Improved Methodology for the Preparation of Chiral Amines

(S)-α-methylbenzylamine[(S)-α-MBA] 1.0 798.00
(R)-α-methylbenzylamine[(S)-α-MBA] 1.0 2.220.00
This auxiliary has been previously explored in literature for the synthesis of chiral amines.
The previous methods were based on the reduction of N-α-methylbenzyl ketimines, not on
reductive amination. [4]
For reductive amination, the principal side-reaction is the formation of an alcohol from the
competing hydrogenation of the carbonyl starting material. It could be stated that a desirable
attributes of an effective reductive amination method is the one capable of using atom
efficient reducing reagents and ideally do not allow alcohol formation. In that sense,
molecular hydrogen is an ideal source of hydride and the reduction of imine or iminium ion
intermediates must be fast relative to the reduction of the starting carbonyl compounds. Thus,
in reductive amination the correct combination of hydride source, catalyst and additives is an
important prerequisite for its success. Few reports are available and they require further
development for optimum reactions. It is a two step process for the final α-chiral primary
amine inhibiting any possibility of imine isolation which is time consuming and low yielding
process. The prochiral ketone is converted to the corresponding secondary amine in a good to
high diastereoselectivity and yield in the presence of Lewis acid/(R)- or (S)-α-MBA/H 2 . The
absolute configuration of the major and minor diastereomer depends on the absolute
configuration of the chiral amine source. This amine can then be purified by column
chromatography or by crystallization. The chiral primary amine is produced from the
secondary amine through hydrogenolysis.
As motioned before, Nugent et al have succeeded to establish a new methodology for
synthesizing α-chiral amines. Reaction conditions as hydrogen pressure, temperature and
time were milder compared to other available methodologies. Reaction time is short
compared to other methodologies adding to the advantages of this strategy. The use of minute
quantities of metal catalysts (Pd and Pt) is another advantage. Another factor which makes
this reaction attractive is the low hydrogen pressure needed; almost 80% of all ketones are
hydrogenated at 8.0 bar and also at room temperature. Usually other methodologies require
the use of higher (up to 100 Bar).
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