Un-catalyzed tandem Knoevenagel-Michael reaction for the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) in aqueous medium

Article abstract of DOI:10.1016/j.cclet.2011.09.004

An environmentally benign un-catalyzed one-pot synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) has been reported via tandem Knoevenagel-Michael reaction of aldehydes with two equivalents of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one in aqueous medium.

Full text of DOI:10.1016/j.cclet.2011.09.004

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1415–1418
www.elsevier.com/locate/cclet
Un-catalyzed tandem Knoevenagel–Michael reaction for
0
the synthesis of 4,4 -(arylmethylene)bis(1H-pyrazol-5-ols)
in aqueous medium
*
Nilesh P. Tale, Girdharilal B. Tiwari, Nandkishor N. Karade
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra 440 033, India
Received 3 May 2011
Available online 12 October 2011
Abstract
0
An environmentally benign un-catalyzed one-pot synthesis of 4,4 -(arylmethylene)bis(1H-pyrazol-5-ols) has been reported via
tandem Knoevenagel–Michael reaction of aldehydes with two equivalents of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one in aqueous
medium.
#
2011 Nandkishor N. Karade. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Knoevenagel reaction; Michael addition; Aldehydes; 3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one; Aqueous medium
A sustaining interest has been focused within the last two decades on the use of water as a medium for some well
known organic reactions. Water has many advantages over general organic solvents when used as a solvent in chemical
reactions. In the past, water was not used as a solvent for synthetic organic chemistry due to the low solubility and, in
some cases, the instability of organic reagents in water. At the present, it has been identified that chemical reactions in
aqueous solutions often give better results than in organic solvents and insolubility of the final products facilitates their
0
isolation [1]. The sub-structural unit of 2,4-dihydro-3H-pyrazol-3-one including 4,4 -(arylmethylene)bis(3-methyl-1-
phenyl-1H-pyrazol-5-ols) is most frequently present in various bioactive molecules showing a wide range of
pharmacological properties such as anti-inflammatory [2], antipyretic [3], anti-bacterial [4], gastric secretion
stimulatory [5], antidepressant [6], and antifilarial agents [7]. Some pyrazoles also display agrochemical properties
(
i.e. herbicidal and soil fungicidal activity) [8] and have applications as pesticides [9] and insecticides [10]. The utility
of certain pyrazole derivatives has also been demonstrated in the extraction of different metal ions [11].
-Methyl-1-phenyl-1H-pyrazol-5(4H)-one is a versatile building block with highly nucleophilic enolic carbon at 4-
3
position. It has been recently used in several multi-component reactions (MCRs) for the synthesis of wide range of
heterocycles [12]. While carrying out three component reaction of aromatic aldehydes, Meldrum acid and 3-methyl-1-
0
phenyl-1H-pyrazol-5(4H)-one in aqueous medium, we noticed the formation of 4,4 -(arylmethylene)bis(3-methyl-1-
0
phenyl-1H-pyrazol-5-ols) as one of the major product. The literature survey showed that the synthesis of 4,4 -
(
arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) can be accomplished by two methods: (i) Knoevenagel
*
Corresponding author.
E-mail address: nnkarade@gmail.com (N.N. Karade).
1001-8417/$ – see front matter # 2011 Nandkishor N. Karade. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.09.004

1416
N.P. Tale et al. / Chinese Chemical Letters 22 (2011) 1415–1418
R
H O
2
N
N
2
N
RCHO
O
N
reflux
N
N
OH OH
Ph
Ph
6-8 h
Ph
1
2
3a-j
Scheme 1.
reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with aldehydes to form the corresponding arylidenepyrazolones
followed by base promoted Michael reaction with second equivalent of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
[
13], (ii) one-pot tandem Knoevenagel–Michael reaction of aldehydes with two equivalents of 3-methyl-1-phenyl-1H-
pyrazol-5(4H)-one under various reaction conditions [14]. The first set of conditions requires piperidine as the base
catalyst and the desired products are formed in poor 15–30% yield [15]. The second set of method has been
demonstrated in refluxing benzene or ethanol under neutral conditions with long duration of time up to 24 h involving
product isolation with ether extraction. The other improved protocol for the tandem Knoevenagel–Michael reaction
either in water or ethanol utilizes the electrolytic system using NaBr as electrolyte [16], sodium dodecyl sulfate (SDS)
as the surfactant catalyst (5 mol%) [17], ceric ammonium nitrate (CAN) as Lewis acid [18] and [Cu(3,4-
tmtppa)](MeSO ) [19] and silica-bonded S-sulfonic acid (SBSSA) [20] as a recyclable catalyst. In spite of these
4
4
literature reports, we have observed that the one-pot tandem Knoevenagel–Michael reaction of aldehydes with two
equivalents of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one can be effected in aqueous medium without any use of
0
catalyst or additive to form 4,4 -(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) in good to excellent yields
(Scheme 1).
1
. Results and discussion
In a typical reaction procedure, a mixture of benzaldehyde (2 mmol) and 5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one (4 mmol) was refluxed in water (20 mL) for 8 h. After the completion of the reaction, the resulting solid
was filtered and recrystallized from methanol to afford 3a, m.p. 172–173 8C (lit. [17] m.p. 171–172 8C) in 76% yield
(
see the supporting information). The results reported in Table 1 showed that a variety of aromatic aldehydes with
Table 1
0
Synthesis of 4,4 -(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) in aqueous medium.
R
H O
2
N
2
N
N
O
RCHO
N
N
N
reflux
Ph
1
Ph
OH OH Ph
6
-8 h
2
3
a-j
a
Yield (%)
No.
R
C
Product 3
Time (h)
M.p. (8C)
Lit. m.p. (8C)
1
2
3
4
5
6
7
8
9
6
H
5
–
3a
3b
3c
3d
3e
3f
8
7
7
8
8
8
6
6
6
8
76
83
81
79
73
76
82
84
81
72
172–173
198–200
173–175
189–190
149–150
164–166
199–201
183–185
146–147
208–209
171–172 [17]
203 [13a]
4-MeC
4-MeOC
3,4-(MeO)
6 4
H –
6
H
4
–
176–177 [16]
195–197 [19]
152–153 [17]
165–168 [19]
210 [13a]
2 6 3
C H –
4-HOC
3-HOC
6
H
H
4
–
6
4
–
4-ClC
4-BrC
3-NO
(CH
6
H
4
–
3g
3h
3i
6
H
4
–
–
2
C
6
H
4
–
149–150 [17]
213–214 [17]
10
3
)
2
CH
2
–
3j
a
Isolated yield after recrystallization.

N.P. Tale et al. / Chinese Chemical Letters 22 (2011) 1415–1418
1417
R
R
R
H
H O
2
N
N
N
N
N
N
RCHO
2
N
O
H
OH
O
N
N
N
N
N
N
N
OH
O
Ph
Ph
OH OH
3
Ph
Ph
Ph
Ph
Ph
1
4
Scheme 2. Reaction mechanism.
electron releasing and withdrawing substituents reacted efficiently with two equivalents of 5-methyl-2-phenyl-2,4-
dihydro-3H-pyrazol-3-one to afford the product 3a–j in good to excellent yields. The reaction is also extended to the
1
use of aliphatic aldehydes such as isobutyraldehyde. The products were characterized by IR, H NMR and LCMS
1
analysis. For example, the H NMR spectra of 3c indicated the presence of singlet at d 4.89 due to arylmethylene
proton and two broad peaks around d 12.4 and d 13.91 reminiscent of two enolisable –OH groups. The IR spectra of 3c
ꢀ
1
indicated peaks at 3498 cm due to –OH and 1581 cm due to C N functional groups. The LCMS of 3c corresponds
ꢀ1
to the expected m/z 467.35.
The tentative reaction mechanism for the formation of 4,4 -(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-
0
ols) is shown in Scheme 2. It involves un-catalyzed Knoevenagel condensation of 5-methyl-2-phenyl-2,4-dihydro-3H-
pyrazol-3-one 1 with aldehydes 2 to form 4 which undergoes Michael addition with second equivalent of 5-methyl-2-
phenyl-2,4-dihydro-3H-pyrazol-3-one 1 to form the product 3.
In conclusion, we have demonstrated an environmentally benign un-catalyzed one-pot tandem Knoevenagel–
0
Michael reaction in aqueous medium for the synthesis of 4,4 -(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-
ols) in good yields.
2
. Experimental
A mixture of appropriate aldehyde (2 mmol) and 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (4 mmol) was
refluxed in water (20 mL) for the time period as shown in Table 1. The progress of the reaction was monitored by TLC.
0
After the completion of reaction, the resulting solid was filtered and recrystallized from methanol to afford 4,4 -
(
arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) in good yields.
Acknowledgment
The authors are thankful to the University Grants Commission, New Delhi, India (No. MRP 32-245/2006 SR) for
the financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/
j.cclet.2011.09.004.
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