Simple Methodology for the Aerobic N-Methylation of Substituted

Article pubs.acs.org/IECR

Simple Methodology for the Aerobic N‑Methylation of Substituted Anilines Catalyzed by Zirconium Oxychloride Octahydrate, ZrOCl2·8H2O Reza Tayebee,*,† Esmail Rezaei Seresht,† Fariba Jafari,‡ and Sima Rabiei§ †

Department of Chemistry, School of Sciences, Hakim Sabzevari University, Sabzevar, 96179-76487, Iran Department of Chemistry, Payam e Noor University, Branch of Jovein, Sabzevar, Iran § Department of Chemical and Petroleum Engineering, Sharif University of Technology, Tehran, Iran ‡

S Supporting Information *

ABSTRACT: A highly chemoselective methodology is described for the N-methylation of functionalized anilines with dimethyl carbonate (MeOCO2Me, DMC) in the presence of ZrOCl2·8H2O. Dimethyl carbonate, which usually promotes methylation at T > 120 °C and eventually under inert atmosphere, was activated in the presence of zirconium oxychloride for the desired transformation at 90 °C under aerobic conditions. Aminophenols showed good reactivity in this transformation and produced the corresponding N-methylanilines, as the major products, with high selectivity. Catalyst reusability study confirmed that ZrOCl2·8H2O is a recyclable catalyst and its catalytic activity was remained unchanged at least after eight runs. Effect of some reaction parameters such as catalyst concentration, aniline/DMC mole ratio, reaction time, and temperature were also investigated.

1. INTRODUCTION In the past few decades, the public dialogue has increasingly addressed the environmental impacts of a wide range of chemical substances. To overcome the problem of artificial wastes, the chemical industry must develop cleaner chemical processes by the design of innovative and environmentally benign chemical reactions.1,2 Dimethyl carbonate (DMC) is a well-known nontoxic reagent that has been used as a green substitute for highly noxious substances such as methyl iodide, dimethyl sulfate, and phosgene in a variety of reactions.3 Moreover, the synergy between its nontoxicity, good biodegradability, and its versatile reactivity imparts to it a great potential as a reagent for the methylation of several O-, S-, C-, and N-nucleophiles.4,5 DMC as a versatile compound represents an attractive eco-friendly alternative for both methylation6 and carboxymethylation processes.7,8 This compound has two electrophilic carbons (alkyl and carbonyl) and may act as both alkylating and carboxyalkylating agent. Furthermore, DMC was found to be as an effective methylating agent of amines,9 phenols,10 and alcohols.11 N-Methylation of aromatic amines is still a challenging process from the catalytic point of view since aromatic amines are considerably more reluctant than aliphatic amines to undergo N-methylation.12 Several reports have disclosed on the N-methylation of anilines using DMC in the presence of various solid acidic or basic catalysts. N-Methylation of aniline in the vapor phase over KX and KY zeolites, as basic catalysts, has been carried out, while only 10−15% of aniline was converted into the desired methylated products.13 Silicasupported vanadia catalysts also were found to exhibit good selectivity toward mono-N-methylation, but the conversion of aniline was still remained negligible.14 Moreover, V-AlPO4 © XXXX American Chemical Society

showed high selectivity for mono-N-methylation of aniline, though the catalytic system was inefficient.15 Herein, an effective and environmentally benign process is presented for the highly selective N-methylation of anilines with DMC leading to moderate to high yields. Effect of reaction temperature, catalyst concentration, reproducibility, and reusability of the catalyst were also investigated.

2. EXPERIMENTAL SECTION 2.1. General Remarks. Reagents and starting materials were purchased from Merck and used as received. Freshly distilled aniline was used in all cases. All products were identified by comparison of their spectral and physical data with those previously reported. Infrared spectra were recorded (KBr pellets) on 8700 Shimadzu Fourier Transform spectrophotometer. 1H and 13C NMR spectra were recorded on a Bruker AVANCE 100 MHz instrument using TMS as internal reference. Data for 1H NMR are reported as follows: chemical shift (δ) and multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, qt = quintuplet, dq = doublet of quartets, br = broad). Melting points were recorded on a Bamstead electrothermal type 9200 melting point apparatus. Dry-column flash chromatography was performed using silica gel (230−400 mesh, 0.040−0.063 μm) from Merck. The gas− liquid chromatography analyzes were obtained with a Shimadzu 17A, chromatograph equipped with a flame ionization detector (FID) and a CPB-5 capillary fused silica column (25 m, 0.25 mm i.d.; 0.25 μm film thickness). The carrier gas nitrogen Received: June 14, 2013 Revised: July 12, 2013 Accepted: July 21, 2013

A

dx.doi.org/10.1021/ie4018786 | Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

Industrial & Engineering Chemistry Research

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(99.999%) with the split ratio of 1:10 and flow rate of 1 mL/s was applied. 2.2. General Procedure for the N-Methylation of Anilines with DMC Catalyzed by ZrOCl2·8H2O. A mixture of aniline (4.5 mmol), DMC (24 mmol), and ZrOCl2·8H2O (360 mg, 25 mol %) was refluxed in a sample tube equipped with a reflux condenser at 90 °C under air for 22 h. Progress of the reactions was carried out with GLC. To isolate the products, after completion, the reaction mixture was cooled to room temperature, filtered, and the mother liquor was concentrated. The crude residue was flash chromatographed (dry-column technique) on silica gel (hexane/EtOAc) to afford the relevant mono(di)methylanilines and carbamate derivatives. 2.3. Physical and Spectral Data of Some Purified Products. Compound 2c. Eluted with n-hexane/EtOAc 80:20. 1 H NMR (CDCl3, 100 MHz): δ 6.86 (d, J 8 Hz, 2 H), 6.60 (d, J 8 Hz, 2 H), 3.83 (s, 1 H, −NH−), 3.76 (s, 3 H, −CH3), 2.81 (s, 3 H, −CH3). IR (KBr, cm−1): 3416,3000, 2950, 1508,1450, 1228, 1038, 823. Compound 3c. Eluted with n-hexane/EtOAc 80:20. mp: 30−32 °C. 1H NMR (CDCl3, 100 MHz): δ 6.88 (s, 4 H), 3.81 (s, 3 H, −CH3), 2.91 (s, 6 H, −CH3). IR (KBr, cm−1): 3000, 2930, 2852, 1508, 1450, 1253, 1047, 817. Compound 4c. Eluted with n-hexane/EtOAc 80:20. mp: 71−74 °C. 1H NMR (CDCl3, 100 MHz): δ 7.28 (d, J 8 Hz, 2H), 6.85 (d, J 8 Hz, 2 H), 6.51 (br, 1 H, −NH−), 3.79 (s, 3 H, −CH3), 3.76 (s, 3 H, −COOCH3). IR (KBr, cm−1): 3350, 3000, 2950, 1718, 1510, 1237, 822, 773. Compound 2d. Eluted with n-hexane/EtOAc 92:8. 1H NMR (CDCl3, 100 MHz): δ 7.02 (d, J 8 Hz, 2 H), 6.55 (d, J 8 Hz, 2 H), 3.41 (s, 1 H, −NH−), 2.82 (s, 3 H, −CH3), 2.26 (s, 3 H, −CH3). IR (KBr, cm−1): 3442, 3000, 2957, 1614, 1528, 1337, 1272, 803. Compound 3d. Eluted with n-hexane/EtOAc 92:8. 1H NMR (CDCl3, 100 MHz): δ 7.05 (d, J 8 Hz, 2 H), 6.68 (d, J 10 Hz, 2 H), 2.93 (s, 6 H, −CH3), 2.29 (s, 3 H, −CH3). IR (KBr, cm−1) 3000, 2930, 2843, 1517, 1463,1370, 1082, 802. Compound 4d. Eluted with n-hexane/EtOAc 92:8. mp: 91− 94 °C. 1H NMR (CDCl3, 100 MHz): δ 7.17 (br, 4 H), 6.53 (s, 1 H, −NH−), 3.77 (s, 3 H, −COOCH3), 2.31 (s, 3 H, −CH3). IR (KBr, cm−1) 3330, 3000, 2904, 1705, 1604, 1531, 1227, 812, 672, 502. Compound 2e. Eluted with n-hexane/EtOAc 96:4. 1H NMR (CDCl3, 100 MHz): δ 7.19 (d, J 8 Hz, 2 H), 6.59 (d, J 8 Hz, 2 H), 3.83 (s, 1 H, −NH−), 2.82 (s, 3 H, −CH3). IR (KBr, cm−1) 3416, 3000, 2930, 1602, 1502, 1332, 812. Compound 3e. Eluted with n-hexane/EtOAc 96:4. mp: 33− 34 °C. 1H NMR (CDCl3, 100 MHz): δ 7.23 (d, J 8 Hz, 2 H), 6.67 (d, J 8 Hz, 2 H), 2.94 (s, 6 H, −CH3). IR (KBr, cm−1) 3050, 2860, 2803, 1600, 1503, 1354, 1215, 810, 612, 520. Compound 4e. Eluted with n-hexane/EtOAc 96:4. mp: 107−110 °C. 1H NMR (CDCl3, 100 MHz): δ 7.34 (S, 4 H), 6.61 (s, 1 H, −NH−) 3.78 (s, 3 H, −COOCH3). IR (KBr, cm−1): 3300, 3170, 2949, 1530, 1274, 850, 764, 722, 603.

Depending on reaction conditions and catalyst, dialkylation of anilines would be carried out. Scheme 1. Two Conceivable Routes for the Reaction of Aniline with DMC

a

Bimolecular, acyl cleavage, nucleophilic substitution. bBimolecular, alkyl cleavage, nucleophilic substitution.

To investigate the catalytic activity of ZrOCl2·8H2O, the reaction of aniline with DMC was selected as a model reaction. Mixtures of anilines (4.5 mmol) and DMC (24 mmol) (molar ratio of aniline:DMC = 1:5.3) in the presence of ZrOCl2·8H2O (25 mol %), were reacted at 90 °C under normal aerobic conditions (Scheme 2). An experiment was also conducted in Scheme 2. Reaction of Aniline with DMC in the Presence of ZrOCl2·8H2O

the absence of the catalyst. The direct reaction of aniline with DMC in the absence of catalyst at 90 °C did not afford an appreciable amount of the N-methylated products; only very low amount (25 mol %) have not influenced

3. RESULTS AND DISCUSSION There are a number of routes describing the reaction of aniline with DMC. N-Alkylation of aniline with DMC would be accompanied with the formation of carbamate, as a result of the transesterification reaction. Carbamates, such as methyl Nphenyl carbamate and methyl N-methyl N-phenyl carbamate, would be formed via the two routes as depicted in Scheme 1. B



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Effect of reaction time on the reaction of aniline with DMC in the presence of catalyst (25 mol %) was studied at 90 °C. Results showed that conversion was increased with prolonging the reaction time (Table 1). Obviously, selectivity for the di-N-

the conversion significantly (Figure 1). Therefore, the catalyst smoothly promoted the conversion of aniline to the expected

Table 1. Effect of Reaction Time on the Reaction of Aniline with DMCa selectivity (%) methylation

Figure 1. Reaction of aniline (4.5 mmol) with DMC (24 mmol) in presence of different amounts of ZrOCl2·8H2O at 90 °C after 22 h.

entry

time (h)

conv. (%)

mono

di

carbamoylation

1 2 3 4 5 6 7

1 5 8 12 15 18 22

0 2 13 30 47 60 74

100 100 83 74 63 55

17 21 23 25

5 13 20

a

products. As indicated in Supporting Information Table S1, monomethylated product was the major compound and the amount of the carbamoylated product was increased with enhancing the catalyst concentration. Table S2 in the Supporting Information shows effect of the molar ratio of aniline:DMC on the conversion of aniline in the presence of 360 mg of catalyst at 90 °C. Aniline led to 58% conversion with the molar ratio of 1:1 (entry 2), whereas conversion was increased to 70% with the molar ratio of 1:20 (entry 6). The highest conversion was reached with the molar ratio of 1:5.3 (entry 4). Moreover, the selectivity for mono-Nmethylated, di-N-methylated, and carbamoylated products was changed smoothly with aniline/DMC molar ratio. Furthermore, to examine the influence of temperature on the conversion percentage, the reaction of aniline with DMC was carried out at different temperatures (see Table S3 in the Supporting Information). Experiments were run under the standard conditions previously determined as the optimum conditions (aniline/DMC = 1:5.3; t = 22 h; catalyst =25 mol %). The obtained results in Figure 2 clearly confirmed that

Reaction conditions: aniline (4.5 mmol), DMC (24 mmol), and catalyst (360 mg) were stirred in a sample tube equipped with a reflux condenser at 90 °C.

methylated and carbamoylated products was also increased with lengthening the reaction time. According to the obtained results, the reaction time 22 h was selected as the suitable time for all reactions. To examine the scope of the methodology, different substituted anilines were reacted with DMC under the optimum conditions (Table 2). In all cases, the N-methylated derivatives were obtained in moderate to high yields. Furthermore, in the case of O-aminophenolic compounds (entries 7−9), which principally contain two nucleophilic sites; different selectivity pattern was observed. In these cases, methylation and/or methoxycarbonylation, were exclusively occurred on the amino group. It was also found that prolonging the reaction time at a given temperature, increased the conversion up to 100% but decreased the selectivity apparently. For example, when the reaction time for anisidine (1c) was extended to 28 h, the conversion was enhanced, whereas the selectivity was definitely declined. The superiority of the present heterogeneous methodology was studied over some reported procedures (Table 3). The comparison was in terms of mol % of the catalyst, temperature, reaction time, and percentage conversion. Obviously, the present catalyst was superior over the reported catalysts considering the above parameters. To investigate the reusability of ZrOCl2·8H2O, it was separated from the reaction mixture and washed with ethyl acetate. The catalyst was slowly dried in air and then was activated in a vacuum oven at 100 °C for 1.5 h. Finally, the recycled catalyst was reused for another condensation reaction. Findings revealed that the catalyst was reusable for at least eight cycles without significant loss of activity (Figure 3). Moreover, to ensure reproducibility of the transformation, repeated experiments were carried out under the standard reaction conditions. The obtained isolated yields were found to be reproducible within ±2.5% variation. In agreement with the previous reports,3,6,19−21 DMC revealed a tunable reactivity and operated as a methoxycarbonylating and methylating agent in the presence of ZrOCl2·8H2O. Undoubtedly, coordination of DMC to Zr4+ activates both carbonyl group and O−CH3 moieties of the carbonic acid diester, therefore, Zr4+ enhances not only the

Figure 2. Effect of temperature on the reaction of aniline with DMC (1:5.3) in the presence of catalyst (25 mol %).

although the conversion was slightly affected by the reaction temperatures below 70 °C, but conversion was significantly improved at the reflux temperature of 90 °C. A comparison of these findings with other methodologies, which have been used temperatures generally greater than 130 °C, confirms feasibility of the present method. As indicated before, higher temperature led to greater selectivity for the formation of carbamoylated product. With enhancing temperature from 70 to 90 °C, the selectivity of carbamoylation was reached 20%. C



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Table 2. Reaction of Some Substituted Anilines with DMC in the Presence of ZrOCl2·8H2Oa

Reaction conditions: Aniline/DMC (1:5.3) and catalyst (25 mol %) were stirred as described in the Experimental Section for 22 h at 90 °C. Determined by GLC. Selectivity of methylation = yield %(mono + di)/conv.% of aniline. Selectivity of carbomoylation = yield % of carbamoylation/conv.% of aniline. cOnly monomethylated product was observed.

a b

Table 3. Comparison of the Efficacy of ZrOCl2·8H2O with Other Reported Catalysts selectivity (%)b

a

catalyst

catalyst (mg)

T (°C)

aniline (mmol)

DMC (mmol)

time (h)

conv. (%)

MNM

ZrOCl2·8H2O H4SiW12O40 H3PW12O40 Al2(BDC)3 Sc(OTf)3 NH2SO3H (Et)4NBr Co-AlPO4 V-AlPO4

360 450 450 100 10 465 1500 500 500

90 90 90 170 90 100 170 250 200

4.5 4.5 4.5 0.53 0.82 24 16.1 1:1a 1:1a

24 24 24 5 eq. 9.03 120 0.19 1:1a 1:1a

22 22 22 8 24 8 2 5c 5c

74 50 46 89 48 10 94 44 36

55 72 70 34 72 87 16 54.5 100

DNM 25 28 30 62 8 78 45.4

carb.

ref

20

3 16 5

17 7 16 18 15 15

Aniline/DMC molar ratio. bMNM: mono-N-methylation. DNM: di-N-methylation. Carb.: Carbamoylation. cFlow rate: 5 mL h−1.

methylation but also the carbomethoxylation activity of the ambident electrophile DMC.7 However, further mechanistic

and kinetic studies should be carried out to establish role of Zr4+ in this transformation. D



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ACKNOWLEDGMENTS Partial financial support from the Research Council of Hakim Sabzevari University is greatly appreciated.

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(1) Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.; Memoli, S.; Miyamoto, J.; GPolyakoff, M.; Tumas, W. Synthetic Pathways and Processes in Green Chemistry. Pure Appl. Chem. 2000, 72, 1207. (2) Anastas, P. T.; Warner, J. C. Green Chemistry Theory and Practice; Oxford University Press: Oxford, U.K., 1998. (3) Tundo, P.; Selva, M. The Chemistry of Dimethyl Carbonate. Acc. Chem. Res. 2002, 35, 706. (4) Shaikh, A. A. G.; Sivaram, S. Organic Carbonates. Chem. Rev. 1996, 96, 951. (5) Bhanage, B. M.; Fujita, S.; Ikushima, T.; Arai, M. Synthesis of Dimethyl Carbonate and Glycols from Carbon Dioxide, Epoxides, and Methanol Using Heterogeneous Basic Metal Oxide Catalysts with High Activity and Selectivity. Appl. Catal., A 2001, 219, 259. (6) Bomben, A.; Selva, M.; Tundo, P. Dimethyl Carbonate as a Methylating Agent. The Selective Mono-C-methylation of Alkyl Aryl Sulfones. J. Chem. Res. Synop. 1997, 448. (7) Distaso, M.; Quaranta, E. Group 3 Metal (Sc, La) Triflates as Catalysts for the Carbomethoxylation of Aliphatic Amines with Dimethyl carbonate Under Mild Conditions. Tetrahedron. 2004, 60, 1531. (8) Tundo, P.; Bressanello, S.; Loris, A.; Sathicq, G. Direct Synthesis of N-methylurethanes from Primary Amines with Dimethyl Carbonate. Pure Appl. Chem. 2005, 77, 1719. (9) Selva, M.; Tundo, P.; Perosa, A. Mono-N-methylation of Primary Amines with Alkyl Methyl Carbonates over Y Faujasites. 2. Kinetics and Selectivity. J. Org. Chem. 2002, 67, 9238. (10) Mei, F. M.; Li, G. X.; Nie, J.; Xu, H. B. A Novel Catalyst for Transesterification of Dimethyl Carbonate with Phenol to Diphenyl Carbonate: Samarium Trifluoromethanesulfonate. J. Mol. Cat. A: Chem. 2002, 184, 465. (11) Selva, M.; Militello, E.; Fabris, M. The Methylation of Benzyltype Alcohols with Dimethyl Carbonate in the Presence of Y- and XFaujasites: Selective Synthesis of Methyl Ethers. Green Chem. 2008, 10, 73. (12) March, J. Advanced Organic Chemistry; Reactions, Mechanisms and Structures, 3rd ed.; McGraw-Hill: New York. 1993. (13) Su, B. L.; Barthomeuf, D. Alkylation of Aniline with Methanol: Change in Selectivity with Acido-Basicity of Faujasite Catalysts. Appl. Catal., A 1995, 124, 73. (14) Narayanan, S.; Deshpande, K. Aniline Alkylation Over Solid Acid Catalysts. Appl. Catal., A 2000, 199, 1. (15) Nagaraju, N.; Kuriakose, G. Activity of Amorphous V-AlPO4 and Co-AlPO4 in the Selective Synthesis of N-Monoalkylated Aniline via Alkylation of Aniline with Methanol or Dimethyl Carbonate. New J. Chem. 2003, 27, 765. (16) Wang, B.; He, J.; Sun, C. R. Carbamate Synthesis from Amines and Dialkyl Carbonate Over Inexpensive and Clean Acidic Catalyst Sulfamic Acid. J. Chin. Chem. Lett. 2010, 21, 794. (17) Dhakshinamoorthy, A.; Alvaro, M.; Garcia, H. Metal Organic Frameworks as Heterogeneous Catalysts for the Selective NMethylation of Aromatic Primary Amines with Dimethyl Carbonate. Appl. Catal. A: Gen. 2010, 378, 19. (18) Shivarkar, A. B.; Gupte, S. P.; Chaudhari, R. V. Selective Synthesis of N,N-dimethyl Aniline Derivatives Using Dimethyl Carbonate as a Methylating Agent and Onium Salt as a Catalyst. J. Mol. Catal. A: Chem. 2005, 226, 49. (19) Tundo, P. Continuous Flow Methods in Organic Synthesis; Horwood: Chichester, U. K., 1991. (20) Fan, S.; Zhao, N.; Li, J.; Xiao, F.; Wei, W.; Sun, Y. Effective and Green Synthesis of Methyl Pyrrole-1-carboxylate with Dimethyl Carbonate Over Solid Base. Catal. Lett. 2008, 120, 299.

Figure 3. Conversion percent as a function of reusability for ZrOCl2·8H2O.

Scheme 3. Proposed Description for the Catalytic Role of ZrOCl2·8H2O

4. CONCLUSION The selective N-methylation of anilines with DMC was studied in the presence of ZrOCl2·8H2O. Anilines can be converted into their corresponding N-methylated derivatives in moderate to high yields, and no C-methylation products were observed. Some notable advantages and remarkable environmentally benign features of this protocol are (1) using cheap and nontoxic DMC as the N-methylation agent; (2) exclusive observation of N-methylation of aminophenols versus Omethylation; (3) no production of hazardous wastes; (4) very high reusability of the catalyst; (5) N-methylation of anilines with DMC at the low temperature of 90 °C and under simple aerobic conditions.

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ASSOCIATED CONTENT

S Supporting Information *

Effect of catalyst concentration, effect of aniline/DMC molar ratio, and effect of temperature on the reaction of anilines with DMC (Tables S1−S3). This information is available free of charge via the Internet at http://pubs.acs.org/.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Tel:+98-571-4410310. Fax: +98-571-4410300. E-mail: [email protected]. Notes

The authors declare no competing financial interest. E



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(21) Fu, Z.-h.; Ono, Y. Selective N-Monomethylation of Aniline With Dimethyl Carbonate Over Y-zeolites. Catal. Lett. 1993, 18, 59.

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Simple Methodology for the Aerobic N-Methylation of Substituted

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