Fast synthesis of pyrano[2,3-c]pyrazoles: Strong effect of Br?nsted and Lewis acidic ionic liquids

Article abstract of DOI:10.1007/s13738-014-0561-0

Abstract In a unique approach, four-component synthesis of some pyrano[2,3-c]pyrazoles by [ChCl][ZnCl₂]₂ and [H-NMP]HSO₄ as inexpensive and recyclable acidic ionic liquids were investigated. Excellent yields of products we

Full text of DOI:10.1007/s13738-014-0561-0

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0561-0
ORIGINAL PAPER
Fast synthesis of pyrano[2,3‑c]pyrazoles: strong effect of Brönsted
and Lewis acidic ionic liquids
Abdol R. Hajipour · Morteza Karimzadeh ·
Hamed Tavallaei
Received: 20 July 2014 / Accepted: 15 November 2014
© Iranian Chemical Society 2015
Abstract In a unique approach, four-component synthe-
sis of some pyrano[2,3-c]pyrazoles by [ChCl][ZnCl2]2 and
[H-NMP]HSO4 as inexpensive and recyclable acidic ionic
liquids were investigated. Excellent yields of products were
obtained using both environmentally friendly safe ionic
liquids. A comparative study of [ChCl][ZnCl2]2 as Lewis
acidic ionic liquid and [H-NMP]HSO4 as Brönsted acidic
ionic liquid was also carried out. The results showed that
advantages of these ionic liquids were their low reaction
time, lack of by-products and their reusability in compari-
son with reported basic ionic liquid.
the reaction, straight-forward reaction pathway, high yield
[1–3], low reaction time and the opportunity to synthesize
products by incorporating several different atoms in a one-
pot reaction [4]. Usually, products separation in such reac-
tions is easier than other processes because approximately
all of the starting materials used are converted to the prod-
uct [5–10].
Interest in ionic liquids has increased in the last few
years. Ionic liquids (ILs) are widely applicable because of
their environmentally compatibility, but it also should be
mentioned that they are not a common ambience for many
organic syntheses [11–16]. More recently, a series of rela-
tively cheap, generally accessible and resistant-to-humidity
acidic ILs have been reported from the reaction of choline
chloride and ZnCl2 [17, 18]. Such prepared acidic ILs have
Lewis character and this is owing to [ZnCl3]−, [Zn2Cl5]−,
and [Zn3Cl7]− ions [19, 20]. Also, we recently presented a
synthetic approach to N-methyl-2-pyrrolidonum hydrogen
sulfate, [H-NMP]HSO4, which is a new Brönsted acidic
ionic liquid, as an inexpensive catalyst [21]. Here, we use
these catalysts for the preparation of fused heterocycles.
The most important utilization of pyrazoles is in phar-
macy especially in the synthesis of drugs [22], as such
compounds give unrivaled biological characteristics to the
studied molecules [23–25]. Also pyrans and pyrano hete-
rocycles have attracted an increasing interest in medicinal
chemistry [26, 27]. Pyranopyrazoles are fused heterocyclic
compounds that exhibit insecticidal [28], fungicidal, anti-
cancer, antimicrobial, and molluscicidal activities [29–31].
One of the most challenging aspects in medicinal chem-
istry is the application of a synthetic method to achieve
multi-substituted fused heterocycles. There are various
methods for the synthesis of multi-substituted fused het-
erocycles using multicomponent reactions and during the
last few years synthesis of these compounds has received
Keywords Ionic liquid · Choline chloride · N-Methyl-
2-pyrrolidonum hydrogen sulfate · Malononitrile ·
Ethyl acetoacetate · Hydrazine hydrate
Introduction
Multicomponent reactions (MCRs) have been shown to
be a completely stringent tool in synthesis of heterocycles
because of some of their advantages such as simplicity of
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0561-0) contains supplementary
material, which is available to authorized users.
A. R. Hajipour (*) · M. Karimzadeh · H. Tavallaei
Pharmaceutical Research Laboratory, Department of Chemistry,
Isfahan University of Technology, Isfahan 84156,
Islamic Republic of Iran
e-mail: haji@cc.iut.ac.ir
A. R. Hajipour
Department of Pharmacology, Medical School,
University of Wisconsin, 1300 University Avenue,
Madison, WI 53706-1532, USA
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J IRAN CHEM SOC
Fig. 1 Four-component synthe-
sis of 5 using [ChCl][ZnCl2]2
great interest [32–35]. Various methods have been reported
for the preparation of pyranopyrazoles [36–46]. Manjula
et al. demonstrated a three-component synthesis of pyrano-
pyrazoles from the reaction of carbonyl compound, malo-
nonitrile and pyrazolin-5-one in aqueous ethanol medium
under totally non-catalytic conditions [47]. Pasha et al.
[48] described a greener procedure for preparing pyrano-
pyrazoles via four-component reaction between differ-
ent aryl aldehydes, malononitrile, ethyl acetoacetate, and
hydrazine hydrate using imidazole as a catalyst. Another
method has been reported by isocyanide-based multicom-
ponent reactions. Nevertheless, previously described reac-
tions have some weaknesses, such as use of solvents and
expensive starting materials, higher reaction time, lower
yields of products, time-consuming work-up methods and
harsh conditions for reactions. Here, we describe a simple
preparation method of pyrano[2,3-c]pyrazoles using four-
component reaction of malononitrile, aldehyde, hydrazine
hydrate and ethyl acetoacetate in the presence of different
ionic liquids as green catalysts at room temperature.
stirrer and at the same time 0.53 ml (10 mmol) of concen-
trated sulfuric acid, was gradually added to the mixture.
After adding the acid, the resulting mixture was stirred for
3 h at ambient temperature and then CH2Cl2 was removed
by evaporation and the product was completely dried by
vacuum pumps. This acidic ionic liquid could be recycled
after using in different reactions.
The general method for the preparation of pyrano[2,3-c]
pyrazoles in the presence of [ChCl][ZnCl2]2 ionic liquid
under solvent-free conditions
1.25 mmol of hydrazine hydrate, 1 mmol of ethyl acetoac-
etate, 1 mmol of malononitrile, 1 mmol of the required
aldehyde and 0.15 mmol of [ChCl][ZnCl2]2 ionic liquid
were added to a flask. The reaction mixture was heated at
90 °C temperature and stirred by a magnetic stirrer. Pro-
gress of the reaction was followed by TLC with a mixture
of cyclohexane and ethyl acetate, in 3 to 1 ratio, respec-
tively. In most cases, the reaction was performed in about
10 min. For some cases, products were obtained with high
purity and did not require further purification. If necessary,
products were further purified by column chromatography
using silica gel or recrystallization of ethanol was done.
Materials and methods
Instruments and materials
The general method for the preparation of pyrano[2,3-c]
pyrazoles in the presence of [H-NMP]HSO4 ionic liquid
under solvent-free conditions
All of the used reagents were procured from Merk and
Fluka Chemical Corporation. 1H NMR spectra were
recorded in DMSO-d6 with a Bruker Avance-400 instru-
ment. FT-IR spectra were taken using a Jasco-680 spectro-
photometer. Melting points were determined with a Gallen-
kamp melting apparatus and are uncorrected.
1.25 mmol of hydrazine hydrate, 1 mmol of ethyl acetoac-
etate, 1 mmol of malononitrile, 1 mmol of the required alde-
hyde and 0.12 mmol of [H-NMP]HSO4 ionic liquid were
added into a flask. The reaction mixture was kept at 90 °C
temperature and stirred by a magnetic stirrer. Progress of
reaction was followed by TLC using a mixture of cyclohex-
ane and ethyl acetate solvents in 3 to 1 ratio, respectively. In
most cases, the reaction was performed in about 4 min. In
some cases, products were obtained with high purity and did
not require further purification. If necessary, products were
further purified by column chromatography using silica gel.
Synthesis of [ChCl][ZnCl2]2 ionic liquid
1 mmol of choline chloride salt and 2 mmol of ZnCl2 were
poured into a 10-ml flask and the flask was placed in a oil
bath over 100 °C temperature and mixture was allowed to
melt, then a magnetic stirrer was placed into the flask and
the mixture stirred gently till a transparent [ChCl][ZnCl2]2
ionic liquid was formed.
Synthesis of [H-NMP]HSO4 ionic liquid
Results and discussion
Dry dichloromethane (10 ml) and 0.96 ml (10 mmol) of
N-methyl-2-pyrrolidone (NMP) were added to a 25-ml
flask and the flask was placed in an ice bath on a magnetic
In this study, a mixture of compounds 1, 2, 3 and 4 in a
1.25:1:1:1 molar ratio in presence of different ionic liquids
was vigorously stirred at room temperature (Fig. 1).
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J IRAN CHEM SOC
All of the starting materials were added simultane-
ously and reaction progress followed by TLC. It must
be noted that TLC showed a mixture of products when
all of the starting materials were added in a domino pro-
cess. So, we concluded that it is important to add starting
materials, respectively, in order to remove any probable
by-products. After ending the reaction, it was filtered to
give the corresponding pyrano[2,3-c]pyrazoles 5 in high
yields.
To optimize the reaction conditions various methods
were applied. 4-Hydroxybenzaldehyde was used as a model
substrate. Performing test reaction using starting materials
at 90 °C and without use of catalyst in order to understand
the role of the catalyst was also performed. No product was
achieved even after 12 h of heating. As most of the methods
are base catalyzed, there might be possibility of formation of
by-products. For this reason, in this work different acidic cat-
alysts were used. First, we used [ChCl][ZnCl2]2 ionic liquid
which has mild acidic property. In order to optimize reaction
conditions different amounts of catalyst were used. As shown
in Table 1, 15 mol % was chosen as the optimum value.
Using a lower value (<15 mol %) of the catalyst, reac-
tion rate decreased due to the low activation of materials.
Also larger amounts (>15 mol %) of the catalyst decreased
reaction rates because nucleophilic properties of some
functional groups declined (Table 1). The same reac-
tion was repeated with [H-NMP]HSO4 rather than [ChCl]
[ZnCl2]2 and the outcome of optimization are presented
in Table 2. Yields of products of these two catalysts were
compared with each other; [H-NMP]HSO4 showed better
yields than the other. It can be attributed to Brønsted acidic
property of [H-NMP]HSO4, while [ChCl][ZnCl2]2 is a cat-
alyst with Lewis acidic property.
We further evaluated a set of additional aromatic alde-
hydes in the multicomponent reaction of 1, 2 and 4 under
our discovered conditions (Table 3). The reaction afforded
good yields for the electron-deficient aldehydes even at
room temperature, but the substituent position on the ben-
zene ring had no more effect on the yields of products.
It should also be noted that reaction time was also not
affected with different substituents.
The structures of fully substituted fused heterocycles
were established by FT-IR, 1H NMR and 13C NMR spectral
1
data. The HNMR spectrum of 5d consists of a singlet for
Table 3 Scope of the reaction in the synthesis of pyrano[2,3-c]pyra-
zoles
Entry Substrate (R1)
Product [ChCl][ZnCl2]2 [H-NMP]HSO4
Time Yielda Time Yielda
(min) (%)
(min) (%)
1
C6H5
5a
5b
5c
5d
5e
16
10
10
10
12
11
13
11
13
13
17
12
15
14
11
77
91
87
88
81
84
85
91
76
80
66
87
75
74
91
5
5
5
4
5
5
5
4
5
4
7
4
5
6
4
71
89
84
89
76
81
82
90
72
77
60
86
69
70
87
2
4-BrC6H4
4-ClC6H4
4-NCC6H4
4-HOC6H4
3
4
5
Table 1 Optimization of the reaction condition for product 5b in
presence of [ChCl][ZnCl2]2
6
5-Br-2-HOC6H3 5f
2,4-(HO)2C6H3 5 g
7
Yield (%)a
8
4-FC6H4
5 h
5i
Product
Reaction conditions
9
2-HOC6H4
2-ClC6H4
5b
5b
5b
5b
5b
5b
No catalyst, 12 h, 90 °C
0
73
80
91
88
84
10
11
12
13
14
15
5j
cat 1 (8 mol %), 26 min, 90 °C
cat 1 (12 mol %), 15 min, 90 °C
cat 1 (15 mol %), 10 min, 90 °C
cat 1 (20 mol %), 13 min, 90 °C
cat 1 (25 mol %), 17 min, 90 °C
4-CH3SC6H4
2,6-Cl2C6H3
4-CH3OC6H4
4-CH3C6H4
2-FC6H4
5 k
5 l
5 m
5n
5o
a
Isolated yields
a
Isolated yields
The products were characterized from 1H NMR
b
Table 2 Optimization of the reaction condition for product 5b in
presence of [H-NMP]HSO4
Table 4 Recyclability of the catalyst
Product
Reaction conditions
Yield (%)a
Run
Yielda (%)
5b
5b
5b
5b
5b
5b
No catalyst, 12 h, 90 °C
0
70
83
89
84
79
[ChCl][ZnCl2]2
[H-NMP]HSO4
cat 2 (5 mol %), 12 min, 90 °C
cat 2 (10 mol %), 5 min, 90 °C
cat 2 (12 mol %), 5 min, 90 °C
cat 2 (15 mol %), 7 min, 90 °C
cat 2 (20 mol %), 9 min, 90 °C
1
2
3
4
91
90
89
87
89
87
86
84
a
a
Isolated yields
Reaction under the optimum condition
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J IRAN CHEM SOC
Fig. 2 Proposed mechanism for
the synthesis of fully substituted
pyranopyrazoles
methyl group (δ = 1.79 ppm), singlet for CH of pyrano ring
(δ = 4.75 ppm), a singlet for amino group (δ = 7.03 ppm),
a doublet for protons of aromatic ring (δ = 7.39 ppm,
3JHH = 8.0 Hz), a doublet for protons of aromatic ring
(δ = 7.80 ppm, 3JHH = 8.0 Hz), and a broad singlet for NH
group of pyrazole ring (δ = 12.19 ppm). The 1H decoupled
13C NMR spectrum of 5d showed 15 distinct resonances.
Separation of products can be achieved by extraction into
another solvent. Partitioning of solutes involving the cata-
lyst and starting materials is a key process. It is notable that
due to the solubility of the product in CH2Cl2 and also due
to the hydrophilic nature of the acidic ionic liquids which
are not soluble in the presence of CH2Cl2, the catalyst and
the product are well separated. In a model reaction (entry 2,
Table 1) after filtering the product, to retrieve the ionic liq-
uid, the aqueous phase containing ionic liquid was washed
with dichloromethane to be separated from the organic
impurities. Finally, water was evaporated to give the recy-
cled ionic liquids and then the recycled ionic liquids were
dried under vacuum at 65 °C for 2 h and were reused. It is
also notable that ionic liquids can be recycled at least four
times (each time 10 ml) for the model reaction (Table 4).
A proposed mechanism for such reaction is given in
Fig. 2. It is reasonable to assume that the intermediate 6
was generated from the condensation reaction between
compounds 1 and 2. Then Lewis acid catalyst activated
the carbonyl group of the intermediate to from 9. Thus,
carbonyl compound 9 is normally in rapid equilibrium
with an enol tautomer 10. In such compound the enol 10 is
important due to the aromatic character of the compound.
Also, condensation of malononitrile 4 with aromatic alde-
hydes 3 afforded 2-arylidene malononitrile 7. 2-Arylidene
malononitrile 7 could undergo nucleophilic addition of
the 3-methyl-1H-pyrazol-5-ol 10 and intermediate 11 was
formed. At last, one of the nitrile groups of intermediate
11 undergoes nucleophilic attack by the neighboring keto
functional group and tautomerizes to give pyrano[2,3-c]
pyrazoles 5.
Conclusion
In summary, a simple and efficient synthetic route to fully
substituted pyranopyrazoles has been developed using envi-
ronmentally friendly safe ionic liquids. Excellent yields of
the products have been obtained under milder conditions
and in short reaction time. These advantages along with the
use of cheap, highly stable and highly recyclable ionic liq-
uids make this protocol a unique method for synthesis of
pyranopyrazole.
Acknowledgments We gratefully acknowledge the funding support
received for this project from the Isfahan University of Technology
(IUT), IR Iran. Further financial support from Center of Excellence in
Green Chemistry Research (IUT) is gratefully acknowledged.
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