Chemistry of Heterocyclic Compounds, Vol. 42, No.

7, 2006

A MODIFIED AND CONVENIENT

METHOD FOR THE PREPARATION OF
N-PHENYLPYRAZOLINE DERIVATIVES

J. Safaei-Ghomi, A. H. Bamoniri, and M. Soltanian-Telkabadi

Ten new N-phenylpyrazoline derivatives have been synthesized in high yields by condensation of
chalcones with phenylhydrazine in the presence of potassium carbonate in reflux conditions. The work-
up is simple and involves treatment with ice-cold water. As compared with the previous method a
considerable increase in the reaction rate with better yields has been observed.

Keywords: chalcones, N-phenylpyrazolines, intramolecular cyclization, Michael addition.

N-Phenylpyrazoline derivatives are important compounds in organic chemistry because of their

application in heterocyclic synthesis and medicine [1]. Pyrazolines have been reported to show a wide spectrum
of biological activity, including antibacterial [2], antifungal [3], anti-inflammatory [4], antiamoebic [5], and
antidepressant activity [6]. The pyrazoline function is quite stable, and has inspired chemists to utilize the
mentioned stable fragment in bioactive moieties to synthesize new compounds possessing biological activity.
Some related compounds were evaluated for anticon- vulsant activity [7]. The antidepressant activity of these
compounds was evaluated by the ''Porsolt Behavioural Despair Test'' on Swiss–Webster mice [8].
The α,β-unsaturated ketones can play the role of versatile precursors in the syntheses of the
corresponding pyrazoline derivatives [9-14]. The reaction of hydrazine and its derivatives with α,β-unsaturated
ketones and α,β-epoxy ketones is one of the preparative methods for the synthesis of pyrazolines and pyrazoles
[15]. Alternatively, the reaction of substituted hydrazines with α,β-unsaturated ketones has been reported to lead
to regioselective formation of pyrazolines [16, 17].
The synthesis of pyrazoline rings from chalcone derivatives containing anisole and the
3,4-methylenedioxyphenyl ring by the conventional method using acetic acid was reported with low yields [18].
We have developed a general and efficient method for the synthesis of N-phenylpyrazoline derivatives from
chalcones and phenylhydrazine under reflux conditions in the presence of potassium carbonate as a catalyst
(Scheme 1).
Chalcones 3a-j were synthesized by aldol condensation reaction of acetophenone derivatives 1 and
aromatic aldehydes 2 in the presence of basic catalysts [19]. Pyrazoline derivatives were synthesized by using
1 mol of chalcones 3a-j and 1.3 mol of phenylhydrazine in the presence of potasium carbonate under reflux
conditions. Compounds 4a-j were prepared in an oil bath (120°C) using potasium carbonate in accordance with
conventional methods. The hydrazination reaction involves initial nucleophilic attack in the β-position of the
chalcone nucleus and ring closure with nucleophilic attack on the carbonyl group of chalcone.

__________________________________________________________________________________________
Department of Chemistry, Faculty of Science, University of Kashan, 51167 Kashan, I. R. Iran. Published
in Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1032-1036, July, 2006. Original article submitted
September 17, 2005; revision submitted January 23, 2006.

892 0009-3122/06/4207-0892©2006 Springer Science+Business Media, Inc.

 Scheme 1

O O
OHC NaOH
Me
+
X Y EtOH
X Y
1 2 3a–j

PhNHNH2 K2CO3,
X reflux
HA HB
H
N Y
N

4a–j

The synthesis of compounds 4a-j using K2CO3 in reflux conditions (Method B) was attempted under
identical conditions using acetic acid (Method A) [18]. Lower yields were obtained in method A as compared
with B. An increase in the polarity of molecules in the presence of the basic catalyst (K2CO3) in polar protic
solvents led to a greater reactivity of the nucleophile in the Michael addition reaction and intramolecular
cyclizations. Meanwhile, this is consistent with the reaction mechanism, which involves a polar transition state
[20] stabilized by polar protic solvents. Finally, nucleophilic attack on the carbonyl group by intramolecular
cyclization resulted in the formation of pyrazoline derivatives. The reaction was clean with good to excellent
yields (Table 1) except 4i which has a low yield of 45%.
In this article, we present an easy and effective method for the preparation of new pyrazoline derivatives
in high yield under reflux conditions using K2CO3. This method may be used to prepare heterocyclic
compounds, which have a wide application in organic synthesis.

TABLE 1. Reaction of Chalcones with Phenylhydrazine in Reflux Conditions

Time, min Yield, %* Time, min Yield, %*

Entry Product X Y
Method A Method B

1 4a H H 110 65 80 80
2 4b Cl H 45 65 14 85
3 4c H Cl 40 58 12 80
4 4d Cl Cl 30 87 5 95
5 4e H Br 45 70 15 90
6 4f Cl Br 38 78 10 93
7 4g H Me 140 43 100 64
8 4h Cl Me 87 53 60 76
9 4i H NMe2 155 28 120 45
10 4j Cl NMe2 105 53 70 70
_______
* Yield of isolated products.

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EXPERIMENTAL

Melting points were determined in open capillaries using an Electrothermal Mk3 apparatus. The progress
of the reactions was monitored by TLC on Riedel-de Haën plates coated with silica gel 60 F254 in a 75:25
petroleum ether–ethyl acetate system. IR spectra were taken in thin layer on Magna-Nicolet IR 550 spectrometer.
1
H NMR and 13C NMR spectra were recorded on a Bruker-Avance DRX-400 spectrometer in CDCl3 with TMS
as an internal reference. Mass-spectra were recorded on a Finnigan MAT 44S, with an ionization voltage of 70
eV. The elemental analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer.
Synthesis of New N-Phenylpyrazoline Derivatives (General Procedure). A. Phenylhydrazine
(13 mmol) was added to a chalcone (10 mmol) in acetic acid (15 ml). The mixture was refluxed under constant
stirring for an appropriate time (Table 1). After completion of the reaction as indicated by TLC, the reaction
mixture was diluted with ice-cold water .The solid was collected, washed with water and recrystallized from
ethanol as pale yellow plates.
B. Potassium carbonate (10 mol% w/w of chalcone) was added to a solution of phenylhydrazine
(13 mmol) and chalcone (10 mmol) in ethanol (15 ml). The mixture was refluxed under constant stirring for an
appropriate time (Table 1). After completion of the reaction as indicated by TLC, the workup was the same as in
method A.
1,3,5-Triphenyl-2-pyrazoline (4a). Yield 2.3 g, 80%, yellow prisms; mp 139-141°C. IR spectrum, ν,
cm : 3027, 1588, 1490. 1H NMR spectrum, δ, ppm (J, Hz): 3.22 (1H, dd, J1 = 17.1, J2 = 7.2, CHAHBC=N); 3.87
-1

(1H, dd, J1 = 17.1, J2 = 12.2, CHAHBC=N); 5.34 (1H, dd, J1 = 12.2, J2 = 7.2, ArCHN); 6.97-7.89 (m, 15 aromatic
H). 13C NMR spectrum, δ, ppm: 43.7 (CH2); 64.90 (ArCHN); 113.8, 119.3, 125.8, 126.0, 127.50, 128.50, 129.1,
133.1, 142.8, 143.9, 145.3, 146.8 (aromatic C), 150.2 (C=N). Mass-spectrum, m/z (Irel, %): 298 [M]+ (83), 91
(100). Found, %: C 84.45; H 6.10; N 4.71. C21H18N4. Calculated, %: C 84.53; H 6.08; N 4.69.
3-(4-Chlorophenyl)-1,5-diphenyl-2-pyrazoline (4b). Yield 2.8 g, 85%, yellow powder; mp 149-151°C.
IR spectrum, ν, cm-1: 3028, 1593, 1490. 1H NMR spectrum, δ, ppm (J, Hz): 3.15 (1H, dd, J1 = 17.2, J2 = 7.2,
CHAHBC=N); 3.80 (1H, dd, J1 = 17.2, J2 = 12.4, CHAHBC=N); 5.29 (1H, dd, J1 = 12.4, J2 = 7.2, ArCHN); 6.68-
7.70 (m, 14 aromatic H). 13C NMR spectrum, δ, ppm: 43.5 (CH2); 65.1 (ArCHN); 113.8, 119.6, 125.9, 126.9,
127.6, 128.8, 129.1, 131.6, 134.4, 142.5, 145.0, 145.5 (aromatic C), 151.2 (C=N). Mass-spectrum, m/z (Irel, %):
332 [M]+ (86), 334 [M+2]+ (28), 91 (100). Found, %: C 75.80; H 5.13; N 8.40. C21H17ClN2. Calculated, %: C
75.78; H 5.14; N 8.41.
5-(4-Chlorophenyl)-1,3-diphenyl-2-pyrazoline (4c). Yield 2.6 g, 80%, yellow powder; mp 147-149°C.
IR spectrum, ν, cm-1: 3057, 1588, 1495. 1H NMR spectrum, δ, ppm (J, Hz): 3.13 (1H, dd, J1 = 17.2, J2 = 7.2,
CHAHBC=N); 3.83 (1H, dd, J1= 17.2, J2 = 12.4, CHAHBC=N); 5.25 (1H, dd, J1 = 12.4, J2 = 7.2, ArCHN);
6.91-7.82 (m, 14 aromatic H). 13C NMR spectrum, δ, ppm: 43.59 (CH2); 65.1 (ArCHN); 113.85, 119.62, 125.86,
127.45, 128.93, 129.33, 130.04, 132.88, 133.51, 141.30, 145.09, 146.85 (aromatic C), 149.1 (C=N). Mass-
spectrum, m/z (Irel, %): 332 [M]+ (83), 334 [M+2]+ (27), 91 (100). Found, %: C 75.76; H 5.13; N 8.40.
C21H17ClN2. Calculated, %: C 75.78; H 5.15; N 8.41.
3,5-Bis(4-chlorophenyl)-1-phenyl-2-pyrazoline (4d). Yield 3.4 g, 95%, yellow powder;
mp 167-169°C. IR spectrum, ν, cm-1: 3029, 1593, 1480. 1H NMR spectrum, δ, ppm (J, Hz): 3.08-3.12 (1H, dd,
J1 = 17.2, J2 = 7.2, CHAHBC=N); 3.82 (1H, dd, J1 = 17.2, J2 = 12.4, CHAHBC=N); 5.28 (1H, dd, J1 = 12.4,
J2 = 7.2, ArCHN); 6.81-7.64 (m, 13 aromatic H). 13C NMR spectrum, δ, ppm: 45.0 (CH2), 66.0 (ArCHN), 106.7,
115.4, 121.4, 126.9, 128.7, 130.5, 131.5, 135.2, 136.2, 142.5, 145.1, 147.1 (aromatic C), 152.6 (C=N). Mass-
spectrum, m/z (Irel, %): 371 [M+4]+ (14), 369 [M+2]+ (60), 367 [M]+ (80), 91 (100). Found, %: C 68.66; H 4.40;
N 7.65. C21H16Cl2N2. Calculated, %: C 68.67; H 4.39; N 7.62.
5-(4-Bromophenyl)-1,3-diphenyl-2-pyrazoline (4e). Yield 3.3 g, 90%, yellow powder; mp 169-171°C.
IR spectrum, ν, cm-1: 3027, 1593, 1495. 1H NMR spectrum, δ, ppm (J, Hz): 3.10 (1H, dd, J1 = 17.2, J2 = 7.2,
CHAHBC=N); 3.84 (1H, dd, J1 = 17.2, J2 = 12.4, CHAHBC=N); 5.23 (1H, dd, J1 = 12.4, J2 = 7.2, ArCHN);

894
6.80-7.72 (m, 14 aromatic H). 13C NMR spectrum, δ, ppm: 43.59 (CH2), 65.1 (ArCHN), 113.85, 119.62, 125.86,
127.45, 128.55, 128.93, 129.33, 130.04, 132.88, 133.51, 141.30, 145.09 (aromatic C), 150.0 (C=N). Mass-
spectrum, m/z (Irel, %): 379 [M+2]+ (80), 377 [M]+ (79), 91 (100). Found, %: C 66.87; H 4.54; N 7.43.
C21H17BrN2. Calculated, %: C 66.85; H 4.54; N 7.42.
5-(4-Bromophenyl)-3-(4-chlorophenyl)-1-phenyl-2-pyrazoline (4f). Yield 3.8 g, 93%, yellow powder;
mp 174-176°C. IR spectrum, ν, cm-1: 3029, 1594, 1495. 1H NMR spectrum, δ, ppm (J, Hz): 3.29 (1H, dd, J1 =
16.8, J2 = 7.2, CHAHBC=N); 4.02 (1H, dd, J1 = 16.8, J2 = 12.4, CHAHBC=N); 5.47 (1H, dd, J1 = 12.4, J2 = 7.2,
ArCHN); 7.04-7.87 (m, 13 aromatic H). 13C NMR spectrum, δ, ppm: 43.3 (CH2), 65.1 (ArCHN), 113.67, 119.75,
125.29, 126.87, 127.63, 128.75, 128.90, 130.16, 131.21, 132.31, 134.55, 141.45 (aromatic C), 149.2 (C=N).
Mass-spectrum, m/z (Irel, %): 415 [M+4]+ (25), 413 [M+2]+ (97), 411 [M]+ (82), 91 (100). Found, %: C 61.26; H
6.90; N 6.81. C21H16N2CLBr. Calculated, %: C 61.26; H 3.91; N 6.80.
5-(4-Methylphenyl)-1,3-diphenyl-2-pyrazoline (4g). Yield 1.9 g, 64%, yellow powder; mp 157-159°C.
IR spectrum, ν, cm-1: 3027, 1598, 1495. 1H NMR spectrum, δ, ppm (J, Hz): 2.91 (1H, dd, J1 = 17.2, J2 = 7.2,
CHAHBC=N); 3.59 (1H, dd, J1 = 17.2, J2 = 12.2, CHAHBC=N); 5.07 (1H, dd, J1 = 12.2, J2 = 7.2, ArCHN); 6.63-
7.47 (m, 14 aromatic H). 13C NMR spectrum, δ, ppm: 21.09 (CH3), 43.50 (CH2), 65.1 (ArCHN), 105.1, 113.9,
119.5, 125.9, 126.9, 127.4, 128.7, 129.1, 131.6, 134.4, 142.5, 145.0 (aromatic C), 148.2 (C=N). Mass-spectrum,
m/z (Irel, %): 312 [M]+ (77), 91 (100). Found, %: C 84.56; H 6.45; N 8.96. C22H20N2 Calculated, %: C 84.58; H
6.45; N 8.96.
3-(4-Chlorophenyl)-5-(4-methylphenyl)-1-phenyl-2-pyrazoline (4h). Yield 2.6 g, 76%, yellow
powder; mp 162-164°C. IR spectrum, ν, cm-1: 3037, 1593, 1490. 1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H,
s); 3.11 (1H, dd, J1 = 17.2, J2 = 7.2, CHAHBC=N); 3.78 (1H, dd, J1 = 17.2, J2 = 12.4, CHAHBC=N); 5.25 (1H, dd,
J1 = 12.4, J2 = 7.2, ArCHN); 6.66-7.69 (m, 16 aromatic). 13C NMR spectrum, δ, ppm: 21.0 (CH3) 43.50 (CH2),
64.7 (ArCHN), 113.70, 119.4, 125.8, 126.9, 128.7, 129.8, 131.6, 134.3, 137.3, 139.5, 144.9, 145.50 (aromatic
C), 149.5 (C=N). Mass-spectrum, m/z (Irel, %): 348 [M+2]+ (26), 346 [M]+ (78), 91 (100) Found, %: C 76.19;
H 5.52; N 8.10. C22H19ClN2. Calculated, %: C 76.18; H 5.52; N 8.07.
5-(4-Dimethylaminophenyl)-1,3-diphenyl-2-pyrazoline (4i). Yield 1.5 g, 45%, yellow powder; mp
161-163°C. IR spectrum, ν, cm-1: 3027, 1603, 1489. 1H NMR spectrum, δ, ppm (J, Hz): 2.96 (6H, s, 2CH3); 3.16
(1H, dd, J1 = 17.1, J2 = 7.2, CHAHBC=N); 3.81 (1H, dd, J1 = 17.1, J2 = 12.2, CHAHBC=N); 5.23 (1H, dd, J1 =
12.2, J2 = 7.2, ArCHN); 6.74-7.78 (m, 14 aromatic H). 13C NMR spectrum, δ, ppm: 40.50 (CH3) 43.7 (CH2),
64.6 (ArCHN), 113.4, 113.8, 119.0, 125.7, 126.8, 128.3, 128.4, 128.7, 131.0, 133.3, 145.4, 146.7 (aromatic C),
150.0 (C=N). Mass-spectrum, m/z (Irel, %): 341 [M]+ (81), 91 (100). Found, %: C 80.91; H 6.78; N 12.30.
C23H23N3. Calculated, %: C 80.90; H 6.78; N 12.30.
3-(4-Chlorophenyl)-5-(4-dimethylaminophenyl)-1-phenyl-2-pyrazoline (4j). Yield 2.6 g, 70%,
yellow powder; mp 167-169°C. IR spectrum, ν, cm-1: 3037, 1588, 1495. H NMR spectrum, δ, ppm (J, Hz): 2.95
(6H, s, 2CH3); 3.11 (1H, dd, J1 = 17.1, J2 = 7.2, CHAHBC=N); 3.75 (1H, dd, J1 = 17.1, J2 = 12.4, CHAHBC=N);
5.23 (1H, dd, J1 = 12.4, J2s = 7.2, ArCHN); 6.73-7.68 (m, 13 aromatic H). 13C NMR spectrum, δ, ppm: 40.50
(CH3) 43.5(CH2), 64.7(ArCHN), 113.4, 113.9, 119.3, 126.8, 127.8, 128.6, 128.7, 130.7, 131.9, 134.2, 145.2,
145.5, (aromatic C) 150.1 (C=N). Mass-spectrum, m/z (Irel, %): 377 [M+2]+ (28), 375 [M]+ (89), 91 (100).
Found, %: C 73.49; H 5.87; N 11.16. C23H22ClN3. Calculated, %: C 73.49; H 5.89; N 11.17.

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