Ultrasound assisted synthesis of 1,5-disubstituted pyrazole using Cu(I) catalyst

Article abstract of DOI:10.14233/ajchem.2020.22432

A new efficient and convenient approach towards the synthesis of pyrazole is described. The α,β-unsaturated cyanoesters were obtained from substituted benzaldehyde and ethyl cyanoacetate by reported methods. 1,5-Disubstituted pyrazoles were synthesized fr

Full text of DOI:10.14233/ajchem.2020.22432

Asian Journal of Chemistry; Vol. 32, No. 3 (2020), 575-579
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22432
Ultrasound Assisted Synthesis of 1,5-Disubstituted Pyrazole using Cu(I) Catalyst
1
2
ASHOK S. PISE , ARVIND S. BURUNGALE2,* and SANTOSH S. DEVKATE
1Department of Chemistry, Dada Patil Mahavidyalaya, Karjat-414402, India
2Department of Chemistry, S.M. Joshi College, Hadapsar, Pune-411028, India
*Corresponding author: E-mail: ashokpise67@gmail.com
Received: 6 September 2019;
Accepted: 26 October 2019;
Published online: 31 January 2020;
AJC-19761
A new efficient and convenient approach towards the synthesis of pyrazole is described. The α,β-unsaturated cyanoesters were obtained
from substituted benzaldehyde and ethyl cyanoacetate by reported methods. 1,5-Disubstituted pyrazoles were synthesized from α,β-
unsaturated cyanoester and phenyl hydrazine using sodium ethoxide as a base in the presence of 10 mol % Cu(I) catalyst in high yields
within 75-90 min under ultrasound irradiation at 60 ºC. The reaction rate is enhanced tremendously under ultrasound irradiation as
compare to conventional methods with improved yields are recorded.
Keywords: Cyanoester, Cu(I) catalyst, Phenyl hydrazine, Pyrazole, Ultrasound irradiation.
iron oxide-supported copper oxide nanoparticles [23], 3-aryl-
1-phenyl-1H-pyrazole-4-carbaldehydes [24], chalcones and
hydrazine in EtOH [25], in glacial acetic acid [26], p-sulfamyl
phenyl hydrazine in EtOH [27], N-alkylated tosylhydrazones
and terminal alkynes in t-BuOK[28], rhodium-catalyzed addition
cyclization [29], in MeOH [30], 1,3-diols via hydrogen transfer
catalysis [31], amberlyst A21 in EtOH [32] and starch solution
[33]. A hypervalent iodine catalyzed synthesis of 3-trifluoro
methyl pyrazole has been developed via trifluoroethylation/
cyclization of α,β-alkynic hydrazones [34] under conventional
method. But these methods also suffer some drawbacks such as
long reaction time, low yield and expensive reagents. Microwave
assisted pyrazoles were also reported using formic acid [35],
sodium acetate in EtOH [36] and POCl3 in DMF [37].
Thus development of facile and efficient, mild, faster and
greener methods is to be required. Therefore, it is essential to
produce effective and environmental procedure for synthesis
of novel pyrazole derivatives using sodium ethoxide in the
presence of nitratobis(triphenyl phosphine)copper(I) as catalyst
and EtOH as a solvent.
INTRODUCTION
Now-a-days, ultrasonic irradiation technique is widely
used in organic synthesis. Ultrasonic irradiation technique reduces
the time of reaction. Ultrasonic technique is widely used for
simple experimental procedure, increased yield and selectivity
of the products. The pyrazole ring emerged as a powerful scaff-
old used extensively in the design of compounds targeted to
block the cell cycle progression in cancer cells. Pyrazole is a
five membered heterocyclic compounds having two adjacent
nitrogen atoms and exists in natural product [1] and synthetic
biologically active compounds [2], such as cyclooxygenase-2
[3], protein kinase [4], and HIV-I reverse transcriptase [5]
inhibitors, as well as antibacterial and antifungal compounds
[6].Various substituted pyrazole derivatives act as an antitumor
[7], antitubercular, antiviral, antiparasitic, antifungal, antibac-
terial and insecticidal agents [8-16]. Some pyrazole derivatives
show antidiabetic, anti-inflammatory, analgesic and anesthetic
properties [17-20]. An I2-catalyzed metal free procedure has
been developed for synthesis of various substituted pyrazole
from conjugated aldehydes or ketones and hydrazine in the
presence of EtOH [21]. In ambient temperature, different pyrazole
derivatives were prepared using Lewis acid catalyst [22]. In
the literature survey, pyrazole derivatives were prepared using
EXPERIMENTAL
The melting points of the compounds were determined in
open capillaries and are uncorrected. Purity of the compounds
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576 Pise et al.
Asian J. Chem.
was checked by TLC aluminum sheets precoated with silica
gel. IR spectra were determined on a Shimadzu Miracle 10
ATR instrument. NMR spectra were recorded on a Bruker 500
MHz spectrometer with CDCl3 as the solvent and TMS as the
internal standard. 13C NMR spectra were recorded on Bruker
125 MHz spectrometer with CDCl3 as the solvent. Column
chromatography was conducted on silica gel (70-230 mesh)
by using pet-ether:ethyl acetate as 7:3. Ultrasound irradiation
was performed in an ultrasonic cleaner with frequency of 33
KHz and a output power of 250 W. Elemental analysis was
performed on a CHN elemental analyzer. The reaction flasks
were located in the maximum energy area of the cleaner.
Synthesis of nitratobis(triphenyl phosphine)copper(I):
A 0.04 mol triphenylphosphine (10.5 g) and Cu(NO3)2·2H2O
(0.01 mol, 2.45 g) was added to 100 mL hot methanol. Immed-
iately, Cu(II) dissolves and white suspension formed. This
suspension was refluxed for 10 min and cooled to ambient
temperature. After filtration, washed with ether, ethanol and
dried. Recrystallization from methanol gave colourless solid.
MHz, CDCl3) δ 6.94 (d, J = 7 Hz, 1H), 7.14 (d, J = 8.5 Hz,
2H), 7.29 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 8.22
(d, J = 8.5 Hz, 2H), 7.31 (m, 1H) 7.77 (d, J = 8.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ ppm: 144.6, 137.3, 135.3, 130.2,
129.3, 128.6, 126.4, 120.1, 119.8, 113.0, 112.5. Anal. calcd.
(%) for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84. Found (%):
C, 67.95; H, 4.16; N, 15.81.
1,5-Diphenyl-1H-pyrazole (3c): Brown solid, TLC Rf =
0.71 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1): 1591, 1494,
1442, 1257, 1134, 1066, 927, 748, 634; 1H NMR (500 MHz,
CDCl3) δ ppm: 6.86 (d, J = 7 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H),
7.26 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.45 (m,
1H), 7.59 (m, 1H) 7.63 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 7 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ ppm: 144.6, 137.3, 135.3,
133.7, 129.5, 128.6, 126.4, 120.1, 119.8, 113.0, 112.7. Anal.
calcd. (%) for C15H12N2: C, 81.79; H, 5.49; N, 12.72. Found
(%): C, 81.81; H, 5.50; N, 12.69.
5-(3-Nitrophenyl)-1-phenyl-1H-pyrazole (3d): Brick
red solid, TLC Rf = 0.63 (PE:EtOAc = 10:2); IR (KBr, νmax
,
m.p.: 232 ºC, soluble in common organic solvents. IR (νmax
,
cm–1): 1595, 1568, 1512, 1489, 1320, 1265, 1143, 1107, 848,
750, 644; 1H NMR (500 MHz, CDCl3) δ ppm: 6.91 (d, J = 7
Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H),
7.50 (m, 1H), 7.53 (m, 1H), 8.09 (d, 8.5 Hz, 1H) 8.10 (d, J =
8.5 Hz, 1H), 8.11 (s, 1H) 8.11 (d, J = 7 Hz, 1H), 13C NMR (125
MHz, CDCl3) δ ppm: 148.7, 143.8, 137.3, 133.8, 131.4, 130.1,
129.5, 129.4, 129.0, 128.5, 122.5, 120.9, 112.9. Anal. calcd.
(%) for C15H11N3O2: C, 67.92; H, 4.18; N, 15.84. Found (%):
C, 67.91; H, 4.17; N, 15.86.
cm-1): 3047, 2924, 1538, 1479, 1464, 1384, 1295, 1096, 810,
741, 693.
Synthesis of 1,5-disubstituted pyrazole: The α,β-cyano-
esters were prepared from ethyl cyanoacetate and aromatic
aldehydes by reported method [38]. Pyrazole derivatives were
prepared by dissolving α,β-cyanoesters (5 mmol) and phenyl
hydrazone (5 mmol) in alcoholic sodium ethoxide (0.5 g EtONa
in 20 mL ethanol) in a 100 mL conical flask. Then Cu(PPh3)2·
NO3 catalyst (10 mol % i.e. 31 mg) was added in the reaction
mixture. The mixture was irradiated in the water bath of an
ultrasonic cleaner at 60 ºC for the period. After completion of
the reaction, the mixture was poured in ice water and filtered.
The crude product was purified using column chromatography
(silica gel 70 % peteroleum ether/30 % EtOAc) to afford pure
compound (Scheme-I). Details of the synthesis of substituted
pyrazoles under ultrasonic irradiation are summarized in Table-1.
1-Phenyl-5-(p-tolyl)-1H-pyrazole (3e): Orange solid,
TLC Rf = 0.66 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1): 1595,
1494, 1442, 1255, 1132, 1070, 1049, 815, 669; 1H NMR (500
MHz, CDCl3) δ ppm: 2.43 (s, 3H), 6.85 (d, J = 7 Hz, 1H),
6.86 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.26 (m,
1H), 7.55 (d, J = 8.5 Hz, 2H), 7.53 (d J = 8.5 Hz, 2H) 7.99 (d,
J = 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm: 144.8,
138.4, 137.5, 132.5, 130.2, 129.9, 127.3, 126.1, 125.6, 113.8,
112.7, 21.7. Anal. calcd. (%) for C16H14N2: C, 82.02; H, 6.02;
N, 11.96. Found (%): C, 82.04; H, 6.03; N, 11.93.
5-(4-Chlorophenyl)-1-phenyl-1H-pyrazole (3f): Brown
solid, TLC Rf = 0.76 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1598, 1519, 1487, 1442, 1257, 1134, 1082, 914, 819, 747,
693; 1H NMR (500 MHz, CDCl3) δ ppm: 6.88 (d, J = 7 Hz,
1H), 7.10 (d, J = 8.5 Hz, 2H), 7.27 (m, 1H), 7.29 (d, J = 8.5
Hz, 2H), 7.33 (d J = 8.5 Hz, 2H) 7.58 (d, J = 8.5 Hz, 2H) 7.61
(d, J = 7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm: 144.8,
138.4, 137.5, 132.5, 130.2, 129.9, 127.3, 126.1, 125.6, 113.8,
112.7, 21.7.Anal. calcd. (%) for C15H11N2Cl: C, 70.73; H, 4.35;
N, 11.00. Found (%): C, 70.70; H, 4.37; N, 10.98.
N
CN
EtONa/EtOH
N
R
+
Ph NH NH2
COOEt
60 °C, Cu(I)
2
1
R
3a-i
Scheme-I: Synthesis of 1,5-disubstituted pyrazole
Spectral data of compounds 3a-i
5-(4-Methoxyphenyl)-1-phenyl-1H-pyrazole (3a): Brown
solid, TLC Rf = 0.77 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1595, 1496, 1242, 1126, 941, 819, 650; 1H NMR (500 MHz,
CDCl3) δ ppm: 3.88 (s, 3H), 6.86 (d, J = 7 Hz, 1H), 6.91 (d,
J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz,
2H), 7.25 (d, J = 8.5 Hz, 2H), 7.36 (m, 1H) 7.60 (d, J = 8.5
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm: 160.0, 146.0,
144.9, 142.2, 137.4, 129.2, 128.1, 127.5, 119.8, 114.3, 112.6,
55.3. Anal. calcd. (%) for C16H14N2O: C, 76.78; H, 5.64; N,
11.19. Found (%): C, 76.80; H, 5.62; N, 11.18.
5-(2-Chlorophenyl)-1-phenyl-1H-pyrazole (3g): Brown
solid, TLC Rf = 0.79 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1600, 1494, 1471, 1438, 1255, 1138, 1049, 1029, 692; 1H NMR
(500 MHz, CDCl3) δ ppm: 6.88 (d, J = 7 Hz, 1H), 7.11 (d, J =
8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.23 (m, 1H), 7.25 (m,
1H), 7.29 (d, J = 8.5 Hz, 1H), 7.32 (d J = 8.5 Hz, 2H) 8.06 (d,
13
J = 7 Hz, 1H); C NMR (125 MHz, CDCl3) δ ppm: 144.3,
135.2, 132.7, 131.0, 130.4, 129.2, 128.0, 127.2, 126.6, 125.8,
118.4, 113.1, 112.8.Anal. calcd. (%) for C15H11N2Cl: C, 70.73;
H, 4.35; N, 11.00. Found (%): C, 70.71; H, 4.34; N, 11.02.
5-(4-Nitrophenyl)-1-phenyl-1H-pyrazole (3b): Brown
solid, TLC Rf = 0.71 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1585, 1494, 1340, 1261, 1143, 1068, 748, 667; 1H NMR (500

Vol. 32, No. 3 (2020)
Compound
Ultrasound Assisted Synthesis of 1,5-Disubstituted Pyrazole using Cu(I) Catalyst 577
TABLE-1
PREPARATION OF SUBSTITUTED PYRAZOLES UNDER ULTRASOUND IRRADIATION
Substrate
Product
Time (min)
m.p. (°C)
Yield (%)
97
H3CO
H3CO
CN
COO Et
90
116-117
3a
3b
N
N
N
Ph
O2N
O2N
CN
CO OEt
75
144-146
96
N
Ph
CN
85
75
90
158-160
118-119
96-98
95
97
92
3c
3d
3e
COOEt
N
N
Ph
CN
O2N
H3C
COOEt
O2N
H3C
N
N
Ph
Ph
CN
COOEt
N
N
Cl
Cl
CN
COOEt
75
130-131
93
3f
N
N
Ph
CN
COOEt
90
80
75
80-82
92
94
95
3g
3h
3i
Cl
Ph
N
Cl
N
CN
COOEt
126-127
146-147
Cl
Br
Cl
N
N
N
Ph
Ph
CN
COOEt
Br
N
5-(3-Chlorophenyl)-1-phenyl-1H-pyrazole (3h): Brown
solid, TLC Rf = 0.79 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1578, 1514, 1477, 1253, 1141, 1074, 921, 885, 792, 632; 1H
NMR (500 MHz, CDCl3) δ ppm: 6.89 (d, J = 7 Hz, 1H), 6.90
(d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5
Hz, 1H), 7.27 (m, 1H), 7.30 (m, 1H), 7.48 (d, J = 8.5 Hz, 2H)
7.59 (d, J = 7 Hz, 1H), 7.66 (s, 1H); C NMR (125 MHz,
CDCl3) δ ppm: 144.2, 137.2, 135.3, 134.6, 129.8, 129.3, 129.1,
128.2, 125.7, 124.3, 120.5, 112.8. Anal. calcd. (%) for
C15H11N2Cl: C, 70.73; H, 4.35; N, 11.00. Found (%): C, 70.74;
H, 4.33; N, 11.02.
5-(3-Bromophenyl)-1-phenyl-1H-pyrazole (3i): Orange
solid, TLC Rf = 0.81 (PE:EtOAc = 10:2); IR (KBr, νmax, cm–1):
1593, 1577, 1514, 1473, 1446, 1253, 1141, 1074, 923, 885,
788, 748; 1H NMR (500 MHz, CDCl3) δ ppm: 7.10 (d, J = 7
Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.26
(d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.40 (m, 1H), 7.52
(m, J = 8.5 Hz, 1H) 7.56 (d, J = 7 Hz, 1H), 7.81 (s, 1H); 13C
13

578 Pise et al.
Asian J. Chem.
NMR (125 MHz, CDCl3) δ ppm: 144.2, 137.4, 135.2, 131.1,
131.0, 130.1, 129.5, 128.7, 124.8, 122.8, 120.5, 118.6, 112.8.
Anal. calcd. (%) for C15H11N2Br: C, 60.22; H, 3.71; N, 9.36.
Found (%): C, 60.25; H, 3.70; N, 9.34.
Cu(PPh3)2NO3 as a catalyst under ultrasound irradiation. The
short reaction time, easy workup and high yields made this
protocol efficient by using Cu(PPh3)2NO3 catalyst.
ACKNOWLEDGEMENTS
RESULTS AND DISCUSSION
The authors thank Central Instrumentation Facility, S.P.
Pune University, Pune and DST-FIST sponsored Central
Instrumentation Laboratory, Dada Patil Mahavidyalaya Karjat,
India for the spectral analysis.
The effect of reaction conditions on the formation of 1,5-di-
substituted pyrazole under ultrasound irradiation is summarized
inTable-2. The reaction was initiated by the nucleophilic addition
of phenyl hydrazine to α,β-unsaturated cyanoester resulting
in different intermediates to form pyrazole 3. Inspired by this
result, a variety of reaction conditions in order to optimize the
catalytic process was explored. When water was used as the
solvent, product 3b was not detected (Table-2, entry 1).
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
TABLE-2
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Temp.
(°)
Yield
(%)
Entry
Catalyst
Base
Solvent
1
2
3
4
5
6
7
8
9
Catalyst free
Cu(PPh3)2NO3
EtONa
LiOH
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EtOH
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RT
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30
55
64
62
65
96
22
96
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featuring electron-donating or withdrawing substituents in an
aromatic ring gave the corresponding pyrazole derivatives
in good to high yields, However, a lower yield was observed
with bases such as LiOH and K2CO3 (Table-2, entry 2,3). Next,
a variety of different solvents were also evaluated, however,
use of DMF, DMSO and CH3CN resulted in poor yields of
compound 3b (Table-2, entries 4-7). A controlled experiment
confirmed that Cu(PPh3)2·NO3 catalyst was essential for the
formation of pyrazoles. Notably, a reaction proceeded smoothly
produced compound 3b in 96% yield (Table-2, entry 8). To study
the effect of temperature, we have performed the reaction at
room temperature but reaction proceeded in low yield (Table-
2, entry 9). To increase the reaction temperature upto 60 ºC,
reaction was proceeded in excellent yield and above 60 ºC there
was no effect on reaction time and yield (Table-2, entry-10). Polar
aprotic solvents such as DMF, DMSO, DCM and CH3CN forms
complex with Cu(I) catalyst, so reaction rate went to be decrease.
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easily to heteroatoms and to π-bond and C-N cross coupling
reactions were obtained. It is cleared that an oxidative addition
and reductive elimination of Cu(I) can occurred, so it is possible
that Cu(I) undergoes steps similar to Pd(0) in cross coupling
reactions [39].
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Conclusion
In the present investigation, a series of novel substituted
pyrazole ring derivatives have been synthesized by using
https://doi.org/10.1021/ja01515a060

Vol. 32, No. 3 (2020)
Ultrasound Assisted Synthesis of 1,5-Disubstituted Pyrazole using Cu(I) Catalyst 579
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