Facile synthesis of mono-, bis-and tris-aryl-substituted aniline derivatives in aqueous DMF

A facile, efficient and general protocol for synthesizing a series of mono-, bis-and tris-aryl-substituted aniline derivatives is described via the Pd(OAc) 2 -catalyzed aerobic and ligand-free Suzuki reaction of mono-, di-and tribromoanilines with aryl boronic acids in aqueous N , N - dimethylformamide (DMF). This is the first example to prepare 2,6-bisaryl-4-nitroanilines and 2,6-bisarylanilines via a palladium-catalyzed ligand-free Suzuki reaction.


Introduction
Mono-, bis-and tris-aryl-substituted aniline derivatives have been extensively used in the synthesis of dyes, pharmaceuticals, ferromagnetic materials, and especially organometallic complexes, [1][2][3][4] because the amino group can react easily with aldehydes or ketones to afford the products with strong electronic donor properties and versatile structures, which have excellent coordinative ability to metals after further modification.[7][8][9][10] So far, several approaches to the construction of mono-, bis-and tris-aryl-substituted aniline derivatives have been developed, such as nitration followed by reduction, [11][12] or via the palladium-catalyzed Suzuki reaction promoted by an oxygen and/or moisture sensitive ligand. 13- 18In 1995, Miura et al. reported Pd(PPh3)4 as catalyst for the Suzuki reaction to synthesize mono-, di-, and triphenylanilines. 13Later, Paul et al. demonstrated a silica supported ligand-free palladium catalyst for the Suzuki reaction to provide 2,4,6-triphenylaniline. 15 In 2004, Zuideveld et al. described a protocol to afford 2,6-bisarylanilines via the Pd(PPh 3 ) 4 -catalyzed Suzuki reaction in toluene/ethanol/H2O. 6 Meinhard et al. in 2007 reported a method to prepare 2,6bisarylanilines using Pd(PPh3)4 in benzene. 4Pisano reported the preparation of 2,6-diphenylaniline product with Pd(PPh3)4 in refluxing DME under N2 to obtain 81% yield in 2 h. 18n 2010, Frech et al. presented the preparation of 2,4,6-triphenylaniline in a Pd-pincer complex mediated system. 17However, these methods are always combined with complex ligands, high palladium loadings, long reaction times, harsh conditions or low yields.
0][21] In 2004, Thiot et al. prepared ionic gel-stabilized palladium nanoparticles to catalyze the cross-coupling of 4-bromoaniline with phenyl boronic acid in MeCN/H2O at 85°C for 6.5 h under argon. 19In 2010, Singh et al. reported the same reaction in aqueous DMF at 110°C. 20Zhang described a ligand-free protocol in 2005 to afford 4-phenylaniline in PEG/H2O at the presence of 1 mol% Pd(OAc)2 at 50°C. 21However, a general and facile protocol for the palladium-catalyzed ligand-free Suzuki reaction for synthesizing mono-, bis-and tris-arylsubstituted aniline derivatives has not been reported.

Investigation of reaction conditions
In our concept, solvents play a crucial role in the palladium-catalyzed ligand-free Suzuki reaction.Thus, we first studied the effects of different solvents on the model cross-coupling of 2,4,6tribromoaniline with phenyl boronic acid under air at 80°C.The results are shown in Table 1 (Table 1, entries 1-5).We tested a series of typical solvents which were commonly used in the palladium-catalyzed ligand-free Suzuki reaction.To our surprise, PEG400 exhibited a rather poor catalytic activity under the reaction conditions (Table 1, entry 1), although the Pd(OAc)2/PEG400 catalytic system could catalyze the Suzuki coupling of aryl chlorides efficiently at room temperature. 35,36However, reactions carried out in aqueous media demonstrated high efficiency.For example, the reaction could finish ini-PrOH/H2O in 60 min (Table 1, entry 2), and a quantitative yield of 2,4,6-triphenylaniline was obtained in DMF/H2O within 30 min (Table 1, entry 4).The results revealed that DMF/H2O (2/1) was the preferred solvent to activate this catalytic system.
The next investigation was to optimize the palladium species.As shown in Table 1, the reaction catalyzed by Pd(OAc)2 resulted in a quantitative yield in 30 min (Table 1, entry 4), while only 2% and 5% yields were obtained using Pd2(dba)3 and 5% Pd/C, respectively (Table 1, entries 7 and 8).8][39] Hence, Pd(OAc)2 is the best choice.2, entries 9 and 10).The results demonstrated that K3PO4•7H2O was the optimum base.Temperature was the last factor which was investigated.From Table 2, it is clear that the higher the temperature was, the better the result was obtained.Therefore, 80°C is the optimal temperature (Table 2, entry 7).

Scope and limitation of substrates
To evaluate the scope and limitations of this procedure, the cross-couplings of 2,4,6tribromoaniline with a series of aryl boronic acids were examined under optimized reaction conditions.As shown in Table 3, aryl boronic acids bearing electron-rich groups afforded good to excellent yields (Table 3, entries 2-4).To the best of our knowledge, the present method is the most effective protocol for the synthesis of such products. 8Apparently, electronic effects did not affect the yields in this methodology (Table 3, entries 5-7).We further investigated the Suzuki reaction of 2,6-dibromo-4-nitroaniline with aryl boronic acids.The results are shown in Table 4.Control experiments were carried out to reveal the effect of temperature on the cross-coupling of 2,6-dibromo-4-nitroaniline with 4-methylphenyl boronic acid (Table 4, entries 1-3).Obviously, the reaction at 80°C was much better than those at 50°C and 25°C.Aryl boronic acids bearing either electron-rich or electron-deficient groups demonstrated high reactivity and afforded the corresponding products in high yields in the presence of 0.5 mol% Pd(OAc)2 (Table 4, entries 3 and 5).Cross-couplings involving mono-, diand trifluorophenyl boronic acids were all completed in short reaction times (Table 4, entries 6-8).To the best of our knowledge, the present method is the first example for the synthesis of 2,6bisaryl-4-nitroanilines in the absence of a ligand.Moreover, this is the fastest and most efficient protocol compared to the reported approaches, which were associated with phosphines, harsh conditions and long reaction times. 4Further investigation was carried out to study the Suzuki reaction of 2,6-dibromoaniline with aryl boronic acids (see Table 5).The results indicated that 4-methylphenyl boronic acid coupled more efficiently than 4-methoxyphenyl boronic acid, resulted in 96% and 62% yields, respectively (Table 5, entries 2 and 3).The reason why 4-methoxyl boronic acid showed much lower activity than 4-methyl boronic acid might be due to the 4-MeO's negative inductive effect, resulting in a decrease of the nucleophilicity of 4-methoxyphenyl boronic acid.6] To our delight, fluoro-substituted phenyl boronic acids all gave good to excellent yields (Table 5, entries 5-7).To further extend the scope of this methodology, we tried to carry out the Suzuki coupling of 4-bromoaniline with a series of aryl boronic acids.As shown in Table 6, aryl boronic acids bearing electron-rich groups or ortho-substituted groups, such as 4-methyl, 2-methyl, 2-methoxyl, and mono-, di-, trifluroro groups, coupled with 4-bromoaniline resulting in excellent yields (Table 6, entries 2-4, 6-8).Compared with the results in Table 5, it was clear that the steric hindrance did not affect the yields (Table 6, entries 3 and 4).The coupling also proceeded readily with electron deficient boronic acids, e.g.4-cyanophenylboronic acid, to afford the product in 62% yield (Table 6, entry 5).Unfortunately, this protocol could not activate chlorinated anilines.

Conclusions
In summary, we have developed a facile and general protocol to synthesize mono-, bis-and trisaryl-substituted aniline derivatives via the Pd(OAc)2-catalyzed ligand-free Suzuki reaction in 67% aqueous DMF under air.It is noteworthy that a wide range of substrates including mono-, di-and tribromoanilines could perform the Suzuki reaction with aryl boronic acids smoothly resulting in good to excellent yields.
Further study including the synthesis and catalytic activity of NHC and nacnac ligands prepared from aryl-substituted anilines described in this paper are currently under investigation in our laboratory.

Experimental Section
General.All the reactions were carried out under air.All aryl halides and aryl boronic acids were purchased from Alfa Aesar, Avocado and used without purification. 1H NMR spectra were recorded on a Varian Inova 400 spectrometer.Chemical shifts are reported in ppm relative to TMS.Mass spectroscopy data of the products were collected on a MS-EI instrument.HPLC yields were recorded on a Waters Alliance 2695-2996-2475 High Performance Liquid Chromatography.Other products were isolated by chromatography on a short silica gel (200-300 mesh) column using petroleum ether (60-90 C), unless otherwise noted.Compounds described in the literature were characterised by comparison of their 1 H NMR spectra with reported data.
Mobile phase consisted of H2O (including 0.3% HOAc and 0.3% N(CH2CH3)3) and MeOH, the gradient elution was adopted, the volume ratio of H2O to MeOH was 30:70 at the beginning to 0:100 at the end, the flow rate was 0.3 mL/min.A variable wavelength UV detector at 246 nm was used.The value of time of retention was 14.2 min.

Table 1 .
Effects of solvents and palladium species on the Suzuki reaction of 2,4,6tribromoaniline with phenyl boronic acid a