Improved Methodology for the Preparation of Chiral Amines

t-Butyl methyl
ether
15 - - 82
Hexane 60 - - 75
THF 20 - - 86
Methanol - - - 81
a
All reactions performed using 1.0 mmol of Benzylacetone, 1.1 mmol of (S)-(−)-α-Methylbenzylamine, 1.1
equiv of Yb(OAc) 3 , room temperature, 120 psi (8.3 bar) of H 2 , 100 wt % Raney Nickel, and solvent as
indicated. All components (except the Raney Ni and H 2 ) are added together and pre-stirred for 30 min. The
heterogeneous hydrogenation catalyst (Raney Ni) is then added and the system pressurized with 8 bar of H 2 . The
indicated data is at 12 h of reaction from the onset of hydrogenation.
The use of THF improved the de but the reaction was slower. Other solvents showed slower
reaction rate with low de. The high de resulting from the use of THF and the fast reaction rate
resulting from the use of methanol was the driving force to test the solvent combination of
THF-MeOH (1:1). The rate of the reaction was acceptable with high de (87-89%). Other
solvent combinations also were tested (table 5.3).
Table 5.3. Screening of Different Solvent Combinations with Ytterbium Acetate Hydrate. a
Solvent Ketone Left% Alc. Formed Imine Left de%
THF-DMF >90 - - NA
DCM-MeOH 77 - - 78
Isopropanol-
MeOH
15 - - 76
Toluene-MeOH 24 - - 82
EtOAc-MeOH 6 - - 86
THF-MeOH 2 - - 89
DME-MeOH 50 - - 85
DCE-MeOH 51 - - 80
DEE-MeOH 55 - - 84
a
All reactions performed using 1.0 mmol of Benzylacetone, 1.1 mmol of (S)-(−)-α-Methylbenzylamine, 1.1
equiv of Yb(OAc) 3 , room temperature, 120 psi (8.3 bar) of H 2 , 100 wt % Raney Nickel, and solvent as
107