Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis

Journal name:
Nature
Volume:
480,
Pages:
224–228
Date published:
DOI:
doi:10.1038/nature10647
Received
Accepted

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

Figures

  1. Direct trifluoromethylation of aryl and heteroaryl C-H bonds.
    Figure 1: Direct trifluoromethylation of aryl and heteroaryl C–H bonds.

    The excretion of medicinal agents is facilitated by remote functionalization of aromatic moieties (a). A common medicinal chemistry approach to block this catabolism involves cross-coupling of CF3 reagents to pre-functionalized arenes (b). In analogy to enzymatic processes, our photoredox strategy (c) enables the direct C–H functionalization of unfunctionalized arenes and heteroarenes with the CF3 pharmacophore using a cheap and easy to handle ·CF3 source.

  2. Proposed mechanism for the direct trifluoromethylation of aryl C-H bonds via photoredox catalysis.
    Figure 2: Proposed mechanism for the direct trifluoromethylation of aryl C–H bonds via photoredox catalysis.

    The photoredox catalytic cycle is initiated via excitation of photocatalyst 1 to excited state 2 with a household light bulb. Subsequent reduction of triflyl chloride by reductant 2 (via single electron transfer, that is, SET) provides oxidant 3 along with the radical anion of triflyl chloride. This high energy species spontaneously collapses to form CF3 radical (top left), which selectively combines with aromatic systems enabling direct CF3 substitution. Catalyst 3-promoted oxidation of the ensuing radical 4 completes the catalytic cycle and provides cyclohexadienyl cation 5, whose facile deprotonation provides the desired CF3 arene. This mechanism is consistent with measured redox values (shown below respective compounds, in maroon).

  3. Radical trifluoromethylation of five- and six-membered heteroarenes and C-H arenes via photoredox catalysis.
    Figure 3: Radical trifluoromethylation of five- and six-membered heteroarenes and C–H arenes via photoredox catalysis.

    Aromatic and heteroaromatic systems with varying stereoelectronics are efficiently trifluoromethylated under these standard conditions (top, generalized reaction). Substrate scope includes electron-rich five-atom heteroarenes (a), electron-deficient six-atom heteroarenes (b), and unactivated arenes (c). Isolated yields are indicated below each entry (19F NMR yields for volatile compounds). See Supplementary Information for experimental details. Abbreviations: X, Y, A, B, C represent either C, N, O, or S; MeCN, acetonitrile; Me, methyl; Boc, tert-butoxycarbonyl; Ac, acyl; tBu, tert-butyl. *The minor regioisomeric position is labelled with the respective carbon atom number.

  4. Direct trifluoromethylation of biologically active molecules.
    Figure 4: Direct trifluoromethylation of biologically active molecules.

    Subjecting common medicinal agents and other biologically active molecules to our standard photoredox protocol enables direct CF3 installation selectively at metabolically susceptible positions of some molecules (a). Alternatively, C–H functionalization of more metabolically stable medicines occurs non-selectively, allowing for rapid access to drug analogues (b). The promiscuous modification of equally reactive π-systems, such as the arenes in Lipitor, may be followed by separation of isomers (for example, via supercritical fluid chromatography, SFC) for rapid screening of biological activity (c).

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Author information

Affiliations

  1. Merck Center for Catalysis at Princeton University, Department of Chemistry, 192 Frick Laboratory, Princeton, New Jersey 08540, USA

    • David A. Nagib &
    • David W. C. MacMillan

Contributions

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. (dmacmill@princeton.edu).

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The authors declare no competing financial interests.

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Supplementary information

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  1. 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.

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