Improved Methodology for the Preparation of Chiral Amines

EtO 2 C
H
H
CO 2 Et
R
O
H
+
H 2 N
OMe
N
H
S
(1.1 equiv)
R
N
H
OMe
H 2 N NH 2
(1.0 equiv)
5 Å MS, toluene, 70 °C
Scheme 3.22. Reductive Amination of Aldehydes Utilizing Thiourea.
One of the milestones in this field was developed by MacMillan, who investigated the
reductive amination of acetophenone with p-anisidine utilizing ethyl Hantzsch ester, and
BINOL-derived phosphoric acids. The catalyst showed high catalytic activity and excellent
enantiocontrol in the reductive coupling reaction. Removal of water by the addition of 5Å
molecular sieves proved to be important for achieving high catalytic activity and selectivity.
Aryl-alkyl ketones were reduced with good yields (70-87%) and high enantioselectivity (85-
97%) and 2-alkanones were also reduced with mediocre to good yields (49-75%) with good
to high enantioselectivities (81-94%). Different aniline derivatives were tested producing the
secondary amine with good to high yields (55-92%) and high enantioselectivities (90-95%).
The overall diversity of ketone substrates makes his work fascinating from all aspects. [64]
O
15 (10 mol%),PMPNH 2 (1 equiv), MS 5A,C 6 H 6 ,50 o C, 96h, 87%
HN PMP
EtOOC
COOEt
N
H
(1.2 equiv)
87% yield, 94 % ee
SiPh 3
O
O
P
O OH
15
SiPh 3
OMe
OMe
OMe
HN
F
HN
F
HN
79 % yield, 91 % ee
60 % yield, 83 % ee
72