title: Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis.
abstract: Modern drug discovery relies on the continual development of synthetic methodology to address the many challenges associated with the design of new pharmaceutical agents. 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 excretion. A commonly used synthetic strategy to protect against in vivo metabolism involves the incorporation of electron-withdrawing functionality, such as the trifluoromethyl (CF(3)) group, into drug candidates. The CF(3) 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 drug. Although common pharmacophores often bear CF(3) motifs in an aromatic system, access to such analogues typically requires the incorporation of the CF(3) 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 CF(3) 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.
authors.affiliation: Merck Center for Catalysis at Princeton University, Department of Chemistry, 192 Frick Laboratory, Princeton, New Jersey 08540, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Nagib
authors.forename: David W C
authors.initials: DW
authors.lastname: MacMillan
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry; D000069059:Atorvastatin; D002384:Catalysis / Q000528:radiation effects; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D000077265:Donepezil; D015195:Drug Design; D047309:Flavones / Q000737:chemistry; D054879:Halogenation / Q000528:radiation effects*; D006538:Heptanoic Acids / Q000737:chemistry; D007189:Indans / Q000737:chemistry; D007536:Isomerism; D008027:Light; D008745:Methylation / Q000528:radiation effects; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000528:radiation effects; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D055668:Photochemical Processes / Q000528:radiation effects*; D010880:Piperidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000924:Anticholesteremic Agents; D002800:Cholinesterase Inhibitors; D047309:Flavones; D006538:Heptanoic Acids; D007189:Indans; D004364:Pharmaceutical Preparations; D010880:Piperidines; D011758:Pyrroles; D014498:Uracil; C008378:6-methyluracil; D000077265:Donepezil; D000069059:Atorvastatin; C043562:flavone