Remote dipole effects as a means to accelerate [Ru(amino alcohol)]-catalyzed transfer hydrogenation of ketones

A new generation of 2-aza-norbornyl amino alcohol ligands for the catalytic transfer hydrogenation reaction of aromatic ketones was synthesized. Extremely active catalysts were formed by introducing a ketal functionality at the rear end of the ligand. Acetophenone was reduced in 96% ee at low catalyst loading, substrate to catalyst ratio, S/C 5000, within 90 minutes with isopropyl alcohol as the hydrogen donor. It was found that the dioxolane substituent in the ligand increased the turnover frequency, TOF50, from 1050 h(-1) to 3000 h(-1) at an S/C ratio of 1000. Introduction of a methyl group at the carbinol carbon resulted in TOF50 as high as 8500 h(-1). Transfer hydrogenation of a range of aromatic ketones was evaluated and found to reach completion within 30 minutes at room temperature, and excellent enantioselectivity, up to 99 % ee, was obtained. A possible explanation for the enhanced activity was provided by density functional calculations, which showed that the presence of a remote dipole in the ligand lowered the transition state energy.