Improved Methodology for the Preparation of Chiral Amines

to 86%, and the de was consistently reported between 87-88%. Aiming to understand the
concept behind this effect, H 2 O or AcOH (50 or 100 mol %) was added to the reaction mixture
containing dried Yb(OAc) 3 . The amount of 2-aminooctane formed increased also to ~10 area %
(GC). For this reason I decided to conduct all experiments using only dried Yb(OAc) 3 . Another
significant finding from this observation was the importance of using ketone as the limiting
reagent instead of α-MBA (1.1 equiv) to obtain the optimal de and yield. The use of ketone as a
limiting reagent adds to the advantages of our methodology as it reduces the expenses of
starting materials especially when using expensive ketones on larger scale.
Regarding the formation of 2-aminooctane, our initial speculation was that the reductive
amination products (S,S)- and (R,S)-secondary amine (scheme 5.1.) were slowly being
hydrogenolyzed under the reaction conditions, but chiral GC analysis (trifluoroacetamide
derivative) established the primary amine side product as a racemate. Based on our prior
experience, regarding the stereoinducing capabilities of (S)- or (R)-α-MBA with Ti(O i Pr) 4 and
2-octanonone, I considered it unlikely that a racemate would form if a sequential reductive
amination-hydrogenolysis scenario had occurred. This led us to examine the possibility that (S)-
α-MBA was being hydrogenolyzed by Raney-Ni, in the presence of Yb(OAc) 3 , in a small but
significant amount, and thereby producing ammonia and ethylbenzene in situ. The subsequent,
but non-productive, reductive amination of ammonia with 2-octanone would then account for
racemic 2-aminooctane formation. In an effort to support this hypothesis, several reactions were
examined by GC in an effort to identify ethylbenzene (relative to an authentic reference
standard), but none was ever observed. To further corroborate those findings, I treated α-MBA
(in the absence of 2-octanone) with Raney-Ni/H 2 . Several repetitions of this experiment failed
to allow the identification of ethylbenzene. The major obstacle for identification of
ethylbenzene was its low boiling point (136 °C). Any low quantities produced could potentially
evaporate on quenching the reaction aliquot at room temperature (work-up: drop aliquot into
sat. aq NaHCO 3 /EtOAc). Hoping to reduce ethyl benzene evaporation the quenching solution of
aqueous NaHCO 3 /EtOAc was cooled to 0 °C. Unfortunately, this did not allow the observation
of ethylbenzene by GC.
While [1,3]-proton shift of imine is known, it is to our knowledge only accomplished under the
presence of a strong base. [16]
112