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Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules

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  • Jin-Fay Tan

    (University of California)

  • Yi Cheng Kang

    (University of California)

  • John F. Hartwig

    (University of California)

Abstract

In pharmaceutical discovery, the “magic methyl” effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp3)−H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp3)−H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp3)−H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C−H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C−H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the “magic methyl” effect in drug discovery.

Suggested Citation

  • Jin-Fay Tan & Yi Cheng Kang & John F. Hartwig, 2024. "Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52245-1
    DOI: 10.1038/s41467-024-52245-1
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