NbCl5-Catalyzed one-pot Mannich-type reaction: three component synthesis of β-amino carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2007.01.142

Three-component Mannich-type reaction of acetophenone, aromatic aldehydes and aromatic amines was catalyzed by NbCl₅ at ambient temperature to give various β-amino ketones in high yields.

Full text of DOI:10.1016/j.tetlet.2007.01.142

Tetrahedron Letters 48 (2007) 2071–2073
NbCl -Catalyzed one-pot Mannich-type reaction:
5
three component synthesis of b-amino carbonyl compounds
Rui Wang, Bo-gang Li, Tai-kun Huang, Lin Shi and Xiao-xia Lu*
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, PR China
Received 29 November 2006; revised 25 January 2007; accepted 26 January 2007
Available online 30 January 2007
Abstract—Three-component Mannich-type reaction of acetophenone, aromatic aldehydes and aromatic amines was catalyzed by
NbCl
5
at ambient temperature to give various b-amino ketones in high yields.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, NbCl has emerged as an efficient Lewis acid in
5
promoting various organic transformation, such as
Diels–Alder reaction, ring-opening of epoxides, Mukai-
yama aldol reaction, Biginelli reaction, dealkylation of
The Mannich-type reactions are very important carbon–
carbon bond-forming reactions in organic synthesis and
one of the most widely utilized chemical transformations
for constructing b-amino ketones and other b-amino
carbonyl compounds, which in turn are important syn-
thetic intermediates for various pharmaceuticals and
8
alkyl aryl ethers and C–H insertion reaction. The versa-
tility of this reagent encourage us to study its utility for
the three-component Mannich-type reaction. To our
knowledge, direct Mannich-type reactions catalyzed by
1
,2
natural products.
Mannich reactions have gained
NbCl have not been reported. Herein, we report an
5
popularity in synthetic chemistry over the past decades.
Recently, direct Mannich reactions of aldehydes,
ketones and aryl amines have been realized via Lewis
NbCl -catalyzed three-component Mannich-type reac-
5
tion of acetophenone, aromatic aldehydes and aromatic
amines, which led to the efficient synthesis of b-amino
ketones under mild conditions (Scheme 1).
3
4
5
acids, lanthanides, transition metal salt catalysis and
6
organocatalytic approaches. Most of these methods
suffer from severe drawbacks including the use of a large
amount of catalysts, expensive reagents or catalysts,
sometimes long reaction times and low yield, etc. Hence,
there is high interest in developing convenient methods
for the synthesis of b-amino ketones. Some of the recent
achievements in the efficient construction of this nucleus
include the development of Lewis acid catalysts, how-
ever, few useful Lewis acid catalysts are developed in
In the initial experiments, we screened different common
Lewis acids for their ability to catalyze the three-compo-
nent Mannich type reaction. To study the feasibility of
the different common Lewis acids-catalyzed Mannich-
type reactions, the reaction of acetophenone, benzalde-
hyde and aniline was selected as model. The common
Lewis acids such as ZnCl , CuCl , AlCl , FeCl LaCl
3
2
2
3
3
and InCl did not furnish the desired products (Table
3
7
the past few years.
1, entries 2–7). However, among the common Lewis
O
NH2
R'
R'
CHO
R
O
HN
NbCl (10 mol%)
CH3
5
+
+
EtOH, r.t.
R
Scheme 1.
5
Keywords: NbCl ; Mannich-type reaction; b-Amino carbonyl compound; One-pot reaction.
*
Corresponding author. Tel.: +86 028 85253276; fax: +86 028 85222753; e-mail: xlua71@yahoo.com.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.142

2072
R. Wang et al. / Tetrahedron Letters 48 (2007) 2071–2073
Table 1. Catalytic activity of solid acid and Lewis acid in Mannich
reaction
none, benzaldehyde and aniline. The controlled three-
component reaction conducted under identical condi-
tions and devoid of Lewis acid gave no coupled product,
despite prolonged reaction times (Table 1, entry 1).
a
b
Entry
Catalyst (10 mol %)
No cat.
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
48
24
24
24
24
24
24
12
NR
NR
NR
NR
NR
NR
NR
95
ZnCl
CuCl
2
In a systematic study (Table 2), acetophenone was
added to a solution of benzaldehyde, aniline and NbCl5
in ethanol and the reaction mixture was stirred for 12 h
at room temperature. Our initial experiments focused on
the optimization of the amount of NbCl5 by using
2
AlCl
FeCl
3
3
LaCl
InCl
NbCl
3
3
5
1
equiv of benzaldehyde, 1 equiv of acetophenone,
a
Reaction conditions: benzaldehyde (1.0 mmol), acetophenone
1.0 mmol), aniline (1.0 mmol), catalyst (0.1 mmol), EtOH (1 mL),
1 equiv of aniline and variable amount of NbCl . We
5
(
observed that 10 mol % of NbCl (based on benzalde-
5
room temperature.
Isolated yield.
hyde) could effectively catalyze the reaction and increas-
ing the amount of NbCl5 to 20 mol % showed no
substantial improvement in the yield (Table 2, entry
b
acids studied for this reaction, NbCl was found to be the
5
3
). Thereafter the reaction was carried out by varying
most effective catalyst for this transformation since it re-
sulted in the highest conversion to the desired product
the amount of acetophenone and aniline. The optimum
ratio of benzaldehyde, acetophenone, aniline and NbCl5
was found to be 1:1:1:0.1 (Table 2, entry 2).
(
Table 1, entry 8). In conclusion, NbCl was an effective
5
catalyst for the Mannich reaction between acetophe-
a
In an effort to obtain improved yields, various solvents
were screened in the three-component reaction of
Table 2. Synthesis of b-amino ketone under different conditions
b
Entry
PhCOCH
mmol)
3
PhNH
(mmol)
2
NbCl
(mmol)
5
Yield
(%)
(
5
Table 3. NbCl -Catalyzed three-component Mannich-type reactions
a
1
2
3
4
5
6
7
8
9
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.5
2.5
5.0
1.0
1.0
1.0
1.1
1.2
1.5
1.0
1.0
1.0
1.0
0.05
0.10
0.20
0.10
0.10
0.10
0.10
0.10
0.10
0.10
52
95
91
92
85
82
94
93
83
82
of benzaldehyde, aniline and acetophenone in different solvents
b
Entry
Solvent
EtOH
Yield (%)
1
2
3
4
5
6
95
94
61
32
3
CH CN
DCE
Toluene
THF
Trace
Trace
1,4-Dioxane
1
0
a
Reaction conditions: benzaldehyde (1.0 mmol), aniline (1.0 mmol),
a
Reaction conditions: benzaldehyde (1.0 mmol), EtOH (1 mL), room
5
acetophenone (1.0 mmol), NbCl (0.1 mmol), room temperature
temperature 12 h.
Isolated yield.
12 h.
Isolated yield.
b
b
a
5
Table 4. NbCl -Catalyzed direct Mannich reaction of various aryl aldehydes and aromatic amines
O
NH2
R'
CHO
O
HN
NbCl (10 mol%)
CH3
5
+
+
EtOH, r.t.
R
R
R'
1
2
3
4
0
b
Entry
R
R
H
Yield (%) (product)
Mp (°C)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
95 (4a)
96 (4b)
—(4c)
92 (4d)
92 (4e)
86 (4f)
85 (4g)
96 (4h)
—(4i)
80 (4j)
76 (4k)
95 (4l)
78 (4m)
169–170
167–168
—
145–146
169–170
131–132
161–162
185–186
—
160–161
161–162
129–130
105–106
4-CH
2-CH
3,4-(CH
4-Cl
3-Cl
4-MeO
4-NO
2-NO
4-HOOC
3
3
3
)
2
2
2
10
11
12
13
3-HOOC
4-CH
4-NO
3
H
H
2
a
Reaction conditions: aromatic aldehydes (1.0 mmol), acetophenone (1.0 mmol), aromatic amines (1.0 mmol), NbCl
room temperature 12 h.
Isolated yield; products were confirmed by H NMR.
5
(0.1 mmol), EtOH (1 mL),
b
1

R. Wang et al. / Tetrahedron Letters 48 (2007) 2071–2073
2073
benzaldehyde, acetophenone and aniline at room tem-
References and notes
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amino ketones were obtained with 10 mol % of NbCl at
5
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Typical procedure for the synthesis of 4: To a mixture
of acetophenone (1.0 mmol), aromatic aldehydes
1
(
1.0 mmol) and aromatic amines (1.0 mmol) in
anhydrous ethanol (1 mL) was added NbCl5
10 mol %). The mixture was stirred at room temperature
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(
for 12 h. After the reaction was completed, saturated
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3
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8
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Acknowledgement
We acknowledge the financial support from Chengdu
Institute of Biology, Chinese Academy of Sciences,
and Diao Pharmaceutical Company.
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(g) Yadav, J. S.; Subba Reddy, B. V.; Eeshwaraiah, B.;
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