Synthesis of 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives in water

Article abstract of DOI:10.1016/j.crci.2012.07.003

An environmentally friendly and simple method for the synthesis of some 4,4′-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives via a one-pot pseudo five-component reaction of hydrazine hydrate, ethyl acetoacetate and aldehydes in water using pyridine trifluoroacetate or acetic acid at 70 °C is reported.

Full text of DOI:10.1016/j.crci.2012.07.003

C. R. Chimie 15 (2012) 955–961
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Preliminary communication/Communication
Synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol)
derivatives in water
a
b
c
Ebrahim Soleimani a, , Somayeh Ghorbani , Mojtaba Taran , Afshin Sarvary
*
a Department of Chemistry, Razi University, Kermanshah 67149-67346, Iran
b Department of Biology, Razi University, Kermanshah 67149-67346, Iran
c Faculty of Basic Science, Babol University of Technology, Babol, Iran
A R T I C L E I N F O
A B S T R A C T
An environmentally friendly and simple method for the synthesis of some 4,40-
(arylmethylene)bis(3-methyl-1H-pyrazol-5-ol) derivatives via a one-pot pseudo five-
component reaction of hydrazine hydrate, ethyl acetoacetate and aldehydes in water using
pyridine trifluoroacetate or acetic acid at 70 8C is reported.
Article history:
Received 10 May 2012
Accepted after revision 5 July 2012
Available online 15 August 2012
ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Keywords:
Pyrazole
Ethyl acetoacetate
Water
Hydrazine hydrate
Multicomponent reactions
1. Introduction
stability. The ‘‘on water’’ effect has been observed in
different types of reactions, such as cycloadditions,
The ‘greening’ of global chemical processes has become
a major issue in the chemical industry [1]. Organic
reactions in water without using harmful organic solvents
have attracted a great deal of interest in both academic and
industrial research because, in addition to environmental
concerns, there are beneficial effects of aqueous solvents
on rates and selectivities of important organic transforma-
tions [2].
In many cases, significant beneficial effects, in terms of
reaction rates and selectivity, have been observed for
reactions between reagents that are insoluble in aqueous
media and therefore take place under suspension in water;
the term ‘‘on water’’ was coined by Sharpless et al. to refer
to this type of reaction [3]. When the rate acceleration is
negligible, the use of water as the only supporting medium
has other advantages including ease of product isolation,
safety, thanks to its high heat capacity and unique redox
pericyclic reactions, nucleophilic substitutions, and in
particular, multicomponent reactions (MCR) [4].
MCR are very efficient synthetic methods. The strategy
offers significant advantages over classical stepwise
approaches allowing the formation of several bonds and
the construction of complex molecular architectures from
simple precursors in a single synthetic operation without
the need for isolation of intermediates [5]. MCRs,
particularly those performed in aqueous media, have
become increasingly useful tools for the synthesis of
chemically and biologically important compounds because
of their environmentally friendly atom economy and green
characteristics [6].
Pyrazolones and pyrazoles are an important class of bio-
active drug targets in the pharmaceutical industry that
exhibit a wide range of biological activities [7]. For example,
pyrazole derivatives such as 4,40-(arylmethylene)bis(3-
methyl-1H-pyrazol-5-ols) have a broad spectrum of ap-
proved biological activity, being used as anti-inflammatory
[8], antipyretic [9], gastric secretion stimulatory [10],
antidepressant [11], antibacterial [12], and antifilarial
* Corresponding author.
E-mail address: e_soleimanirazi@yahoo.com (E. Soleimani).
1631-0748/$ – see front matter ß 2012 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2012.07.003

956
E. Soleimani et al. / C. R. Chimie 15 (2012) 955–961
R
Me
Me
O
O
CHO
NH2
Pyridine trifluoroacetate
H2O, 70 oC
N
N
+
+
R
H2N
Me
OEt
NH
HN
OH HO
3
1
2
4
Scheme 1. Synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) derivatives.
agents [13]. Also these derivatives are applied as fungicides
[14], pesticides [15], insecticides [16], and dyestuffs [17],
and as the chelating and extracting reagents for different
metal ions [18].
The conventional chemical approach to 4,40-(aryl-
methylene)bis(3-methyl-1H-pyrazol-5-ols) involves the
successive Knoevenagel synthesis of the corresponding
arylidenepyrazolones and its base-promoted Michael
reaction, and also one-pot tandem Knoevenagel–Michael
reaction of arylaldehydes with 2 equiv of 3-methyl-1H-
of 3-methyl-1H-pyrazol-5-ol in above reaction, theoret-
ically using these substrates could allow instead 3-
methyl-1H-pyrazol-5-ol.
Therefore, we examined the reaction between ethyl
acetoacetate 1, hydrazine hydrate 2, and aldehydes 3 in
water using pyridine trifluoroacetate or acetic acid at 70 8C.
Gratifyingly, this reaction worked well leading to the
expected product 4 (Scheme 1).
2. Results and discussion
pyrazol-5-ol performed under
a variety of reaction
conditions [19]. However, most of the methods have one
or more limitations that may include moderate yields, long
reaction times, harsh reaction conditions, or tedious
workup procedures. Also one limitation special for this
method is two components of reaction; first 3-methyl-1H-
pyrazol-5-ol should be synthesised from condensation
hydrazine hydrate, ethyl acetoacetate and then condensa-
tion with aldehyde afforded 4,40-(arylmethylene)bis(3-
methyl-1H-pyrazol-5-ols).
As
a model reaction we first investigated the
condensation of ethyl acetoacetate 1 (2 equiv) and
hydrazine hydrate 2 (2 equiv) with 3-nitrobenzaldehyde
3 (1 equiv) under various conditions (Table 1). We first
investigated the model reaction rate catalyzed by
pyridine trifluoroacetate (20 mol%) in different solvents
by measuring the isolated yield using identical amounts
of reactants for a fixed reaction time of 5 h at reflux
temperature of solvents. The desired product obtained in
protic solvents such as water, ethanol, and methanol but
water can afford the product in good yield even better
than ethanol and methanol (Table 1, entries 1, 2 and 3).
Herein, we aimed to modify the reaction to make
it more convenient and efficient. Since hydrazine
hydrate and ethyl acetoacetate could be used instead
Table 1
Optimization of the reaction.
NO2
Me
Me
O
O
O2N
+
CHO
NH2
N
N
+
H2N
Me
OEt
HN
NH
OH HO
Entry
Solvent
Temperature (8C)
Pyridine trifluoroacetate (mol%)
Yield (%)
1
2
Water
70
20
20
20
20
20
20
20
20
10
15
25
95
85
75
65
60
70
40
20
85
90
96
Ethanol
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
70
3
Methanol
4
Ethyl acetate
Acetonitrile
Benzene
5
6
7
1,4-dioxane
8
Dichloromethane
Water
9
10
11
Water
70
Water
70

E. Soleimani et al. / C. R. Chimie 15 (2012) 955–961
957
Table 2
Synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) derivatives from condensation hydrazine hydrate, ethyl acetoacetate and aldehydes.
Entry
1
Aldehyde
Time (h)
12
Product
Yield (%)
85
CHO
NO2
O2N
Me
Me
N
N
NH
HN
OH HO
OH
4a
2
12
90
CHO
HO
Me
Me
N
N
NH
HN
OH HO
OMe
4b
3
13
75
CHO
MeO
Me
Me
N
N
NH
HN
OH HO
4c
4
5
87
CHO
NO2
Me
Me
NO2
N
N
HN
NH
OH HO
4d
5
11
75
CHO
OH
Me
Me
N
OH
N
HN
NH
OH HO
4e
6
10
85
CHO
NO2
NO2
Me
Me
N
N
HN
NH
OH HO
4f

958
E. Soleimani et al. / C. R. Chimie 15 (2012) 955–961
Table 2 (Continued )
Entry
Aldehyde
Time (h)
12
Product
Yield (%)
95
7
CHO
OH
OH
Me
Me
N
N
HN
NH
OH HO
Cl
4g
8
15
94
Cl
CHO
Cl
Cl
Me
Me
N
N
HN
NH
OH HO
4h
9
15
95
O2N
CHO
OH
O2N
Me
Cl
Me
N
N
HN
NH
OH HO
O
4i
10
13
80
CHO
Me
Me
O
N
N
HN
NH
OH HO
4j
The desired product was scarcely obtained in aprotic or
non-polar solvent as dichloromethane, benzene, and
ethyl acetate, 1,4-dioxane and acetonitrile (Table 1,
entries 4, 5, 6, 7 and 8). This effect can be explained by a
simple acid-catalysis mechanism facilitated by the
strong hydrogen bond interaction at the organic-water
interface which stabilizes the reaction intermediate [20].
Also to evaluate the effect of catalyst concentration, the
O
O
HN
N
NH2
+
2
H2N
2
Me
OEt
O
Me
1
2
5
O
R
H
Me
Me
R
HN
N
HN
N
N
O
N
Me
O
Me
5
NH
HN
OH HO
R
6
4
Scheme 2. Proposed mechanism reaction.

E. Soleimani et al. / C. R. Chimie 15 (2012) 955–961
959
model reaction was carried out in the presence of
different amounts of catalyst (10, 15, 20 and 25 mol%)
at 70 8C. The result showed that 20 mol% of catalyst was
sufficient to achieve a fairly high yield (Table 1, entry 1).
It is worth mentioning here that during the optimization
of this reaction we used acetic acid as acid catalyst and
result was similar but pyridine trifluoroacetate was a
little better (yield of reaction in pyridine trifluoroacetate
was 1–3% more than when acetic acid was used).
Therefore it was decided to employ this reagent for
the synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-
pyrazol-5-ols) derivatives 4.
To explore the substrate scope, we examined a range
various aromatic aldehydes under the optimized reaction
conditions. The results are summarized in Table 2. The
structures of the products were established by spectro-
scopic methods. In all cases, good yields were obtained,
regardless of the nature of the substituent present on the
aldehyde (electron-donating or electron-withdrawing).
The independency of the reaction outcome to the
electronic nature of aromatic aldehyde could be rational-
ized by high reactivity of pyrazolone (5) (for more details
see Scheme 2). This confirms the reliability of the synthetic
method.
DRX-200 Avance spectrometer at 300 and 75 MHz. NMR
spectra were obtained on solutions in DMSO using TMS
as internal standard. All of the chemicals were purchased
from Fluka, Merck and Aldrich and used without
purification.
4.2. General procedure for the synthesis of pyrazole
compounds 4
A
solution of hydrazine hydrate (2 mmol), ethyl
acetoacetate (2 mmol), and pyridine trifluoroacetate
(0.2 mmol) in water (10 mL) was stirred at 70 8C. After
15 min, aldehyde (1 mmol) was added and the mixture
stirred at 70 8C for appropriate time indicated in Table 1.
After completion of the reaction, as indicated by TLC,
the precipitated solid was filtered and washed with
mixture water/ethanol (1:1) and products obtained as
pure.
4.3. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(4-
nitrophenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4a)
White powder (0.28 g, yield 85%). mp 275–278 8C. IR
(KBr) (
z): 330 (M + 1), 241, 232, 135, 97. 1H NMR (300 MHz,
DMSO-d6): H (ppm) 2.12 (6H, s, 2CH3), 3.54 (2NH and 2OH
n
max/cmꢀ1): 3405, 2922, 1706, 1598, 1482. MS, (m/
Mechanistically, it is conceivable that the reaction
involves the initial formation pyrazolone (5) by reaction
between ethyl acetoacetate (2 equiv) and hydrazine
hydrate (2 equiv). Afterwards the intermediate 5 under-
goes Knoevenagel condensation with aldehyde 3 to afford
activated alkene 6. Michael addition reaction activated
alkene 6 with pyrazolone 5 to give 4,40-(arylmethylene)-
bis(3-methyl-1H-pyrazol-5-ols) derivatives as shown in
Scheme 2.
d
exchanged with water of DMSO-d6), 5.00 (1H, s, CH), 7.40
(2H, d, 3JHH = 8.8 Hz, H-Ar), 8.13 (2H, d, 3JHH = 8.8 Hz, H-Ar).
13C NMR (75 MHz, DMSO-d6): dC (ppm) 10.3 (CH3), 33.0
(CH), 103.3, 123.0, 128.8, 140.0, 145.6, 151.7, 160.9 (C-Ar).
Anal. Calcd for C15H15N5O4: C, 54.71; H, 4.59; N, 21.27.
Found: C, 54.77; H, 4.49; N, 21.33.
4.4. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(4-
hydroxyphenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4b)
3. Conclusion
White powder (0.27 g, yield 90%). mp 267–270 8C. IR
In conclusion, the efficient synthesis of 4,40-(arylmethy-
lene)bis(3-methyl-1H-pyrazol-5-ols) derivatives in water,
in the presence of pyridine trifluoroacetate as catalyst has
been described. A pseudo five-component reaction involv-
ing ethyl acetoacetate (2 equiv) and hydrazine hydrate (2
equiv), and an aromatic aldehyde (1 equiv) afforded the
desired products with good yields. A wide range of
aromatic aldehydes were tested, bearing either electron-
donating or electron-withdrawing substituent’s, suggest-
ing that this method can be used to synthesize a large
variety of compounds. It has therefore been demonstrated
that using water as the solvent and is ideally suited for the
synthesis of 4,40-(arylmethylene)bis(3-methyl-1H-pyra-
zol-5-ols) derivatives.
(KBr) (n
max/cmꢀ1): 3403, 2924, 1709, 1595, 1483. MS, (m/
z): 301 (M + 1), 299, 267, 241, 203, 186, 115. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 2.12 (6H, s, 2CH3), 4.78
(1H, s, CH), 5.54 (2NH and 3OH exchanged with water of
3
DMSO-d6), 6.67 (2H, d, JHH = 8.4 Hz, H-Ar), 7.00 (2H, d,
3JHH = 8.4 Hz, H-Ar). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 10.3 (CH3), 31.9 (CH), 104.8, 114.6, 128.3, 133.3,
140.1, 155.1, 161.1 (C-Ar). Anal. Calcd for C15H16N4O3: C,
59.99; H, 5.37; N, 18.66. Found: C, 59.96; H, 5.33; N,
18.71.
4.5. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(4-
methoxyphenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4c)
White powder (0.23 g, yield 75%). mp 200–203 8C. IR
4. Experimental
(KBr) (
z): 315 (M + 1), 283, 241, 217, 97. 1H NMR (300 MHz,
DMSO-d6): H (ppm) 2.11 (6H, s, 2CH3), 3.72 (3H, s, OCH3),
n
max/cmꢀ1): 3231, 2930, 2827, 1607, 1508. MS, (m/
4.1. Materials and techniques
d
4.79 (1H, s, CH), 6.80 (2H, d, 3JHH = 8.4 Hz, H-Ar), 7.05 (2H,
d, 3JHH = 8.4 Hz, H-Ar), 11.82 (4H, brs, 2OH, 2NH). 13C NMR
(75 MHz, DMSO-d6): dC (ppm) 10.3 (CH3), 31.7 (CH), 55.0
(OCH3), 104.6, 113.4, 128.3, 134.9, 140.1, 157.3, 169.9 (C-
Ar). Anal. Calcd for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82.
Found: C, 61.17; H, 5.75; N, 17.87.
Melting points were taken on an Electrothermal 9100
apparatus and left uncorrected. IR spectra were obtained
on a Shimadzu IR-470 spectrometer. Elemental analyses
were performed using a Heraeus CHN elemental analyz-
er. 1H and 13C NMR spectra were recorded on a Bruker

960
E. Soleimani et al. / C. R. Chimie 15 (2012) 955–961
4.6. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(3-
nitrophenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4d)
(CH3), 31.1 (CH), 101.8, 126.5, 128.3, 130.9, 131.9, 133.1,
138.6, 140.0, 160.5 (C-Ar). Anal. Calcd for C15H14Cl2N4O2: C,
51.01; H, 4.00; N, 15.86. Found: C, 51.11; H, 4.01; N, 15.75.
White powder (0.29 g, yield 87%). mp 288–291 8C. IR
(KBr) (
(M + 1), 241, 232, 135, 97. 1H NMR (300 MHz, DMSO-d6):
H (ppm) 2.16 (6H, s, 2CH3), 5.02 (1H, s, CH), 5.27 (2NH and
n
max/cmꢀ1): 3400, 2920, 1700, 1598. MS, (m/z): 330
4.11. 4-((5-hydroxy-3-methyl-1H-pyrazol-4-yl)(2-hydroxy-
5-nitrophenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4i)
d
2OH exchanged with water of DMSO-d6), 7.58–8.02 (4H,
m, H-Ar). 13C NMR (75 MHz, DMSO-d6): dC (ppm) 10.2
(CH3), 32.5 (CH), 103.4, 120.8, 121.9, 129.3, 134.6, 140.1,
145.6, 147.6, 160.9 (C-Ar). Anal. Calcd for C15H15N5O4: C,
54.71; H, 4.59; N, 21.27. Found: C, 54.73; H, 4.47; N, 21.31.
White powder (0.33 g, yield 95%). mp 269–272 8C. IR
(KBr) (n
max/cmꢀ1): 3400, 2921, 1704, 1598. MS, (m/z): 347
(M + 1), 299, 248, 241, 217, 97. 1H NMR (300 MHz, DMSO-
d6): dH (ppm) 2.11 (6H, s, 2CH3), 3.65 (2OH and 2NH
exchanged with water of DMSO-d6), 5.04 (1H, s, CH), 6.99-
7.41 (3H, m, H-Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm)
4.7. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(3-
10.4 (CH3), 27.3 (CH), 102.8, 114.9, 123.5, 125.3, 131.2,
140.0, 141.0, 160.0, 161.0 (C-Ar). Anal. Calcd for
hydroxyphenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4e)
C
15H15N5O5: C, 52.17; H, 4.38; N, 20.28. Found: C, 52.20;
White powder (0.22 g, yield 75%). mp 209–211 8C. IR
H, 4.33; N, 20.29.
(KBr) (n
max/cmꢀ1): 3404, 2923, 1706, 1598, 1483. MS, (m/
z): 301 (M + 1), 299, 267, 241, 203, 186, 115. 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 2.09 (6H, s, 2CH3), 3.92
(2NH and 2OH exchanged with water of DMSO-d6), 4.74
4.12. 4-((furan-2-yl)(5-hydroxy-3-methyl-1H-pyrazol-4-
yl)methyl)-3-methyl-1H-pyrazol-5-ol (4j)
(1H, s, CH), 6.56–7.02 (4H, m, H-Ar), 9.20 (H, brs, OH). 13
NMR (75 MHz, DMSO-d6): C (ppm) 10.3 (CH3), 32.5 (CH),
C
White powder (0.22 g, yield 80%). mp 270–272 8C. IR
d
(KBr) (n
max/cmꢀ1): 3429, 1600, 1515. MS, (m/z): 275
104.3, 112.4, 114.5, 118.2, 138.5, 140.1, 144.7, 156.9, 161.1
(C-Ar). Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N,
18.66. Found: C, 59.93; H, 5.35; N, 18.65.
(M + 2), 241, 178, 177, 175, 149. 1H NMR (300 MHz, DMSO-
d6): dH (ppm) 2.05 (6H, s, 2CH3), 4.00 (2OH and 2NH
exchanged with water of DMSO-d6), 4.84 (1H, s, CH), 5.95–
8.66 (3H, m, H-Ar). 13C NMR (75 MHz, DMSO-d6):
dC (ppm)
4.8. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(2-
nitrophenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4f)
10.0 (CH3), 27.8 (CH), 102.4, 105.9, 110.2, 139.2, 141.0,
155.6, 160.6 (C-Ar). Anal. Calcd for C13H14N4O3: C, 56.93;
H, 5.14; N, 20.43. Found: C, 56.96; H, 5.17; N, 20.38.
White powder (0.28 g, yield 85%). mp 237–240 8C. IR
(KBr) (
z): 330 (M + 1), 241, 232, 135, 97. 1H NMR (300 MHz,
DMSO-d6): H (ppm) 2.07 (6H, s, 2CH3), 3.55 (2NH and 2OH
exchanged with water of DMSO-d6), 5.44 (1H, s, CH), 7.40–
7.66 (4H, m, H-Ar). Anal. Calcd for C15H15N5O4: C, 54.71; H,
4.59; N, 21.27. Found: C, 54.79; H, 4.46; N, 21.31.
n
max/cmꢀ1): 3403, 2923, 1706, 1593, 1483. MS, (m/
Acknowledgements
d
We gratefully acknowledge financial support from the
Iran National Science Foundation (INSF) and Research
Council of Razi University.
References
4.9. 4-((5-Hydroxy-3-methyl-1H-pyrazol-4-yl)(2-
hydroxyphenyl)methyl)-3-methyl-1H-pyrazol-5-ol (4g)
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(KBr) (n
max/cmꢀ1): 3410, 2987, 1593, 1527. MS, (m/z): 301
(M + 1), 299, 267, 241, 203, 186, 115. 1H NMR (300 MHz,
DMSO-d6): dH (ppm) 2.07 (6H, s, 2CH3), 3.43 (2OH
exchanged with water of DMSO-d6), 5.08 (1H, s, CH),
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112.5, 118.2, 126.3, 129.3, 130.4, 140.0, 153.8, 161.5 (C-Ar).
Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66.
Found: C, 59.91; H, 5.39; N, 18.66.
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White powder (0.33 g, yield 94%). mp 267–270 8C. IR
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