Amide Hydrogenation: for Every Demand a Catalyst

For the preparation of structurally complex bio-active compounds and natural products a preferred route to C-N bond formation combines amidation followed by reduction. Compared to classical reduction methods (LiAlH4 and B2H6) and heterogeneous catalysts, homogeneous catalysts offer a greener alternative to the former and operate under milder reaction conditions than the latter, which is beneficial for selectivity and functional group tolerance. We have developed two catalytic systems: a novel ruthenium pincer phosphinoaminoimidazolyl complex has been synthetized1 which is competent for the hydrogenolysis of different substituted amides to the corresponding alcohols and amines without base under relatively mild conditions (path a).1a Less reactive aliphatic and aromatic primary amides have been successfully reduced with such a system for the first time. The higher amine is preferentially obtained by applying [Ru(acac)3]/Triphos (path b):2 key to the transformation is Yb(OTf)3, in the presence of which the activity and substrate scope of this catalyst for the hydrogenation of aliphatic and aromatic secondary and tertiary amides could be improved significantly compared to previous work.3 No special care is needed and the reactions can be simply set in air. Control experiments indicate a different mechanism for this important transformation: after the initial reduction of the amide carbonyl group to the hemiaminal, this intermediate collapses to give the alcohol and the non-alkylated amine. These compounds slowly produce the desired product via a hydrogen borrowing mechanism. The synergistic combination of Ru/Triphos and the metal triflate is necessary for both steps.