerworkings of Lewis basic catalyst control in order to develop more specialized catalysts for a variety of reaction systems.

Catalyst-controlled regioselective trifluoromethylations of arenes and hetero arenes

ACS Spring 2022

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