Microwave-assisted aromatization of 1,3,5-trisubstituted 2-pyrazolines by silica-supported N-bromosuccinimide as a useful reagent under solvent free 'dry' condition

Article abstract of DOI:10.3987/COM-04-10276

An efficient aromatization of 1,3,5-trisubstituted 2-pyrazolines to theircorresponding pyrazoles by NBS was carried out under microwave irradiation and solvent-free conditions in moderate yields. It has also been observed that, by activating the NBS reage

Full text of DOI:10.3987/COM-04-10276

HETEROCYCLES, Vol. 65, No. 4, 2005
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HETEROCYCLES, Vol. 65, No. 4, 2005, pp. 865 - 870
Received, 8th November, 2004, Accepted, 7th February, 2005, Published online, 8th February, 2005
MICROWAVE-ASSISTED
AROMATIZATION
OF
1,3,5-
TRISUBSTITUTED 2-PYRAZOLINES BY SILICA-SUPPORTED N-
BROMOSUCCINIMIDE AS A USEFUL REAGENT UNDER SOLVENT
FREE ‘DRY’ CONDITION
Davood Azarifar * and Behrooz Maleki
Department of Chemistry, School of Science, Bu-Ali Sina University, Postal code
65174, Hamadan, Iran
*Corresponding author; Fax: +98(811) 8272404, e-mail: azarifar@basu.ac.ir
Abstract- An efficient aromatization of 1,3,5-trisubstituted 2-pyrazolines to their
corresponding pyrazoles by NBS was carried out under microwave irradiation and
solvent-free conditions in moderate yields. It has also been observed that, by
activating the NBS reagent on silica gel as a support the reaction times can be
dramatically reduced and good yields are obtained.
The use of microwave irradiation as a non-conventional energy source has become of considerable
interest in organic chemistry. The frequency of publications and reviews during the last decade has
substantiated the advantages and versatility of microwave irradiation in easy and high yielding
oxidation of organic compounds. This novel method is therefore a fast growing and clean practice in
organic synthesis which has several advantages over classical thermal conditions, including increased
reaction rates, simplicity and improved reaction yields.1-4 The use of supported reagents has gained
popularity because of the improved selectivity, reactivity and associated ease of manipulation.5-8 Since
only the polar reagents activated on the surfaces of various supporting minerals can efficiently absorb
microwave energy, a variety of reagents supported on such surfaces can be utilized to enhance the
organic reactions using a simple microwave (MW) oven.1,3,9-13 Microwave-assisted chemical reactions,
especially when activated on inorganic solid supports and conducted under solvent-free conditions,11,12
have been of great interest to chemists. They offer several advantages over the conventional
homogeneous and heterogeneous reactions in view of the rapid reaction rates and higher yields of the
ensuing pure products. Solvent-free organic synthesis seems to be highly useful technique, especially
when inorganic solid supports are employed.10-12
The oxidative aromatization of 1,3,5-trisubstituted 2-pyrazolines to pyrazoles is biologically
important, since many pyrazole derivatives possess analgesic, anti-inflammatory, antipyretic,
antiarrhythmic, muscle relaxant, psychoanaleptic, antidiabetic and antibacterial activities.14,15 1,3,5-
Trisubstituted 2-pyrazolines can be conveniently prepared from phenylhydrazine and chalcone
intermediates.16-18 Therefore, oxidative aromatization of 2-pyrazolines by oxidizing agents should
provide an efficient method for the preparation of pyrazole derivatives. A variety of reagents such as
Zr(NO3)4,19 Pd/C,20 oxygen activated on carbon,21 Co(II) and oxygen,22 iodobenzene diacetate,23 lead
tetraacetate,24 MnO2,25 and KMnO4,26 have been previously reported most of which suffer from the use
of excess reagent, longer reaction times, higher temperatures, acidity, formation of side products and
toxicity due to the presence of toxic transition metal cations like Co(II), Pb(IV), Hg(II), Mn(IV and
VII), Ag(I), Zr(IV) within the structural formula of the reagents used. Following our previously
reported protocols on the oxidative aromatization of pyrazolines,27-31 we report herein on a facile
microwave-accelerated oxidation of 2-pyrazolines to pyrazoles by NBS under solvent-free condition
using silica gel support.

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HETEROCYCLES, Vol. 65, No. 4, 2005
Our objective in this work focused on some interesting features such as (a) the rapid reaction rates,
higher yields and cleaner reaction conditions and (b) solvent-free condition which seems to be a
highly useful technique, especially it is of many industrial advantages including reduced pollution,
low costs, simplicity in processing and handling.32,33
The reaction of 1,3,5-trisubstituted 2-pyrazolines with NBS using silica gel under microwave
irradiation afforded pyrazoles with no side products (Scheme 1).
R
R
1
2
R
R
MW, NBS / Solid phase
or
N
N
N
N
MW, Silica-supported NBS / Solid phase
Ph
Ph
(1a-l)
(2a-l)
Scheme 1
Table 1. Optimization of Silica Gel for Substrate (1a) (1 mmol)
SiO2 (g)
0.02
0.04
NBS (mmol)
Time (min)
Yield (%)
3.5
3.5
3.5
8
5
6
70
92
75
0.06
The results obtained from the conversion of various 1,3,5-trisubstituted 2- pyrazolines (1a-l) into their
corresponding pyrazoles (2a-l) are recorded in Tables 2 and 3.
Table 2. Substrates (1a-l) and their corresponding products (2a-l).
Substrate
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
Product
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
R1
R2
2-Naphthyl
Ph
o-CH3C6H4
Ph
m-CH3C6H4
o-CH3C6H4
m-CH3C6H4
Ph
p-ClC6H4
m-CH3C6H4
p-ClC6H4
o-ClC6H4
p-(CH3)2NC6H4
o-ClC6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
2-Naphthyl
2-Naphthyl
2-Naphthyl
m-CH3C6H4
p-CH3OC6H4

HETEROCYCLES, Vol. 65, No. 4, 2005
867
Table 3. Microwave-assisted aromatization of 1,3,5-trisubstituted 2-pyrazolines by
NBS and silica-supported NBS under solvent-free conditiona
Substrate Product
NBS (mmol) SiO2 (g)
Time (min)
Yield (%)
60 (92)
58 (88)
49 (90)
64 (86)
54 (91)
60 (88)
58 (86)
52 (76)
56 (82)
54 (92)
46 (90)
58 (86)
3.50
3.25
4.75
5.50
5.25
4.25
4.75
5.00
5.00
4.75
4.25
3.50
0.040
0.037
0.054
0.078
0.060
0.048
0.054
0.057
0.057
0.054
0.048
0.040
10 (5)
7 (3)
10 (4)
9 (3)
8 (3)
7 (2)
10 (3)
8 (3)
10 (4)
7 (2)
8 (2)
8 (3)
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
1g
1h
1i
2g
2h
2i
1j
2j
1k
1l
2k
2l
aThe reaction times and yields obtained using silica-supported NBS are shown in the
parentheses.
EXPERIMENTAL
All melting points were determined on a Büchi 530 melting point apparatus, and reported uncorrected.
1
IR spectra were recorded using a Shimadzu 435-U-04 spectrophotometer (KBr pellets). H-NMR and
13C-NMR spectra were obtained using 90 MHz JEOL FT NMR spectrometer. The CHN analysis was
carried out in Iranian Petroleum Research Center (Ray city, Tehran).
GENERAL PROCEDURE:
Oxidation of 1,3,5-trisubstituted 2-pyrazolines with NBS
The amounts of silica gel and NBS used for 1 mmol of the substrates (1a-l) in all the experiments are
calculated (Table 3) on the basis of the previously optimized amount of SiO2 (0.04 g) for the substrate
(1a) (1 mmol) and NBS (3.50 mmol) (Table 1).
In a flask, a mixture of substrate (1a-l) (1 mmol) and the appropriate amount of NBS (Table 3) was
thoroughly mixed. The resulting mixture was then placed in an alumina bath inside a MW oven and
irradiated (900 W) for 7-10 min in the solid state. After complete conversion of the substrate as
monitored by TLC, the mixture was quenched with 5% NaHCO3 solution and extracted with Et2O.
The organic layer was then separated, washed with H2O, dried over anhydrous MgSO4 and finally
evaporated to give the products (2a-l), which were recrystalized from MeOH (Table 3). In a separate
set of experiments, these reactions were all repeated exactly under the same conditions in the presence
of an appropriate amount of 70-230 mesh silica gel mixed with other components of the reaction and
the results obtained are quoted in the parentheses in Table 3.
3-(2-Naphthyl)-1-phenyl-5-o-tolylpyrazole (2a)
Yield: 332 mg (92%): yellow colored solid; mp 148-150 ºC. IR (KBr): 1589, 1494 cm . H-NMR
(90 MHz, CDCl3):  2.22 (s, 3H, CH3), 6.80 (s, 1H, C4 in pyrazole), 7.16-8.27 (m, 16H, arom). C-
-1
1
υ
13
MNR (22.5 MHz, CDCl3):  9.49 (CH3), 96.51 (C5 in pyrazole), 95.12 (C4 in pyrazole), 149.28,
142.5, 138.92, 137.71, 133.21, 131.92, 120.86, 123.44, 124.56, 125.54, 126.23, 127.05, 127.69,
128.05, 128.46, 129.21, 129.95, 130.57. Anal. Calcd for C26H20N2: C, 86.67; H, 5.56; N, 7.78. Found:
C, 86.62; H, 5.54; N, 7.72.
1,3,5-Triphenylpyrazole (2b)

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HETEROCYCLES, Vol. 65, No. 4, 2005
19
υ
Yield: 260 mg (88%): yellow colored solid; mp 136-138 ºC (lit., mp 138-139 ºC). IR (KBr): 1582,
1491 cm-1. 1H-NMR (90 MHz, CDCl3):  6.93 (s, 1H, C4 in pyrazole), 7.21-7.93 (m, 15H, arom). 13C-
MNR (22.5 MHz, CDCl3):  95.44 (C5 in pyrazole), 90.79 (C4 in pyrazole), 150.08, 142.08, 138.80,
135.99, 121.21, 126.06, 128.06, 128.42, 128.71, 129.26, 129.86, 130.16, 131.99. Anal. Calcd for
C21H16N2: C, 85.11; H, 5.44; N, 9.45. Found: C, 85.00; H, 5.45; N, 9.20.
1-Phenyl-3-p-tolyl-5-m-tolylpyrazole (2c)
Yield: 291 mg (90%): yellow colored solid; mp 94-96 ºC. IR (KBr): 1589,1493 cm . H-NMR (90
MHz, CDCl3):  2.20 (s, 6H, 2CH3), 7.02 (s, 1H, C4 in pyrazole), 7.25-7.61 (m, 13H, arom). C-
-1
1
υ
13
MNR (22.5 MHz, CDCl3):  21.35 (2CH3), 114.11 (C5 in pyrazole), 111.61 (C4 in pyrazole), 149.99,
142.30, 138.134, 133.21, 131.89, 120.34, 122.97, 125.21, 126.31, 126.92, 127.71, 128.22, 129.32,
130.12. Anal. Calcd for C23H20N2: C, 85.18; H, 6.17; N, 8.65. Found: C, 85.10; H, 6.00; N, 8.60.
3-p-Anisyl-1-phenyl-5-o-tolylpyrazole (2d)
-1
1
υ
Yield: 293 mg (86%): yellow colored solid; mp 73-75 ºC. IR (KBr): 1600,1500 cm . H-NMR (90
MHz, CDCl3):  2.19 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.72 (s, 1H, C4 in pyrazole), 7.05-7.83 (m,
13H, arom). 13C-MNR (22.5 MHz, CDCl3):  9.19, 55.08, 113.42 (C5 in pyrazole), 115.68 (C4 in
pyrazole), 150.86, 160.92, 142.22, 140.06, 133.63, 130.12, 121.53, 122.12, 123.42, 125.14, 126.12,
127.28, 128.39, 129.20, 129.82. Anal. Calcd for C23H20N2O: C, 81.18; H, 5.89; N, 8.23. Found: C,
81.10; H, 5.90; N, 8.18.
3-p-Anisyl-1-phenyl-5-m-tolylpyrazole (2e)
-1
1
υ
Yield: 310 mg (91%): yellow colored solid; mp 82-85 ºC. IR (KBr): 1589, 1494 cm . H-NMR (90
MHz, CDCl3):  2.23 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.84 (s, 1H, C4 in pyrazole), 7.06-7.85 (m,
13H, arom). 13C-MNR (22.5 MHz, CDCl3):  21.09, 55.30, 115.12 (C5 in pyrazole), 112.45 (C4 in
pyrazole), 150.96, 160.16, 146.87, 145.30, 139.87, 137.12, 123.12, 125.64, 126.12, 127.24, 127.92,
128.87, 129.12, 130.99, 131.42. Anal. Calcd for C23H20N2O: C, 81.18; H, 5.89; N, 8.23. Found: C,
81.00; H, 5.86; N, 8.20.
3-p-Anisyl-1,5-diphenylpyrazole (2f)
-1
1
υ
Yield: 287 mg (88%): yellow colored solid; mp 78-80 ºC. IR (KBr): 1645, 1594 cm . H-NMR (90
MHz, CDCl3):  3.76 (s, 3H, OCH3) 6.48 (s, 1H, C4 in pyrazole), 6.95-7.78 (m, 14H, arom). 13C-MNR
(22.5 MHz, CDCl3):  56.25, 111.85 (C5 in pyrazole), 106.42 (C4 in pyrazole), 148.30, 158.13,
136.36, 132.18, 131.02, 122.60, 127.21, 127.94, 128.62, 129.04, 129.79, 130.15, 130.73. Anal. Calcd
for C22H18N2O: C, 80.98; H, 5.52; N, 8.59. Found: C, 80.96; H, 5.50; N, 8.57.
3-p-Anisyl-5-p-cholorophenyl-1-phenylpyrazole (2g)
-1
1
υ
Yield: 311 mg (86%): yellow colored solid; mp 99-102 ºC. IR (KBr): 1612, 1500 cm . H-NMR (90
MHz, CDCl3):  3.87 (s, 3H, OCH3) 6.98 (s, 1H, C4 in pyrazole), 7.26-7.91 (m, 13H, arom). 13C-MNR
(22.5 MHz, CDCl3):  54.92, 114.12 (C5 in pyrazole), 111.42 (C4 in pyrazole), 150.09, 159.91, 144.69.
140.95. 132.08, 130.51, 120.53, 121.96, 124.92, 126.82, 127.04, 128.79, 129.26. Anal. Calcd for
C22H17N2O Cl: C, 73.13; H, 4.71; N, 7.75. Found: C, 73.10; H, 4.68; N, 7.72.
3-(2-Naphthyl)-1-phenyl- 5-m-tolylpyrazole (2h)
-1
1
υ
Yield: 274mg (76%): yellow colored solid; mp 80-82 ºC. IR (KBr): 1612, 1500 cm . H-NMR (90
MHz, CDCl3):  3.87 (s, 3H, OCH3) 6.98 (s, 1H, C4 in pyrazole), 7.26-7.91 (m, 13H, arom). 13C-MNR
(22.5 MHz, CDCl3):  54.92, 114.12 (C5 in pyrazole), 111.42 (C4 in pyrazole), 150.09, 159.91, 144.69.
140.95. 132.08, 130.51, 120.53, 121.96, 124.92, 126.82, 127.04, 128.79, 129.26. Anal. Calcd for
C22H17N2O Cl: C, 73.13; H, 4.71; N, 7.75. Found: C, 73.10; H, 4.68; N, 7.72.

HETEROCYCLES, Vol. 65, No. 4, 2005
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5-p-Cholorophenyl-3-(2-naphthyl)-1-phenylpyrazole (2i)
-1
1
υ
Yield: 313 mg (82%): yellow colored solid; mp 134-137 ºC. IR (KBr): 1600,1500 cm . H-NMR (90
MHz, CDCl3):  7.03 (s, 1H, C4 in pyrazole), 7.25-8.29 (m, 16H, arom). 13C-MNR (22.5 MHz,
CDCl3):  116.46 (C5 in pyrazole), 112.11 (C4 in pyrazole), 150.08, 144.43, 139.12, 133.18, 132.08,
130.42, 123.31, 124.11, 126.33, 126.92, 127.12, 127.42, 127.95, 128.42, 129.12, 129.98. Anal. Calcd
for C25H17N2Cl: C, 78.74; H, 4.46; N, 7.35. Found: C, 78.72; H, 4.42; N, 7.20.
5-o-Cholorophenyl-3-(2-naphthyl)-1-phenylpyrazole (2j)
-1
1
υ
Yield: 350 mg (92%): yellow colored solid; mp 77-79 ºC. IR (KBr): 1599,1491 cm . H-NMR (90
MHz, CDCl3):  7.00 (s, 1H, C4 in pyrazole), 7.30-8.51 (m, 16H, arom). 13C-MNR (22.5 MHz,
CDCl3):  115.32 (C5 in pyrazole), 110.80 (C4 in pyrazole), 151.82, 136.08, 134.77, 134.26, 133.24,
132.12, 123.88, 125.05, 125.58, 126.23, 126.80, 127.19, 127.74, 128.12, 128.52, 129.12, 129.91,
130.61. Anal. Calcd for C25H17N2Cl: C, 78.74; H, 4.46; N, 7.35. Found: C, 78.72; H, 4.44; N, 7.00.
5-p-Dimethylaminophenyl-1-phenyl-3-m-tolylpyrazole (2k)
-1
1
υ
Yield: 318 mg (90%): yellow colored solid; mp 68-72 ºC. IR (KBr): 1590, 1520 cm . H-NMR (90
MHz, CDCl3):  2.43 (s, 3H, CH3), 2.87 (s, 6H, NMe2), 7.00 (s, 1H, C4 in pyrazole), 7.24-7.74 (m,
13H, arom). 13C-MNR (22.5 MHz, CDCl3):  19.47, 42.10 (2C), 111.34 (C5 in pyrazole), 106.82 (C4
in pyrazole), 151.22, 165.09, 144.21, 142.17, 136.42, 132.12, 124.32, 125.10, 126.06, 127.12, 127.99,
128.09, 128.92, 129.82, 130.12. Anal. Calcd for C24H23N3: C, 81.59; H, 6.51; N, 11.90. Found: C,
81.52; H, 6.40; N, 11.86.
3-p-Anisyl-5-o-cholorophenyl-1-phenylpyrazole (2l)
Yield: 310 mg (86%): yellow colored solid; mp 60-62 ºC. IR (KBr): 1590,1490 cm . H-NMR (90
MHz, CDCl3):  3.78 (s, 3H, OCH3), 6.87 (s, 1H, C4 in pyrazole), 6.97-7.85 (m, 13H, arom). C-
-1
1
υ
13
MNR (22.5 MHz, CDCl3):  54.97, 112.42 (C5 in pyrazole), 110.02 (C4 in pyrazole), 149.46, 161.12,
144.87, 139.14, 131.22, 130.72, 120.23, 121.82, 124.42, 126.96, 127.04, 128.79, 128.86, 129.20,
129.94. Anal. Calcd for C22H17N2OCl: C, 73.13; H, 4.71; N, 7.75. Found: C, 73.14; H, 4.66; N, 7.35.
ACKNOWLEDGMENT
We wish to thank the University of Bu-Ali Sina, Hamadan, Iran, for financial support to carry out this
research.
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