An easy direct arylation of 5-pyrazolones

Summary A mild, efficient and catalytic ligand-free method for the direct arylation of 5-pyrazolones by Pd-catalyzed C–H bond activation is reported. The process smoothly proceeds and yields are moderate to excellent.

Introduction 5-Pyrazolones are attracting considerable research interest because of their unique chemical properties and their structures that facilitate their application as biological and pharmaceutical intermediates and products [1][2][3]. Over the years, many of the biological activities of pyrazolones such as their antipyretic, analgesic [4,5], anti-inflammatory [6,7], antitumor [8,9], antiviral, antibacterial [10], and herbicidal [11] properties have been discovered and investigated. Pyrazolones are also potent inhibitors of telomerase, cyclooxygenase isoenzymes, platelet tromboxane synthesis, and prostanoid synthesis in humans [12,13]. Recently, pharmacologists have developed a novel class-II c-met inhibitor, whose structural unit is a pyrazolone ring [14]. The great medicinal significance and broad applications of pyrazolones prompted us to synthesize a new series of heterocyclic compounds containing the pyrazolone moiety.
The reaction of pyrazolones with arylboronic acids is an attractive approach for the synthesis of arylpyrazolone [15,16]. However, it often needs pre-formation of halo-pyrazolones. Transition metal-catalyzed direct arylation of (hetero)arenes has emerged over the past few years as a rapidly growing field of syntheses [17][18][19][20][21][22][23][24][25][26]. The direct arylation of pyrazolones by using aryl halides offers a cleaner and more efficient method of meeting such goals and rare examples of such transformations have been described [15].
In this paper, we report a convenient and catalytic ligand-free synthesis of a series of 4-aryl-5-pyrazolones 3 from 5-pyrazolones 1 and aryl halides 2 (Scheme 1). The direct arylation of 5-pyrazolones by Pd-catalyzed C-H bond activation was utilized.

Results and Discussion
We commenced this study by performing the direct arylation of phenazone (1a) in the presence of 2 equiv of iodobenzene (2a), 10 mol % of Pd(OAc) 2 as a catalyst in acetonitrile in a sealed tube. The results are shown in Table 1. Gratifyingly, a 45% yield of the desired product 3a was achieved after stirring for 12 h at 90 °C. Encouraged by this preliminary result, we continued to optimize reaction conditions to further improve the chemical yield.
When 1a reacted with 2a in the presence of K 2 CO 3 as a base in acetonitrile (90 °C, 12 h), the desired product 3a was generated in 43% yield (   31%, 0% and 22%, respectively (Table 1, entries 10-13). Other reaction parameters such as temperature and oxidants were also screened. When the reaction temperatures were 25 °C, 60 °C, and 120 °C, the yields decreased to 0%, 31% and 35%, respectively (Table 1, entries [14][15][16]. When the reaction was under oxygen (1 atm) in a sealed tube and oxygen was used as an oxidant, product 3a was obtained in 55% yield ( Under the optimized conditions (Table 1, entry 10), the scope of aryl halides was examined and the results are summarized in Table 2. The reactions of aryl halides 2 with phenyl moieties carrying either an electron-donating group such as methyl (2d and 2i), ethyloxy (2e) or an electron-withdrawing substituent such as methoxycarbonyl (2c and 2g), trifluoromethyl (2f) or formyl (2h) proceeded smoothly with moderate to good yields ( Table 2, entries 3-10). When the phenyl moiety of the aryl halides 2 carried an electron-donating group, higher yields were obtained (Table 2, entries 4, 5, 9). On the other hand, an electron-withdrawing group on the phenyl moiety of the aryl halides (2c, 2f, 2g and 2h) provided 4-aryl-5-pyrazolones 3 in relatively low yields (Table 2, entries 3, 6-8). Entries 1 and 2 show  that the yield of products was lower when using aryl bromide than when using aryl iodide, and 2-bromopyridine also provided 3i in moderate yield (Table 2, entry 10).
Next, we investigated the scope of 5-pyrazolone 1 substrates. Table 3 shows that in most cases, the desired pyrazolones 3 were generated smoothly in moderate to good yields. When the phenyl moiety of pyrazolones 1 carried an electron-donating substituent such as methoxy (1b) and methyl (1c), the reactions provided pyrazolones 3 in high yields (Table 3, entries 1, 2). On the other hand, when pyrazolones 1 carried an electron-withdrawing substituent such as nitro (1f) and halogens (1g, 1i and   1k) in the aromatic portion, relatively low yields were obtained (Table 3, entries 5, 6, 8, 10). Compared with 5-pyrazolones containing a butyl or a phenyl substituent on the 3-position of the heterocycle (1d and 1e), the methyl (1a) on the same position resulted in a higher yield (Table 3, entries 3 and 4). The cause might be the steric hindrance of phenyl or butyl. The same trend could be seen from 1g to 1l (cf. 3o, 3q and 3s with 3p, 3r and 3t) ( Table 3, entries 6-11).

Conclusion
In summary, we developed a mild, simple and efficient method for the direct arylation of 5-pyrazolones by Pd-catalyzed C-H bond activation. This approach resulted in the construction of 4-aryl-5-pyrazolones, which are important heterocyclic compounds used in medicinal and biological research. The investigations on the reaction mechanism are still in progress.

Supporting Information
Supporting Information File 1 Experimental details and characterization data for all compounds.