Electro-catalyzed multicomponent transformation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one to 1,4-dihydropyrano[2,3-c]pyrazole derivatives in green medium

Article abstract of DOI:10.1016/j.cclet.2015.04.016

Abstract An efficient and convenient synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives is described, using the electrogenerated anion of ethanol as the base in the presence of sodium bromide as an supporting electrolyte in a one-pot, three compone

Full text of DOI:10.1016/j.cclet.2015.04.016

Accepted Manuscript
Title: Electro-catalyzed multicomponent transformation of
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one to
1,4-dihydropyrano[2,3-c]pyrazole derivatives in green
medium
Author: Zahra Vafajoo Nourallah Hazeri Malek Taher
Maghsoodlou Hojat Veisi
PII:
S1001-8417(15)00149-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.04.016
CCLET 3283
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
1-2-2015
10-3-2015
19-3-2015
Please cite this article as: Z. Vafajoo, N. Hazeri, M.T. Maghsoodlou, H. Veisi,
Electro-catalyzed multicomponent transformation of 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one to 1,4-dihydropyrano[2,3-c]pyrazole derivatives in green medium, Chinese
Chemical Letters (2015), http://dx.doi.org/10.1016/j.cclet.2015.04.016
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Graphical Abstract
Electro-catalyzed multicomponent transformation of 3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one to 1,4-dihydropyrano[2,3-c]pyrazole derivatives in
green medium
Zahra Vafajoo*,a, Nourallah Hazeri*,a, Malek Taher Maghsoodlou a, Hojat Veisi b
Ar
H3C
H3C
CN
Electrolysis, 0.62 F mol-1
NaBr, EtOH, r.t.
CN
CN
O
N
N
H
Ar
N
NH2
O
N
O
Ph
Ph
An efficient and convenient synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives is described, using the electrogenerated
anion of ethanol as the base in the presence of sodium bromide as an supporting electrolyte in a one-pot, three component
condensation of malononitrile, aromatic aldehydes and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one.
Page 1 of 7

Original article
Electro-catalyzed multicomponent transformation of 3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one to 1,4-dihydropyrano[2,3-c]pyrazole derivatives in
green medium
Zahra Vafajoo a,∗, Nourallah Hazeri a,*, Malek Taher Maghsoodlou a, Hojat Veisib
a Department of Chemistry, Faculty of Sciences, University of Sistan and Baluchestan, Zahedan 98135-674, Iran
b Department of Chemistry, Payame Noor University, Tehran 19395-4697, Iran
ARTICLE INFO
ABSTRACT
Article history:
An efficient and convenient synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives is
described, using the electrogenerated anion of ethanol as the base in the presence of
sodium bromide as an supporting electrolyte in a one-pot, three component condensation of
malononitrile, aromatic aldehydes and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one. The
reaction is carried out in an undivided cell containing an iron electrode as the cathode and a
graphite electrode as the anode, at a constant current at room temperature.
Received 1 February 2015
Received in revised form 10 March 2015
Accepted 19 March 2015
Available online
Keywords:
1,4-Dihydropyrano[2,3-c]pyrazole
Multicomponent
Electrosynthesis
1. Introduction
Multi-component reactions (MCRs) constitute an especially attractive synthetic strategy for rapid and efficient library generation
due to the fact that the diversity can be achieved simply by varying the reacting components. To promote the mentioned reactions,
various catalytic systems have been used [1-3]. Recently, the development and application of electrodes as catalyst in organic
chemistry, have received considerable attention. Also, electrochemical synthesis as unique technique is valuable for large-scale
processes because electricity is a cheap and environmentally responsible chemical reagent and its interest behavior to produce initial
base as catalyst can be used at ambient temperature and pressure [4]. According to this information, many chemical transformations
such as MCRs to prepare various suitable compounds can be performed.
1,4-Dihydropyrano[2,3-c]pyrazole derivatives are a class of important heterocycles with a wide range of biological and
pharmacological properties such as antimicrobial [5], insecticidal and molluscicidal activities [6], anticancer, anticoagulant, diuretic,
spasmolytic and antianaphylactic agents [7]. Many methods with different conditions have been reported. Some of these compounds
have been already prepared in the presence of CuO–CeO2 [7], triethylammonium acetate (TEAA) [6], imidazole [8], L-proline or KF-
alumina [9], Silica bonded n-propyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride (SB-DABCO) [10] and H14[NaP5W30O110] [11].
However, some of these protocols require long reaction times, multi-step reactions and complex synthetic pathways and afford
products with only modest yields. Therefore, the introduction of milder, faster and more ecofriendly methods, accompanied with higher
yields are needed.
In continuation of previous work [12] to develop efficient and environmentally benign procedures, we report the successful synthesis
of 4-dihydropyrano[2,3-c]pyrazole derivatives via direct addition of various aromatic aldehydes, malononitrile and 3-methyl-1-phenyl-
∗ Corresponding author.
E-mail address: zahravafajou@pgs.usb.ac.ir
nhazeri@chem.usb.ac.ir
Page 2 of 7

1H-pyrazol-5(4H)-one in an undivided cell at room temperature under a constant current density and without base or any additive
catalyst in green media.
2. Experimental
The structural evaluation studies of compounds were performed with various experimental techniques such as IR, elemental
analysis, 1H NMR and 13C NMR spectroscopies. Complete relevant spectra (1H NMR, 13C NMR and IR) for the products are available
in the supporting information.
2.1 Typical experimental procedure for electrocatalytic synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives
A mixture of aryl aldehyde (2 mmol), malononitrile (3 mmol), 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol), and NaBr (0.05
g, 0.5 mmol) in EtOH (20 mL) was electrolyzed in an undivided cell equipped with a magnetic stirrer, a graphite anode, and an iron
cathode at 25 °C under a constant current density of 10 mA/cm2 [electrodes square 5 cm2] until the catalytic quantity of 0.62 F/mol of
electricity was passed. After the electrolysis was finished, the precipitated products were separated by filtration which was then twice
rinsed with an ice-cold ethanol/water solution (9:1, 5 mL), and dried under reduced pressure.
2.2 Analytical data for selected compounds
6-Amino-4-(3-ethoxy-4-hydroxyphenyl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4o): mp: 189-171 oC;
1
IR (KBr, cm-1): νmax 2195 (C≡N);3329-3420 (NH2), H NMR (400 MHz, DMSO-d6): δ 1.29-1.33 (t, 3H, J= 7.2 HzCH3), 1.83 (s, 3H,
CH3), 3.96-4 (q, 2H, J= 7.2 Hz CH2), 4.58 (s, 1H, CH), 6.60- 7.82 (m, NH2 and Ar), 8.85 (s, 1H, OH); 13C NMR (100 MHz, DMSO-
d6): δ 13 (CH3), 15 (CH3), 36.7 (CH), 59 (CN), 64 (CH2), 99.4, 114, 116, 120.3, 120.6, 120.65, 126.5, 130, 135, 138. 144, 145.9, 146,
146.3, 146.8, 146.9, 159.6, 159.7; Anal. Calcd. for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42%. Found: C, 68.12; H, 5.21; N, 14.38.
4,4'-(1,4-Phenylene)bis(6-amino-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile) (4p): mp: 236-238 oC; IR
1
(KBr, cm-1): νmax 2191 (C≡N);3329-3366 (NH2), H NMR (400 MHz, DMSO-d6): δ 1.79 (s, 3H, CH3), 4.80 (s, 1H, CH), 7.3 -8.6 (m,
NH2 and Ar); 13C NMR (100 MHz, DMSO-d6): δ 13 (CH3), 34.7 (CH), 57.7, 98.2, 120.4, 120.6, 124.4, 126.7, 129.8, 136, 137.9, 139.4,
144.5, 145.5, 149, 149.5,160, 160.1, Anal. Calcd. for C34H26N8O2: C, 70.58; H, 4.53; N, 19.37% Found: C, 70.33; H, 4.53; N, 19.59.
6-Amino-4-(biphenyl-4-yl)-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4q): mp: 193-194oC; IR (KBr, cm-
1
1): νmax 2196 (C≡N);3328-3471(NH2), H NMR (400 MHz, DMSO-d6): δ 1.77 (s, 3H, CH3), 4.88 (s, 1H, CH), 7.31-7.95 (m, NH2 and
Ar); 13C NMR (100 MHz, DMSO-d6): δ 13.4 (CH3), 37 (CH), 58, 99, 120.4, 120.6, 126.6, 127, 127.3, 127.8, 129, 129.8, 138, 139, 140,
143,144, 145.8, 159.95, 160 , Anal. Calcd. for C26H20N4O: C, 77.21; H, 4.98; N, 13.85%. Found: C, 77.14; H, 4.99; N, 14.01.
3. Results and discussion
Our investigations on the electrocatalytic multicomponent chain transformation of aryl aldehydes, 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one and malononitrile into 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles under neutral and
mild conditions by electrolysis in an undivided cell, began with the optimization of the reaction conditions. The synthetic pathway is
shown in Scheme 1.
Scheme 1. Synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives catalyzed by an electrogenerated base.
Table 1 illustrates the obtained data for the synthesis of 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile 4a under various experimental conditions. The reaction is performed in alcohols or acetonitrile as solvent in the presence
of an electrolyte at room temperature. The reaction progress was monitored with TLC.
Page 3 of 7

Table 1
Optimization of reaction conditions for synthesis of 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile at room
temperature.a
Entry
Electrolyte
I (mA)
Current
Time (min)
Catalyst
Solvent
Electricity passed
Yield
(%)b
−1
density
(F mol )
(mA/ cm2)
1
2
3
4
5
6
7
8
9
10
11
12
13
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
NaBr
-
KBr
KI
Bu4NBr
Bu4NBr
5
1
2
4
200
120
60
20
20
20
20
20
20
20
20
20
20
-
-
-
-
-
-
-
-
Na
-
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
MeOH
n-PrOH
EtOH
EtOH
EtOH
0.62
0.74
0.74
0.62
0.93
0.48
0.62
0.62
-
0.62
0.62
0.48
0.62
70
75
80
90
75
94
80
70
<5
40
45
95
95
10
20
50
75
50
50
50
-
50
50
50
50
10
15
10
10
10
-
10
10
10
10
-
-
-
CH3CN
EtOH
a General procedure: Aldehyde (2 mmol), malononitrile (3 mmol), 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol), and electrolyte (0.5
mmol), solvent (20 mL), iron cathode (5 cm2), and graphite anode (5 cm2)
b Isolated Yield.
Various amounts of current were applied under the mentioned conditions. Excellent conversions of the starting materials were
obtained under 10 mA/cm2 current densities after 0.48 F/mol of electricity had been passed and I=50 mA, electrodes surface (5 cm2)
was found to be optimal for the electrochemically induced chain process and allowed for the highest yield of 4a in solvent of CH3CN
and electrolyte of tetrabutyl ammonium bromide.
As seen in Table 1, acetonitrile as solvent can be useful and the related yield is excellent especially when combined with
tetrabutylammonium bromide (Bu4NBr) but this solvent is more expensive rather than an alcohol such as ethanol. Also, Acetonitrile
has a modest toxicity in small doses. It can be metabolized to produce hydrogen cyanide, which is the source of the observed toxic
effects [13, 14]. Meanwhile, Bu4NBr commonly used as a phase transfer catalyst. We applied this compound as electrolyte in
acetonitrile and ethanol. The results were shown Bu4NBr can be effective and the product was formed in excellent yield even when
EtOH was used as solvent. However, as mentioned in acetonitrile, Bu4NBr is more expensive and very hazardous.
Under these conditions, conversions of the starting materials were allowed for the excellent yield of 4a in ethanol as a solvent and
sodium bromide was used as an electrolyte.
An increase in the current density up to 15 mA/cm2 (I=75 mA) resulted in a slight decrease in the reaction yield, and may be a result
of the activation of the undesired direct electrochemical processes that lead to oligomerization of the starting material.
In comparison of electrocatalytic method with chemical method, we used sodium metal as catalyst (10 mol%) for preparation of 4a,
but desired product was obtained in low yields. So it seem this method hasn’t preferable for certainly economical advantages.
Regarding to Table 1, electrocatalytic method in comparison with other chemical methods has some advantages that it is green and
environmentally friendship and catalyst is produced and consumed in reaction media.
Using the optimized conditions, we also probed the scope and generality of the reaction of several aryl aldehydes with malononitrile
and 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one for synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivatives (Table 2, 4a-q).
Table 2
Electrocatalytic multicomponent synthesis of 1,4-dihydropyrano[2,3-c]pyrazole derivative under optimized conditions.a
Ar
H3C
O
CN
Electrolysis, 0.62 F mol-1
NaBr, EtOH, r.t.
CN
CN
N
+
O
+
Ar
H
N
N
N
O
NH2
Ph
Ph
1-17
4a-q
Entry
Aldehyde
Time Product Yield M.p (oC)
(min)
(%)b
90
Ref
1
20
168-170
169-171 [15]
4a
Page 4 of 7

2
3
20
20
95
95
196-198
195-197 [15]
4b
4c
190-192
190-192 [7]
4
5
6
20
20
20
90
90
90
174-176
173-175 [7]
4d
4e
4f
145-146
143-145[7]
180-182
181-183 [7]
7
8
9
20
20
20
85
85
80
211-213
210-212 [15]
4g
4h
4i
172-174
171-173 [7]
198-200
198-200 [7]
10
11
20
20
85
95
158-160
157-159 [7]
4j
182-184
4k
182-184 [10]
12
13
20
20
95
85
215-217
217-219 [10]
4l
172-173
4m
173-175 [7]
14
15
20
20
85
80
156-158
158–160 [10]
4n
4o
189-171
-
16
17
20
20
80
75
236-238
-
4p
4q
193-194
-
a General procedure: Aldehyde (2 mmol), malononitrile (3 mmol), 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol), and NaBr (0.05 g, 0.5
mmol), EtOH (20 mL), iron cathode (5 cm2), graphite anode (5 cm2), current density 10 mA/cm2, at room temperature.
bYield
As shown in Table 2, products were obtained in excellent yields. It was found that aromatic aldehydes both with electron
withdrawing and donating groups in reaction with other starting material have excellent isolated yield. Notably, in examining their
synthetic performance, it has been shown that this method is capable of promoting organic synthesis of 1,4-dihydropyrano[2,3-
Page 5 of 7

c]pyrazole derivatives in an environmentally friendly condition. A catalytic amount of an electrogenerated base can efficiently induce
the catalytic chain transformation of organic compounds. All these qualities agree well with the rules of green chemistry [4].
The proposed mechanism for the preparation of related products is depicted in Scheme 2. The initial formation of bromine on the
anode is a well-known process and the corresponding halogen color was observed at the anode when the electrolysis was conducted
without stirring the reaction mixture[10]. Deprotonation of an alcohol at the cathode leads to formation of alkoxide anion [16-19]. Its
subsequent reaction in solution with malononitrile gives rise to malononitrile anion.
Scheme 2. The proposed mechanism for the formation of 1,4-dihydropyrano[2,3-c]pyrazole derivatives.
Then Knoevenagel condensation of aldehyde with malononitrile anion takes place in the solution with the elimination of water and
formation of the corresponding α-cyanocinnamonitrile derivatives 5.
We perform a control experiment to detect of intermediate 5. The reaction was take placed in presence of benzaldehyde and
malononitrile at mentioned conditions (room temperature, I = 50 mA, EtOH and NaBr) and the intermediate 5 was formed at 5 min in
excellent yield (96%). Michael addition between 5 and 6 furnished 7, which upon intramolecular cyclization and isomerization gave
rise to product 4.
4. Conclusion
In conclusion, we have developed an efficient green procedure for the one-pot synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives in excellent yields under neutral and mild conditions in the presence of sodium bromide as an electrolyte. The very short
reaction time, high yields, simple workup the non-chromatographic purification of products will make the present method an important
addition to the available methodologies for synthesis of the products.
Acknowledgment
We are thankful to University of Sistan and baluchestan and Payame Noor University for partial support of this work.
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