Continuous Flow Asymmetric Transfer Hydrogenation with Long Catalyst Lifetime and Low Metal Leaching

Homogenous iridium complexes with asymmetric ligands and different tether lengths have been solid-supported and prepared in multi-gram quantities. Packed in a fixed-bed, they have been used in continuous flow for up to 120 hours in the asymmetric transfer hydrogenation of APs in 2-propanol to make 1-phenethyl alcohols in > 95 % conversion and ee. The CsDPEN ligand and C-5 tether showed higher performance than TsDPEN and the C-14 tether, whilst the ketone feed concentration and reaction temperature were optimized to enable the catalyst to be used at 5 mol-% loading with a residence time of 39 minutes. The total amount iridium leaching of from the support during sustained operation was 58-147 ppm. The flow system gives higher catalyst turnover numbers than the related batch reactions, but the nature and concentration of the base were found to influence strongly the catalyst's performance, with the finding that triethylamine maintains high enantioselectivity but slowly deactivates the catalyst, whilst potassium tert-butoxide does the opposite. The utility of the system is shown in the high ee's and good conversions achieved for a range of aryl alcohols.