Journal of Medicinal Chemistry × CH3). 13C NMR (CDCl3): δ 154.9, 149.4, 145.1, 139.9, 129.9, 127.4, 122.8, 117.9, 112.5, 44.3, 41.9, 40.5. MS (ESI+) m/z found 397.9; C17H21ClN3O4S (M+ + H) requires 398.1. 4-(tert-Butyldimethylsilyloxy)phenyl 4-[3-(2-Chloroethyl)- ureido]benzenesulfonate (9). Method D was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (80:20)). Yield, 99%; yellow oil. IR ν: 3321 (NH), 1670 (CO) cm−1. 1H NMR (CDCl3): δ 7.96 (s, 1H, NH), 7.65−7.51 (m, 4H, Ar), 6.82−6.68 (m, 4H, Ar), 5.97 (brs, 1H, NH), 3.61 (brs, 4H, 2 × CH2), 0.94 (s, 9H, 3 × CH3), 0.15 (s, 6H, 2 × CH3). 13C NMR (CDCl3): δ 154.8, 154.7, 145.2, 143.3, 130.0, 127.1, 123.3, 120.8, 118.0, 44.3, 42.0, 25.6, 18.2, −4.5. 4 - H y d r o x y p h e n y l 4 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - benzenesulfonate (10). Method E was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, ethyl acetate to ethyl acetate/methanol (90:10)). Yield, 80%; white solid; mp, 247 °C. IR ν: 3625−3050 (OH), 1686 (CO), 1334 (OH) cm−1. 1H NMR (acetone-d6): δ 8.60 (s, 1H, NH), 7.89−7.86 (m, 2H, Ar), 7.73−7.70 (m, 2H, Ar), 6.85−6.82 (m, 2H, Ar), 6.78−6.75 (m, 2H, Ar), 6.37 (brs, 1H, NH), 4.04 (t, 2H, J = 7.9 Hz, CH2), 3.65−3.60 (m, 2H, CH2), 3.31 (brs, 1H, OH). 13C NMR (CDCl3/DMSO-d6): δ 158.5, 156.1, 145.6, 141.6, 129.2, 126.3, 122.9, 116.1, 115.7, 44.4, 36.6. MS (ESI−) m/z found 369.0; C15H14ClN2O5S (M− − H) requires 369.0. 2-Tolyl 3-[3-(2-Chloroethyl)ureido]benzenesulfonate (11). Method A in dry DCM was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (90:10)). Yield, 57%; sticky solid. IR ν: 3330 (NH), 1658 (CO) cm−1. 1H NMR (CDCl3): δ 8.26 (s, 1H, NH), 7.97 (s, 1H, Ar), 7.68−7.65 (m, 1H, Ar), 7.83−7.30 (m, 2H, Ar), 7.14−7.02 (m, 3H, Ar), 6.93−6.90 (m, 1H, Ar), 6.18 (brs, 1H, NH), 3.57 (s, 4H, 2 × CH2), 2.07 (s, 3H, CH3). 13C NMR (CDCl3): δ 155.7, 148.2, 140.4, 136.3, 131.7, 131.5, 129.9, 127.2, 127.0, 124.6, 122.1, 122.0, 118.0, 44.2, 41.9, 16.3. MS (APSI+) m/z found 369.1; C16H18ClN2O4S (M+ + H) requires 369.1. 2-Ethylphenyl 3-[3-(2-Chloroethyl)ureido]benzenesulfonate (12). Method A in dry DCM was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (90:10)). Yield, 53%; colorless oil. IR ν: 3343 (NH), 1658 (CO) cm−1. 1H NMR (CDCl3): δ 8.17 (s, 1H, NH), 7.95 (s, 1H, Ar), 7.70−7.68 (m, 1H, Ar), 7.41−7.34 (m, 2H, Ar), 7.19−7.03 (m, 3H, Ar), 6.92−6.90 (m, 1H, Ar), 6.08 (brs, 1H, NH), 3.56 (s, 4H, 2 × CH2), 2.50 (q, 2H, J = 7.5 Hz, CH2), 1.07 (t, 3H, J = 7.5 Hz, CH3). 13C NMR (CDCl3): δ 155.8, 147.7, 140.4, 137.2, 136.4, 130.0, 127.4, 127.0, 124.6, 121.9, 121.9, 118.0, 102.7, 44.1, 41.9, 22.8, 14.1. MS (APSI+) m/z found 383.1; C17H20ClN2O4S (M+ + H) requires 383.1. 2 - P r o p y l p h e n y l 3 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - benzenesulfonate (13). Method A in dry DCM was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (90:10)). Yield, 12%; yellow oil. IR ν: 3300 (NH), 1657 (CO) cm−1. 1H NMR (CDCl3): δ 8.42 (s, 1H, NH), 8.08 (s, 1H, Ar) 7.57−7.55 (m, 1H, Ar), 7.38−7.32 (m, 2H, Ar), 7.14−7.05 (m, 3H, Ar), 6.93−6.91 (m, 1H, Ar), 6.29 (brs, 1H, NH), 3.55 (s, 4H, 2 × CH2), 2.45−2.41 (m, 2H, CH2), 1.49−1.45 (m, 2H, CH2), 0.84−0.80 (m, 3H, CH3). 13C NMR (CDCl3): δ 155.9, 147.9, 140.4, 136.5, 135.8, 130.7, 129.9, 127.2, 127.0, 124.6, 121.9, 118.0, 102.7, 44.1, 41.9, 31.8, 23.0, 13.9. MS (APSI+) m/z found 397.1; C18H22ClN2O4S (M+ + H) requires 397.1. 4-(tert-Butyldimethylsilyloxy)phenyl 3-[3-(2-Chloroethyl)- ureido]benzenesulfonate (14). Method D was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (90:10)). Yield, 85%; white sticky solid. IR ν: 3004 (NH), 1710 (CO) cm−1. 1H NMR (CDCl3): δ 8.16 (s, 1H, NH), 7.90 (s, 1H, Ar), 7.75−7.72 (m, 1H, Ar), 7.33−7.24 (m, 2H, Ar), 6.82−6.79 (m, 2H, Ar), 6.69−6.66 (m, 2H, Ar), 6.09 (brs, 1H, NH), 3.61 (s, 4H, 2 × CH2), 0.93 (s, 9H, 3 × CH3), 0.14 (s, 6H, 2 × CH3). 13C NMR (CDCl3): δ 155.3, 154.7, 143.3, 140.4, 135.3, 129.8, 124.6, 123.2, 122.3, 120.8, 118.0, 44.3, 42.0, 25.6, 18.2, −4.5. Article 4 - H y d r o x y p h e n y l 3 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - benzenesulfonate (15). Method E was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, ethyl acetate to ethyl acetate/methanol (90:10)). Yield, 78%; white solid; mp, 156 °C. IR ν: 3500−3100 (OH), 1688 (CO), 1330 (OH) cm−1. 1H NMR (acetone-d6): δ 8.60 (s, 1H, NH), 8.29 (s, 1H, Ar), 7.93−7.90 (m, 1H, Ar), 7.57−7.52 (m, 1H, Ar), 7.40−7.37 (m, 1H, Ar), 6.90−6.86 (m, 2H, Ar), 6.80−6.76 (m, 2H, Ar), 6.27 (brs, 1H, NH), 4.00 (t, 2H, J = 7.9 Hz, CH2), 3.63−3.58 (m, 2H, CH2), 2.87 (brs, 1H, OH). 13C NMR (DMSO-d6): δ 158.9, 155.6, 155.6, 142.4, 141.0, 135.7, 129.4, 123.2, 123.1, 121.9, 115.9, 44.8, 37.0. MS (APSI+) m/z found 371.1; C15H16ClN2O5S (M+ + H) requires 371.0. 2-Ethylphenyl 4-[3-(2-Chloroethyl)ureido]benzenesulfonate (16). Method C in dry MeCN under microwave at 130 °C for 40 min with washing with HCl (1 N) was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, hexanes/ethyl acetate (75:25) to hexanes/ethyl acetate (50:50)). Yield, 8%; white solid; mp, 127−128 °C. IR ν: 3338 (NH), 1685 (CO) cm−1. 1H NMR (CDCl3): δ 8.44 (s, 1H, NH), 7.86−7.83 (m, 2H, Ar), 7.73−7.70 (m, 2H, Ar), 7.27−6.97 (m, 4H, Ar), 4.03−3.95 (m, 4H, 2 × CH2), 2.53− 2.45 (m, 2H, CH2), 1.12−1.07 (m, 3H, CH3). 13C NMR (CDCl3): δ 154.5, 147.8, 143.9, 137.2, 130.5, 129.9, 129.6, 127.2, 126.9, 122.0, 117.7, 43.6, 41.9, 22.8, 14.1. MS (APSI+) m/z found 383.1; C17H20ClN2O4S (M+ + H) requires 383.1. 2 - P r o p y l p h e n y l 4 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - benzenesulfonate (17). Method C in dry MeCN under microwave at 130 °C for 50 min with washing with HCl (1 N) was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, hexanes/ethyl acetate (75:25) to hexanes/ethyl acetate (50:50)). Yield, 75%; yellow solid; mp, 95 °C. IR ν: 3326 (NH), 1669 (CO) cm−1. 1H NMR (CDCl3): δ 7.76−7.73 (m, 2H, Ar), 7.54−7.52 (m, 2H, Ar), 7.32 (brs, 1H, NH), 7.29−6.99 (m, 4H, Ar), 5.58 (brs, 1H, NH), 3.65−3.64 (m, 4H, 2 × CH2), 2.43 (t, 2H, J = 7.7 Hz, CH2), 1.57−1.51 (m, 2H, CH2), 0.86 (t, 3H, J = 7.3 Hz, CH3). 13C NMR (CDCl3): δ 154.3, 148.0, 144.7, 135.8, 130.7, 129.8, 128.7, 127.1, 127.0, 122.0, 118.1, 44.4, 42.0, 31.9, 23.0, 13.9. MS (APSI+) m/z found 397.1; C18H22ClN2O4S (M+ + H) requires 397.1. 3-[3-(2-Chloroethyl)ureido]-N-2-tolylbenzenesulfonamide (18). Method B was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ ethyl acetate (90:10)) and was crystallized with methylene chloride and ﬁltered. Yield, 45%; white solid; mp, 164−165 °C. IR ν: 3267 (NH), 1642 (CO) cm−1. 1H NMR (DMSO-d6): δ 9.58 (s, 1H, NH), 9.06 (s, 1H, NH), 7.94 (s, 1H, Ar), 7.62−7.01 (m, 7H, Ar), 6.51 (brs, 1H, NH), 3.71−3.68 (m, 2H, CH2), 3.48−3.45 (m, 2H, CH2), 2.05 (s, 3H, CH3). 13C NMR (DMSO-d6): δ 154.8, 141.3, 141.0, 134.9, 134.3, 130.7, 129.5, 126.5, 126.4, 126.3, 121.3, 119.2, 115.4, 44.3, 41.3, 17.7. MS (APSI−) m/z found 366.0; C16H17ClN3O3S (M− − H) requires 366.1. 3 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - N - ( 2 - e t h y l p h e n y l ) - benzenesulfonamide (19). Method B was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (90:10)) and was crystallized with methylene chloride and ﬁltered. Yield, 35%; white solid; mp, 170−171 °C. IR ν: 3274 (NH), 1643 (CO). 1H NMR (DMSO-d6): δ 9.58 (s, 1H, NH), 9.06 (s, 1H, NH), 7.95 (s, 1H, Ar), 7.63−6.91 (m, 7H, Ar), 6.50 (brs, 1H, NH), 3.72−3.68 (m, 2H, CH2), 3.47−3.45 (m, 2H, CH2), 2.58−2.54 (m, 2H, CH2), 1.01 (t, 3H, J = 7.5 Hz, CH3). 13C NMR (DMSO-d6): δ 154.9, 141.3, 141.0, 140.5, 134.2, 129.5, 129.0, 126.8, 126.6, 126.2, 121.2, 119.2, 115.4, 44.3, 41.3, 23.2, 14.4. MS (APCI−) m/z found 379.9; C17H19ClN3O3S (M− − H) requires 380.1. 3 - [ 3 - ( 2 - C h l o r o e t h y l ) u r e i d o ] - N - ( 2 - p r o p y l p h e n y l ) - benzenesulfonamide (20). Method D was used. The crude product was puriﬁed by ﬂash chromatography (silica gel, methylene chloride to methylene chloride/ethyl acetate (80:20)). Yield, 12%; yellow solid; mp, 207 °C. IR ν: 3318 (NH), 1633 (CO) cm−1. 1H NMR (acetone-d6): δ 8.55 (s, 1H, NH), 8.01−7.98 (m, 1H, Ar), 7.81 (s, 1H, Ar), 7.52−6.92 (m, 6H, Ar), 6.41 (brs, 1H, NH), 3.74−3.70 (m, 2H, CH2), 3.61−3.57 (m, 2H, CH2), 2.48−2.42 (m, 2H, CH2), 1.63−1.53 6201 dx.doi.org/10.1021/jm3006492 | J. Med. Chem. 2012, 55, 6194−6208