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

Jin-Fay Tan, Yi Cheng Kang and John F. Hartwig ()
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Jin-Fay Tan: University of California
Yi Cheng Kang: University of California
John F. Hartwig: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52245-1

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