H14[NaP5W30O110] catalyzed one-pot three-component synthesis of dihydropyrano[2,3-c]pyrazole and pyrano[2,3-d]pyrimidine derivatives

Article abstract of DOI:10.1007/BF03246049

This is a report of an efficient, clean and facile method for the synthesis of 1,4-dihydropyrano[2,3-c] pyrazole and pyrano[2,3d]pyrimidine derivatives via three-component one-pot condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one or barbituric acid,

Full text of DOI:10.1007/BF03246049

J. Iran. Chem. Soc., Vol. 7, No. 3, September 2010, pp. 615-620.
JOURNAL OF THE
Iranian
Chemical Society
H14[NaP5W30O110] Catalyzed One-Pot Three-Component Synthesis of
Dihydropyrano[2,3-c]pyrazole and pyrano[2,3-d]pyrimidine Derivatives
M.M. Heravia,*, A. Ghodsa, F. Derikvanda,*, K. Bakhtiaria and F.F. Bamoharramb
aDepartment of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
bDepartment of Chemistry, Islamic Azad University-Mashhad Branch, Mashhad, Iran
(Received 20 May 2009, Accepted 4 September 2009)
This is a report of an efficient, clean and facile method for the synthesis of 1,4-dihydropyrano[2,3-c] pyrazole and pyrano[2,3-
d]pyrimidine derivatives via three-component one-pot condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one or barbituric
acid, aldehydes and malononitrile in the presence of a catalytic amount of preyssler type heteropolyacid as a green and reusable
catalyst in water or ethanol under refluxing conditions.
Keywords: 1,4-Dihydropyrano[2,3-c]pyrazoles, Pyrano[2,3-d]pyrimidines, On water reactions, Preyssler type heteropoly acid,
Multi-component reactions
INTRODUCTION
considerable attention [8,9]. Several pyrano[2,3-c]pyrazoles
are reported to have useful biological effects, such as analgesic
and anti-inflammatory activities [10]. Moreover, the biological
activity of fused azoles has led to intensive research on their
synthesis [11-13]. Recently, 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
under different conditions [14-18]. However, most of the
reported methods have their drawbacks. For example,
Combinatorial chemistry is being increasingly applied for
the discovery of novel biologically active compounds. In this
context, multicomponent reactions (MCRs) are a powerful tool
in the modern drug discovery process in terms of lead finding
and lead optimization [1,2].
The synthesis, reactions and biological activities of 4H-
pyrane-containing molecules afford an ever-expanding area of
research in heterocyclic chemistry. This structural motif
appears in a large number of pharmaceutical agents, drug
candidates [3,4], photoactive materials [5] and natural
products [6]. These interesting activities have stimulated
chemists to develop the chemistry of such a class of
compounds [7].
hexadecyltrimethylammonium bromide (HTMAB) is
a
harmful and irritant catalyst which is dangerous for the
environment [16]. In addition, the reusability of the catalysts
such as D,L-proline is not reported in a number of cases [17].
In recent years, special attention has been focused on the
use of water as a green solvent in various organic
transformations. In addition to its abundance and for
economical and safety reasons, water has naturally become a
substitute and an alternative environmentally benign solvent in
organic synthesis [19,20]. The use of aqueous medium as
Condensed pyrazoles are also biologically interesting
compounds and their chemistry has recently received
*Corresponding author. E-mail: mmh1331@yahoo.com and
f_derikvand@yahoo.com

Heravi et al.
solvent further reduces the harmful effects of organic solvents
on the environment.
the use of heteropolyacids as catalysts to help organic
reactions to occur [25-28], we examined the possibility of
using H14[NaP5W30O110] as a catalyst for three-component
one-pot synthesis of 1,4-dihydropyrano[2,3-c]pyrazole
derivatives (compound II) via condensation of 3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one, malononitrile and a variety of
aldehydes in water or ethanol under heating conditions
(Scheme 1).
The growing environmental awareness in chemical
research and pharmaceutical chemistry, due to their
traditionally large volume of waste/product ratios, is perhaps
the ripest area for greening [21]. Green chemistry approaches
have considerable potential not only for the reduction of by-
products, decreasing waste produced and lowering energy
costs, but for the development of new methodologies for the
previously inaccessible materials, using existing technologies
[21]. The importance of green chemistry is highly valued in
medicinal chemistry.
There has been considerable interest in the use of
heteropolyacids as environmentally benign catalysts due to
their unique properties such as high thermal stability, low cost,
ease of preparation and recyclability. Numerous chemical
reactions can occur in the presence of heteropolyacids [22].
Preyssler type heteropolyacid, H14[NaP5W30O110], is
remarkable owing to its exclusive physicochemical properties.
These include strong Bronsted acidity, reversible
transformations, solubility in polar and non-polar solvents,
high hydrolytic and thermal stability, which are all essential in
catalytic processes. Preyssler polyanion, as a large anion, can
provide many ‘‘sites’’ on the oval-shaped molecule that are
likely to render the catalyst effective [23]. This
heteropolyanion with [9] acidic protons, is an efficient
‘‘supper acid’’ solid catalyst which can be used both in the
homogeneous and heterogeneous phases [24]. In addition,
both pure and supported catalysts can be easily recovered and
recycled without degradation and loss of activity.
EXPERIMENTAL
All the chemicals were purchased from Merck Company.
All products were known compounds and identified by
comparing their spectra and all the physical data available in
the literature [16,29-32,36]. Melting points were measured by
using the capillary tube method with an electro thermal 9200
1
apparatus. H NMR spectra were recorded on a Bruker ARX
300 (300 MHz) instrument, using TMS as an internal standard
(DMSO-d6 solution). IR spectra were recorded from KBr disk
on the FT-IR Bruker Tensor 27. The reactions were monitored
by TLC.
Preyssler type heteropolyacid was prepared by the passage
of a solution of the potassium salt in water through a column
(50 cm ꢀ 1 cm) of Dowex 50 W ꢀ 8 in the H+ form and
evaporation of the elute to dryness under vacuum.
Synthesis
of
1,4-Dihydropyrano[2,3-c]pyrazole
Derivatives: General Procedure
A mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one or
barbituric acid (1 mmol), aldehyde (1 mmol), malononitrile (1
mmol) and a catalytic amount of H14[NaP5W30O110] (1 mol%)
was refluxed in water or ethanol (5 cc) for indicated time as
required to complete the reaction (Table 3). Upon completion
Recently, we have reported on catalytic behavior of
Preyssler’s anion [19]. Making use of the experience gained
from this study and based on our previous investigations into
Ar
H3C
CH3
N
N
I
N
Ph
O
N
H3C
Ph
CN
CN
H14[NaPW12O40
]
N
+
ArCHO
+
N
Ph
O
Water or Ethanol
Refluxing
Ar
O
H3C
CN
N
II
N
NH2
Ph
Scheme 1
616

H14[NaP5W30O110] Catalyzed One-Pot Three-Component Synthesis
of the reaction, monitored by TLC, the mixture was cooled to
room temperature. The precipitated products were separated
by filtration and recrystallized in ethanol.
2.28 (s, 3H, CH3), 4.62 (s, 1H, 4-H), 6.96 (s, 2H, NH2),
7.02 (d, 2H, J = 8.4 Hz, ArH), 7.08 (d, 2H, J = 8.4 Hz,
ArH), 7.30-7.34 (m, 1H, ArH), 7.46 (d, 2H, J = 8.0 Hz,
ArH), 7.78 (d, 2H, J = 8.0 Hz, ArH) ppm. IR (KBr): 2max
=
Recycling of the Catalyst in Aqueos Media
3414, 3314, 2178, 1658, 1594, 1398, 1258, 1128, 1026, 754
After the filtration of the products, the catalyst was
recycled by evaporation of the aqueous solution and washing
with diethyl ether in each case. The recovered catalyst was
dried and reused for the next reaction with only a modest loss
in activity. The catalyst was recovered and reused for five
times in the model reaction in aqueous media. The obtained
results are summarized in Table 3.
cm-1.
RESULTS AND DISCUSSION
In order to get the best reaction conditions the efficiency of
a variety of solvents in the synthesis of 6-amino-5-cyano-4-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole in the presence of a
catalytic amount of H14[NaP5W30O110] (1 mol%) as a model
reaction was studied.
Selected Spectroscopic Data
6-Amino-5-cyano-3-methyl-1,4-diphenyl-1,4-dihydro-
pyrano[2,3-c]pyrazole. (Table 2, entry 1): 1H NMR
(DMSO-d6, 300 MHz): ꢀ = 1.93 (s, 3H, CH3), 4.68 (s, 1H,
4-H), 4.75 (s, 2H, NH2), 7.16-7.32 (m, 10H, ArH) ppm. IR
(KBr): 2max = 3472, 3320, 2195, 1660, 1590, 1264, 1125,
1027, 753 cm-1.
Firstly, we carried out the model reaction under solvent-
free conditions at room temperature. The reaction was not
completed. The temperature of the reaction mixture started to
rise for 4 h but the reaction was not completed. Then, we
examined the effect of the solvent on the reaction. As shown
in Table 1, the best results were obtained in refluxing water
and ethanol. This could be due to two reasons: a) the first
stage of the reaction includes Knoevenagel condensation,
which is faster in water [28]; b) the PKa of HPA depends on
the solvent [33].
We also studied the relation between the rate of the model
reaction and temperature. It was found that there was a
correlation between reaction rate and the temperature and the
best results were obtained in refluxing water and ethanol
(Table 1).
6-Amino-4-(4-methoxyphenyl)-5-cyano-3-methyl-1-
phenyl-1,4-dihydropyrano [2,3-c]pyrazole. (Table 2,
1
entry 4): H NMR (DMSO-d6, 300 MHz): ꢀ = 1.78 (s, 3H,
CH3), 3.72 (s, 3H, OCH3), 4.88 (s, 1H, 4-H), 6.82 (d, 2H,
J = 8.0 Hz, ArH), 6.96 (s, 2H, NH2), 7.04 (d, 2H, J = 8.0
Hz, ArH), 7.20-7.24 (m, 1H, ArH), 7.40 (d, 2H, J = 8.0 Hz,
ArH), 7.58 (d, 2H, J = 8.0 Hz, ArH) ppm. IR (KBr): 2max
=
3395, 3322, 2192, 1660, 1595, 1394, 1250, 1128, 813 cm-1.
6-Amino-4-(4-methylphenyl)-5-cyano-3-methyl-1-
phenyl-1,4-dihydropyrano[2,3-c]pyrazole. (Table 2, entry
In order to establish the scope of this novel methodology,
we tested a variety of aldehydes and methylene active
8): 1H NMR (DMSO-d6, 300 MHz): ꢀ = 1.78 (s, 3H, CH3),
Table1. Optimization of the Reaction Conditions in the Model Reaction
Entry
Solvent
Solvent free
CHCl3
H2O
H2O
CH2Cl2
EtOH
Temperature (°C)
Time (h)
Yield (%)a
1
2
2
3
4
5
6
100
62
25
100
40
25
4
4
2
1
4
2
1
44
46
80
89
40
75
84
EtOH
78
aYields are related to isolated pure products.
617

Heravi et al.
compounds under the optimized reaction conditions. The
H14[NaP5W30O110] is soluble in water and could be recovered
by filtration of the product, evaporation of the residue solution
and washing with diethyl ether. The recycled catalyst could be
subjected to a second or even a third reaction. In the case of
the model reaction in water, after five runs, the catalytic
activity of the catalyst was almost the same as that of the
freshly used catalyst. (Table 3)
Bykova has reported an unprecedented route for this kind
of condensation reaction [34]. He obtained compound (I) as
the major product in the presence of piperidine as a basic
catalyst (Scheme 1). For another derivative, as reported by
Madkour, compound (I) was obtained under the same reaction
conditions in 15% but the major product was compound (II)
[35]. We did not obtain the same byproduct (I) under our
optimized conditions.
reaction was found to be tolerating a range of Ar groups with
different electronic demands including aromatic rings
involving electron-donating and electron-withdrawing groups
(Scheme 1). Unfortunately, ethylcyanoacetate, diethyl-
malonate,
ethylbenzoylacetate,
ethylacetoacetate
and
acetophenone were not active under these conditions (Table 2,
entries 9-12). We also examined the reaction of 3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one with chalcone, but the desired
product was not obtained even after prolonged reaction times
(Table 2, entry 13). When 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one was replaced by barbituric acid the related products
(III) were obtained in good yields (Table 2, entries 14-18).
It is noteworthy that the catalyst is recyclable and could be
reused without any
significant loss of activity.
Table 2. Synthesis of 1,4-Dihydropyrano[2,3-c]pyrazole Derivatives under Optimized Conditions in Refluxing Water or
Ethanol
Yield (%)a
H2O EtOH H2O EtOH
Time (min)
m.p. (oC)
Obtained, Reported
Product
Methylene active
compound
Entry
Ar-
1
2
3
4
5
6
7
8
Ph-
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Ethylcyanoacetate
Ethylacetoacetate
Diethylmalonate
Ethylbenzoylacetate
Acetophenoneb
Malononitrile
Malononitrile
Malononitrile
Malononitrile
Malononitrile
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
-
-
-
-
-
94
95
95
92
90
95
90
85
93
92
90
91
87
90
90
84
60 55
45 55
45 50
50 60
60 60
167-171, 169-171 [21]
190-192, 191-192 [21]
195-197, 196-198 [21]
174-177, 174-176 [21]
145-147, 145-146 [34]
174-177, 175-177 [21]
210-213, 211-212 [21]
178, 177-179 [21]
-
3-NO2-Ph-
4-NO2-Ph-
4-MeO-Ph-
2-Cl-Ph-
4-Cl-Ph-
4-HO-Ph-
4-Me-Ph-
Ph-
50
50
55
60
60 65
9
N.R N.R 24 h 24 h
N.R N.R 24 h 24 h
N.R N.R 24 h 24 h
N.R N.R 24 h 24 h
N.R N.R 24 h 24 h
-
-
-
-
10
11
12
13
14
15
16
17
18
Ph-
Ph-
-
-
-
-
Ph-
Ph-b
Ph-c
IIIa
IIIb
IIIc
IIId
IIIe
85
90
90
90
88
-
-
60
30
223-226, 224-5 [36]
265, 262-263 [36]
270-272, 238-239 [36]
245-247, 242-244 [36]
230-233, 280-281 [36]
3-NO2-Ph-
4-NO2-Ph-
4-Cl-Ph-
4-MeO-Ph-
-
-
-
50
30
45
-
aYields are related to isolated pure products. bIn this reaction, firstly benzaldehyde, acetophenone, catalyst and solvent were
treated together under refluxing conditions, to produce the chalcone and then pyrazolone derivative was added to the
mixture. cIn 14-18 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one was replaced by barbituric acid.
618

H14[NaP5W30O110] Catalyzed One-Pot Three-Component Synthesis
Table 3. Reusability of the Catalyst in the Model Reaction
the versatility of clean organic reactions in water.
in Refluxing Water
ACKNOWLEDGEMENTS
Entry
1
Number of
recycle
Time
(min)
Yield
(%)a
MMH is thankful to Iran National Science Foundation for
the partial financial support of this research work.
Fresh
60
94
2
3
4
5
1
2
3
4
60
60
60
60
89
85
83
78
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