Selective transfer hydrogenations : Catalyst development and mechanistic investigations

Abstract: By generating a library of amino acid-based ligands, pseudo-dipeptides, and combining them with transition metals, we have created selective and efficient ruthenium and rhodium catalysts for the asymmetric transfer hydrogenation of ketones. The ruthenium-catalyzed reaction was studied in detail, and we found that alkali metals play a crucial role for the reactivity and selectivity of the reaction. Furthermore, we have performed kinetic studies on the catalytic system, and the experimental data does neither support the established inner-sphere nor the classical outer-sphere mechanism. Hence, a novel mechanism for the ruthenium-pseudo-dipeptide-catalyzed transfer hydrogenation is proposed. In this unprecedented outer-sphere mechanism, a hydride and an alkali metal ion are transferred from the donor to the ruthenium complex in the rate determining step. In addition, the pseudo-dipeptide ligands were employed in the rhodium-catalyzed transfer hydrogenation of aryl alkyl ketones to yield the corresponding alcohols in high yields and excellent enantioselectivities (up to 98% ee). The study revealed that the alkali metals, so important in the ruthenium analogue of the reaction, do not improve the enantioselectivity of the reaction. Deuterium labeling experiments showed that the reaction follows the mono hydridic route. Furthermore, a novel method for efficient catalyst screening has been developed. We have demonstrated that ligand synthesis, catalyst formation, and enantioselective catalysis can be performed using an in situ one-pot procedure. The efficacy of the concept was demonstrated in the enantioselective reduction of ketones. In addition to the simplification of the catalyst formation, this approach resulted in improvement of the product ee.Finally, the development of a reduction protocol for the transfer hydrogenation of ketones to alcohols without the involvement of transition metal catalysts is described. Using microwave irradiation, a range of ketones was efficiently reduced in high yields using catalytic amounts of lithium 2-propoxide in 2-propanol.