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

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

Nature chemistry (2020-03-24)
Patrick J Sarver, Vlad Bacauanu, Danielle M Schultz, Daniel A DiRocco, Yu-Hong Lam, Edward C Sherer, David W C MacMillan
摘要

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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