New one step synthesis of 3,5-disubstituted pyrazoles under microwave irradiation and classical heating

Article abstract of DOI:10.1002/jhet.5570450231

(Chemical Equation Presented) A convenient one pot procedure for the synthesis of 3,5-disubstituted pyrazoles by condensation of chalcones, hydrazine hydrate and sulfur in ethanol under microwave irradiation and conventional heating method is reported. The hydrogen sulfide is produced during the reaction. The pyrazoles are obtained in good yields and excellent state of purity. The structures of new compounds were confirmed by IR, ¹H, and ¹³C NMR, MS and elemental analysis.

Full text of DOI:10.1002/jhet.5570450231

Mar-Apr 2008
503
New One Step Synthesis of 3,5-Disubstituted Pyrazoles under
Microwave Irradiation and Classical Heating
Moha Outirite a, Mounim Lebrini a, Michel Lagrenéea,* and Fouad Bentiss b
a Unité de Catalyse et de Chimie du Solide, CNRS UMR 8181, ENSCL,
B.P. 90108, F-59652 Villeneuve d’Ascq Cedex, France
b Laboratoire de Chimie de Coordination et d'Analytique, Université Chouaib Doukkali,
Faculté des Sciences, B.P. 20, M-24000 El Jadida, Morocco
Received July, 3 2007
O
Ar1
Ar2
NH2NH2, H2O
S
+
Ar2
+
Ar1
N
N
H
A convenient one pot procedure for the synthesis of 3,5-disubstituted pyrazoles by condensation of
chalcones, hydrazine hydrate and sulfur in ethanol under microwave irradiation and conventional heating
method is reported. The hydrogen sulfide is produced during the reaction. The pyrazoles are obtained in
good yields and excellent state of purity. The structures of new compounds were confirmed by IR, 1H, and
13C NMR, MS and elemental analysis.
J. Heterocyclic Chem., 45, 503 (2008).
improving yields, as well as to produce new reactions
[14]. This technique has been applied with success to a
number of synthesis of heterocylic compounds proceeding
with or without solvent such as 1,2,4-triazoles [15,16],
1,3,4-oxadiazoles [17] and 1,3,4-thiadiazoles [18,19].
INTRODUCTION
The synthesis of pyrazoles remains of great interest
because they constitute an important class in pharma-
ceutical and agrochemical industry [1]. The 3,5-
Disubstituted pyrazoles have displayed a wide range of
biological activities such as in inhibiting lung cancer cell
growth [2,3]. For many years, numerous methods have
been developed in order to synthesize this class of
heterocycles [4]. Very little is known concerning the
synthesis of pyrazoles using chalcones as starting
compounds [5]. The synthesis of 3,5-disubstituted
pyrazoles by condensation of 1,3-diketones with hydra-
zine or its derivatives is the most widely used method [6],
but unfortunately this condensation leads to the formation
of undesired isomers as major components [7-9]. As a
part of a program directed to obtain 3,5-disubstituted
pyrazole molecules which can be used as corrosion
inhibitors and organic ligands in coordination chemistry
[10,11], we have particularly developed a simple new one
step synthesis of the 3,5-disubstited pyrazoles from
chalcones with hydrazine hydrate in the presence of sulfur
(Scheme 1. We have compared the results obtained by
microwave irradiation and conventional heating. This
reaction was easily achieved by microwave irradiation
and the pyrazoles are obtained in good yields and
excellent state of purity. The chalcones used are either
commercialized products or quickly prepared by a general
procedure [12]. The application of microwave in organic
synthesis for conducting reactions at highly accelerated
rates is an emerging technique [13]. In recent years, the
use of microwave energy has become popular among
synthetic organic chemists both to improve classical
organic reactions, shortening reaction times and
Scheme 1
O
Ar1
Ar2
NH2NH2, H2O
S
+
Ar2
+
Ar1
N
N
H
1, 2a
Ar1 = C6H5
Ar2 = C6H5
b
c
d
e
f
g
h
i
Ar1 = 4-CH3OC6H4
Ar1 = 4-CH3C6H4
Ar1 = 4-CH3C6H4
Ar1 = 4-CH3C6H4
Ar1 = 4-ClC6H4
Ar1 = 4-FC6H4
Ar2 = 4-CH3OC6H4
Ar2 = 4-CH3C6H4
Ar2 = 4-ClC6H4
Ar2 = C6H5
Ar2 = 4-ClC6H4
Ar2 = 4-FC6H4
Ar2 = 4-FC6H4
Ar2 = 4-ClC6H4
Ar1 = 4-CH3OC6H4
Ar1 = 4-FC6H4
j
Ar1 = 4-NO2C6H4
Ar2 = 4-NO2C6H4
RESULTS AND DISCUSSION
The 3,5-disubstituted pyrazoles prepared from
chalcones by the action of hydrazine in presence of sulfur
are obtained in good yield. We have compared the speeds
of reactions performed under microwave irradiation with
those performed under classical heating. The results show
that for products 2a-j, the microwave irradiation appeared
to be more rapid, indeed, after 2 h of microwave heating,
the compounds 2a-j can be obtained in excellent yields
and good purity whereas with conventional heating, 15 h
were required. The reaction between chalcones and
hydrazine leads first to the formation of the corresponding

504
M. Outirite, M. Lebrini, M. Lagrenée and F. Bentiss
Vol 45
EXPERIMENTAL
dihydropyrazoles. This latter is rapidly dehydrogenated by
sulfur (Scheme 2). The hydrogen sulfide is produced
during this reaction.
Melting points were determined on an IA 9000 series
Electrothermal apparatus and are uncorrected. IR spectra were
recorded on Perkin-Elmer a Spectrum One FTIR Spectrometer
(values in cm-1). H and 13C nmr spectra were recorded on a
The elemental analysis (Table) and mass spectra are in
accordance with the proposed structures of new pyrazole
derivatives. The melting points of the already known
pyrazoles agree with those reported in the literature
(Table). The IR, 1H and 13C nmr data are given.
1
1
Bruker F.T. AC 300 spectrometer (300 MHz for H nmr and 75
MHz for 13C nmr) using dimethyl-d6 sulfoxide (DMSO) solvent.
Matrix assisted laser desorption ionization (MALDI) and time-
of-flight mass spectrometry (TOF-MS) are used to record the
mass spectra of the pyrazole compounds. All starting materials
were of reagent grade and used as purchased.
Scheme 2
General Procedure for the Synthesis of 3.5-disubstituted
pyrazoles (2a-j).
O
Ar1
Ar2
H2N_ NH2
+
Ar1
Ar2
Microwave irradiation method. A mixture of chalcones
(1a-j) (0.02 mole), sulfur (0.03 mole) and hydrazine
monohydrate (0.04 mole) in ethanol (20 ml) was introduced
into a fluoropolymere cylindrical flask placed in a MARS5
XP-1500 PLUS CEM multimode microwave reactor and
irradiated (300 W) for 2 h at 150°C under pressure. After
cooling, the solvent was evaporated under reduced pressure.
The hydrogen sulfide was trapped using liquid nitrogen. The
residue was treated with ethanol or ethyl acetate and filtered
to remove the excess of sulfur. The solid compound is
collected by filtration and dried.
N
NH2
Ar1
Ar2
Ar1
Ar2
_
NH2
H
N
N
H
N
S
Classical heating method. The mixture of chalcones
(1a-j) (0.05 mole), sulfur (0.07 mole) and hydrazine
monohydrate (0.1 mole) in ethanol (50 ml) was introduced into a
steel autoclave. The resulting mixture was heated to 140°C for
15 hours with vigorous stirring. After cooling, the residue was
treated in the same procedure as described above.
Ar1
Ar2
H
N
N
Table
Physical and Analytical Data of 3,5-Disubstuted Pyrazoles 2a-j.
Yield
Analysis %
Compound
No.
Mp
Molecular
Formula
(%)
Calcd./Found
Ar1
Ar2
(°C)
MW
87
Heating
C
H
N
2a
2b
2c
2d
2e
2f
C6H5
C6H5
83
91
83
91
82
70
68
61
75
55
199
[20,21]
172
C15H12N2
C17H16N2O2
C17H16N2
81.79
81.57
72.84
72.91
82.22
82.34
71.51
71.54
82.02
82.17
62.31
62.63
70.31
70.55
71.63
71.34
66.06
65.96
58.07
58.10
5.49
5.72
5.75
5.98
6.49
6.61
4.88
4.67
6.02
5.98
3.49
3.42
3.93
3.87
4.88
4.93
3.70
3.52
3.25
3.33
12.72
12.48
9.99
4-OCH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-OCH3C6H4
4-CH3C6H4
4-ClC6H4
C6H5
94
89
92
90
78
75
82
79
63
[22]
10.37
11.28
11.24
10.42
10.28
11.96
12.01
9.69
234
212
C16H13Cl N 2
C16H14N2
[21]
175
4-ClC6H4
4-FC6H4
241
[21]
210
[22]
182
C15H10Cl2N2
C15H10F2N2
C16H13FN2O
C15H10ClFN2
C15H10N4O4
9.45
2g
2h
2i
4-FC6H4
10.93
10.89
10.44
10.69
10.27
10.35
18.06
18.17
4-OCH3C6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-NO2C6H4
220-222
[21]
2j
4-NO2C6H4
266-268
[22]

Mar-Apr 2008
New one step synthesis of 3,5-disubstituted pyrazoles
505
1
IR, H, and 13C nmr, MS and elemental analysis. Data are
in accordance with the proposed structures, are given below.
The general formula of the parent pyrazoles (2a-j) is given
below:
55.43, 99.57, 115.23, 123.92, 125.23, 128.68, 132.33, 136.08,
142.94 MALDI-TOFMS: m/z 269 (M +1).
3-(4-Chlorophenyl)-5-(4-fluorophenyl)-1H-pyrazole (2i). ir
(cm-1) : 3140, 3101, 2919, 2851, 1884, 1611, 1502, 1448, 1227,
1
1093, 826, 784. H nmr (DMSO-d6) : δ (ppm) 7.22 (s,1H),7.50-
7.54 (m, 4H); 7.83-7.86 (d, 4H, J = 7.1), 13.36 (s, 1H). 13C nmr
(DMSO-d6): δ (ppm) 102.15, 114.83, 126.49, 129.73, 149.38.
MALDI-TOFMS: m/z 273, 274, 275 (M +1).
R1
R2
N
N
3,5-Bis(4-nitrophenyl)-1H-pyrazole (2j). ir (cm-1): 3147,
3085, 2987, 2841, 1888, 1605, 1572, 1505, 1492, 1400 1328,
H
3,5-Diphenyl-1H-pyrazole (2a). ir (cm-1) : 3137, 3085,
1
2987, 2841, 1888, 1606, 1486, 1308, 1087, 971, 828, 769. H
nmr (DMSO-d6): δ (ppm) 7.01 (s, 1H), 7.37-7.43 (m, 6H); 7.66-
7.70 (m, 4H), 13.38 (s, 1H). 13C nmr (DMSO-d6): δ (ppm) 99.60,
125.07, 127.77, 128.81, 129.40, 133.52, 144.2 MALDI-TOFMS:
m/z 221 (M +1).
1
1302, 1240, 1111, 971, 833, 757. H nmr (DMSO-d6): δ (ppm)
6.88 (s,1H); 7.18(d, J = 8.54 Hz, 4H); 7.76 (d, 4H, J = 8.54 Hz),
13.35 (s, 1H). 13C nmr (DMSO-d6): δ (ppm) 100.01, 124.18,
125.63, 128.13, 130.02, 137.90, 148.41. MALDI-TOFMS: m/z
311 (M +1).
3,5-Bis(4-methoxyphenyl)-1H-pyrazole (2b). ir (cm-1) :
3320, 3210, 2961,2836, 1188, 1608, 1572, 1530, 1240, 1173,
1020, 833, 789. 1H nmr (DMSO-d6): δ (ppm) 3.85 (s, 6H) OCH3;
6.95 (s, 1H); 7.00 (d, 4H, J = 8.4); 7.71 (d, 4H, J = 8.4), 13.34 (s,
1H). 13C nmr (DMSO-d6): δ (ppm) 55.47, 98.30, 116.30, 126.97,
128.40, 146.44, 162.97. MALDI-TOFMS: m/z 281 (M +1).
3,5-Bis(4-methylphenyl)-1H-pyrazole (2c). ir (cm-1) : 3111,
3018, 2914, 2905, 2851, 1882, 1609, 1502, 1458, 1170, 968, 813,
764. 1H nmr (DMSO-d6): δ (ppm) 2.32 (s, 6H) CH3; 7.07 (s,
REFERENCES AND NOTES
*
Corresponding author. Tel.: +33-320-337-746; fax: +33-320-
436-814; E-mail address: michel.lagrenee@ensc-lille.fr (Michel Lagrenée).
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1H); 7.25 (d, 4H, J = 7.9); 7.71 (d, 4H, J = 7.9), 13.25 (s, 1H). 13
C
nmr (DMSO-d6): δ (ppm) 20.79, 98.91, 124.95, 127.16, 129.30,
131.51, 136.24, 145.38. MALDI-TOFMS: m/z 249 (M +1).
3-(4-Chlorophenyl)-5-(4-methylphenyl)-1H-pyrazole (2d).
ir (cm-1) : 3111, 2992, 2909, 2846, 1880, 1613, 1502, 1466,
1442, 1168, 968, 821, 769. 1H nmr (DMSO-d6): δ (ppm) 2.33 (s,
3H) CH3; 7.16 (s, 1H); 7.49-7.51 (d, 4H, J = 8.2); 7.80-7.84 (d,
4H, J = 8.2), 13.37 (s, 1H). 13C nmr (DMSO-d6): δ (ppm) 20.79,
99.48, 124.99, 126.71, 128.74, 129,39, 132.03, 137.29, 143.90
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3-(4-Methylphenyl)-5-(4-phenyl)-1H-pyrazole (2e). ir (cm-1) :
3111, 3018, 2987, 2909, 2849, 1880, 1603, 1502, 1461, 1179, 971,
831, 769. 1H nmr (DMSO-d6): δ (ppm) 2.33 (s, 3H) CH3; 7.13 (s,
1H); 7.28-7.36 (m, 5H); 7.77 (d, 4H, J = 7.9), 13.30 (s, 1H). 13C
nmr (DMSO-d6): δ (ppm) 14.52, 92.97, 118.75, 121.39, 122.47,
123.06, 130.81, 146.25 MALDI-TOFMS: m/z 235 (M +1)
3,5-Bis(4-chlorophenyl)-1H-pyrazole (2f). ir (cm-1) : 3139,
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1
3105, 2853, 1888, 1610, 1492, 1230, 1156, 970, 825, 767. H
nmr (DMSO-d6): δ (ppm) 7.17 (s, 1H); 7.41-7.47 (d, 4H, J =
7.4); 8.05-8.11 (d, 4H, J = 7.4), 13.34 (s, 1H). 13C nmr (DMSO-
d6): δ (ppm) 99.90, 126.39, 128.71, 130.74, 137,39, 147,23
MALDI-TOFMS: m/z 289, 290, 291, 292, 293 (M +1).
3,5-Bis(4-fluorophenyl)-1H-pyrazole (2g). ir (cm-1) : 3142,
3002, 2857, 1598, 1515, 1328, 1308, 1108, 973, 852, 751, 678.
1H nmr (DMSO-d6): δ (ppm) 7.21 (s, 1H); 7.49-7.53 (m, 4H);
7.82-7.85 (d, 4H, J = 7.0), 13.35 (s, 1H). 13C nmr (DMSO-d6): δ
(ppm) 98.54, 123.60, 125.71, 128.09, 132.29, 135.48, 144.82
MALDI-TOFMS: m/z 257 (M +1).
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3-(4-Fluorophenyl)-5-(4-methoxyphenyl)-1H-pyrazole (2h).
ir (cm-1) : 3107, 2991, 2913, 2843, 1610, 1486, 1518, 1492,
1
1305, 1282, 1080, 973, 852, 753, 680. H nmr (DMSO-d6): δ
(ppm) 3.79 (s, 3H) OCH3; 6.95 (s,1H), 7.16 (d, 2H, J = 7.63 Hz);
7.45-7.59 (m, 6H), 13.34 (s, 1H). 13C nmr (DMSO-d6): δ (ppm)
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