Asymmetric Hydrogenation of Quinolines and Isoquinolines Activated by ChloroformatesWe are grateful for the financial support from the National Science Foundation of China and Dalian Institute of Chemical Physics (K2004Eo3), Chinese Academy of Sciences

Despite significant progress in the area of asymmetric hydrogenation, the enantioselective hydrogenation of aromatic and heteroaromatic compounds still remains a major challenge. Only a few examples with moderate enantioselectivity, which rely on unique catalyst systems and suffer from a limited scope of suitable substrates, have been described so far. There are several reasons that might explain this situation. First, heteroaromatic compounds have a resonance stability that might impede enantioselective reduction with hydrogen. Second, heteroaromatic compounds containing nitrogen and sulfur atoms may poison the catalyst. Third, little attention has been directed to these challenging substrates relative to alkenes, ketones, and imines. The low activity of aromatic compounds may be the main reason. In spite of these difficulties, the search for an effective asymmetric hydrogenation of heteroaromatic compounds continues because of the usefulness and importance of a method for the preparation of optically active heteroaromatic compounds. Recently, we developed the first asymmetric hydrogenation of quinolines using [{IrCl(cod)}2]/MeO-biphep/I2 (cod= 1,5-cyclooctadiene; MeO-biphep= (2,2’-dimethoxybiphenyl6,6’-diyl)bis(diphenylphosphine) as the catalyst system. It was found that the substrate scope was limited to quinoline derivatives and that the hydrogenation reaction cannot proceed for isoquinolines under standard conditions. As tetrahydroquinolines and tetrahydroisoquinolines are important structural units in naturally occurring alkaloids and biologically active compounds, we are interested in exploring a general strategy for the asymmetric hydrogenation of aromatic compounds containing nitrogen. By analysis of the possible mechanism of the reported hydrogenation of aromatic compounds, we envisioned that the key factor for such reactions is to find a way to activate the substrate, and we selected chloroformates as the activating reagent for the following reasons: 1) the aromaticity should be partially destroyed by the formation of quinolinium and isoquinolinium salts; 2) bonding of the activating reagent to the N atom may avoid poisoning of the catalyst; and 3) the attached CO2R group is probably important for coordination between substrate and catalyst, and thus is beneficial to the control of enantioselectivity. Herein, we present our preliminary results on the asymmetric hydrogenation of quinolines and isoquinolines by this strategy (Scheme 1).