Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents1. One such challenge arises from the enzymatic metabolism of drugs in vivo by cytochrome P450 oxidases, which use single-electron oxidative mechanisms to rapidly modify small molecules to facilitate their excretion2. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF3) group, into drug candidates3. The CF3 group enjoys a privileged role in the realm of medicinal chemistry because its incorporation into small molecules often enhances efficacy by promoting electrostatic interactions with targets, improving cellular membrane permeability, and increasing robustness towards oxidative metabolism of the drug4,5,6. Although common pharmacophores often bear CF3 motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF3 group, or a surrogate moiety, at the start of a multi-step synthetic sequence. Here we report a mild, operationally simple strategy for the direct trifluoromethylation of unactivated arenes and heteroarenes through a radical-mediated mechanism using commercial photocatalysts and a household light bulb. We demonstrate the broad utility of this transformation through addition of CF3 to a number of heteroaromatic and aromatic systems. The benefit to medicinal chemistry and applicability to late-stage drug development is also shown through examples of the direct trifluoromethylation of widely prescribed pharmaceutical agents.
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Financial support was provided by the NIH General Medical Sciences (R01 01 GM093213-01) and gifts from Merck, Amgen, Abbott and Bristol-Myers Squibb. We thank C. Kraml and N. Byrne of Lotus Separations LLC for their development of preparatory supercritical fluid chromatography (SFC) methods and for the separation of all three CF3-Lipitor analogues.
The authors declare no competing financial interests.
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Nagib, D., MacMillan, D. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480, 224–228 (2011). https://doi.org/10.1038/nature10647
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