Methylations with Methanol via Bioinspired Catalytic C–O bond Cleavage

Nature has a delicate system for catalysis due to optimization through evolution, which often displays unparalleled efficiency and selectivity. “learning from nature” is a popular and effective approach in designing new reactions and catalysts when traditional strategies fail. Here, we proved that it can be highly rewarding to consider nature’s repertoire of catalysis during the effort to facilitate the challenging heterolytic C–O bond cleavage of methanol (MeOH) by studying its metabolism by methyltransferase complex in certain methanogenic microorganisms that contains a Brønsted acid cluster flanked by a Zinc moiety, which led to the identification of the combination of an easily available Brønsted acid Cat.1 and Zn(OTf)2 as a highly efficient and practical binary catalyst for cooperative MeOH activation in various important methylation reactions, including some of those carried out in large scale in industry with significantly increased selectivity under relatively less demanding reaction conditions. This method activates MeOH via heterolytic C–O bond cleavage rather than C–H bond cleavage, therefore, inexpensive and less toxic CD3OD could be used directly as an effective d3-methylating agent. Mechanistic studies and density functional theory (DFT) calculations suggest a synergy between Cat.1 and Zn(OTf)2, suggestive of that found in methanol-activating MtaBC complex in Methanosarcina barkeri.