Highly efficient solvent-free synthesis of pyranopyrazoles by a Bronsted-acidic ionic liquid as a green and reusable catalyst

Article abstract of DOI:10.1007/s12039-012-0310-9

A simple, green and efficient protocol for synthesis of dihydropyrano[2,3-c]pyrazole derivatives is developed by a four component reaction of various benzaldehydes, ethyl acetoacetate, hydrazine hydrate and malononitrile in the presence of 3-methyl-1-(4-s

Full text of DOI:10.1007/s12039-012-0310-9

J. Chem. Sci. Vol. 124, No. 5, September 2012, pp. 1013–1017. ꢀc Indian Academy of Sciences.
Highly efficient solvent-free synthesis of pyranopyrazoles by a
Brønsted-acidic ionic liquid as a green and reusable catalyst
JAVAD EBRAHIMI , ALI MOHAMMADI , VAHID PAKJOO , EHSAN BAHRAMZADEc
a,∗
b,∗
c
c
and AMIR HABIBI
a
Young Researchers Club, Islamic Azad University, Mashhad Branch, P.O. Box 9187147578, Mashhad, Iran
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, P.O. Box 91775,
b
Mashhad, Iran
c
Department of Chemistry, Islamic Azad University, Mashhad Branch, P.O. Box 9187147578, Mashhad, Iran
e-mail: javad_ebrahimi@ymail.com; a.mohammdy62@yahoo.com
MS received 7 September 2011; revised 2 April 2012; accepted 6 June 2012
Abstract. A simple, green and efficient protocol for synthesis of dihydropyrano[2,3-c]pyrazole deriva-
tives is developed by a four component reaction of various benzaldehydes, ethyl acetoacetate, hydrazine
hydrate and malononitrile in the presence of 3-methyl-1-(4-sulphonic acid)butylimidazolium hydrogen sul-
phate [(CH2)4SO3HMIM][HSO4], an acidic ionic liquid and as a catalyst, under solvent-free conditions. The
key advantages of this process are high yields, shorter reaction times, easy work-up, purification of products by
non-chromatographic method and the reusability of the catalyst.
Keywords. Pyranopyrazoles; solvent-free synthesis; multicomponent reaction; ionic liquid;
heterogeneous catalysts.
1
. Introduction
between 3-methyl-1-phenylpyrazolin-5-one and tetra-
cyano ethylene. In addition, weak bases can also
be used for this Michael-type cyclization.7 Other
recent methods for the synthesis of pyranopyrazoles
include a three-component condensation between N-
methylpiperidone, pyrazolin-5-one and malononitrile in
Multicomponent reactions (MCRs) have drawn great
interest enjoying an outstanding status in modern
organic synthesis and medicinal chemistry because they
are one-pot processes bringing together three or more
components and show high atom economy and high
selectivity. MCRs have great contribution in con-
vergent synthesis of complex and important organic
molecules from simple and readily available starting
materials, and have emerged as powerful tools for
8
absolute ethanol, a two-component reaction involv-
1,2
9
ing pyran derivatives and hydrazine hydrate, use of
10
piperidine as a base in water, N-methylmorpholine in
1
1
12
ethanol, microwave irradiation and also solvent-free
13
conditions.
3,4
drug discovery. The pyranopyrazole nucleus is a fer-
tile source of biologically important molecules. Com-
pounds containing this moiety have many pharmaco-
logical properties and play important roles in biochem-
ical processes. They are well-known as antimicrobial,
insecticidal and antiinflammatory compounds. Further-
more, these compounds showed molluscicidal activ-
ity and was identified as a screening kit for Chk1
In the recent years, ionic liquids have become a
powerful alternative to conventional molecular organic
solvents due to their particular properties, such as unde-
tectable vapour pressure and the ability to dissolve
14
many organic and inorganic substances. In addition,
the ionic liquids are readily recycled and tunable to
specific chemical tasks. One type is Brønsted-acidic
task-specific ionic liquids (BAILs). Among these, ionic
5
kinase inhibitor. During the last few years, some meth-
liquids possessing HSO as a counteranion find a broad
4
ods were introduced for the synthesis of these com-
pounds. Otto had proposed the first synthesis of the
dihydropyrano[2,3-c]-pyrazoles in 1974, via the base
application in organic synthesis, acting as both sol-
vents and catalysts. Recently, immobilization processes
involving acidic ionic liquids on solids supports have
6
catalysed cycloaddition of 4-aryliden-5-pyrazolone.
15–21
been designed.
The heterogenization of catalysts
Pyranopyrazole is also synthesized from the reaction
and reagents can offer important advantages in han-
dling, separation and reuse procedures. Based on eco-
nomic criteria, it is desirable to minimize the amount
∗
For correspondence
1013

1014
Javad Ebrahimi et al.
R
O
O
O
CN
NH2
[
(CH2)4SO3HMIM][HSO4]
Solvent free/ rt
+
+
+
NC
H2N
HN
O
R
H
CN
N
O
NH2
2a−j
Figure 1. [(CH2)4SO3HMIM][HSO4] catalysed synthesis of pyranopyrazoles.
of ionic liquid utilized in a potential process. Immobi- Table 1. Reuse of the acidic ionic liquid for synthesis
lized acidic ionic liquids have been used as novel solid of 1a.
catalysts for a wide spectrum of reactions.2
2–26
With
Entry
Time (min)
Yield (%)
these considerations in mind and our interest in the
development of new synthetic method in heterocyclic
chemistry, we introduce here a facile method for
synthesis of biologically active dihydropyrano[2,3-c]-
pyrazoles systems.
1
2
3
4
30
30
30
30
85
85
82
80
In this work, we report the solvent-free synthesis
of dihydropyrano[2,3-c]-pyrazoles via four component
reaction of various benzaldehydes, ethyl acetoacetate, rated by filtration. The filtrate was concentrated in
hydrazine hydrate and malononitrile in the presence of vacuo to remove the ethanol and the acidic ionic liquid
3
-methyl-1-(4-sulphonic acid)butylimidazolium hydro- remains. The recycled catalyst was employed consecu-
gen sulphate [(CH ) SO HMIM][HSO ], an acidic tively for four reactions and no significant loss in its
2
4
3
4
ionic liquid as a catalyst. We examined a wide variety efficiency was observed (table 1).
of benzaldehydes with various substituents to establish
the catalytic importance of this catalyst for this reaction
2.2 General procedure for preparation of 2a–j
(
figure 1).
At first, substituted benzaldehyde (1 mmol) and
[
(CH ) SO HMIM][HSO ] (0.25 mmol) as a catalyst,
2. Experimental
2 4 3 4
was mixed for 5 min then ethyl acetoacetate (1 mmol),
Melting points were measured with an Electrother- hydrazine hydrate (1 mmol) and malononitrile (1 mmol)
mal 9100 apparatus. IR spectra were recorded with a was added to this mixture and stirred at room tem-
Varian 3100 FTIR spectrometer. CHN analyses were perature for 30 min. The reaction was monitored by
performed on Exeter Analytical Inc. ‘Model CE-400 TLC. After completion of the reaction, appropri-
1
13
CHN Analyzer’. H and C NMR spectra were ate amounts of EtOH (96%) were added and the
recorded with a BRUKER DRX-400 AVANCE spec- mixture was stirred for 10 min then, the catalyst was
◦
trometer at 298 K and 75.47 MHz, respectively. NMR separated by filtration. The precipitation was washed
spectra were obtained on solutions in DMSO-d . All by cold ethanol and after that was crystallized from hot
6
7,10–13
the products are known compounds,
which were ethanol to afford the pure products.
1
characterized by IR and H NMR spectral data and
their melting points were compared with literature
reports.
2.3 Selected spectral data
2.3a 6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-
2
.1 Preparation and reusability of the acidic
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (2d):
Mp 171–173 C. FTIR (KBr,cm ): υ = 3483.51 (NH),
◦
−1
ionic liquid
3
256.70 and 3105.54 (NH ), 2191.93 (CN), 1612.09
2
1
3
-Methyl-1-(4-sulphonic acid)butylimidazolium hydro- (C=N), 1583.27 (C=C); H NMR (400 MHz, DMSO-
gen sulphate [(CH ) SO HMIM][HSO ] was prepared d ): δ = 1.79 (s, 3H, CH3), 3.75 (s, 3H, O-CH3),
2
4
3
4
6
according to the literature.27 When the acidic ionic 4.50 (s, 1H, C-4 pyran), 6.85 (d, 2H, p-anisyl-H), 6.88
liquid was used in the reaction and the reaction was (d, 2H, p-anisyl-H), 7.09 (s, 2H, NH2), 12.08 (s, 1H,
13
completed, appropriate amounts of EtOH (96%) was NH); C NMR (75 MHz, DMSO-d ): δ = 9.8, 35.5,
6
added. The ionic liquid solved in EtOH and was sepa- 54.7, 57.6, 117.5, 105.7, 110.3, 113.75, 136.5, 142.28,

Synthesis of pyranopyrazoles
1015
1
54.74, 155.72, 160.68; Anal. Calcd for C H N O : Table 2. Eaffects of different solvents on the reaction
15
14
4
2
C, 63.82; H, 5.00; N, 19.85. Found: C, 63.24; H, 4.87; productivity .
N, 19.81.
Entry
Catalystb
Solvent
Time Yield (%)
1
2
3
4
Acidic ionic liquid
Acidic ionic liquid
Acidic ionic liquid
–
0.5 h
1 h
1 h
75
67
55
–
2
.3b 6-Amino-4-(4-methylphenyl)-3-methyl-2,4-
Water
Ethanol
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (2j):
◦
−1
Mp 175–177 C. FTIR (KBr,cm ): υ = 3448.78 (NH),
Acidic ionic liquid Acetonitrile 24 h
3418.4 and 3353.51 (NH ), 2188.78 (CN), 1624.91
2
a4-Chlorobenzaldehyde/ethylacetoacetat/hydrazine hydrate/
1
(
C=N), 1579.37 (C=C); H NMR (400 MHz, DMSO-
malonitrile (1:1:1:1 mmol)
d ): δ = 1.8 (s, 3H, CH3), 2.28 (s, 3H, Ar-CH3), 4.52
b
6
0
.15 mmol
(s, 1H, C-4 pyran), 6.85 (d, 2H, p-tolyl-H), 7.00 (d, 2H,
p-tolyl-H), 7.18 (s, 2H, NH2), 12.09 (s, 1H, NH);
13
Table 3. Optimization of amount of catalyst for synthesis
of pyranopyrazol from 4-chlorobenzaldehyde .
C NMR (75 MHz, DMSO-d ): δ = 9.9, 20.7, 36.7,
6
a
4
0.1, 78.3, 97.4, 120.7, 127.2, 128.6, 135.4, 140.9,
1
54.7, 160.6; Anal. Calcd for C H N O: C, 67.65;
15
14
4
Catalyst
(mmol)
Time
(min)
H, 5.30; N, 21.04. Found: C, 67.15; H, 5.17; N, 21.00.
Entry
Yield
1
2
3
4
5
6
0.05
0.10
0.15
0.20
0.25
0.30
30
30
30
30
30
30
50
65
75
81
85
85
3
. Results and discussion
Several methods are used in the synthesis of these
dihydropyrano[2,3-c]pyrazole derivatives. In addition,
the synthesis of these heterocycles has been usually
carried out in polar organic solvents such as water, a4-Chlorobenzaldehyde/ethylacetoacetat/hydrazine hydrate/
malonitrile (1:1:1:1 mmol)
ethanol, DMF and DMSO leading to complex isolation
and recovery procedures. These processes also gene-
rate waste containing catalyst and solvent, which have
Table 4. Synthesis of substituted pyranopyrazoles using
to be recovered, treated and disposed of.7 The toxi-
,28
[(CH2)4SO3HMIM][HSO4] (0.25 mmol) as a catalyst under
city and volatile nature of many organic solvents, par- solvent-free conditions.
ticularly chlorinated hydrocarbons that are widely used
◦
Mp/ C
Found Reported
in huge amounts for organic reactions have posed a
serious threat to the environment.29 Thus, design of Producta
solvent-free catalytic reaction has received tremendous
R
Yields (%)b
30
2a
4-ClPh
3-ClPh
2-ClPh
4-MeOPh
Ph
4-BrPh
3-BrPh
4-NO2Ph
3-NO2Ph
4-MePh
85
80
80
85
80
80
80
90
85
90
173–175 174–1757
157–158 158–1607
attention in recent times in the area of green synthesis.
2
2
2
2
b
c
d
e
The choice of a solvent is a crucial factor for mul-
ticomponent reactions. So at the first step we looked
into the solvent effect for this reaction. We tested
7
145–147 145–146
171–173 170–1727
7
166–168 167–169
181–183 180–1837
the reaction in some protic and aprotic solvents such 2f
2
2
2
2
g
h
i
177–179
–
as ethanol, water and acetonitrile in the presence of
(CH ) SO HMIM][HSO ] as a catalyst. The reaction
193–194 192–1947
190–193 190–1927
175–177 175–1767
[
2
4
3
4
in the aprotic solvent had satisfying performance but
in the aprotic solvent (acetonitrile) efficiency was poor,
even after 24 h. Also the reaction was carried out at
the solvent-free conditions. By omitting the solvent, the
productivity of the reaction was better and addition-
ally, the reaction time decreased. The related results are
given in table 2. Hence, in the next steps we have used
j
a
All the isolated products were characterized on the basis of
their physical properties and IR, H- and C-NMR spectral
analysis and by direct comparison with authentic materials
1
13
b
Isolated yields
the solvent free conditions for synthesis of substituted of 4-chloro benzaldehyde (1 mmol), ethyl acetoacetate
pyranopyrazoles. (1 mmol), hydrazine hydrate (1 mmol), malononitrile
Apart from the solvent, the efficiency of the multi- (1 mmol) and [(CH ) SO HMIM][HSO ] (0.05 mmol),
2
4
3
4
component reactions is mainly affected by the amount as a catalyst at room temperature for 30 min, which
of catalyst and the reaction time. In the next stage for led to low yield (55%) of the product. To enhance the
getting the best conditions, we started the condensation yield of the desired product, the amount of catalyst was

1016
Javad Ebrahimi et al.
increased to 0.3 mmol. With increasing the amount of electron-releasing or electron-withdrawing substituents
the catalyst, the productivity of the reaction increased. on aryl ring of aldehyde.
As indicated in table 3, maximum yield was obtained
Possible mechanism for the [(CH ) SO HMIM]-
2 4 3
(
85%) when the reaction was loaded with 0.25 mmol of [HSO ] catalysed synthesis of substituted pyranopy-
4
the catalyst. A further increasing of catalyst loading did razoles has been proposed in figure 2. In summary,
not affect the yield. this paper describes a convenient and efficient pro-
After optimizing the conditions, we applied this cata- cess for the solvent-free synthesis of substituted pyra-
lyst for synthesis of substituted pyranopyrazoles by nopyrazoles through the four components coupling of
using different aromatic aldehydes with a wide range of aldehydes, ethyl acetoacetate, hydrazine hydrate, mal-
ortho-, meta- and para-substitutions under solvent-free ononitrile using [(CH ) SO HMIM][HSO ] as a cata-
2
4
3
4
classical heating conditions to establish the catalytic lyst. Reaction profile is very clean and no side prod-
importance of [(CH ) SO HMIM][HSO ] for this reac- ucts are formed. All the synthesized pyranopyrazoles
2
4
3
4
tion. The corresponding results are given in table 4. We have been characterized on the basis of elemental
found that the reaction proceeded efficiently by either and spectral studies. We believe that this procedure is
H
O
O
NH2
1
) [(CH2)4SO3HMIM][HSO4]
H2N
2
) H2NNH2
EtO
O
EtO
H
O
-
-
H2O
NC
CN
EtOH
H2NNH2
H
O
N
+
N
NC
CN
H
O
H
R
H2NNH2
- H O
2
NC
CN
N
CH
R
N
H
O
R
H
CN
N
N
C
N
H
O
H2NNH2
R
R
O
CN
CN
H[1,5]
N
HN
N
N
H
O
NH2
NH2
Figure 2. Probable mechanism for the formation of substituted pyranopyrazoles using
(CH2)4SO3HMIM][HSO4] as a catalyst.
[

Synthesis of pyranopyrazoles
1017
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