Development of a Stepwise Reductive Deoxygenation Process by Ru-Catalysed Homogeneous Ketone Reduction and Pd-Catalysed Hydrogenolysis in the Presence of Cu Salts

A stepwise catalytic reduction of ketone 1 to alcohol 2 and subsequently to aryl(imidazo[1,2-b]pyridazinyl)methane 3 is described, which provides synthetically useful chemoselectivity at acceptably low catalyst loadings. Undesired reactive sites include an aryl chloride, heteroarylchloride and benzylic amine group. The presence of these functional groups presents a significant challenge to chemoselectivity for both reduction steps. For selective CO reduction of highly functionalised 1, high chemoselectivity was observed at low catalyst loading by using Wills' tethered Ru transfer-hydrogenation catalyst 13. The selective hydrogenolysis of 2 was then accomplished under acidic hydrogenation conditions by using a Pd/C catalyst in the presence of Cu salts. This procedure has been demonstrated on a multi-gram scale, which makes this approach a viable method to use a combination of homogeneous and heterogeneous catalysis.