Improved Methodology for the Preparation of Chiral Amines

Table 7.1. Closer Examination of the Reductive Amination of 2-Octanone. a Amine 2d
fully consistent with that found at the end of the reaction (table 7.1). The consistent
diastereoselectivity throughout the whole reaction suggests that one mechanism is operating
from the first minute till the end of the reaction. This conclusion is applicable on Yb(OAc) 3
,Ti(O i Pr) 3 system and even when no Lewis acid was used. Despite the importance of this
conclusion the origin of enhanced diastereoselectivity was not clarified.
entry additive time
(h)
2-octanone
(S)-α-
(%) b
MBA (%)
2-octanol (%) yield (%) de (%)
1 Yb(OAc) 3 1 c
3 d 18.1
12.5
6.5
2.5
0.5
1.0
73.9
81.5
87.1
87.2
2 Ti(O i Pr) 4 1
43.9
7.9
0.63
47.6
67.0
3
8.5
4.0
2.1
85.4
67.0
3 none 1
47.1
10.5
16.6
25.8
72.0
3
29.2
1.1
27.6
42.2
72.1
a 2-octanone (2.5 mmol, 1.0 equiv), (S)-α-MBA (1.1 equiv), Yb(OAc) 3 or Ti(O i Pr) 4 (1.1 equiv) are stirred in
MeOH (1.0 M) for 90 min at rt, then THF (final molarity 0.5 M) and Ra-Ni (100 wt %) are added, and the
reaction pressurized with H 2 (8.3 bar/120 psi). All data is based on GC area % analysis. b Sum of (S)-α-MBA
and imine remaining. c 1.0 area % of (±)-2-aminooctane was noted. d 2.5 area % (±)-2-aminooctane was noted.
In the process of searching for the origin of enhanced diastereoselectivity I tried to collect
information about the in situ imine formation. Samples were taken from mixture of 2-
octanone and (S)-α-MBA after 30 min with no additive or with Ti(O i Pr) 4 (1.25 equiv) and
analyzed by GC. In both reactions the area % of the imine was almost similar. Comparing
these results with results obtained from mixing 2-octanone and (S)-α-MBA after 30 min with
Yb(OAc) 3 (1.1 equiv) showed that no appreciable amounts of imine (< 3 area %) was
detected when Yb(OAc) 3 was used. Extending the reaction time upto 12 h aiming to force the
imine formation did not show any success (table 7.2).
Table 7.2. In Situ Imine Formation Study: 2-Octanone and (S)-α-MBA. a
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