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Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis


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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Figure 1: Direct trifluoromethylation of aryl and heteroaryl C–H bonds.
Figure 2: Proposed mechanism for the direct trifluoromethylation of aryl C–H bonds via photoredox catalysis.
Figure 3: Radical trifluoromethylation of five- and six-membered heteroarenes and C–H arenes via photoredox catalysis.
Figure 4: Direct trifluoromethylation of biologically active molecules.


  1. Li J. J., Johnson, D. S., eds. Modern Drug Synthesis (Wiley, 2010)

    Book  Google Scholar 

  2. Montellano P. R. O., ed. Cytochrome P450: Structure, Mechanism, and Biochemistry (Springer, 2005)

    Book  Google Scholar 

  3. Filler R., Kobayashi Y., Yagupolskii L. M., eds. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications (Elsevier, 1993)

    Google Scholar 

  4. Muller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007)

    Article  ADS  Google Scholar 

  5. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 37, 320–330 (2008)

    Article  CAS  Google Scholar 

  6. Hagmann, W. K. The many roles for fluorine in medicinal chemistry. J. Med. Chem. 51, 4359–4369 (2008)

    Article  CAS  Google Scholar 

  7. Tomashenko, O. A. & Grushin, V. V. Aromatic trifluoromethylation with metal complexes. Chem. Rev. 111, 4475–4521 (2011)

    Article  CAS  Google Scholar 

  8. Furuya, T., Kamlet, A. S. & Ritter, T. Catalysis for fluorination and trifluoromethylation. Nature 473, 470–477 (2011)

    Article  CAS  ADS  Google Scholar 

  9. Oishi, M., Kondo, H. & Amii, H. Aromatic trifluoromethylation catalytic in copper. Chem. Commun. 1909–1911 (2009)

  10. Cho, E. J. et al. The palladium-catalyzed trifluoromethylation of aryl chlorides. Science 328, 1679–1681 (2010)

    Article  CAS  ADS  Google Scholar 

  11. Wang, X., Truesdale, L. & Yu, J. Q. Pd (II)-catalyzed ortho-trifluoromethylation of arenes using TFA as a promoter. J. Am. Chem. Soc. 132, 3648–3649 (2010)

    Article  CAS  Google Scholar 

  12. Xu, J. et al. Copper-catalyzed trifluoromethylation of aryl boronic acids using a CF3+ reagent. Chem. Commun. 47, 4300–4302 (2011)

    Article  CAS  Google Scholar 

  13. Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: the direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008)

    Article  CAS  ADS  Google Scholar 

  14. Yoon, T. P., Ischay, M. A. & Du, J. Visible light photocatalysis as a greener approach to photochemical synthesis. Nature Chem. 2, 527–532 (2010)

    Article  CAS  ADS  Google Scholar 

  15. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011)

    Article  CAS  Google Scholar 

  16. Juris, A. et al. Ru(II) polypyridine complexes: photophysics, photochemistry, electrochemistry, and chemiluminescence. Coord. Chem. Rev. 84, 85–277 (1988)

    Article  CAS  Google Scholar 

  17. Nagib, D. A., Scott, M. E. & MacMillan, D. W. C. Enantioselective α-trifluoromethylation of aldehydes via photoredox organocatalysis. J. Am. Chem. Soc. 131, 10875–10877 (2009)

    Article  CAS  Google Scholar 

  18. Andrieux, C. P., Gelis, L., Medebielle, M., Pinson, J. & Saveant, J.-M. 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)

    Article  CAS  Google Scholar 

  19. Skarda, V. et al. 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)

  20. Heaton, C. A., Miller, A. K. & Powell, R. L. Predicting the reactivity of fluorinated compounds with copper using semi-empirical calculations. J. Fluor. Chem. 107, 1–3 (2001)

    Article  CAS  Google Scholar 

  21. Heaton, C. A. & Powell, R. L. Introduction of perfluoroalkyl groups — a new approach. J. Fluor. Chem. 45, 86 (1989)

    Article  Google Scholar 

  22. Kamigata, N., Fukushima, T. & Yoshida, M. Reactions of perfluoroalkanesulfonyl chlorides with aromatic compounds catalyzed by a ruthenium (II) complex. Chem. Lett. 19, 649–650 (1990)

    Article  Google Scholar 

  23. Kamigata, N., Ohtsuka, T., Fukushima, T., Yoshida, M. & Shimizu, T. 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)

  24. Dolbier, W. Fluorinated free radicals. Top. Curr. Chem. 192, 97–163 (1997)

    Article  CAS  Google Scholar 

  25. Langlois, B. R., Laurent, E. & Roidot, N. Trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. Tetrahedron Lett. 32, 7525–7528 (1991)

    Article  CAS  Google Scholar 

  26. Wiehn, M. S., Vinogradova, E. V. & Togni, A. Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents. J. Fluor. Chem. 131, 951–957 (2010)

    Article  CAS  Google Scholar 

  27. Bahtia, K. & Schuler, R. H. Oxidation of hydroxycyclohexadienyl radical by metal ions. J. Phys. Chem. 78, 2335–2338 (1974)

    Article  Google Scholar 

  28. Dexter, D. L., Wolberg, W. H., Ansfield, F. J., Helson, L. & Heidelberger, C. The clinical pharmacology of 5-trifluoromethyl-2'-deoxyuridine. Cancer Res. 32, 247–253 (1972)

    CAS  PubMed  Google Scholar 

  29. Roth, B. D. The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem. 40, 1–22 (2002)

    Article  CAS  Google Scholar 

  30. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011)

    Article  CAS  ADS  Google Scholar 

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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.

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D.A.N. performed and analysed experiments. D.A.N. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and also prepared this manuscript. Correspondence and requests for materials should be addressed to D.W.C.M. (

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Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Text and Data including Supplementary Figures 1-2 (sections 1-5) and NMR Spectra (section 6) - see contents for details. (PDF 8857 kb)

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Nagib, D., MacMillan, D. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480, 224–228 (2011).

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