In recent years, there has been growing interest in reactions designed to form carbon-nitrogen bonds, which is a useful strategy in synthetic organic chemistry. In the past few decades, the synthesis of amines has attracted considerable attention because of their industrial and commercial importance [1, 2] and also for the synthesis of various dyes. The traditional synthetic approach to N-substituted amines is direct N- alkylation [3], but this procedure is problematic owing to over- alkylation, the toxic nature of many alkyl halides [4], and poor selectivity [5]. Furthermore, various bases including NaOH [6], cesium hydroxide [7], PhN(n-Pr)2 [8], and Hunig’s base [9] have been used for synthesis of N-substituted amines, but they require harsh reaction conditions.
Transition metal catalysis has proved useful in selective and atom-economical transformations. Although C-N couplings using palladium [10, 11], ruthenium [4], iridium [12, 13], and platinum [14, 15] catalysts have been explored, copper- catalyzed C-N bond formation has gained more attention because of its low cost, non-toxic nature, and excellent selectivity [16, 17, 18, 19, 20]. Heterogenous catalysts have recently gained much importance because they are more selective, stable at high temperature, easily separated from the reaction mixture at the end of the process, and can be reused. These factors favor the cost effectiveness of what can be regarded as a “green reaction”. Among the alkylations of amines, benzylation continues to be one of the most commonly used reactions in pharmaceutical chemistry [21, 22] because of the medicinal importance of N-benzylated amines. Here we report a selective procedure for mono N-benzylation and N,N-dibenzylation of anilines (Scheme 1) and N-benzylation of secondary amines (Scheme 2) using silica-supported copper(I) oxide in aqueous media.
To a round-bottom flask containing activated silica (10 g), Fehling solution (50 mL) was added and the reaction mixture was stirred at 100 °C. After every interval of 30 min, 2 mL of glucose solution (0.5 g in 96 mL of water) was added up to 24 h. Then the catalyst was filtered off, washed with water until the washings were colorless, and dried in an oven at 110 °C. To remove excess glucose, the catalyst was refluxed in water at 120 °C for 6 h (3 × 2 h). Then the catalyst was dried at 110 °C for 5 h in an oven.
The general preparation procedure for silica-supported nano copper(I) oxide (SiO2-Cu2O) is shown in Scheme 3.
A mixture of aniline (0.5 mmol), benzyl chloride (0.5 mmol for mono N-benzylation and 2 mmol for N,N-dibenzylation), K2CO3 (0.5 mmol for mono N-benzylation and 1 mmol for N,N-dibenzylation), SiO2-Cu2O (0.1 g, 2.5 mol% Cu for mono N-benzylation and 0.2 g, 5 mol% Cu for N,N-dibenzylation), and tetra-n-butylammonium bromide (TBAB, 0.082 g, 0.25 mmol, only in the case of N,N-dibenzylation) in water (5 mL) in a round-bottom flask (50 mL) was stirred at 30 °C for mono N-benzylation and 100 °C for N,N-dibenzylation. On completion of the reaction monitored by thin-layer chromatography (TLC), the reaction mixture was filtered, and the residue was washed with water followed by ethyl acetate (3 × 10 mL). The combined organic extracts were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the product was obtained by crystallization from petroleum ether or ethyl acetate/ petroleum ether, or by eluting the crude product through a column of silica gel with ethyl acetate/petroleum ether.
A mixture of secondary amine (0.5 mmol), benzyl chloride (0.127 g, 1 mmol), K2CO3 (0.139 g, 1 mmol), TBAB (0.082 g, 0.25 mmol), and SiO2-Cu2O (0.2 g, 5 mol% Cu) in water (5 mL) in a round-bottom flask (50 mL) was stirred at 100 °C. On completion of the reaction (monitored by TLC), the flask was cooled to room temperature and the mixture filtered. The residue was washed with water followed by ethyl acetate (3 × 10 mL). The combined organic extracts were washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the product was obtained by crystallization from petroleum ether or ethyl acetate/ petroleum ether, or by eluting the crude product through a column of silica gel with ethyl acetate/petroleum ether.
N-Benzyl-3-methoxyaniline (Table 3). IR (υmax in cm−1, KBr): 1042 (C-O-C symm. str.), 1582 (aromatic C=C str.), 3029 (aromatic C-H str.), 3422 (NH str.). 1H NMR (CDCl3): δ 3.82 (s, 3H, OCH3), 4.0 (bs, 1H, NH), 4.33 (s, 2H, CH2Ph), 6.85-7.0 (m, 4H, Ar-H), 7.16-7.32 (m, 5H, Ar-H). MS: m/z 213 (M+).
N-Benzyl-4-methylaniline (Table 3). IR (υmax in cm−1, KBr): 1575 (aromatic C=C str.), 2918 (C-H str.), 3021 (aromatic C-H str.), 3427 (N-H str.). 1H NMR (CDCl3): δ 2.27 (s, 3H, CH3), 4.02 (bs, 1H, NH), 4.37 (s, 2H, CH2Ph), 6.86-6.96 (d, 2H, Ar-H), 7.06-7.17 (d, 2H, Ar-H), 7.33-7.46 (m, 5H, Ar-H). MS: m/z 197 (M+).
N-Benzyl-4-chloroaniline (Table 3). IR (υmax in cm−1, KBr): 740 (C-Cl str.), 1580 (aromatic C=C str.), 3029 (aromatic C-H str.), 3420 (N-H str.). 1H NMR (CDCl3): δ 4.13 (bs, 1H, NH), 4.29 (s, 2H, CH2Ph), 6.89-6.97 (d, 2H, Ar-H), 7.21-7.34 (m, 5H, Ar-H), 7.50-7.58 (d, 2H, Ar-H). MS: m/z 217 (M+), 219 (M+2).
N-Benzyl-4-nitroaniline (Table 3). IR (υmax in cm−1, KBr): 865 (C-NO2 str.), 1530 (NO2 str.), 1585 (aromatic C=C str.), 3039 (aromatic C-H str.), 3460 (N-H str.). 1H NMR (CDCl3): δ 4.10 (bs, 1H, NH), 4.25 (s, 2H, CH2Ph), 6.94-7.03 (d, 2H, Ar-H), 7.46-7.59 (m, 5H, Ar-H), 8.01-8.12 (d, 2H, Ar-H). MS: m/z 228 (M+).
N,N-Dibenzyl-3-methoxyaniline (Table 3). IR (υmax in cm−1, KBr): 1052 (C-O-C symm. str.), 1579 (aromatic C=C str.), 3029 (aromatic C-H str.). 1H NMR (CDCl3): δ 3.83 (s, 3H, OCH3), 4.35 (s, 4H, 2 × CH2Ph), 6.87-7.20 (m, 4H, Ar-H), 7.29-7.34 (m, 10H, Ar-H). MS: m/z 303 (M+).
N,N-Dibenzyl-4-methylaniline (Table 3). IR (υmax in cm−1, KBr): 1572 (aromatic C=C str.), 2925 (C-H str.), 3017 (aromatic C-H str.). 1H NMR (CDCl3): δ 2.28 (s, 3H, CH3), 4.42 (s, 4H, 2 × CH2Ph), 6.89-6.97 (d, 2H, Ar-H), 7.08-7.18 (d, 2H, Ar-H), 7.29-7.46 (m, 10H, Ar-H). MS: m/z 287 (M+).
N,N-Dibenzyl-4-chloroaniline (Table 3). IR (υmax in cm−1, KBr): 743 (C-Cl str.), 1582 (aromatic C=C str.), 3030 (aromatic C-H str.), 3422 (N-H str.). 1H NMR (CDCl3): δ 4.13 (s, 4H, 2 × CH2Ph), 6.93-7.02 (d, 2H, Ar-H), 7.25-7.40 (m, 10H, Ar-H), 7.48-7.57 (d, 2H, Ar-H). MS: m/z 307 (M+), 309 (M+2).
N,N-Dibenzyl-3-nitroaniline (Table 3). IR (υmax in cm−1, KBr): 860 (C-NO2 str.), 1530 (NO2 str.), 1585 (aromatic C=C str.), 3047 (aromatic C-H str.). 1H NMR (CDCl3): δ 4.33 (s, 4H, 2 × CH2Ph), 7.13-7.21 (m, 2H, Ar-H), 7.53-7.63 (m, 10H, Ar-H), 8.16-8.27 (m, 2H, Ar-H). MS: m/z 318 (M+).
N-Benzylmorpholine (Entry 1, Table 4). IR (υmax in cm−1, KBr): 1050 (C-O-C str.), 1340 (C-N str.), 1565 (C=C aromatic str.), 3070 (C-H symm. str.). 1H NMR (CDCl3): δ 2.43 (t, 4H, CH2), 4.92 (s, 2H, CH2Ph), 3.70 (t, 4H, CH2), 7.04-7.16 (m, 5H, Ar-H). MS: m/z 177 (M+).
N-Benzylpiperidine (Entry 2, Table 4). IR (υmax in cm−1, KBr): 1310 (C-N str.), 1560 (C=C aromatic str.), 3085 (C-H aromatic str.). 1H NMR (CDCl3): δ 1.40 (m, 6H, CH2), 2.24 (m, 4H, CH2), 4.90 (s, 2H, CH2Ph), 7.12-7.23 (m, 5H, Ar-H). MS: m/z 175 (M+).
Prepared SiO2-Cu2O was characterized by Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic absorption spectroscopy (AAS). In the FTIR spectra, the activated silica showed absorption peaks at 459, 800, 964, 1344, 1384, 1400, 1598, 2341, 2362, 2856, and 2929 cm−1, and wide absorption bands were observed at 1078 and 3396 cm−1 (Fig. 1). For SiO2-Cu2O, an additional peak observed at 669 cm−1 was attributed to Cu2O (Fig. 2).
The stability of the SiO2-Cu2O was determined by TGA (Fig. 3). The curve showed an initial weight loss up to 116 °C, which was attributed to the loss of residual water trapped onto the surface of the silica. This was followed by a slight weight loss up to 325 °C, which was considered to be caused by the loss of unreacted glucose or components of Fehling solution. Further continuous weight loss occurred up to 648 °C. This indicates that the catalyst is stable up to 325 °C and is safe to use in reactions at 100 °C.
The XRD diffraction patterns for SiO2-Cu2O showed peaks that were indexed on the basis of crystallographic data for the known structure of silica. In addition, reflection patterns were found corresponding to 2θ = 36.3° and 42.2°, which were attributed to Cu2O. The absence of a peak at 2θ = 38.7° excluded the possibility of CuO formation (Fig. 4).
The oxidation state of copper in the SiO2-Cu2O was determined by measurements of binding energies using XPS. The spectrum of Cu 2p3/2 photoelectrons is shown in Fig. 5. The intense and broad peak at 933 eV corresponds to Cu(I) and is in accordance with the literature values [23, 24].
The amount of copper loaded onto the silica surface was determined by AAS analysis. The catalyst was stirred in dilute HNO3 solution and then subjected to AAS analysis. The SiO2-Cu2O contained 0.0158 g of copper per gram of catalyst. The microstructure and morphology of the SiO2-Cu2O was studied by SEM and TEM. The SEM image revealed a fine homogenous powder with a porous structure (Fig. 6).
The TEM micrographs of the catalyst showed that copper was uniformly distributed on the surface of silica (Fig. 7). The mean particle diameter was found to be 7 nm. Furthermore, no bulk aggregation of the metal was observed, indicating that the copper was evenly dispersed onto the surface of the silica.
The reaction conditions for selective mono N-benzylation were optimized by using 4-nitroaniline as the test substrate and benzyl chloride as the benzylating agent. The reaction was carried out under different conditions with respect to solvent, temperature, and molar ratios of SiO2-Cu2O. After carrying out a series of reactions, 2.5 mol% of Cu in SiO2-Cu2O was found to be sufficient to complete the reaction selectively and give maximum yield of N-benzyl-4-nitroaniline. Solvents of different polarities were also tried, and the results are presented in Table 1.
The best results were obtained when water was used as solvent, with consideration to environmental impact, reaction time, yield, and selectivity. The reaction temperature also plays a crucial role in the N-benzylation of anilines; therefore, the reaction of the test substrate was also conducted at different temperatures, and the yield of mono N-benzyl-4-nitroaniline was determined (Table 2).
For N,N-dibenzylation, 4-chloroaniline was selected as the test substrate, and benzyl chloride was used as the benzylating agent. At room temperature, no dibenzylated product was formed, so the reaction temperature was increased to 100 °C. The dibenzylated product formed as the major product with a small amount of mono benzylated product. Further addition of TBAB increased the amount of dibenzylated product. With 4-toluidine, 2-toluidine, 4-chloroaniline, or 4-bromoaniline as the substrates, the N,N-dibenzylated product was formed exclusively. However, for 2-chloroaniline and 2-nitroaniline, only the N-benzylated product was formed, and no N,N-dibenzylated product was observed. For N-benzylation of secondary amines, morpholine was used as the test substrate and benzyl chloride as the benzylating agent. After carrying out a series of reactions, 5 mol% of Cu in SiO2-Cu2O was found to be sufficient to achieve good yields. Being benign and environmentally friendly, water was used as the solvent. Furthermore, the addition of base was found to have a profound effect on the rate of the reaction. Various bases were screened for the test reaction, and K2CO3 was selected because of its wide availability and low cost. A reaction temperature of 100 °C was found to be the optimum reaction temperature. Addition of TBAB as phase transfer catalyst was also found to enhance the reaction rate.
To study the generality of the developed protocol for mono N-benzylation and N,N-dibenzylation, various anilines substituted with electron-withdrawing and electron-releasing groups were chosen. The results are presented in Table 3. For N-benzylation of secondary amines, various secondary amines were chosen and products were obtained in almost quantitative yields (Table 4). To confirm the role of the catalyst for N-benzylation of primary and secondary amines, the test reaction was also carried out with the test substrate in the absence of catalyst. The reaction was observed to proceed very slowly in the absence of catalyst, confirming the catalytic effect of SiO2-Cu2O.
The mechanism for the N-benzylation of amines catalyzed by SiO2-Cu2O is considered to proceed through a recyclable coordination process via oxidative addition followed by reductive elimination (Scheme 4). First, the oxidative addition of amine to copper is thought to occur in the presence of base to give a copper complex (I), followed by the addition of benzyl chloride to form the second intermediate (II). Intermediate II then undergoes reductive elimination to give the product.
In the use of heterogeneous catalysts, the recyclability of the catalyst is an important factor. To determine the recyclability, a series of five consecutive runs were carried out (reactions of entry 8, Table 3 and entry 1, Table 4). Almost no change was observed in the catalyst activity after the fifth use (Fig. 8).
The catalyst after fifth use showed the presence of Cu(II), as indicated by magnetic moment measurements. A comparison of the fresh catalyst and that after a fifth use is shown in Fig. 9.
We have prepared an efficient and recyclable silica- supported copper(I) oxide catalyst and studied its application for the selective mono N-benzylation and N,N- dibenzylation of primary aromatic amines. The catalytic system has also been used for the N-benzylation of secondary amines. The environmentally friendly nature of the reaction is underscored by the use of water as the reaction solvent.
Acknowledgements
We are grateful to Director, SAIF, Punjab University, Chandigarh for SEM, TEM, and XRD and also extend our sincere thanks to UGC, New Delhi for financial support to purchase FTIR; awarding Major Research Project (F 41-281/2012 (SR)), and Prof. R. K. Bamezai, Department of Chemistry, University of Jammu for recording TGA.
2014, Vol. 35 Issue (3): 444-450
PDF (17002KB)
2014, Vol. 35 Issue (3): 444-450
PDF (17002KB)