Silica-supported 1,3-dichloro-5,5-dimethylhydantoin (DCH) as a useful reagent for microwave-assisted aromatization of 1,3,5-trisubstituted pyrazolines under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2010.10.023

1,3,5-Trisubstituted pyrazolines are rapidly and conveniently oxidized to their corresponding pyrazoles by 1,3-dichloro-5,5-dimethylhydantoin (DCH) in solution and solvent-free conditions under microwave irradiation. The presence of silica gel as a suppor

Full text of DOI:10.1016/j.cclet.2010.10.023

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 447–450
www.elsevier.com/locate/cclet
Silica-supported 1,3-dichloro-5,5-dimethylhydantoin (DCH)
as a useful reagent for microwave-assisted aromatization of
1,3,5-trisubstituted pyrazolines under solvent-free conditions
Davood Azarifar a, Elahe Nadimi b, Mohammd Mehdi Ghanbari c,
*
a Department of Chemistry, School of Science, Bu Ali Sina University, 65174 Hamadan, Iran
b Department of Chemistry, Kavar Branch, School of Applied Scientific and Technology, Kavar, Iran
c Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
Received 26 August 2010
Available online 15 January 2011
Abstract
1,3,5-Trisubstituted pyrazolines are rapidly and conveniently oxidized to their corresponding pyrazoles by 1,3-dichloro-5,5-
dimethylhydantoin (DCH) in solution and solvent-free conditions under microwave irradiation. The presence of silica gel as a
supporting agent is shown to be effective in reducing the reaction times and increasing the yields.
# 2010 Mohammd Mehdi Ghanbari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Pyrazolines; 1,3-Dichloro-5,5-dimethylhydantoin (DCH); Aromatization; Solid-surface; Microwave irradiation
Microwave irradiation is an unconventional energy source, which has recently become of considerable interest in
organic chemistry. During the last decade, a number of publications and reviews have advocated 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 high reaction yields [1]. The use of supported reagents
has gained popularity because of the improved selectivity, reactivity and associated ease of manipulation [2]. Since
only the polar reagents adsorbed on the surfaces of various supporting mineral adsorb microwave energy, a variety of
reagent supported on such surfaces can be utilized for the enhancement of organic reactions using a simple microwave
(MW) oven. Solvent free organic synthesis seems to be highly useful technique, especially when inorganic solid
supports are used [3]. The oxidation of 1,3,5-trisubstituted pyrazolines 1 to pyrazoles 2 is biologically very important,
since many pyrazole derivatives 2 possess analgesic, anti-inflammatory, anti-pyretic, anti-arrhythmic, muscle
relaxant, psychoanaleptic, anti-diabetic and anti-bacterial activities [4]. 1,3,5-Trisubstituted pyrazolines 1 can be
easily prepared from phenylhydrazine and chalcon derivatives [5]. Therefore, oxidative aromatization of pyrazolines 1
by oxidizing reagents should provide an efficient method for the preparation of pyrazole derivatives 2. Although a
variety of reagents such as Zr(NO3)4 [6], Pd/C [7], Co(II) and oxygen [8], iodobenzene diacetate [9], lead tetraacetate
[10], MnO2 [11], potassiumpermanganate [12], and N-bromosuccinimide (NBS) [13], have been previously reported,
* Corresponding author.
E-mail address: M.Mehdi.Ghanbari@Gmail.com (M.M. Ghanbari).
1001-8417/$ – see front matter # 2010 Mohammd Mehdi Ghanbari. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.10.023

[()TD$FIG]
448
D. Azarifar et al. / Chinese Chemical Letters 22 (2011) 447–450
Cl
H
R1
R1
R2
N
N
R2
MW
O
O
+
+
N
N
N
N
AcOH or Solvent-Free
NH
N
O
O
Ph
Ph
Cl
1
2
Scheme 1.
we report here in a facile microwave-accelerated oxidation of pyrazolines 1 to pyrazoles 2 by 1,3-dichloro-5,5-
dimethylhydantoin (DCH) in solution (AcOH) and under solvent-free conditions using silica gel. As part of our current
studies on the development of new routes in heterocyclic synthesis [14–16], we now report an efficient one-pot
synthesis of pyrazoles 2 (Scheme 1).
Our objective in this work focused on some interesting features such as the rapid reaction rates, higher yields,
cleaner reaction conditions and solvent-free conditions which seems to be a highly useful technique, especially it has
many industrial advantages including reduced pollution, low costs, inprocessing and handling [17]. The reaction of
1,3,5-trisubstituted pyrazolines 1 with DCH in solution and using silica gel under microwave irradiation afforded
pyrazoles 2 with no side products (Scheme 1). The results obtained from the conversion of various 1,3,5-trisubstituted
pyrazolines 1 to their corresponding pyrazoles 2 are recorded in Table 1.
Although we have not yet established the mechanism of formation of 2 in an experimental manner, a possible
explanation is proposed in Scheme 2. Presumably, the ionic intermediate 3, formed from the Cl+ and the pyrazolines,
undergo eliminate HCl to produce the intermediates 5, which apparently 4 is attacked by the 5. Finally, a proton shift
and the rearrangement to produce the final products 2 in excellent yields.
In conclusion, solvent-free microwave-assisted thermolysis proved to be a rapid oxidation of pyrazolines 1 to
pyrazoles 2 when compared with conventional solution phase or heterogeneous reactions. The results indicated that
the presence of silica gel support in the reaction can increase the efficiency of the oxidant in reducing the reaction
times and improving the yields. Finally, the proposed procedure for the synthesis of pyrazole derivatives 2 is
advantageous due to its experimental simplicity, short reaction time, and excellent yields.
Table 1
Oxidative aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles (1 mmol) 2a–r with DCH in AcOH at r.t (I) and under microwave-
irradiated condition in AcOH (II) and under microwave-irradiated condition in solvent free (III).
2
R
Substrate
Producta
R1
Time (h)
Yieldb(%)
Mp (8C)
I
II
III
I
II
III
Found
Reporteda
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
Ph
Ph
4
0.16
0.25
0.16
0.13
0.16
0.183
0.2
0.083
0.1
79
85
78
86
78
89
80
82
73
75
88
95
98
98
97
86
80
78
86
78
70
78
69
82
72
76
68
62
87
90
95
85
86
89
68
78
86
82
69
78
70
80
89
87
78
95
87
89
80
79
77
90
76
86
134–136
116–118
80–82
139–140
112–114
78–80
Ph
3-ClC6H4
4-CH3OC6H4
4-NO2C6H4
4-(CH3)2NC6H4
3-CH3C6H4
2-Furyl
5
Ph
4.5
5
0.05
0.06
0.05
0.05
0.083
0.05
0.06
0.05
0.083
0.083
0.05
0.083
0.06
0.06
0.083
0.06
Ph
140–142
68–70
142–143
68–71
Ph
4.5
5
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
3-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
2-Thienyl
2-Thienyl
3-Thienyl
2-Naphthyl
2-Naphthyl
4-CH3C6H4
2-Thienyl
92–94
94–96
1g
1h
1i
2g
2h
2i
5
90–92
96–98
4-(CH3)2NC6H4
2-Thienyl
Ph
5
0.16
0.16
0.25
0.25
0.16
0.2
118–120
126–128
77–79
118–120
128–129
74–76
4.5
5.7
5.5
4
1j
2j
1k
1l
2k
2l
2-ClC6H4
4-ClC6H4
Ph
69–71
66–68
126–128
113–115
117–119
146–148
125–127
57–59
135–138
118–120
120–123
148–150
128–132
–
1m
1n
1o
1p
1q
1r
2m
2n
2o
2p
2q
2r
4.5
5
4-(CH3)2NC6H4
2-CH3C6H4
3-Thienyl
4-i-PrC6H4
C6H5CH CH
0.25
0.18
0.16
0.16
0.13
5
4.5
4.7
5
71–73
71–73
a
All the products were characterized on the basis of their IR, 1H NMR and 13C NMR spectral analysis and compared with the literature data [18–21].
Isolated yields.
b

[()TD$FIG]
D. Azarifar et al. / Chinese Chemical Letters 22 (2011) 447–450
449
Cl
Cl
R1
N
N
R2
1
O
O
+
N
N
N
N
Cl
O
O
Ph
Cl
3
4
-HCl
R2
R1
R1
R2
4
N
N
N
N
Ph
Ph
5
2
Scheme 2.
1. Experimental
Aldehydes, ketones, acetic acid and 1,3-dichloro-5,5-dimethylhydantoin (DCH) were obtained from Fluka and
were used without further purification. 2-pyrazolines 1 was prepared by known methods [5]. Melting points
(uncorrected) were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, N and S were
performed using a Heraeus CHN–O-Rapid analyzer. The experimental data were in good agreement with the
calculated values. 1H and 13C NMR spectra (CDCl3) were measured with a Bruker DRX-300 Avance spectrometer. IR
spectra were recorded on a Shimadzu IR-460 spectrometer. The microwave oven used for this work was an ETHOS-
MR (800W, 180 8C) operating at 2450 MHz.
1.1. General procedure for the preparation of 2 in AcOH
To a solution of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 1a-r (1 mmol) in AcOH (10 mL) was added DCH
(4 mmol), and the mixture was stirred vigorously at room temperature. The progress of the reaction was monitored by
TLC using EtOAc/n-hexane (1/4). The reactions completed in 4–5 h (Table 1). After complete conversion as indicated
by TLC, the mixture was quenched with an aq NaHCO3 solution and extracted with Et2O. The organic layer washed
with H2O, derived and evaporated to give the products 2a-r in 73–98% yields (Table 1).
1.2. General procedure for the preparation of 2 using microwave irradiation in AcOH
A mixture of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 1a–r (1 mmol) and DCH (4 mmol) was dissolved in
AcOH (15 ml), the solution was placed in an alumina bath inside a MW oven and irradiated at 300 W for 0.2–0.183 h
(Table 1). After complete conversion as indicated by TLC, the mixture was quenched with an aq NaHCO3 solution and
extracted with Et2O. The organic layer washed with H2O, derived and evaporated to give the products 2a–r in 62–95
yields (Table 1). All of the isolated products except 2q are known compounds and their spectra and physical data have
been reported in the literature [18–21].
1.3. General procedure for the preparation of 2 using microwave irradiation under solvent-free (silica-supported)
In solvent-free (silica-supported) a mixture of DCH (the molar ratios of DCH to substrate 1a–r are 4/1) and the
substrate 1a–j (1 mmol), was thoroughly mixed with 70–320 mesh silica gel (9 mg per mmol of the reagent) and the
mixture was placed in an alumina bath inside a MW oven and irradiated (300 W) for the time given in Table 1. After
complete conversion as indicated by TLC, the mixture was quenched with an aq NaHCO3 solution and extracted with
Et2O. The organic layer washed with H2O, and evaporated to give the products 2a–r.
3-(4-Methylphenyl)-1-phenyl-5-(4-i-propylphenyl)pyrazole (2q): yellow solid; mp: 57–59 8C; yield: 0.30 g (86%);
IR (KBr) (nmax/cmÀ1): 1597 (C N), 1498 (C C); Anal. Calcd. (%) for C25H24N2 (352.47): C, 85.19; H, 6.86; N, 7.95.

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D. Azarifar et al. / Chinese Chemical Letters 22 (2011) 447–450
Found: C 85.28; H, 6.78; N, 7.92; 1H NMR (300 MHz, CDCl3): d 1.27 (d, 6H, 3JHH = 7.0 Hz, 2 Me), 2.40 (s, 3H, Me),
2.89 (m, 1H, CH), 7.22–7.90 (m, 14H, ArH); 13C NMR (75 MHz, CDCl3): d 21.3 (Me), 23.9 (2 Me), 33.7 (CH),
106.4(CH), 125.9 (2 CH), 126.3 (CH), 126.7 (2 CH), 127.2 (2 CH), 127.4 (2 CH), 128.5 (2 CH), 128.7 (2 CH), 130.0
(C), 130.3 (C), 138.4 (C), 139.5 (C), 144.5 (C N), 148.6 (C), 152.8 (C N).
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