Silica sulfuric acid, an efficient and recyclable solid acid catalyst for the synthesis of 4,4'-(arylmethylene)bis (1h-pyrazol-5-ols)

Article abstract of DOI:10.1080/00397911.2010.502999

Silica sulfuric acid (SSA) is employed as a recyclable catalyst for the condensation reaction of aromatic aldehydes with 3-methyl-l-phenyl-5-pyrazolone. This condensation reaction is performed in a mixture (1:1v/v) of water-ethanol at 70C, giving 4,4'-alk

Full text of DOI:10.1080/00397911.2010.502999

This article was downloaded by: [Moskow State Univ Bibliote]
On: 23 January 2014, At: 11:28
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Silica Sulfuric Acid, an Efficient and
Recyclable Solid Acid Catalyst for the
Synthesis of 4,4′-(Arylmethylene)bis
(1H-pyrazol-5-ols)
Khodabakhsh Niknam a & Salimeh Mirzaee a
a Department of Chemistry, Faculty of Sciences , Persian Gulf
University , Bushehr , Iran
Published online: 14 Jun 2011.
To cite this article: Khodabakhsh Niknam & Salimeh Mirzaee (2011) Silica Sulfuric Acid, an Efficient
and Recyclable Solid Acid Catalyst for the Synthesis of 4,4′-(Arylmethylene)bis (1H-pyrazol-5-ols),
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:16, 2403-2413, DOI: 10.1080/00397911.2010.502999
To link to this article: http://dx.doi.org/10.1080/00397911.2010.502999
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 41: 2403–2413, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.502999
SILICA SULFURIC ACID, AN EFFICIENT AND
RECYCLABLE SOLID ACID CATALYST FOR THE
SYNTHESIS OF 4,4’-(ARYLMETHYLENE)BIS
(1H-PYRAZOL-5-OLS)
Khodabakhsh Niknam and Salimeh Mirzaee
Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
GRAPHICAL ABSTRACT
Abstract Silica sulfuric acid (SSA) is employed as a recyclable catalyst for the condensation
reaction of aromatic aldehydes with 3-methyl-l-phenyl-5-pyrazolone. This condensation
reaction is performed in a mixture (1:1 v/v) of water–ethanol at 70 ꢀC, giving 4,40-
alkylmethylene-bis(3-methyl-5-pyrazolones) in 75–93% yields.
Keywords Aldehydes; 4,40-(arylmethylene)bis(1H-5-pyrazol-5-ols); 5-methyl-2-phenyl-
2,4-dihydro-3H-pyrazol-3-one; silica sulfuric acid; solid acid
INTRODUCTION
Pyrazoles are an important class of bio-active drug targets in the pharmaceuti-
cal industry, as they are the core structure of numerous biologically active
compounds.[1–3] For example, they exhibit anti-anxiety, antipyretic, analgesic, and
anti-inflammatory properties. 2,4-Dihydro-3H-pyrazol-3-one derivatives including
4,40(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) have a broad spectrum
of approved biological activity, being used as anti-inflammatory,[4] antipyretic,[5] gas-
tric secretion stimulatory,[6] antidepressant,[7] antibacterial[8] and antifilarial agents.[9]
Moreover, the corresponding 4,40(arylmethylene)-bis-(1H-pyrazol-5-ols) are applied
as fungicides,[10] pesticides,[11]insecticides,[12] and dyestuffs[13–15] and as the chelating
and extracting reagents for different metal ions.[16,17]
The conventional chemical approach to 4,40(arylmethylene)bis(3-methyl-1-
phenyl-pyrazol-5-ols) synthesis involves the successive Knoevenagel synthesis of the
corresponding arylidenepyrazolones and base-promoted Michael reaction, and also
one-pot tandem Knoevenagel–Michael reaction of arylaldehydes with 2 equivalents
Received April 30, 2010.
Address correspondence to Khodabakhsh Niknam, Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr 75169, Iran. E-mail: niknam@pgu.ac.ir; khniknam@gmail.com
2403

2404
K. NIKNAM AND S. MIRZAEE
of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one performed under a variety of
reaction conditions.[18,19] The first set of procedures utilizes the catalysis of the
components with piperidine in ethanolic solution.[20,21] The second set of methods
involves the noncatalyzed tandem Knoevenagel–Michael reaction under neutral
conditions in either ethanol[22] or benzene[23] solutions. Although it affords the corre-
sponding 4,40(arylmethylene)bis(1H-pyrazol-5-ols) reliable in 70–90% yields, the
reaction requires 3–12 h of initial reflux with a further 24-h period under ambient
temperature to go to completion. Wang et al. reported its synthesis in water using
sodium dodecyl sulfate as surfactant catalyst over a 1-h period, but the process
requires a temperature of 100 ꢀC.[24] Elinson et al. utilized an electrocatalytic pro-
cedure for its synthesis.[25] Further, Perumal and co-workers reported the synthesis
and antiviral activity of 4,40(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols)
using ceric ammonium nitrate (CAN) as a catalyst.[26] However, most of the methods
suffer from at least one limitation, including moderate yields, long reaction times,
harsh reaction conditions, or tedious workup procedures.
Silica sulfuric acid (SSA) has been widely used as a reusable, heterogeneous, inex-
pensive, solid Brønsted acid catalyst and has received much attention.[27–29] There has
been increasingly awareness of the use of solid acids such as SSA for synthesizing
organic intermediates and fine chemicals.[30–35] SSA is a strong Brønsted and Lewis
acid, presumably arising from the formation of SiO2-SO3H sites on the surface. This
heterogeneous catalyst can be easily separated from the reaction media, has greater sel-
ectivity, and is recyclable, easier to handle, more stable, nontoxic, and insoluble in
organic solvents. In the current study, it was hoped that SSA would be a superior proton
source to the standard acidic solid supports for the preparation of 4,40(arylmethylene)-
bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) under heterogeneous conditions.
RESULTS AND DISCUSSION
In a set of initial experiments, benzaldehyde was allowed to react with two
equivalents of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one in the presence of
varying quantities of SSA in a mixture of water–ethanol (1:1 v=v) at 70 ꢀC. The
results clearly show that SSA is an effective catalyst for this condensation, and in
the absence of SSA the condensation reaction gave very poor yield after 24 h.
Although lower catalyst loading of 0.05 g of SSA accomplished this condensation,
0.08 g of SSA per 1 mmol of aldehyde was optimum in terms of reaction time and
isolated yield. Also, the model reaction was examined under optimum amounts
and room temperature. The gas chromatographic (GC) yield of the corresponding
product was 70% (Table 1, entry 19). In addition, the results of this condensation
in the presence of commercially available solid acids such as amberlyst, montmoril-
lonite K10, zeolite-HY, and H2SO4 are shown in Table 1.
The effects of different solvents on the model reaction were investigated. The
yield of the reaction in a mixture of EtOH–H2O (1:1 v=v) was great and the reaction
time was shorter (Table 2). Therefore, we employed the optimized conditions [0.08 g
mmolꢁ1 of SSA in a mixture of water–ethanol (1:1 v=v) at 70 ꢀC] for the conden-
sation reaction of various aryl aldehydes with 3-methyl-l-phenyl-5-pyrazolone into
the corresponding 4,40-(arylmethylene) bis (3-methyl-1-phenyl-1H-pyrazol-5-ols)
(Scheme 1).

SYNTHESIS OF BIS(PYRAZOL-5-OLS)
2405
Table 1. Condensation reaction of benzaldehyde with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
in the presence of different amounts of catalystsa
Entry
Catalyst
Catalyst loading (g)
Time (min)
Yield (%)b
1
2
No catalyst
SSA
–
0.05
24 h
90
<10
80
3
SSA
SSA
0.08
0.15
60
93
88
4
240
240
120
120
120
120
120
120
120
120
120
240
180
70
5
SSA
0.20
0.1
80
45
6
Zeolite-HY
Zeolite-HY
Zeolite-HY
Amberlyst
Amberlyst
Amberlyst
Montmorillonit K10
Montmorillonit K10
Montmorillonit K10
H2SO4
7
0.2
0.3
71
87
8
9
0.1
0.2
35
55
10
11
12
13
14
15
16
17
18
19
0.3
0.1
73
60
0.2
0.3
65
85
0.2 mmol
1.0 mmol
4.0 mmol
10.0 mmol
0.08
44c
44c
45c
47c
70d
H2SO4
H2SO4
H2SO4
SSA
40
480
aReaction conditions: benzaldehyde (1 mmol), 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2 mmol), H2O=EtOH (10 mL) at 70 ꢀC.
bIsolated yield.
cThe same yield was obtained for a by-product.
dGC yield of conversion at room temperature.
As shown in Table 3, both aromatic and heteroaromatic aldehydes reacted
with 3-methyl-l-phenyl-5-pyrazolone to afford 4,40(arylmethylene)-bis-(3-methyl-1-
phenyl-1H-pyrazol-5-ols) in excellent yields. Benzaldehydes with electron-donating
or electron-withdrawing groups, that is, 4-methylbenzaldehyde and 3,4-dimethoxy-
benzaldehyde (Table 3, entries 2 and 11) or 4-nitro, 3-nitro, and 4-cyanobenzaldehyde
(Table 3, entries 5–7), were condensed into the corresponding 4,40(arylmethylene)-bis-
(3-methyl-1-phenyl-1H-pyrazol-5-ols) 3b, 3k, and 3e–g respectively in good yields.
Table 2. Condensation reaction of benzaldehyde with 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
in different solvents (10 mL)a
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
CH2Cl2
CH3CN
CH3CH2OH
240
240
150
180
60
55
60
85
H2O
CH3CH2OH: H2O (1:1)
CH3CH2OH: H2O (1:2)
<25
93
120
90
aReaction conditions: benzaldehyde (1 mmol), 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one
(2 mmol), and catalyst SSA (0.08 g), at 70 ꢀC.
bIsolated yield.

2406
K. NIKNAM AND S. MIRZAEE
Scheme 1. Synthesis of 4,40(arylmethylene)-bis-(3-methyl-1-phenyl-1H-pyrazol-5-ols) derivatives catalyzed
by SSA.
The acid-sensitive substrates 3-pyridine carbaldehyde and thiophene-2-carbaldehyde
(Table 3, entries 13 and 14) were converted into the corresponding products 3 m and
3n in 86% and 75% yields, respectively.
The practical synthetic efficiency of this reaction was highlighted by the reac-
tion of terephthaldehyde with 3-methyl-1-phenyl-5-pyrazolone to give structurally
complex pyrazol-5-ol derivatives (4) (Scheme 2).
The possibility of recycling the catalyst was examined using the reaction of
benzaldehyde and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one under the opti-
mized conditions. Upon completion, the reaction mixture was washed with warm
ethanol (3 ꢂ 30 mL). The recovered catalyst was washed with diethyl ether, dried,
and reused for subsequent runs. The recycled catalyst could be reused eight times
without any additional treatment. No observation of any appreciable loss in the
catalytic activity of SSA was made (Figure 1).
In conclusion, we have prepared some new 4,40(arylmethylene)-bis-(3-methyl-
1-phenyl-1H-pyrazol-5-ols) by a tandem condensation reaction of aromatic
Table 3. Preparation of 4,40(arylmethylene)-bis-(3-methyl-1-phenyl-1H-pyrazol-5-ols) derivatives cata-
lyzed by SSA (0.08 g) in a mixture of water–ethanol at 70 ꢀCa
Entry
Ar (3)
Product
Time (min)
Yield (%)b
Mp (ꢀC)
Lit. mp (ꢀC)
1
2
C6H5-
3a
3b
3c
3d
3e
3f
60
50
93
82
170–172
202–204
215–217
235–237
225–227
151–153
210–212
155–157
165–168
201–203
195–197
206–208
238–240
181–183
213–216
171–172[24]
203[19]
4-Me-C6H4-
4-Cl-C6H4-
2-Cl-C6H4-
4-O2N-C6H4-
3-O2N-C6H4-
4-(CN)-C6H4-
4-HO-C6H4-
3-HO-C6H4-
4-MeS-C6H4-
3,4-(MeO)2-C6H3-
2-naphthyl-
3-pyridyl-
3
70
75
90
78
210[19]
4
236–237[24]
224–226[24]
149–150[24]
210–212[32]
152–153[24]
165–168[32]
201–203[32]
195–197[32]
—
5
20
40
90
83
6
7
3g
3h
3i
50
80
91
82
8
9
130
75
84
90
10
11
12
13
14
15
3j
3k
3l
70
65
87
90
3m
3n
4
40
86
75(80)c
90d
—
181–183[32]
—
2-thienyl-
-C6H4-
150
45
aReaction conditions: aromatic aldehyde (1 mmol) and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-
one (2 mmol) in a mixture of (1:1 v=v) of H2O-EtOH (10 ml) and SSA (0.08 g) at 70 ꢀC.
bIsolated yield.
cConversion.
dTerephthaldehyde (1 mmol), and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (4 mmol), in a
mixture of (1:1 v=v) of H2O–EtOH (10 ml) and SSA (0.16 g).

SYNTHESIS OF BIS(PYRAZOL-5-OLS)
2407
Scheme 2. Synthesis of di(bis-pyrazol-5-ols).
Figure 1. Recyclability of SSA (0.08 g) in the reaction of benzaldehyde (1 mmol) and 5-methyl-2-phenyl-
2,4-dihydro-3Hpyrazol-3-one (2 mmol) in H2O=EtOH (1:1 v=v) at 70 ꢀC. Reaction time 60 min.
aldehydes with 2 equiv of 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one in the
presence of SSA in a mixture of water–ethanol (1:1 v=v) at 70 ꢀC.
EXPERIMENTAL
Chemicals were purchased from Fluka, Merck, and Aldrich Chemical
Companies. All the products were characterized by comparison of their infrared
1
(IR), H NMR, and 13C NMR spectroscopic data and their melting points with
the reported values.[19–24] Amberlyst (Alderich, Dowex Maraton C [mesh 30–40]),
montmorillonite K10 (Sigma-Aldrich, powder, pH 3–4), and Zeolite (Sigma-Aldrich,

2408
K. NIKNAM AND S. MIRZAEE
powder, catalyst support, ammonium Y zeolite) were purchased from Sigma-Aldrich
Chemical Companies. SSA was prepared according to the previously reported
procedure[27] (0.05 g of equal to 0.13 mmol).[27c]
General Procedure for the Synthesis of 4,4’(Arylmethylene)-bis-
(3-methyl-1-phenyl-1H-pyrazol-5-ols) Derivatives
A mixture of aromatic aldehyde (1 mmol), 5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (2 mmol), and SSA (0.08 g) in a mixture of water–ethanol (1:1 v=v)
(10 mL) was added to a flask and heated with stirring at 70 ꢀC for an appropriate
time. After completion of the reaction, as indicated by thin-layer chromatography
(TLC), the reaction mixture was washed with warm ethanol (3 ꢂ 30 mL). After cool-
ing, the crude products were precipitated. The crude products were purified by
recrystallization from ethanol (95%). The recovered catalyst was washed with diethyl
ether, dried, and reused for subsequent runs.
Spectral Data
4,4’-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3a). Mp
170–172 ꢀC (lit.[24] 171–172 ꢀC); IR (KBr): 3400, 3080, 2900, 1593, 1494, 1410, 1275,
1
1020, 730, 690 cmꢁ1. H NMR (DMSO-d6, 300 MHz): d 2.32 (s, 6H), 4.96 (s, 1H),
7.17–7.27 (m, 7H), 7.44 (t, 4H, J ¼ 7.72 Hz), 7.71 (d, 4H, J ¼ 7.91 Hz), 13.96 (brs,
2H). 13C NMR (DMSO-d6, 75 MHz): d 33.13, 120.52, 125.55, 125.88, 127.17,
128.12, 128.90, 142.22, 146.29.
4,4’-[(4-Methylphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3b). Mp 202–204 ꢀC (lit.[19] 203 ꢀC); IR (KBr): 3440, 3075, 3830, 1590, 1495, 1408,
1294, 1020, 800, 744, 688 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz), d: 2.24 (s, 3H), 2.30
(s, 6H), 4.90 (s, 1H), 7.07 (d, 2H, J ¼ 8.29 Hz), 7.13 (d, 2H, J ¼ 8.10 Hz), 7.24 (t, 2H,
J ¼ 7.35 Hz), 7.44 (t, 4H, J ¼ 7.72 Hz), 7.70 (d, 4H, J ¼ 7.91 Hz), 13.93 (brs, 2H).
13C NMR (75 MHz, DMSO-d6): d 18.55, 32.39, 114.85, 120.47, 125.49, 128.08,
128.89, 132.27, 137.39, 146.18, 155.49.
4,4’-[(4-Chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3c). Mp 215–217 ꢀC (lit.[19] 210 ꢀC); IR (KBr): 3430, 3085, 2920, 1595, 1490, 1410,
1290, 804, 742, 690 cmꢁ1. 1H NMR (DMSO-d6, 300 MHz): d 2.30 (s, 6H), 4.98 (s, 1H)
7.22–7.28 (m, 4H), 7.35 (d, 2H, J ¼ 8.48 Hz), 7.44 (t, 4H, J ¼ 7.91 Hz), 7.71 (d, 4H,
J ¼ 7.91 Hz), 13.90 (brs, 2H). 13C NMR (DMSO-d6, 75 MHz): d 32.56, 120.54,
125.62, 128.00, 128.90, 129.13, 130.56, 137.18, 141.14, 146.23.
4,4’-[(2-Chlorophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3d). Mp 235–237 ꢀC, (Lit.[24] 236–237 ꢀC); IR (KBr): 3450, 3070, 2910, 1610, 1555,
1495, 1395, 1360, 1300, 835, 740, 690 cmꢁ1. 1H NMR (DMSO-d6, 400 MHz): d 2.29
(s, 6H), 5.14 (s, 1H), 7.22–7.33 (m, 4H), 7.40 (d, 1H, J ¼ 7.82 Hz), 7.44 (t, 4H,
J ¼ 7.57 Hz), 7.70 (d, 4H, J ¼ 7.57 Hz), 7.80 (d, 1H, J ¼ 7.06 Hz), 13.92 (brs, 2H).
13C NMR (DMSO-d6, 100 MHz): d 32.41, 120.67, 123.62, 126.92, 128.05, 128.93,
129.45, 130.32, 135.94, 137.36, 140.60, 141.18.

SYNTHESIS OF BIS(PYRAZOL-5-OLS)
2409
4,4’-[(4-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3e). Mp 225–227 ꢀC, (lit.[24] 224–226 ꢀC); IR (KBr): 3440, 3090, 2920, 1595, 1495,
1
1410, 1340, 744, 689 cmꢁ1. H NMR (DMSO-d6, 400 MHz): d 2.28 (s, 6H), 5.06
(s, 1H), 7.18 (t, 2H, J ¼ 7.06Hz), 7.38 (t, 4H, J ¼ 7.31Hz), 7.45 (d, 2H, J ¼ 8.32Hz),
7.64 (d, 4H, J ¼ 7.82Hz), 8.10 (d, 2H, J ¼ 8.58Hz), 13.81 (brs, 2H). 13C NMR
(DMSO-d6, 100 MHz): d 34.45, 121.91, 124.65, 127.03, 129.92, 130.25, 147.20,
147.58, 151.63.
4,4’-[(3-Nitrophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3f). Mp 151–153 ꢀC, (lit.[24] 149–150 ꢀC); IR (KBr): 3420, 3085, 2910, 1595, 1495,
1
1340, 758, 735, 692, 598 cmꢁ1. H NMR (DMSO-d6, 400 MHz): d 2.35 (s, 6H),
5.14 (s, 1H), 7.26 (t, 2H, J ¼ 7.31 Hz), 7.45 (t, 4H, J ¼ 7.57 Hz), 7.60 (t, 1H,
J ¼ 8.32 Hz), 7.68–7.74 (m, 5H), 8.06–8.10 (m, 2H), 13.91 (brs, 2H). 13C NMR
(DMSO-d6, 100 MHz): d 32.80, 120.63, 121.21, 121.70, 125.78, 125.81, 128.98,
129.71, 134.34, 137.39, 144.56, 146.30, 147.72.
4,4’-[(4-Cyanophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(3g). Mp 210–212 ꢀC, (lit.[32] 210–212 ꢀC); IR (KBr): 3420, 3090, 2921, 2230, 1595,
1
1495, 1410, 1290, 810, 750, 690 cmꢁ1. H NMR (400 MHz, DMSO-d6): d (ppm)
2.33 (s, 6H), 5.07 (s, 1H), 7.25 (t, 2H, J ¼ 7.31 Hz), 7.42–7.46 (m, 6H), 7.40 (d, 4H,
J ¼ 7.82 Hz), 7.76 (d, 2H, J ¼ 8.32 Hz), 13.89 (brs, 2H). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 33.23, 119.00, 120.61, 125.57, 128.38, 128.94, 133.36, 142.59,
148.15. Elemental analysis: for C28H23N5O2: C, 72.87; H, 5.02; N, 15.17. Found:
C, 72.96; H, 4.97; N, 15.33.
4,4’-[(4-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (3h). Mp 155–157 ꢀC, (lit.[24] 152–153 ꢀC); IR (KBr): 3420, 3150, 3090, 2920,
1
1593, 1492, 1410, 1270, 744, 690 cmꢁ1. H NMR (DMSO-d6, 300 MHz): d 2.30
(s, 6H), 4.85 (s, 1H), 6.67 (d, 2H, J ¼ 7.72 Hz), 7.05 (d, 2H, J ¼ 7.16 Hz), 7.24
(t, 2H, J ¼ 5.0 Hz), 7.42–7.45 (m, 4H), 7.66–7.77 (m, 4H), 9.19 (s, 1H), 13.96 (brs,
2H). 13C NMR (DMSO-d6, 75 MHz): d 18.55, 32.39, 114.85, 120.47, 125.49,
128.08, 128.89, 132.27, 137.39, 146.18, 155.49.
4,4’-[(3-Hydroxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (3i). Mp 165–168 ꢀC, (lit.[32] 165–168 ꢀC); IR (KBr): 3410, 3150, 3080, 2920,
1
1592, 1495, 1270, 1168, 1042, 750, 690 cmꢁ1. H NMR (400 MHz, DMSO-d6): d
(ppm) 2.42 (s, 6H), 4.98 (s, 1H), 6.67 (dd, 1H, J1 ¼ 8.14 Hz, J2 ¼ 1.5 Hz), 6.76–6.80
(m, 2H,), 7.17 (t, 1H, J¼ 7.82 Hz), 7.36 (t, 2H, J¼ 7.31 Hz), 7.56 (t, 4H, J¼ 7.82 Hz),
7.83 (d, 4H, J¼ 7.82 Hz), 9.34 (s, 1H), 14.08 (brs, 2H). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 32.52, 114.20, 119.54, 120.48, 128.92, 128.97, 132.72, 137.47,
143.67, 147.04, 157.17. Elemental analysis: for C27H24N4O3: C, 71.67; H, 5.35; N,
12.38. Found: C, 71.22; H, 5.22; N, 12.32.
4,4’-[(4-Methylthiophenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (3j). Mp 201–203 ꢀC, (Lit.[32] 201–203 ꢀC); IR (KBr): 3425, 3085, 2918, 1592,
1
1495, 1186, 779, 748 cmꢁ1. H NMR (400 MHz, DMSO-d6): d (ppm) 2.3 (s, 6H),
2.43 (s, 3H), 4.92 (s, 1H), 7.18 (s, 4H), 7.25 (t, 2H, J ¼ 7.31 Hz), 7.44 (t, 4H,
J ¼ 7.82 Hz), 7.70 (d, 4H, J ¼ 7.82 Hz), 13.92 (brs, 2H). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 14.96, 31.86, 120.45, 120.55, 126.88, 127.82, 128.92, 129.71,

2410
K. NIKNAM AND S. MIRZAEE
131.41, 136.44, 143.57, 146.97, 147.57. Elemental analysis for C28H26N4O2S: C,
69.69; H, 5.43; N, 11.61. Found: C, 69.22; H, 5.64; N, 11.67.
4,4’-[(3,4-Dimethoxyphenyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (3k). Mp 195–197 ꢀC (lit.[32] 195–197 ꢀC); IR (KBr): 3428, 3085, 2920, 1580,
1
1508, 1410, 1133, 1025, 804, 685 cmꢁ1. H NMR (400 MHz, DMSO-d6): d (ppm)
2.33 (s, 6H), 3.67 (s, 3H), 3.71 (s, 3H), 4.90 (s, 1H), 6.82–6.88 (m, 2H), 6.91
(d, 1H, J ¼ 1.77 Hz), 7.25 (t, 2H, J ¼ 7.31 Hz), 7.45 (t, 4H, J ¼ 7.94 Hz), 7.72 (d,
4H, J ¼ 7.57 Hz), 14.06 (brs, 2H). 13C NMR (100 MHz, DMSO-d6): d (ppm)
32.91, 55.45, 111.54, 111.66, 119.28, 120.58, 125.56, 134.90, 146.17, 147.21, 148.37.
Elemental analysis for C29H28N4O4: C, 70.15; H, 5.68; N, 11.28. Found: C, 69.78;
H, 5.78; N, 11.22.
4,4’-[(2-Naphthyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3l).
Mp 206–208 ꢀC; IR (KBr): 3410, 3030, 1590, 1490, 1392, 1360, 1280, 1020, 810, 780,
1
740, 690 (cmꢁ1); H NMR (DMSO-d6, 500 MHz), d: 2.36 (s, 6H), 5.14 (s, 1H), 7.24
(t, 2H, J ¼ 6.9 Hz), 7.41–7.45 (m, 7H), 7.71–7.73 (m, 5H), 7.81–7.85 (m, 3H), 12.41
(brs, 1H), 13.93 (s, 1H); 13C NMR (DMSO-d6, 125 MHz), d: 12.50, 34.22, 121.46,
125.80, 126.30, 126.83, 127.36, 128.16, 128.52, 128.59, 129.79, 132.54, 133.73,
140.55, 147.19. Elemental analysis for C31H26N4O2: C, 76.52; H, 5.39; N, 11.51.
Found: C, 76.35; H, 5.30; N, 11.46.
4,4’-[(3-Pyridyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3m).
Mp 238–240 ꢀC; IR (KBr): 3410, 3050, 2900, 1595, 1490, 1410, 1345, 1280, 1020, 850,
1
790, 745, 695 (cmꢁ1); H NMR (DMSO-d6, 500 MHz), d: 2.34 (s, 6H), 5.05 (s, 1H),
7.23 (t, 2H, J ¼ 7.1 Hz), 7.34 (t, 1H, J ¼ 6.0 Hz), 7.43 (t, 4H, J ¼ 7.5 Hz), 7.71–7.73
(m, 5H), 8.41 (d, 1H, J ¼ 3.6 Hz), 8.51 (s, 1H), 12.10 (brs, 1H), 14.12 (brs, 1H);
13C NMR (DMSO-d6, 125 MHz), d: 12.54, 31.96, 104.68, 121.45, 124.22, 126.44,
129.76, 136.16, 138.25, 138.91, 147.04, 147.61, 149.32. Elemental analysis: for
C26H23N5O2: C, 71.38; H, 5.30; N, 16.01. Found C, 71.20; H, 5.25; N, 15.87.
4,4’-[(2-Thienyl)methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (3n).
Mp 181–183 ꢀC, (lit.[32] 181–183 ꢀC); IR (KBr): 3420, 3080, 2920, 1595, 1490, 1410,
1
1284, 779, 690 cmꢁ1. H NMR (DMSO-d6, 400 MHz): d 2.32 (s, 6H), 5.13 (s, 1H),
6.75–6.77 (m, 1H), 6.90–6.92 (m, 1H), 7.24–7.30 (m, 3H), 7.45 (t, 4H, J ¼ 7.82 Hz),
7.71 (d, 4H, J ¼ 7.82 Hz) 14.01 (brs, 2H). 13C NMR (DMSO-d6, 100 MHz): d
29.43, 120.58, 124.05, 124.15, 126.75, 128.94, 132.99, 134.13, 147.73. Elemental
analysis for C25H22N4O2S: C, 67.85; H, 5.01; N, 12.66. Found: C, 67.38; H, 4.99;
N, 12.25.
1,4-Diphenylene-4,4’-(methylene)bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol) (4). Mp 213–216 ꢀC; IR (KBr): 3410, 3020, 1590, 1490, 1410, 1350, 1290,
1
1120, 1020, 850, 745, 690 cmꢁ1. H NMR (DMSO-d6, 500 MHz): d 2.29 (s, 12H),
5.05 (s, 2H), 7.17 (s, 4H), 7.22 (t, 4H, J ¼ 7.1 Hz), 7.41 (t, 8H, J ¼ 7.8 Hz), 7.69 (d,
8H, J ¼ 7.9 Hz), 12.41 (brs, 2H) 14.11 (s, 2H). 13C NMR (DMSO-d6, 125 MHz): d
12.51, 33.69, 121.50, 127.84, 129.72, 140.93, 147.07, 155.01. Elemental analysis for
C48H42N8O4: C, 72.52; H, 5.32; N, 14.09. Found: C, 72.35; H, 5.29; N, 13.85.

SYNTHESIS OF BIS(PYRAZOL-5-OLS)
2411
ACKNOWLEDGMENTS
Financial support for this work by the Research Council of Persian Gulf
University, Bushehr, Iran, is gratefully acknowledged, and we thank Prof. E. J.
Thomas’s research group for running the FT-IR and NMR.
REFERENCES
1. McDonald, E.; Jones, K.; Brough, P. A.; Drysdale, M. J.; Workman, P. Discovery and
development of pyrazole-scaffold Hsp90 inhibitors. Curr. Top. Med. Chem. 2006, 6,
1193–1203.
2. Elguero, J. In Comprehensive Heterocyclic Chemistry; A. R. Katritzky, C. W. Rees, and
E. F. V. Scriven (Eds.); Pergamon: Oxford, 1996; vol. 5.
3. Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S. Pyrazoles as drugs: Facts and fantasies.
Targets Heterocycl. Syst. 2002, 6, 52–98.
4. Sugiura, S.; Ohno, S.; Ohtani, O.; Izumi, K.; Kitamikado, T.; Asai, H.; Kato, K.
Syntheses and anti-inflammatory and hypnotic activity of 5-alkoxy-3-(N-substituted
carbamoyl)-1-phenylpyrazoles, 4. J. Med. Chem. 1977, 20, 80–85.
5. Behr, L. C.; Fusco, R.; Jarboe, C. H. In The Chemistry of Heterocyclic Compounds,
Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings; A. Weissberger,
(Ed.); Interscience: New York, 1967.
6. Rosiere, C. E.; Grossman, M. I. An analog of histamine that stimulates gastric acid
secretion without other actions of histamine. Science 1951, 113, 651–651.
7. Bailey, D. M.; Hansen, P. E.; Hlavac, A. G.; Baizman, E. R.; Pearl, J.; Defelice, A. F.;
Feigenson, M. E. 3,4-Diphenyl-1H-pyrazole-1-propanamine antidepressants. J. Med.
Chem. 1985, 28, 256–260.
8. Mahajan, R. N.; Havaldar, F. H.; Fernandes, P. S. J. Indian Chem. Soc. 1991, 68, 245–246.
9. Chauhan, P. M. S.; Singh, S.; Chatterjee, R. K. Indian J. Chem., Sect. B 1993, 32, 858–861.
10. Singh, D.; Singh, D. J. Indian Chem. Soc. 1991, 68, 165–167.
11. Londershausen, M. Review: Approaches to new parasiticides. Pestic. Sci. 1996, 48, 269–292.
12. Lubs, H. A. (Ed.). The Chemistry of Synthetic Dyes and Pigments; American Chemical
Society: Washington, DC, 1970.
13. Uzoukwu, A. B. The synthesis and crystal structures of 1-phenyl-3-methyl-4-butanolypyr-
azol-5-one and of two pyrazolonato complexes of iron. Polyhedron 1993, 12, 2719–2724.
14. Maurya, R. C.; Verma, R. Indian J. Chem., Sec. A 1997, 36, 596–598.
15. Garnovskii, A. D.; Uraev, A. I.; Minkin, V. I. Metal complexes from aryl and hetaryla-
zocompounds. Arkivoc 2004, 3, 29–41.
16. Sridhar, R.; Perumal, P. T.; Etti, S.; Shanmugam, G.; Ponnusamy, M. N.; Prabavathy, V.
R.; Mathivanan, N. Design, synthesis, and antimicrobial activity of 1H-pyrazole carbox-
ylates. Bioorg. Med. Chem. Lett. 2004, 14, 6035–6040.
17. Sivaprasad, G.; Perumal, P. T.; Prabavathy, V. R.; Mathivanan, N. Synthesis and
anti-microbial activity of pyrazolylbisindoles—Promising antifungal compounds. Bioorg.
Med. Chem. Lett. 2006, 16, 6302–6305.
18. Hamama, W. S. Pyrazolones as versatile precursors for the synthesis of fused and binary
heterocycles. Synth. Commun. 2001, 31, 1335–1345.
19. Li, X.-L.; Wang, Y.-M.; Tian, B.; Matsuura, T.; Meng, J.-B. The solid-state Michael
addition of 3-methyl-1-phenyl-5-pyrazolone. J. Heterocycl. Chem. 1998, 35, 129–134.
20. Singh, D.; Singh, D. Syntheses of 1,3-disubstituted 4-arylidenepyrazolin-5-ones and the
keto and enol forms of 4,40-arylidenebis(1,3-disubstituted pyrazolin-5-ones). J. Chem.
Eng. Data 1984, 29, 355–356.

2412
K. NIKNAM AND S. MIRZAEE
21. Mitra, A. S.; Rout, M. K. J. Indian Chem. Soc. 1961, 38, 893.
22. Pavlov, P. T.; Goleneva, A. F.; Lesnov, A. E.; Prokhorova, T. S. Biological activity of
some pyrazolone derivatives. Pharm. Chem. J. 1998, 32, 370–372.
23. Buzykin, B. I.; Lonshchakova, T. I. Bull. Acad. Sci. USSR, Div. Chem. Sci. 1971,
2224–2226.
24. Wang, W.; Wang, S.-X.; Qin, X.-Y.; Li, J.-T. Reaction of aldehydes and pyrazolones in
the presence of sodium dodecyl sulfate in aqueous media. Synth. Commun. 2005, 35,
1263–1269.
25. Elinson, M. N.; Dorofeev, A. S.; Nasybullin, R. F.; Nikishin, G. I. Facile and convenient
synthesis of 4,40-(arylmethylene)bis(1H-pyrazol-5-ols) by electrocatalytic tandem Knoeve-
nagel–Michael Reaction. Synthesis 2008, 12, 1933–1937.
26. Sujatha, K.; Shanthi, G.; Selvam, N. P.; Manoharan, S.; Perumal, P. T.; Rajendran, M.
Synthesis and antiviral activity of 4,40-(arylmethylene)bis(1H-pyrazol-5-ols) against peste
des petits ruminant virus (PPRV). Bioorg. Med. Chem. Lett. 2009, 19, 4501–4503.
27. (a) Zolfigol, M. A. Silica sulfuric acid=NaNO2 as a novel heterogeneous system for
production of thionitrites and disulfides under mild conditions. Tetrahedron 2001, 57,
9509–9511; (b) Salehi, P.; Zolfigol, M. A.; Shirini, F.; Baghbanzadeh, M. Silica sulfuric
acid and silica chloride as efficient reagents for organic reactions. Curr. Org. Chem.
2006, 10, 2171–2189; (c) Shaterian, H. A.; Ghashang, M.; Feyzi, M. Silica sulfuric acid
as an efficient catalyst for the preparation of 2H-indazolo[2,1-b]phthalazine-triones. Appl.
Catal. A: Gen. 2008, 345, 128–133.
28. (a) Niknam, K.; Zolfigol, M. A.; Khorramabadi-Zad, A.; Zare, R.; Shayegh, M. Silica sul-
furic acid as an efficient and recyclable catalyst for the methoxymethylation of alcohols
under solvent-free conditions. Catal. Commun. 2006, 7, 494–498; (b) Niknam, K.; Karami,
B.; Zolfigol, M. A. Silica sulfuric acid–promoted aromatization of 1,2-dihydroquinolines
by using NaNO2 as oxidizing agent under mild and heterogeneous conditions. Catal.
Commun. 2007, 8, 1427–1430.
29. (a) Pore, D. M.; Soudagar, M. S.; Desai, U. V. Potassium phosphate or silica sulfuric
acid–catalyzed conjugate addition of thiols to a,b-unsaturated ketones at room tempera-
ture under solvent-free conditions. Tetrahedron Lett. 2006, 47, 9325–9328; (b) Wang, Y.;
Yuan, Y.-Q.; Guo, S.-R. Silica sulfuric acid promotes aza-Michael addition reactions
under solvent-free condition as a heterogeneous and reusable catalyst. Molecules 2009,
14, 4779–4789; (c) Veisi, H. Silica sulfuric acid (SSA) as a solid acid heterogeneous catalyst
for one-pot synthesis of substituted pyrroles under solvent-free conditions at room
temperature. Tetrahedron Lett. 2010, 51, 2109–2114.
30. (a) Wu, H.; Shen, Y.; Fan, L. Y.; Wan, Y.; Zhang, P.; Chen, C. F.; Wang, W. X. Stereo-
selective synthesis of b-amino ketones via direct Mannich-type reaction catalyzed with sil-
ica sulfuric acid. Tetrahedron 2007, 63, 2404–2408; (b) Modaresi, A. R.; Nasrollahzadeh,
M.; Khamooshi, F. Solvent-free preparation of primary carbamates using silica sulfuric
acid as an efficient reagent. Arkivoc 2007, 16, 238–245.
31. (a) Niknam, K.; Saberi, D.; Nouri Sefat, M. Silica-bonded S-sulfonic acid as a recyclable
catalyst for chemoselective synthesis of 1,1-diacetates. Tetrahedron Lett. 2009, 50, 4058–
4062; (b) Niknam, K.; Saberi, D.; Mohagheghnejad, M. Silica bonded S-sulfonic acid: A
recyclable catalyst for the synthesis of quinoxalines at room temperature. Molecules
2009, 14, 1915–1926; (c) Niknam, K.; Saberi, D.; Baghernejad, M. Silica-bonded S-sulfonic
acid, a recyclable catalyst for the synthesis of coumarins. Chin. Chem. Lett. 2009, 20, 1444–
1448; (d) Niknam, K.; Saberi, D. Silica-bonded N-propyl sulfamic acid as an efficient
catalyst for the formylation and acetylation of alcohols and amines under heterogeneous
conditions. Tetrahedron Lett. 2009, 50, 5210–5214; (e) Niknam, K.; Saberi, D. Preparation
of sulfuric acid ([3-(3-silicapropyl)sulfanyl]propyl)ester: A new and recyclable catalyst for
the formylation and acetylation of alcohols under heterogeneous conditions. Appl. Catal.

SYNTHESIS OF BIS(PYRAZOL-5-OLS)
2413
A: Gen. 2009, 366, 220–225; (f) Niknam, K.; Saberi, D.; Baghernejad, M. Preparation
of silica-bonded S-sulfonic acid: A recyclable catalyst for the synthesis of bis-
indolylmethanes. Phosphorus, Sulfur Silicon Relat. Elem. 2010, 185, 875–882; (g) Niknam,
K.; Panahi, F.; Saberi, D.; Mohagheghnejad, M. Silica-bonded S-sulfonic acid as
recyclable catalyst for the synthesis of 1,8-dioxo-decahydroacridines and 1,8-dioxo-
octahydroxanthenes. J. Heterocycl. Chem. 2010, 47, 292–300; (h) Niknam, K.; Saberi,
D.; Nouri Sefat, M. Silica-bonded S-sulfonic acid: An efficient and recyclable solid acid
catalyst for the three-component synthesis of a-amino nitriles. Tetrahedron Lett. 2010,
51, 2959–2962.
32. Niknam, K.; Saberi, D.; Sadegheyan, M.; Deris, A. Silica-bonded S-sulfonic acid: An
efficient and recyclable solid acid catalyst for the synthesis of 4,40-(arylmethylene)bis(1H-
pyrazol-5-ols). Tetrahedron Lett. 2010, 51, 692–694.