Design, characterization and application of new ionic liquid 1-sulfopyridinium chloride as an efficient catalyst for tandem Knoevenagel-Michael reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with aldehydes

Article abstract of DOI:10.1016/j.apcata.2013.07.004

In this work, novel ionic liquid 1-sulfopyridinium chloride {[Pyridine-SO₃H]Cl} is synthesized, and characterized by IR, ¹H and ¹³C NMR, UV as well as mass spectra. The ionic liquid is used as an efficient, homogeneous and reusable catalyst for the synthesis of 4,4′-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s by tandem Knoevenagel-Michael reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with various aromatic and hetero-aromatic aldehydes under mild reaction conditions.

Full text of DOI:10.1016/j.apcata.2013.07.004

Accepted Manuscript
Title: Design, characterization and application of new ionic
liquid 1-sulfopyridinium chloride as an efficient catalyst for
tandem Knoevenagel–Michael reaction of
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with aldehydes
Author: Ahmad Reza Moosavi-Zare Mohammad Ali Zolfigol
Mahmoud Zarei Abdolkarim Zare Vahid Khakyzadeh Alireza
Hasaninejad
PII:
S0926-860X(13)00402-X
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.apcata.2013.07.004
APCATA 14320
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Applied Catalysis A: General
Received date:
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Accepted date:
26-2-2013
25-6-2013
3-7-2013
Please cite this article as: A.R. Moosavi-Zare, M.A. Zolfigol, M. Zarei,
A. Zare, V. Khakyzadeh, A. Hasaninejad, Design, characterization and
application of new ionic liquid 1-sulfopyridinium chloride as an efficient
catalyst for tandem Knoevenagel–Michael reaction of 3-methyl-1-phenyl-
1H-pyrazol-5(4H)-one with aldehydes, Applied Catalysis A, General (2013),
http://dx.doi.org/10.1016/j.apcata.2013.07.004
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Design, characterization and application of new ionic liquid
1-sulfopyridinium chloride as an efficient catalyst for tandem
Knoevenagel–Michael reaction of 3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one with aldehydes
Ahmad Reza Moosavi-Zare,*a Mohammad Ali Zolfigol,*b Mahmoud Zarei,b Abdolkarim
Zare,c Vahid Khakyzadehb and Alireza Hasaninejadd
aDepartment of Chemistry, University of Sayyed Jamaleddin Asadabadi, Asadabad,
6541835583, Iran
bFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran
cDepartment of Chemistry, Payame Noor University, PO BOX 19395-4697 Tehran, Iran
dDepartment of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169,
Iran
*Corresponding
author.
Fax:
+988118257407,
E-mail
addresses:
moosavizare@yahoo.com, mzolfigol@yahoo.com.
Abstract: In this work, novel ionic liquid 1-sulfopyridinium chloride {[Pyridine–
SO3H]Cl} is synthesized, and characterized by IR, 1H and 13C NMR, UV as well as mass
spectra. The ionic liquid is used as an efficient, homogeneous and reusable catalyst for
the synthesis of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s by
tandem Knoevenagel–Michael reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with
various aromatic and hetero-aromatic aldehydes under mild reaction conditions.
1
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Keywords: 1-Sulfopyridinium chloride {[Pyridine–SO3H]Cl}, 3-Methyl-1-phenyl-1H-
pyrazol-5(4H)-one, Aldehyde, 4,4´-(Arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol), Ionic liquid
1. Introduction
Pyrazolone derivatives are of importance as they have various biological activities; these
compounds are essential scaffold of many commercialized drugs for brain ischemia [1],
and myocardial ischemia [2]. Moreover, 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s, as an important class of pyrazolones, have been used as anti-inflammatory
[3], antipyretic [4], gastric secretion stimulatory [5], antidepressant [6], antibacterial [7],
and antifilarial [8] agents. These compounds have been also applied as fungicides [9],
pesticides [10], insecticides [11], dyestuffs [12], and chelating as well as extracting
reagents for different metal ions [12]. In spite of extensive application of 4,4´-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s, a few methods have been
reported for their preparation. These methods include application of piperidine in
ethanolic solution [13], tandem Knoevenagel-Michael reaction in benzene solution [14],
application of sodium dodecyl sulfate in aqueous media [15], and electrocatalytic
synthesis [16-18]. Furthermore, most of these methods are associated with limitations
such as moderate yields, long reaction times, harsh reaction conditions, application of
hazardous solvents and tedious workup procedures. Therefore, search for finding an
efficient and capable protocol for the preparation of 4,4´-(arylmethylene)-bis(3-methyl-1-
phenyl-1H-pyrazol-5-ol)s is very important.
Ionic liquids (ILs) could be considered as organocatalysts. Considering this subject, we
have recently introduced a new category of ionic liquids, namely sulfonic acid
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functionalized imidazolium salts (SAFIS) (in which a S-N bond has formed in the
imidazole ring as five members heterocycle [19-32]), and used them as organocatalysts or
organoreagents for preparation of bis(indolyl)methans [19], N-sulfonyl imines [20], nitro
aromatic compounds [21,22], 1-amidoalkyl-2-naphthols [23], benzimidazoles [24],
xanthenes [25], 1-carbamatoalkyl-2-naphthols [26], 4,4'-(arylmethylene)-bis(3-methyl-1-
phenyl-1H-pyrazol-5- ol)s [27], t-butyl aryl carbamates [28], 1,2,4,5-tetrasubstituted
imidazoles [29], β-acetamido ketones [30], hexahydroquinolines [31] and
trimethylsilylated hydroxyl compounds [32]. In continuation of our previous studies on
the preparation and applications of acidic ILs and solid salts in organic transformations
[19-31], we have prepared and characterized novel acidic ionic liquid
1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} wherein a S-N bond has formed in a six
members heterocycle (Scheme S1), and utilized it as an efficient, homogeneous and
reusable organocatalyst for the tandem Knoevenagel–Michael reaction of
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with aldehydes to afford 4,4´-(arylmethylene)-
bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s (Scheme 1a).
2. Experimental
2.1. Materials
All chemicals were purchased from Merck or Fluka Chemical Companies. The known
products were identified by comparison of their melting points and spectral data with
those reported in the literature.
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2.2. Catalyst preparation (Scheme S1)
A solution of pyridine (0.395 g, 5 mmol) in CH2Cl2 (40 mL) was added dropwise to a
stirring solution of chlorosulfonic acid (0.58 g, 5 mmol) in dry CH2Cl2 (40 mL) over a
period of 10 min at 0 ºC. After the addition was completed, the reaction mixture was
stirred for 20 min, stand for 5 min, and the CH2Cl2 was decanted. Afterward, the liquid
residue was triturated with CH2Cl2 (3×10 mL), and dried under powerful vacuum
at 90 °C to give [Pyridine–SO3H]Cl as a viscous colorless oil in 95 % yield (0.929 g).
2.3. Catalyst characterization
The reaction conversions were measured by GC on a Shimadzu model GC-16A
instrument using a 25m CBPI-S25 (0.32 mm ID, 0.5 µm coating) capillary column. For
GC analysis, at first, the apparatus was calibrated with n-Octane as internal standard.
THF was used as solvent in which the starting materials and product was dissolved in it.
The conversion after doing the required program was obtained.
1
13
The H NMR (500 or 400 MHz) and C NMR (125 or 100 MHz) were run on a Bruker
Avance DPX-250 FT-NMR spectrometer (δ in ppm).
IR spectra were run on a Shimadzu FTIR-8300 spectrophotometer.
UV-vis spectra were recorded by a Shimadzu UV-mini-1240V spectrophotometer with
1-cm quartz cells (0.5ml)
Mass spectra were obtained with a Shimadzu GC–MS-QP 1100 EX model.
Thermal gravimetry (TG) and differential thermal gravimetric (DTG) were analyzed by a
Perkin Elmer (Model: Pyris 1). TG/DTG analysis (25 to 600 °C, temperature increase
rate of 10 °C. min-1, nitrogen atmosphere).
Melting points were recorded on a Büchi B-545 apparatus in open capillary tubes.
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2.4. Catalytic tests
General procedure for the synthesis of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s (3a-t) using [Pyridine–SO3H]Cl
A mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1.74 g, 10 mmol), aldehyde (5
mmol) and [Pyridine–SO3H]Cl (0.0097 g, 1 mol%) in a test tube was stirred at 50 ºC.
After completion of the reaction, as monitored by TLC, the reaction mixture was cooled
to room temperature, extracted with warm EtOAc (20 mL) to separate the catalyst (the
product is soluble in warm EtOAc; however, the catalyst is not soluble in this solvent).
Then, EtOAc was evaporated and the solid residue (crude product) was triturated by a
mixture of ethanol and water (9/1) to give the pure product. The recovered catalyst was
washed with EtOAc (2×20 mL), dried at 90 ºC under vacuum condition, and reused for
the preparation of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s
according to the mentioned procedure. The catalyst was recovered and reused for five
times without any significant changes in the yield and the reaction time. The pure
1
products were identified by IR, H and 13C NMR spectra. Also mass spectrum was
recorded for unknown products.
3. Results and discussion
3.1. Studies to confirm the structure of 1-sulfopyridinium chloride {[Pyridine–SO3H]Cl}
The structure of 1-sulfopyridinium chloride was identified by IR, 1H and 13C NMR,
UV as well as mass spectra. The spectral data include:
UV-vis (DMSO): λmax 285 nm; TG/DTG analysis (25 to 600 °C): dec. point 295
°C; IR (Nujol): 750, 866, 1042, 1174, 1488, 1543, 1637, 2650-3550 cm-1; 1H NMR (300
MHz, DMSO-d6): δ (ppm) 8.11 (t, J = 7.45 Hz, 2H), 8.65 (t, J = 7.81 Hz, 1H), 8.94 (d, J
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= 5.76 Hz, 2H), 13.67 (s, 1H); 13C NMR (75 MHz, DMSO-d6): δ (ppm) 127.9, 142.4,
147.1; MS: m/z = 196 (M++1), 195 (M+).
The IR spectrum of the catalyst has been displayed in Figure 1. The broad peak at
2650-3550 cm-1 can be related to O-H stretching of the SO3H group. Moreover, the two
peaks observed at 1042 cm-1 and 1174 cm-1 correspond to vibrational modes of N-SO2
and O-SO2 bonds, and confirm boding SO3H group with the N of pyridine [22,26-
29,31,32]. In other hand, the C-H stretching and bending vibrations of pyridine ring in 1-
sulfopyridinium chloride appeared at 3078 and 866 cm-1, respectively. The C=C and C=N
vibrations assigned at 1543 and 1637 cm-1, correspondingly. These mentioned peaks
clearly confirmed the structure of [Pyridine–SO3H]Cl.
1
Moreover, the graphical H and 13C NMR spectra of [Pyridine–SO3H]Cl are
1
presented in Figures S1 and S2. Here, we study H NMR data of the catalyst. The
1
important peak of H NMR spectra of [Pyridine–SO3H]Cl is related to the acidic
hydrogen (SO3H) which observed in 13.67 ppm. To confirm that this peak (13.67 ppm) is
correctly related to the hydrogen of SO3H in the compound, not hydrogen of ClSO3H (its
unreacted starting material) or another possible product formed from the reaction of
pyridine with ClSO3H (i.e. pyridinium chlorosulfonate), we also run the 1H NMR spectra
of ClSO3H and pyridinium chloride (the acidic hydrogens of pyridinium chlorosulfonate
and pyridinium chloride are same) in DMSO-d6 (the concentration of these compounds
and [Pyridine–SO3H]Cl in DMSO-d6 for the NMR study was 0.08 mol.L-1). In these
spectra, the peaks of the acidic hydrogens of [pyridine–SO3H]Cl, ClSO3H and pyridinium
chloride were observed in 13.67, 13.45 and 11.37 ppm, respectively. The difference
between the peaks of the acidic hydrogens in [pyridine–SO3H]Cl, ClSO3H and
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1
pyridinium chloride confirmed that the peak observed in 13.67 ppm of the H NMR
spectra of [Pyridine–SO3H]Cl is correctly related to the SO3H group of this compound.
UV spectra was another evidence to confirm that [Pyridine–SO3H]Cl was really
synthesized. For this purpose, UV-vis spectra of the catalyst, pyridine and pyridinium
chloride were recorded. At first, some solutions of the mentioned compounds in DMSO
with the same concentration were prepared. The concentration of these compounds in
DMSO for UV study was 0.005 mol.L-1. The maximum absorptions of pyridine and
pyridinium chloride appeared at ca. 270 and 295 nm, correspondingly. But λmax of
1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} was observed at ca. 285 nm (Figure 2).
The difference between maximum absorptions of 1-sulfopyridinium chloride and other
compounds (pyridine and pyridinium chloride) confirmed the preparation of the catalyst.
In another procedure, the formation of N-S bond was investigated. For this
purpose, hydrogen chloride gas was transferred to a two-necks round-bottomed flask in
the presence of sulfur trioxide pyridine complex as a white solid powder. HCl was reacted
with this complex to give 1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} (Scheme S1).
After completion of the reaction, the white solid powder was converted to a viscous
1
colorless oil. IR, H and 13C NMR spectra of this compound showed that [Pyridine–
SO3H]Cl (produced by the another method) and this presented product was the same.
1
The H NMR spectra of the compound which produced by two different methods are
given in Figure 3. This evidence was clearly showed that [Pyridine–SO3H]Cl was really
synthesized.
–
Moreover, it is well-known that sulfur trioxide pyridine complex [C5H5N+SO3 ]
has produced by the dropwise addition of chlorosulfonic acid (1 equiv.) to pyridine (2
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equiv.) dissolved in dichloroethane at low temperature (Scheme S2) [33-35]. In these
conditions, in each time, there were excess amount of pyridine besides ClSO3H in the
reaction mixture; thus, 1 equiv. of pyridine (as a nucleophile) attacks to the sulfur of
ClSO3H to give [Pyridine–SO3H]Cl, and another 1 equiv. of pyridine acted as a base and
–
abstracts the acidic hydrogen of [Pyridine–SO3H]Cl to afford [C5H5N]+SO3 and
[C5H5NH]Cl. In the synthesis of [Pyridine–SO3H]Cl, we added 1 equiv. of pyridine
dropwise to 1 equiv. of chlorosulfonic acid at low temperature. In these conditions, in
each time, there were excess amount of ClSO3H besides pyridine in the reaction mixture;
thus, when pyridine reacted with ClSO3H, and [Pyridine–SO3H]Cl formed, there is no
base in the reaction media to abstract the acidic hydrogen of the compound to afford
–
[C5H5N]+SO3 and [C5H5NH]Cl. Also, according to the literature [33,35], in the reaction
of pyridine with chlorosulfonic acid at low temperature, the reaction route was the
nucleophilic substitution (substitution of Cl of ClSO3H by the nitrogen of pyridine), not
the acid–base reaction (abstraction of the hydrogen of ClSO3H by pyridine to give
[C5H5N–H][ClSO3]).
The amount of acid sites in [Pyridine-SO3H]Cl was determined by titration of
aqueous solution of [Pyridine-SO3H]Cl (0.1 M) with NaOH (0.1 M). It was found that
three mole of NaOH reacts with one mole of [Pyridine-SO3H]Cl. It means that the
catalyst was hydrolyzed to pyridinium chloride and sulfuric acid (Scheme S3). This result
indicates that the catalyst has one acidic-SO3H group (Scheme S3).
In another study, thermal gravimetric (TG) and derivative thermal gravimetric
(DTG) analysis of 1-sulfopyridinium chloride was investigated at range of 25 to 600 °C,
with a temperature increase rate of 10 °C.min-1 in a nitrogen atmosphere. The
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corresponding diagrams are shown in Figure 4. In TG pattern, we observed multi-stage
decomposition pattern in [Pyridine–SO3H]Cl. Some weight losses were observed about
18%, 40% and 14% which can be related to loss of HCl, SO3 and CH2=CH2, respectively.
Therefore, 1-sulfopyridinium chloride could be applied as catalysts below 200 °C, and
decomposed after 200 ºC.
3.2. The synthesis of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s 3a-t
using [Pyridine-SO3H]Cl
After full characterization of [Pyridine-SO3H]Cl, we examined its catalytic activity for
the preparation of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s. For
this purpose, as a model reaction, the condensation of 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one (1) (2 mmol) with 4-nitrobenzaldehyde (1 mmol), was examined in the
presence of different quantities of the 1-sulfopyridinium chloride, at range of 25-70 °C
under solvent-free conditions (Scheme 1a). The results are summarized in Table 1.
Interestingly, 1 mol% of [Pyridine–SO3H]Cl was sufficient to afford the product in
excellent yields and in very short reaction times at 50 °C (Table 1, entry 3). No
improvement in the reaction results was observed by increasing the amount of the
catalysts and the temperature. The solvent-free condensation was also tested at 50 °C
without catalyst in which the reaction was not progressed even after long reaction time (2
h).
The results of catalytic tests in the solvent-free reaction of 3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one (1) with 4-nitrobenzaldehyde over [Pyridine-SO3H]Cl at 50 °C
(variation of conversion or yield with time), are shown in Fig. 5. It was found that after 8
min of the reaction, conversion of (1) was 96%.
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To compare the efficiency of solution conditions versus the solvent-free conditions, a
mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1) (2 mmol) and 4-
nitrobenzaldehyde (1 mmol) in the presence of [Pyridine–SO3H]Cl was heated in an oil-
bath (50 °C) in various solvents for 90 min. Low yields of the product was obtained, even
after elongated reaction times (Table 2). In the solvent-free conditions, the starting
materials (3-methyl-1-phenyl-1H-pyrazol-5(4H)-one and 4-nitrobenzaldehyde) and the
catalyst formed a homogeneous system in the reaction media. This homogeneous system
was changed to a bi-phase system when the reaction was examined solvents including
CHCl3, EtOAc, EtOH, CH3CN and CH2Cl2; because the starting materials were soluble
in the mentioned solvents, but the ionic liquid was insoluble. Therefore, the catalytic
activity of [Pyridine–SO3H]Cl decreased in these solvents. In the case of H2O solvent,
[Pyridine-SO3H]Cl was soluble in water, but the starting materials were insoluble;
moreover, the catalyst hydrolyzed in the aqueous media. Therefore, the yield also
decreased when H2O was applied as solvent. Therefore, the solvent-free reaction was
more efficient.
After optimization of the reaction conditions, the condensation of 3-methyl-1-
phenyl-1H-pyrazol-5(4H)-one with various aryl and hetero-aryl aldehydes was examined
in the presence of 1 mol% [Pyridine–SO3H]Cl at 50 °C in the absence of solvent, in order
to assess the scope and the generality of the catalyst. The results are displayed in Table 3.
As it is shown in Table 3, arylaldehydes possessing electron-releasing substituents,
electron-withdrawing substituents and halogens on their aromatic rings were utilized
successfully in the reaction, and gave the desired products in high yields and in very short
reaction times. The catalyst was also efficient when hetero-arylaldehydes were applied in
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the reaction (Table 3, entries 3i, 3j and 3k). Interestingly, the condensation of 3-methyl-
1-phenyl-1H-pyrazol-5(4H)-one (2 eq.) with terephthaldehyde (1 eq.) in the presence of
[Pyridine–SO3H]Cl (2 mol%) at 50 °C under solvent-free conditions, afforded di-4,4'-
(arylmethylene)-bis(3-methyl-1-phenylpyrazol-5-ol) 5 in 78 % yield within 15 min
(Scheme 1b). Thus, the catalyst was general and highly efficient.
3.3. Comparison of the efficiency of [Pyridine–SO3H]Cl with the recently reported
catalysts for the synthesis of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-
ol)s
To compare the efficiency of our catalyst with the reported catalysts for the
synthesis of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s, we have
tabulated the results of these catalysts to perform the condensation of
3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with 4-nitrobenzaldehyde, in Table 4. As
Table 4 indicates, [Pyridine–SO3H]Cl has remarkably improved the synthesis of 4,4´-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s in different terms {reaction
time, yield and turn-over frequency (TOF)}. The TOF values were calculated by the
equation TOF = Yield (%)/[Time (min)×Catalyst amount (mol%)]. The reaction times
were shorter, and the yields and TOFs were higher when our catalysts were utilized.
3.4. Recovering and reusing the catalyst
In another study, recyclability of the catalyst was examined upon the
condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with 4-nitrobenzaldehyde.
After completion the reaction, the reaction mixture was extracted by the warm EtOAc
and separated from the catalyst. The recycled catalyst was triturated with CH2Cl2, and
11
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used for another reaction. We observed that the catalytic activity of the catalyst was
restored within the limits of the experimental errors for five successive runs (Table 5).
1
[Pyridine–SO3H]Cl was also characterized by TG, UV, H NMR and IR spectra after its
application in the reaction. These spectra were same as those of the fresh catalyst (Figure
6).
3.5. Effect of impurity of water on the catalytic activity of 1-sulfopyridinium chloride
The ionic liquid is sensitive to moisture and water. To study effect of impurity of water
on the catalyst activity, the condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(1.74 g, 10 mmol), aldehyde (5 mmol) using [Pyridine–SO3H]Cl (0.0097g, 1 mol%) was
examined in the presence of different amounts of H2O at 50 ºC (Table 6). As Table 5
indicates, 12 mmol of H2O did not affect significantly on the catalytic activity of
[Pyridine–SO3H]Cl; however, more increasing the amount of H2O decreased their
activity. This can be attributed to hydrolysis of the catalyst to pyridinium chloride and
H2SO4 in the peresence of very excess amount of water. In the synthesis of 4,4´-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s, water produces as a side
product (Scheme 6); due to this point, after any cycle of recovery and before reusing the
catalyst, it was heated at 90 ºC under vacuum to dry and remove the produced water
during the reaction.
4. Conclusions
In summary, we have reported the synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-
phenylpyrazol-5-ols) using 1-sulfopyridinium chloride [Pyridine–SO3H]Cl as a new,
homogeneous and reusable catalyst in a green recyclable media. The promising points for
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the presented methodology are efficiency, generality, high yield, relatively short reaction
time, low cost, cleaner reaction profile, ease of product isolation, simplicity, and finally
compliance with the green chemistry protocols.
Acknowledgements
The authors gratefully acknowledge partial support of this work by the Research
Affairs Office of Bu-Ali Sina University (Grant number 32-1716 entitled development of
chemical methods, reagents and molecules), and Center of Excellence in Development of
Chemical Method (CEDCM), Hamedan, I.R. Iran.
References:
[1] J. Elguero, A. R. Katritzky, C.W. Rees (Eds.), Comprehensive Heterocyclic
Chemistry: Pyrazoles and their Benzo Derivatives, Vol. 5, Pergamon Press, Oxford,
1984.
[2] T. Kessler, T. Aybek, G. Neidhart, S. Dogan, D. Bremerich, D. Lischke, C. Byhahan,
J. Cardiothorac. Vasc. Anesth. 19 (2005) 32-39.
[3] S. Sugiura, S. Ohno, O. Ohtani, K. Izumi, T. Kitamikado, H. Asai, K. Kato, J. Med.
Chem. 20 (1977) 80-85.
[4] L. C. Behr, R. Fusco, C. H. Jarboe, The Chemistry of Heterocyclic Compounds,
Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings, A. Weissberger
(Ed.), Interscience Publishers, New York, 1967.
[5] C. E. Rosiere, M. I. Grossman, Science 113 (1951) 651-651.
[6] D. M. Bailey, P. E. Hansen, A. G. Hlavac, E. R. Baizman, J. Pearl, A. F. Defelice, M.
E. Feigenson, J. Med. Chem. 28 (1985) 256-260.
13
Page 13 of 32

[7] R. N. Mahajan, F. H. Havaldar, P. S. Fernandes, J. Ind. Chem. Soc. 68 (1991) 245-
246.
[8] P. M. S. Chauhan, S. Singh, R. K. Chatterjee, Ind. J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 32 (1993) 858-861.
[9] D. Singh, D. Singh, J. Ind. Chem. Soc. 68 (1991) 165-167.
[10] M. Londershausen, Pestic. Sci. 48 (1996) 269-292.
[11] The Chemistry of Synthetic Dyes and Pigments, H.A. Lubs (Ed.), American
Chemical Society, Washington D.C., 1970.
[12] A. D. Garnovskii, A. I. Uraev, V. I. Minkin, ARKIVOC iii (2004) 29-41.
[13] D. Singh, D. Singh, J. Chem. Eng. Data 29 (1984) 355-364.
[14] B. I. Buzykin, T. I. Lonshchakova, Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl.
Transl.) 20 (1971) 2224-2226.
[15] W. Wang, S.-X. Wang, X.-Y. Qin, J.-T. Li, Synth. Commun. 35 (2005) 1263-1269.
[16] M. N. Elinson, A. S. Dorofeev, R. F. Nasybullin, G. I. Nikishin, Synthesis 12 (2008)
1933-1937.
[17] A. Hasaninejad, A. Zare, M. Shekouhy, S. M. S. H. Ghattali, N. Golzar, J. Iran.
Chem. Soc. 8 (2011) 411-423.
[18] A. Hasaninejad, A. Zare, M. Shekouhy, N. Golzar, Org. Prep. Proced. Int. 43 (2011)
131-137.
[19] M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, Zare, A. Org. Prep. Proced. Int. 42
(2010) 95-102.
[20] M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare, J. Iran. Chem. Soc. 7
(2010) 646-651.
14
Page 14 of 32

[21] A. Khazaei, M. A. Zolfigol, A. R. Moosavi-Zare, A. Zare, Scientia Iranica: Trans. C:
Chem. Chem. Engin. 17 (2010) 31-36.
[22] M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare, H. G. Kruger, Z. Asgari,
V. Khakyzadeh, M. Kazem-Rostami, J. Org. Chem. 77 (2012) 3640-3645.
[23] M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare and V. Khakyzadeh, Appl.
Catal A: Gen., 400 (2011) 70-81.
[24] A. Khazaei, M. A. Zolfigol, A. R. Moosavi-Zare, A. Zare, E. Ghaemi, V.
Khakyzadeh, Z. Asgari and A. Hasaninejad, Scientia Iranica: Trans. C: Chem. Chem.
Engin. 18 (2011) 1365-1371.
[25] M. A. Zolfigol, V. Khakyzadeh, A.R. Moosavi-Zare, A. Zare, S.B. Azimi, Z. Asgari,
A. Hasaninejad, C. R. Chim. 15 (2012) 719-736.
[26] A. Zare, T. Yousofia, A. R. Moosavi-Zare, RSC. Adv. 2 (2012) 7988-7991.
[27] A. Khazaei, M. A. Zolfigol, A. R. Moosavi-Zare, Z. Asgari, M. Shekouhy, A. Zare,
A. Hasaninejad, RSC. Adv. 2 (2012) 8010-8013.
[28] M. A. Zolfigol, V. Khakyzadeh, A. R. Moosavi-Zare, G. Chehardoli, F. Derakhshan-
Panah, A. Zare, O. Khaledian Scientia Iranica: Trans. C: Chem. Chem. Engin. 19 (2012)
1584-1590.
[29] M. A. Zolfigol, A. Khazaei, A. R. Moosavi-Zare, A. Zare, Z. Asgari, V.
Khakyzadeh, A. Hasaninejad, J. Ind. Eng. Chem. 19 (2013) 721–726.
[30] A. Zare, T. Hekmat-Zadeh, S. Mirzaei-Monfared, M. Merajoddin, H. Torabi-
Monfared, M. A. Zolfigol, A. R. Moosavi-Zare, E. Rostami, M. Mokhlesi, F.
Derakhshan-Panah, S. Porbahi, S. Balandeh, S. Afr. J. Chem. 65 (2012) 63–68.
15
Page 15 of 32

[31] A. Zare, F. Abi, A. R. Moosavi-Zare, M. H. Beyzavi, M. A. Zolfigol, J. Mol. Liq.
178 (2013) 113−121.
[32] F. Shirini, N. G. Khaligh, S. Akbari-Dadamahaleh, J. Mol. Catal. A: Chem. 365
(2012) 15-23.
[33] Ajinomoto Co Inc, Jpn. Patent 59134751, A, 1984.
[34] N. Sakota, S. Nomura, S. Ito, Jpn. Patent 03024039 A 19910201, 1991.
[35] Zare, A.; Moosavi-Zare, A. R.; Merajoddin, M.; Zolfigol, M. A.; Hekmat-Zadeh, T.;
Hasaninejad, A.; Khazaei, A.; Mokhlesi, M.; Khakyzadeh, V.; Derakhshan-Panah, F.;
Beyzavi, M. H.; Rostami, E.; Arghoon, A.; Roohandeh, R. J. Mol. Liq. 167 (2012)
69−77.
[36] K. Niknam, D. Saberi, M. Sadegheyan, A. Deris, Tet. Lett. 51 (2010) 692–694.
[37] S. Sobhani, A. Hasaninejad, M. F. Maleki, Z. P. Parizi, Synth. Commun. 42 (2012)
2245-2255.
16
Page 16 of 32

Figure captions
Figure 1. IR spectrum of 1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} in
comparison with pyridine.
Figure 2. UV spectra of pyridine, pyridinium chloride and [Pyridine–SO3H]Cl} at room
temprature in DMSO (the concentration of these compounds in DMSO was 0.005 mol.L-
1).
1
Figure 3. H NMR spectra of the compound which produced by two different methods.
(the concentration of [Pyridine–SO3H]Cl in DMSO-d6 as solvent for the NMR study was
0.08 mol.L-1).
Figure 4. Thermal gravimetric (TG) and derivative thermal gravimetric (DTG) analysis
of 1-sulfopyridinium chloride at range of 25 to 600 °C, with a temperature increase rate
of 10 °C.
Figure 5. Variation of the reaction conversion and yield with time on the solvent-free
condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol) with 4-
nitrobenzaldehyde (1 mmol) in the presence of [Pyridine–SO3H]Cl (1 mol%) at 50 °C.
Figure 6. The characterization of reused catalysts after five runs using TG (a), UV-vis (b)
1HNMR (c) and IR (d) spectra.
17
Page 17 of 32

Table 1. Effect of different amounts of catalysts and temperature on the synthesis of 4,4´-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s.a
Mol% of
Catalysts
Temp. (°C) Time (min) Yieldb/Conv.c (%)
Catalysta
0.5
[Pyridine–SO3H]Cl
[Pyridine–SO3H]Cl
50
50
50
25
8
8
71/74
94/96
94/96
trace
1
3
1
1
[Pyridine–SO3H]Cl
[Pyridine–SO3H]Cl
8
15
[Pyridine–SO3H]Cl
-
70
50
8
94/96
28/33
d
-
3 h
aThe reactions were carried out by the condensation of 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one (2 mmol) with 4-nitrobenzaldehyde (1 mmol) in the absence of solvent.
c
d
bIsolated yield. Conversion. The reaction was carried out in the absence of solvent and
catalyst.
18
Page 18 of 32

Table 2. Effect of various solvents on the synthesis of 4,4´-(arylmethylene)-bis(3-methyl-
1-phenyl-1H-pyrazol-5-ol)s.a
Temp. (°C)
Entry
Solvent
CHCl3
EtOAc
EtOH
Time (min) Yieldb/Conv.c (%)
50
50
1
2
30
30
30
30
30
30
40/44
33/37
29/32
10/14
25/28
50/54
50
3
50
4
H2O
50
5
6d
CH3CN
CH2Cl2
Reflux
aThe reaction was carried out by the reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-
one (2 mmol) with 4-nitrobenzaldehyde (1 mmol) in the presence of [Pyridine–SO3H]Cl
b
c
d
(1 mol%). Isolated yield. Conversion. The reaction was carried out under reflux
condition.
19
Page 19 of 32

Table 3. The preparation of 4,4'-(arylmethylene)-bis(3-methyl-1-phenylpyrazol-5-ol)s
using 1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} as catalyst at 50 °C.a
OH HO
Ph
Ph
O
N
N
[Pyridine-SO3H]Cl, 1 mol%
50 oC, Solvent-free
N
+
O
N
N
Ar
H
N
Ph
1
Ar
2
3a-t
Entry
Ar
Time (min)
11
Yieldb/Conv.c (%)
mp. °C (lit.)
C6H5
89/92
168-170 (171-172)15
3a
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-EtOC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2-Thienyl
2-Furyl
8
8
94/97
92/96
91/95
87/91
94/96
96/98
93/96
80/85
71/76
77/81
93/96
90/93
88/91
92/95
96/98
84/86
90/93
93/96
90/92
213-215 (207-209)15
150-152 (153-154)15
235-236 (236-237)15
184-186(186-188)18
229-231(230-232)15
145-147 (149-150)15
221-223 (224-225)15
189-190 (190-192)18
190-193 (189-191)18
228-231 (230-232)18
173-175 (172-175)18
201-203 (203-204)15
3b
3c
3d
3e
3f
8
10
8
9
3g
3h
3i
9
16
10
10
8
3j
2-Pyridyl
3-BrC6H4
4-MeC6H4
4-FC6H4
3k
3l
10
8
3m
3n
3o
3p
3q
3r
3s
143-150
248-250
2-BrC6H4
8
4-Cl-3- NO2C6H4
2,5-diMeOC6H4
4-BrC6H4
9
232-238
133-141
203-209
214-219
203-207
10
8
4-CNC6H4
8
2-Naphtyl
11
3t
aThe amounts of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one, aldehyde and [Pyridine–
SO3H]Cl in all reactions were 10, 5 and 0.05 mmol, respectively, and the reactions were
carried out at 50 ºC under solvent-free condition. bIsolated yield. cConversion.
20
Page 20 of 32

Table 4. Comparison of the results on the synthesis of 4,4'-((4-
nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) catalyzed by our new
catalysts with those obtained by the recently reported catalysts.a
Catalyst
loading
Time Yieldb
(min) (%)
TOFc
Reaction Condition
Ref.
(min-1)
c
[Pyridine–SO3H]Cl, solvent-free, 50 ºC
1 mol%
18 mol%
1 mol%
8
94
90
91
11.7500
0.1250
2.2750
-
Silica-bonded S-sulfonic acid (SBSSA),
EtOH, reflux condition
40
40
36
27
[Dsim]AlCl4, solvent-free, 90 ºC
PEG-400, 110 ºC
282 mol%
30 mol%
60
10
94
98
0.0055
0.3266
18
37
17
3-Aminopropylated silica gel, CH3CN, r.t.
Poly(ethylene glycol)-bound sulfonic acid
(PEG-SO3H), water, reflux condition
1.5 mol%
1 mol%
1 mol%
15
25
17
93
20
93
4.1333
0.8000
5.4705
d
p-Toluenesulfonic acid, solvent-free, 50 ºC
-
d
ClSO3H, solvent-free, 50 ºC
-
aThe reactions were carried out by the condensation of 3-methyl-1-phenyl-1H-pyrazol-
d
5(4H)-one with 4-nitrobenzaldehyde. bIsolated yield. cTurn-over frequency. Our work.
21
Page 21 of 32

Table 5
Recycling experiments for 1-sulfopyridinium chloride.a
Entry
Cycle
1st run
2st run
3st run
4st run
5st run
Time (min) Yieldb (%)
1
2
3
4
5
8
8
94
92
91
89
88
9
10
11
aThe reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol) with
4-nitrobenzaldehyde (1 mmol) in the presence of reused [Pyridine–SO3H]Cl (1 mol%)
under solvent-free conditions at 50 ºC. bIsolated yield.
22
Page 22 of 32

Table 6
Effect of impurities of water on the condensation of 3-methyl-1-phenyl-1H-pyrazol-
5(4H)-one and 4-nitrobenzaldehyde.a
Entry
Water Amount (mmol)
Time (min)
Yieldb/Conv.c (%)
1
2
3
4
5
6
7
8
1
2
4
6
8
10
12
14
8
94/96
94/96
93/95
91/94
90/92
89/91
88/90
78/81
12
19
22
26
30
41
60
aThe amounts of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one, aldehyde and [Pyridine–
SO3H]Cl in all reactions were 10, 5 and 0.05 mmol, respectively, and the reactions were
carried out at 50 ºC under solvent-free condition. bIsolated yield. cConversion.
23
Page 23 of 32

OH HO
O
N
a
O
N
N
N
+
Ar
H
N
N
Ar
1
2
3a-m
Yield: 72-93%
Conversion: 76-98%
OH HO
N
N
N
N
CHO
N
b
O
N
+
CHO
N
N
N
N
1
4
OH HO
5
Yield: 78%
Conversion: 83%
[Pyridine-SO3H]Cl (1 mol%), 50 oC, Solvent-free, 8-16 min
a)
b)
o
[Pyridine-SO3H]Cl (2 mol%), 50 C, Solvent-free, 15 min
Scheme 1. a) The preparation of 4,4´-(arylmethylene)-bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s by the condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with
arylaldehyde using [Pyridine–SO3H]Cl (1 mol%) as catalyst at 50 ºC under solvent-free
conditions. b) The preparation of di-4,4'-(arylmethylene)-bis(3-methyl-1-phenylpyrazol-
5-ol) by the condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with
terephthaldehyde using [Pyridine–SO3H]Cl (2 mol%) at 50 ºC under solvent-free
conditions.
24
Page 24 of 32

Figure 1. IR spectrum of 1-sulfopyridinium chloride {[Pyridine–SO3H]Cl} in
comparison with pyridine.
25
Page 25 of 32

Figure 2. UV spectra of pyridine, pyridinium chloride and [Pyridine–SO3H]Cl at room
temprature in DMSO (the concentration of these compounds in DMSO was 0.005 mol.L-
1).
26
Page 26 of 32

1
Figure 3. H NMR spectra of the compound which produced by two different methods.
(the concentration of [Pyridine–SO3H]Cl in DMSO-d6 as solvent for the NMR study was
0.08 mol.L-1).
27
Page 27 of 32

Figure 4. Thermal gravimetric (TG) and derivative thermal gravimetric (DTG) analysis
of 1-sulfopyridinium chloride at range of 25 to 600 °C, with a temperature increase rate
of 10 °C.
28
Page 28 of 32

Figure 5. Variation of the reaction conversion and yield with time on the solvent-free
condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2 mmol) with 4-
nitrobenzaldehyde (1 mmol) in the presence of [Pyridine–SO3H]Cl (1 mol%) at 50 °C.
29
Page 29 of 32