Cobalt/Lewis acid cooperative catalysis for reductive etherification of ketones and aldehydes with alcohols

Ether synthesis is a ubiquitous transformation in both research and industrial settings. In this respect, reductive etherification of carbonyl compounds with alcohols using H2 as the reductant represents an ideal approach due to the ready availability of reactants, high atom economy, and potential for product diversity. Nevertheless, in contrast to the well-established reductive amination, the development of reductive etherification has fallen far behind, limited by more side reaction pathways. Herein we report a novel cooperative cobalt/Lewis acid (LA)-catalyzed reductive etherification of ketones and aldehydes with alcohols using H2 as the reductant. The LA co-catalyst is crucial for the effective control of chemoselectivity by facilitating the formation and hydrogenolysis of (hemi)ketal intermediates. In addition, the direct hydrogenation products of ketone can be further converted to ether products via LA-catalyzed etherification with alcohol substrates. The utility and scope were demonstrated by an efficient synthesis of multifarious ether molecules, including pharmaceuticals and nature product derivatives.