Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-coupling reaction

Article abstract of DOI:10.1016/j.cclet.2014.03.013

Pyrazoles and their derivatives are important heterocycles found in nature and present in numerous bioactive compounds. In contrast to 3 or 5-aryl pyrazole, the preparation of 4-aryl pyrazole is fairly rare. Utilizing microwave irradiation, the synthesis of 4-substituted-arylpyrazole via Suzuki cross-coupling has been developed with a wide range of substrates. The remarkable advantages of this method are mild reaction conditions, simple operation, high yield, and short reaction time. Product structures were identified by MS, ¹H NMR, ¹³C NMR, and elemental analysis.

Full text of DOI:10.1016/j.cclet.2014.03.013

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CCLET-2897; No. of Pages 5
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Efficient synthesis of 4-substituted pyrazole via microwave-promoted
Suzuki cross-coupling reaction
*
*
Hua Cheng, Qiong-You Wu , Fan Han, Guang-Fu Yang
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Pyrazoles and their derivatives are important heterocycles found in nature and present in numerous
bioactive compounds. In contrast to 3 or 5-aryl pyrazole, the preparation of 4-aryl pyrazole is fairly rare.
Utilizing microwave irradiation, the synthesis of 4-substituted-arylpyrazole via Suzuki cross-coupling
has been developed with a wide range of substrates. The remarkable advantages of this method are mild
reaction conditions, simple operation, high yield, and short reaction time. Product structures were
identified by MS, 1H NMR, 13C NMR, and elemental analysis.
Received 20 December 2013
Received in revised form 21 January 2014
Accepted 21 February 2014
Available online xxx
Keywords:
ß 2014 Qiong-You Wu and Guang-Fu Yang. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
4-Aryl pyrazoles
Suzuki cross-coupling reactions
4-Iodo-1-methyl-1H-pyrazole
Microwave irradiation
1. Introduction
Chemical Industry (Fig. 1). They exhibit broad spectrum fungicidal
activity and good environmental compatibility by inhibition of
Pyrazoles and their derivatives are well-known as an important
class of compounds that are extensively used in the pharmaceuti-
cal industry [1–3]. Compounds containing the pyrazole scaffold are
being developed for the treatment of metabolic, central nervous
system, and oncological diseases [4,5]. A number of pyrazole
containing medicines have been successfully commercialized such
as Celebrex, Viagra, and Acompli. In the meantime, some of them
are currently being tested or clinically evaluated for new drug
discovery, such as pyrazole diamide A (Fig. 1) [4], which is being
evaluated for the treatment of human cancers. In addition, some
pyrazole derivatives have been discovered as biocides, including
acaricides, herbicides, and fungicides. Among the pyrazole
derivatives, aryl pyrazoles are of special interest due to their
striking bioactivity. For example, fluazolate [6] and pyraflufen-
ethyl [7] are two representative phenyl pyrazole herbicides
targeting protoporphyrinogen oxidase which were developed
and commercialized in the 1990s to control broadleaf weeds in
wheat, cotton, and soybean fields. They displayed excellent weed
control potency with an application rate as low as 6–12 g ai/ha.
Pyraoxystrobin [8] and pyrametostrobin [9] are commercialized
fungicides developed by the Shenyang Research Institute of
complex III cytochrome bc1 at the Qo site. The 3-piperidinyl-4-aryl
pyrazole B (Fig. 1) [10] has been recognized as a lead candidate to
generate novel DNA gyrase inhibitors. Based on this lead structure,
Tanitame et al. have discovered novel analogs with potent
antibacterial activity against not only susceptible strains but also
multidrug-resistant strains.
Due to their widespread biological activities in medicinal
chemistry aswellasinagrochemical industry, the efficient synthesis
of pyrazoles has received considerable attention from synthetic
chemists. Traditionally, synthesis of pyrazoles involves the conden-
sation of a 1,3-dicarbonyl compound or their equivalent 1,3-
dienophilic synthons with a hydrazine derivatives. The required
dicarbonyl precursor must be prepared in advance, particularly for
aryl dicarbonyl precursors [11]. To address this limitation, an
alternate transition-metal catalysis cross-coupling reaction was
developed and has been widely applied to incorporate the aryl unit
into the pyrazole backbone. For instance, Wang et al. [12] performed
Suzuki couplings on 1-aryl-5-bromopyrazoles to prepare asymmet-
rical 3,5-disubstituted 1-arylpyrazoles in excellent yields. Dvorak
and co-workers [13] disclosed a general protocol to furnish 5-aryl
pyrazoles by using palladium-mediated Suzuki coupling reaction of
pyrazole triflates and ary boronic acids. In addition, Zhang and co-
workers [14] utilized a Negishi coupling of pyrazole triflates with
aryl zinc halide to synthesize 3-aryl substituted pyrazole analogs.
Similarly, Organ and Mayer [15] prepared a library of COX-2
inhibitors from 4-(5-iodo-3-methylpyrazolyl) phenylsulfonamide
*
Corresponding authors.
E-mail addresses: qywu@mail.ccnu.edu.cn (Q.-Y. Wu), gfyang@mail.ccnu.edu.cn
(G.-F. Yang).
http://dx.doi.org/10.1016/j.cclet.2014.03.013
1001-8417/ß 2014 Qiong-You Wu and Guang-Fu Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: H. Cheng, et al., Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-
coupling reaction, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.013

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Fig. 1. The structure of diverse biologically active aryl pyrazole.
and aryl boronic acids by solution phase Suzuki coupling utilizing a
solid-supported catalyst.
considerable improvement of product yield. In recent years, we
have developed some new methods [27,28] for the efficient
synthesis of heterocyclic compounds under microwave irradiation.
Herein, as a continuation of our research on the development of
novel methods to construct biologically important heterocycles,
we report the synthesis of pyrazole derivatives bearing substi-
tuents on the 4-position via a Suzuki cross-coupling method under
microwave irradiation. This method achieved the title compounds
in very short time with excellent yields.
In contrast to 3 or 5-aryl pyrazoles [16–20], the preparation of
4-aryl pyrazoles is fairly rare. Even though a novel titanium-
catalyzed multicomponent coupling reaction has been discovered
to incorporate the aryl unit into the 4-positon of pyrazole [21], the
most common method remains the coupling of pyrazole-4-boronic
acid or pyrazole-4-boronic acid pinacol ester with aryl halides
[22,23]. However, these methods usually suffer from some
drawbacks, such as limited substrate scope, uncommon phospho-
rus ligands needed, poor yields, and time consuming reaction.
Thus, the development of a general, mild, and efficient method for
the preparation of 4-substituted pyrazole is still of great interest.
Microwave irradiation has emerged as a powerful technique for
promoting a variety of chemical reactions [24–26]. The main
benefits of performing reactions under microwave irradiation
conditions are significant enhancement in reaction rate and
2. Experimental
Unless otherwise noted, materials were purchased from
commercial suppliers and used without further purification. All
of the solvents were treated according to general methods. Flash
column chromatography (FC) was performed using 200–300 mesh
silica gel. 1H NMR spectra were recorded on 400/600 (400/
Table 1
Optimization of the cross coupling reaction conditions.a
B(OH)2
I
+
N
.
N
N
N
1
2
3
Entry
Temp. (8C)
Solvent
Pd(PPh3)4 (mol%)
Base
Time
Yieldb (%)
1
2
Refluxc
60
DME:H2O = 10:1
DME:H2O = 10:1
DME:H2O = 10:1
DME:H2O = 10:1
DME:H2O = 10:4
DME:H2O = 10:5
DME:H2O = 10:4
DME:H2O = 10:4
DME:H2O = 10:4
DME:H2O = 10:4
DME:H2O = 10:4
DME:H2O = 10:4
DMF:H2O = 10:4
Dioxane:H2O = 10:4
THF:H2O = 10:4
Toluene:H2O = 10:4
2
2
2
2
2
2
1
0
4
2
2
2
2
2
2
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
16 h
14
24
67
65
78
48
45
Trace
63
63
85
95
90
88
90
47
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
5 min
3
90
4
100
90
5
6
90
7
90
8
90
9
90
10
11
12
13
14
15
16
90
90
90
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
90
90
90
90
a
Unless otherwise noted, all the reactions were carried out at 0.5 mmol scale in the solution of DME (3 mL) and H2O (1.2 mL) with 2 mol% of Pd(PPh3)4, 2.5 equiv. of base
under microwave irradiation, protected by N2.
b
Isolated yields.
c
Conventional heating method [29].
Please cite this article in press as: H. Cheng, et al., Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-
coupling reaction, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.013

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H. Cheng et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
600 MHz) spectrophotometers, Chemical shifts (
d
) were reported
column chromatography using petroleum ether/acetone as eluent
to give the title compound.
Characterization data of the 3-ylideneoxindoles can be found in
Supporting information.
in ppm from the solvent resonance as the internal standard (CDCl3:
7.26 ppm, DMSO: 2.50 ppm). 13C NMR spectra were recorded on
400/600 (100/150 MHz) spectrophotometers (CDCl3: 77.0 ppm,
DMSO: 39.5 ppm) with complete proton decoupling. Mass spectra
were measured on a Trace MS spectrometer. Elemental analysis
was determined on an elementary analysis instrument.
3. Results and discussion
General procedure for the synthesis of compounds 3–32: 4-
Iodo-1-methyl-1H-pyrazole 1 (101 mg, 0.5 mmol) and phenyl-
boronic 2 (59 mg, 0.5 mmol) were dissolved in DME (3 mL) and
H2O (1.2 mL) in a microwave vial under a nitrogen atmosphere.
Pd(PPh3)4 (2 mmol%, 11.6 mg) and Cs2CO3 (407.3 mg, 1.25 mmol)
were added, and the reaction mixture was irradiated in a
microwave apparatus at 90 8C for 5–12 min. After the reaction
mixture was cooled to ambient temperature, the product was
concentrated, and the crude mixture was purified by silica gel
Initially, we examined the Suzuki cross-coupling reaction by
using 1.0 equiv. 4-iodo-1-methyl-1H-pyrazole 1 and 1.0 equiv.
phenylboronic acid 2 in the presence of 2 mol% catalyst Pd(PPh3)4
and 2.5 equiv. Na2CO3 under refluxing solution of DME/H2O with a
ratio of 10:1 (v/v) as described in the literature. However, the
target product was isolated in 14% yield after a long reaction time
(Table 1, entry 1). In contrast to the conventional heating, when the
same reaction was carried out under microwave irradiation, it
completed within 5 min and produced a slightly improved yield of
Fig. 2. Synthesis of 4-substituted pyrazole derivatives.
Please cite this article in press as: H. Cheng, et al., Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-
coupling reaction, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.013

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24%. This inspired us to further optimize the reaction conditions.
Firstly, we investigated the effect of temperature on the product
yield. It was found that when the reaction temperature increased
from 60 8C to 90 8C, the yield increased sharply from 24% to 67%.
However, further increasing the reaction temperature to 100 8C led
to the decrease of the yield to 65%. We then optimized the solvent
on the reaction. The percentage of water has a remarkable
influence on the product yield. The results showed that increasing
the ratio of H2O to DME from 1:10 to 4:10 led to a significant
enhancement of the yield from 67% to 78%. Further increasing the
water percentage would result in the decrease of the product
dramatically to 48% (Table 1, entry 6). After setting up the reaction
temperature at 90 8C and DME/H2O volumetric ratio of 10:4, we
next optimized the palladium catalyst to get better yield. It should
be noted that palladium catalyst plays a critical role in the coupling
reaction and without the catalyst, only trance product was
observed (Table 1, entry 8). Usually, 2 mol% loading of the catalyst
is optimal for this kind of coupling reaction. Increasing the catalyst
loading to 4 mol% would result in a slight decrease of the yield,
while reducing the catalyst loading to 1 mol% provided only 45%
yield of the product.
such as phenylvinyl boronic acid and pentenyl boronic acid were
employed as the substrate, the coupling products 31 and 32 were
prepared smoothly, but in a lower yield.
4. Conclusion
In summary, we have developed a convenient method for the
synthesis of 4-substituted 1-methyl-1H-pyrazole from 4-iodo-1-
methyl-1H-pyrazole by using microwave-assisted Suzuki cross-
coupling reactions. The reaction is applicable to a wide range of
substrates and produces a variety of 4-substituted 1-methyl-1H-
pyrazole in moderate to good yields within a very short time.
Acknowledgments
We thank the National Nature Science Foundation of China
(Nos. 21002038 and 21272091) for the financial support.
Appendix A. Supplementary data
Furthermore, the effect of the base on the reaction was also
evaluated. Among the bases we examined (Na2CO3, NaHCO3,
K2CO3, Cs2CO3), Cs2CO3 is superior. The yield was notably
increased to 95% when the reaction was carried out in the
presence of CeCO3 at 90 8C under microwave irradiation in a mixed
solution of DME/H2O (Table 1, entry 12). In comparison, NaHCO3
was the worst base, while K2CO3 produced acceptable yield as
compared to Cs2CO3.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2014.03.013.
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coupling reaction, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.03.013