Improved Methodology for the Preparation of Chiral Amines

2-octanone starting material. When the binary solvent system of MeOH-THF (1:1) was
examined, an 86% de was consistently achieved with a fast reaction time of 10-12 h. The
same solvent systems which proved to be efficient in the reductive amination of
benzylacetone were also useful in the reductive amination of 2-octanone. From solvent
screening studies it was obvious that the presence of MeOH in the solvent mixture is essential
for the fast reaction rate. Replacement of THF in THF-MeOH mixture with other solvents
resulted in lower de or/and prolonged reaction time. The same de was obtained through
replacing THF in the THF-MeOH system with toluene, Et 2 O, or 1,3-dioxolane but with
moderately longer reaction times. Replacing MeOH with EtOH in THF-MeOH system
resulted in the same de but the reaction time was longer (24h). To ensure that this high
diastereoselectivity is maintained and no racemization is occurring, I hydrogenolyzed the
reductive amination product to ensure that the enantiopurity of the primary amine is
preserved (scheme 5.1.). This level of diastereoselectivity represents a 15-16% increase in the
de over the best previously reported for 2-octanone and α-MBA.
1d
O
+
H 2 N
Ph
(S)-α-MBA
Yb(OAc)3 ,MeOH-THF
Raney-Ni, H 2 (120 psi)
(S,S)-2d HN Ph Pd-C
(S)-3d NH 2
H 2 (60 psi)
86% de 85% ee
Scheme 5.1. Two-Step Procedure for Producing (2S)-Aminooctane in High ee.
The high de obtained in reductive amination of benzylacetone and 2-ocatnone utilizing
Yb(OAc) 3 encouraged us to test and evaluate other ytterbium salts present commercially. As
mentioned before Yb(OTf) 3 is the most common derivative of ytterbium used in organic
synthesis. When Yb(OTf) 3 was used in reductive amination of 2-ocatnone alcohol was the
major product. No amine was detected after 10 h or the reaction. YbCl 3 provided the product
in 66% de, but in only 23 area % (GC) after 24 h (Table 5.4, entries 2 and 3). The use of
highly expensive salt of ytterbium which is Yb(O i Pr) 3 resulted also in alcohol formation and
no secondary amine was detected. From previous findings it is obvious that Yb(OAc) 3 is the
best form of ytterbium to be used in reductive amination. Of course to eliminate any doubts
regarding free acetate in solution modifying the heterogeneous metal surface of the catalyst,
acetate salts were tested alone in the reaction. The addition of NaOAc was examined (Table
5.4, entry 9). In the event, gross quantities of the alcohol by-product resulted, making this
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