Cross-selective Deoxygenative Coupling of Aliphatic Alcohols: Installation of Methyl Groups including Isotopic Labels by Nickel Catalysis

Nickel-catalyzed cross-electrophile coupling reactions of two aliphatic alcohol derivatives remain a challenge. Herein, we report a nickel-catalyzed reductive methylation reaction of aliphatic mesylates with methyl tosylate. This reaction provides straightforward access to compounds bearing aliphatic methyl groups from alkyl alcohol derivatives. Isotopically labelled substrates and reagents can be employed in the reaction to provide perdeuterated and 13C-labelled products. This transformation can be achieved by employing stoichiometric Mn reductant or electrochemically. Additionally, mechanistic experiments show that alkyl iodides are key intermediates in the transformation which undergo a stereoablative reaction via radical intermediates. This nickel-catalyzed cross-electrophile coupling reaction provides, for the first time, a cross-selective reaction of two alcohols. Methanol, activated as methyl tosylate, undergoes XEC with a range of secondary alcohols activated as the corresponding mesylates. Catalyst turnover is achieved with a stoichiometric reducing metal or electrochemically. This transformation provides facile incorporation of isotopic labels, by deuteration of ketone intermediates and/or employing isotopically labelled methanol. image