Copper Hydride-Catalyzed Enantioselective Olefin Hydromethylation

18 July 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The enantioselective installation of a methyl group onto a small molecule can result in the significant modification of its biological properties. While hydroalkylation of olefins represents an attractive approach to introduce alkyl substituents, asymmetric hydromethylation protocols are often hampered by the incompatibility of highly reactive methylating reagents and a lack of general applicability. Herein, we report an asymmetric olefin hydromethylation protocol enabled by CuH catalysis. This approach leverages methyl tosylate as a methyl source compatible with the reducing base-containing reaction environment, while a catalytic amount of iodide ion transforms the methyl tosylate in situ into the active reactant, methyl iodide, to promote the hydromethylation. This method tolerates a wide range of functional groups, heterocycles, and pharmaceutically-relevant frameworks. Density functional theory studies suggest that the methylation step is stereoretentive, taking place through an SN2-type oxidative addition mechanism followed by a reductive elimination. The enantioselectivity is enforced by ligand–substrate steric repulsions during the hydrocupration step.


CuH Catalysis
Enantioselective Catalysis

Supplementary materials

Supporting Information
Experimental procedures and characterization data for all new compounds, including NMR spectra, SFC traces, computational details, and Cartesian coordinates of all computed structures


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