Improved Methodology for the Preparation of Chiral Amines

progress of the reaction was monitored with NMR. The use of DIBAL-H resulted in the (S)
conformation and the use of L-Selectride resulted in (R) conformation (scheme 3.14). [49]
F
R 1
O
H
R 2
H 2 N
O
tBu
1) Ti(OEt) 4 ,THF,reflux
2) Reducing agent, THF
F
HN S O
R 2
tBu
Scheme 3.14. Reductive Amination of α-Fluoro α,β-Unsaturated Ketones.
R 1
H
3.3.3. Reductive Amination Utilizing Molecular Hydrogen:
Alexakis, utilized a combination of Ti(OiPr) 4 /Pd-C/H 2 to synthesize C2 symmetric secondary
amines with 70-82% de and 88-92% yield. His system was only applicable for the aromatic
substrates. [50] Nugent and Seemayer developed a highly efficient methodology for the
synthesis of quinuclidine. [51] Through utilization molecular hydrogen, heterogeneous
hydrogenation catalysts Pt-C or Pd-C and Ti(OiPr) 4 for the reductive amination of a labile α-
chiral quinuclidinone they were successful in incorporation the amine without epimerization,
a feat not previously accomplished (scheme 3.15).
N
Ph
O
Ph
Ph NH 2
Ti(OiPr) 4 /Pt-C/H 2 (4.2 bar)
25 o C, 15h, 80% de
N
Ph
NHCH 2 Ph
Ph
N
Ph
NHCH 2 Ph
Ph
Scheme 3.15. Reductive Amination of a Quinuclidinone
Nugent group recently developed a two-step methodology relying on the asymmetric
reductive amination of prochiral ketones with the chiral ammonia equivalent (R)- or (S)-αmethylbenzylamine
for α-chiral primary amine synthesis. They found that the use of
(Ti(O i Pr) 4 (1.2 equiv)) with ((R)- or (S)-α- methylbenzylamine (α-MBA) (1.1 equiv)) and
heterogeneous catalyst (Ra-Ni, Pd-C, Pt-C) produced the secondary amine of different 2-
alkanones, cyclic ketones, and aryl alkyl ketones in high yields and diastereoselectivities. The
secondary amine is produced in a single step without the need for the tedious process of
imine isolation and purification. Simple acid base work is usually enough to purify the
65