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Ultrasonics Sonochemistry 15 (2008) 828–832

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Convenient ultrasound mediated synthesis of substituted

pyrazolones under solvent-free conditions
Mohammad M. Mojtahedi *, Mashal Javadpour, M. Saeed Abaee *

Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran

Received 5 November 2007; received in revised form 17 February 2008; accepted 20 February 2008
Available online 29 February 2008

Abstract

Smooth condensation of hydrazine derivatives with various ß-keto esters was performed under solvent-free conditions by using ultra-
sound irradiation to facilitate the formation of pyrazolone derivatives in good to excellent amounts within very short time periods.
Ó 2008 Elsevier B.V. All rights reserved.

Keywords: Pyrazolone; Hydrazine; Ultrasound irradiation; Solvent-free reaction

1. Introduction some illustrative examples, ring opening of epoxides [11],

Pyrazolone derivatives are of particular importance in
pharmaceutical chemistry [1] due to their numerous appli-
cations as analgesic, antipyretic, antiarthritic, uricosuric,
antiinflammatory, and antiphlogistic properties. Particu-
larly, the 3-methyl-1-phenyl-2-pyrazolin-5-one derivative
(edaravone) [2] acts as a radical scavenger to interrupt
the preoxidative chain reactions and membrane disintegra-
tions associated with ischemia [3]. In addition, these com-
pounds are appropriate precursors for industrial
preparation of herbicides [4], liquid crystals [5], dyes [6],
thermally stable polymers [7], and color photographical
compounds [8]. On the other hand, chemical oxidation of
pyrazolones to azo dienophiles provides suitable substrates
for hetero Diels–Alder cycloadditions [9].
In recent years, synthetic applications of ultrasonic irra-
diation in various types of organic transformations are
demonstrated widely in chemical literature [10]. Conse-
quently, many protocols have been developed to carry out
chemical processes in shorter reaction times and under
milder and more environmentally friendly conditions. As
*
Corresponding authors. Tel.: +98 21 44580720; fax: +98 21 44580762.
E-mail addresses: mojtahedi@ccerci.ac.ir (M.M. Mojtahedi), abaee@
ccerci.ac.ir (M.S. Abaee).
reduction of carbonyl compounds [12], Suzuki cross-cou-
pling reaction [13], acetylation of alcohols [14], aldol reac-
tion [15], oximes synthesis [16], reductive coupling of
amines [17], and alcohols protection [18] can be pointed out.
Pyrazolones are traditionally synthesized by treatment
of b-keto esters with hydrazine substrates under acidic con-
ditions at elevated temperature [19]. A number of alterna-
tive methods have been documented in the literature for
the synthesis of these compounds [20]. Recent develop-
ments include solid-phase synthesis [21], a two-step reac-
tion of benzoyl hydrazones with silyl enolates in the
presence of catalytic amounts of Sc(OTf)3 [22], and micro-
wave irradiation techniques [23]. In the framework of our
investigations on the development of green chemical proce-
dures [24], we would like to herein report a novel and envi-
ronmentally safe procedure for rapid preparation of
various pyrazolone derivatives using ultrasound irradiation
(Scheme 1).
2. Method
2.1. Apparatus and analysis
Reactions were monitored by TLC and GC. FT-IR
spectra were recorded using KBr disks on a Bruker

1350-4177/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2008.02.010
 M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832
O O O 43.5, 119.3, 125.5, 129.3, 138.5, 156.7, 171.0; MS m/z (%)
PhNHNH2
R
R O )))) N N
Ph
1a-h 2a-k
Scheme 1.
Vector-22 infrared spectrometer and absorptions were
reported as wave numbers (cm 1). NMR spectra were
obtained on a FT-NMR Bruker Ultra ShieldTM
(500 MHz) or Bruker AC 80 MHz instrument as CDCl3,
DMSO-d6, or CDCl3-DMSO-d6 solutions and the chemical
shifts were expressed as d units with Me4Si as the internal
standard. Mass spectra were obtained on a Finnigan Mat
8430 apparatus at ionization potential of 70 eV. Com-
pound 1c was prepared using available methods [25]. All
other chemicals and reagents were purchased from com-
mercial sources and were used without further purification.
Sonication was performed using a Sartorius Ultrasonic-
homogenizer LABSONICÒP 230 V/50 Hz instrument with
a frequency of 24 KHz and nominal power of 460 W/cm2.
The intensity level of irradiation was adjusted at 90% and
40% levels for the synthesis of 2a–h and 2i–k, respectively.
In all reactions the tip of the sonotrode was located in the
same position just under the liquid surface in order to
obtain optimal sonication and reproducible results.
2.2. General procedure
A mixture containing phenyl hydrazine or hydrazine
(5 mmol) and 1 (5 mmol) was sonicated in a 10 mL test
tube for appropriate length of time (as indicated in Table
1) until TLC showed complete disappearance of the start-
ing materials. In temperature controlled experiments, reac-
tions were performed in a water bath at 25 ± 1 °C. The
reaction mixture was poured into ice–water mixture and
the precipitates were collected by filtration. The pure prod-
uct was obtained by recrystallization of the precipitates
using ethanol and water. Products were identified based
on their melting point, 1H NMR, 13C NMR, and IR data.
Known structures were verified by comparison of their
data with those reported in the literature [26].
2.2.1. 1-Phenyl-3-propyl-1H-pyrazol-5(4H)-one (2a)
M.p. 110 °C; 1H NMR (CDCl3) d 1.06 (t, J = 7.4 Hz,
3H), 1.68–1.76 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 3.44 (s,
2H), 7.21 (t, J = 7.4 Hz, 1H), 7.43 (dd, J = 7.4, 7.7 Hz,
2H), 7.91 (d, J = 7.7 Hz, 2H); 13C NMR (CDCl3) d 14.2,
20.4, 33.5, 42.2, 119.3, 125.4, 129.2, 138.6, 160.3, 171.0;
MS m/z (%) 202 (M+, 100), 173 (59), 105 (32), 91 (99),
77 (97); IR (KBr, cm 1) 2928, 1595, 1540.
2.2.2. 3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one (2b)
M.p. 127 °C; 1H NMR (CDCl3) d 2.24 (s, 3H), 3.47 (s,
2H), 7.22 (t, J = 7.3 Hz, 1H), 7.44 (dd, J = 7.3, 8 Hz,
2H), 7.91 (d, J = 8 Hz, 2H); 13C NMR (CDCl3) d 17.4,
829
174 (M+, 100), 105 (55), 91 (94), 77 (92); IR (KBr, cm 1)
2420, 1594, 1530.
2.2.3. 3-(Furan-3-yl)-1-phenyl-1H-pyrazol-5(4H)-one (2c)
M.p. 182 °C; 1H NMR (DMSO-d6) d 5.92 (s, 2H), 6.80–
8.00 (m, 8H), 11.90 (br s, 1H); MS m/z (%) 226 (M+, 52), 93
(100), 77 (68); IR (KBr, cm 1) 2900, 1595, 1557.
2.2.4. 4-Ethyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(2d)
M.p. 108 °C; 1H NMR (CDCl3) d 0.85 (t, J= 7.5 Hz, 3H),
1.88–2.06 (m, 2H), 2.19 (s, 3H), 7.23 (t, J = 7.4 Hz, 1H), 7.43
(dd, J = 7.4, 7.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 2H); 13C NMR
(CDCl3) d 7.3, 13.4, 29.7, 81.3, 119.3, 125.8, 129.2, 137.9,
162.4, 174.3; MS m/z (%) 202 (M+, 63), 174 (23), 91 (42),
77 (100); IR (KBr, cm 1) 2965, 1687, 1496.
2.2.5. 1,3-Diphenyl-1H-pyrazol-5(4H)-one (2e)
M.p. 88 °C; 1H NMR (CDCl3) d 3.90 (s, 2H), 7.27 (t,
J = 7.4 Hz, 1H), 7.45–7.52 (m, 5H), 7.81–7.84 (m, 2H),
8.02 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3) d 40.0,
119.5, 125.7, 126.5, 129.3, 129.4, 131.1, 131.3, 138.6,
155.1, 170.7; MS m/z (%) 236 (M+, 91), 194 (42), 103
(80), 91 (79), 77 (100); IR (KBr, cm 1) 2965, 1705, 1593.
2.2.6. 3-Isopropyl-1-phenyl-1H-pyrazol-5(4H)-one (2f)
M.p. 78 °C; 1H NMR (CDCl3) d 1.28 (d, J = 7 Hz, 6H),
2.79 (m, 1H), 3.45 (s, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.41
(dd, J = 7.4, 8 Hz, 2H), 7.92 (d, J = 8 Hz, 2H); 13C
NMR (CDCl3) d 20.5, 31.2, 40.3, 119.3, 125.4, 129.2,
138.7, 164.7, 171.1; MS m/z (%) 202 (M+, 100), 187 (42),
91 (28), 40 (97).
2.2.7. 1-Phenyl-3-(trifluoromethyl)-1H-pyrazol-5(4H)-one
(2g)
M.p. 170 °C; 1H NMR (CDCl3-DMSO-d6) d 5.62 (s,
1H), 7.11 (t, J = 7.5 Hz, 1H), 7.24 (dd, J = 7.5, 8 Hz,
2H), 7.54 (d, J = 8 Hz, 2H); 13C NMR (CDCl3-DMSO-
d6) d; MS m/z (%) 228 (M+, 18), 105 (20), 95 (33), 77
(100); IR (KBr, cm 1) 2720, 1758, 1599.
2.2.8. 2-Phenyl-4,5,6,7-tetrahydro-2H-indazol-3(3aH)-one
(2h)
M.p. 160 °C; 1H NMR (CDCl3) d 1.46–1.57 (m, 2H),
1.74–1.82 (m, 1H), 1.98–2.01 (m, 1H), 2.17–2.21 (m, 1H),
2.39 (ddd, J = 5.7, 12.9, 13, 1H), 2.55–2.59 (m, 1H), 2.82
(dd, J = 3, 15, 1H), 3.18 (dd, J = 7.4, 11.9, 1H), 7.19–7.22
(m, 1H), 7.41–7.45 (m, 2H), 7.92–7.95 (m, 2H); 13C NMR
(CDCl3) d 24.7, 27.9, 29.1, 29.8, 50.0, 119.2, 125.3, 129.2,
138.7, 163.8, 173.8; MS m/z (%) 214 (M+, 100), 185 (12),
109 (24), 77 (25), 40 (25); IR (KBr, cm 1) 2935, 1705, 1635.
2.2.9. 3-(Furan-3-yl)-1H-pyrazol-5(4H)-one (2i)
M.p. 212 °C; 1H NMR (DMSO-d6) d 5.73 (s, 1H), 6.64–
7.75 (m, 3H), 11.20 (br s, 2H); MS m/z (%) 150 (M+, 100),
121 (31), 93 (45); IR (KBr, cm 1) 2598, 1608, 954.
830 M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832

Table 1
Ultrasound promoted synthesis of pyrazolone derivatives
Entry Substrate Hydrazine Product Time (min) Yield (%)a
O O 20
1 C6H5NHNH2 91
O 1a N 2a
O N
Ph

O O
2 C6H5NHNH2 N 2
2b 15 84
O O N
1b
Ph

O O O

3 O C6H5NHNH2 2c
2 95
1c N
O N
O
Ph
Et
O O

4 O C6H5NHNH2 N 2d 20 85
1d O N
Et
Ph

Ph
O O
5 C6H5NHNH2 N 2e 2 95
O 1e Ph O N
Ph

O O
6 C6H5NHNH2 2f 5 94
O 1f N
O N
Ph
CF3
O O
7 C6H5NHNH2 2g 25 95
N
O 1g CF3 O N
Ph

Ph
O O
N N
8 O 1h C6H5NHNH2 2h 15 94
O

O O O
9 O NH2NH2 2b 92
1c N 2i
O O N
H

O O Et

10 O NH2NH2 N 2j 2b 94
1d
O N
Et H

O O
11 NH2NH2 N 2k 2b 90
O 1a O N
H
a
Isolated yields.
b
Lower power.

2.2.10. 4-Ethyl-3-methyl-1H-pyrazol-5(4H)-one (2j) 2.2.11. 3-Propyl-1H-pyrazol-5(4H)-one (2K)

M.p. 222 °C; 1H NMR (DMSO-d6) d 1.12 (t, J = 7 Hz, M.p. 207 °C; 1H NMR (CDCl3) d 0.96 (t, J = 7.5 Hz,
3H), 2.11 (s, 3H), 2.42 (q, J = 7 Hz, 2H), 10.30 (br, 2H); 3H), 1.57 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 5.32 (s, 1H),
MS m/z (%), 126 (M+, 76), 111 (90), 98 (42), 42 (100); IR 10.50 (br s, 2H); MS m/z (%) 126 (M+, 52), 111 (25), 98
(KBr, cm 1) 2965, 1616, 1404. (100); IR (KBr, cm 1) 2735, 1620, 1507.
 M.M. Mojtahedi et al. / Ultrasonics Sonochemistry 15 (2008) 828–832
2.2.12. Ethyl 4,4,4-trifluoro-3-(2-phenylhydrazono)butano-
ate (3g)
M.p. 170 °C; 1H NMR (CDCl3) d 1.35 (t, J = 7.1 Hz,
3H), 3.55 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 7.04 (t,
J = 7.3 Hz, 1H), 7.20 (d, J = 8 Hz, 2H), 7.35 (dd, J = 7.3,
8 Hz, 2H), 9.12 (s, 1H); 13C NMR (CDCl3) d 14.4, 32.6,
62.8, 114.4, 120.0, 122.6, 123.0, 129.7, 143.8, 168.5; MS
m/z (%) 274 (M+, 10), 228 (45), 105 (10), 40 (100); IR
(KBr, cm 1) 2733, 1720, 1601, 1565.
3. Results and discussion
First, an equimolar mixture of phenyl hydrazine and
ethyl butrylacetate 1a (R = n-Pr) was sonicated under var-
ious sets of conditions. The best results were obtained in
the presence of no solvent leading to sole formation of 1-
phenyl-3-propyl-1H-pyrazol-5(4H)-one 2a via elimination
of water and ethanol after 15 min sonication (Table 1,
entry 1). The solid product was easily separated from the
reaction mixture by aqueous work up. Control experiments
showed the crucial rule of the ultrasonic irradiation for the
reaction to proceed and excluded the effect of a possible
simultaneous thermal activation. Therefore, conduction
of the reaction by maintaining the temperature at
25 ± 1 °C yielded similar results after 17 min sonicaion.
Alternatively, in the absence of irradiation, the same mix-
ture gave only 41% of 2a after several hours treatment of
the mixture at elevated temperatures (140 °C). These obser-
vations suggest that the ultrasonic irradiation can signifi-
cantly assist the process, as also previously proposed by
Wang [27] and Entezari [28], presumably by providing
the required energy for the transition state of the reaction.
To examine the feasibility of a relatively large-scale synthe-
sis, a mixture containing 50 mmol of each of the two reac-
tants was subjected to the reaction conditions for 25 min
leading to isolation of more than 90% of 2a.
Other b-keto esters reacted in the same manner with
phenyl hydrazine (entries 2–8) or hydrazine (entries 9–11)
to obtain 84–95% of their respective pyrazolone derivatives
in short time periods. In case of hydrazine, reactions could
complete at lower power level of sonication within shorter
time periods. All reactions proceeded cleanly and resulted
easily in precipitation of single products.
O O O OH
EtO CF3 H2..
NNHPh EtO CF3
HN
.. NHPh
CF3
CF3
N O OH2
N NHPh
O N O O EtO CF3
2g 3g HN
Ph Et .. NHPh
Fig. 1. Proposed mechanism for the condensation of hydrazines with
acetoacetates.
831
Based on these observations, a mechanistic pathway as
depicted in Fig. 1 can be proposed in which an immine
intermediate is formed first which subsequently undergoes
intermolecular condensation to form the final product.
This hypothesis was supported by isolation of the pro-
posed immine intermediate 3g for the reaction between
phenyl hydrazine and ethyl 4,4,4-trifluoro-3-oxobutanoate
(entry 7).
4. Conclusion
We have reported a rapid and efficient solvent-free
method for the preparation of substituted pyrazolones
via condensation of hydrazine derivatives with various b-
keto esters under ultrasonic conditions. Yields of products
are high, reactions proceed at ambient temperature, no
extra catalyst or additive is required, and the conditions
are safe from environmental point of view.
Acknowledgement
Partial financial support by the Ministry of Science, Re-
search, and Technology of Iran is greatly appreciated.
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