One-pot efficient pseudo-five-components synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) at room temperature assisted by K2CO3

Article abstract of DOI:10.1080/00397911.2017.1298134

A convenient approach for the synthesis of 4,4′-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) by an efficient one-pot reaction of aromatic aldehydes, phenylhydrazine, and ethyl acetoacetate by using substoichiometric amount of K₂CO

Full text of DOI:10.1080/00397911.2017.1298134

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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One-Pot Efficient Pseudo Five Components
Synthesis of 4,4′-(Arylmethylene)bis(3-methyl-1-
phenyl-1H-pyrazol-5-ols) at Room Temperature
Assisted by K2CO3
Dipanwita Banerjee, Rajiv Karmakar, Utpal Kayal & Gourhari Maiti
To cite this article: Dipanwita Banerjee, Rajiv Karmakar, Utpal Kayal & Gourhari Maiti (2017):
One-Pot Efficient Pseudo Five Components Synthesis of 4,4′-(Arylmethylene)bis(3-methyl-1-
phenyl-1H-pyrazol-5-ols) at Room Temperature Assisted by K2CO3, Synthetic Communications
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Date: 08 March 2017, At: 12:44

One-Pot Efficient Pseudo Five Components Synthesis of 4,4'-(Arylmethylene)bis(3-
methyl-1-phenyl-1H-pyrazol-5-ols) at Room Temperature Assisted by K2CO3
Dipanwita Banerjee1, Rajiv Karmakar1, Utpal Kayal1, Gourhari Maiti1
1Department of Chemistry, Jadavpur University, Kolkata , India
Corresponding author, Gourhari Maiti, Department of Chemistry, Jadavpur University,
Kolkata 700 032, India. E-mail address: ghmaiti123@yahoo.co.in
Abstract
A convenient approach for the synthesis of 4, 4'-(arylmethylene)-bis (3-methyl-1-phenyl-
1H-pyrazol-5-ols) by an efficient one-pot reaction of aromatic/aliphatic aldehydes,
phenylhydrazine and ethyl acetoacetate by using sub-stoichiometric amount of K2CO3 in
acetonitrile solvent at room temperature is described. This protocol of one-pot synthesis
produced a library of bis-pyrazolylmethane derivatives, a potential bioactive compound
in very good to excellent yields.
Graphical Abstract
KEYWORDS: Phenyl hydrazine; β-keto ester; Aromatic aldehyde; Bis-
pyrazolylmethane; Multicomponent reaction; K2CO3-catalyst
1

INTRODUCTION
Pyrazoles and their derivatives are an important class of biologically active drug targets
in the pharmaceutical industry, because they are found as the core structures of numerous
biologically active compounds.[1, 2] For example, they exhibit antipyretic, ant-anxiety,
anti-inflammatory and analgesic properties.[3-4] Moreover, 2,4-dihydro-3H-pyrazol-3-one
derivatives including 4, 4′-(arylmethylene) bis(3-methyl-1-phenyl-1H-pyrazol-5-ols)
have a broad spectrum of approved biological activity, being used as gastric secretion
stimulatory,[5] antipyretic,[6] anti-inflammatory,[7] antidepressant,[8] antibacterial,[9] and
anti filarial agents.[10] 4,4′-(arylmethylene) bis(1H-pyrazol-5-ol)s are also useful as
insecticides,[11] pesticides,[12] fungicides,[13] and dyestuffs.[14] Furthermore, pyrazoles are
not only of interest as intermediates in chemical synthesis but also as chelating and
extracting reagents for different metal ions.[15] The studies on bis-pyrazolone-based
complexes reveal that they have strong fluorescence properties[16-18] and some of them
have antitumor activities in vitro and high herbicidal activities. The conventional
chemical approach for the synthesis of 4, 4′-(arylmethylene) bis(3-methyl-1-phenyl-1H-
pyrazol-5-ols) involves successive Knoevenagel synthesis to the corresponding
arylidenepyrazolones followed by base-promoted Michael reaction and also one-pot
tandem Knoevenagel-Michael reaction of arylaldehydes with two equivalents of 5-
methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one performed under a variety of reaction
conditions.[19]
There are quite a good number of catalysts have been used for this transformation. These
include acetic acid or piperidine in ethanolic solution,[20] sodium dodecyl sulfate
2

(SDS),[21] silica-bonded S-sulfonic acid,[22a] 3-aminopropylated silica gel (AP-SiO2),[22b]
silica-sulfuric acid (SSA),[22c] PEG-SO3H,[23] PEG-400 at 110 °C,[24] lithium hydroxide
monohydrate (LiOH.H2O),[25a] SBPPSA catalyst,[25b] ([Sipmim]HSO4),[25c] CAN,[26] and
an electrocatalytic tandem Knoevenagel-Michael reaction,[27] Ce(SO4)2.4H2O,[28]
ammonium acetate[29] etc. Recently, Hasaninejed et al. [30] reported the pseudo five
component methods for the synthesis of title compound under ultrasound irradiation.
Under solvent free conditions pseudo five component reaction in the presence of 2-
hydroxy ethylammonium propionate[31a] as a recyclable catalyst and acidic ionic liquid
[Et3NH][HSO4] [31b] as reusable catalyst was reported by Zhang et al. Very recently,
acetic acid functionalized ionic liquid, pyridinium salt (1-carboxymethyl)pyridinium
chloride [cmpy]Cl)[32] has been reported for the synthesis of bis-pyrazolylmethane
derivatives as homogeneous organic catalyst by Moosavi-Zare and his coworkers.
RESULTS AND DISCUSSION
Carbonates of alkali metals are weak bases and have eco-friendly features such as water
soluble, not contaminated with product and in principle can be recovered by evaporation
of water. Both cesium carbonate and potassium carbonate (K2CO3) are extensively used
in synthetic organic chemistry.[33-34] Potassium carbonate base has been employed in
many common organic reactions such as Micheal addition,[35] reaction of carbonyl
compounds with active methylene compounds[36] and C/N/O-alkylation[37] etc.
We wish to report here an efficient method for the synthesis of 4,4'-(arylmethylene)bis(3-
methyl-1-phenyl-1H-pyrazol-5-ol)s via K2CO3 assisted one-pot pseudo-five-component
3

condensation- reaction. In our initial endeavour, to find an appropriate reaction condition
for K2CO3-promoted synthesis of 4,4′-(arylmethylene)-bis-(3-methyl-1-phenyl-1H-
pyrazol-5-ol), a one-pot-pseudo-five-component reaction between m-nitrobenzaldehyde
(1 mmol), phenylhydrazine (2 mmol), and ethyl acetoacetate (2 mmol) was selected as a
model reaction and was examined under different bases, solvents and reaction conditions.
The results are summarized in Table 1.
From the results of Table 1, it clearly show that potassium carbonate is an effective
catalyst for this pseudo five component reaction, and in the absence of K2CO3 the
condensation reaction gave low yield (<25%) after 24 h at room temperature. Amongst
the solvents tested CHCl3, 1,4-dioxane, DCE and THF, acetonitrile was found to be the
best in terms of yield of the reaction.
With the optimized condition in our hand we have investigated the applicability of this
synthetic methodology for 4, 4′-(arylmethylene) bis(3-methyl-1- phenyl-1H-pyrazol-5-
ols) derivative. Thus a series of reaction of -ketoester (2 mmol), phenyl hydrazine (2
mmol), and a wide range of structurally diverse aromatic aldehydes (1 mmol) were
treated in the presence of K2CO3 at room temperature. Almost in all cases the desired
product was obtained in good to excellent yields. The results are summarized in Table 2.
It was found that aromatic aldehydes with electron withdrawing (Table 2, entries 1-12)
substituent gave the desired product 4,4′-(arylmethylene) bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s in high yield and within short reaction times. However, in case of aromatic
4

aldehydes with moderately strong electron donating groups gave the desired products
with lower yield (Table 2, entries 13-17). Interestingly, the condensation of -ketoester (2
mmol), phenyl hydrazine (2 mmol) with terephthalaldehyde (1 mmol) in the presence of
K2CO3 under acetonitrile solvent, afforded 4,4′-(arylmethylene)-bis (3-methyl-1-phenyl-
1H-pyrazol-5-ol) in 78% yield, as the only isolable product. This observation is in
contrast with that reported by Khazaei et al. But, we did not get di-4,4′-
(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) which have been discussed by
Khazaei, and Niknam group[38,39] (Table 2, entry 19). When the similar protocol was
applied for the condensation of -ketoester, phenyl hydrazine with 4-N,N-
dimethylaminobenzaldehyde (Table 2, entry 20), did not respond to the reaction probably
due to the +R effect of dimethylamino group which decreases the reactivity of the
aldehyde group. To show, the generality and scope of this synthetic method further,
substituted phenyl hydrazines (Table 2, entries 21-22) and ethyl benzoylacetate (Table 2,
entries 23-24) was used to afford the corresponding products in good yield. Aliphatic
aldehydes (Table 3, entries 1-4) also reacted with phenyl hydrazine and -ketoester under
similar condition to afford the title compounds in good to moderate yield.
EXPERIMENTAL
General Procedure For The Synthesis Of 4,4-(Arylmethylene)-Bis(3-Methyl-1-
Phenyl-1H-Pyrazol-5-Ol) (4).
A magnetically stirred mixture of β-ketoester (2 mmol) and phenyl hydrazine (2 mmol) in
acetonitrile (2 ml) was assisted by K2CO3 (50 mol %) at room temperature for 10 to 15
min., and then aldehyde (1 mmol) was added to the reaction mixture and continued for
5

the required time (Table 2). Progress of the reaction was monitored by TLC. After the
completion of the reaction, the residue was filtered. The solvent was removed under
reduced pressure and the crude residue was purified by column chromatography over
silica gel (100-200 mesh), eluting with 25 % to 30 % ethyl acetate in petroleum ether to
afford compound 4/6. The structures of all products were confirmed from physical and
spectroscopic data such as melting points, IR, 1H NMR, 13C NMR spectra and mass
spectra.
SPECTRAL DATA OF PRODUCTS
4,4'-((2-Fluorophenyl)Methylene)Bis(3-Methyl-1-Phenyl-1H-Pyrazol-5-Ol) (4h):
A mixture of ethyl acetoacetate (260 mg, 2.0 mmol), phenyl hydrazine (216 mg 2.0
mmol) and K2CO3 (69 mg, 0.5 mmol) in acetonitrile (2 ml) was stirred at room
temperature for 15 min., then 2-fluorobenzaldehyde (124 mg, 1.0 mmol) was added to
the reaction mixture and stirring was continued for stipulated time. Following the general
procedure as mentioned above, 4h (375 mg, 83 %) was isolated as light brown solid after
column chromatography by using 25% ethyl acetate in petroleum ether. Melting point:
170-171 C; IR (KBr): 3446, 3056, 2922, 1595, 1491, 1412, 1293, 1221, 1158, 744, 680
1
cm-1; H NMR (300 MHz, DMSO-d6): δ 2.30 (s, 6H), 5.14 (s, 1H), 7.09-7.17 (m, 2H),
7.24-7.28 (m, 3H), 7.42-7.47 (m, 4H), 7.63-7.73 (m, 5H), 14.33 (s,1H); 13C NMR (75
MHz, DMSO-d6): δ 12.0, 27.9, 104.0, 115.5, 115.8, 121.2, 124.5, 124.5, 126.1, 128.6,
128.7, 129.0, 129.4, 129.8, 129.9, 130.0, 137.7, 146.4, 158.1, 158.6, 161.8; HRMS (ES+):
calcd for [C27H23FN4O2] Na+: 477.1697; found: 477.1701.
6

CONCLUSION
In conclusion, we have demonstrated that one-pot pseudo five component reaction
between phenylhydrazine, -keto esters and aromatic/aliphatic aldehyde to gave a library
of 4,4'-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ols) in very good to
excellent yields using anhydrous K2CO3 is an efficient and an inexpensive, mild, green
and basic common laboratory chemicals. We believe that these protocols will be a good
addition to the most recent environmentally benign methods for the synthesis of this class
of compounds.
ACKNOWLEDGEMENTS
The authors are thankful to the Department of Chemistry, Jadavpur University for
financial and infrastructural support from CAS and PURSE-DST programme. DB, RK
and UK thank CSIR, New Delhi for award of fellowship.
SUPPLEMENTARY DATA
Full experimental detail, 1H and 13C NMR spectra etc, this material can be found via the
“Supplementary Content” section of this article’s webpage.’
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11

Table 1. Effect of catalysts and temperature on the Synthesis of 4, 4'-((3-
nitrophenyl)methylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)a.
Entry
Catalysts
Mol% of catalyst
T(°C)
Time
Yield(%)c
1
2
3
4
5
6
7
8
K CO
25.0
40.0
50.0
50.0
55.0
60.0
70.0
-
50.0
50.0
50.0
50.0
rt
rt
rt
70
rt
rt
rt
rt
rt
rt
rt
rt
4 h
2 h
1 h
1 h
1 h
1 h
1 h
24 h
1 h
1 h
1 h
1 h
64
72
90
57
87
83
75
<25
49
31
52
46
2
3
3
3
3
3
3
3
K CO
2
K CO
2
K CO
2
K CO
2
K CO
2
K CO
2
-
9
CS2C03
Ag2C03
Et3N
10
11
12
13
14
15
DIPAb
K+tBuO'
Pyrollidine
N32003
50.0
50.0
50.0
rt
rt
rt
1 h
1 h
1 h
35
51
65
aReaction condition: 3-nitrobenzaldehyde (1.0 mmol), phenylhydrazine (2.0 mmol),
ethylacetoacetate (2.0 mmol), catalyst, in 2 mL acetonitrile.
b diisopropylamine,
cPure, isolated yield after column chromatography.
12

Table 2. One-pot synthesis of 4,4'-(arylmethylene) bis(3-methyl-1-phenyl-1H-pyrazol-5-
a
ols) derivatives using K2CO3.
Entr
1
R
R1
H
R2
Time(h)
1
Products
4a
Yield(
90
3-Nitro
Me
2
3
4
5
6
7
8
4-Nitro
2-Nitro
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
1
1
1.5
1.5
1.5
2
4b
4c
4d
4e
4f
93
89
87
88
91
89
83
4-Chloro
4-Bromo
4-Fluoro
3-Bromo
2-Fluoro
4g
4h
1.5
9
2-Chloro
4-Bromo-2-
2,6- Dichloro
4-CN
H
H
H
H
H
H
H
H
H
H
H
H
4-
4-
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1.5
2
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
82
86
71
84
76
74
68
73
70
88
78
-
10
11
12
13
14
15
16
17
18
19
20c
21
22
4
1
2
2
2
2.5
2
1
1.5
24
2
4-Methyl
4-Methoxy
2-Methoxy
3,4-Dimethoxy
3,4,5-
H
4-CHO
4-N,N-
H
3-Nitro
83
77
3
4v
23
24
4-Chloro
4-CN
H
H
Ph
Ph
4
4.5
4w
4x
56
58
aReaction condition: Aromatic aldehyde (1.0 mmol), phenylhydrazine (2.0 mmol), β-keto
ester (2.0 mmol), potassium carbonate (50 mol%), in 2 mL solvent.
bPure, isolated yield after column chromatography.
cNo product was isolated only starting materials.
13

Table 3. One-pot synthesis of bis-pyrazolylmethane derivatives using aliphatic
aldehydes.a
Entr Aldehyde (5)
R2
cyclohexanecarbaldehyd Me
Time(h)
Products
Yield(
1
2.5
6a
79
2
3
4
octanal
isobutyraldehyde
isobutyraldehyde
Me
Me
Ph
4
3
4
6b
6c
6d
85
88
69
aReaction condition: Aliphatic aldehyde (1.0 mmol), phenylhydrazine (2.0 mmol),
ethylacetoacetate or ethyl benzoylacetate (2.0
in 2 mL acetonitrile.
mmol), potassium carbonate (50 mol%),
b Pure, isolated yield after column chromatography.
14

Scheme 1. K2CO3-assisted one-pot pseudo-five-component synthesis of 4,4'-
(arylmethylene) -bis (3-methyl-1- phenyl-1H-pyrazol-5-ol).
15