Facile sonochemical synthesis of novel pyrazolyne derivates at ambient conditions

Article abstract of DOI:10.1016/j.ultsonch.2012.11.018

Claisen-Schmidt condensation reaction of 4-acetamidoacetophenone with aromatic aldehydes under ultrasonic irradiation affords acetylaminochalcones (yields: 71-90%) which also under ultrasonic irradiation and in the presence of sodium acetate and acetic ac

Full text of DOI:10.1016/j.ultsonch.2012.11.018

Ultrasonics Sonochemistry 20 (2013) 1033–1036
Contents lists available at SciVerse ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Facile sonochemical synthesis of novel pyrazolyne derivates at ambient conditions
b
Dency José Pacheco a, Luis Prent a, Jorge Trilleras a, , Jairo Quiroga
⇑
a Grupo de Investigación en Compuestos Heterocíclicos, Programa de Química, Facultad de Ciencias Básicas, Universidad del Atlántico, Km 7 Antigua vía Puerto Colombia,
Barranquilla-Atlántico, Colombia
b Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A 25360 Cali, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Claisen–Schmidt condensation reaction of 4-acetamidoacetophenone with aromatic aldehydes under
ultrasonic irradiation affords acetylaminochalcones (yields: 71–90%) which also under ultrasonic irradi-
ation and in the presence of sodium acetate and acetic acid aqueous undergo facile and clean cyclocon-
densation with hydrazine to afford 3-(4-acetamidophenyl)-5-(aryl)-1-H-pyrazolines. The pyrazolines
were obtained in good to excellent yields (81–89%), and were characterized by conventional spectral
data. The work-up is simple and the results obtained indicate that, unlike classical heating, ultrasonic
irradiation results in higher yields, shorter reaction times (1.5–2.3 h) and milder conditions.
Ó 2012 Elsevier B.V. All rights reserved.
Received 22 February 2012
Received in revised form 2 October 2012
Accepted 30 November 2012
Available online 20 December 2012
Keywords:
Pyrazolines
Cyclocondensation
Sonication
Chalcones
1. Introduction
On the other hand, recently ultrasound has been utilized to
accelerate a wide number of synthetically useful organic reactions.
Chalcones are one of the major classes of natural product with
wide spread distribution in nature and food, which have attracted
great interest, in addition to their pharmacological activities [1].
They display a wide range of pharmacological properties, including
cytotoxity towards cancer cell lines [2], antiviral [3], anti-inflam-
matory [4], antiulcerative [5], and hepatoprotective chalconas [6].
Chalcones are an-easy-to synthesize template five-, six- and
seven-membered heterocyclic compounds [7]. It is therefore not
surprising that many synthetic methods have been developed for
the preparation of chalcones and heterocycles starting from chal-
cones precursors that have been tested for their potential applica-
tions.
Compared with traditional methods, the procedure is more conve-
nient and can be carried out in higher yields, shorter reaction time
or milder conditions [17]. Among the ultrasound-promoted reac-
tions are heterocyclization of suitably functionalized substrates
[18], in this sense, recently reported the synthesis assisted by
ultrasound of pyrazolines [19] and chalcones, using KOH and KF-
Al2O3 as catalysts [20]. With this in mind, we decided to direct
our efforts towards the synthesis of various pyrazolinic derivatives
using the ultrasound-assisted methodology. Our interest in these
target heterocycles is stimulated by their close structural relation-
ship to molecules of known biological activity [13,15].
Pyrazolines are important nitrogen-containing five-membered
heterocyclic compounds and have attracted interest because of
their broad spectrum of biological activities [8] such as antimicro-
bial [9], antidepressant [10], insecticidal [11], anti-inflammatory
[12], antitumor [13] and antinociceptive activities [14]. 2-Pyrazo-
lines are the most frequently studied isomers, and various methods
have been worked out for their synthesis. Among them are the
2. Methods
2.1. Apparatus and analysis
Melting points were determined using a Thermo Scientific Fluke
51 II, model IA 9100 melting point apparatus and are reported
uncorrected. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded at room temperature on a Bruker Ultra Shield 400
using TMS as internal standard and deuterated chloroform (CDCl3)
as solvent. EIMS were run on a Shimadzu GC–MS 2010 spectrom-
eter, which was operating at 70 eV. IR spectra were recorded as
KBr pellets on a Shimadzu FTIR-8400 instrument. The ultrasonic
irradiation was performed by using a Branson ultrasonic cleaner
bath, model 1510, 115v, 1.9 L with mechanical timer (60 min with
continuous hold) and heater switch, 47 kHz. The aromatic alde-
hydes and solvents used, such as, ethanol, dichloromethane, glacial
reactions of a,b-unsaturated ketones with diazomethane [15] and
cycloaddition reactions [16]. The cyclocondensation of chalcones
with hydrazines has become one of the most popular methods
[17].
⇑
Corresponding author. Tel.: +57 5 3599484; fax: +57 5 3599481.
E-mail addresses: dencypacheco@mail.uniatlantico.edu.co (D.J. Pacheco),
luisprent@gmail.com (L. Prent), jorgetrilleras@mail.uniatlantico.edu.co (J. Trilleras),
jairo.quiroga@correounivalle.edu.co (J. Quiroga).
1350-4177/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ultsonch.2012.11.018

1034
D.J. Pacheco et al. / Ultrasonics Sonochemistry 20 (2013) 1033–1036
acetic acid and ethyl acetate were obtained from Merck Chemical
Company. 4-Acetylaminoacetophenone and hydrazine monohy-
drate were obtained from Aldrich.
1H, N–H acetylamino),7.45 (s, 1H, N–H pyrazoline), 7.21 (d, 2H,
Ho, phenyl), 7.11 (d, 2H, Hm, phenyl), 7.01 (d, J = 8.03 Hz, 2H, Ho,
3-aryl), 6.72 (t, 1H, Hp, phenyl), 5.18 (dd, J = 12.2, 7.4 Hz, 1H, –
CH), 3.75 (dd, J = 16.9, 12.3 Hz, 1H, –CH), 3.05 (dd, J = 17.0,
7.3 Hz, 1H, –CH), 2.11 (s, 3H, –CH3). MS: m/z (%), 279 (100, M+),
278 (23), 91 (50), 77 (20), 43 (33).
2.2. General procedure for the synthesis of 4-acetylaminochalcones 3
A mixture of 4-acetamidoacetophenone (5 mmol), appropriate
aromatic aldehyde (5 mmol), KOH (1 mmol) and ethanol (2 mL),
was sonicated for 5–20 min in the water bath of an ultrasonic clea-
ner bath. The progress of the reaction was monitored by TLC using
dichlorometane:ethyl acetate (9:1 v/v) as eluent. The reaction mix-
ture was cooled in ice-water bath. The formed precipitate was fil-
tered, washed with cool water and purified by recrystallization
from ethanol to give the target compounds in high yields of 71–
92%. The spectral data and melting point of compounds 3a–c were
consistent with literature values [21].
2.3.2. Compound 4b
3-(4-Acetylaminophenyl)-5-(4-clorophenyl)-1H-pyrazoline 4b:
Yield = 89%, m.p. = 222–223 °C; FT-IR (m
, cmꢀ1): 3297–3039 (H–N
amide, N–H pirazoline, st), 1667 (NC@O, st), 1596 (C@N, st), 1498
(C@C, st); 1H NMR: d (ppm), 8.01 (d, J = 8.78 Hz, 2H, Hm, 3-Ar),
7.57 (s, 1H, N–H acetylamino), 7.55 (s, 1H, N–H pyrazoline),
7.17–7.39 (m, 4H, 5-Ar), 7.03 (d, J = 8.78 Hz, Ho, 3-Ar), 5.22 (dd,
J = 12.2, 7.2 Hz, 1H, –CH), 3.80 (dd, J = 17.0, 12.3 Hz, 1H, –CH),
3.07 (dd, J = 17.0, 7.2 Hz, 1H, –CH), 2,18 (s, 3H, CH3). MS: m/z (%),
313 (100, M+), 278 (20), 91 (60), 77 (20), 43 (95).
2.2.1. Compound 3a–c
(2E)-1-(4-acetylaminophenyl)-3-(phenyl)prop-2-enone
Yield: 71% (lit: 80%); m.p. = 161–163 °C (lit: 161.7–162.2 °C).
3a:
2.3.3. Compound 4c
3-(4-Acetylaminophenyl)-5-(4-methylphenyl)-1H-pyrazoline 4c:
(2E)-1-(4-acetylaminophenyl)-3-(4-chlorophenyl)prop-2-enone
3b: Yield = 84% (lit: 79%); m.p. = 215–217 °C (lit: 215–215.7 °C).
(2E)-1-(4-acetylaminophenyl)-3-(4-methylphenyl)prop-2-enone
3c: Yield = 75% (lit: 83%); m.p. = 198–199 °C (lit: 197.5–199 °C).
The authenticity of the products (3d–e) was established by their
1H NMR, IR, MS data.
Yield = 85%, m.p. = 223.3–225.5 °C; FT-IR (m
, cmꢀ1): 3299–3040
(H–N amide, N–H pyrazoline, st), 1667 (NC@O, st), 1596 (C@N,
st), 1498 (C@C, st); 1H NMR: d (ppm), 7.66 (d, J = 8.5 Hz, 2H, Hm,
3-Ar), 7.52 (s, 1H, N–H acetylamino), 7.50 (s, 1H, N–H pyrazoline),
7.20–7.13 (m, 4H, 5-Ar), 7.07 (d, J = 7.8 Hz, 2H, Ho, 3-Ar), 5.18 (dd,
J = 12.2, 7.4 Hz, 1H, –CH), 3.75 (dd, J = 16.9, 12.3 Hz, 1H, –CH), 3.05
(dd, J = 17.0, 7.3 Hz, 1H, –CH), 2.32 (s, 3H, -CH3, 5-Ar), 2,17 (s, 3H, –
CH3, acetylamino). MS: m/z (%), 293 (100, M+), 278 (20), 91 (35), 77
(15), 43 (25).
2.2.2. Compound 3d
(2E)-1-(4-acetylaminophenyl)-3-(3,4-metilendioxyphenyl)prop-
2 -enone 3d: Yield = 92%; m.p. = 175 °C (dec); FT-IR (m
, cmꢀ1): 3287
(H–NCO, st), 1673 (NC@O, st), 1598 (–C@O, st), 1532 (–C@C, st); 1H
NMR: d (ppm), 8.00 (d, J = 8.7 Hz, 2H, Hm, 1-Aryl), 7.72 (d,
J = 15.6 Hz, 1H, Hb), 7.63 (d, J = 8.6 Hz, 2H, 1-Ar), 7.35 (d,
2.3.4. Compound 4d
3-(4-Acetylaminophenyl)-5-(3,4-metilendioxyphenyl)-1H-pyr-
azoline 4d: Yield = 82%, m.p. = 219–221 °C; FT-IR (m
, cmꢀ1): 3306–
J = 15.5 Hz, 1H, Ha), 7.15 (d, J = 1.5 Hz, 1H, Ho, 3-Ar), 7.12 (dd,
J = 8.03, 1.5 Hz, 1H, Ho, 3-Ar), 6.84 (d, J = 8.03 Hz, 1H, Hm, 3-Ar),
6.02 (d, J = 8.0 Hz, 1H, –CH2), 2.21 (s, 3H, –CH3). MS: m/z (%), 309
(100, M+), 308 (18), 267 (20), 145 (25), 120 (30), 89 (20), 43 (50).
3058 (H–N amide, N–H pyrazoline, st), 1667 (NC@O, st), 1596
(C@N, st), 1499 (C@C, st); 1H-NMR: d (ppm), 7.66 (d, J = 8.7 Hz,
2H, Hm, 3-Ar), 7.52 (s, 1H, N–H acetylamino), 750 (s, 1H, N–H pyr-
azoline), 7.18 (dd, J = 8.7, 7.3 Hz, 2H, Ho, 5-Ar), 7.08 (d, J = 8.7 Hz,
2H, Ho 3-Ar), 6.67 (m, 5H, Hm, 5-Ar), 5.91 (s, 2H, –CH2, 5-Ar),
5.15 (dd, J = 12.2, 7.2 Hz, 1H, –CH), 3.75 (dd, J = 17.0, 12.2 Hz, 1H,
CH), 3.07 (dd, J = 17.0, 7.2 Hz, 1H, CH), 2.17 (s, 3H, CH3). MS: m/z
(%), 323 (100, M+), 278 (15), 91 (45), 77 (12), 43 (32).
2.2.3. Compound 3e
(2E)-1-(4-acetylaminophenyl)-3-(3,4,5-trimetoxyphenyl)prop-2-
enone 3e: Yield = 83%, m.p. = 150 °C (dec); FT-IR (m
, cmꢀ1): 3312
(H–NCO, st), 1661 (NC@O, st), 1599 (–C@O, st), 1535 (–C@C, st);
1H NMR: d (ppm), 7.99 (d, J = 8.5 Hz, 2H, Hm, 1-Ar), 7.93 (s, 1H,
N–H), 7.68 (m, 3H, Ho, 1-Ar y Ha), 7.39 (d, J = 15.6 Hz, 1H, Hb),
2.3.5. Compound 4e
6.84 (s, 2H, Ho, 3-Ar), 3.91 (s, 6H, m (OCH3)2), 3.89 (s, 3H, p
OCH3), 2.21 (s, 3H, –CH3). MS: m/z (%), 355 (100, M+), 340 (30),
334 (35), 120 (25), 43 (40).
3-(4-Acetylaminophenyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyr-
azoline 4e: Yield = 81%, m.p. = 248–249 °C; FT-IR (m
, cmꢀ1): 3344–
3042 (H–N amide, N–H pyrazoline, st), 1689 (NC@O, st), 1596
(C@N, st), 1500 (C@C, st); 1H NMR: d (ppm), 7.68 (d, J = 8.42, 2H,
Hm, 3-Ar), 7.53 (s, 1H, N–H acetylamino), 7.51 (s, 1H, N–H pyrazo-
line), 7.09 (d, 2H, Ho, 3-Ar), 6.54 (s, 2H, Ho, 5-Ar), 5.12 (dd, J = 12.2,
7.8 Hz, 1H, –CH), 3.82 (m, 9H, Cm –OCH3, 1H, CH2) 3.12 (dd,
J = 17.0, 7.8 Hz, 1H, –CH), 2.18 (s, 3H, CH3). MS: m/z (%), 369
(100, M+), 278 (25), 91 (35), 77 (8), 43 (20).
2.3. General procedure for the synthesis of 3-(4-acetylaminophenyl)-
5-(aryl)-1H-pyrazolines 4
A
mixture of respective acetylaminochalcone 3 (1 mmol),
hydrazine hydrate (150 mg, 3 mmol) and sodium acetate
(24.6 mg, 0.3 mmol) in 3 mL acid acetic–water (2:1), were soni-
cated for 1.5–2.3 h. The progress of the reaction was monitored
by TLC using dichlorometane:ethyl acetate (9:1 v/v) as eluent.
The reaction mixture was placed on ice-water. The obtained pre-
cipitate was filtered, washed with cool water and purified by
recrystallization from ethanol to give the target compounds in high
yield. The obtained yields are summarized in Table 1.
3. Results and discussion
The aim of present study was to synthesize novel 2-pyrazolines
with an acetylamino type side-chain, which were synthetized in
two steps (Scheme 1). In the first step, the acetylaminochalcones
3 were obtained by Claisen–Schmidt condensation reaction be-
tween 4-acetylaminoacetophenone 1 and aromatic aldehydes 2
in ethanol with basic catalysis and under ultrasonic irradiation at
room temperature during 5–20 min. Although the yields are simi-
lar those reported in the literature for conventional method
[21,22], the reaction times were significantly shorter.
2.3.1. Compound 4a
3-(4-Acetylaminophenyl)-5-(phenyl)-1H-pyrazoline 4a: Yield =
82%, m.p. = (220–223) °C; FT-IR (m
, cmꢀ1): 3309–3062 (H–N amide,
N–H pyrazoline, st), 1671 (NC@O, st), 1598 (C@N, st), 1497 (C@C,
st); 1H NMR: d (ppm), 7.61 (d, J = 8.3 Hz, 2H, Hm, 3-Ar), 7.47 (s,

D.J. Pacheco et al. / Ultrasonics Sonochemistry 20 (2013) 1033–1036
1035
Table 1
Synthesized chalcones and pyrazolines: advantage of sonochemical method over conventional method.
Ar
Compound 3
Compound 4
Conventional method
Ultrasonic method
Conventional method
Ultrasonic method
1:1 mol ratio
Time (h)
% Yield
Time (min)
% Yield
Time (h)
% Yield
1:2 mol ratio
1:3 mol ratio
Time (h)
% Yield
Time (h)
% Yield
Time (h)
% Yield
a
b
c
d
e
C6H5
4-ClC6H4
4-CH3C6H4
3,4-(OCH2O)C6H3
3,4,5-tri-CH3OC6H2
Overnighta
80a
79a
83a
–
20
8
17
6
71
84
75
90
83
3
3
3
3.5
3.5
70
75
75
75
75
1.5
2
2
2.2
2.3
70
80
78
73
75
1.5
2
2
2.2
2.3
75
83
81
75
78
1.5
2
2
2.2
2.3
82
89
85
82
81
Overnighta
Overnighta
–
–
–
5
a
Time and % yield reaction reported in the literature [21].
H
N
O
O
N
Ar
ArCHO 2
H2NNH2
O
Ar
O
O
KOH/EtOH
Sonication
AcONa/AcOH
Sonication
N
N
N
H
H
H
1
3
4
Scheme 1. Synthesis of 3-(4-acetylaminophenyl)-5-(aryl)-1H-pyrazolines 4 by ultrasonic-assisted.
H
N
Ar
Hx
Ha Hb
onstrated by the IR spectra of 4a–e compounds, which showed the
characteristic band for NH at 3344–3297 cmꢀ1 and a band at
1596 cmꢀ1 corresponding to C@N stretching. The 1H NMR spectra
showed an ABX spin system caused by the coupling of three hydro-
gen atoms attached to the C-4 and C-5 of the heterocyclic ring
(Fig. 1). Methylene protons of heterocyclic ring appeared as two
double doublets, one at d = 3.75–3.82 ppm (H4a, J = 17, 12.3 Hz)
and the other at d = 3.05–3.12 ppm (H4b, J = 17, 7.2 Hz). The exis-
tence of these double doublets clearly indicates the magnetic non-
equivalence of these two protons for being adjacent to a chiral
center, whose hydrogen have chemical shift at 5.2 ppm (Hx,
J = 12.2, 7.2 Hz). The NH’s protons of compounds 4 were observed.
These spectral data unequivocally prove the 2-pyrazoline
structure.
As depicted from Table 1, the yields of compound 4 were excel-
lent. It is worth noting that the electronic nature of the substitu-
ents affects only to a lesser extent the yields of the products and
the reaction proceeds quite well with both electron-withdrawing
and electron-releasing substituents on acetylaminochalcones. In
contrast, the presence of various electron-releasing substituents
on the aryl decreases the rate, because of the lower electrophilicity
N
O
N
H
Fig. 1. Structures of 3-(4-acetylaminophenyl)-5-(aryl)-1H-pyrazolines 4.
The reaction time for the conventionally synthesized chalcones
was overnight while reaction times used for sonochemically syn-
thesized chalcones were 5–20 min. In the next step, the substi-
tuted chalcones were cyclized to 2-pyrazolines using hydrazine
monohydrate under ultrasound irradiation. The effect of the reac-
tion conditions on the reaction of chalcones with hydrazine mono-
hydrate under ultrasound irradiation was summarized in (Table 1).
When the molar ratio of chalcones/hydrazine monohydrate was
1:1, the yield of 2-pyrazoline obtained was around 70%. The use of
a 1:2, and 1:3 M ratios led to an increase of reaction yield 75% and
82%, respectively (Table 1). The results showed that the optimum
molar ratio of chalcones/hydrazine monohydrate was found to be
1:3. In order to verify the effect of ultrasound irradiation, we have
performed the reaction of chalcone with hydrazine monohydrate
by conventional heating in ethanol for 3.5 h. The yield of 2-pyraz-
olines was lesser as compared to ultrasonic induced synthesis (Ta-
ble 1). Unlike literature reports [13b,23], when the same reaction
was carried out starting with chalcones in the presence of formic
or acetic acid by microwave assisted heating, formation of N-
formyl or N-acetyl derivatives was observed. Our sonochemical
methodology is presented as an efficient method to obtain N-
unsubstituted pyrazolines.
caused by these groups on a,b-unsaturated system. In addition to
test the usefulness of the sonication, the appropriate reaction con-
ditions allow obtain NH-pyrazolines stable at ambient conditions
and exhibiting a high fluorescence in both solution and solid state.
The reaction may tentatively be visualized to occur via a tandem
sequence of reactions depicted in reaction mechanism (Scheme 2)
involving (i) attack of nitrogen on carbonyl carbon to yield an
imine derivative, (ii) attack of nitrogen on carbon–carbon double
leading to a five membered ring in either a sequential or a con-
certed manner, and (iii) proton transfer and removal of water mol-
ecule resulting to 2-pyrazolines [13b,15].
The structures of pyrazolinic derivates were elucidated on the
basis of its 1H NMR, IR and mass spectra. The ring closure is dem-
NH2
H2N
H
N
H
H2N
O
N
N
Ar
- H+
- H2O
Ar
Ar
O
O
O
N
H
H+
N
H
N
H
Scheme 2. Plausible formation of 3-(4-acetylaminophenyl)-5-(aryl)-1H-pyrazolines 4 ultrasonic-assisted.

1036
D.J. Pacheco et al. / Ultrasonics Sonochemistry 20 (2013) 1033–1036
(c) A.C. Grosscurt, R. Van Hes, K. Wellinga, Synthesis and insecticidal
4. Conclusion
properties of 3,4-diphenyl-1-phenylcarbamoyl-2-pyrazolines J, Agric. Food
Chem. 27 (1979) 406–409.
In the present paper, we report the preparation in two steps of
pyrazolinic derivates under ultrasonic irradiation. This mild, conve-
nient and improved protocol for the ultrasound-promoted prepara-
tion of pyrazolinic derivates indicate that, unlike classical heating,
ultrasonic irradiation results in higher yields, shorter reaction times
and milder conditions. Due to the broad spectrum of biological activ-
ities of pyrazolines, evaluation of the biological activity and fluores-
cence properties of the new compounds is in progress.
[12] (a) S. Bano, K. Javed, S. Ahmad, I.G. Rathish, S. Singh, M.S. Alam, Synthesis and
biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide
moiety as potential anti-inflammatory and anti-cancer agents, Eur. J. Med.
Chem. 46 (2011) 5763–5768;
(b) S. Khode, V. Maddi, P. Aragade, M. Palkar, P.K. Ronad, S. Mamledesai,
A.H.M. Thippeswamy, D. Satyanarayana, Synthesis and pharmacological
evaluation of
a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-
phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents, Eur.
J. Med. Chem. 44 (2009) 1682–1688;
(c) I.G. Rathish, K. Javed, S. Ahmad, S. Bano, M.S. Alam, K.K. Pillai, S. Singh, V.
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Acknowledgments
[13] (a) B. Insuasty, A. García, J. Quiroga, R. Abonía, A. Ortiz, M. Nogueras, J. Cobo,
´
Efficient microwave-assisted synthesis and antitumor activity of novel 4,4-
The authors thanks to Universidad del Atlántico, Universidad
del Valle and COLCIENCIAS for financial support.
methylenebis[2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols], Eur. J. Med.
Chem. 46 (2011) 2436–2440;
(b) B. Insuasty, A. Tigreros, F. Orozco, J. Quiroga, R. Abonía, M. Nogueras, A.
Sánchez, J. Cobo, Synthesis of novel pyrazolic analogues of chalcones and their
3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole
derivatives as potential antitumor agents, Bioorg. Med. Chem. 18 (2010) 4965–
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