Solvent-free synthesis of 1, 3-diphenyl-5-arylpyrazole derivatives

Article abstract of DOI:10.2174/157017809788681383

The synthesis of 1, 3-diphenyl-5-arylpyrazoles via the reactions of 2, 3-epoxy-1-phenyl-3-aryl-1-propanones with phenylhydrazine was carried out in 48-84% yields at 230 °C under solvent-free condition within 1.5 h. This method provides several advantages

Full text of DOI:10.2174/157017809788681383

384
Letters in Organic Chemistry, 2009, 6, 384-386
Solvent-Free Synthesis of 1,3-Diphenyl-5-arylpyrazole Derivatives
Ji-Tai Li*, Ying Yin and Xian-Tao Meng
College of Chemistry and Environmental Science, Hebei University; Key Laboratory of Analytical Science and Technol-
ogy of Hebei Province, Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, Baod-
ing 071002, P.R. China
Received December 29, 2008: Revised April 16, 2009: Accepted April 23, 2009
Abstract: The synthesis of 1,3-diphenyl-5-arylpyrazoles via the reactions of 2,3-epoxy-1-phenyl-3-aryl-1-propanones
o
with phenylhydrazine was carried out in 48-84% yields at 230 C under solvent-free condition within 1.5 h. This method
provides several advantages such as operational simplicity, higher yield and solvent-free.
Keywords: cyclization, 1,3-diphenyl-5-arylpyrazole, synthesis, solvent-free reaction, heterocycles.
INTRODUCTION
RESULTS AND DISCUSSION
Aryl pyrazoles are ubiquitous substructures with impor-
tant biological activity and pharmacological properties [1],
including antimicrobial [2], anti-inflammatory [3], hypogly-
cemic [4], anti-hypertensive [5] and analgesic [6] properties.
As a part of drug development program, numerous methods
for the synthesis of 1,3,5-triarylpyrazoles have been reported
[7-12]. However, in spite of their potential utility, some of
the reported methods suffer from draw-backs such as longer
reaction time, lower yield, expensive transition metal
oxidantꢀꢁuse of toxic organic solvent and complexity of
work-up. Thus, the development of a simple, efficient and
green method for the preparation of 1,3-diphenyl-5-
arylpyrazoles is an active area of research.
Under solvent-free condition, the effect of the reaction
conditions on the condensation of 2,3-epoxyl-1,3-diphenyl-
1-propanone (1a) and 2 was observed. The results are sum-
marized in Table 1.
As shown in Table 1 (Entries 1-5), the yield of 3a in-
creased from 48% to 82 % by changing the temperature from
170 oC to 230 oC. When the temperature was 240 oC, the 3a
was obtained in 77 % yield. The results showed that 230 oC
was the appropriate temperature for this reaction.
The molar ratio of substrate and reagent showed crucial
effect on the reaction yield. When the molar ratio of 1a and 2
was 1:1.1, 3a was obtained in 82% yield (Entry 4). When the
O
O
Ar
230 oC
Ar
N
N
NHNH2
+
1a-j
Scheme 1. Synthesis of 1,3-diphenyl-5-arylpyrazoles.
3a-j
2
One of the greatest environmentally problematic aspects
of organic synthetic chemistry is the use of solvent. The best
way is to eliminate the use of solvent [13]. Refraining from
the use of solvents in organic synthesis has led to improved
results and milder synthetic procedures in some cases.
Moreover, solvent-free thermal reactions are more important
for practical synthetic processes in the industry [14,15].
molar ratio was 1:1 or 1:1.2, the yield of 3a was 70% and
82% respectively (Entries 6 and 7).
In order to examine the effect of reaction times, the reac-
tion of 1a and 2 was selected as a model reaction. It was
found that when the reaction time was 1.5 h, the yield of 3a
was 82%, and prolonged reaction time had little effect on
yield.
All of the results stated above spur us to study the possi-
bility of solvent-free synthesis of 1,3-diphenyl-5-
arylpyrazoles. Herein, we wish to report a simple and effi-
cient method for synthesis of 1,3-diphenyl-5-arylpyrazoles
under the solvent-free condition (Scheme 1).
From the results above, the reaction conditions we chose
were as follows: the ratio of 1a and 2 was 1:1.1, the tempera-
o
ture was 230 C and the reaction time was 1.5 h. Using this
reaction system, a series of 1,3-diphenyl-5-arylpyrazoles
were prepared. The results are summarized in Table 2.
From these results, we can deduce that the yields are in
general, similar or higher than those described in literatures
[7-12]. Compared with other reported methods, the main
*Address correspondence to this author at the College of Chemistry and
Environmental Science, Hebei University, Baoding, 071002, Hebei Prov-
ince, P.R. China; Fax: +86-312-5079628; E-mail: lijitai@ hbu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Solvent-Free Synthesis of 1,3-Diphenyl-5-arylpyrazole
Letters in Organic Chemistry, 2009, Vol. 6, No. 5
385
Table 1. The Effect of Reaction Conditions on the Condensation of 1a and 2
Entry
Molar ratioa
Time (h)
Temp. (oC) b
Isolated yield (%)
1
2
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1
2
2
170
190
210
230
240
230
230
230
230
230
48
55
74
82
77
70
82
82
82
79
3
2
4
2
5
2
6
2
7
1:1.2
1:1.1
1:1.1
1:1.1
2
8
1.5
2.5
3
9
10
aMolar ratio of 1a and 2.
bThe temperature of oil bath.
Table 2. Condensation of 2,3-Epoxy-1-phenyl-3-aryl-1-propanones and Phenylhydrazinea
Entry
Ar
Product
Isolated yield (%)
m.p. (oC) (lit.)
a
b
c
d
e
f
C6H5
3a
3b
3c
3d
3e
3f
82
56
48
84
75
81
77
81
82
79
138-139(138-138.5) [17]
128-130(130) [18]
137-139(139-141) [8]
yellow liquid
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
3-ClC6H4
91-93(93-95) [8]
106-108(104-105) [7b]
yellow liquid
4-ClC6H4
g
h
i
2, 4- Cl2C6H3
3, 4- Cl2C6H3
2-CH3OC6H4
3-BrC6H4
3g
3h
3i
83-84
145(116-117) [7b]
107
j
3j
aReaction temperature, 230 oC; reaction time,1.5 h ; the molar ratio of 1a and 2, 1:1.1.
advantages of the procedure are operational simplicity,
higher yields and solvent-free, which make it a useful and
attractive process for the synthesis of these compounds.
Typical Procedure for the Preparation of 1,3-Diphenyl-5-
arylpyrazoles
A 25 mL round-bottomed flask was charged with 1a-j
(1.0 mmol), and 2 (0.119 g, 1.1 mmol). The mixture was
In conclusion, we have found an efficient and practical
procedure for the synthesis of some 1,3-diphenyl-5-
arylpyrazoles via the condensation of 2,3-epoxy-1-phenyl-3-
aryl-1-propanones and phenylhydrazine under a solvent-free
condition.
o
heated at 230 C. After completion of the reaction (the reac-
tion was followed by TLC), the reaction mixture was puri-
fied by column chromatography on silica gel (200-300 mesh)
eluted with a mixture of petroleum ether and ethyl acetate to
afford the product 3a-j, The authenticity of the products 3d,
3g, 3h, 3i and 3j were established by their 1H NMR, MS; the
rest known compounds were established by their MS and
melting points compared with that reported in literatures
[7, 8, 17,18].
EXPERIMENTAL
2,3-Epoxy-1-phenyl-3-aryl-1-propanones were prepared
according to literature [16]. Melting points was uncorrected.
The 1H NMR spectras were recorded on a Bruker AVANCE
400 (400 MHz) spectrometer using TMS as internal standard
and CDCl3 as solvent. MS were determined on SHIMADZU
(LCMS-2010EA, UVD/ELSD) using CH3CN & H2O (0.05%
TFA) as mobile phase, the column type is Shim_pack XR-
ODS with length 50 mm and internal 3 mm, the flow rate is
Compound 3a
1,3,5-triphenyl-1H-pyrazole, yellow solid, m.p.138-139
oC; m/z (ES): 297 [M+H]+.
Compound 3b
5-(3-nitrophenyl)-1,3-diphenyl-1H-pyrazole, yellow solid,
1
mL/min, and the gradient is as follows. Time
m.p. 128-130 oC; m/z (ES): 342 [M+H]+.
(min.)/CH3CN (%): 0/15, 1.70/100, 3.20/100, 3.33 /10,
3.60/stop.

386 Letters in Organic Chemistry, 2009, Vol. 6, No. 5
Li et al.
Compound 3c
ACKNOWLEDGEMENTS
5-(4-nitrophenyl)-1,3-diphenyl-1H-pyrazole, yellow solid,
The project was supported by Natural Science Founda-
tion of Hebei Province (B2006000969), China.
m.p. 137-139 oC; m/z (ES): 342 [M+H]+.
Compound 3d
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Compound 3i
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o
1
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Compound 3j
5-(3-bromophenyl)-1,3-diphenyl-1H-pyrazole, yellow
o
1
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