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The merger of decatungstate and copper catalysis to enable aliphatic C(sp3)–H trifluoromethylation

Nature Chemistry volume 12, pages 459–467 (2020)Cite this article

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Abstract

The introduction of a trifluoromethyl (CF3) group can dramatically improve a compound’s biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C–H bonds remain elusive. Here we report the development of a dual-catalytic C(sp3)–H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C–H bonds into the corresponding C(sp3)–CF3 products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a ‘Cu–CF3’ species is formed during this process and the critical C(sp3)–CF3 bond-forming step involves the copper catalyst.

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Fig. 1: Dual decatungstate/copper metallaphotoredox catalysis enables direct C(sp3)–H trifluoromethylation.
Fig. 2: Mechanistic design for direct C(sp3)–H trifluoromethylation via decatungstate and copper catalysis.
Fig. 3: Effect of chloride anion on reaction efficiency.
Fig. 4: Extension to benzylic C–H trifluoromethylation and application to natural products and pharmaceuticals.
Fig. 5: Mechanistic investigations into the role of copper.

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The data supporting the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

We acknowledge financial support from the National Institute of General Medical Sciences (NIGMS), the NIH (award no. R01 GM078201-05) to D.W.C.M., V.B. and P.J.S., and gifts from MSD, Abbvie, Pfizer and Janssen. P.J.S. and V.B. acknowledge Princeton University, E. Taylor and the Taylor family for an Edward C. Taylor Fellowship. We thank L. Wilson (Lotus Separations) for assistance with compound purification, D. Abrams for helpful discussions, I. Pelczer for assistance with NMR spectroscopy, O. Garry for synthesizing a batch of sodium decatungstate, I. Perry for providing a graphical rendering of the decatungstate anion and R. Martinie, H. Zhong and J. Eng for assistance with EPR spectroscopy. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.

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  1. These authors contributed equally: Patrick J. Sarver, Vlad Bacauanu.

Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, NJ, USA

    Patrick J. Sarver, Vlad Bacauanu & David W. C. MacMillan

  2. Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Danielle M. Schultz & Daniel A. DiRocco

  3. Computational and Structural Chemistry, Merck & Co., Inc., Rahway, NJ, USA

    Yu-hong Lam & Edward C. Sherer

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Contributions

P.J.S. and V.B. performed and analysed the experiments. P.J.S., V.B., D.M.S., D.A.D. and D.W.C.M. designed the experiments. Y.-h.L. and E.C.S. performed the computational analysis. P.J.S., V.B. and D.W.C.M. prepared the manuscript.

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Correspondence to David W. C. MacMillan.

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Experimental procedures, optimization data, mechanistic studies, computational data and product characterization data.

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Sarver, P.J., Bacauanu, V., Schultz, D.M. et al. The merger of decatungstate and copper catalysis to enable aliphatic C(sp3)–H trifluoromethylation. Nat. Chem. 12, 459–467 (2020). https://doi.org/10.1038/s41557-020-0436-1

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