Catalyst-free tandem Knoevenagel-Michael reaction of aldehydes and pyrazolin-5-one: Fast and convenient approach to medicinally relevant 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s

Article abstract of DOI:10.1515/hc-2015-0046

Catalyst-free tandem Knoevenagel-Michael reaction of aryl aldehydes and two equivalents of 3-methyl-1-phenyl-2-pyrazolin-5-one results in fast (5 min) formation of medicinally relevant 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s in excellent 93%-99% yield.

Full text of DOI:10.1515/hc-2015-0046

Heterocycl. Commun. 2015; 21(2): 97–101
MCiachtaail Nl.yEslints-ofnr*,eOelgatOa. Snodkoelovma anKd nRuoslaenvF.eNansyabgulleinl-Michael
reaction of aldehydes and pyrazolin-5-one: fast
and convenient approach to medicinally relevant
4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s
Abstract: Catalyst-free tandem Knoevenagel-Michael reac- stimulatory [12], antidepressant [13], and antibacterial [14]
tion of aryl aldehydes and two equivalents of 3-methyl- properties. Moreover, the analogous 4,4′-(arylmethylene)
1-phenyl-2-pyrazolin-5-one results in fast (5 min) formation bis(1H-pyrazol-5-ols) are used as fungicides [15], pesticides
of medicinally relevant 4,4′-(arylmethylene)bis(1H-pyra- [16], insecticides [16], dyestuffs [17], and chelating and
zol-5-ol)s in excellent 93%–99% yield.
extracting reagents for different metal ions [18, 19].
The most common method for the synthesis of
Keywords:
4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s; 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s involves one-
catalyst-free; Knoevenagel reaction; Michael addition; pot pseudo-three-component condensation of aldehydes
pyrazolin-5-one; tandem reaction.
with 3-methyl-1-phenyl-2-pyrazolin-5-one. Several cata-
lysts have been used for this transformation, including
LiOH·H2O [20], 1,3-disulfonic acid imidazolium tetra-
chloroaluminate [21], sulfuric acid ([3-(3-silicapropyl)
sulfanyl]propyl)ester [22], melamine trisulfonic acid [23],
nano n-propylsulfonated γ-Fe2O3 [24], and silica-bonded
N-propyltriethylenetetramine [25]. However, most of these
synthetic methods suffer from several drawbacks such as
moderate yields, long reaction times, complex and expen-
sive catalysts, or tedious workup procedures. Furthermore,
the previously mentioned techniques require additional
purification steps of target compounds, for instance, crys-
tallization [20–23, 25] or flash chromatography [24].
Taking into consideration the basic principles of
“green chemistry”, catalyst-free procedures are particu-
larly welcome [26]. Two catalyst-free methods for synthe-
sis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s have been
reported. In the first method, a mixture of an aldehyde and
3-methyl-1-phenyl-2-pyrazolin-5-one is heated under reflux
in ethanol for 4 h [27], but the yields and melting points of
the resultant 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s thus
prepared have not been reported [27]. Recently, another sol-
vent-free method has been published (heating to 120°C for
10 min) [28]. Unfortunately, aldehydes are easily oxidized
under this high temperature conditions, which results in
the formation of many by-products. Crystallization from
ethanol is necessary to isolate pure 4,4′-(arylmethylene)
bis(1H-pyrazol-5-ol)s from the bulk solid obtained by this
reaction [28]. When we repeated this experiment with ben-
zaldehyde and 3-methyl-1-phenyl-2-pyrazolin-5-one, the
expected product was formed in 83% yield by NMR data,
DOI 10.1515/hc-2015-0046
Received February 5, 2015; accepted March 5, 2015
Introduction
Continuously growing interest in convenient and green
techniques motivates chemists to increase the tools of
their arsenal [1]. In recent years, tandem reactions have
emerged as a very attractive method giving access to
complex molecules in a facile and efficient manner [2].
Tandem Knoevenagel-Michael reaction is well known
in classic organic chemistry [2–6]. Recently, we have
published several variants of either chemically or elec-
trochemically induced tandem Knoevenagel-Michael
reaction [7–9]. Now we wish to report the fast tandem
transformation of aryl aldehydes and two equivalents
of 3-methyl-1-phenyl-2-pyrazolin-5-one into substituted
4,4′-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol)s, which proceeds under catalyst-free conditions.
4,4′-(Arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol)s have a broad spectrum of biological activities, such
as anti-inflammatory [10], antipyretic [11], gastric secretion
*Corresponding author: Michail N. Elinson, N. D. Zelinsky Institute
of Organic Chemistry, Leninsky prospect 47, Moscow 119991,
Russia, e-mail: elinson@ioc.ac.ru
Olga O. Sokolova and Ruslan F. Nasybullin: N. D. Zelinsky Institute
of Organic Chemistry, Leninsky prospect 47, Moscow 119991, Russia but it was isolated in 71% yield only after crystallization.
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98ꢀ ꢀM.N. Elinson et al.: Convenient approach to 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s
R
Me
N
Me
N
Me
Me
CHO
EtOH
R
+
+
O
O
N
N
N
N
Ph
N
N
Ph
78°C, 5 min
1a-i
Ph
Ph
OH HO
2a-i
a: R = H
f: R = 2-Cl
b: R = 4-Me
c: R = 4-Cl
d: R = 4-Br
e: R = 4-F
g: R = 4-NO2
h: R = 2,4-OCH3
i: R = 2-Cl, 6-F
Scheme 1ꢀ
Taking into consideration the basic principles of bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (2a) was obtained
“green chemistry”, catalyst-free procedures are par- in 63% yield. The replacement of water with ethanol
ticularly welcome [28–31]. In this report, we describe a resulted in the formation of product 2a in 91% yield
convenient, fast, and efficient catalyst-free tandem trans- (Table 1, entry 2). The next experiment was conducted
formation of aldehydes and pyrazolin-5-ones into substi- without any catalyst and solvent under heating at 100°C
tuted 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s 2a–i.
(Table 1, entry 3). To our surprise, even in this case,
the tandem Knoevenagel-Michael reaction proceeded
smoothly without noticeable changes in the yield of 2a
(90%). It became evident that the presence of NaOAc had
no significant influence on the outcome of the reaction,
and the effect of the solvent should be studied. It was
found that the tandem reaction of benzaldehyde 1a and
two equivalents of 3-methyl-1-phenyl-2-pyrazolin-5-one
proceeds better when ethanol is used as solvent (Table 1,
entries 4 and 8). After increasing the reaction time from 3
to 5 min, product 2a was obtained in 98% yield (Table 1,
entry 8). Under such optimized conditions, the scope of
the reaction was studied.
Various substituted aryl aldehydes 1a–i bearing either
electron-withdrawing or electron-donating groups were
allowed to react with two equivalents of 3-methyl-1-phe-
nyl-2-pyrazolin-5-one. The tandem Knoevenagel-Michael
reaction proved to be general because excellent (93%–
99%) yields of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol)s 2a–i were achieved in all cases. It is also
worth noting that this tandem process is performed under
catalyst-free conditions within the unprecedented reac-
tion time of 5 min and the analytically pure products are
obtained by simple filtration.
Results and discussion
Synthesis of the desired products 2a–i is easily accom-
plished under neutral and mild conditions by heating a
mixture of an aldehyde and a pyrazolin-5-one in EtOH
under reflux for 5 min (Scheme 1).
At the outset of these studies, investigations were
conducted to find the optimal conditions (Table 1). The
reaction between benzaldehyde 1a and two equivalents
of 3-methyl-1-phenyl-2-pyrazolin-5-one was chosen as a
model. First, the experiment was performed at 80°C in
water in the presence of 10 mol% of NaOAc as catalyst
(Table 1, entry 1). Within 3 min, 4,4′-(phenylmethylene)
Table 1:ꢀTandem Knoevenagel-Michael transformation of benzal-
dehyde (1a) and two equivalents of 3-methyl-1-phenyl-2-pyrazolin-
5-one into 2a.a
Entryꢁ
Catalyst
(mol.%)
ꢁ
Solventꢁ
Tꢁ
(°C)
Timeꢁ
(min)
Yield of
2a (%)b
1
2
3
4
5
6
7
8
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
NaOAc (10)ꢂ
NaOAc (10)ꢂ
H2O
EtOH
–
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
80ꢂ
78ꢂ
3ꢂ
3ꢂ
3ꢂ
3ꢂ
3ꢂ
3ꢂ
ꢂ
63
91
90
95
88
76
Taking into consideration the previously discussed
results and the mechanistic data on the related electrocata-
lytic tandem transformation previously reported by us [7],
the following mechanism for the catalyst-free tandem Kno-
evenagel-Michael reaction of aryl aldehydes 1 with 3-methyl-
–
–
–
–
–
–
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
ꢂ
100ꢂ
78ꢂ
EtOH
PrOH
80ꢂ
MeOH ꢂ
65ꢂ
H2O
ꢂ
ꢂ
80ꢂ
65 1-phenyl-2-pyrazolin-5-one can be proposed (Scheme 2).
EtOH
78ꢂ
5ꢂ
98
The initial step of this catalyst-free tandem process
a
begins with ionization of 3-methyl-1-phenyl-2-pyrazolin-
1a (5 mmol), 3-methyl-2-pyrazol-5-one (10 mmol), 3 mL of solvent.
bIsolated yield.
5-one leading to anion A. This process can be thermally
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M.N. Elinson et al.: Convenient approach to 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)sꢃ
ꢃ99
Me
Me
Heating
N
N
O
O
N
N
A
Ph
Ph
Me
R
R
R
R
N
O
N
Me
Me
N
Me
N
Me
Me
Me
N
Me
A
Ph
R
N
N
N
N
Ph
N
N
N
Ph
N
N
N
Ph
N
O
O
O
HO
OH
CHO
O
O
Ph
Ph
Ph
Ph
B
1
3
2
Scheme 2ꢀ
or internal calibration was performed using Electrospray Calibrant
Solution (Fluka). All starting materials were obtained from commer-
cial sources and used without purification.
activated. Subsequent Knoevenagel condensation of A
and aryl aldehyde 1 takes place affording the intermedi-
ate product 3. This step is followed by Michael addition
of another equivalent of 3-methyl-1-phenyl-2-pyrazolin-
5-one with 3 to give rise to anion B. Finally, the anion B
undergoes intramolecular tautomeric transformation with
the formation of corresponding 4,4′-(arylmethylene)bis(3-
methyl-1-phenyl-1H-pyrazol-5-ol)s 2.
General procedure
A mixture of 3-methyl-1-phenyl-2-pyrazolin-5-one (10 mmol) and
a benzaldehyde 1a–i (5 mmol) in ethanol (3 mL) was stirred under
reflux for 5 min then cooled to room temperature. The resultant pre-
cipitate was filtered off, rinsed with ice-cold ethanol (2ꢀ×ꢀ1 mL), and
dried under reduced pressure.
Conclusion
4,4′-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)
(2a)ꢁWhite solid; yield 2.14 g (98%); mp 170–172°C (lit. [22] 170–
172°C); 1H NMR: δ 2.33 (s, 6H, 2CH3), 4.97 (s, 1H, CH), 7.15–7.29 (m, 7H,
Ar), 7.44 (t, J ꢀ=ꢀ 7.9 Hz, 4H, Ar), 7.72 (d, J ꢀ=ꢀ 7.6 Hz, 4H, Ar).
A novel, fast, and efficient catalyst-free Knoevenagel-
Michael reaction of aryl aldehydes and two equiva-
lents of 3-methyl-1-phenyl-2-pyrazolin-5-one leading to
4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-
5-ol)s in excellent yields was developed. Noncatalytic
conditions of this cascade procedure correspond to pre-
sent-day demands of “green chemistry”. This tandem
procedure uses simple equipment and readily available
starting materials. The final compounds are isolated by
simple filtration of the reaction mixture and do not need
further purification. The technique described offers an
efficient and convenient way to 4,4′-(arylmethylene)
bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s, the prominent
compounds with approved practical utilities and different
biomedical applications.
4,4′-[(4-Methylphenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2b)ꢁWhite solid; yield 2.16 g (96%); mp 205–
1
207°C (lit. [22] mp 202–204°C); H NMR: δ 2.31 (s, 6H, 2CH3), 2.51 (s,
3H, CH3), 4.91 (s, 1H, CH), 7.06–7.27 (m, 6H, Ar), 7.44 (t, J ꢀ=ꢀ 7.6 Hz, 4H,
Ar), 7.72 (d, J ꢀ=ꢀ 7.9 Hz, 4H, Ar).
4,4′-[(4-Chlorophenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2c)ꢁWhite solid; yield 2.19 g (93%); mp 215–216°C
(lit. [22] mp 215–217°C); 1H NMR: δ 2.30 (s, 6H, 2CH3), 4.95 (s, 1H, CH),
7.20–7.34 (m, 6H, Ar), 7.42 (t, J ꢀ=ꢀ 7.8 Hz, 4H, Ar), 7.69 (d, J ꢀ=ꢀ 7.6 Hz, 4H,
Ar).
4,4′-[(4-Bromophenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2d)ꢁWhite solid; yield 2.50 g (97%); mp 220–222°C
(lit. [23] mp 183–184°C); 1H NMR: δ 2.32 (s, 6H, 2CH3), 4.95 (s, 1H, CH),
7.19–7.27 (m, 4H, Ar), 7.42–7.48 (m, 5H, Ar), 7.71 (d, J ꢀ=ꢀ 7.9 Hz, 4H, Ar).
4,4′-[(4-Fluorophenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2e)ꢁOrange solid; yield 2.25 g (99%); mp 181–
182°C (lit. mp [22] 181–183°C); 1H NMR: δ 2.32 (s, 6H, 2CH3), 4.96 (s, 1H,
CH), 7.07–7.12 (m, 2H, Ar), 7.22–7.27 (m, 4H, Ar), 7.44 (t, J ꢀ=ꢀ 7.3 Hz, 4H,
Ar), 7.71 (d, J ꢀ=ꢀ 7.6 Hz, 4H, Ar).
Experimental
Melting points were measured with a Gallenkamp melting point
apparatus and are uncorrected. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded with a Bruker Avance II-300 at
ambient temperature in DMSO-d6 solutions. IR spectra were reg-
istered with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets.
HRMS (ESI) were run on Bruker micrOTOF II instrument; external
4,4′-[(2-Chlorophenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2f)ꢁWhite solid; yield 2.21 g (94%); mp 239–241°C
(lit. [22] mp 235–237°C); 1H NMR: δ 2.08 (s, 6H, 2CH3), 5.04 (s, 1H, CH),
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pyrazol-5-ols) by electrocatalytic tandem Knoevenagel-Michael
reaction. Synthesis 2008, 1933–1937.
7.00–7.19 (m, 8H, Ar), 7.24 (d, J ꢀ=ꢀ 6.6 Hz, 1H, Ar), 7.38 (d, J ꢀ=ꢀ 7.9 Hz, 4H,
Ar), 7.79 (d, J ꢀ=ꢀ 7.8 Hz, 1H, Ar).
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Knoevenagel-Michael reaction of 3-methyl-2-pyrazolin-5-ones,
aryl aldehydes and cyano-functionalized C-H acids: facile and
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3-methylpyrazol-4-yl)-3-arylpropionitriles. Electrochim. Acta
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catalyzed tandem Knoevenagel-Michael multicomponent
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alized C-H acids: facile and efficient way to 3-(5-hydroxypyra-
zol-4-yl)-3-arylpropionitriles. C. R. Chim. 2013, 16, 789–794.
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4,4′-[(4-Nitrophenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2g)ꢁYellowish solid; yield 2.36 g (98%); mp 230–
232°C (lit. [22] mp 225–227°C); 1H NMR: δ 2.35 (s, 6H, 2CH3), 5.13 (s, 1H,
CH), 7.23–7.29 (m, 2H, Ar), 7.42–7.55 (m, 6H, Ar), 7.71 (d, J ꢀ=ꢀ 7.7 Hz, 4H,
Ar), 8.17 (d, J ꢀ=ꢀ 8.6 Hz, 2H, Ar).
4,4′-[(2,4-Dimethoxyphenyl)methylene)]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2h)ꢁOrange solid (2.41 g, 97%); mp 198–200°C; 1H
NMR: δ 2.27 (s, 6H, 2CH3), 3.71 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 5.09
(s, 1H, CH), 6.46 (d, J ꢀ=ꢀ 8.4 Hz, 1H, Ar), 6.51 (s, 1H, Ar), 7.21–7.26 (m,
2H, Ar), 7.41–7.50 (m, 5H, Ar), 7.71 (d, J ꢀ=ꢀ 7.9 Hz, 4H, Ar); 13C NMR: δ 11.7
(2C), 27.1, 55.0, 55.5, 98.4, 104.2, 104.7 (2C), 120.5 (4C), 123.1, 125.4 (2C),
128.9 (5C), 129.1 (2C), 137.5 (2C), 146.3 (2C), 156.8, 159.0; IR: ν 2959, 2421,
1614, 1504, 1406, 1294, 1210, 1123, 840, 758 cm-1. HRMS (ESI). Calcd for
+
C29H29N4O4 ([M+H] ): m/z 497.2183. Found: m/z 497.2174.
4,4′-[(2-Chloro-6-fluorophenyl)methylene)]bis(3-methyl-1-phe-
nyl-1H-pyrazol-5-ol) (2i)ꢁWhite solid; yield 2.33 g (95%); mp 215–
216°C; 1H NMR: δ 2.20 (s, 6H, 2CH3), 5.36 (s, 1H, CH), 7.09–7.16 (m, 1H,
Ar), 7.21–7.29 (m, 4H, Ar), 7.43 (t, J ꢀ=ꢀ 7.6 Hz, 4H, Ar), 7.71 (d, J ꢀ=ꢀ 7.9 Hz,
4H, Ar); 13C NMR: 11.9 (2C), 29.3, 102.7 (2C), 115.6 (d, J ꢀ=ꢀ 24.5 Hz, 1C),
120.1 (4C), 125.4 (d, J ꢀ=ꢀ 25.3 Hz, 1C), 127.4 (d, J ꢀ=ꢀ 14.9 Hz, 1C), 128.6,
128.8 (6C), 133.6, 137.4 (2C), 146.5 (2C), 158.2 (2C), 161.7 (d, J ꢀ=ꢀ 250.5 Hz,
1C); IR: ν 3061, 2912, 2874, 2791, 1619, 1566, 1500, 1399, 789, 748 cm-1.
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M.N. Elinson et al.: Convenient approach to 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)sꢃ
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