Chinese Chemical Letters  2014, Vol.25 Issue (12):1540-1544   PDF    
Direct N-alkylation of amines with alcohols using AlCl3 as a Lewis acid
Ya-Qiong Lia,, Yun-Bin Chenb, Zhi-Zhen Huanga,c     
a. Department of Chemistry, Zhejiang University, Hangzhou 310028, China;
b. Zhejiang Jianye Chemical Co., Ltd., Hangzhou 311604, China;
c. State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
Abstract: A substitution reaction of amines with alcohols for N-alkylated amines has been developed using inexpensive AlCl3 without any ligand or additive. Either aromatic or aliphatic amines and primary or secondary alcohols perform the AlCl3-mediated reaction smoothly to afford various N-alkylated amines in satisfactory yields.
Key words: Amine     Alcohol     N-Alkylated amine     Lewis acid     Synthesis    
1. Introduction

N-Alkylated amines are very important intermediates in the pharmaceutical,agrochemical,and fine chemical industries [1]. The most common method for the synthesis of N-alkylated amines is the nucleophilic substitution reaction of amines or ammonia with alkyl halides,sulfonates,etc.[2]. The reductive amination of aldehydes or ketones is another reaction scheme to synthesizeNalkylated amines. Using alcohols as starting materials,which are readily available and less hazardous,is more attractive in the preparation of N-alkylated amines,because the process is more atom economical and environmentally friendly,owing to the generation of water as a side-product. Recently,‘‘borrowing hydrogen’’ methodology for the synthesis of N-alkylated amines from alcohols was developed by using transition metal complexes [3]. Directly using alcohols instead of alkyl halides or sulfonates to react with amines for N-alkylated amines has been realized by using hydrochloric acid as a Brønsted acid [4],and montmorillonite [5a] or sulfated tungstate [5b] as a solid Brønsted acid to activate the hydroxyl group of alcohols. Furthermore,Lewis acids have a lot of advantages and have been widely applied in modern organic synthesis [6]. They activate hydroxyl groups in alcohols, creating suitable substrates for substitution reactions. From 1924, it was reported that under vapor phase conditions,aniline reacted with methanol,ethanol,or propanol to form correspondingNalkylated amines at high temperature (300-500°C) catalyzed by SiO2[7] or mediated by Al2O3[8]. In 2011,Saitoet al.disclosed that FeBr3 was employed as a Lewis acid and 1,2,3,4,5-pentamethylcyclopenta-1,3-diene as a ligand to catalyze the N-alkylation of anilines or benzyl amines at 160-200°C [9]. Very recently,Jiet al. developed In(OTf)3 -catalyzed N-benzylation of amines with benzyl alcohols [10]. However,these methods suffer from limited scope in alcohols or amines. Herein,we wish to present our recent results on the reaction of various amines with a broad range of alcohols for the synthesis of N-alkylated amines using inexpensive AlCl 3a s a Lewis acid. 2. Experimental 2.1. The AlCl3-mediated reaction of aromatic amines1a-dwith

alcohols 2a-e for N-alkylated amines 3a -h A mixture of aromatic amines1a-d(3.28 mmol,2.0 equiv.), alcohols 2a-e (1.64 mmol) and AlCl3 (436 mg,3.28 mmol, 2.0 equiv.) in mesitylene (2 mL) was stirred for 4 h at 166°C. Then,ethyl acetate (50 mL) was added. The mixture was washed with aqueous NaOH (1 mol/L,50 mL) and brine (50 mL) and dried over Na2SO4. After evaporation,the residue was purified by column chromatography (silica gel,petroleum ether/ethyl acetate (100/1,v/v) as eluent) to give the desired N-alkylated amines 3a-h.

N-(2-Phenylethyl)aniline 3a [11]: Yield 80%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.32-7.27 (m,2H),7.24-7.15 (m, 5H),6.70 (t,1H,J= 7.4 Hz),6.59 (d,2H,J= 8.0 Hz),3.64 (brs,1H), 3.37 (t,2H,J= 7.2 Hz),2.89 (t,2H,J= 7.2 Hz),MS (EI):m/z 197 (M+ ), 133,106,91,77,65. N-(3-Phenylpropyl)aniline 3b[12]: Yield 84%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.29-7.25 (m,2H),7.20-7.13 (m,5H), 6.67 (t,1H,J= 7.4 Hz),6.55 (d,2H,J= 8.4 Hz),3.54 (brs,1H),3.11 (t, 2H,J= 7.0 Hz),2.70 (t,2H,J= 7.6 Hz),1.95-1.88 (m,2H),MS (EI): m/z 211 (M+ ),118,106,91,77,65.

N-Butylaniline 3c [12]: Yield 55%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.18-7.14 (m,2H),6.67 (t,1H,J= 7.4 Hz), 6.58 (d,2H,J= 7.6 Hz),3.52 (brs,1H),3.09 (t,2 H,J= 7.2 Hz),1.62- 1.55 (m,2H),1.46-1.37 (m,2H),0.95 (t,3H,J= 7.4 Hz),MS (EI):m/z 149 (M+ ),106,77,65,41.

N-Pentylaniline 3d [13]: Yield 41%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.18-7.14 (m,2H),6.67 (t,1H,J= 7.4 Hz),6.59 (d,2H,J= 7.6 Hz),3.55 (brs,1H),3.09 (t,2H,J= 7.2 Hz),1.64-1.57 (m,2H),1.39-1.35 (m,4H),0.92 (t,3H,J= 7.0 Hz),MS (EI):m/z 163 (M+ ),106,77,29.

N-Hexylaniline 3e [12]: Yield 58%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.18-7.13 (m,2H),6.69-6.65 (m,1H),6.59- 6.56 (m,2H),3.56 (brs,1H),3.08 (t,2H,J= 7.2 Hz),1.63-1.56 (m, 2H),1.42-1.26 (m,6H),0.90 (t,3H,J= 7.0 Hz),MS (EI):m/z 177 (M+ ),106,77,41,29.

N-(m-Chlorophenyl)-3-phenylpropylamine 3f: Yield 76%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.32-7.28 (m,2H),7.22- 7.18 (m,3H),7.04 (t,1H,J= 8.0 Hz),6.64 (ddd,1H,J1=0.8Hz, J2=1.6Hz,J3= 7.6 Hz),6.52 (t,1H,J= 2.2 Hz),6.41 (ddd,1H, J1= 0.8 Hz,J2= 2.0 Hz,J3= 8.0 Hz),3.67 (brs,1H),3.12 (t,2H, J= 6.8 Hz),2.72 (t,2H,J= 7.4 Hz),1.98-1.90 (m,2H),MS (EI):m/z 245 (M+ ),140,91,77.

N-(m-Tolyl)-3-phenylpropylamine 3g [14]: Yield 66%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.29-7.26 (m,2H),7.20- 7.15 (m,3H),7.06-7.02 (m,1H),6.50 (d,1H,J= 7.6 Hz),6.38-6.36 (m,2H),3.51 (brs,1H),3.10 (t,2H,J=7.0Hz),2.70 (t,2H, J= 7.6 Hz),2.25 (s,3H),1.95-1.87 (m,2H),MS (EI):m/z 225 (M+ ), 120,91,77,65.

N-(p-Tolyl)-3-phenylpropylamine 3h[15]: Yield 64%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.29-7.26 (m,2H),7.20-7.16 (m, 3H),6.96 (d,2H,J= 8.0 Hz),6.51-6.47 (m,2H),3.43 (brs,1H),3.10 (t,2H,J= 7.0 Hz),2.71 (t,2H,J= 7.6 Hz),2.22 (s,3H),1.95-1.88 (m, 2H),MS (EI):m/z 225 (M+ ),120,91,77,65. 2.2. The AlCl3-mediated reaction of aniline 1a with benzyl alcohol 2f for N-alkylated amine 3i

A mixture of aniline1a(305 mg,3.28 mmol,2.0 equiv.),benzyl alcohol2f(177 mg,1.64 mmol) and AlCl3 (218 mg,1.64 mmol, 1.0 equiv.) in mesitylene (2 mL) was stirred for 12 h at 100°C. The similar work-up to that for 3a -hled to N-benzylaniline3i. N-Benzylaniline 3i [11]: Yield 57%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.37-7.15 (m,7H),6.71 (t,1H,J= 7.4 Hz),6.63 (d,2H,J= 8.0 Hz),4.32 (s,2H),3.98 (brs,1H),MS (EI):m/z 183 (M+ ), 106,91,77,65. 2.3. The AlCl3-mediated reaction of aliphatic amines 1e-f with

alcohols 2a-b for N-alkylated amines 3j-l A mixture of aliphatic amines1e-f (3.28 mmol,2.0 equiv.), alcohols 2a-b (1.64 mmol),diethyl amine (478 mg,6.56 mmol, 4.0 equiv.) and AlCl3(436 mg,3.28 mmol,2.0 equiv.) in mesitylene (2 mL) was stirred for 20 h at 176 °C. Then ethyl acetate (50 mL) was added. The mixture was washed with aqueous NaOH (1 mol/L, 50 mL) and brine (50 mL) and dried over Na2SO4. After evaporation,the residue was purified by column chromatography (silica gel,dichloromethane/methanol (50/1,v/v) as eluent) to give the desired N-alkylated amines 3j-l .

N-Octyl-2-phenylethylamine 3j[16]: Yield 40%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.30-7.27 (m,2H),7.21-7.17 (m,3H), 2.89-2.79 (m,4H),2.60 (t,2H,J= 7.4 Hz),1.47-1.44 (m,2H),1.30- 1.26 (m,10H),0.88 (t,3H,J= 6.8 Hz),MS (EI):m/z 234 (M+H)+ ,91,65,43,29.

N-Octyl-3-phenylpropylamine 3k[17]: Yield 62%,colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.29-7.25 (m,2H),7.19-7.15 (m,3H), 2.67-2.56 (m,6H),1.86-1.78 (m,2H),1.48-1.43 (m,2H),1.30-1.25 (m,10H),0.88 (t,3H,J= 6.8 Hz),MS (EI):m/z 248 (M+H)+ ,148,142,91,57,44.

N-(2-Phenylethyl)-3-phenylpropylamine 3l [18]: Yield 66%, colorless oil. 1H NMR (400 MHz,CDCl3): δ 7.30-7.13 (m,10H), 2.88-2.77 (m,4H),2.65-2.59 (m,4H),1.83-1.75 (m,2H),MS (EI): m/z 240 (M+H)+ ,148,91,65,44. 2.4. The AlCl3-mediated reaction of butyl amine 1g with 3-phenylpropanol 2b for N-alkylated amine 3m

A mixture of butyl amine1g(359 mg,4.92 mmol,3.0 equiv.),3-phenylpropanol 2b (223 mg,1.64 mmol) and AlCl3 (436 mg, 3.28 mmol,2.0 equiv.) in mesitylene (2 mL) was stirred for 20 h at 176°C. The similar work-up to that for 3j-l led to N-butyl-3-phenylpropylamine3m. N-Butyl-3-phenylpropylamine3m[19]: Yield 83%,yellow oil. 1H NMR (400 MHz,CDCl3): δ 7.29-7.25 (m,2H),7.19-7.15 (m,3H), 2.67-2.56 (m,6H),1.85-1.78 (m,2H),1.49-1.42 (m,2H),1.37-1.28 (m,2H),0.91 (t,3H,J= 7.2 Hz),MS (EI):m/z 192 (M+H)+ ,148,91, 86,57,44. 2.5. The AlCl3-mediated reaction of aniline1awith secondary alcohol 2g for N-alkylated amine 3n

A mixture of aniline 1a (762 mg,8.20 mmol,5.0 equiv.), secondary alcohol 2g(246 mg,1.64 mmol) and AlCl3 (436 mg, 3.28 mmol,2.0 equiv.) in mesitylene (2 mL) was stirred for 4 h at 166°C. The similar work-up to that for 3a-h led to N-phenyl-4-phenyl-2-butylamine 3n.

N-Phenyl-4-phenyl-2-butylamine 3n[20]: Yield 51%,yellow oil. 1H NMR (400 MHz,CDCl3): δ 7.28-7.25 (m,2H),7.19-7.11 (m, 5H),6.65 (t,1H,J= 7.4 Hz),6.52-6.50 (m,2H),3.51-3.43 (m,1H), 3.38 (brs,1H),2.71 (t,2H,J= 8.0 Hz),1.90-1.81 (m,1H),1.79-1.70 (m,1H),1.19 (d,3H,J= 6.4 Hz),MS (EI):m/z 225 (M+ ),210,134, 120,106,91,77. 2.6. The AlCl3-mediated reaction of diethyl amine 1h with benzyl alcohol 2f for N-alkylated amine 3o

A mixture of diethyl amine1h(359 mg,4.92 mmol,3.0 equiv.), benzyl alcohol 2f (177 mg,1.64 mmol) and AlCl3 (436 mg, 3.28 mmol,2.0 equiv.) in toluene (2 mL) was stirred for 12 h at 100°C. The similar work-up to that for 3j-l led to N,Ndiethylbenzylamine 3o. N,N-Diethylbenzylamine 3o[21]. Yield 51%,yellow oil. 1H NMR (400 MHz,CDCl3): δ 7.34-7.27 (m,4H),7.24-7.20 (m,1H),3.56 (s, 2H),2.52 (q,4H,J= 7.2 Hz),1.04 (t,6H,J= 7.0 Hz),MS (EI):m/z 163 (M+ ),148,91,86,29. 1H NMR and MS (EI) spectra of some N-alkylated amines3can be found in Supporting information. 3. Results and discussion

Initially,aniline1aand phenylethanol2awere chosen as model substrates to explore and optimize their reaction for N-alkylated amine 3a . It was found that when AlCl3 was employed as a Lewis acid,the desired N-alkylated amine 3a was obtained in 10% yield using chlorobenzene as a solvent at 140°C (Table 1,entry 1). Encouraged by this result,other Lewis acids were tested. BF3·Et2O, ZnCl2,and BiCl3 did not initiate the reaction,and Al2(SO4)3 led to only a trace amount of 3a (Table 1,entries 2-5). When xylene was employed as a solvent,a similar yield of 3a was obtained (Table 1, entry 6). Using mesitylene as a solvent resulted in the improvement of the yield (Table 1,entry 7; also see Table S1 in Supporting Information). When the reaction temperature was raised to 166°C, the yield of 3a was increase to 36% (Table 1,entry 8). However, further raising the reaction temperature to 1768C had no favorable effect on the yield of 3a (Table 1,entry 9). To our delight,when loading of AlCl3 was increased to 2 equiv.,the yield of 3a was remarkably improved to 80% (Table 1,entry 10). Thus,the optimized reaction should be performed in the presence of AlCl3 (2 equiv.) using mesitylene as a solvent under 166°C.

Table 1
Optimizing reaction of amine 1a with alcohol 2a for N-alkylated amine 3a.a

After we established the optimized reaction conditions,various amines 1 and alcohols 2 were probed to evaluate the generality of the N-alkylation reaction. It was found that in the presence of AlCl3, various arylamines 1a-dunderwent the substitution reaction readily with alcohols 2a-e at 166°C to give the desired N-alkylated amines 3a-h(Table 2,entries 1-8). Probably due to the better activity of the hydroxyl group in benzyl alcohol 2f as compared to the alcohols 2a-e,its substitution reaction with aniline 1a proceeded at a lower temperature (Table 2,entry 9). Under the same reaction conditions,switching arylamines1a-dto aliphatic amines1e-f led to no desired N-alkylated product. This may be because aliphatic amines1e-f,which has stronger basicity as compared to aryl amines1a-d,bound more tightly with AlCl3. Gratifyingly,when an excess of diethylamine was added,the substitution reactions of aliphatic amines1e-fwith alcohols 2a-b were able to occur at 176 °C,affording the desired N-alkylated amines 3j-l (Table 2,entries 10-12). Diethylamine itself as a secondary amine did not perform the N-alkylation reaction readily with alcohols 2a-b under the same conditions. Therefore,diethylamine in this reaction may displace aliphatic amines1e-fin AlCl3-amine complexes 4c to form AlCl3-diethylamine complex 4d,which may more easily release diethylamine and regenerate AlCl3 due to its lower boiling point. Forn-butyl amine1g,which has a low boiling point as well,its substitution reaction with alcohol2bproceeded smoothly in the absence of diethylamine, affording the expected amine 3m in a high yield (Table 2,entry 13). It was also found that,similar to the above primary alcohols, secondary alcohol 2g could also react expediently with aniline1a to afford the N-alkylated amine 3n at 166°C (Table 2,entry 14).

Table 2
AlCl3-mediated reaction of amine 1 with alcohol 2 forN-alkylated amine 3.

Although primary amines1a-dunderwent the substitution reaction with various alcohols 2a-f,diethylamine 1h as a secondary amine performed the reaction only with benzyl alcohol 2f as an active alcohol to furnish the desired alkyl amine 3o (Scheme 1).

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Scheme 1. AlCl3-mediated reaction of diethylamine 1h with benzyl alcohol 2f forNalkylated amine 3o.

The possible mechanism of the N-alkylation reaction of amines 1with alcohols 2 is outlined in Scheme 2. First,amines 1a-d,1g,or 1e-f may combine with AlCl3 to form the corresponding complexes 4a,4b or 4c,respectively. Because arylamines 1a-d are weaker bases,their binding with AlCl3 in 4a is not fast. Thus complex 4a is easily decomposed into amines 1a-d and AlCl3by heating. For complex 4b,heating may lead to its release of low boiling point amine1gand regenerate AlCl3. Because the basicity of diethylamine as a secondary aliphatic amine is stronger than that of primary aliphatic amine,diethylamine may replace primary aliphatic amines1e-fin complex 4c to form complex 4d,which then releases diethylamine with regenerating AlCl3 by heating. Subsequently,alcohol 2 combines with AlCl3 to form complex 5, activating the C-O bond. Finally,amine1nucleophilically attacks complex 5 to produce N-alkylated amine 3.

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Scheme 2. The possible mechanism of amines 1 with alcohols 2 for N-alkylated amines 3.
4. Conclusion

In conclusion,we have developed an N-alkylation reaction of amines 1 with alcohols 2 using inexpensive AlCl3 without any ligand or additive. Either aromatic or aliphatic amines and primary or secondary alcohols perform the AlCl3-mediated reaction smoothly to afford various N-alkylated amines.

Acknowledgments

Financial supports from MOST of China (973 program,No. 2011CB808600),National Natural Science Foundation of China (Nos. 21072091 and 21372195) and the Low Carbon Fatty Amine Engineering Research Center of Zhejiang Province (No. 2012E10033) are gratefully acknowledged.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version,at http://dx.doi.org/10.1016/j.cclet.2014.07.006.

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