KAl(SO4)2·12H2O catalyzed efficient synthesis of 3,4,6-trisubstituted 2-pyridone in water

Article abstract of DOI:10.1016/j.cclet.2011.03.012

An efficient green protocol for the preparation 3,4,6-trisubstituted 2-pyridone of employing a condensation reaction of cyanoacetamide and acetylacetone in the presence of KAl(SO₄)₂·12H ₂O in water has been described. The present procedure offers advantage such as shorter reaction time, simple workup, and excellent yields.

Full text of DOI:10.1016/j.cclet.2011.03.012

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1059–1062
www.elsevier.com/locate/cclet
KAl(SO ) Á12H O catalyzed efficient synthesis of
4
2
2
3
,4,6-trisubstituted 2-pyridone in water
*
Majid M. Heravi , Hossein A. Oskooie, Narges Karimi, Hoda Hamidi
Department of Chemistry, School of Sciences, Alzahra University, Tehran, Iran
Received 15 December 2010
Available online 25 June 2011
Abstract
An efficient green protocol for the preparation 3,4,6-trisubstituted 2-pyridone of employing a condensation reaction of
cyanoacetamide and acetylacetone in the presence of KAl(SO ) Á12H O in water has been described. The present procedure offers
4
2
2
advantage such as shorter reaction time, simple workup, and excellent yields.
#
2011 Majid M. Heravi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Water; Alum; 3,4,6-Trisubstituted 2-pyridone; Click reaction
Most chemical reactions by organic substances conducted in the laboratory as well as in industry need organic
solvent as reaction media, although water is safe, benign, environmentally friendly, and cheap compared with organic
solvent. Around 1980, Breslow et al. discovered that the Diels–Alder reaction performed in water can be subject to
huge accelerations [1]. The observation led to increased interest from synthetic organic chemists in organic reaction in
water. Soon it was discovered that other organic reactions, such as the Claisen rearrangement [2], the aldol
condensation [3], exhibit rate enhancements in water.
2
-Pyridones represent a unique class of pharmacophore, which are observed in various therapeutic agents and
antibiotics [4]. Substituted 3-cyano-2-pyridones are important intermediates in the pharmaceutical, dye, and photo
industries. Their syntheses have been widely studied using conventional heating in the presence of various catalysts
and usually in polar solvents [5,6]. There are methods for their preparation [7], but most of these procedures have
significant drawbacks such as long reaction time, low yields, harsh reaction conditions, difficult work-up and use of
environmentally toxic reagents or media.
In recent KAl(SO ) Á12H O (Alum) has been used in organic synthesis because it is stable, inexpensive and
4
2
2
nontoxic, such as cis-isoquinolonic acids [8].
We herein describe a practical, inexpensive method for the preparation of 3,4,6-trisubstituted 2-pyridone
derivatives via reaction cyanoacetamide and acetylacetone in the presence of Alum.
*
Corresponding author.
E-mail address: mmh1331@Yahoo.com (M.M. Heravi).
1001-8417/$ – see front matter # 2011 Majid M. Heravi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.03.012

1060
M.M. Heravi et al. / Chinese Chemical Letters 22 (2011) 1059–1062
1
. Experimental
A mixture of cyanoacetamide (1 mmol), acetylacetone (1 mmol) and Alum (0.35 mmol) was rapidly stirred and
heated at 100 8C in water for the specified time. After completion of the reaction, water (20 mL) was added to the
reaction mixture and the resulting solid was separated by filtration. For further purification it was crystallized with
ethanol to afford the pure product.
À1 1
Compound 3a: Yellow solid; mp 280–282 8C, IR (KBr): 3431, 3136, 3000, 2852, 2789 cm ; H NMR (300 MHz,
DMSO-d ): d 2.21 (s, 3H, CH ), 2.86 (s, 3H, CH ), 6.15 (s, 1H, CH), 12.29(s, 1H, NH).
6
3
3
2
. Results and discussion
We first investigated the catalytic activities of various catalysts, which promoted the model reaction of
cyanoacetamide (1 mmol) and acetylacetone (1 mmol) using 0.15 mmol of catalyst at 50 8C in water (Scheme 1 and
Table 1).
In the course of this study it was found that Alum was the most effective catalyst in terms of yield of 3a (75%) while
other catalysts formed the product in moderate yields.
By changing the amount of the catalyst from 0.15 mmol to 0.25 mmol and 0.35 mmol, the reaction resulted in the
formation of 3a in 83, 89% yield, respectively. The results showed that 0.35 mmol of catalyst was sufficient to achieve
a fairly high yield.
Alum of 0.35 mmol gave excellent yield in 100 min. To optimize the temperature in the mentioned reaction, we
have carried out a model study with cyanoacetamide and acetylacetone using 0.35 mmol of catalyst at various
temperatures in water conditions (Table 1).
Table 1 clearly demonstrates that 100 8C is an effective temperature in terms of reaction time and yield obtained.
To select a suitable solvent for the reaction of cyanoacetamide and acetylacetone was carried out in different solvent
methanol, acetonitrile, ethanol and water under reflux. Water was found to be the best solvent.
We extended our study using Alum (0.35 mmol) as catalysts in water with different 1,3-dicarbonyl compounds to
prepare a series of 3,4,6-trisubstituted 2-pyridones derivative. A series of 3,4,6-trisubstituted 2-pyridones were
prepared in high to excellent yields in this method (Table 2).
[(Scheme_1)TD$FIG]
R2
X
O
O
O
Alum
H O, reflux
X
+
H N
2
R1
R2
R1
N
H
O
2
1
2
3
Scheme 1.
Table 1
Catalyst activity of various catalysts.
Entry
Catalyst
Temperature (8C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
Basic alumina
50
50
180
300
220
200
150
100
85
65
30
55
60
75
89
75
90
TiO
NH
Morpholine
2
4
Cl
50
50
KAl(SO
KAl(SO
KAl(SO
KAl(SO
4
)
4
)
4
)
4
)
2
2
2
2
Á12H
Á12H
Á12H
Á12H
2
O (Alum)
2
O (Alum)
2
O (Alum)
2
O (Alum)
50
50
75
100
45

M.M. Heravi et al. / Chinese Chemical Letters 22 (2011) 1059–1062
1061
Table 2
Synthesis of compound 3a–h by Alum.
Entry
1
1
2
Product
Time/min
45
Yield(%)
90
mp (8C)
O
O
O
280–282 [9]
[
T
D
$
I
N
L
I
N
E
]
CN
O
[DT$INLE]
CN
[DT$INLE]
H N
2
N
H
3a
2
3
4
O
O
O
O
O
Ph
70
85
80
72
43
>300 [9]
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
CN
CN
Ph
Ph
Ph
2
H N
[DT$INLE]
Ph
N
H
O
3b
3c
O
O
Ph
207–209 [9]
[
T
D
$
I
N
L
I
N
E
]
[TD$INLE]
Ph
H2N
[DT$INLE]
Ph
N
H
O
O
O
180
272–273 [10]
[
T
D
$
I
N
L
I
N
E
]
[
$
N
I
E
CN
O
CN
Ph
[TD$INLE]
H N
2
Ph
N
H
3d
5
6
7
8
O
O
O
O
O
O
140
140
210
220
50
50
52
50
293–294 [9]
293–294 [9]
272–275 [11]
174–175 [11]
[
T
D
$
I
N
L
I
N
E
]
[
T
$
N
I
E
CN
CN
O
H2N
OCH3
[TD$INLE]
HO
N
H
3e
O
[
T
D
$
I
N
L
I
N
E
]
[
D
N
I
]
CN
O
CN
CN
OEt
H
2
N
[TD$INLE]
HO
N
H
3f
O
O
O
O
CN
[DT$INLE]
[
T
D
$
I
N
L
I
N
E
]
OCH3
H2N
[TD$INLE]
HO
N
O
H
3g
O
CN
[DT$INLE]
[
T
D
$
I
N
L
I
N
E
]
CN
OEt
H N
[TD$INLE]
2
HO
N
O
H
3h
3
. Conclusion
In conclusion, we have demonstrated that Alum is a new efficient catalyst for synthesis of 3,4,6-trisubstituted 2-
pyridones. 3,4,6-Trisubstituted 2-pyridones derivatives were prepared via a reaction of cyanoacetamide and 1,3-
dicarbonyl compounds in the presence of catalytic Alum. Shorter reaction times, simple work-up and excellent yield
are advantages of this method.
Acknowledgment
We are grateful to Iran national Science Foundation for partial support of this work.
References
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[
[
[
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M.M. Heravi et al. / Chinese Chemical Letters 22 (2011) 1059–1062
[
[
[
[
[
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[
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