Microwave-promoted aromatization of 1,3,5-trisubstituted 4,5-dihydro-ih-pyrazoles by calcium hypochlorite under solvent-free conditions

Article abstract of DOI:10.3987/COM-06-10701

An efficient microwave-promoted aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles using calcium hypochlorite [Ca(OCl)₂] has been reported. The reaction proceeds very fast to give pyrazoles in good yields on irradiation of a mixture

Full text of DOI:10.3987/COM-06-10701

HETEROCYCLES, Vol. 68, No. 6, 2006
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HETEROCYCLES, Vol. 68, No. 6, 2006, pp. 1209 - 1215. © The Japan Institute of Heterocyclic Chemistry
Received, 14th February, 2006, Accepted, 14th April, 2006, Published online, 18th April, 2006. COM-06-10701
MICROWAVE-PROMOTED
AROMATIZATION
OF
1,3,5-
TRISUBSTITUTED 4,5-DIHYDRO-1H-PYRAZOLES BY CALCIUM
HYPOCHLORITE UNDER SOLVENT-FREE CONDITIONS
Davood Azarifar* and Azadeh Gharshasbi
Department of Chemistry, School of Science, Bu-Ali-Sina University, Hamadan,
Postal code 65174, Iran
*Corresponding author; Fax: +98-811-8272404, e-mail: azarifar@basu.ac.ir
Abstract - An efficient microwave-promoted aromatization of 1,3,5-trisubstituted
4,5-dihydro-1H-pyrazoles using calcium hypochlorite [Ca(OCl)2] has been
reported. The reaction proceeds very fast to give pyrazoles in good yields on
irradiation of a mixture of the dihydropyrazole and Ca(OCl)2 on alumina without
using solvent.
Application of microwave irradiation technique has received much attention in organic synthesis because
it requires short reaction times and provides simplicity in handling, enhanced reaction yields, and high-
purity products.1 This is evidenced by a considerable research publications and reviews appeared during
the last few decades.2 Five- and six-membered heterocyclic compounds are important constituents that
often exist in biologically active natural products and synthetic compounds of medicinal interest.3 Among
them, 1,3,5-trisubstituted 2-pyrazolines and the corresponding pyrazoles have attracted attention in recent
years because of their various biological activities.4-9 In this regard, the oxidative aromatization of
pyrazolines to the corresponding pyrazoles is, therefore, of considerable importance in medicinal
chemistry.10 However, the aromatization of pyrazolines has not been extensively studied so far. For this
oxidative conversion of pyrazolines, a limited number of reports existed in the literature which include
use of cobalt soap of fatty acids,11 lead tetraacetate,12 manganese dioxide,13 mercury oxide,14 potassium
permanganate,15,16 silver nitrate,17 iodobenzene diacetate,18 and zirconium nitrate.19 Most of these suffer
from the use of excess reagent, longer reaction time, higher temperature, acidity of the reaction media,
formation of by-products and toxicity of transition metal cations required like Co(II), Pb(IV), Hg(II),
Mn(IV and VII), Ag(I), Zr(IV). To avoid these problems, we have previously reported the oxidative
aromatization of several 2-pyrazolines into the corresponding pyrazoles by using readily accessible
oxidants, such as trichloroisocyanuric acid,20,21 1,3-dibromo-5,5-dimethylhydantoin (DBH),22,23 N-bromo-
sulphonamides,24,25 silica-supported N-bromosuccinimide,26 and 4-(4-chlorophenyl)-1,2,4-triazole-3,5-

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HETEROCYCLES, Vol. 68, No. 6, 2006
dione.27
In continuation of our search for other convenient oxidizing reagents, herein, we report a simple and
efficient procedure for the preparation of pyrazoles (2a-m) by oxidative aromatization of 1,3,5-
trisubstituted 4,5-dihydro-1H-pyrazoles (1a-m) on alumina without solvent using calcium hypochlorite
[Ca(OCl)2] under microwave irradiated conditions (Scheme 1).
R1
R1
R2
R2
Ca(OCl)
2
H
or
l , rt
2
C
C
N
N
N
N
2
h
P
h
P
olid phase, MW
s
1a-m
2a-m
Scheme 1
Thus, various substituted 2-pyrazolines were prepared according to our previously reported procedure.8 We
first examined the oxidation of these 2-pyrazolines (1a-m) with Ca(OCl)2 in CH2Cl2. The reaction proceeded
facilely at rt within 4.5 h to give the corresponding yields in high yields (Table 1, CH2Cl2). We found that
the same reaction also took place under solvent-free conditions in much shorter reaction time in better
yields by microwave irradiation (Table 1, Microwave). As shown, all the reactions proceeded in shorter
reaction times (10-20 min) and high yields (85-98%) when the mixture of the pyrazolines and Ca(OCl)2
on alumina was irradiated under solvent-free conditions. Most of the products were obtained in high
1
purity (> 95% by H NMR) after usual work-up and were further purified using silica gel column
chromatography or by recrystallization for analysis. All the products were characterized on the basis of
their 1H NMR, 13C NMR, IR, and mass spectra and elemental analysis.
Table 1. Oxidative Aromatization of 1,3,5-Trisubstituted 2-Pyrazolines (1a-m) in CH2Cl2 and under Solvent-Free Microwave-Irradiated
Conditions.
Substratea
Product
R1
R2
CH2Cl2
Time
(h)
1
4
2.25
1
4.5
2.25
2
2
4
Microwave
Time
Ca(OCl)2
(equiv)
Yieldb
(%)
83
75
88
80
78
85
85
73
78
75
82
75
80
Ca(OCl)2
(equiv)
1
3.5
2
1
3.5
2
1
1
1
2.75
1
2.5
2.5
Yieldb
(%)
98
90
95
97
92
88
98
94
85
96
94
87
98
(h)
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
3-Thienyl
3-Thienyl
3-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Thienyl
2-Naphthyl
Ph
2-Naphthyl
2-Naphthyl
4-CH3OC6H4
4-CH3C6H4
4-ClC6H4
Ph
4-(CH3)2NC6H4
4-ClC6H4
Ph
4-(CH3)2NC6H4
1-Naphthyl
3-Thienyl
4-(CH3)2NC6H4
2-CH3C6H4
4-ClC6H4
Ph
3
5
8
3
5
8
3
3
3
5
3
5
4
0.17
0.17
0.33
0.17
0.17
0.33
0.2
0.2
0.2
0.17
0.17
0.17
0.17
1j
1k
1l
2j
2k
2l
3
1
2.5
3.5
1m
2m
4-(CH3)2NC6H4
a 2-Pyrazolines were prepared according to the literature8 and characterized by IR, 1H-NMR and by direct comparison with authentic
materials. b Isolated yields.

HETEROCYCLES, Vol. 68, No. 6, 2006
1211
The advantages of the present protocol compared to our previously reported methods20-27 are safe,
inexpensive, mild, short reaction time, high reaction yield and environmentally benign.
In conclusion, a practical and efficient microwave-assisted aromatization of 1,3,5-trisubstituted 2-
pyrazolines has been developed using Ca(OCl)2 under solvent-free condition which afforded the
corresponding pyrazoles in shorter reaction times in good yields.
EXPERIMENTAL
IR spectra were recorded using a Shimadzu 435-U-04 spectrophotometer (KBr pellets) and NMR spectra
were obtained using 90 MHz JEOL FT NMR spectrometer. The microanalyses was carried out in Iranian
Petroleum Research Center (Ray city, Tehran, Iran). All 2-pyrazolines were prepared according to our
previously reported procedure.6 Microwave-assisted reactions were conducted in a commercial Panasonic
model NNS59BH microwave oven.
Oxidation of 1,3,5-Trisubstituted 2-Pyrazolines with Ca(OCl)2
General Procedure in CH2Cl2 at rt: A suspension of calcium hypochlorite, pyrazoline (1a-m) (2 mmol)
(the molar ratios of Ca(OCl)2 to the substrate (1a-m) are given in Table 2), and CH2Cl2 (10 mL) were
stirred vigorously at rt. The progress of the reactions was monitored by TLC. The reactions completed in
1.0 - 4.5 h (Table 2). After the reactions have completed, dry silica gel (1g) was added to the reaction
mixture, the solid materials were removed by filteration and washed with CH2Cl2 (10 mL). The solvent
was then evaporated to leave the solid product which was further purified by flash chromatography on
silica gel using acetone / petroleum ether (1:5) as an eluent to give high purity pyrazoles (2a-m) in 73-
88% yields.
General Procedure for solvent-free and microwave irradiation condition: Calcium hypochlorite (the
molar ratios of Ca (OCl)2 to the substrate (1a-m) are given in Table 2) was thoroughly mixed with
pyrazoline (1a-m) (2 mmol), and the mixture was placed in an alumina bath inside a MW oven and
irradiated (900 W) for 0.17-0.33 h in the solid state. After complete conversion of the substrate (TLC), the
resulting mixture was dissolved in CH2Cl2 (20 mL), filtered off and the filtrate was then evaporated under
reduced pressure to yield pyrazolines (2a-m) in 85-98% yields (Table 2). Where necessary, flash
chromatography on silica gel using acetone/petroleum ether (1:5) as an eluent was employed to obtain
1
13
high purity product. All the 2-pyrazoles were characterized on the basis of their IR, H NMR, and C
NMR spectral and micro-analytical data as indicated bellow.
5-(4-Chlorophenyl)-1-phenyl-3-(3-thienyl)pyrazole (2a): Yield: 98%; yellow solid; mp 145-148 ºC
1
(recrystallization from EtOH). IR (KBr): 1591, 1490, 1400, 1356, 968, 832 cm-1. H NMR (90 MHz,

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HETEROCYCLES, Vol. 68, No. 6, 2006
13
CDCl3) δ ppm 7.15-8.05 (m, 12H, ArH), 6.85 (s, 1H, pyrazole). C NMR (22.5 MHz, CDCl3) δ ppm
149.50 (C=N), 138.83, 136.22, 133.42, 132.84 (Carom), 132.35, 131.03, 130.65, 129.21, 126.27, 124.98,
123.51, 121.32 (CHarom), 96.50 (C5 in pyrazole), 95.12 (C4 in pyrazole). Anal. Calcd for C19H13N2SCl: C
67.76; H, 3.86; N, 8.32. Found: C 67.72; H, 3.83; N, 8.28.
1,5-Diphenyl-3-(3-thienyl)pyrazole (2b): Yield: 90%; yellow solid; mp 138-140 ºC. IR (KBr):1587,
1488, 1402, 1357, 969, 769 cm-1. 1H NMR (90 MHz, CDCl3) δ ppm 7.25-8.08 (m, 13H, ArH), 7.05 (s,1H,
13
pyrazole). C NMR (22.5 MHz, CDCl3) δ ppm 150.12 (C=N), 137.16, 134.93, 133.87 (Carom), 132.12,
131.34, 130.70, 129.13, 128.50, 126.88, 125.48, 123.64, 121.26 (CHarom), 103.12 (C5 in pyrazole), 99.36
(C4 in pyrazole). Anal. Calcd for C19H14N2S: C 75.49; H, 4.63; N, 9.27. Found: C 75.32; H, 4.53; N, 9.18.
5-(4-Dimethylaminophenyl)-1-phenyl-(3-thienyl)pyrazole (2c): Yield: 95%; yellow solid; mp120-123
1
ºC. IR (KBr): 1604, 1504, 1402, 1325, 980, 827 cm-1. H NMR (90 MHz, CDCl3) δ ppm 6.99-7.58 (m,
12H, ArH), 6.95 (s, 1H, pyrazole), 2.82 (s, 6H, NMe2 ). 13C NMR (22.5 MHz, CDCl3) δ ppm 151.24 (C=
N), 148.09, 144.23, 142.53, 139.65 (Carom), 130.14, 129.82, 128.94, 128.09, 127.12, 126.06, 125.10,
124.32 (CHarom), 111.34 (C5 in pyrazole), 106.82 (C4 in pyrazole), 42.12 (NMe2). Anal. Calcd for
C21H19N3S: C 73.04; H, 5.51; N, 12.17. Found: C 72.95; H, 5.48; N, 12.04.
5-(4-Chlorophenyl)-1-phenyl-3-(2-thienyl)pyrazole (2d): Yield: 97%; yellow solid; mp 135-138 ºC. IR
1
(KBr): 1572, 1491, 1467, 1371, 969, 829 cm-1. H NMR (90 MHz, CDCl3) δ ppm 6.99-7.69 (m, 12H,
ArH), 6.90 (s,1H, pyrazole). 13C NMR (22.5 MHz, CDCl3) δ ppm 150.17 (C=N), 137.64,136.53, 135.37,
133.20, (Carom), 132.45, 132.02, 130.65, 129.36, 125.63, 124.75, 123.27, 122.06 (CHarom), 96.98 (C5 in
pyrazole), 96.01 (C4 in pyrazole). Anal. Calcd for C19H13N2SCl: C 67.76; H, 3.86; N, 8.32. Found: C
67.68; H, 3.82; N, 8.28.
1,5-Diphenyl-3-(2-thienyl)pyrazole (2e): Yield: 92%; yellow solid; mp 118-120 ºC. IR (KBr): 1580,
1
1495, 1452, 1353, 960, 833 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.00-7.90 (m, 13H, ArH), 6.85 (s,
1H, pyrazole). 13C NMR (22.5 MHz, CDCl3) δ ppm 150.53 (C=N), 139.38, 136.31, 134.15 (Carom),
132.69, 132.02, 130.86, 129.82, 128.30, 126.29, 125.06, 123.94, 122.64 (CHarom), 110.22 (C5 in
pyrazole), 100.14 (C4 in pyrazole). Anal. Calcd for C19H14N2S: C 75.49; H, 4.63; N, 9.27. Found: C
75.68; H, 4.58; N, 9.12.
5-(4-Dimethylaminophenyl)-1-phenyl-(2-thienyl)pyrazole (2f): Yield: 88%; yellow solid; mp 112-115
1
ºC. IR (KBr): 1604, 1488, 1461, 1377, 921, 828 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.06-7.59 (m,
13
12H, ArH), 6.90 (s, 1H, pyrazole), 2.88 (s, 6H, NMe2). C NMR (22.5 MHz, CDCl3) δ ppm 150.54
(C=N), 148.98, 147.73, 145.47, 142.48 (Carom), 133.59, 131.84, 130.10, 129.17, 128.67, 127.02, 126.66,
125.73 (CHarom), 114.27 (C5 in pyrazole), 109.83 (C4 in pyrazole), 42.84 (NMe2). Anal. Calcd for
C21H19N3S: C 73.04; H, 5.51; N, 12.17. Found: C 72.95; H, 5.38; N, 12.14.

HETEROCYCLES, Vol. 68, No. 6, 2006
1213
5-(1-Naphthyl)-1-phenyl-3-(2-thienyl)pyrazole (2g): Yield: 98%; yellow solid; mp115-118 ºC. IR
1
(KBr): 1598, 1490, 1444, 1338, 973, 812 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.00-7.89 (m, 15H,
ArH), 6.77 (s, 1H, pyrazole ). 13C NMR (22.5 MHz, CDCl3) δ ppm 150.68 (C=N), 139.56, 139.16,138.18,
136.57, 134.91 (Carom), 133.17, 132.45, 132.24, 131.03, 130.65, 129.21, 126.27, 124.98, 124.35, 123.51,
123.96, 121.32 (CHarom), 115.31 (C5 in pyrazole), 112.77 (C4 in pyrazole). Anal. Calcd for C23H16N2S: C
78.41; H, 4.54; N, 7.95. Found: C 78.45; H, 4.43; N, 7.92.
3-(2-Naphthyl)-1-phenyl-5-(3-thienyl)pyrazole (2h): Yield: 94%; yellow solid; mp128-132 ºC. IR
1
(KBr): 1590, 1493, 1439, 1375, 964, 815 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.14-8.54 (m, 15H,
ArH), 7.04 (s, 1H, pyrazole). 13C NMR (22.5 MHz, CDCl3) δ ppm 150.34 (C=N), 139.16, 138.18, 136.57,
134.91, 134.50 (Carom), 134.23, 133.98, 133.59, 131.84, 130.10, 129.17, 128.67, 127.02, 126.66, 125.73,
125.13, 124.75 (CHarom), 107.32 (C5 in pyrazole), 99.12 (C4 in pyrazole). Anal. Calcd for C23H16N2S: C
78.41; H, 4.54; N, 7.95. Found: C 78.21; H, 4.24; N, 7.85.
5-(4-Dimethylaminophenyl)-1,3-diphenylpyrazole (2i): Yield: 85%; yellow solid; mp 68-71 ºC. IR
1
(KBr): 1538, 1506, 1456, 1329, 971, 772 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.07-7.56 (m, 15H,
13
ArH), 6.93 (s,1H, pyrazole), 2.86 (s, 6H, NMe2). C NMR (22.5 MHz, CDCl3) δ ppm 151.53 (C=N),
142.33, 140.51, 138.61, 134.29 (Carom), 129.20, 127.02, 126.41, 125.72, 124.81, 122.42, 121.61, 120.35
(CHarom), 102.12 (C5 in pyrazole), 95.14 (C4 in pyrazole), 42.26 (NMe2). Anal. Calcd for C23H21N3: C
81.42; H, 6.19; N, 12.39. Found: C 81.38; H, 6.12; N, 12.35.
3-(2-Naphthyl)-1-phenyl-5-(2-methylphenyl)pyrazole (2j): Yield: 96%; yellow solid; mp 149-152 ºC
(Lit.,20 mp 151-152 ºC).
5-(4-Chlorophenyl)-3-(2-naphthyl)-1-phenylpyrazole (2k): Yield: 94%; yellow solid; mp 128-130 ºC
(Lit.,20 mp 130-133 ºC).
3-(4-Methoxyphenyl)-1,5-diphenylpyrazole (2l): Yield: 87%; yellow solid; mp 74-76 ºC (Lit.,20 mp 75-
77 ºC).
5-(Dimethylaminophenyl)-1-phenyl-3-(4-methylphenyl)pyrazole (2m): Yield: 98%; yellow solid; mp
1
118-120 ºC. IR (KBr): 1600, 1520,1440, 1370, 990, 773 cm-1. H NMR (90 MHz, CDCl3) δ ppm 7.18-
7.75 (m, 13H, ArH), 7.10 (s, 1H, pyrazole), 2.85 (s, 6H, NMe2), 2.68 (s, 3H, Me). 13C NMR (22.5 MHz,
CDCl3) δ ppm 151.45 (C=N), 165.80, 143.92, 142.28, 136.22, 132.07 (Carom), 128.92, 128.09, 127.99,
127.12, 126.06, 125.10, 124.32 (CHarom), 111.24 (C4 in pyrazole), 107.12 (C5 in pyrazole), 41.83
(NMe2), 19.62 (CH3). Anal. Calcd for C24H23N3: C 81.59; H, 6.51; N, 11.90. Found: C 81.55; H, 6.45; N,
11.78.
ACKNOWLEDGMENT
We wish to thank the University of Bu-Ali Sina, Hamadan, Iran, for financial support to carry out this

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research.
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