N-arylheterocycles represent an interesting structural motif frequently utilized by chemical,pharmaceutical,and materials industries . Thus,the development of correspondingly convenient and efficient synthetic methods using these compounds has attracted considerable attention. In the successful C- N coupling methods,palladium ,nickel  and copper  catalysts,have been employed in the coupling of nucleophilic aromatic substituents with aryl halides. The lower cost of copper-based catalytic systems makes them particularly attractive for large-scale industrial applications,but requires synthetic chemists to devise milder synthetic methods. The development of new ligand structures for copper-catalyzed,cross-coupling protocols also constitutes an area of considerable interest. Recently,a series of novel mono- and bidentate ligands for Cubased C-N coupling were discovered,such as organic phosphane ligands [5, 6],N,N-bidentate ligands [7, 8],O,O-bidentate ligands [9, 10, 11, 12, 13, 14],and N,O-bidentate ligands [15, 16, 17, 18]. In spite of the significant recent progress,it is still necessary to search for more efficient,air-stable and cheaper ligands,or metal-complexes,to facilitate these coupling reactions under relatively milder conditions.
P,O-bidentate derivatives are well-known ligands for organic reactions catalyzed by transition metals. The P,O chelating ligands can provide additional coordination sites for the catalytic metal center and,thus enhance their efficiency because they not only supply suitable electrons,but also make available steric properties to the phosphorus coordinating atom. Since Keim first reported that nickel(Ⅱ)/P,O chelating ligands were highly active in oligomerization and polymerization of ethylene ,this class of ligands became the focal point and center of interest,and many analogous ligands had been successively synthesized,especially the ligands found in the development of novel homogeneous catalysts . In addition,a notable achievement had been made in the utilization of P,O chelating ligands. The Pd- and Ni-catalyzed C- C coupling reactions could be achieved under mild conditions [21,22,23]. However,investigations on the Cu-catalyzed C-N coupling reactions in the presence of P,O chelating ligands were seldom reported. Based on our previous research ,herein,we report our recent results on Cu-catalyzed N-arylation of nitrogencontaining heterocycles with aryl iodides and bromides under mild conditions by using P,O bidentate derivatives as ligands. 2. Experimental
2.1. Materials and instruments
All reactions were carried out in air under magnetic stirring conditions unless otherwise noted. 1H NMR spectral data were recorded on a Bruker DPX-400 spectrometers using TMS as internal standard and CDCl3 or DMSO-d6 as solvent. EI-Mass spectra were measured on a LC/Q-TOF MS (Micromass,England). All other reagents were of analytical grade quality and commercially obtained. 2.2. General procedure for N-arylation of imidazoles and 1H-pyrazole
(2-(Diphenylphosphino)acetic acid) L1 and (3-(diphenylphosphino) propanoic acid) L2 (Fig. 1) were synthesized by the literature methods .
Procedure for N-arylation of imidazoles: CuCl (0.04 mmol),L2 (0.08 mmol),aryl idione or bromide (0.5 mmol),imidazole or 1Hbenzo[ d]imidazole (0.75 mmol),NaOH (1 mmol),and DMSO (1 mL) was added to a 5 mL tube,then sealed. The mixture was stirred at 100 ℃ for certain time. After cooling to room temperature,the mixture was quenched with 10 mL H2O and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were dried with anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc (from 2:1 (v/v) to pure EtOAc) as the eluent to afford the desired products.
Procedure for N-arylation of 1H-pyrazole: Cu(OAc)2 (0.03 mmol),L2 (0.06 mmol),aryl idione or bromide (0.5 mmol), 1H-pyrazole (0.75 mmol),NaOH (1 mmol),and 1,4-dioxane (1 mL) was added into a 5 mL tube,then sealed. The mixture was stirred at 100 ℃ for certain time. After cooling to room temperature,the mixture was quenched with 10 mL H2O and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were dried with anhydrous Na2SO4 and filtrated and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with PE/EtOAc,as the eluent,to afford the desired products. 3. Results and discussion
3.1. Copper-catalyzed N-arylation reactions of imidazoles
To optimize the reaction conditions,a series of reactions between 4-iodotoluene (3a) and imidazole (4a) were performed in the presence of base and solvent to evaluate the roles of various ligands and copper sources for the N-arylation process. As shown in Table 1, among the explored different ligands and copper sources,L2 exhibited the highest catalytic activity with 41% yield (Table 1, entries 1 and 2). The comparison of different copper sources indicated that CuCl was superior to other sources,including Cu(OAc)2,Cu2O,and CuI (Table 1,entries 3-5). The screening results of bases suggested that NaOH was the best (Table 1,entries 6-9) and that 66% yieldwas achieved. The amount of Cu resource/L2 was another important factor of the reaction investigated.When the amount of Cu resource/L2 was increased from 2 mol%/8 mol% to 4 mol%/16 mol%,the isolated yield of the product (5a) increased to 97% (Table 1,entries 10 and 11). Solvent was another important factor in the catalysis. It was confirmed that DMSOwas much better than DMF. Meanwhile,and both toluene and 1,4-dioxane were not suitable for use as reaction solvents (Table 1,entries 12-14). The combination of CuCl (8 mol%)/L2 (16 mol%),NaOH (2 equiv.) at 100 ℃ for 12 h in DMSOwas chosen as the optimal conditions for Narylation of imidazole with 4-iodotoluene.
The role of the CuCl/2 system for general N-arylation of imidazoles with various aryl halides was further evaluated and summarized in Table 2. In general,most of aryl iodides reacted with imidazole smoothly and the desired products were obtained with moderate to excellent yields. Iodobenzene,as a substrate, reacted with imidazole with only 62% yield (Table 2,entry 1), but 1-chloro-4-iodobenzene,1-fluoro-4-iodobenzene and 4-iodo- 1,1'-biphenyl led to the N-arylated products with yields of 90-98% (Table 2,entries 5-7). Furthermore,the catalytic system could tolerate a variety of functional groups,including the nitro, and ether groups (Table 2,entries 2,4,and 8). When 1-(4-iodophenyl)ethanone was used as the coupling partner,the yield dropped to 20% (Table 2,entry 3). Notably,the sterically demanding ortho substituents,such as 1-iodo-2-methylbenzene, 1-iodo-2-methoxybenzene,and 2-iodoaniline,did not hamper the N-arylation reactions and gave the coupling products with 61-92% yields (Table 2,entries 9-11). In order to expand the scope of this methodology,this new catalytic system was applied in the reaction of imidazole derivatives. To our delight,aryl iodides reacted with the 1H-benzo[d]imidazole and the corresponding products were obtained with moderate to excellent yields under the optimized reaction conditions. For example,1-chloro-4-iodobenzene,and 1- iodo-4-nitrobenzene afforded the corresponding products with 87-94% yields (Table 2,entries 12 and 14). When the substrate,4- iodo-1,10-biphenyl,reacted with 1H-benzo[d]imidazole,the arylated product with 70% yield was produced (Table 2,entry 13).
Then,we expanded the scope of the substrates to 1H-pyrazole, but the above-mentioned catalytic system was not suitable for Narylation reaction of the pyrazole and required further optimization of the N-arylation conditions. Subsequently,we selected the 1H-pyrazole and 4-iodotoluene as the substrates to further investigate the effects of other factors on the N-arylation, including copper resources,bases,solvents,reaction time and reaction temperature. Among the different,investigated copper sources,Cu(OAc)2 is the most efficient,while CuCl,Cu2O,and CuI were less efficient. For example,the reaction with 4 mol% Cu(OAc)2 afforded the coupling product with 49% yield at 100 ℃ after 12 h,while only 16%-22% yields were obtained for the same reaction with CuCl,Cu2O,and CuI (Table 3,entries 1-4). Among the tested various bases,NaOHwas still themost effective (Table 3,entries 4-7). Solvent was an important factor of the catalysis. When 1,4-dioxane was used as the prime solvent,60% yield was obtained. DMSO,DMF and toluene gave relatively low yields (Table 3,entries 7-9).Meanwhile,the increasing amount of Cu(OAc)2/L2 and reaction temperature led to the increasing yields (Table 3,entries 11-13). Furthermore,when the reaction time was extended to 24 h,the highest yield is up to 91% (Table 3,entry 15). Finally,the combination of Cu(OAc)2 (6 mol%)/L2 (12 mol%), NaOH (2 equiv.) at 100 ℃ for 24 h in 1,4-dioxane was chosen as the optimal conditions for N-arylation of 1H-pyrazole with 4- iodotoluene.
The scope of substrates was then investigated with this catalytic system under the optimized reaction conditions. As shown in Table 4,in general,most of aryl iodides reacted with 1Hpyrazole smoothly and the desired products were produced with moderate to excellent yields. Iodobenzene,as a substrate,reacted readily with 1H-pyrazole and gave 83% yield (Table 2,entry 1),and electronic effects seem to have no significant impact on the coupling reactions. For example,aryl iodide with an electrondonating group could be coupled with 1H-pyrazole to give corresponding product with 84%-98% yield (Table 4,entries 2 and 9),and aryl iodides with electron-withdrawing groups, including 1-chloro-4-iodobenzene,1-fluoro-4-iodobenzene,1- bromo-4-iodobenzene,1-iodo-4-nitrobenzene and 1-(4-iodophenyl) ethanone also afforded the corresponding arylated products with 60%-89% yields (Table 4,entries 3,4 and 6-8). When 4-iodo- 1,1'-biphenyl was used as the coupling partner,the 90% yield was obtained (Table 4,entry 5). Furthermore,the sterically demanding ortho substituents,such as 1-iodo-2-methylbenzene,1-iodo-2- methoxybenzene,and 2-iodoaniline,did not hamper the arylation reaction and 40%-74% yields were achieved (Table 4,entries 10- 12). In addition,the reactions of aryl bromides,such as 1-bromo-4- methylbenzene,1-bromo-4-nitrobenzene,and 1-bromo-2-methoxybenzene with 1H-pyrazole,were also successful and provided the desired products in 51%-71% yields at 120 ℃ for 36 h (Table 4, entries 13-15).
In conclusion,L2 was proved to be an efficient ligand for not only the CuCl-catalyzed N-arylation of imidazoles with aryl iodides in DMSO,but also the Cu(OAc)2-catalyzed N-arylation of 1Hpyrazole with aryl iodides and even aryl bromides in 1,4-dioxane. The proposed catalytic method is characterized by a facile catalytic system,mild reaction conditions,experimental simplicity,and broad substrate scope. The reaction mechanism and the expansion of the scope of the catalytic system are currently studied in our laboratory.Acknowledgments
We gratefully acknowledge financial support of this work by the National Basic Research Program of China (973 Program,No. 2012CB722603),the Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1161),the National Natural Science Foundation of China (No. 21103114), and the Doctor Foundation of Xinjiang Bingtuan (No. 2012BB010).
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