Mesoporous SBA-15 Silica Phenylsulfonic Acid (SBA-15-Ph-SO3H) as Efficient Nanocatalyst for One-pot Three-component Synthesis of 3-Methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones

Article abstract of DOI:10.1002/jhet.2689

A simple, economical, and efficient approach to the one-pot synthesis of 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones by multicomponent assembling of 5-methylpyrazol-3-amine, aldehydes, and Meldrum's acid using mesoporous silica phenylsulfonic acid (SBA-15-Ph-SO₃H) as recyclable and heterogonous solid acid nanocatalyst has been described. This protocol has the advantages of high yields, wide application scope, and an environmental benign procedure.

Full text of DOI:10.1002/jhet.2689

Month 2016
Mesoporous SBA-15 Silica Phenylsulfonic Acid (SBA-15-Ph-SO3H) as
Efficient Nanocatalyst for One-pot Three-component Synthesis of 3-
Methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones
a
b
c
*
Hojat Veisi, Malak Hekmati, and Saba Hemmati
aDepartment of Chemistry, Payame Noor University, Tehran, Iran
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmaceutical Chemistry, Pharmaceutical Sciences Branch,
(IAUPS), Tehran, Iran
cYoung Researchers and Elite Club, Kermanshah Branch, Islamic Azad University, Kermanshah, Iran
*
E-mail: hojatveisi@yahoo.com
Received January 21, 2016
DOI 10.1002/jhet.2689
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A simple, economical, and efficient approach to the one-pot synthesis of 3-methyl-4-aryl-2,4,5,7-
tetrahydropyrazolo[3,4-b]pyridine-6-ones by multicomponent assembling of 5-methylpyrazol-3-amine,
aldehydes, and Meldrum’s acid using mesoporous silica phenylsulfonic acid (SBA-15-Ph-SO3H) as recycla-
ble and heterogonous solid acid nanocatalyst has been described. This protocol has the advantages of high
yields, wide application scope, and an environmental benign procedure.
J. Heterocyclic Chem., 00, 00 (2016).
© 2016 Wiley Periodicals, Inc.

H. Veisi, M. Hekmati, and S. Hemmati
Vol 000
Scheme 1. Synthesis of 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-
b]pyridine-6-ones using SBA-15-Ph-SO3H. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
INTRODUCTION
Pyrazolo[3,4-b]pyridines are gaining importance in
medicinal and organic chemistry. They have displayed
broad spectrum of pharmacological and biological activi-
ties such as antibacterial [1], antimicrobial [2], antiviral
[3], oncogenic Ras-inhibiting [4], and cyclooxygenase-
inhibiting activities [5]. The synthesis of pyrazolopyridone
derivatives has been extensively explored in recent years
[6–14]. However, some of the reported methodologies for
the synthesis of these products are associated with several
drawbacks such as prolonged reaction time, low yields,
harsh reaction conditions, use of expensive reagents and
catalysts, and tedious workup. Therefore, any new facile
and highly efficient synthetic approach to corresponding
pyrazolopyridones is highly desirable.
There has been considerable interest in the development
of heterogeneous solid acid catalysts to avoid the use of
traditional homogeneous acid catalytic systems (H2SO4,
HF, AlCl3, BF3,…) that present serious drawbacks includ-
ing hazards in handling, corrosiveness, production of toxic
waste, and difficulties in separation. In this context, organ-
ically functionalized ordered mesoporous silicas [15–18]
with a tunable pore structure, high surface area, and tai-
lored composition have received great attention with broad
applications. The catalytic activity of the sulfonic acid-
functionalized mesoporous silica materials is controlled
by location and distribution of the acidic sites and solvent
interactions [19]. While several types of solid sulfonic
acids, based on ordered mesoporous silicas, have been
created in recent years [20].
observed morphology for SBA-15. This indicates that
during the surface modifications, morphology of solid
was saved without significant change. Also the
transmission electron microscopy image of SBA-15-Ph-
SO3H in Figure 1 (right) shows the parallel channels,
which is similar to the pore configuration of SBA-15. It
means that during tree step reactions, the pore of SBA-
15-Ph-SO3H was not collapsed.
General procedure for synthesis of pyrano[2,3-d]
In our continued interest in the development of a highly
expedient methodology [21] for the synthesis of fine
chemicals and heterocyclic compounds of biological
importance, we report here a simple and efficient method
for the one-pot synthesis of 3-methyl-4-aryl-2,4,5,7-
tetrahydropyrazolo[3,4-b]pyridine-6-ones by multicompo-
nent assembling of 5-methylpyrazol-3-amine, aldehydes,
and Meldrum’s acid using mesoporous silica
phenylsulfonic acid (SBA-15-Ph-SO3H) as recyclable and
heterogonous solid acid nanocatalyst to promote the reac-
tions (Scheme 1).
pyrimidine-2,4,7-trione derivatives in the presence of
SBA-15-Ph-SO3H.
A mixture of aldehydes (1mmol),
Meldrum’s acid (1 mmol), and 5-methylpyrazol-3-amine
(1 mmol) were taken in a mixture of SBA-15-Ph-SO3H
(10 mol%) and ethanol (5 mL) in a round bottomed flask.
The resulting mixture was vigorously stirred at reflux
temperature until completion of the reaction as monitored
by thin-layer chromatography (n-hexane/acetone, 4:1).
After complication of reaction, the insoluble solid catalyst
was removed by filtration. The crude products were
obtained after cooling of the filtrates and purified by
recrystallization from ethanol afforded pure products. All
the products were characterized by spectroscopy and
from physical data.
EXPERIMENTAL
Synthesis and functionalization of SBA-15. According
to our previous report,20h the nanoporous compound
SBA-15 was synthesized and functionalized (Fig. 1).
Figure 1 also illustrated the scanning electron microscopy
and transmission electron microscopy images of SBA-
15-Ph-SO3H. As can be seen in Figure 1 (left),
functionalized SBA-15 has uniform particles about 1 lm
in scanning electron microscopy image that is same as
RESULTS AND DISCUSSION
Initially, to evaluate the synthetic potential of the proce-
dure proposed, the one-pot multicomponent condensation
of benzaldehyde, Meldrums acid, and 5-methylpyrazol-3-
amine into 3-methyl-4-phenyl-2,4,5,7-tetrahydropyrazolo
[3,4-b]pyridine-6-one in the presence of SBA-15-Ph-
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One-pot Three-component Synthesis of Pyrazolo[3,4-b]pyridines
Figure 1. Preparation of SBA-15-Ph-SO3H and its scanning electron microscopy and transmission electron microscopy images. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 1
Effect of the solvent, temperature, reaction time, amount of catalyst on the synthesis of 3-methyl-4-phenyl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-one.a
Entry
Solvent
Catalyst (mol%)
Temperature (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
MeOH
H2O
10a
10
10
10
10
10
10
20
5
65
78
60
40
110
82
80
80
80
25
80
240
240
240
240
240
240
120
120
120
240
240
70
60
65
50
55
70
96
96
80
CH3Cl
CH2Cl2
Toluene
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
9
10
11
10
0
45
Trace
a5-methylpyrazol-3-amine (1 mmol), aldehydes (1 mmol), Meldrum’s acid (1 mmol), and solvent (5 mL).
SO3H was chosen as model. In order to establish the opti-
mum conditions for this reaction, initially, the influence of
the reaction temperature, the amounts of catalyst, and the
reaction time were tested and optimized. The results are
summarized in Table 1. As it is indicated in Table 1 (entry
7), the optimal catalyst loading (10 mol%) and the temper-
ature at 80°C in EtOH were found to be the optimum one
for the synthetic process and afforded the highest yield of
Journal of Heterocyclic Chemistry
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H. Veisi, M. Hekmati, and S. Hemmati
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Table 2
Synthesis of 3-methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones.
Entry
Aldehyde
Yield (%)b
Mp (°C)a
Mp (°C)ref
1
2
3
4
5
6
7
8
C6H5CHO
4-Me-C6H4CHO
4-MeO-C6H4CHO
3-NO2-C6H4CHO
4-Cl-C6H4CHO
2-Me-C6H4CHO
4-N(Me)2-C6H4CHO
2-Cl-C6H4CHO
3,4,5-(MeO)3-C6H2CHO
2,4-Cl2-C6H3CHO
4-OH-C6H4CHO
2-MeO-C6H4CHO
2-thienylaldehyde
Butanal
96
96
95
92
92
92
96
92
96
90
88
96
90
80
75
303–305
>300
>300
266–268
>300
>300
>300
>300
>300
>300
274–276
278–280
300–302
258–260
290–292
304–306 [12]
>300 [11]
308–310 [12]
264–266 [14]
>300 [14]
>300 [11]
>300 [14]
>300 [16]
>300 [16]
9
10
11
12
13
14
15
>300 [14]
274–276 [14]
279–280 [14]
303–305 [12]
259–260 [11]
290–292 [14]
2-Propanal
aGeneral procedure, 5-methylpyrazol-3-amine (1 mmol), aldehydes (1 mmol), Meldrum’s acid (1 mmol), SBA-15-Ph-SO3H (10 mol%), EtOH (5 mL),
120 min at 80 °C.
bYield of isolated product.
product (96%). It should be noted that the optimal catalyst
loading in the synthesis of 3,3-dimethyl-13-(4-
chlorophenyl)-3,4-dihydro-1H-indazolo[1,2-b]
analyses and those of known products by comparison of their
spectral data and melting points with literature reports.
With the previous results taken into consideration and
the mechanistic data on the catalytically induced Henry
and aldol reactions and also tandem Knoevenagel–Michael
reactions, the following mechanism for the preparation of
the related products is depicted in Scheme 2 [13]. The first
step involves the Knoevenagel reaction of Meldrum’s acid
with aldehyde to form an intermediate A. The next step is
phthalazine-1,6,11(2H,13H)-trione product peaked at a
concentration of 10 mol%. When the amount of catalyst
was lower, the yield of the product decreased (Table 1,
entry 9), whereas raising the catalyst concentration did
not lead to a pronounced increase to the product yield
(Table 1, entry 8). In the absence of catalyst, low product’s
yield was observed, even after prolonged reaction time
(Table 1, entry 11).
Scheme 2. Proposed mechanism for the preparation of 3-methyl-4-aryl-
Under the optimal conditions, the scope and generality
of the reaction was explored. A variety of aryl aldehydes
were investigated to react with Meldrum’s acid and
5-methylpyrazol-3-amine over a 120min reaction period,
and the results are summarized in Table 2. Aldehydes
containing various electron-donating and electron-
withdrawing substituents were reacted under the
experimental conditions, and the corresponding products
were obtained in good yields. Therefore, no remarkable
electronic effects were observed in the reaction. Good yield
was also obtained when the alkyl aldehydes was reacted
(Table 2, entries 14 and 15).
2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones.
The structures of all compounds were established by spectro-
scopic (FTIR, [1]H-NMR, [13]C-NMR, Mass) and elemental
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One-pot Three-component Synthesis of Pyrazolo[3,4-b]pyridines
Table 3
Comparison of the activity of different catalysts in the synthesis of pyrazolo[3,4-b]pyridine-6-ones.
Aldehyde
Catalyst
Reaction conditions
Yield (%)
Ref.
SBA-15-Ph-SO3H
Ultrasound
EtOH, 80 °C, 120 min.
EtOH, 60 °C, 3 min.
100 °C, 8 min.
H2O 100 °C, 12 min.
90 °C, 15 min.
EtOH, 80 °C, 120 min.
90 °C, 10 min.
100 °C, 9 min.
EtOH, 60 °C, 3 min.
96
87
92
90
89
96
90
90
95
This study
12
13
14
4-MeOC6H4CHO
Microwave Irradiation
Fe+3@K10
(PEG)-400
11
SBA-15-Ph-SO3H
This study
C6H5CHO
Fe+3@K10
14
13
12
Microwave Irradiation
Ultrasound
nanocatalyst (10 mol%) for the facile synthesis of 3-
methyl-4-aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6
-ones via one-pot, three component condensation of alde-
hyde, Meldrum’s acid, and 5-methylpyrazol-3-amine. The
advantages of the method include (i) reusability of the
catalyst, (ii) high yields, (iii) easy workup, (iv) short reac-
tion times, and furthermore, this procedure is cheap, safe,
and environmentally benign. Moreover, the catalyst has
suitable hydrophobicity to drive out the water that is
formed during the reaction from mesochannels.
Figure 2. The reusability of SBA-15-Ph-SO3H. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Acknowledgment. We are thankful to Payame Noor University
for partial support of this work.
the Michael addition of 5-methylpyrazol-3-amine to the
electron-deficient Knoevenagel adduct A. Cyclization of
B via a translactonization reaction leads to liberation of
an acetone molecule and a molecule CO2 and also pro-
duced the final product C.
Finally, to assess the present protocol with respect to
other reported methods for the preparation of 3-methyl-4-
aryl-2,4,5,7-tetrahydropyrazolo[3,4-b]pyridine-6-ones, the
presented procedure was compared with some of the
reported catalysts. From Table 3, it can be seen that present
system exhibited higher conversions and yields compared
with the other reported system.
The reusability of the catalyst in the reaction of benzalde-
hyde, Meldrums acid and 5-methylpyrazol-3-amine in etha-
nol at 80°C was studied. In this procedure, after completion
of each reaction, hot ethanol was added to the reaction
mixture and was shaken for a few minutes to dissolve the
product. The catalyst (insoluble in solvent) was filtered
and washed with hot ethanol and dried. The recovered cata-
lyst was reused seven times, and smooth loss of catalytic ac-
tivity was observed from the seventh time of reuse (Fig. 2).
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Journal of Heterocyclic Chemistry
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