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

Abstract

Ether synthesis is a ubiquitous transformation in both research and industrial settings. In this respect, reductive etherification of carbonyl compounds with alcohols using H 2 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 H 2 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. • Cobalt/Lewis acid cooperative catalysis for reductive etherification • A slight excess of alcohols • Excellent functional group tolerance and high selectivity • Detailed mechanistic investigations Ether synthesis is a ubiquitous transformation in both research and industrial settings. The Williamson ether synthesis is a long-established method for the synthesis of primary alkyl ethers via SN2 substitution. However, in contexts involving secondary or tertiary alkyl halides, the reaction often derails, leading to elimination byproducts or to no reaction at all. In this respect, reductive etherification of carbonyl compounds with alcohols using H 2 as the reductant represents an alternative ideal approach. Nevertheless, in contrast to the well-established reductive amination, the development of reductive etherification has fallen far behind, being restricted by more side reaction due to a slower formation of oxocarbenium intermediates. In this work, we disclosed a novel cooperative cobalt/Lewis acid (LA)-catalytic system, which enabled effective reductive etherification of ketones and aldehydes with alcohols using H 2 as the reductant. A cobalt/Lewis acid cooperative catalytic process for reductive etherification of ketones and aldehydes with alcohols was developed. The notable feature of this methodology is the ability to effectively control reaction selectivity, enabling different reaction pathways to form the same ether product rather than accessing to various possible side products.