Pyrazoles and their derivatives are well-known as an important class of compounds that are extensively used in the pharmaceutical industry ^{[1, 2, 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 pyraflufenethyl ^[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 Chemical Industry (Fig. 1). They exhibit broad spectrum fungicidal activity and good environmental compatibility by inhibition of complex III cytochrome bc1 at the Qo site. The 3-piperidinyl-4-aryl pyrazoleB(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.

Fig. 1

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Fig. 1. The structure of diverse biologically active aryl pyrazole.

Due to their widespread biological activities in medicinal chemistry as well as in agrochemical industry,the efficient synthesis of pyrazoles has received considerable attention from synthetic chemists. Traditionally,synthesis of pyrazoles involves the condensation 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,Wanget al.^[12] performed Suzuki couplings on 1-aryl-5-bromopyrazoles to prepare asymmetrical 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 coworkers ^[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 and aryl boronic acids by solution phase Suzuki coupling utilizing a solid-supported catalyst.

In contrast to 3 or 5-aryl pyrazoles ^{[16, 17, 18, 19, 20]},the preparation of 4-aryl pyrazoles is fairly rare. Even though a novel titaniumcatalyzed 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 phosphorus 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, 25, 26]}. The main benefits of performing reactions under microwave irradiation conditions are significant enhancement in reaction rate and 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 substituents on the 4-positionviaa Suzuki cross-coupling method under microwave irradiation. This method achieved the title compounds in very short time with excellent yields. 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 (400/600 MHz) spectrophotometers,Chemical shifts (δ) were reported 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.

General procedure for the synthesis of compounds 3-32 :4-Iodo-1-methyl-1H-pyrazole 1 (101 mg,0.5 mmol) and phenylboronic 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°C 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 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. 3. Results and discussion

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 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°Cto90°C,the yield increased sharply from 24% to 67%. However,further increasing the reaction temperature to 100°C 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°C 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.

Table 1

Table 1 Optimization of the cross coupling reaction conditions.a aUnless 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. bIsolated yields. cConventional heating method [29]

Table 1 Oligonucleotides designed in the present study.a

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 CeCO3at 90°C 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.

With the optimized conditions of temperature,base,and catalyst loading,we reexamined the solvent effect on the reaction. It was noted that the reaction could proceed in several reaction systems. When the reaction was performed in DMF/H₂O,dioxane/H₂O,or THF/ H₂O system,the isolated yields were 90%,88%,and 90% respectively (Table 1,entries 13-15). In comparison,toluene/H₂Omedium produced much poorer yield (Table 1,entry 16). Thus,we chose the following reaction conditions as optimumfor all subsequent cross coupling reaction: 2 mol% Pd (PPh₃)₄,2.5 equiv. CsCO3and 1.0 equiv. arylboronic acids in the reaction medium of DME/H₂Owitha volumetric ratio of 10:4 under microwave irradiation.

Fig. 2 demonstrated the scope of this coupling protocol toward the synthesis of 4-substituted pyrazole derivatives. From the results listed in Fig. 2,it was clearly indicated that various functional groups were well tolerated under these conditions. Both electron-rich and electron-poor aryl boronic acids could be successfully utilized in this transformation to give moderate to excellent yields (Fig. 2,compounds 3-17). It should be noted that incorporation of halogen-substituents at the ortho,metaorpara positions in arylboronic acids did not retard the reaction significantly,demonstrating that steric modification can be accomplished without compromising the efficiency of the process. In comparison,the para-halogen bearing arylboronic acid was favored over the orthoormetasubstituted ones in terms of their corresponding product yield. More importantly,the reaction proved to be tolerant of valuable but unstable substituents,such as formyl and acetyl (Fig. 2,compounds 14 and 15). As expected,a series of polysubstituted phenylboronic acids reacted with 4-iodo-1-methyl-1H-pyrazole very well and gave the products in moderate to excellent yields. Additionally,the bulky boronic acids such as naphthyl and dibenzo^{[b, d]}furanyl were converted to the coupling products 26 and 28 smoothly. Furthermore,heterocyclic boronic acid can also participate in this reaction and afford the desired coupling product in moderate yield. For instance,pyridinyl boronic acid and furanyl boronic acid were transformed to the coupling products in good yield (compounds 29,30,and 27, respectively). In addition,when the alkenyl bearing boronic acids 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.

Fig. 2

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Fig. 2. Synthesis of 4-substituted pyrazole derivatives.

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 crosscoupling reactions. The reaction is applicable to a wide range of substrates and produces a variety of 4-substituted 1-methyl-1Hpyrazole 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

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. References