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.

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 ^•NCF₃ source.

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).

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.

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).