HETEROCYCLES

Short Paper | Regular issue | Vol. 83, No. 6, 2011, pp. 1371-1376
Received, 15th February, 2011, Accepted, 28th March, 2011, Published online, 14th April, 2011.
DOI: 10.3987/COM-11-12176

■ An Efficient Arylation of Benzoazoles with Aryl Bromides by a Practical Palladium-Copper Cocatalytic System

Xue-Ming Yan, Xue-Rong Mao, and Zhi-Zhen Huang*

School of Chemistry and Chemical Engineering , Nanjing University, Nanjing 210093, China

Abstract

A practical, efficient Pd(OAc)2/Cu(II)/PPh3 cocatalytic system has been developed. With only 1 mol% Pd(OAc)2, 20 mol% copper(II) salt, and 0.5 equiv of inexpensive PPh3 as ligand, the direct arylation of benzoazoles with aryl bromides could be performed smoothly in mild condition, affording the desired arylated benzoazoles in good yields (75-93%).

Arylated azoles are ubiquitous in natural products and pharmaceuticals, agrochemicals.1 The transition-metal catalyzed direct arylation of azoles is a powerful strategy for the synthesis of arylated azoles, and has recently received much attentions.2 In this rapidly growing field, the direct cross-coupling between azoles and aryl halides is a main protocol.2 As one of the most common arylated azoles, arylated benzoazoles have many biologically important activities.3 In most cases, the direct arylation of benzoazoles catalyzed by transition-metal required more reactive aryl iodides as arylating reagents.2b-d The direct arylation of benzoazoles using aryl bromides, which are cheaper and more commonly used than aryl iodides, did not studied so widely as that using aryl iodides.4,5 In 2005, Alagille et al. disclosed a Pd(OAc)2/Cu(I)Br/P(t-Bu)3 cocatalytic system for the direct arylation of benzoazoles with aryl bromides, affording arylated benzoazoles in 8-84% yields.5a Very recently, Huang et al.5b developed an arylation of benzoazoles with aryl bromides by a palladium-copper cocatalytic system, which employed a complicated cocatalytic system: dichlorobis(chloro-di-tert-butylphosphine)/Cu(Xantphos)I. Herein we wish to report our recent work on the efficient arylation of benzoazoles with aryl bromides by a practical Pd(OAc)2/Cu(II)/PPh3 cocatalytic system.
The direct coupling of benzoxazole 1a with bromobenzene 2a using K2CO3 as a base in toluene was chosen as a model reaction. Initially, various copper salts and Pd(OAc)2 with various N- and P-ligands were probed. It was found that N-ligands such as 1,10-phenanthroline or 2,2-bipyridine led to no desired coupling product (Table 1, entry 1). To our delight, when the inexpensive PPh3 was used, the coupling reaction performed smoothly with only. 1 mol% Pd(OAc)2 and 20 mol% copper (II) salt such as Cu(OAc)2.H2O and CuCl2.2H2O under air, affording the desired arylated benzoxazole 3a in good yields (Table 1, entries 2 and 3). In the presence of other P-ligands such as (n-Bu)3P and bisdiphenylphosphinopropane (DPPP), good yields were also obtained (Table 1, entries 5-8). In contrast, no reaction proceeded in the absence of P-ligands (Table 1, entry 9). The screening of bases revealed that K2CO3 was much better than other bases for the reaction (Table 1, entries 10-12). Other palladium catalyst such as PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dba)2 with copper (II) salts can also give the desired product 3a in good yields (Table 1, entries 13-17). Notably, if either copper or palladium catalyst was present, no arylated product 3a was obtained under the above standard conditions (Table 1, entries 18, 19).

After screening of various copper and palladium catalysts, ligands, bases etc, it can be concluded that the optimized reaction should be performed by the cocatalytic system of 1 mol% Pd(OAc)2 and 20 mol% Cu(OAc)2.H2O or CuCl2.2H2O in the presence of PPh3 (0.5 equiv) and K2CO3 (2.0 equiv). Under the optimal reaction conditions, a series of aryl bromides 2a-l were examined in the coupling reaction. It was found that the aryl bromides bearing either electron-donating or withdrawing groups on benzene rings 2a-i could perform the coupling reaction smootly with benzoxazole 1a under air, furnishing the desired arylated benzoxazole 3a-i in good yields (Table 2, compare entries 1-10). Heteroaryl bromides 2k-l were also good coupling partners, giving the biheteroarenes 3k-l in good yields (Table 2, entries 11, 12).

Moreover, benzothiazole 1b and benzoimidazole 1c were also tested in the coupling reaction using Pd(OAc)2/Cu(OAc)2.H2O/PPh3 as a cocatalytic system. It was found that both benzothiazole 1b and benzoimidazole 1c could react smoothly with various aryl bromides 2 to give the desired arylated products 4 and 5 in moderate to good yields (Table 3). Compared with benzoxazole 1a, benzothiazole 1b and benzoimidazole 1c were less reactive and required longer reaction time (3 h for 1a, 6 h for 1b and 10h for 1c), probably because the acidities of H-2 in 1b and 1c are weaker than that in 1a.6

In summary, a practical Pd(OAc)2/Cu(II)/PPh3 cocatalytic system has been developed for the direct arylation of benzoazoles 1a, benzothiazole 1b or benzoimidazole 1c with various aryl bromides 2. The yields (75-93%) are better than that using Pd(OAc)2/Cu(I)Br/P(t-Bu)3.5a This synthetic reaction also has the advantages of readily available catalysts, low palladium catalyst loading, mild reaction conditions, and simple manipulations.

EXPERIMENTAL
General procedure for the arylation of benzoazoles 1a-c with aryl bromide 2: The reaction mixture of benzoazoles 1a-c (1.0 mmol), aryl bromide 2 (1.2 mmol), Pd(OAc)2 (2.2 mg, 1.0 mol%), Cu(OAc)2.H2O or CuCl2.2H2O (20 mol%), and K2CO3 (2.0 equiv, 0.276 g) in toluene (3 mL) was refluxed for 3-10 h. Then, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ EtOAc as eluent) to give arylated benzoxazole 3-5 (All the coupling products 3a7a,b7b,c7b,d7c,e7c,f7b,g7b,h7a,i7a,j7b,k7b,l7b; 4a5b,b4c,c4c,d5b,e5b,f5b,g5b,h4c,i4c; 5a7b,b7a,c7b,d7a,e7a,f7a are known compounds).

ACKNOWLEDGEMENTS
Financial supports from National Natural Science Foundation of China (No. 20872059 and 21072091) and MOST of China (973 program 2011CB808600) are gratefully acknowledged.

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