A facile and convenient approach to the synthesis of 3,5-diaryl-1H- pyrazoles

Article abstract of DOI:10.1007/s00706-007-0829-5

A simple and convenient one-pot synthesis route is described for the synthesis of 3,5-diaryl-1H-pyrazoles in short reaction times from the reaction of α-epoxyketones with semicarbazide hydrochloride under mild conditions.

Full text of DOI:10.1007/s00706-007-0829-5

Monatsh Chem 139, 821–824 (2008)
DOI 10.1007/s00706-007-0829-5
Printed in The Netherlands
A facile and convenient approach to the synthesis of 3,5-diaryl-1H-pyrazoles
Farzad Nikpour, Mahdi Beigvand
Department of Chemistry, Faculty of Sciences, University of Kurdistan, Sanandaj, Iran
Received 11 October 2007; Accepted 18 October 2007; Published online 19 May 2008
#
Springer-Verlag 2008
Abstract A simple and convenient one-pot synthesis
route is described for the synthesis of 3,5-diaryl-1H-
pyrazoles in short reaction times from the reaction
of ꢀ-epoxyketones with semicarbazide hydrochloride
under mild conditions.
been reported already. In some of them the ꢀ-epoxy-
ketones are first reacted with an acidic solution of
hydrazine hydrate under reflux in xylene or EtOH
for about 3–6 h; then, in the second step, the pro-
duced hydroxypyrazoles were dehydrated in acidic
solution to obtain the desired 3,5-diarylpyrazoles
Keywords 3,5-Diaryl-1H-pyrazoles; ꢀ-Epoxyketones; Semi-
carbazide hydrochloride; Heterocycles; One-pot synthesis.
[
5]. However, in the present article we wish to report
a facile and convenient synthesis of the 3,5-diaryl-
H-pyrazoles 2 from the reaction of the ꢀ-epoxyke-
1
Introduction
tones 1 with semicarbazide hydrochloride salt under
simple and mild conditions (Scheme 1). The synthe-
sis strategy reported in this article improves on times
and reaction steps under mild conditions as com-
pared with the previous ones. All reactions were car-
ried out in one reaction vessel without separation and
purification of the intermediates. Furthermore, the
use of semicarbazide hydrochloride as the reagent
in place of hydrazine has advantages for this trans-
formation. Semicarbazide hydrochloride is signifi-
cantly easier to handle and safe to use in organic
synthesis in comparison with the highly toxic hydra-
zine hydrate. Also, it is convenient to use this route
for various aromatic substituents. The results are
summarized in Table 1.
The pyrazole ring is one of the fundamental hetero-
cycles. Its derivatives have certainly been shown to
exhibit various pharmaceuticals and biological activi-
ties [1]. In recent years, there have been enhanced
interests in the synthesis of pyrazole derivatives due
to their wide applications [2]. The reaction between
hydrazine and ꢁ-difunctional compounds [3] and 1,3-
dipolar cycloaddition of diazo compounds to triple
bonds [4] are more common strategies for pyrazoles
synthesis. It is important that general effective meth-
ods to synthesize or to modify such compounds are
improved and exploitation of non-toxic molecules
and simple reagents with different functionalities is a
worthwhile effort among organic synthesis chemists.
Two plausible mechanisms are proposed in
Scheme 2. In the first way (Path A) the ꢀ-epoxyke-
tone derivatives 1 are condensed with semicarbazide
hydrochloride salt to produce the corresponding
semicarbazones 3. These semicarbazones are cy-
clized to the intermediates 4 through the ring open-
ing of the epoxide in the presence of released HCl.
Dehydration of 4 following with hydrolysis of 5
under the reaction condition employed gives the pyr-
Results and discussion
The synthesis and biological evaluation of 3,5-di-
arylpyrazoles as the most interesting pyrazoles has
Correspondence: Farzad Nikpour, Department of Chemistry,
Faculty of Sciences, University of Kurdistan, P.O. Box 66315-
4
16, Sanandaj, Iran. E-mail: fnikpour@uok.ac.ir

8
22
F. Nikpour, M. Beigvand
Scheme 1
Table 1 Reaction of the ꢀ-epoxyketones 1a–1k with semi-
carbazide hydrochloride in EtOH
produce the intermediates 8. Hydrolysis of 8 in the
same reaction conditions and then, aromatization of
9 with removal of water proceeds to 2. Since the
epoxide ring, in particular in conjugate forms as in
the ꢀ-epoxyketones is stable against non-anionic nu-
cleophiles in neutral solutions, and their ring open-
ing is carried out in acidic solution or in the presence
of suitable Lewis acids, the pathway A is more prob-
able for beginning and progression of the reaction.
We wish to report that EtOH is an eco-friendly
solvent for this reaction procedure; however, it was
found that the reaction yields were increased about
ꢀ
1
Time= Yield 2= M:p:= C Ref.
a,b
min
%
0
R
R
a
b
c
d
e
f
g
h
i
H
4-Cl
H
H
H
4-Me
4-Me
4-MeO
H
H
H
20
30
30
30
20
20
15
20
80
87
85
83
83
79
70
63
65
60
85
199–200 [5d]
215–217 [2e]
216–217 [2e]
124–126 [2e]
175–177
174–176
221–223
167–169 [5d]
167–169 [5d]
153–154 [5d]
196–198
4-Cl
2-Cl
4-Me
H
4-Me
H
10–15% by using of DMF instead of EtOH, because
4-MeO 20
j
k
4-MeO 4-MeO 15
45
semicarbazide hydrochloride is more soluble in DMF
than in EtOH.
H
3-NO2
a
The identification and characterization of the prod-
ucts were carried out by their physical and spectro-
scopic data and comparison of them with those of
authentic samples. In the IR spectra of the com-
pounds 2 and comparing them with the ꢀ-epoxyke-
tones 1, the CO-stretching of the ketone carbonyl
disappears completely and the NH-stretching of the
Products were identified and characterized by their physical
and spectral data and comparison of them with those of
b
authentic samples. Isolated yields
azoles 2. In the second pathway (Path B), ring open-
ing of the ꢀ-epoxyketones 1 gives the intermediates
6
, which are first cyclized and then dehydrated to
Scheme 2

Synthesis of 3,5-diaryl-1H-pyrazoles
823
ꢁ
1
pyrazol rings appears at about ꢂꢀ ¼ 3120 cm . The
3-(2-Chlorophenyl)-5-phenylpyrazol (2d, C15
1
H
11ClN
2
)
1
ꢁ1
IR (KBr): ꢂꢀ ¼ 3135 (NH) cm ; H NMR (250MHz, DMSO-
NH-signal in H NMR appears in about ꢃ ¼ 13.60–
3
d ): ꢃ ¼ 13.52 (bs, 1H, NH), 7.82 (d, JHH ¼ 7.7 Hz, 2H–Ar),
6
13.15 ppm, probably because of its dislocation on the
two nitrogen atoms of pyrazol ring. Also, the C -H
3
7
.76 (m, 1H–Ar), 7.68 (d, JHH ¼ 7.5 Hz, 1H–Ar), 7.46–7.22
4
4
m, 5H–Ar), 7.10 (s, 1H, C -H) ppm; C NMR (250 MHz,
13
(
3
appears as singlet in aromatic region. The C and
DMSO-d ): ꢃ ¼ 145.6, 136.5, 131.5, 130.9, 130.7, 129.9,
6
4
13
C -H peaks are observed in the C NMR spectrum
in about ꢃ ¼ 148–139 and 103–99 ppm. Also, in all
cases molecular ion-peaks were observed in the mass
spectra.
129.3, 128.1, 128.4, 127.8, 125.6, 125.5, 103.6ppm; MS
, 100), 256 [(M
þ
þ
(EI): m=z (%) ¼ 254 (M
ꢃ
ꢃ
þ 2), 35].
3
-(4-Methylphenyl)-5-phenylpyrazol (2e ¼ 2f, C H N )
1
1
6 14 2
ꢁ
1
IR (KBr): ꢂꢀ ¼ 3115 (NH) cm ; H NMR (250MHz, DMSO-
In conclusion, a facile, safe, and convenient ap-
proach is reported for the synthesis of 3,5-1H-diaryl-
pyrazoles involving the reaction of ꢀ-epoxyketones
with semicarbazide hydrochloride under mild condi-
tions. The reactions were carried out in a single re-
action vessel without separation and purification of
the intermediates. This strategy can be used for var-
ious aromatic substituents in short reaction times
and good yields of the products of high purity are
obtained.
3
d ): ꢃ ¼ 13.27 (bs, 1H, NH), 7.81 (d, JHH ¼ 7.3 Hz, 2H–Ar),
6
3
7
.72 (d, JHH ¼ 7.5 Hz, 2H–Ar), 7.45–7.23 (m, 5H–Ar), 7.10
4
13
s, 1H, C -H), 2.32 (s, 3H–CH ) ppm; C NMR (250 MHz,
(
DMSO-d
3
): ꢃ ¼ 139.1, 138.2, 136.3, 129.8, 129.7, 129.2,
6
1
(
29.1, 125.5, 125.4, 125.3, 99.7, 21.3ppm; MS (EI): m=z
, 100).
%) ¼ 234 (Mþ
ꢃ
3
-(4-Methylphenyl)-5-(4-methylphenyl)pyrazol
(
2g, C H N )
1
7 16 2
ꢁ1
1
IR (KBr): ꢂꢀ ¼ 3120 (NH) cm ; H NMR (250MHz, DMSO-
3
d ): ꢃ ¼ 13.18 (bs, 1H, NH), 7.69, 7.23 (2d, JHH ¼ 7.2 Hz,
6
4
H–Ar), 7.05 (s, 1H, C -H), 2.31 (s, 6H-CH ) ppm;
13
C
8
3
NMR (250MHz, DMSO-d ): ꢃ ¼ 145.1, 137.8, 132.5, 129.8,
6
Experimental
1
25.4, 99.4, 21.3ppm; MS (EI): m=z (%) ¼ 248 (Mþ
ꢃ
, 100).
Melting points were measured with an Electrothermal 9100
apparatus. IR spectra were measured with a Shimadzu IR-460
spectrometer. NMR spectra were recorded with a Bruker
3-(3-Nitrophenyl)-5-phenylpyrazol (2k, C H N O )
1
5 11 3 2
ꢁ
1
1
IR (KBr): ꢂꢀ ¼ 3170 (NH) cm ; H NMR (250MHz, DMSO-
1
3
DRX-250 AVANCE instrument (250.1 MHz for H and
6
d ): ꢃ ¼ 13.60 (bs, 1H, NH), 8.64 (s, 1H–Ar), 8.27 (d, J
¼
6
HH
1
2.9MHz for C). Chemical shifts are given in ppm (ꢃ) rela-
3
3
7.5 Hz, 1H–Ar), 8.14 (d,
J
HH
¼ 7.2 Hz, 1H–Ar), 7.82 (d,
3
HH
3
tive to internal TMS, and coupling constants J are reported in
Hz. Mass spectra were recorded with a Finnigan-MAT 8430
mass spectrometer operating at an ionization potential of
70eV. The synthesis of the ꢀ-epoxyketones was achieved by
using the published methods [6].
JHH ¼ 6.2 Hz, 2H–Ar), 7.69 (dd,
J
¼ 7.5, 7.5 Hz, 1H–
4
13
C
Ar), 7.49–7.40 (m, 3H–Ar), 7.39 (s, 1H, C -H) ppm;
NMR (250MHz, DMSO-d ): ꢃ ¼ 149.8, 148.8, 144.4, 135.8,
6
131.8, 130.7, 129.4, 129.1, 125.6, 125.7, 122.4, 119.6,
, 100).
101.2 ppm; MS (EI): m=z (%) ¼ 265 (Mþ
ꢃ
Typical procedure for the example of 2c
To a solution of 0.258g (1mmol) of the ꢀ-epoxyketone 1c in
Acknowledgements
ꢁ
1
1
cm of EtOH, 0.123 g (1.1mmol) of semicarbazide hydro-
We are thankful to the University of Kurdistan Research
Council for the partial support of this work.
ꢀ
chloride was added and the mixture was stirred at 40–50 C for
about 30 min. After completion of the reaction, the reaction
mixture was poured over crushed ice, filtered, and washed
with water (three times) to remove the solvent and the residues
of semicarbazide hydrochloride. The product 2c was dried first
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