Azidation of aromatic compounds is one of the useful chemical transformations leading to versatile synthetic intermediates and industrially important derivatives with nitrogen-containing functionalities [1,2]. In general, aromatic azides can be prepared by conventional methods such as displacement of the appropriate diazonium salt with azide ions, nucleophilic aromatic substitution of aryl halides, and diazotization of aryl hydrazines[3,4]. However, these methods have sometimes led to problems with functional group tolerance, poor regioselectivity, reaction scope, and yields in many cases of functionalized aromatic compounds. Among the recently improved synthetic methods of aryl azides, copper-catalyzed azidation of aryl halide with inorganic azides has been explored to be an attractive alternative under rather mild conditions[5,6].
Along with successful application of this copper-catalyzed azidation, amination of aryl halide with various nitrogen-based nucleophiles also has been achieved with much progress[7,8]. More interestingly, few studies of copper catalyzed azidation of aryl halides with sodium azide revealed that the corresponding aryl amines rather than the expected azides were produced depending on substituent pattern of aryl halides and/or reaction conditions[9-12]. Quio et al. reported a copper catalyzed direct amination of ortho-functionalized haloarenes bearing carboxyl or carbamoyl groups using sodium azide[9]. Ham and coworkers also reported an interesting few cases of the direct amine formation from haloaryltrifluoroborates having meta-substituted trifluoromethoxy or chloro substituents employing NaN3 in the presence of CuI and N,N’-dimethylethylenediamine in DMSO[10]. Recently, Helquist et al. pointed out some confused results in previous literature with respect to whether products are aryl azides or the corresponding amines on the copper-catalyzed reaction of aryl halides with metal azide, and have reported a selective amination protocol of aryl halides in the presence of 100 mol % of CuI and described that a large excess of azide ion was crucial to obtain amines in DMSO at 100 ℃[11]. During the course of our research on copper catalyzed azidation of aryl halides with sodium azide, we also observed a mixture of aryl amines and azides as products in most cases.
Herein, we report our findings on a selective copper-catalyzed azidation and amination of aryl halides with sodium azide under microwave irradiation leading to rapid reactions within 10 min. We also first report that a selective amination of aryl halides with sodium azide can be achieved increasing the reaction temperature in DMSO as solvent.
In order to find an optimal reaction condition for Cu-catalyzed amination using NaN3 and clarify a little confusing results on Cu-catalyzed azidation with NaN3 as indicated by Helquist[11], our previously established condition for Cu-catalyzed nitration (10 mol % of CuI, 20 mol % of ligand, 20 mol % of base) was attempted using 4-iodoanisole (1) as a model substrate with NaN3 under microwave irradiation for 10 min (Table 1)[13]. Most of the reactions ended up with a mixture of 4-azidoanisole (2) with varying amounts of 4-aminoanisole (3) relying on the reaction conditions such as catalysts, ligands, bases, solvents, temper- atures, etc. Above 85% yields of 2 were obtained regardless of copper sources such as CuI, CuO, CuCN, Cu2O, Cu, CuOAc, Cu(OAc)2, Cu(NO3)2 and CuCO3, of which CuI was selected for further selective amination due to the formation of aminoanisole 3 in a considerable amount depending on reaction conditions (Table 1). Of the various diamine ligands examined, N,N’-dimethylethylenediamine (DMEDA) was the most effective for the transformation to the azide 2 in above 90% yields; the use of proline as a ligand afforded 2 in 70% with 30% of unchanged starting material (entry 3). The reactions were also influenced by solvents, of which polar solvents such as DMSO, NMP, DMF and 80% EtOH were found to be equally effective leading to 2 in above 90% yields (entries 2 and 4~15).
With the formation of a significant amount of the amine 3 (5~14%; entries 1, 2 and 4~15) along with the corresponding azide 2 as a major product depending on the reaction conditions, the possibility of the selective amination of aryl iodide with NaN3 was further examined using CuI and DMEDA as catalyst and ligand respectively (Table 2).
In general, it has been well known that aryl azides are readily converted to the corresponding amines by a variety of reducing agents such as metal catalysts and hydride reducing agents, and more recently copper nanoparticle has also been reported to be the active reducing species for aryl azides[14]. Thus, an attempt to find an optimum condition for the selective amination of iodoanisole as a model compound with NaN3 was first examined with a varied amount of CuI, which could be expected to function as reducing active species of aryl azide. As shown in Table 2, the reaction in the absence of CuI in DMSO at 100 ℃ was unchanged indicating that a copper catalyst was crucial for the azidation and amination (Table 2, entry 1). A gradual increase of the catalyst loading from 10 to 50 mol % enhanced the amination to 53% with 9% of unidentified impurities (Table 1, entry 2 and Table 2, entry 2); the use of 100 mol % CuI, however, led to an increase of the unidentified impurities (33%) with 38% of the amination product (entry 3). These results indicated that the catalytic loading of CuI had limited effects on the selective amination of aryl iodide with NaN3. Next, the reaction temperature was gradually increased with caution due to a potential problem for explosions of azides[15]. At 180 ℃ with 10 mol % CuI and 1.2 equiv NaN3, complete conversion of the aryl iodide was observed affording 83% of the amine 3 with 17% of the azide 2 (entries 4 and 5). Finally, almost a complete amination (> 99%) was achieved by using 2 equiv of NaN3 in the presence of 10 mol % CuI in DMSO (entries 6 and 7); no other impurities was observed. This successful selective amination protocol (10 mol % CuI, 20 mol % of DMEDA, and 2 equiv of NaN3 in DMSO at 180 ℃ with microwave irradiation for 10 min) were applied to the amination of various aryl halides to study the scope of the reaction (Table 3).
4-Iodotoluene and 1-iodo-3,5-dimethyltoluene also led to the complete conversion to the corresponding amines (entries 4 and 5). The reaction of iodobenzene as a substrate afforded a mixture of the amine as the major product (94% conversion) with 6% of the corresponding azide (entry 6). However, meta-substituted 3-iodoanisole or 4-bromoanisole having a bromide substituent in place of iodide resulted in lower conversions in the same reaction condition (entries 2 and 3). A substrate containing electron-withdrawing nitro group was evaluated to be relatively good providing 79% conversion (entry 7).
In summary, a rapid and selective copper-catalyzed amination of aryl halides has been most efficiently carried out under microwave irradiation using 2 equiv of NaN3 at 180 ℃. The catalytic systems were found to be the most effective with 4-substituted aryl iodides leading to nearly complete conversions.
