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Facile synthesis of thiourea derivatives in ionic liquid
Chinese Chemical Letters 18 (2007) 258–260 www.elsevier.com/locate/cclet
Facile synthesis of thiourea derivatives in ionic liquid Min Liang Xiao a, Feng Huang Chen b, Zhi Juan Chen a, Bao Shou Guo a, Xian Hai Lv a,c, Wen Ming Tang a,* a
Center for Research & Development of Fine Chemicals, Guizhou University, Guiyang 550025, China b Guiyang Environmental Monitoring Center, Guiyang 550001, China c School of Science, Anhui Agricultural University, Hefei 230036, China Received 7 November 2006
Abstract The synthesis of cinnamoyl thiourea derivatives from cinnamoyl isothiocyanate (CIT) with substituted aniline (RC6H4NH2) was investigated in the mostly used ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [Bmim][BF4]. Significant enhancements in reactivity, yield and reaction rate were achieved. The products could be recovered by simple filtration. [Bmim][BF4] could be recycled simply by removing water under vacuum and reused at least 9 times without significant decrease in activity. # 2007 Wen Ming Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Ionic liquid; Cinnamoyl isothiocyanate; Substituted aniline; Cinnamoyl thiourea derivatives; Synthesis
Many methods for the synthesis of thioureas have been developed and reported including: (a) direct reaction of isothiocyanates or carbon disulfide with anilines [1]; (b) reaction catalyzed by phase transfer catalysts [2], supported reagents [3] or peptide coupling reagents [4]; (c) activation of dithiocarbamates or related salts [5]; (d) catalytic synthesis promoted by microwave [6]. However, these methods still involve many limitations: harsh reaction conditions, multistep operations, long reaction time, high reaction temperature, noxious reagents or volatile solvents, poor yields or too much site-products. Room temperature ionic liquids have been accepted as green, alternatives to traditional organic solvents for their unique physical and chemical properties [7], they can act both as reaction medium and promoter in many reactions [8]. Acyl thioureas are not only important intermediates, but also valuable compounds with broad bioactivities [1,2,4]. In our previous work, the synthesis and bioactivities of cinnamoyl thioureas were studied. But the reaction time was long, the solvent was noxious and volatile, and the yield was low. Now we reported the synthesis of cinnamoyl thiourea derivatives from cinnamoyl isothiocyanate (CIT) and substituted anilines (RC6H4NH2) in the mostly used ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [Bmim][BF4] (Scheme 1). All the products were obtained in good to excellent yields. For each reaction, CIT, ionic liquid and substituted aniline were charged into the flask, and the mixture was stirred at room temperature. Then 10 mL water was added into the flask. The crude product was filtrated, washed with water and
* Corresponding author. E-mail address: [email protected] (W.M. Tang). 1001-8417/$ – see front matter # 2007 Wen Ming Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.01.036
M.L. Xiao et al. / Chinese Chemical Letters 18 (2007) 258–260
259
Scheme 1.
recrystallized from ethanol/DMF/H2O. The melting points, elemental analysis, IR, 1H NMR spectra of the compounds were consistent with those synthesized in conventional organic solvent. The reaction time was optimized (Table 1) subsequently. In the reaction of CIT with 4-methylaniline, the reaction could proceed quantitatively within 5 min. In the reaction of CIT with 4-nitroaniline, longer time had negative effect on the yield. In the reaction of CIT with 4-methylaniline, the yield was almost quantitative (Table 2, Entry 1). In the reaction of CIT with 4-nitroaniline and 4-trifluoromethylani-line, the yields were 89.1 and 70.1%, respectively. It implied that the nucleophilic addition is influenced by the electronic effect of the substituents. In the reaction of CIT with 4-methylaniline, the ionic liquid [Bmim][BF4] could be recycled and reused at least 9 cycles without significant decrease in activity (Table 3).
Table 1 Effect of reaction time on the reactiona Entry
R
Compound
Time (min)
Yieldb (%)
1 2 3 4 5
4-CH3 4-CH3 4-NO2 4-NO2 4-NO2
C17H16N2OS C17H16N2OS C16H13N3O3S C16H13N3O3S C16H13N3O3S
2 5 6 10 12
61.8 98.3 57.0 89.1 71.2
a b
All reactions were run with CIT (2 mmol) and RC6H4NH2 (1.2 mmol) in [Bmim][BF4] (1.5 mL) at room temperature (24–26 8C). Isolated yield based on RC6H4NH2.
Table 2 Results of reactions of CIT with RC6H4NH2 in [Bmim][BF4]a Entry
R
Compound
Color
mp (8C)
Time (min)
Yield (%)
1 2 3 4 5 6 7
4-CH3 4-Cl 3-Cl 4-OCH3 4-NO2 3-NO2 4-CF3
C17H16N2OS C16H13ClN2OS C16H13ClN2OS C17H16N2O2S C16H13N3O3S C16H13N3O3S C17H13F3N2OS
White Yellow White Yellow Yellow Yellow White
183–186 193–195 182–184 165–167 163–165 183–184 206–208
5 10 10 10 10 10 10
98.3 88.0 95.2 83.9 89.1 86.5 70.1
a
All reactions were the same as those in Table 1.
Table 3 Recycle of [Bmim][BF4] Cycle
Yield (%)
Cycle
Yield (%)
1 2 3 4 5
97.2 97.7 96.9 98.3 96.1
6 7 8 9 10
96.1 95.5 96.9 95.5 81.5
260
M.L. Xiao et al. / Chinese Chemical Letters 18 (2007) 258–260
Table 4 Reactions of CIT with RC6H4NH2 in [Bmim][PF6]a Entry
R
Compound
Time (min)
Yieldb (%)
1 2
4-CH3 4-NO2
C17H16N2OS C16H13N3O3S
5 10
50.7 67.8
a b
All reactions were run with CIT (3 mmol) and RC6H4NH2 (2.4 mmol) in [Bmim][PF6] (1.5 mL) at room temperature (24–26 8C). Isolated yield based on RC6H4NH2.
The reaction of CIT with 4-methylaniline and 4-nitroaniline was also tested in another mostly used ionic liquid 1butyl-3-methylimidazolium hexafluorophosphate, [Bmim][PF6] (Table 4). The yields were lower than those observed in [Bmim][BF4]. It indicated that [Bmim][BF4] was more suitable for this reaction than [Bmim][PF6]. In conclusion, we have demonstrated that the ionic liquid [Bmim][BF4] acted as powerful medium and promoter in the synthesis of cinnamoyl thiourea derivatives showing great advantages over conventional solvents. In this method, the procedure is easily operated and friendly to environment. Acknowledgment This work was financially supported by elitist funds from the governor of Guizhou Province, China. References [1] (a) D. Sriram, P. Yogeeswari, K. Madhu, Bioorg. Med. Chem. Lett. 16 (2006) 876; (b) X.Q. He, W.M. Tang, B.A. Song, et al. Chin. J. Org. Chem. 24 (10) (2004) 1284; (c) S.J. Xue, L.P. Duan, S.Y. Ke, et al. Chin. J. Org. Chem. 24 (6) (2004) 686; (d) K. Bhandari, S. Srivastava, G. Shakar, Bioorg. Med. Chem. 12 (2004) 4189. [2] (a) G.C. Yang, Z.X. Chen, Z.J. Zhang, React. Funct. Polym. 51 (2002) 1; (b) C.J. Ru, Y.J. Wang, J.P. Li, et al. Chin. J. Appl. Chem. 11 (1994) 92; (c) Y.H. Dong, Z.X. Si, Chin. J. Appl. Chem. 12 (1995) 62. [3] T. Aoyama, S. Murata, Y. Nagata, et al. Tetrahedron Lett. 46 (2005) 4875. [4] U. Boas, H. Gertz, J.B. Christensen, et al. Tetrahedron Lett. 45 (2004) 269. [5] (a) T.K. Venkatachalam, E.A. Sudbeck, F.M. Uckun, Tetrahedron Lett. 42 (2001) 6629; (b) P.K. Mohanta, S. Dhar, S.K. Samal, et al. Tetrahedron 56 (2000) 629; (c) J.J. Byrne, Y. Vallee, Tetrahedron Lett. 40 (1999) 489. [6] Z. Li, Z.J. Quan, X.C. Wang, Chin. J. Org. Chem. 23 (2003) 822. [7] (a) T. Welton, Coord. Chem. Rev. 248 (2004) 2459; (b) O.B. Helene, M. Lionel, J. Mol. Catal. A: Chem. 182–183 (2002) 419; (c) J.S. Wilkes, J. Mol. Catal. A: Chem. 214 (2004) 11. [8] (a) Z.G. Le, Z.C. Chen, Y. Hu, et al. Chin. Chem. Lett. 16 (2) (2005) 201; (b) P. Wassercheid, T. Welton (Eds.), Ionic Liquids in Synthesis, VCH Wiley, Weinheim, Germany, 2002; (c) H. Ohara, H. Kiyokane, T. Itoh, Tetrahedron Lett. 43 (2002) 3041.
Facile synthesis of thiourea derivatives in ionic liquid Min Liang Xiao a, Feng Huang Chen b, Zhi Juan Chen a, Bao Shou Guo a, Xian Hai Lv a,c, Wen Ming Tang a,* a
Center for Research & Development of Fine Chemicals, Guizhou University, Guiyang 550025, China b Guiyang Environmental Monitoring Center, Guiyang 550001, China c School of Science, Anhui Agricultural University, Hefei 230036, China Received 7 November 2006
Abstract The synthesis of cinnamoyl thiourea derivatives from cinnamoyl isothiocyanate (CIT) with substituted aniline (RC6H4NH2) was investigated in the mostly used ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [Bmim][BF4]. Significant enhancements in reactivity, yield and reaction rate were achieved. The products could be recovered by simple filtration. [Bmim][BF4] could be recycled simply by removing water under vacuum and reused at least 9 times without significant decrease in activity. # 2007 Wen Ming Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Ionic liquid; Cinnamoyl isothiocyanate; Substituted aniline; Cinnamoyl thiourea derivatives; Synthesis
Many methods for the synthesis of thioureas have been developed and reported including: (a) direct reaction of isothiocyanates or carbon disulfide with anilines [1]; (b) reaction catalyzed by phase transfer catalysts [2], supported reagents [3] or peptide coupling reagents [4]; (c) activation of dithiocarbamates or related salts [5]; (d) catalytic synthesis promoted by microwave [6]. However, these methods still involve many limitations: harsh reaction conditions, multistep operations, long reaction time, high reaction temperature, noxious reagents or volatile solvents, poor yields or too much site-products. Room temperature ionic liquids have been accepted as green, alternatives to traditional organic solvents for their unique physical and chemical properties [7], they can act both as reaction medium and promoter in many reactions [8]. Acyl thioureas are not only important intermediates, but also valuable compounds with broad bioactivities [1,2,4]. In our previous work, the synthesis and bioactivities of cinnamoyl thioureas were studied. But the reaction time was long, the solvent was noxious and volatile, and the yield was low. Now we reported the synthesis of cinnamoyl thiourea derivatives from cinnamoyl isothiocyanate (CIT) and substituted anilines (RC6H4NH2) in the mostly used ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [Bmim][BF4] (Scheme 1). All the products were obtained in good to excellent yields. For each reaction, CIT, ionic liquid and substituted aniline were charged into the flask, and the mixture was stirred at room temperature. Then 10 mL water was added into the flask. The crude product was filtrated, washed with water and
* Corresponding author. E-mail address: [email protected] (W.M. Tang). 1001-8417/$ – see front matter # 2007 Wen Ming Tang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2007.01.036
M.L. Xiao et al. / Chinese Chemical Letters 18 (2007) 258–260
259
Scheme 1.
recrystallized from ethanol/DMF/H2O. The melting points, elemental analysis, IR, 1H NMR spectra of the compounds were consistent with those synthesized in conventional organic solvent. The reaction time was optimized (Table 1) subsequently. In the reaction of CIT with 4-methylaniline, the reaction could proceed quantitatively within 5 min. In the reaction of CIT with 4-nitroaniline, longer time had negative effect on the yield. In the reaction of CIT with 4-methylaniline, the yield was almost quantitative (Table 2, Entry 1). In the reaction of CIT with 4-nitroaniline and 4-trifluoromethylani-line, the yields were 89.1 and 70.1%, respectively. It implied that the nucleophilic addition is influenced by the electronic effect of the substituents. In the reaction of CIT with 4-methylaniline, the ionic liquid [Bmim][BF4] could be recycled and reused at least 9 cycles without significant decrease in activity (Table 3).
Table 1 Effect of reaction time on the reactiona Entry
R
Compound
Time (min)
Yieldb (%)
1 2 3 4 5
4-CH3 4-CH3 4-NO2 4-NO2 4-NO2
C17H16N2OS C17H16N2OS C16H13N3O3S C16H13N3O3S C16H13N3O3S
2 5 6 10 12
61.8 98.3 57.0 89.1 71.2
a b
All reactions were run with CIT (2 mmol) and RC6H4NH2 (1.2 mmol) in [Bmim][BF4] (1.5 mL) at room temperature (24–26 8C). Isolated yield based on RC6H4NH2.
Table 2 Results of reactions of CIT with RC6H4NH2 in [Bmim][BF4]a Entry
R
Compound
Color
mp (8C)
Time (min)
Yield (%)
1 2 3 4 5 6 7
4-CH3 4-Cl 3-Cl 4-OCH3 4-NO2 3-NO2 4-CF3
C17H16N2OS C16H13ClN2OS C16H13ClN2OS C17H16N2O2S C16H13N3O3S C16H13N3O3S C17H13F3N2OS
White Yellow White Yellow Yellow Yellow White
183–186 193–195 182–184 165–167 163–165 183–184 206–208
5 10 10 10 10 10 10
98.3 88.0 95.2 83.9 89.1 86.5 70.1
a
All reactions were the same as those in Table 1.
Table 3 Recycle of [Bmim][BF4] Cycle
Yield (%)
Cycle
Yield (%)
1 2 3 4 5
97.2 97.7 96.9 98.3 96.1
6 7 8 9 10
96.1 95.5 96.9 95.5 81.5
260
M.L. Xiao et al. / Chinese Chemical Letters 18 (2007) 258–260
Table 4 Reactions of CIT with RC6H4NH2 in [Bmim][PF6]a Entry
R
Compound
Time (min)
Yieldb (%)
1 2
4-CH3 4-NO2
C17H16N2OS C16H13N3O3S
5 10
50.7 67.8
a b
All reactions were run with CIT (3 mmol) and RC6H4NH2 (2.4 mmol) in [Bmim][PF6] (1.5 mL) at room temperature (24–26 8C). Isolated yield based on RC6H4NH2.
The reaction of CIT with 4-methylaniline and 4-nitroaniline was also tested in another mostly used ionic liquid 1butyl-3-methylimidazolium hexafluorophosphate, [Bmim][PF6] (Table 4). The yields were lower than those observed in [Bmim][BF4]. It indicated that [Bmim][BF4] was more suitable for this reaction than [Bmim][PF6]. In conclusion, we have demonstrated that the ionic liquid [Bmim][BF4] acted as powerful medium and promoter in the synthesis of cinnamoyl thiourea derivatives showing great advantages over conventional solvents. In this method, the procedure is easily operated and friendly to environment. Acknowledgment This work was financially supported by elitist funds from the governor of Guizhou Province, China. References [1] (a) D. Sriram, P. Yogeeswari, K. Madhu, Bioorg. Med. Chem. Lett. 16 (2006) 876; (b) X.Q. He, W.M. Tang, B.A. Song, et al. Chin. J. Org. Chem. 24 (10) (2004) 1284; (c) S.J. Xue, L.P. Duan, S.Y. Ke, et al. Chin. J. Org. Chem. 24 (6) (2004) 686; (d) K. Bhandari, S. Srivastava, G. Shakar, Bioorg. Med. Chem. 12 (2004) 4189. [2] (a) G.C. Yang, Z.X. Chen, Z.J. Zhang, React. Funct. Polym. 51 (2002) 1; (b) C.J. Ru, Y.J. Wang, J.P. Li, et al. Chin. J. Appl. Chem. 11 (1994) 92; (c) Y.H. Dong, Z.X. Si, Chin. J. Appl. Chem. 12 (1995) 62. [3] T. Aoyama, S. Murata, Y. Nagata, et al. Tetrahedron Lett. 46 (2005) 4875. [4] U. Boas, H. Gertz, J.B. Christensen, et al. Tetrahedron Lett. 45 (2004) 269. [5] (a) T.K. Venkatachalam, E.A. Sudbeck, F.M. Uckun, Tetrahedron Lett. 42 (2001) 6629; (b) P.K. Mohanta, S. Dhar, S.K. Samal, et al. Tetrahedron 56 (2000) 629; (c) J.J. Byrne, Y. Vallee, Tetrahedron Lett. 40 (1999) 489. [6] Z. Li, Z.J. Quan, X.C. Wang, Chin. J. Org. Chem. 23 (2003) 822. [7] (a) T. Welton, Coord. Chem. Rev. 248 (2004) 2459; (b) O.B. Helene, M. Lionel, J. Mol. Catal. A: Chem. 182–183 (2002) 419; (c) J.S. Wilkes, J. Mol. Catal. A: Chem. 214 (2004) 11. [8] (a) Z.G. Le, Z.C. Chen, Y. Hu, et al. Chin. Chem. Lett. 16 (2) (2005) 201; (b) P. Wassercheid, T. Welton (Eds.), Ionic Liquids in Synthesis, VCH Wiley, Weinheim, Germany, 2002; (c) H. Ohara, H. Kiyokane, T. Itoh, Tetrahedron Lett. 43 (2002) 3041.