Application of a biological-based nanomagnetic catalyst in the synthesis of bis-pyrazols and pyrano[3,2-c]pyrazoles

Article abstract of DOI:10.1002/aoc.3633

{Fe₃O₄@SiO₂@(CH₂)₃-thiourea dioxide-SO₃H/HCl}, a newly reported nanomagnetic core–shell supported solid acid catalyst, was successfully employed in the preparation of 4,4′-(arylmethylene)bi

Full text of DOI:10.1002/aoc.3633

Received: 1 August 2016
DOI 10.1002/aoc.3633
Accepted: 21 August 2016
F U L L PA P E R
Application of a biological‐based nanomagnetic catalyst in the
synthesis of bis‐pyrazols and pyrano[3,2‐c]pyrazoles
*
Mohammad Ali Zolfigol | Mahdiyeh Navazeni | Meysam Yarie | Roya Ayazi‐Nasrabadi
Department of Organic Chemistry, Faculty of
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl}, a newly reported nanomag-
netic core–shell supported solid acid catalyst, was successfully employed in the
preparation of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol) and pyrano[3,2‐c]pyrazole
derivatives. The presented methods are very efficient and high‐yielding. Also, the
Chemistry, Bu‐Ali Sina University, PO Box
6517838683, Hamedan, Iran
Correspondence
Mohammad Ali Zolfigol, Department of Organic
Chemistry, Faculty of Chemistry, Bu‐Ali Sina
University, PO Box 6517838683, Hamedan, Iran.
catalyst exhibited powerful potential for reusability in both types of reactions.
Email: zolfi@basu.ac.ir; mzolfigol@yahoo.com
KEYWORDS
4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol), nanomagnetic catalyst, pyrano[3,2‐c]
pyrazole, solvent‐free condition
1
|
INTRODUCTION
that the solvent‐free types of reactions are emerging as a great
tool for various organic interconversions in the absence of
any harmful organic solvents. Also, solvent‐free conditions
present various advantages such as marked reduction in
reaction times and lead to an increase of desired product
yields and facile work‐up.[5–7]
The construction of pharmaceutically and medicinally
activeheterocycliccompounds,usingone‐potmulticomponent
strategies, has attracted much attention due to excellent
merits such as enhancement of atom‐ and step‐economy and
improvement of efficiency for the synthesis of complex
scaffolds. Also, this technique offers meaningful benefits
over conventional linear‐type synthesis protocols such as
productivity, ease of execution and high yields.[8–12]
Molecules containing heterocyclic rings are ubiquitous
in nature and are fundamental to life. Among such hetero-
cyclic compounds, pyrazole derivatives are influential
structural motifs as they exhibit various therapeutic and
pharmaceutical applicabilities.[13–16] More specifically,
among them, bis(pyrazolyl)methane derivatives like 4,4′‐
(arylmethylene)bis(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol)
derivatives have an extensive domain of pharmacological
applications.[17–20] Also, they can be utilized as fungicides,[21]
pesticides,[22] insecticides,[23] dyestuffs, and chelating and
extracting agents for metal ions.[24] In addition, a survey of
the literatures discloses that pyrano[2,3‐c]pyrazole derivatives
are established as significant precursor materials for the
synthesis of promising drugs in the medicinal chemistry field
and have a wide variety of biological and pharmaceutical
Nowadays, knowledge‐based design, synthesis and applica-
tions of nanomagnetic particles are in great demand, and a
wide variety of nanostructured magnetic catalysts have been
used because of their recyclability and reusability, high
activity and selectivity in chemical processes. Application
of recyclable and reusable catalysts or catalytic systems in
chemical processes is in close accord with green chemistry
disciplines because their use will decrease activation energy,
waste of reactions and energy consumption. The develop-
ment of nanomagnetic catalysts and their roles in pollution
prevention in the environment at the past, present and future
have been extensively reviewed.[1–3] To the best of our
knowledge, employing nanomagnetic core–shell catalysts as
heterogeneous promoters for various organic transformations
is preferred over the use of homogeneous catalytic systems
due to countless merits such as the recyclability and reusabil-
ity. Furthermore, this influential and persuasive alternative
for ordinary homogeneous catalysts is compatible with green
chemistry protocols.[2,3]
Green chemistry principles emphasize the design and use
of safe procedures in order to increase efficiency and produc-
tivity, reduce the steps of synthetic pathways, use less toxic
solvents and minimize waste production as much as possi-
ble.[4] One of the main areas in the field of practical green
chemistry is the replacement of unsafe volatile organic
solvent with eco‐friendly gentle ones or accomplishment of
reactions under solvent‐free conditions. It is demonstrable
Appl Organometal Chem 2016; 1–7
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
ZOLFIGOL ET AL.
applications such as potential inhibitors of human Chk1
kinase,[25] and anti‐inflammatory,[26] anticancer,[27] analge-
sic,[28] molluscicidal[29] and antimicrobial[30] activities have
been reported for these versatile heterocyclic compounds.
Hence, owing to the varied practical beneficial properties
as therapeutic and curative agents in clinical applications, a
great deal of attention of synthetic and medicinal chemists
has been focused on the topic of the preparation of 4,4′‐
(arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives and pyrano
[3,2‐c]pyrazoles.[31–47] Although a number of procedures
have been reported for the synthesis of 4,4′‐(arylmethylene)
bis(1H–pyrazol‐5‐ol) derivatives and pyrano[3,2‐c]pyrazoles,
all of the investigated methods suffer from one or more
defects, including difficult‐to‐prepare catalysts, prolonged
reaction times with low or moderate yields, employing toxic
and hazardous organic solvents, harsh reaction conditions
and tedious work‐up protocols. Therefore, the development
of a cost‐effective and eco‐friendly catalyst and procedure
for the preparation of these valuable heterocyclic molecules
is highly desirable.
should have a great many pores, many active acidic sites,
high stability with good selectivity, recyclability and reus-
ability, high turnover number and turnover frquency and also
should be economically and environmentally sustainable.[53]
In this regard, we decided to apply a new biological‐based
nanomagnetic solid acid with sulfonic acid tag, namely
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl},[54] in
the synthesis of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol)
derivatives and pyrano[3,2‐c]pyrazoles under mild and
solvent‐free conditions (Scheme 2).
In the first place, in attempting to find the best operational
experimental reaction conditions for the synthesis of 4,4′‐
(arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives, we investi-
gated the optimal reaction temperature, the amount of catalyst
that was required and also the solvent for the reaction of 4‐
chlorobenzaldehyde and 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5
(4H)‐one (Scheme 3). The data obtained, as summarized in
Table 1, reveal that the best results are achieved with 7 mg
of nanomagnetic catalyst at 90°C under solvent‐free condi-
tions (Table 1, entry 4).
In continuation of our efforts for the development of
knowledge‐based design and construction of applicable solid
acids,[48,49] inorganic acidic salts,[50] nanomagnetic catalysts
with a tag of ionic liquid[51] and novel nanostructured ionic
liquids and molten salt catalyst[52] for organic functional
group interconversion, herein we explore the catalytic perfor-
mance of {Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/
HCl} as a newly reported nanomagnetic core–shell supported
solid acid catalyst in the synthesis of 4,4′‐(arylmethylene)bis
(1H–pyrazol‐5‐ol) derivatives and pyrano[3,2‐c]pyrazoles
under mild and solvent‐free conditions (Scheme 1).
After determination of the optimal reaction conditions for
the synthesis of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol)
derivatives, to confirm the generality, scope and limitations
of the presented protocol, different arylaldehydes (bearing
electron‐withdrawing and electron‐donating groups and halo-
gens) were subjected to reaction with 3‐methyl‐1‐phenyl‐1H‐
pyrazol‐5(4H)‐one, to afford the corresponding desired
compounds in relatively short reaction times with good to
high yields. The obtained data are summarized in Table 2.
In another assay, the applicability of the nanomagnetic
core–shell catalyst was explored for the synthetic reaction
of pyrano[3,2‐c]pyrazole derivatives. Initially, to find the
2
| RESULTS AND DISCUSSION
A catalytic reaction is a cyclic system and separation of a
heterogeneous catalyst from a reaction mixture should be
easier than that of a homogeneous one. Usual heterogeneous
nanomagnetic solid acid catalysts are hybrids of organic and
inorganic materials with suitable tags. Solid acid catalysts
SCHEME
2
Stepwise synthesis pathway of {Fe3O4@SiO2@(CH2)3‐
thiourea dioxide‐SO3H/HCl}as a nanomagnetic core–shell supported
solid acid catalyst.
SCHEME 1 Synthesis of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol) deriva-
tives and pyrano[3,2‐c]pyrazoles under mild and solvent‐free conditions.
SCHEME
3
Optimized reaction conditions for the synthesis of 4,4′‐
(arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives.

ZOLFIGOL ET AL.
3
TABLE 1 Optimization of reaction conditions for synthesis of 4,4′‐
(arylmethylene)bis(1H–pyrazol‐5‐ol) derivativesa
Load of
catalyst (mg)
Temperature
(°C)
Time
(min)
Yield
(%)b
Entry
Solvent
1
—
—
7
7
r.t.
50
70
90
110
90
90
90
90
135
70
30
55
74
94
88
72
78
90
33
85
88
87
76
2
3
—
7
60
SCHEME 4 Optimized reaction conditions for the preparation of pyrano
[3,2‐c]pyrazole derivatives.
4
—
7
15
5
—
7
15
6
—
3
30
7
—
5
30
TABLE 3 Optimization of reaction conditions for synthesis of pyrano[3,2‐
c]pyrazole derivativesa
8
—
10
—
7
19
9
—
70
Load of
catalyst (mg)
Temperature
(°C)
Time
(min)
Yield
(%)b
10
11
12
13
H2O
EtOH
CH3CN
n‐Hexane
120
60
Entry
Solvent
7
1
—
—
7
7
90
70
25
40
25
30
90
30
140
75
90
60
65
70
91
85
90
85
87
72
58
33
66
68
70
25
7
160
100
2
7
3
—
7
110
90
aReaction conditions: 4‐chlorobenzaldehyde (1 mmol, 0.144), 3‐methyl‐1‐phenyl‐
1H‐pyrazol‐5(4H)‐one (2 mmol, 0.348).
bIsolated yield.
4
—
3
5
—
5
90
6
—
10
—
7
90
7
—
90
8
EtOAc
H2O
EtOH
CH3CN
n‐Hexane
TABLE 2 Synthesis of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol) deriva-
tives under solvent‐free conditions in the presence of {Fe3O4@SiO2@(CH2)
3‐thiourea dioxide‐SO3H/HCl} at 90°Ca
9
7
Reflux
Reflux
Reflux
Reflux
10
11
12
7
7
Time
Product (min)
Yield
(%)b
Entry
R
M.p. (°C): found (lit.)
7
1
H
1a
1b
1c
25
15
10
20
28
25
45
40
10
17
25
20
15
40
25
15
93
94
95
91
87
90
89
92
87
89
90
92
98
98
89
94
169–171 (168–170)[34]
213–215 (213–215)[34]
224–226 (229–231)[34]
186–188 (180–182)[40]
214–217(156–158)[40]
193–196 (201–203)[34]
154–156 (172–173)[41]
193–196 (145–147)[34]
229–232 (229–230)[41]
235–237 (235–236)[34]
174–176 (173–175)[40]
213–216 (212–214)[40]
207–209 (205–207)[41]
157–158 (173–175)[34]
187–190 (189–190)[34]
184–186 (192–194)[40]
aReaction conditions: 4‐chlorobenzaldehyde (1 mmol, 0.144), 3‐methyl‐1‐phenyl‐
1H‐pyrazol‐5(4H)‐one (1 mmol, 0.174), malononitrile (1 mmol, 0.066).
bIsolated yield.
2
4‐Cl
3
4‐NO2
4‐F
4
1d
1e
5
4‐OH
4‐Me
7 mg of the nanomagnetic core–shell supported solid acid
catalyst at 90°C (Table 3, entry 1).
6
1f
7
4‐N(Me)2
3‐NO2
2,4‐Cl2
2‐Cl
1 g
1 h
1i
Afterwards, as in the case of the synthesis of 4,4′‐
(arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives, the versa-
tility and the generality of the optimized reaction conditions
were checked for the preparation of various pyrano[3,2‐c]
pyrazoles. From the data obtained (Table 4), it can be inferred
that the desired products are obtained in relatively short reac-
tion times with good to high isolated yields.
Besides the easy separation of the catalyst after the
completion of the reaction, as an additional merit of
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} as a
magnetic solid acid supported catalyst, the recycling
possibility was investigated for both of the presented methods
for eight times. After accomplishment of each run, in order to
dissolve the crude product and separate the catalyst, 10 ml of
acetone was added to the reaction mixture and stirred for
5 min. Afterwards, the core–shell catalyst was easily sepa-
rated through applying a simple external magnet. The
separated nanomagnetic catalyst washed repeatedly with
ethanol, weighed and recovered for the next run. The crude
products were purified by recrystallization from ethanol. In
the case of preparation of 4,4′‐(arylmethylene)bis(1H–
pyrazol‐5‐ol) derivatives, the reaction of benzaldehyde and
8
9
10
11
12
13
14
15
16
1j
4‐OMe
4‐Br
1 k
1 l
3‐OEt‐4‐OH 1 m
3‐Br
1n
1o
1p
2‐Thienyl
3‐OMe
aReaction conditions: arylaldehyde (1 mmol), 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5
(4H)‐one (2 mmol, 0.348 g), catalyst (7 mg).
bIsolated yield.
optimal reaction conditions for the synthesis, the
reaction of 4‐chlorobenzaldehyde, malononitrile and 3‐
methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one was chosen as a test
reaction (Scheme 4). The related data obtained for the
screening of different temperatures, loads of catalyst and
solvents are summarized in Table 3. The resulting data dem-
onstrate that the best conditions are when the reaction is
performed under solvent‐free conditions in the presence of

4
ZOLFIGOL ET AL.
TABLE 4 Synthesis of pyrano[3,2‐c]pyrazole derivatives under solvent‐
free conditions in the presence of {Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐
SO3H/HCl} at 90°Ca
Time
Product (min)
Yield
(%)b
Entry
R
M.p. (°C): found (lit.)
1
H
2a
2b
2c
25
25
37
30
45
30
35
30
45
30
33
35
25
30
35
91
95
96
96
86
82
93
95
89
90
88
91
89
82
95
178 (161–163)[43]
179–182 (172–174)[43]
193–195 (187–188)[43]
163–165 (170–171)[45]
215–216(206–207)[43]
177–178 (174–175)[43]
174–177 (new)
2
4‐Cl
3
4‐NO2
4‐F
4
2d
2e
5
4‐OH
6
4‐Me
2f
7
2‐NO2
3‐NO2
2,4‐Cl2
2‐Cl
2 g
2 h
2i
8
207 (193–194)[43]
9
189–194 (182–184)[43]
164–167 (144–146)[43]
204–206 (171–173)[43]
178 (169–171)[41]
10
11
12
13
14
15
2j
4‐OMe
3‐OEt‐4‐OH
3‐Br
2 k
2 l
2 m
2n
2o
156–158 (new)
2‐OH
216–217 (not reported)[55]
212–214 (not reported)[55]
4‐CN
aReaction conditions: arylaldehyde ( 1 mmol), 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5
(4H)‐one (1 mmol, 0.174 g), malononitrile (1 mmol, 0.066 g), catalyst (7 mg).
bIsolated yield.
SCHEME 6 Suggested mechanism for the synthesis of compound 1a in the
presence of the described nanomagnetic catalyst.
corresponding intermediate A via dehydration. Subsequently,
a second molecule of 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐
one in its tautomer form attacks the intermediate A to give
the intermediate B. Finally, through the tautomerization and
aromatization of the intermediate B the desired product 1a
is obtained.
In the case of compound 2a as a model for the synthesis
of pyrano[3,2‐c]pyrazoles, the suggested mechanism is as
follows. Initially, the Knoevenagel adduct C generated from
the reaction of benzaldehyde and malononitrile is subjected
to reaction with the enol form of 3‐methyl‐1‐phenyl‐1H‐
pyrazol‐5(4H)‐one to produce the related intermediate D.
The cyclization of intermediate D in the presence of the
nanomagnetic catalyst yields the intermediate E which could
be tautomerized to compound 2a as a desired product
through the interaction with the catalyst (Scheme 7).
3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one in 25 min was
selected as a model reaction, and for the synthesis of
pyrano[3,2‐c]pyrazoles the reusability of the catalyst was
examined in the reaction of benzaldehyde, 3‐methyl‐1‐
phenyl‐1H‐pyrazol‐5(4H)‐one and malononitrile in 35 min.
The resulting data reveal that regardless of the type of
multicomponent reaction, the catalyst can be used for several
runs (up to eight runs) without any discernible reduction of
its initial catalytic performance. The achieved results are
described in Scheme 5.
For a plausible mechanistic pathway for the synthesis of
4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives, the
preparation of the target molecule 1a in the presence of the
nanomagnetic catalyst was chosen as a model (Scheme 6).
At first, 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one converts
to its enol form through interaction with the nanomagnetic
catalyst and attacks the activated benzaldehyde to yield the
SCHEME 5 Reusability of the nanomagnetic solid acid supported catalyst
SCHEME 7 Plausible mechanism for the synthesis of compound 2a in the
in both multicomponent reactions.
presence of the described nanomagnetic catalyst.

ZOLFIGOL ET AL.
5
3
|
CONCLUSIONS
optimized reaction conditions, was added
7
mg of
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} as a
nanomagnetic core–shell supported solid acid catalyst.
The resulting mixture was heated in an oil bath at 90°C
under solvent‐free conditions. The mixture was stirred vig-
orously for the required time (Table 4). After completion of
the reaction as monitored by TLC (using n‐hexane and
EtOAc as solvent system), the mixture was cooled to room
temperature. Then, in order to separate the nanomagnetic
catalyst, boiling ethanol was added to the reaction mixture
and the catalyst was isolated using an external magnet.
Finally, the pure products were obtained via recrystalliza-
tion from ethanol with good to excellent yields (Scheme 1
and Table 4).
In this presentation, the catalytic applicability of
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} as a
nanomagnetic core–shell supported solid acid catalyst was
successfully examined in the synthetic reactions for the
preparation of 4,4′‐(arylmethylene)bis(1H–pyrazol‐5‐ol) de-
rivatives and pyrano[3,2‐c]pyrazoles. The catalyst shows
excellent catalytic activity and the presented protocols are
efficient and high‐yielding. Also, the catalyst exhibited reus-
ability in both the multicomponent reactions investigated.
4
| EXPERIMENTAL
4.1 | General
All chemicals were purchased from Merck. The structural
confirmation of the known products was made by compar-
ison of their physical properties and spectral data with
those of authentic samples reported in the literature. The
reaction progress and purity of the compounds were deter-
mined using TLC performed with silica gel SIL G/UV 254
4.4 | Selected spectral data of 4,4′‐(Arylmethylene)bis
(1H–pyrazol‐5‐ol) derivatives (Table 2)
4,4′‐(Phenylmethylene)bis(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐
ol) (1a). Melting point: 169–171°C. FT‐IR (KBr, ν, cm−1):
1
3443, 3067, 1601, 1580, 1501, 1488, 1298, 1015, 748. H
1
plates. The H NMR (400 MHz) and 13C NMR (100 MHz)
NMR (400 MHz, DMSO, δ, ppm): 13.87 (s, 2H, OH),
7.71 (s, 5H, aromatic), 7.45–7.27 (m, 11H, aromatic), 4.97
(s, 1H, CH), 2.33 (s, 6H, 2 × CH3). 13C NMR (101 MHz,
DMSO, δ, ppm): 146.22, 141.14, 130.52, 129.11, 128.89,
127.98, 125.59, 120.53, 32.53, 11.51.
spectra were recorded with a Bruker spectrometer. Melting
points were recorded with a Buchi B‐545 apparatus in open
capillary tubes.
4,4′‐(p‐Tolylmethylene)bis(3‐methyl‐1‐phenyl‐1H‐pyrazol‐
4.2 | General procedure for synthesis of 4,4′‐
(Arylmethylene)bis(1H–pyrazol‐5‐ol) derivatives in the
presence of {Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐
SO3H/HCl} as reusable catalyst
5‐ol) (1f). Melting point: 193–196°C. FT‐IR (KBr, ν, cm−1):
1
3443, 3050, 1601, 1580, 1505, 1407, 1025, 749. H NMR
(400 MHz, DMSO, δ, ppm): 13.93 (s, 2H, OH), 7.71 (brs,
4H, aromatic), 7.45 (brs, 4H, aromatic), 7.25 (s, 2H, aromatic),
7.14–7.09 (m, 4H, aromatic), 4.91 (s, 1H, CH), 2.32 (s, 6H,
2 × CH3), 2.26 (s, 3H, CH3). 13C NMR (101 MHz, DMSO,
δ, ppm): 146.20, 139.13, 134.78, 128.88, 128.65, 127.04,
125.48, 120.47, 32.73, 20.49, 11.61.
4,4′‐((3‐Ethoxy‐4‐hydroxyphenyl)methylene)bis(3‐methyl‐
1‐phenyl‐1H‐pyrazol‐5‐ol) (1 m). Melting point: 207–209°C.
FT‐IR (KBr, ν, cm−1): 3217, 2988, 1599, 1578, 1498, 1486,
1276, 1127, 753. 1H NMR (400 MHz, DMSO, δ, ppm):
14.06 (s, 2H, OH), 8.73 (s, 1H, OH), 7.77 (brs, 4H, aromatic),
7.51 (brs, 4H, aromatic), 7.32 (s, 2H, aromatic), 6.91 (s, 1H,
aromatic), 6.75 (s, 2H, aromatic), 4.90 (s, 1H, CH), 3.99 (brs,
2H, ─O─CH2), 2.38 (s, 6H, 2 × CH3), 1.34 (s, 3H, CH3).
13C NMR (101 MHz, DMSO, δ, ppm): 146.13, 145.17,
133.22, 128.88, 125.60, 120.52, 119.69, 115.25, 113.47,
63.95, 32.77, 14.69.
To a test tube containing a mixture of aromatic alde-
hydes (1 mmol) and 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5
(4H)‐one (2 mmol, 0.384 g) was added 7 mg of
{Fe3O4@SiO2@(CH2)3‐thiourea dioxide‐SO3H/HCl} which
was heated in an oil bath at 90°C. The resulting mixture
was stirred vigorously under solvent‐free conditions for the
required time (Table 2). After completion of the reaction
as determined by TLC monitoring (using n‐hexane and
EtOAc as solvent system), the mixture was cooled to room
temperature. Afterwards, in order to separate the catalyst,
10 ml of acetone was added to the reaction mixture and
the crude products were extracted. The acetone was evapo-
rated and the pure products were obtained via recrystallized
from ethanol with good to excellent yields (Scheme 1 and
Table 2).
4,4′‐((3‐Bromophenyl)methylene)bis(3‐methyl‐1‐phenyl‐
1H‐pyrazol‐5‐ol) (1n). Melting point: 157–158°C. FT‐IR
(KBr, ν, cm−1): 3136, 3081, 1605, 1596, 1501, 1473, 1300,
4.3 | General procedure for synthesis of pyrano[3,2‐c]
pyrazoles in the presence of {Fe3O4@SiO2@(CH2)3‐
thiourea dioxide‐SO3H/HCl} as reusable catalyst
1
1055, 763. H NMR (400 MHz, DMSO, δ, ppm): 13.98 (s,
2H, OH), 7.75 (d, 4H, J = 8 Hz, aromatic), 7.49 (t, 4H,
J = 8 Hz, aromatic), 7.44 (s, 2H, aromatic), 7.32–7.28 (m,
4H, aromatic), 5.04 (s, 1H, CH), 2.37 (s, 6H, 2 × CH3).
13C NMR (101 MHz, DMSO, δ, ppm): 146.32, 146.25,
To a mixture of aromatic aldehydes (1 mmol), 3‐methyl‐1‐
phenyl‐1H‐pyrazol‐5(4H)‐one (1 mmol, 0.174 g) and
malononitrile (1 mmol, 0.066 g), according to the

6
ZOLFIGOL ET AL.
145.12, 130.32, 129.83, 128.93, 128.87, 126.45, 125.70,
121.54, 120.57, 118.45, 32.79, 11.51.
7.51–7.48 (m, 4H, aromatic), 7.35–7.31 (m, 3H, NH2 and
aromatic), 4.84 (s, 1H, CH), 1.79 (s, 3H, CH3). 13C NMR
(101 MHz, DMSO, δ, ppm): 159.7, 149.1, 145.1, 144.0,
137.4, 132.6, 129.3, 128.9, 126.2, 120.1, 119.7, 118.7,
110.0, 97.6, 57.1, 36.7, 12.5.
4,4′‐((3‐Methoxyphenyl)methylene)bis(3‐methyl‐1‐phenyl‐
1H‐pyrazol‐5‐ol) (1p). Melting point: 184–186°C. FT‐IR (KBr,
ν, cm−1): 3512, 2972, 1604, 1582, 1503, 1486, 1275, 1043,
1
752. H NMR (400 MHz, DMSO, δ, ppm): 14.01 (s, 2H,
OH), 7.72 (d, 4H, J = 8 Hz, aromatic) 7.45 (t, 4H, J = 8 Hz,
aromatic), 7.27–7.19 (m, 3H, aromatic), 6.87–6.76 (m, 3H, aro-
matic), 4.92 (s, 1H, CH), 3.70 (s, 3H, ─O&─CH3) , 2.33 (s,
6H, 2 × CH3). 13C NMR (101 MHz, DMSO, δ, ppm):
159.15, 146.27, 143.96, 129.15, 128.90, 125.56, 120.54,
119.61, 113.77, 110.40, 54.83, 33.15, 11.61.
ACKNOWLEDGEMENTS
We thank Bu‐Ali Sina University and Iran National Science
Foundation (INSF) for financial support (Allameh Tabataba'i's
Award, grant number: BN093) of our research group.
REFERENCES
[1] a) B. Karimi, F. Mansouri, H. M. Mirzaei, Chem. Cat. Chem. 2015, 7, 1736;
b) S. Ganesh Babu, R. Karvembu, Catal. Surv. Asia 2013, 17, 156; c) D.
Zhang, C. Zhou, Z. Sun, L. Z. Wu, C. H. Tung, T. Zhang, Nanoscale
2012, 4, 6244; d) V. Polshettiwar, R. Luque, A. Fihri, H. Zhu, M. Bouhrara,
J. M. Basset, Chem. Rev. 2011, 111, 3036; e) S. Shylesh, V. Schunemann,
W. R. Thiel, Angew. Chem. Int. Ed. 2010, 49, 3428; f) S. Laurent, D. Forge,
M. Port, A. Roch, C. Robic, L. V. Elst, R. N. Muller, Chem. Rev. 2008, 108,
2064; g) A. H. Lu, E. L. Salabas, F. Schìth, Angew. Chem. Int. Ed. 2007, 46,
1222; Angew. Chem. 2007, 119, 1242.
4.5 | Selected spectral data of pyrano[3,2‐c]pyrazole
derivatives (Table 4)
6‐Amino‐3‐methyl‐4‐(2‐nitrophenyl)‐1‐phenyl‐1,4‐dihydro-
pyrano[2,3‐c]pyrazole‐5‐carbonitrile (2 g). Melting point:
174–177°C. FT‐IR (KBr, ν, cm−1): 3486, 3337, 2197,
1655, 1520, 1402, 1129, 750. 1H NMR (400 MHz, DMSO,
δ, ppm): 7.99 (d, 1H, J = 8 Hz, aromatic), 7.89 (d, 2H,
J = 8 Hz, aromatic), 7.79 (t, 1H, J = 8 Hz, aromatic),
7.65–7.58 (m, 4H, aromatic), 7.45–7.42 (m, 3H, NH2 and
aromatic), 5.30 (s, 1H, CH), 1.85 (s, 3H, CH3). 13C NMR
(101 MHz, DMSO, δ, ppm): 159.7, 149.3, 144.9, 144.3,
137.4, 136.7, 133.4, 131.6, 129.3, 128.6, 126.3, 123.7,
120.1, 119.4, 97.3, 56.8, 31.9, 12.2.
[2] T. Cheng, D. Zhang, H. Li, G. Liu, Green Chem. 2014, 16, 340.
[3] R. Hudson, Y. Feng, R. S. Varma, A. Moores, Green Chem. 2014, 16, 4493.
[4] K. Tanaka, Solvent‐Free Organic Synthesis, Wiley‐VCH, Weinheim 2004.
[5] G. H. Imanzadeh, A. Khalafi‐Nezhad, A. Zare, A. Hasaninejad, A. R.
Moosavi‐Zare, A. J. Parhami, J. Iran. Chem. Soc. 2007, 4, 229.
[6] D. Warren, Green Chemistry, A Teaching Resource, Royal Society of
Chemistry, Cambridge 2001 292.
[7] J. Zhu, H, Bienayme Multicomponent Reactions, Wiley‐VCH, Weinheim
2005.
6‐Amino‐4‐(3‐ethoxy‐4‐hydroxyphenyl)‐3‐methyl‐1‐phe-
nyl‐1,4‐dihydropyrano[2,3‐c]pyrazole‐5‐carbonitrile (2 l).
Melting point: 178°C. FT‐IR (KBr, ν, cm−1): 3503, 3420,
[8] G. Yanlong, Green Chem. 2012, 14, 2091.
[9] S. Samai, G. C. Nandi, R. Kumar, M. S. Singh, Tetrahedron Lett. 2009, 50,
7096.
1
3328, 2196, 1660, 1596, 1514, 1398, 1126, 755. H NMR
[10] H. V. Chavan, S. B. Babar, R. U. Hoval, B. P. Bandgar, Bull. Korean Chem.
Soc. 2011, 32, 3963.
(400 MHz, DMSO, δ, ppm): 8.86 (s, 1H. OH), 7.84–7.82
(brs, 2H, aromatic), 7.53 (brs, 2H, aromatic), 7.35 (brs, 1H,
aromatic), 7.16 (s, 2H, NH2), 6.84–6.78 (m, 2H, aromatic),
6.67–6.65 (brs, 2H, aromatic), 4.60 (s, 1H, CH), 4.03–4.02
(brs, 2H, ─O─CH2), 1.86 (s, 3H, ─O─CH2─CH3), 1.35 (s,
3H, CH3). 13C NMR (101 MHz, DMSO, δ, ppm): 159.18,
146.40, 145.80, 145.37, 143.73, 137.58, 134.47, 129.28,
126.03, 120.16, 120.06, 119.82, 115.59, 113.48, 98.86,
63.94, 58.67, 36.29, 14.68, 12.62.
[11] N. M. H. Elnagdi, N. S. Al‐Hokbany, Molecules 2012, 17, 4300.
[12] P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice, Oxford
Univer‐ity Press, Oxford 1998 290.
[13] H. J. Park, K. Lee, S. J. Park, B. Ahn, J. C. Lee, H. Y. Cho, K. I. Lee, Bioorg.
Med. Chem. Lett. 2005, 15, 3307.
[14] M. R. Nadia, Y. K. Nahed, A. Fahmyb, A. A. F. El‐Sayeda, Pharm. Chem. J.
2010, 2, 400.
[15] E. McDonald, K. Jones, P. A. Brough, M. J. Drysdale, P. Workman, Curr.
Top. Med. Chem. 2006, 6, 1193.
6‐Amino‐4‐(3‐bromophenyl)‐3‐methyl‐1‐phenyl‐1,4‐dihy-
dropyrano[2,3‐c]pyrazole‐5‐carbonitrile (2 m). Melting point:
156–158°C. FT‐IR (KBr, ν, cm−1): 3454, 3338, 2195, 1656,
[16] J. Elguero, P. Goya, A. M. S. S. Jagerovic, Targets Heterocycl. Syst. 2002,
6, 52.
[17] S. Sugiura, S. Ohno, O. Ohtani, K. Izumi, T. Kitamikado, H. Asai, K. Kato,
1
J. Med. Chem. 1977, 20, 80.
1591, 1519, 1390, 1127, 753. H NMR (400 MHz, DMSO,
[18] D. M. Bailey, P. E. Hansen, A. G. Hlavac, E. R. Baizman, J. Pearl, A. F.
δ, ppm): 7.90 (d, 2H, J = 8 Hz, aromatic), 7.62–7.58 (m, 4H,
aromatic), 7.46–7.41 (m, 3H, aromatic), 7.39 (s, 2H, NH2),
4.85 (s, 1H, CH), 1.91 (s, 3H, CH3). 13C NMR (101 MHz,
DMSO, δ, ppm): 159.6, 146.4, 145.1, 137.5, 130.8, 130.4,
130.0, 129.3, 127.0, 126.2, 121.8, 120.1, 119.8, 98.0, 57.5,
36.3, 12.6.
Defelice, M. E. Feigenson, J. Med. Chem. 1985, 28, 256.
[19] P. M. S. Chauhan, S. Singh, R. K. Chatterjee, Ind. J. Chem. B 1993, 32, 858.
[20] R. N. Mahajan, F. H. Havaldar, P. S. Fernandes, J. Ind. Chem. Soc. 1991,
68, 245.
[21] D. Singh, D. Singh, J. Ind. Chem. Soc. 1991, 68, 165.
[22] M. Londershausen, Pestic. Sci. 1996, 48, 269.
6‐Amino‐4‐(4‐cyanophenyl)‐3‐methyl‐1‐phenyl‐1,4‐di-
hydropyrano[2,3‐c]pyrazole‐5‐carbonitrile (2o). Melting
point: 212–214°C. FT‐IR (KBr, ν, cm−1): 3400, 3112,
[23] H. A. Lubs (Ed), The Chemistry of Synthetic Dyes and Pigments, American
Chemical Society, Washington, DC 1970.
[24] A. D. Garnovskii, A. I. Uraev, V. I. Minkin, Arkivoc 2004, iii, 29.
1
2236, 2192, 1653, 1593, 1516, 1388, 1124, 759. H NMR
[25] N. Foloppe, L. M. Fisher, R. Howes, A. Potter, A. G. Robertson, A. E.
(400 MHz, DMSO, δ, ppm): 7.84–7.79 (m, 4H, aromatic),
Surgenor, Bioorg. Med. Chem. 2006, 14, 4792.

ZOLFIGOL ET AL.
7
[26] M. E. A. Zaki, H. A. Soliman, O. A. Hiekal, A. E. Rashad, Z. Naturforsch
2006, 61, 1.
[48] For a review, see P. Salehi, M. A. Zolfigol, F. Shirini, M. Baghbanzadeh,
Curr. Org. Chem. 2006, 10, 2171.
[27] J. L. Wang, D. Liu, Z. J. Zheng, S. Shan, X. Han, S. M. Srinivasula, C. M.
Croce, E. S. Alnemri, Z. Huang, Proc. Natl. Acad. Sci. U. S. A. 2000, 97,
7124.
[49] a) M. Daraei, M. A. Zolfigol, F. Derakhshan‐Panah, M. Shiri, H. G.
Kruger, M. Mokhlesi, J. Iran. Chem. Soc. 2015, 12, 855; b) D. Azarifar,
S. M. Khatami, M. A. Zolfigol, R. Nejat‐Yami, J. Iran. Chem. Soc.
2014, 11, 1223; c) M. Safaiee, M. A. Zolfigol, M. Tavasoli, M.
Mokhlesi, J. Iran. Chem. Soc. 2014, 11, 1593.
[28] C. Kuo, J. Huang, H. Nakamura, J. Med. Chem. 1984, 27, 539.
[29] F. M. Abdelrazek, P. Metz, O. Kataeva, A. Jaeger, S. F. El‐Mahrouky, Arch.
Pharm. 2007, 340, 543.
[50] For a review, see: F. Shirini, M. A. Zolfigol, P. Salehi, M. Abedini, Curr.
Org. Chem. 2008, 12, 183.
[30] I. B. Seiple, Z. Zhang, P. Jakubec, A. Langlois‐mercier, P. M. Wright, D. T.
Hog, K. Yabu, S. R. Allu, T. Fukuzaki, P. N. Carlsen, Y. Kitamura, X. Zhou,
M. L. Condakes, Nature 2016, 533, 338.
[51] a) M. Aghayee, M. A. Zolfigol, H. Keypour, M. Yarie, L. Mohammadi,
Appl. Organometal. Chem. 2016, 30, 612; b) M. A. Zolfigol, M. Yarie,
RSC Adv. 2015, 5, 103617; c) M. A. Zolfigol, T. Azadbkht, V. Khakizadeh,
R. Nejat‐Yami, D. Perrin, RSC Adv. 2014, 4, 40036; d) T. Azadbakht, M.
A. Zolfigol, R. Azadbakht, V. Khakizadeh, D. Perrin, New J. Chem.
2015, 39, 439; e) M. A. Zolfigol, V. Khakyzadeh, A. R. Moosavi‐Zare,
A. Rostami, A. Zare, N. Iranpoor, M. H. Beyzavie, R. Luque, Green Chem.
2013, 15, 2132; f) N. Koukabi, E. Kolvari, A. Khazaei, M. A. Zolfigol, B.
Shirmardi‐Shaghasemi, H. R. Khavasi, Chem. Commun. 2011, 47, 9230.
[31] E. S. El‐Tamany, F. A. El‐Shahed, B. H. Mohamed, J. Serb. Chem. Soc.
1999, 64, 9.
[32] A. Hasaninejad, M. Shekouhy, A. Zare, S. M. S. Hoseini Ghattalia, N.
Golzar, J. Iran. Chem. Soc. 2011, 8, 411.
[33] M. N. Elinson, A. S. Dorofeev, R. F. Nasybullin, G. I. Nikishin, Synthesis
2008, 12, 1933.
[52] M. A. Zolfigol, M. Yarie, S. Bagheri, Synlett 2016, 27, 1418, and references
[34] A. Khazaei, M. A. Zolfigol, A. R. Moosavi‐Zare, Z. Asgari, M. Shekouhy,
A. Zare, A. Hasaninejad, RSC Adv. 2012, 2, 8010.
therein.
[53] a) M. A. Zolfigol, R. Ayazi‐Nasrabadi, S. Baghery, Appl. Organometal.
Chem. 2016, 30, 500; b) M. A. Zolfigol, R. Ayazi‐Nasrabadi, S. Baghery,
Appl. Organometal. Chem. 2016, 30, 273.
[35] A. Zare, M. Merajoddin, A. R. Moosavi‐Zare, M. Zarei, Chinese J. Catal.
2014, 35, 85.
[36] K. Sujatha, G. Shanthi, N. P. Selvam, S. Manoharan, P. T. Perumal, M.
[54] M. A. Zolfigol, R. Ayazi‐Nasrabadi, RSC Adv. 2016, 6, 69595.
Rajendran, Bioorg. Med. Chem. Lett. 2009, 19, 4501.
[55] E. Fadavipoor, S. Nazari, A. Zarei Ahmadi, M. Gorgizadeh, M. Afshari, M.
[37] W. Wang, S.‐X. Wang, X.‐Y. Qin, J.‐T. Li, Synth. Commun. 2005, 35, 1263.
[38] M. Barge, R. Salunkhe, RSC Adv. 2014, 4, 31177.
Keshavarz, Orient. J. Chem. 2015, 31, 733.
[39] M. N. Elinson, O. O. Sokolova, R. F. Nasybullin, Heterocycl. Commun.
2015, 21, 97.
SUPPORTING INFORMATION
[40] M. Seddighi, F. Shirini, M. Mamaghani, RSC Adv. 2013, 3, 24046.
Additional Supporting Information may be found online in
the supporting information tab for this article.
[41] M. A. Zolfigol, R. Ayazi‐Nasrabadia, S. Baghery, V. Khakyzadehb, S.
Azizian, J. Mol. Catal. A 2016, 418, 54.
[42] A. Saha, S. Payra, S. Banerjee, Green Chem. 2015, 17, 2859.
[43] S. B. Guo, S. X. Wang, J. T. Li, Synth. Commun. 2007, 37, 2111.
How to cite this article: Zolfigol, M. A., Navazeni,
M., Yarie, M., and Ayazi‐Nasrabadi, R. (2016), Appli-
cation of a biological‐based nanomagnetic catalyst in
the synthesis of bis‐pyrazols and pyrano[3,2‐c]
pyrazoles, Appl Organometal Chem, doi: 10.1002/
aoc.3633
[44] M. Ali Zolfigol, M. Tavasoli, A. R. Moosavi‐Zare, P. Moosavi, H. G. Kruger,
M. Shiri, V. Khakyzadeh, RSC Adv. 2013, 3, 25681.
[45] K. Niknam, A. Piran Green, Sustain. Chem. 2013, 3, 1.
[46] A. Azarifar, R. Nejat‐Yami, M. Al‐Kobaisi, D. Azarifar, J. Iran Chem. Soc.
2013, 10, 439.
[47] D. Azarifar, S. M. Khatami, R. Nejat‐Yami, J. Chem. Sci. 2014, 126, 95.