An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives catalyzed by tungstate sulfuric acid

Article abstract of DOI:10.1016/j.cclet.2014.07.012

An efficient three-component synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles via a reaction between 3-methyl-1-phenyl-2-pyrazolin-5-one, aromatic aldehydes and malononitrile using tungstate sulfuric acid as a cataly

Full text of DOI:10.1016/j.cclet.2014.07.012

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CCLET 3074 1–4
Chinese Chemical Letters xxx (2014) xxx–xxx
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Chinese Chemical Letters
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1
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Original article
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4
An environmentally friendly synthesis of 1,4-dihydropyrano
[2,3-c]pyrazole derivatives catalyzed by tungstate sulfuric acid
*
5
6
Q1 Mahnaz Farahi, Bahador Karami , Iman Sedighimehr, Hamideh Mohamadi Tanuraghaj
Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient three-component synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydro-
Received 27 May 2014
Received in revised form 9 June 2014
Accepted 25 June 2014
Available online xxx
pyrano[2,3-c]pyrazoles via
a reaction between 3-methyl-1-phenyl-2-pyrazolin-5-one, aromatic
aldehydes and malononitrile using tungstate sulfuric acid as a catalyst was described. Mild conditions,
good to excellent yields, easily available catalyst and easy work-up are the key features of this method.
ß 2014 Bahador Karami. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
6-Amino-4-aryl-5-cyano-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazoles
3-Methyl-1-phenyl-2-pyrazolin-5-one
Aromatic aldehyde
Malononitrile
Tungstate sulfuric acid
7
8
1. Introduction
of their reusability, lack of toxicity, and easy work-up [10]. 29
Recently, we found that anhydrous sodium tungstate (1) reacts 30
9
There has been considerable interest in syntheses, reactions and
biological activities of 4H-pyrane-containing molecules. Further-
more, 4H-pyrane derivatives also constitute a structural unit of
some pharmaceutical agents, drug candidates, photoactive mate-
rials and natural products [1,2]. These high profile applications and
variety of biological activities have promoted extensive studies for
the synthesis of 1,4-dihydropyrano[2,3–c]pyrazole derivatives [3].
Condensed pyrazoles are also biologically interesting com-
pounds and their chemistry has recently received considerable
attention [4]. Several pyrano[2,3-c]pyrazoles are reported to have
useful biological effects, such as analgesic and anti-inflammatory
activities [5]. Moreover, the biological activity of fused azoles has
led to intensive research on their synthesis [6,7]. Recently, the
three component, one-pot condensation of 3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one, aldehydes and malononitrile for the
construction of 1,4-dihydropyrano[2,3-c]pyrazole derivatives has
been reported using different conditions [8,9].
with chlorosulfonic acid (2) to give tungstate sulfuric acid (3) 31
10
11
12
13
14
15
16
17
18
19
20
21
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25
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27
28
(Scheme 1).
32
2. Experimental
33
Catalyst preparation: Firstly, 25 mL of dry n-hexane was taken in 34
a 100 mL round bottom flask, equipped with ice bath and overhead 35
stirrer, and 5.876 g (2 mmol) of anhydrous sodium tungstate was 36
added to the flask, then 0.266 mL (4 mmol) of chlorosulfonic acid 37
was added dropwise to the flask in 30 min. This solution was 38
stirred for 1.5 h, the reaction mixture was slowly poured into 39
25 mL of chilled distilled water with agitation. The yellowish solid 40
was filtered, washed with distilled water five times till the filtrate 41
showed negative for chloride ion test, and dried at 120 8C for 5 h. 42
The catalyst was obtained in 98% yield and decomposed at 285 8C 43
[11].
44
General procedure for the preparation of 6-amino-4-aryl-5-cyano- 45
3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles: A mixture of 46
3-methyl-1-phenyl-2-pyrazolin-5-one (1 mmol), aromatic alde- 47
hyde (1 mmol), malononitrile (1 mmol), and TSA (10 mol%) in 48
ethanol (10 mL) was refluxed for an appropriate period of time. 49
After the completion of the reaction (monitored by TLC analysis), 50
the catalyst was separated by filtration. The solvent was removed 51
Solid acids have been used as eco-friendly and reusable
catalysts in various organic transformations. The solid acid
catalysts were well received by the synthetic community because
*
Corresponding author.
E-mail address: karami@yu.ac.ir (B. Karami).
http://dx.doi.org/10.1016/j.cclet.2014.07.012
1001-8417/ß 2014 Bahador Karami. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: M. Farahi, et al., An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives catalyzed by tungstate sulfuric acid, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.07.012

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M. Farahi et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Scheme 1. Preparation of tungstate sulfuric acid (TSA).
Scheme 2. TSA-catalyzed synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles 7.
52
53
under vacuum and the products 7 were purified by recrystalliza-
tion from EtOH/H2O.
To determine the suitable reaction conditions, a solvent-free
reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one, benzaldehyde
and malononitrile was performed at room temperature. A low
conversion was observed. Then, the reaction was heated for 4 h,
but again full conversion was not achieved. So, we studied the
effect of solvent, temperature and various catalytic amount of the
TSA catalyst on the model reaction (Table 2).
As can be seen, the best results were obtained by performing the
reaction in the presence of 10 mol% of TSA in refluxing ethanol.
Then the generality of the procedure was evaluated using various
aromatic aldehydes under optimized reaction conditions. It was
found that both, electron rich and electron poor aryl aldehydes
reacted well in this process to afford the corresponding products in
good to excellent yields (Table 3).
82
83
84
85
86
87
88
89
90
91
92
93
94
95
54
3. Results and discussion
55
56
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60
61
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63
64
65
66
67
68
69
70
71
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73
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75
76
77
78
79
80
81
Fig. 1(A) shows the XRD patterns of tungstate sulfuric acid
(TSA). It was reported that high degree mixing of W–S in
chlorosulfonic acid often led to the absence of XRD pattern for
anhydrous sodium tungstate. The broad peak around 25.78 (2u) (u
is the Bragg0s angle) from the smaller inset could be attributed to
insertion of W into the framework of chlorosulfonic acid.
The FT-IR spectra of anhydrous sodium tungstate and TSA are
shown in Fig. 1(B). The spectrum of tungstate sulfuric acid shows
the characteristic bonds of anhydrous sodium tungstate and
chlorosulfonic acid. The adsorption bands in 3406, 1820, 1725,
1702, 1620, 1290, 1060, 1005 and 860 cmꢀ1 in the catalyst
spectrum reveal both bonds in anhydrous sodium tungstate and
the –OSO3H group. Hence titration of catalyst with NaOH (0.1 mol/
L) was conducted. Catalyst (1 mmol) was dissolved in 100 mL of
water and titrated with NaOH (0.1 mol/L) using phenolphthalein as
an indicator. It was found that for 1 mmol of catalyst, 4 mmol of
NaOH was utilized. This result shows that each complex contains
two acidic groups. The XRF data of tungstate sulfuric acid indicates
the presence of WO4 and SO3 in this catalyst (Table 1).
Table 2
Optimization of the reaction conditions.
Entry
Solvent
Catalyst
loading
Temperature
Time
Yield
(%)
(8C)
(min)
1
2
None
EtOH
EtOH
EtOH
EtOH
CH3CN
CH2Cl2
H2O
–
–
80–90
70–80
70–80
70–80
70–80
70–80
40
240
240
120
100
10
20
25
60
60
95
50
40
70
60
65
60
65
3
1 mol%
5 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
1 mol%
4
In continuation of our interest in using solid catalysts in the
synthesis of heterocycles [11–13], in this work, we describe a
simple and green strategy based on the condensation of 3-methyl-
1-phenyl-2-pyrazolin-5-one (4), aromatic aldehydes (5) and
malononitrile (6) using TSA as a powerful, recyclable and safe
catalyst for the preparation of novel and known 6-amino-4-aryl-5-
cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles (7)
(Scheme 2).
5
6
70
7
120
120
50
8
90–100
70–80
100
9
None
None
None
None
10
11
12
40
70–80
70–80
60
100
Fig. 1. (A): The powder X-Ray diffraction pattern of the tungstate sulfuric acid. (B): FT-IR spectra of TSA and sodium tungstate.
Table 1
XRF data of TSA.
Compound
WO4
SO3
Na2O
0.190
Cl
CuO
Fe2O3
0.015
CaO
LOIa
79.82
Total
Concentration (% w/w)
19.49
0.317
0.056
0.023
0.014
99.93
a
Loss on ignition.
Please cite this article in press as: M. Farahi, et al., An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives catalyzed by tungstate sulfuric acid, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.07.012

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M. Farahi et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
Table 3
Synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles by TSA.
Entry
Ar
Time (min)
Yield (%)a
Mp (8C)
Ref.
7a
7b
7c
7d
7e
7f
C6H5
10
20
30
20
32
30
35
20
35
20
25
15
30
20
95
92
88
80
88
86
85
95
92
88
90
90
85
88
171–173
145–146
159–160
190–192
174–175
176–177
182–184
195–197
167–169b
175–176b
158–159b
159–160b
185–186
170–171b
[8]
[8]
[9]
[8]
[8]
[8]
[4]
[8]
2-Cl-C6H4
3-Br-C6H4
3-NO2-C6H4
4-MeO-C6H4
4-Me-C6H4
7g
7h
7i
4-Br-C6H4
4-NO2-C6H4
4-Iso-propyl-C6H4
4-Bisphenyl-C6H4
4-Benzyloxy-C6H4
1-Naphthyl
7j
7k
7l
7m
7n
2,4-Cl2-C6H3
3-OEt-4-HO-C6H3
[6]
a
Isolated yields.
b
Novel compounds.
Scheme 3. The proposed mechanism for the TSA-catalyzed formation of 1,4-dihydropyrano[2,3-c]pyrazoles 7.
Table 4
Comparison of the results for the synthesis of 7a by the other catalysts.
Entry
Catalyst
Catalyst loading
Condition
Time (min)
Yield (%)
Ref.
1
2
3
4
5
6
Mg/Al HT
0.1 g
EtOH, rt
60
87
80
93
99
86
95
[14]
[15]
[6]
g
-Alumina
30 mol%
1 mol%
0.15 g
H2O, reflux
H2O or EtOH, reflux
H2O, 90 8C
H2O, reflux
EtOH, reflux
50
H14[NaP5W30O110
]
55–60
360
55
Triethylbenzylammoniumchloride
p-Toluene sulfonic acid
[16]
[17]
0.05 g
Tungstate sulfuric acid
10 mol%
10
96
97
98
We propose the possible following mechanism for the reaction.
One molecule of malononitrile is firstly condensed with the
aromatic aldehyde activated by the strong solid acid TSA to afford
catalyst compared favorably in the synthesis of 1,4-dihydropyr- 116
ano[2,3-c]pyrazole derivatives with the other reported catalysts 117
and methods.
118
99
a-cyanocinnamonitrile derivative 8. Then nucleophilic attack of
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
the active methylene of 4–8 gives the intermediate 9 followed by
tautomerization to produce 10. Cyclization of 10 by the
nucleophilic attack of the OH group in the cyano moiety gives
11 and subsequently products 7 (Scheme 3).
As an eco-friendly procedure, the recovery and reusability of
the catalyst are quite preferable. The recovered TSA from the model
reaction was regenerated by washing with ethylacetate and dried
at 100 8C for 1 h. The recycled catalyst can be used at least four
consecutive times in the model reaction, albeit in gradually
decreased yields.
From these results, we identified the best conditions for the
synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-
dihydropyrano[2,3-c]pyrazoles with the TSA catalyst. Comparison
of this method with others in the synthesis of 6-Amino-5-cyano-3-
methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole (7a) as a
model reaction is shown in Table 4. These results show that this
4. Conclusion
119
In summary, the reaction between 3-methyl-1-phenyl-2- 120
pyrazolin-5-one, aromatic aldehydes and malononitrile using 121
tungstate sulfuric acid as a catalyst provides a simple and efficient 122
one-pot entry for the synthesis of 1,4-dihydropyrano[2,3-c]pyr- 123
azole derivatives. The use of a green and recyclable catalyst, high 124
yield of products, and a simple workup procedure make the 125
present method a valuable contribution in accord with green 126
chemistry principles.
127
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Please cite this article in press as: M. Farahi, et al., An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives catalyzed by tungstate sulfuric acid, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.07.012

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Please cite this article in press as: M. Farahi, et al., An environmentally friendly synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives catalyzed by tungstate sulfuric acid, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.07.012