Improved Methodology for the Preparation of Chiral Amines

Pérez reported the use of BINAP derived palladium catalyst for the reductive amination of
alkyl and cycloaliphatic ketones (scheme 3.11). He used o-, m- and p-substituted aniline
derivatives as the source of nitrogen, molecular hydrogen at 800 psi (55 bar), in CHCl 3 at 70
°C for 24 h. The use of molecular sieves was crucial for obtaining the product in high yields.
He observed that the presence of substituents on the aniline improved stereoselectivity with a
little effect on reactivity as they increase the steric bulk of the nitrogen source improving the
interaction. When isobutyl methyl ketone reacted with aniline the ee was 51% but when p-
anisidine was used the ee jumped to 90%. One of the remarkable examples was the success in
reductive amination of 3-alkanones (2-heptanone). Although the ee was mediocre (49-59%)
but it is known that these substrates are only accessible through carbanion chemistry. 2,3-
butanedione underwent chemoselective reductive amination in good yields (83-85%) and low
enantioselectivity (2-20% ee). Aryl ketones were also tested resulting in poor to mediocre ee
(35-43%). One of the draw backs of this methodology is the harsh conditions needed for the
removal of phenyl ring to obtain the primary amine. [45]
(MeCN) 2 PdBr 2 + P P
Benzene
rt, overnight
P
PdBr 2
P
P
=
P
Me
PPh 2
PPh 2
P(p-Tolyl) 2
PPh
PPh 2
P(p-Tolyl) 2
2
Me
O
R 1 R 2
+
R 3
NH 2
Catalyst (2.5 mol%)
5Åms,CHCl 3
H 2 (800 psi),
70 °C, 24 h
HN
R 1 * R 2
R 3
Scheme 3.11. BINAP Derived Palladium Catalyst in Asymmetric Reductive Amination
Xiao extended his work on imine reduction and tested his iridium based catalysts for
reductive amination (scheme 3.12). He reported high ees and high yields for different
acetophenone derivatives with para-anisidine as nitrogen source. The catalyst loading was
1.0 mol% with 5.0 mol% of phosphoric acid derivative as Lewis acid. The addition of
molecular sieves was crucial for faster reaction. Using aniline with electron withdrawing
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