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Synthesis and herbicidal activities of pyridyl sulfonylureas: More convenient preparation process of phenyl pyrimidylcarbamates
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Chinese Chemical Letters 19 (2008) 1268–1270 www.elsevier.com/locate/cclet
Synthesis and herbicidal activities of pyridyl sulfonylureas: More convenient preparation process of phenyl pyrimidylcarbamates Ning Ma a, Zhi Jin Fan b, Bao Lei Wang b, Yong Hong Li b, Zheng Ming Li b,* a
b
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China State Key Laboratory of Elemento Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Received 21 April 2008
Abstract Four 4-monosubstituted pyrimidine pyridyl sulfonylureas were synthesized from pyridinesulfonamide and phenyl pyrimidylcarbamate and screened for herbicidal activities. We also reported a convenient preparation process of phenyl pyrimidylcarbamates from pyrimidineamine and phenyl chloroformate. # 2008 Zheng Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Sulfonylurea; Herbicidal activity; Phenyl carbamate
As a kind of herbicides, sulfonylureas were taken great interest in due to their high activity, high selectivity and low toxicity. Up to now, more than 30 kinds of sulfonylurea herbicides were commercialized all over the world. Most of these compounds contain 4,6-disubstituted pyrimidine or triazine cycles. In our laboratory, many 4-monosubstituted pyrimidine sulfonylureas were synthesized and screened for herbicidal activities, and some of them showed high activities [1–4]. In this article, we will report the synthesis and herbicidal activities of 4 new 4-monosubstituted pyrimidine pyridyl sulfonylureas 2a–d (Scheme 1). It is common to synthesize sulfonylureas by addition of heterocyclic amines to arylsulfonylisocyanates. But the most convenient method in laboratory is condensation of sulfonamide with phenyl pyrimidylcarbamates or triazinylcarbamates at the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). It was reported by Ishida et al. that phenyl pyrimidylcarbamates were prepared through reaction of heterocyclic amines with phenyl chloroformate in mole ratio of 2:1 catalyzed by DMAP (4-dimethylaminopyridine) at room temperature, then purified by column chromatography [5]. Here we report a more economic method to synthesize phenyl pyrimidylcarbamates using K2CO3 as a base (Scheme 1). In this process the crude products 1a–d can be used directly to the synthesis of pyridine sulfonylureas 2a–d without further purification [6]. We initially used the method reported by Ishida et al. to synthesize the carbamates, while the yields of the crude products calculated by phenyl chloroformate were 40–60% and the yields of purified products after column chromatography were only 20–40%. Moreover, in the reaction half of the amine was converted to its unsoluble salt
* Corresponding author. E-mail address: [email protected] (Z.M. Li). 1001-8417/$ – see front matter # 2008 Zheng Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.09.019
N. Ma et al. / Chinese Chemical Letters 19 (2008) 1268–1270
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Scheme 1. Reaction conditions: (i) ClCO2Ph, K2CO3/acetone, r.t., 2 h, 73–85%; (ii) N,N-dimethyl-2-aminosulfony-3-pyridineformamide, DBU/ acetonitrile, r.t., 2 h, 53–67%.
instead of the product. A part of amine was inevitably lost in the recycle process. So we tried a new method, in which K2CO3 served as a base and DMAP was not used. The preparation of the crude phenyl pyrimidylcarbamates 1a–d turned out satisfactory with yields of 73–85%. The unconverted amines, as the main impurities, were found in the crude carbamates. All of them were taken away easily in the process of sulfonylureas synthesis, and the sulfonylurea products were not contaminated by them. Due to this, the crude phenyl pyrimidylcarbamates can be used directly in the subsequent sulfonylurea synthesis, which increased the yield of sulfonylureas and made the process easier. The structures of compounds 2a–d were confirmed by 1H NMR and elemental analysis [7]. The herbicidal activities of 2a–d were screened by rape-root growth method. As the result, 2a–c showed herbicidal activities, but their activities were lower than nicosulforon which possesses two methoxy groups at 4- and 6-positions of pyrimidine ring. Acknowledgments This work was supported by the National Basic Research Program (No. 2003CB114406), the National Natural Science Foundation of China (No. 20672062) and the Tianjin Natural Science Foundation (No. 07JCYBJC01200). References [1] [2] [3] [4] [5] [6]
Z.M. Li, C.M. Lai, Chin. J. Org. Chem. 21 (2001) 810. N. Ma, P.F. Li, Y.H. Li, et al. Chem. Chin. J. Univ. 25 (2004) 2259. P.F. Li, N. Ma, B.L. Wang, et al. Chem. Chin. J. Univ. 26 (2005) 1459. J.G. Wang, Z.M. Li, N. Ma, et al. J. Comput. Aided Mol. Des. 19 (2005) 801. Y. Ishida, K. Ohta, T. Nakahama, et al., US Patent 5,017,212 (1991). Preparation of 1a: 250 mL acetone, 0.1 mol 2-amino-4-substitued pyrimidine and 16.6 g (0.12 mol) K2CO3 was added into a 500 mL three-neck flask with a condenser, then 15.7 g (0.1 mol) phenyl chloroformate was dropped in through a pressure-equalization funnel within 30 min. After the mixture was stirred at room temperature for 2 h, the solid was filtered and washed with 45 mL acetone, all the filtrate was combined and evaporated in vacuum. The residue solid was washed with 30 mL 5% HCl, 40 mL 10% Na2CO3 and 45 mL water in sequence. Then 16.7 g yellow crude product was obtained after dryness with a yield of 73%. Preparation of 1b–d: 150 mL acetone, 0.1 mol 2-amino-4-alkoxy (or alkylthio) pyrimidine and 16.6 g (0.12 mol) K2CO3 was added into a 500 mL three-neck flask with a condenser, then 15.7 g (0.1 mol) phenyl chloroformate was dropped in through a pressure-equalization funnel during 20–30 min. After the mixture was stirred at room temperature for 2 h, the solid was filtered and washed with 50 mL H2O, 30 mL 5% HCl, 40 mL 10% Na2CO3 and 45 mL water in sequence, then the crude products were obtained after dryness (yield 76–85%). Typical procedure for the synthesis of 2a–d: Solution of 0.23 g (1.5 mmol) DBU in 1 mL acetonitrile was added to the suspension of 0.34 g (1.5 mmol) N,N-dimethyl-2-aminosulfony-3-pyridineformamide and 1.5 mmol crude 1a–d in 6 mL acetonitrile. After stirred at room temperature for 2 h, 15 mL water was added. The mixture was filtered and the filtrate was acidified to pH = 4–5 with 20% HCl, extracted with 20 mL 2 dichloromethane. The organic layer was dried with anhydrous Na2SO4, then evaporated in vacuum, and the residue solid was recrystallized in acetone-ligroin to give 2a–d. [7] Selected data of compounds: Crude 1a: mp: 118–123 8C, 1H NMR (CDCl3, 200 MHz, d ppm): 2.50 (s, 3H, CH3), 6.89 (d, 1H, J = 5.7 Hz, pyrimH5), 7.18–7.24 (m, 3H, Ar-H), 7.33–7.41(m, 2H, Ar-H), 8.50 (d, 2H, J = 5.7 Hz, pyrim-H6), 8.88 (br, s, 1H, pyrim-NHCO). Crude 1b: mp: 147– 148 8C, 1H NMR (CDCl3, 200 MHz, d ppm): 3.97 (s, 3H, OCH3), 6.43 (d, 1H, J = 6.0 Hz, pyrim-H5), 7.18–7.26 (m, 3H, Ar-H), 7.35–7.42 (m, 2H, Ar-H), 8.31 (d, 2H, J = 6.0 Hz, pyrim-H6), 9.16 (br, s, 1H, pyrim-NHCO). 2a: Yield 53%, mp: 159–160 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.48 (s, 3H, CH3), 2.89 (s, 3H, NCH3), 3.09 (s, 3H, NCH3), 6.84 (d, 1H, J = 5.1 Hz, pyrim-H5), 7.48 (dd, 1H, J = 7.8 Hz, 4.8 Hz, Py-H), 7.69 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Py-H), 8.40 (d, 1H, J = 5.1 Hz, pyrim-H6), 8.62 (dd, 1H, J = 4.8 Hz, 1.2 Hz, Py-H). Anal. Calcd. for C14H16N6O4S: C 46.15, H 4.43, N 23.06; Found: C 45.75, H 4.68, N 22.84. 2b: Yield 62%, 158–160 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.83 (s, 3H, NCH3), 2.96 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 6.69 (d, 1H, J = 6.3 Hz, pyrim-H5), 7.75 (dd, 1H, J = 7.8 Hz, 4.8 Hz, Py-H), 7.99 (d, 1H, J = 7.8 Hz, Py-H), 8.41 (d, 1H, J = 6.0 Hz, pyrim-H6), 8.73 (d, 1H, J = 4.8 Hz, Py-H). Anal. Calcd. for C14H16N6O5S: C 44.21, H 4.24, N 22.09; Found: C 44.23, H 4.33, N 21.95. 2c: Yield 67%, mp: 200–202 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.57 (s, 3H, SCH3), 2.83 (s,
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3H, NCH3), 2.96 (s, 3H, NCH3), 7.19 (d, 1H, J = 5.7 Hz, pyrim-H5), 7.77 (dd, 1H, J = 7.8 Hz, 4.5 Hz, Py-H), 8.02 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Py-H), 8.38 (d, 1H, J = 5.7 Hz, pyrim-H6), 8.74 (dd, 1H, J = 4.5 Hz, 1.2 Hz, Py-H). Anal. Calcd. for C14H16N6O4S2: C 42.42, H 4.07, N 21.20; Found: C 42.38, H 4.04, N 21.33. 2d: Yield 64%, mp: 172–174 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 1.34 (t, 3H, J = 7.8 Hz, SCH2CH3), 2.88 (s, 3H, NCH3), 3.08-3.16 (m, 5H, NCH3, SCH2CH3), 6.79 (d, 1H, J = 5.7 Hz, pyrim-H5), 7.48 (dd, 1H, J = 7.5 Hz, 4.5 Hz, Py-H), 7.70 (d, 1H, J = 7.5 Hz, Py-H), 8.13 (d, 1H, J = 5.7 Hz, pyrim-H6), 8.61 (d, 1H, J = 4.5 Hz, Py-H). Anal. Calcd. for C15H18N6O4S2: C 43.89, H 4.42, N 20.47; Found: C 43.73, H 4.54, N 20.45.
Chinese Chemical Letters 19 (2008) 1268–1270 www.elsevier.com/locate/cclet
Synthesis and herbicidal activities of pyridyl sulfonylureas: More convenient preparation process of phenyl pyrimidylcarbamates Ning Ma a, Zhi Jin Fan b, Bao Lei Wang b, Yong Hong Li b, Zheng Ming Li b,* a
b
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, China State Key Laboratory of Elemento Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Received 21 April 2008
Abstract Four 4-monosubstituted pyrimidine pyridyl sulfonylureas were synthesized from pyridinesulfonamide and phenyl pyrimidylcarbamate and screened for herbicidal activities. We also reported a convenient preparation process of phenyl pyrimidylcarbamates from pyrimidineamine and phenyl chloroformate. # 2008 Zheng Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Sulfonylurea; Herbicidal activity; Phenyl carbamate
As a kind of herbicides, sulfonylureas were taken great interest in due to their high activity, high selectivity and low toxicity. Up to now, more than 30 kinds of sulfonylurea herbicides were commercialized all over the world. Most of these compounds contain 4,6-disubstituted pyrimidine or triazine cycles. In our laboratory, many 4-monosubstituted pyrimidine sulfonylureas were synthesized and screened for herbicidal activities, and some of them showed high activities [1–4]. In this article, we will report the synthesis and herbicidal activities of 4 new 4-monosubstituted pyrimidine pyridyl sulfonylureas 2a–d (Scheme 1). It is common to synthesize sulfonylureas by addition of heterocyclic amines to arylsulfonylisocyanates. But the most convenient method in laboratory is condensation of sulfonamide with phenyl pyrimidylcarbamates or triazinylcarbamates at the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). It was reported by Ishida et al. that phenyl pyrimidylcarbamates were prepared through reaction of heterocyclic amines with phenyl chloroformate in mole ratio of 2:1 catalyzed by DMAP (4-dimethylaminopyridine) at room temperature, then purified by column chromatography [5]. Here we report a more economic method to synthesize phenyl pyrimidylcarbamates using K2CO3 as a base (Scheme 1). In this process the crude products 1a–d can be used directly to the synthesis of pyridine sulfonylureas 2a–d without further purification [6]. We initially used the method reported by Ishida et al. to synthesize the carbamates, while the yields of the crude products calculated by phenyl chloroformate were 40–60% and the yields of purified products after column chromatography were only 20–40%. Moreover, in the reaction half of the amine was converted to its unsoluble salt
* Corresponding author. E-mail address: [email protected] (Z.M. Li). 1001-8417/$ – see front matter # 2008 Zheng Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2008.09.019
N. Ma et al. / Chinese Chemical Letters 19 (2008) 1268–1270
1269
Scheme 1. Reaction conditions: (i) ClCO2Ph, K2CO3/acetone, r.t., 2 h, 73–85%; (ii) N,N-dimethyl-2-aminosulfony-3-pyridineformamide, DBU/ acetonitrile, r.t., 2 h, 53–67%.
instead of the product. A part of amine was inevitably lost in the recycle process. So we tried a new method, in which K2CO3 served as a base and DMAP was not used. The preparation of the crude phenyl pyrimidylcarbamates 1a–d turned out satisfactory with yields of 73–85%. The unconverted amines, as the main impurities, were found in the crude carbamates. All of them were taken away easily in the process of sulfonylureas synthesis, and the sulfonylurea products were not contaminated by them. Due to this, the crude phenyl pyrimidylcarbamates can be used directly in the subsequent sulfonylurea synthesis, which increased the yield of sulfonylureas and made the process easier. The structures of compounds 2a–d were confirmed by 1H NMR and elemental analysis [7]. The herbicidal activities of 2a–d were screened by rape-root growth method. As the result, 2a–c showed herbicidal activities, but their activities were lower than nicosulforon which possesses two methoxy groups at 4- and 6-positions of pyrimidine ring. Acknowledgments This work was supported by the National Basic Research Program (No. 2003CB114406), the National Natural Science Foundation of China (No. 20672062) and the Tianjin Natural Science Foundation (No. 07JCYBJC01200). References [1] [2] [3] [4] [5] [6]
Z.M. Li, C.M. Lai, Chin. J. Org. Chem. 21 (2001) 810. N. Ma, P.F. Li, Y.H. Li, et al. Chem. Chin. J. Univ. 25 (2004) 2259. P.F. Li, N. Ma, B.L. Wang, et al. Chem. Chin. J. Univ. 26 (2005) 1459. J.G. Wang, Z.M. Li, N. Ma, et al. J. Comput. Aided Mol. Des. 19 (2005) 801. Y. Ishida, K. Ohta, T. Nakahama, et al., US Patent 5,017,212 (1991). Preparation of 1a: 250 mL acetone, 0.1 mol 2-amino-4-substitued pyrimidine and 16.6 g (0.12 mol) K2CO3 was added into a 500 mL three-neck flask with a condenser, then 15.7 g (0.1 mol) phenyl chloroformate was dropped in through a pressure-equalization funnel within 30 min. After the mixture was stirred at room temperature for 2 h, the solid was filtered and washed with 45 mL acetone, all the filtrate was combined and evaporated in vacuum. The residue solid was washed with 30 mL 5% HCl, 40 mL 10% Na2CO3 and 45 mL water in sequence. Then 16.7 g yellow crude product was obtained after dryness with a yield of 73%. Preparation of 1b–d: 150 mL acetone, 0.1 mol 2-amino-4-alkoxy (or alkylthio) pyrimidine and 16.6 g (0.12 mol) K2CO3 was added into a 500 mL three-neck flask with a condenser, then 15.7 g (0.1 mol) phenyl chloroformate was dropped in through a pressure-equalization funnel during 20–30 min. After the mixture was stirred at room temperature for 2 h, the solid was filtered and washed with 50 mL H2O, 30 mL 5% HCl, 40 mL 10% Na2CO3 and 45 mL water in sequence, then the crude products were obtained after dryness (yield 76–85%). Typical procedure for the synthesis of 2a–d: Solution of 0.23 g (1.5 mmol) DBU in 1 mL acetonitrile was added to the suspension of 0.34 g (1.5 mmol) N,N-dimethyl-2-aminosulfony-3-pyridineformamide and 1.5 mmol crude 1a–d in 6 mL acetonitrile. After stirred at room temperature for 2 h, 15 mL water was added. The mixture was filtered and the filtrate was acidified to pH = 4–5 with 20% HCl, extracted with 20 mL 2 dichloromethane. The organic layer was dried with anhydrous Na2SO4, then evaporated in vacuum, and the residue solid was recrystallized in acetone-ligroin to give 2a–d. [7] Selected data of compounds: Crude 1a: mp: 118–123 8C, 1H NMR (CDCl3, 200 MHz, d ppm): 2.50 (s, 3H, CH3), 6.89 (d, 1H, J = 5.7 Hz, pyrimH5), 7.18–7.24 (m, 3H, Ar-H), 7.33–7.41(m, 2H, Ar-H), 8.50 (d, 2H, J = 5.7 Hz, pyrim-H6), 8.88 (br, s, 1H, pyrim-NHCO). Crude 1b: mp: 147– 148 8C, 1H NMR (CDCl3, 200 MHz, d ppm): 3.97 (s, 3H, OCH3), 6.43 (d, 1H, J = 6.0 Hz, pyrim-H5), 7.18–7.26 (m, 3H, Ar-H), 7.35–7.42 (m, 2H, Ar-H), 8.31 (d, 2H, J = 6.0 Hz, pyrim-H6), 9.16 (br, s, 1H, pyrim-NHCO). 2a: Yield 53%, mp: 159–160 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.48 (s, 3H, CH3), 2.89 (s, 3H, NCH3), 3.09 (s, 3H, NCH3), 6.84 (d, 1H, J = 5.1 Hz, pyrim-H5), 7.48 (dd, 1H, J = 7.8 Hz, 4.8 Hz, Py-H), 7.69 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Py-H), 8.40 (d, 1H, J = 5.1 Hz, pyrim-H6), 8.62 (dd, 1H, J = 4.8 Hz, 1.2 Hz, Py-H). Anal. Calcd. for C14H16N6O4S: C 46.15, H 4.43, N 23.06; Found: C 45.75, H 4.68, N 22.84. 2b: Yield 62%, 158–160 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.83 (s, 3H, NCH3), 2.96 (s, 3H, NCH3), 3.95 (s, 3H, OCH3), 6.69 (d, 1H, J = 6.3 Hz, pyrim-H5), 7.75 (dd, 1H, J = 7.8 Hz, 4.8 Hz, Py-H), 7.99 (d, 1H, J = 7.8 Hz, Py-H), 8.41 (d, 1H, J = 6.0 Hz, pyrim-H6), 8.73 (d, 1H, J = 4.8 Hz, Py-H). Anal. Calcd. for C14H16N6O5S: C 44.21, H 4.24, N 22.09; Found: C 44.23, H 4.33, N 21.95. 2c: Yield 67%, mp: 200–202 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 2.57 (s, 3H, SCH3), 2.83 (s,
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3H, NCH3), 2.96 (s, 3H, NCH3), 7.19 (d, 1H, J = 5.7 Hz, pyrim-H5), 7.77 (dd, 1H, J = 7.8 Hz, 4.5 Hz, Py-H), 8.02 (dd, 1H, J = 7.8 Hz, 1.2 Hz, Py-H), 8.38 (d, 1H, J = 5.7 Hz, pyrim-H6), 8.74 (dd, 1H, J = 4.5 Hz, 1.2 Hz, Py-H). Anal. Calcd. for C14H16N6O4S2: C 42.42, H 4.07, N 21.20; Found: C 42.38, H 4.04, N 21.33. 2d: Yield 64%, mp: 172–174 8C, 1H NMR (DMSO-d6, 300 MHz, d ppm): 1.34 (t, 3H, J = 7.8 Hz, SCH2CH3), 2.88 (s, 3H, NCH3), 3.08-3.16 (m, 5H, NCH3, SCH2CH3), 6.79 (d, 1H, J = 5.7 Hz, pyrim-H5), 7.48 (dd, 1H, J = 7.5 Hz, 4.5 Hz, Py-H), 7.70 (d, 1H, J = 7.5 Hz, Py-H), 8.13 (d, 1H, J = 5.7 Hz, pyrim-H6), 8.61 (d, 1H, J = 4.5 Hz, Py-H). Anal. Calcd. for C15H18N6O4S2: C 43.89, H 4.42, N 20.47; Found: C 43.73, H 4.54, N 20.45.