Improved Methodology for the Preparation of Chiral Amines

Later he utilized this methodology for the synthesis of important pharmaceutical building
blocks. He reported the enantioselective synthesis of pharmaceutically relevant 3-substituted
cyclohexylamines from 2,6-diketones via an aldolization-dehydrationconjugate reductionreductive
amination cascade that is catalyzed by a chiral Brønsted acid and accelerated by the
achiral amine substrate, which is ultimately incorporated into the product. 2,6-diketone was
treated with 1.0 equiv of an achiral amine, 2.0 equiv of a Hantzsch ester, and 10 mol % of a
chiral Brønsted acid resulted in the formation of the corresponding cyclohexylamines with
mediocre to good yield (35-79%) and with good to high diastereoselectivity (82-96%). Alkyl,
aryl and sterically congested aryl substituted 2,6-diketones were reductively aminated with
high stereoselectivities. [62]
NHR 2
+ NHR 2 + NHR
X - 2
X -
R 1
X
OR 1
R 1
i-Pr
i-Pr
Y
i-Pr
O
O
OOH
P EtO 2 C CO 2 Et
i-Pr
N
O
H
3(2.2equiv)
i-Pr i-Pr
R 2 NH 2 (1.5 equiv)
(R)-TRIP (10mol%)
MS 5Å, cyclohexane, 50
OR o C
1
Y
HN R 2
R 1
Scheme 3.21. Synthesis of Pharmaceutical Building Blocks Utilizing Reductive Amination.
Menche have also demonstrated that thiourea acts as an efficient organocatalyst for the
reductive amination of aldehydes using aniline derivative and the ethyl Hantzsch ester
providing the corresponding achiral N-benzylanilines in good to excellent yields (72-93%).
Using 1.1 equiv of Hantzsch ester and 1.0 equiv of thiourea with molecular sieves in toluene
at 70 °C for 24 h substituted benzaldehydes as well as two aliphatic aldehydes were reacted
with p-anisidine forming the secondary amines in good isolated yields (scheme 3.22). [63]
71