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.
At a glance
- 2010) , , eds. Modern Drug Synthesis (Wiley,
- 2005) , ed. Cytochrome P450: Structure, Mechanism, and Biochemistry (Springer,
- 1993) , , , eds. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications (Elsevier,
- Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007) , &
- Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008) , , &
- The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359–4369 (2008)
- Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011) &
- Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011) , &
- Aromatic trifluoromethylation catalytic in copper. Chem. Commun. 1909–1911 (2009) , &
- The palladium-catalyzed trifluoromethylation of aryl chlorides. Science 328, 1679–1681 (2010) et al.
- Pd (II)-catalyzed ortho-trifluoromethylation of arenes using TFA as a promoter. J. Am. Chem. Soc. 132, 3648–3649 (2010) , &
- Copper-catalyzed trifluoromethylation of aryl boronic acids using a CF3+ reagent. Chem. Commun. 47, 4300–4302 (2011) et al.
- Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008) &
- Visible light photocatalysis as a greener approach to photochemical synthesis. Nature Chem. 2, 527–532 (2010) , &
- Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011) &
- Ru(II) polypyridine complexes: photophysics, photochemistry, electrochemistry, and chemiluminescence. Coord. Chem. Rev. 84, 85–277 (1988) et al.
- Enantioselective α-trifluoromethylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 131, 10875–10877 (2009) , &
- Outer-sphere dissociative electron transfer to organic molecules: a source of radicals or carbanions? Direct and indirect electrochemistry of perfluoroalkyl bromides and iodides. J. Am. Chem. Soc. 112, 3509–3520 (1990) , , , &
- Luminescent metal complexes. Part 3. Electrochemical potentials of ground and excited states of ring-substituted 2,2’-bipyridyl and 1,10-phenanthroline tris-complexes of ruthenium. J. Chem. Soc. Perkin Trans. 2 1309–1311 (1984) et al.
- Predicting the reactivity of fluorinated compounds with copper using semi-empirical calculations. J. Fluor. Chem. 107, 1–3 (2001) , &
- Introduction of perfluoroalkyl groups — a new approach. J. Fluor. Chem. 45, 86 (1989) &
- Reactions of perfluoroalkanesulfonyl chlorides with aromatic compounds catalyzed by a ruthenium (II) complex. Chem. Lett. 19, 649–650 (1990) , &
- Direct perfluoroalkylation of aromatic and heteroaromatic compounds with perfluoroalkanesulfonyl chlorides catalysed by a ruthenium(II) phosphine complex. J. Chem. Soc. Perkin Trans. 1 1339–1346 (1994) , , , &
- Fluorinated free radicals. Top. Curr. Chem. 192, 97–163 (1997)
- Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. Tetrahedron Lett. 32, 7525–7528 (1991) , &
- Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents. J. Fluor. Chem. 131, 951–957 (2010) , &
- Oxidation of hydroxycyclohexadienyl radical by metal ions. J. Phys. Chem. 78, 2335–2338 (1974) &
- The clinical pharmacology of 5-trifluoromethyl-2'-deoxyuridine. Cancer Res. 32, 247–253 (1972) , , , &
- The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem. 40, 1–22 (2002)
- Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011) et al.
- Supplementary Information (8.6M)
This file contains Supplementary Text and Data including Supplementary Figures 1-2 (sections 1-5) and NMR Spectra (section 6) - see contents for details.