(α-Fe2O3)-MCM-41 as a magnetically recoverable nanocatalyst for the synthesis of pyrazolo[4,3-c]pyridines at room temperature

Article abstract of DOI:10.1016/j.catcom.2012.05.022

MCM-41 embedded magnetic nanoparticles which was prepared through the formation of MCM-41 in the presence of Fe₃O₄ nanoparticles has been used as a magnetically recoverable catalyst for the synthesis of new series of pyrazolo[3,4-c]pyridine derivatives. This catalyst with 10 wt.% of loaded iron oxide nanoparticles was highly recyclable (up to 5 times), and was easily recovered from the reaction mixture using an external magnet without loss of activity. The prepared magnetic catalyst is characterized by X-ray powder diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), nitrogen physisorption measurements, and acid-base titration.

Full text of DOI:10.1016/j.catcom.2012.05.022

Catalysis Communications 26 (2012) 218–224
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Catalysis Communications
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Short Communication
(α-Fe2O3)-MCM-41 as a magnetically recoverable nanocatalyst for the synthesis of
pyrazolo[4,3-c]pyridines at room temperature
⁎
Shahnaz Rostamizadeh , Nasrin Shadjou, Mohammad Azad, Nima Jalali
Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
MCM-41 embedded magnetic nanoparticles which was prepared through the formation of MCM-41 in the
presence of Fe3O4 nanoparticles has been used as a magnetically recoverable catalyst for the synthesis of
new series of pyrazolo[3,4-c]pyridine derivatives. This catalyst with 10 wt.% of loaded iron oxide nanoparticles
was highly recyclable (up to 5 times), and was easily recovered from the reaction mixture using an external
magnet without loss of activity. The prepared magnetic catalyst is characterized by X-ray powder diffraction
(XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), nitrogen physisorption
measurements, and acid–base titration.
Received 23 April 2012
Received in revised form 24 May 2012
Accepted 28 May 2012
Available online 2 June 2012
Keywords:
Pyrazolo[4,3-c]pyridines
Magnetically separable catalyst
(α-Fe2O3)-MCM-41
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
The pyrazolo[4,3-c]pyridine ring system is present in numerous
biologically active natural products as well as many synthetic com-
The magnetic iron oxide nanoparticles are particularly attractive
owing to their unique properties and potential applications in various
fields, such as magnetically assisted drug delivery, magnetic resonance
imaging (MRI) contrast agents, hyperthermia, and magnetic separation
of biomolecules [1–3]. In general, the naked nanoparticles always tend
to aggregate into large clusters and thus lose their specific properties.
This problem can be overcome by coating the nanoparticles with silica,
polymer or carbon shells [4–6].
Since the first discovery in 1992, mesoporous molecular sieves
have attracted significant attention in the field of adsorption, catalysis,
and separation as they exhibit excellent characteristics such as a high
surface area up to 1500 m2 g−1, a large pore volume, and a narrow
pore size distribution between 2 and 15 nm [7–10]. MCM-41 (Mobil
Composition of Matter No. 41)—as a highly ordered mesoporous
material—was used as one of the best neutral coating layers to confine
magnetic nanoparticles, due to its high chemical and thermal stability,
large surface area and good compatibility [11].
pounds. They are important heterocyclic compounds, which exhibit
a diverse range of biological properties such as inhibitors of xanthine
oxidases, and as compounds for the inhibition of cholesterol forma-
tion [13]. A new series of these types of compounds also exhibit a
modest CNS depressant and anti-inflammatory activity [14].
In view of these useful properties, an efficient and general method
for the synthesis of these compounds and their derivatives has not
been reported yet. But microwave heating in the solid state [15], and
refluxing α,β-unsaturated ketones with hydrazine hydrate in ethanol
and methanol for 10 h in the presence of Na are the only previously
reported methods [16]. However, these methods are time-consuming
The integration of mesoporous silica with magnetic nanoparticles to
form porous magnetic nanocomposite is undoubtedly of great interest
for practical applications. This type of magnetic nanocomposites, have
the advantages of both mesoporous silica and magnetic nanoparticles.
Magnetic separation provides a convenient method for removing and
recycling magnetized species by applying an appropriate magnetic field.
Up to now, several papers have reported the synthesis and application
of these magnetic nanocomposites in organic manufacturing [12].
⁎
Corresponding author. Fax: +98 21 22853650.
Scheme 1. Synthesis of pyrazolo[4,3-c]pyridine derivatives in the presence of (α-Fe2O3)–
E-mail address: rostamizadeh@kntu.ac.ir (S. Rostamizadeh).
MCM-41.
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2012.05.022

S. Rostamizadeh et al. / Catalysis Communications 26 (2012) 218–224
219
Scheme 2. Preparation of (α-Fe2O3)–MCM-41 nanocatalyst.
Fig. 1. The IR spectra of a) as prepared and b) recovered (α-Fe2O3)–MCM-41.

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and use toxic solvents and reagents. Thus, the development of a green,
simple, efficient, and general method for the synthesis of these widely
used organic compounds from readily available reagents remains one
of the major challenges in organic synthesis.
In connection with our interest in the preparation and use of solid
catalysts for the production of fine chemicals [17], and because of
the inherent properties like environmental friendliness, greater selec-
tivity, operational simplicity, non-corrosive nature, moisture insensi-
tivity, and ease of isolation, it is of interest to determine the behavior
of this catalytic system (α-Fe2O3)–MCM-41) for the synthesis of
pyrazolo[4,3-c]pyridine derivatives from the reaction of α,β-unsaturated
ketones with hydrazine hydrate, methyl hydrazine, and hydrazine hy-
drate together with acetic anhydride in ethanol at room temperature
(Scheme 1).
2. Experimental
2.1. Preparation of the catalyst
A solution with molar composition of 3.2 FeCl3:1.6 FeCl2:1 CTABr:39
NH4OH: 2300 H2O was used for preparation of naked Fe3O4 nanoparticles
at room temperature. Typically, 2 g of iron (III) chloride (FeCl3. 6H2O) and
0.8 g of iron (II) chloride (FeCl2·4H2O) were dissolved in 10 mL of dis-
tilled water under N2 atmosphere. The resultant solution dropwisely
was added to a 100 mL solution of 1.0 M NH4OH containing 0.4 g of
cetyltrimethylammonium bromide (CTABr) to construct a colloidal sus-
pension of iron oxide magnetic nanoparticles. The magnetic MCM-41
was prepared by adding 20 mL of the magnetic colloid to a 1 L solution
with the molar composition of 292 NH4OH:1 CTABr: 2773 H2O under
vigorous mixing and sonication. Then sodium silicate (16 mL) was
added, and the mixture was allowed to react at room temperature for
24 h under stirring. The magnetic MCM-41 was filtered and washed.
The surfactant template was then removed from the synthesized material
by calcination at 450 °C for 4 h and the (Fe3O4)–MCM-41 converted to
(α-Fe2O3)–MCM-41. It is worth mentioning that in the absence of nitro-
gen the magnetic property of Fe3O4 is decreased.
Fig. 2. XRD patterns of the (α-Fe2O3)–MCM-41 in the region of (2θ) equal to a) 1.0° to
10.0° (2θ) and b) 10.0° to 80.0°.
(BET) method [20] were 1213 m2 g−1 and 1.59 cm3 g−1 respectively.
The pore diameter of the (α-Fe2O3)–MCM-41 was 5.26 nm derived
from the adsorption and desorption branches by the Broekhoff and
deBoer model (Fig. 5) [21].
In addition surface acidity of the catalyst was determined with
acid–base titration and it was found that the catalyst has not consid-
erable acidic property.
During optimization of the reaction conditions, at first we chose
3,5-bis(4-chlorobenzylidene)-1-methylpiperidin-4-one (0.16 mmol)
and hydrazine hydrate (0.16 mmol) in ethanol as model reactants
and examined the effect of the amount of the catalyst. According to
these data, the optimum amount of catalyst was 0.015 g. Increasing
the amount of catalyst did not improve the yield and the reaction
time, while in the absence of the catalyst the low yield of product was
achieved (Table 1 entries 1–3). It should be mentioned that in the pres-
ence of pure MCM-41, amino-functionalized MCM-41 (MCM-41–
nPrNH2) and Fe3O4 nanoparticles (Table 1 entries 4–6) the time and
3. Results and discussion
At first the (α-Fe2O3)–MCM-41 with 10 wt.% of loaded iron oxide
nanoparticles was prepared according to the method reported in
literature with some modifications (Scheme 2) [18].
The prepared and recovered catalyst was characterized with IR
spectra. In IR spectra, the band from 400–650 cm−1 is assigned to
the stretching vibrations of (Fe\O) bond in α-Fe2O3, and the band
at about 1100 cm−1 is belong to the stretching of the (Si\O) bond
(Fig. 1).
The XRD analysis of was performed from 1.0° (2θ) to 10.0° (2θ).
The sample of (α-Fe2O3)–MCM-41 showed relatively well-defined
XRD patterns, with one major peak along with two small peaks iden-
tical to those of MCM-41 materials (Fig. 2a). In addition, XRD pattern
in the region of 10.0° (2θ) to 80.0° (2θ) confirmed that change of
sample's color from black to brick-red after calcination of the catalyst
is due to the oxidation of embedded Fe3O4 to α-Fe2O3 nanoparticles
(Fig. 2b) [19].
Also the XRD analysis of recovered catalyst was recorded in the
region of 2.0° (2θ) to 80.0° (2θ) in which the position and relative
intensities of all peaks was confirmed well with the XRD pattern of
as prepared catalyst and no leaching of embedded nanoparticles
was observed (Fig. 3).
TEM micrograph of prepared catalyst (Fig. 4c) shows an ordered
hexagonal pore system with embedded α-Fe2O3 nanoparticles. Also
uniform and spherical morphology of the catalyst was confirmed by
SEM images (Fig. 4a, b).
The specific surface area and pore volume obtained by the N2
adsorption isotherms and calculated by the Brunauer–Emmett–Teller
Fig. 3. The XRD patterns of recovered catalyst in the region of 2.0° to 80.0° (2θ).

S. Rostamizadeh et al. / Catalysis Communications 26 (2012) 218–224
221
Fig. 4. The SEM (a, b) and TEM (c) images of (α-Fe2O3)–MCM-41.
Fig. 5. (a) Nitrogen adsorption/desorption isotherm, (b) BJH and (c) Pore size distribution of (α-Fe2O3)–MCM-41.
Table 1
Comparison of the amount of the catalyst and yields for the synthesis of 5j.
Table 2
Solvent screening for the synthesis of 5j in the present of 0.015 g of (α-Fe2O3)–MCM-41.
Entry Catalyst
Amount of the catalyst (g) Time (min) Yield (%)
1
2
3
4
5
6
–
–
>240
20
20
60
40
40
96
97
85
92
95
Entry
Solvent
Time (min)
Yield (%)
(α-Fe2O3)–MCM-41 0.015
(α-Fe2O3)–MCM-41 0.02
Pure MCM-41
MCM-41–nPrNH2
Fe3O4 nanoparticles 0.015
1
2
3
4
CH3CN
CH3OH
C2H5OH
H2O
60
25
20
70
95
96
0.015
0.015
30
180
No reaction

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S. Rostamizadeh et al. / Catalysis Communications 26 (2012) 218–224
Table 3 (continued)
Table 3
The reaction time (min) and the yield (%) of pyrazolo[4,3-c]pyridine product.
Entry
Product
Time
(min)
Yield*
(%)
M.P (°C)
Found
M.P (°C)
Reported
Entry
Product
Time
Yield*
(%)
M.P (°C)
Found
M.P (°C)
Reported
(min)
5m
40
95
130–132
–
5a
30
97
98
143–144
212–214
118–120
[16]
5n
5o
30
45
96
98
149–150
186–189
–
–
5b
5c
15
–
–
15
30
90
95
160–161
166–167
5d
–
the yield of the reaction was satisfactory, but because of the ease of re-
covery and reusability of (α-Fe2O3)–MCM-41, this catalyst was there-
fore chosen (Table 1).
To check the effect of solvents the model reaction was separately
performed in different solvents such as CH3CN, CH3OH, C2H5OH, and
H2O in the present of 0.015 g of catalyst from which C2H5OH was
found to be the best (Table 2).
5e
5f
15
15
98
98
205
–
–
With these results in hand, a variety of aromatic aldehydes,
possessing both electron-donating and electron-withdrawing groups
were employed for pyrazolo[4,3-c]pyridine formation and the results
indicated that for 3,5-dibenzylidenepiperidin-4-one bearing different
functional groups, the reaction proceeded smoothly in all cases. It
is worth mentioning that 3,5-dibenzylidenepiperidin-4-one with
electron-withdrawing groups on the phenyl rings induce greater
electronic positive charge on the corresponding β-atoms and reacted
rapidly whereas electron-rich groups on the phenyl rings require longer
reaction times. Also N-acetyldihydropyrazoles (5j–5l) were also synthe-
sized by addition of hydrazine hydrate to 3,5-dibenzylidenepiperidin-4-
one (1) and subsequent acylation of bicyclic compounds with acetic
anhydride. Among the six derivatives of 3,5-dibenzylidenepiperidin-4-
one (4-chloro, 4-benzyloxy, 4-cyano, 2,3-dichloro, 3-nitro, 2,4-dichloro)
that have been used, only 4-chloro, 4-benzyloxy and 4-cyano reacted
with hydrazine and then acylated with acetic anhydride (Table 3).
A plausible mechanism for the formation of pyrazolo[4,3-c]
pyridines is shown in Scheme 3. Because of the Lewis acidity property
148–149
5g
5h
20
10
90
98
183–184
121–123
182–183
[16]
–
5i
5j
10
20
98
96
207–208
156–157
–
–
5k
>60
90
95
189–190
255–256
–
5l
30
–
Scheme 3. A proposed mechanism for the synthesis of pyrazolo[4,3-c]pyridines.

S. Rostamizadeh et al. / Catalysis Communications 26 (2012) 218–224
223
Table 4
Other reported methods for the synthesis of pyrazolo[4,3-c]pyridines.
Product
Reaction
condition/Solvent
Time
(h)
Yield
(%)
Reflux/MeOH
0.5–7
53 [22]
Reflux/EtOH
6
72 [23]
Reflux/MeOH
Reflux/MeOH
4
4
78 [14]
80 [14]
Fig. 6. Catalyst recovery at the end of the reaction.
Reflux/EtOH
10
28 [16]
and reusability of the catalyst, good to high yields, short reaction
times, simple work-up, and the ecologically clean procedure make
this method attractive and useful.
Room temperature/EtOH
1/2
97
Acknowledgments
Authors gratefully acknowledge the Research Council of K. N. Toosi
University of Technology for partial financial support of this work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.05.022.
of the Fe3+, the intermediate (3) can be formed through the reaction
of hydrazine hydrate (1) with activated C_C double bond of 3,5-
dibenzylidenepiperidin-4-one (2). Then, the nucleophilic attack of the
other NH2 group on the carbonyl (C_O) moiety gives intermediate
(4). Finally, the expected product (5) is afforded by water elimination.
Also, our synthetic method has been compared with other methods
reported in the literature (Table 4). As can be seen, most of them have
been synthesized at high temperature or reflux conditions. By using
the (α-Fe2O3)–MCM-41 as catalyst, the reaction has been done at
room temperature without any need to heating or refluxing.
It is important to note that the magnetic property of this catalyst
facilitates its efficient recovery from the reaction mixture during
work-up procedure. In the presence of an external magnet, recover-
able (α-Fe2O3)–MCM-41 moved onto the magnet steadily and the
reaction mixture turned clear within 10 s. Thus, the catalyst effectively
collected and the recovered catalyst was used in subsequent runs with-
out observation of significant decrease in activity even after 5 runs
(Fig. 6).
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