Improved Methodology for the Preparation of Chiral Amines

indicated. All components (except the Raney Ni and H 2 ) are added together and pre-stirred for 30 min. The
heterogeneous hydrogenation catalyst (Raney Ni) is then added and the system pressurized with 8 bar of H 2 . The
indicated data is at 12 h of reaction from the onset of hydrogenation.
Ethyl acetate-MeOH and THF-MeOH combinations showed the highest possible de with
acceptable reaction time (12 h). The use of THF-MeOH resulted in slightly higher de
compared to EtOAc-MeOH encouraging us to proceed using this solvent combination for the
rest of the study. The addition of an anhydrous MgSO 4 or NaSO 4 as desiccants to the reaction
mixture before hydrogenation did not have any effect on the reaction profile.
After using several bottles of Yb(OAc) 3 , which is sold and described as a semihydrated form
(Sigma-Aldrich catalogue no. 544973), I noted that it was sometimes free flowing while other
bottles from the same lot were not. In our attempt to eliminate any variation of results and to
get consistent reaction profile for all substrates, I decided to dry Yb(OAc) 3 powder obtained
from the commercial supplier. The powder was high vacuum dried to constant weight at 80
°C (12 h). The dried powder was kept in airtight container and used for further reactions.
Through this drying procedures all reactions results were reproducible and constant reaction
profile was obtained. In the rest of this study the term “dry Yb(OAc) 3 ” means dried as just
stated. The dried Yb(OAc) 3 could be stored in a dry screw cap glass bottle at room
temperature. The container could be repeatedly opened to the atmosphere (at least 6 times
without detrimental effect) and the desired quantity of Yb(OAc) 3 weighed out without the
need for a glovebox. This is one of the significant advantage of Yb(OAc) 3 use in reductive
amination compared to other air sensitive Lewis acids. Moisture and air stability of Yb(OAc) 3
will open the door for its applications on industrial scale.
After initial optimization of the reaction using benzylacetone as the substrate other ketone
substrates were also tested. 2-octanone is another example of 2-alkanones which has been
reductively aminated with Ti(O i Pr) 4 system with a de of (72%), was one of the interesting
substrates to be tested with Yb(OAc) 3 system. Solvent screening was carried also to this
substrate utilizing all findings obtained from benzylacetone results. For example 2-octanone,
in MeOH, was fully consumed within 8 h providing the secondary amine in 82% de in the
presence of Raney-Ni (Scheme 5.1). When the solvent was changed to THF, the
stereoselectivity increased to 87-88% de, but 24 h were required to completely consume the
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