Improved Methodology for the Preparation of Chiral Amines

The reactions described above all used 100 wt % Raney-Ni, based on the limiting ketone
reagent, and this quantity is not untypical for the use of this heterogeneous hydrogenation
catalyst regarding reductive amination and imine reduction. [3]
I tried to study the effect of reducing heterogeneous catalyst loading on the rate of the
reaction and the de. I found that using 50 wt % of Raney-Ni in combination with dried
Yb(OAc) 3 did not allow complete consumption of the ketone (8 area % remained unreacted)
within the standard room temperature and 12 h reaction time. It is known that increasing the
temperature increases reaction rate, so I increased the temperature (40 o C) and pressure (20
bar) simultaneously (table 6.2, compare entries 2 and 3), the reaction could be completed
before 12 h without compromising the diastereoselectivity of the secondary amine.
When 25 wt % of Raney-Ni was used 50% of unreacted ketone was detected after 12 h.
Table 6.2. Raney-Ni loading: Reductive Amination of 2-Octanone for 12 h a
Entry Raney-Ni (wt %) Ketone (area %) [b] de [b]
1 100 0 72
2 50 8 72
3 [c] 50 0 71
4 25 47 71
a
Reaction conditions: 2-octanone (2.5 mmol), Yb(OAc) 3 (15 mol %), (S)-α-methylbenzylamine (1.1
equiv), Raney-Ni, H 2 (8.3 bar), 0.5 M, 12 h, 22 o C. b GC analysis. c H 2 (20 bar), T= 40 o C.
After finalizing the different useful Lewis acids categories, I tested the use of 10 mol % of
Yb(OAc) 3 for reductive amination of different ketone substrates. The following table
summarizes the results obtained from our study.
Table 6.3. 10 mol % Yb(OAc) 3 Catalyzed Reductive Amination: Substrate Breadth. a
entry ketone 1
secondary amine 2
yield % b
de % c
121