Asymmetric Hydrogenations One by One: Differentiation of up to Three β‐Ketocarboxylic Acid Derivatives Based on Ruthenium(II)–Binap Catalysis

Abstract Noyori‐type reductions of pairs of β‐ketoamides and β‐ketoesters with elemental hydrogen (4 bar) proceeded substrate by substrate. When Et 2 NH 2 + [{RuCl( S )‐binap} 2 ](μ‐Cl) 3 − was employed as a catalyst in a methanol or ethanol solution, the substrates were reduced at room temperature in the order β‐ketopyrrolidide ≥ β‐ketopiperidide ≥ β‐keto( N , N ‐diethylamide) > β‐keto(alkyl esters) > β‐keto(oligofluoroalkyl esters). This is the first time that β‐ketoamides have been reduced asymmetrically (91 to >98 % ee ) under such mild conditions. Monitoring the concentrations of these β‐ketocarboxyl acid derivatives and their respective hydrogenation products over the course of time showed that the most electron‐rich substrate is captured by the catalyst preferentially and exothermically; whether this occurs reversibly or irreversibly remains to be determined. The hydrogenation product is subsequently formed. The last transformation includes the rate‐determining step. The combination of these events explains why starting from appropriate mixtures of substrates a “first‐choice substrate” reacted from early on while the “second‐choice substrate” stayed virtually untouched over an extended period of time and reacted no earlier than after the “first‐choice substrate” had disappeared. From then onward, however, the “second‐choice substrate” also reacted relatively rapidly.