Catalyst-Free and Highly Selective N , N-Diallylation of Anilines in Aqueous Phase

N-alkylation of aniline derivatives is an important reaction in organic synthesis, which has been widely applied in the preparation of dyes, �uorescence probes, agrochemicals, and pharmaceuticals [1].e challenge of this reaction is to obtain excellent selectivity for monoor dialkylation products and to avoid the formation of corresponding quaternary ammonium salts fromN,N-dialkylaryl amines.Manymethods have been reviewed for the synthesis of substituted amines [2, 3]. However, they are still suffering some problems, such as the use of toxic reagents [4] and the control of the selectivity of monoand dialkylation-aniline derivatives [5]. In order to overcome these problems, noble metal complexes and salts involving Ru [6], Ir [7, 8], Pt [9], Au [10, 11], and Pd [12, 13] as catalysts and alcohols as alkylating agents have been reported extensively in homogeneous phase. Transition metal-free protocols have also been described, although they normally require harsh reaction conditions, such as high temperatures and pressures, to achieve reasonable yields of products [14]. Compared to homogeneous catalysts, heterogeneously catalysed methodologies based on Ra-Ni [15] and magnetite [16] have been proposed as alternatives to prepare monoalkylation products. Recently, microwave irradiation has been proved to be efficient for the syntheses of N-alkyl anilines [17]. However, they all suffered from high temperatures and long reaction times. Moreover, the dialkylation products were not involved or were only byproducts in the previously mentioned literatures. In recent years, Ju and Varma [18, 19] disclosed direct generation of tertiary amines by N-alkylation reaction of amines with alkyl halides in aqueous phase under microwave irradiation. But the alkylations focused mainly on the reactions of secondary amines with alkyl halides and primary amines with dihaloalkanes. e ionic liquid BMImPF6 and silica were also reported to improve the N,N-bisallylation of amines with allyl bromide [20, 21]. But the conversion of most of substrates is very low, the selectivity of diallylation products is poor, and the needed reaction time is long. Besides, few of literatures were reported for bisallylation reaction of anilines. erefore, it is necessary to make great efforts on the preparation of N,N-diallylanilines derivatives by one-step diallylation of anilines. As a basis of this investigation, we report herein onestep diallylation of anilines by allyl bromide in mildly basic aqueous media to afford a series of N,N-diallylanilines in a simple and straightforward manner (Scheme 1).


Introduction
N-alkylation of aniline derivatives is an important reaction in organic synthesis, which has been widely applied in the preparation of dyes, �uorescence probes, agrochemicals, and pharmaceuticals [1].e challenge of this reaction is to obtain excellent selectivity for mono-or dialkylation products and to avoid the formation of corresponding quaternary ammonium salts from N,N-dialkylaryl amines.Many methods have been reviewed for the synthesis of substituted amines [2,3].However, they are still suffering some problems, such as the use of toxic reagents [4] and the control of the selectivity of mono-and dialkylation-aniline derivatives [5].In order to overcome these problems, noble metal complexes and salts involving Ru [6], Ir [7,8], Pt [9], Au [10,11], and Pd [12,13] as catalysts and alcohols as alkylating agents have been reported extensively in homogeneous phase.Transition metal-free protocols have also been described, although they normally require harsh reaction conditions, such as high temperatures and pressures, to achieve reasonable yields of products [14].Compared to homogeneous catalysts, heterogeneously catalysed methodologies based on Ra-Ni [15] and magnetite [16] have been proposed as alternatives to prepare monoalkylation products.Recently, microwave irradiation has been proved to be efficient for the syntheses of N-alkyl anilines [17].However, they all suffered from high temperatures and long reaction times.Moreover, the dialkylation products were not involved or were only byproducts in the previously mentioned literatures.
In recent years, Ju and Varma [18,19] disclosed direct generation of tertiary amines by N-alkylation reaction of amines with alkyl halides in aqueous phase under microwave irradiation.But the alkylations focused mainly on the reactions of secondary amines with alkyl halides and primary amines with dihaloalkanes.e ionic liquid BMImPF 6 and silica were also reported to improve the N,N-bisallylation of amines with allyl bromide [20,21].But the conversion of most of substrates is very low, the selectivity of diallylation products is poor, and the needed reaction time is long.Besides, few of literatures were reported for bisallylation reaction of anilines.erefore, it is necessary to make great efforts on the preparation of N,N-diallylanilines derivatives by one-step diallylation of anilines.
As a basis of this investigation, we report herein onestep diallylation of anilines by allyl bromide in mildly basic aqueous media to afford a series of N,N-diallylanilines in a simple and straightforward manner (Scheme 1).

Experimental
A mixture of aniline (0.5 mmol), allyl bromide (1.5 mmol), potassium carbonate (2 mmol), ethanol (2 mL), and water (1 mL) was added to a 50 mL round �ask and stirred at T 1: Optimization of the reaction conditions of aniline with allyl bromide a .

Results and Discussion
To begin our study, a standard reaction between aromatic amines and allyl bromide was carried out under different reaction conditions.e reaction of commercial available and inexpensive aniline (1a) with allyl bromide was chosen as a model under catalyst-free conditions.e reaction progress was detected by TLC until aniline disappeared completely (Table 1).When aniline reacted with excess of allyl bromide in the absence of any base in ethanol at 70 ∘ C, the desired product N,N-diallylaniline (2a) was obtained only in 14% of yield, whereas N-allylaniline (3a) was a major product with the yield of 32% (Table 1, entry 1).Subsequently, various bases were investigated for this reaction.Poor selectivity and low yield of 2a were observed in the presence of Na 2 CO 3 and NaHCO 3 (Table 1, entries 2 and 3).However, the good yield of 86% was achieved, and only trace of 3a was observed when using K 2 CO 3 as a base ( of potassium carbonate was further examined and found that 4 equivalents were bene�cial to the aimed product (Table 1, entries 4-6).e exploration of this reaction at different temperature revealed that the yield and the selectivity of 2a increased simultaneously with the temperature increase (Table 1, entries 4, 7, and 8).Considering the solubility of K 2 CO 3 in ethanol is very low, the mixture of ethanol and water was used as reaction medium.It is found that water can affect the alkylation manifestly (Table 1, entries 4 and 9-12).e presence of a small quantity of water in the reaction system is in favour of shortening reaction times and improving the yield and selectivity of 2a.A brief optimization reveals that a mixture of ethanol and water (2/1 mL) is the most suitable medium for the desired transformation, in which aniline can be completely converted to the dialkylation product with the yield of 86% in 2 hours (Table 1, entry 9).e molar ratio of aniline and allyl bromide was also optimized.As seen in Table 2, the ratio affected the reaction signi�cantly.e best yield of N,N-diallylaniline was obtained when 3 equivalents of allyl bromide relative to aniline were used (Table 2, entry 3).
In this regard, the direct diallylation reactions of various substituted anilines were explored under the above optimized conditions, and the results are listed in Table 3. From this Table, it can be seen that the electronic and steric hindrance effects of substituents affect the reaction time and the yield of aimed product signi�cantly.Anilines with electron-donating substituents, such as methoxy and methyl, were smoothly converted to the corresponding diallylation products in good-to-excellent yield with excellent selectivity (Table 3, entries 1-8).Halogen atom(s) attached on the aromatic ring decreased the yield and selectivity of 2, as a little of 3 was observed as byproduct (Table 3, entries 9-11).For 2,5-dichloroaniline, trace of the diallylation product was detected, whereas the monoalkylation product was obtained in 74% of yield (Table 3, entry 12), which might be due to the large steric hindrance of the substrate.e electronwithdrawing substituents, such as nitrogroup, reduced the electron cloud density of nitrogen on amino group, thus reducing the nucleophilicity of anilines.As a result, the diallylation almost could not occur, and only about 40% of monoallylation products were gained for ortho-and paranitroaniline (Table 3, entries [14][15][16].It is unexpected that 3-nitroaniline gave 80% of N,N-diallylaniline as well as 15% of N-allylaniline (Table 3, entry 13).is may be the cause of none of hindrance and small effect on the nucleophilicity of amino group.2,4-Dichloro-6-nitroaniline did not react with allyl bromide under the same conditions (Table 3, entry 17).Obviously, it is the result of synergetic effect of steric hindrance and electronic effect of substituents.

Conclusions
In conclusion, we have developed a direct, green, and highly efficient method for the synthesis of N,N-diallylaniline in aqueous phase under mild conditions.e advantages of this protocol include avoiding the use of any catalyst and toxic organic solvents, complete conversion of anilines, highto-excellent yield and selectivity, short reaction times, and avoiding the overalkylation to form quaternary ammonium salts.

Table 1 ,
entry 4).e amount T 3: Synthesis of N,N-diallylanilines from various anilines and allyl bromide a .Isolated yield; all known products are characterised thoroughly by NMR, IR, MS, and elemental analysis, which were consistent with literature data.
∘ C, TLC detection.b c Not observed.