Highly chemoselective reductive amination by one pot reaction of aldehydes, amines and dihydropyridine catalyzed by TMSCl

Article abstract of DOI:10.1007/BF03246028

More efficient, cost effective and metal free DHP/TMSCl system for one pot reductive amination of aldehydes was developed. The method allows the efficient one pot synthesis of structurally diverse amines with Hantzsch ester as the hydrogen source in the presence of trimethylsilyl chloride as a catalyst in high to quantitative yields under mild conditions.

Full text of DOI:10.1007/BF03246028

J. Iran. Chem. Soc., Vol. 7, No. 2, June 2010, pp. 428-431.
JOUIRrNaAnLiaOnF THE
Chemical Society
Highly Chemoselective Reductive Amination by One Pot Reaction of Aldehydes,
Amines and Dihydropyridine Catalyzed by TMSCl
N. Azizi*, A.R. Khajeh Amiri, H. Ghafuri, M.R. Saidi and M. Bolourtchian
Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Payam Noor University-Damavand Branch, Damavand, Iran
(Received 9 May 2009, Accepted 7 July 2009)
More efficient, cost effective and metal free DHP/TMSCl system for one pot reductive amination of aldehydes was developed.
The method allows the efficient one pot synthesis of structurally diverse amines with Hantzsch ester as the hydrogen source in the
presence of trimethylsilyl chloride as a catalyst in high to quantitative yields under mild conditions.
Keywords: Aldehydes, Amines, Dihydropyridine, Reductive amination, TMSCl
INTRODUCTION
chemicals [2]. In addition, optically active amines have
important applications in asymmetric synthesis as chiral
auxiliaries [3,4], catalysts [5], and resolving agents [6].
Consequently, efforts are focused on the development of a
methodology for the simple and practical synthesis of amine
derivatives in modern organic syntheses.
The direct reductive amination of aldehydes and ketones
with metal hydride reagents is one of the most useful methods
for the synthesis of secondary and tertiary amines and in
recent years, different methods have been developed to carry
out this transformation [7]. The choice of the reductant is very
critical because the undesirable reduction of starting carbonyls
must be suppressed [8].
However, most of these reagents may have some
drawbacks. For examples, catalytic hydrogenation is
incompatible with compounds containing a carbon-carbon
double or triple bond and other reducible functional groups
such as nitro, cyano and furyl. Cyanoborohydride and tin
hydride reagents are highly toxic and generate toxic by-
products such as cyanide or organotin compounds upon
workup, which may result in the contamination of the product.
On the other hand, in recent years dihydropyridines were
found to serve as mild, useful reagents capable of reducing
Nonmetallic systems are efficient for catalytic reduction
and are complementary to the metallic catalytic methods. For
example, lithium aluminium hydride, sodium borohydride and
borane-tetrahydrofuran have been extensively used as the most
efficient and convenient reducing agent to prepare a wide
range of pure compounds (e.g., ꢀ-amino acids can be prepared
from ꢀ-enamides, alcohols from ketones and amines from
oximes or imines). Nevertheless, application of these protocols
to sensitive, acid-labile or polyfunctional substrates is limited.
On the other hand, in recent years, novel methods of substrate
activation have been achieved using organic catalysts that can
now deliver unique, orthogonal, or complementary selectivity
in comparison with many established metal-catalyzed
transformations. This renders the development of metal-free
catalytic concepts for a mild direct reductive amination a very
important research goal [1].
Amines and their derivatives exist in many biologically
important molecules, and are important intermediates in the
synthesis of pharmaceutically active substances, dyes, and fine
*Corresponding author. E-mail: azizi@ccerci.ac.ir

Azizi et al.
organic substrates in the absence of metal ions under either
RESULTS AND DISCUSSION
thermal or acid-catalyzed conditions. Hantzsch dihydro-
pyridine is readily obtained in multi-gram scale by the reaction
of ammonia, formaldehyde, and two equivalents of ethyl
acetoacetate in any laboratory without any difficulty [9].
Furthermore, organocatalyst-based reduction with dihydro-
pyridine have received considerable attention in contrast to
metal-based reductions in recent years, because complete
removal of metal impurities from reaction products is often
difficult but necessary, especially in the production of
pharmaceutical intermediates and natural products due to
toxicity problems [10].
In pursuit of our interest to develop organic transformation
by using simple reagent, catalyst and reaction media [11], we
have disclosed the chemoselective one-pot reductive
amination of aldehydes using inexpensive, safe to handle and
environmental friendly dihydropyridines (DHP) in the
presence of a catalytic amount of trimethyl silyl chloride.
To explore the possibility of the reductive amination of
primary and secondary amines and aldehydes, a model
reaction, between benzaldehyde and aniline was performed in
the presence of TMSCl. By optimizing the solvent, reaction
temperature and the amount of the reagents, the conditions
shown in Scheme 1 were found to be suitable. In the absence
of TMSCl, only a trace amount of imines and starting material
was obtained. After optimization of reaction condition, we
then studied the general applicability of this procedure for the
synthesis of sterically, electronically, and functionally diverse
amines (Table 1). The data in Table 1 show that different
aldehydes are successfully converted to the corresponding
amines in high yields at room temperature. The presence of
electron-withdrawing or electron-donating substituents on the
aromatic ring did not affect the course of the reaction.
Sensitive functionalities such as OMe and NO2 were tolerated
under the mild reaction conditions.
The scope of our method could be extended to other
amines. In the case of amines having an electron-donating
group such as 4-methoxy aniline and 4-buthyl aniline the
corresponding products were obtained in good yields.
Especially, sterically hindered amines, 2,4,6-trimethyl
anilines, developed the corresponding products in moderate
yields. Furthermore, electron-withdrawing amines such a 4-
chloroaniline and 3,4-dichloroaniline launched the desired
products in good yields.
EXPERIMENTAL
General
1H NMR spectra were recorded on 500 MHz NMR
spectrometer and 13C NMR spectra were recorded on 125
MHz NMR spectrometer respectively using CDCl3, as a
solvent (Chemical shifts have been expressed in ppm
downfield from TMS). Melting points were measured on a
Buchi Melting Point B-545 apparatus. Amines, aldehydes,
TMSCl and the solvent, all commercially available, were
purchased and used without further purification. Water and
other solvents were distilled before use.
Moreover, the data in Table 1 clearly show that the reaction
of different aliphatic amines such as diethylamine, pyrrolidine
or piperidine with benzaldehyde produces the corresponding
General procedure for reductive amination in the
presence of trimethyl silyl chloride. To a stirred solution of
amines (2 mmol) and aldehydes (2 mmol) in anhydrous
CH2Cl2 (3 ml), dihydropyridine (2.5 mmol) and TMSCl (10
mol%) were added in one portion under argon. The reaction
mixture was stirred for 3-8 h, then poured into saturated
aqueous NaHCO3 solution (20 ml) and extracted with CH2Cl2
(10 ml). The organic layer was washed with water (20 ml),
dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash column chromatography or acidic workup to
provide the corresponding pure product.
O
O
O
NHPh
H
TMSCl (10 mol%)
Solvent, rt, 4 h
Ph
H
OEt
EtO
Ph
+
N
H
Me
Me
PhNH2
Solvent CH2Cl2 ClCH2CH2Cl CH3CN Ether THF Toluene
Yields (%) 95 90 40 35 45 92
benzaldehyde, 2 mmol, aniline, 2 mmol, DHP, 2.5 mmol
Scheme 1. Optimization of reaction conditions
429

Highly Chemoselective Reductive Amination
O
O
NH2
Table 1. One Pot Reductive Amination of
H
Aromatic Aldehydes
+
+
O
O
2 mmmol
2 mmmol
2.2 mmmol
OEt
EtO
DHP 3.3 eq.
R'CHO
CH2Cl2, rt, 6 h
R"NH2
+
+
TMSCl (10 mol%)
N
H
Me
Me
Ph
Ph
HN
TMSCl (10 mol%)
CH2Cl2, rt, 3-8 h
HN
H
R'
+
NHR"
90 %
00%
H
Entry
R'
R"
Yields%
Scheme 2. Selective amination of benzaldehyde with aniline in
the presence of acetophenone
4-ClC6H4
Ph
4-BrC6H4
Ph
90
95
92
90
92
83
80
1
2
3
4
5
6
7
8
Ph
Ph
Ph
amines in high yields at room temperature. The reactions are
clean and highly selective, affording exclusively the desired
yields in short times. The reaction conditions are mild enough
to perform these reactions in the presence of either acid or
base sensitive functional groups. Furthermore, this method is
equally effective for aromatic, hindered, and unhindered
amines. The yields of products were not affected by the nature
of amines.
This method is highly selective for the preparation of
amines from aldehydes. Thus, reductive amination of an
aldehyde in the presence of a ketone, using TMSCl as the
catalyst in CH2Cl2 at room temperature, gave only secondary
amine from aldehyde and ketone remained intact (Scheme 2).
In conclusion, in this article we have reported amination of
aromatic and aliphatic aldehydes with primary and secondary
amines using DHP as a reducing agent catalyzed with TMSCl
at room temperature in good to excellent yields. We believe
this methodology to be a useful addition to the available
methods regarding this transformation.
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-NO2C6H4
4-IC6H4
4-IC6H4
3-NO2C6H4
3-NO2C6H4
80
82
4-ClC6H4
Ph
9
10
11
3-NO2C6H4
4-NO2C6H4
85
80
3-i-prPh
4-ClC6H4
93
80
75
75
4-NO2C6H4
12
13
14
4-BrC6H4
3,4-diClC6H3
2,4-diClC6H3
4-ClC6H4
3,4-diClC6H3
4-ClC6H4
Ph
2,4-diClC6H3
15
16
17
18
2,4-diClC6H3
3-MeOC6H4
80
77
Ph
4-ClC6H4
4-OMeC6H4
77
90
88
90
19
20
4-CO2MeC6H4
4-CO2MeC6H4
4-ClC6H4
Ph
4-ClC6H4
4-BuC6H4
ACKNOWLEDGMENTS
21
2,4,6 trimetylC6H2
4-ClC6H4
22
23
4-ClC6H4
2,4-diClC6H3
70
75
78
The authors gratefully acknowledge the financial support
they received from the Chemistry and Chemical Research
Center of Iran.
24
25
26
27
28
2-Furyl
2-Thienyl
Ph
Ph
Ph
Pyrrolidine
Pypiridine
Diethylamine
75
95
95
92
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Ph
Ph
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