T. M. Rana et al.
MED
J=7.6, 2.0 Hz, 1H), 7.57–7.48 (m, 3H), 7.30–7.26 (m, 2H), 7.06 (ddd,
J=8.0, 8.0, 1.6 Hz, 1H), 6.97 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 6.85 (dd,
J=8.0, 1.2 Hz, 1H), 3.79 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=165.4, 148.2, 146.9, 146.2, 140.6, 135.8, 131.7, 130.1, 129.9,
129.5, 128.8 (2C), 127.5, 124.5, 124.4 (2C), 121.4, 120.1, 110.2,
55.9 ppm; HRMS (ESI): m/z [M+H]+ calcd for C20H17N2O4S:
381.0909, found: 381.0916. A similar procedure was used to pre-
pare RN18 on a multigram scale; details are provided in the Sup-
porting Information.
(ESI): m/z [M+H]+ calcd for C19H17N2O5S2: 417.0579, found:
417.0596.
2-(2-Methoxyphenyl)-N-(2-((4-nitrophenyl)thio)phenyl)acetamide
(5 f): Reaction of 1 f and 4-nitrothiophenol gave product 5 f
(0.178 g, 45%): 1H NMR (400 MHz, CDCl3): d=8.59 (dd, J=8.0,
1.2 Hz, 1H), 8.46 (s, 1H), 7.98–7.94 (m, 2H), 7.54–7.49 (m, 2H),
7.18–7.11 (m, 2H), 7.07 (dd, J=7.6, 1.6 Hz, 1H), 6.83–6.79 (m, 3H),
6.66 (d, J=8.4 Hz, 1H), 3.67 (s, 3H), 3.65 ppm (s, 2H); 13C NMR
(100 MHz, CDCl3): d=169.9, 157.1, 146.1, 145.6, 141.2, 137.4, 132.6,
131.4, 129.4, 125.6 (2C), 125.0, 124.3 (2C), 122.5, 121.3, 121.3, 116.5,
110.7, 55.6, 40.3 ppm; HRMS (ESI): m/z [M+H]+ calcd for
C21H19N2O4S: 395.1066, found: 395.1058.
N-(2-Methoxyphenyl)-2-(phenylthio)benzamide (4a): Reaction of
1a and thiophenol gave product 4a as a white solid (0.350 g,
1
98%): H NMR (400 MHz, CDCl3): d=8.65 (s, 1H), 8.51 (d, J=7.2 Hz,
1H), 7.72 (m, 1H), 7.42–7.38 (m, 2H), 7.34–7.28 (m, 5H), 7.21–7.19
(m, 1H), 7.07 (ddd, J=8.0, 8.0, 2.0 Hz, 1H), 7.0 (ddd, J=7.6, 7.6,
1.2 Hz, 1H), 6.89 (dd, J=8.0, 1.6 Hz, 1H), 3.83 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=165.9, 148.4, 136.9, 136.1, 134.6, 132.8 (2C),
131.8, 131.2, 129.7 (2C), 129.0, 128.1, 128.0, 127.0, 124.2, 121.4,
120.2, 110.2, 55.6 ppm; HRMS (ESI): m/z [M+H]+ calcd for
C20H17NO2S: 335.0980, found: 335.0984.
2-(2-Fluorophenyl)-N-(2-((4-nitrophenyl)thio)phenyl)acetamide
(5g): Reaction of 1g and 4-nitrothiophenol gave product 5g
(0.142 g, 37%): 1H NMR (400 MHz, CDCl3): d=8.57 (dd, J=8.0,
1.2 Hz, 1H), 8.19 (s, 1H), 8.02–7.98 (m, 2H), 7.57–7.52 (m, 2H),
7.22–7.11 (m, 3H), 7.0 (ddd, J=8.0, 8.0, 1.2 Hz, 1H), 6.87–6.84 (m,
3H), 3.67 ppm (d, J=1.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
168.3, 160.9 (d, J=245.4 Hz), 145.8, 145.7, 140.6, 137.4, 132.8, 131.8
(d, J=3.7 Hz), 130.0 (d, J=8.1 Hz), 125.5 (2C), 125.3, 124.9 (d, J=
3.7 Hz), 124.4 (2C), 121.2, 121.1, 116.7, 115.9 (d, J=22.0 Hz),
38.6 ppm (d, J=2.9 Hz); HRMS (ESI): m/z [M+H]+ calcd for
C20H16FN2O3S: 383.0866, found: 383.0862.
N-(2-Methoxyphenyl)-3-(4-nitrophenylthio)benzamide (5b): Reac-
tion of 1b and 4-nitrothiophenol gave product 5b as a pale yellow
solid (0.236 g, 62%): 1H NMR (400 MHz, CDCl3): d=8.51 (s, 1H),
8.48 (dd, J=8.0, 1.6 Hz, 1H), 8.13–8.09 (m, 2H), 8.06 (t, J=1.6 Hz,
1H), 7.93 (ddd, J=7.6, 1.6, 1.2 Hz, 1H), 7.69 (ddd, J=7.6, 1.6,
1.2 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.28–7.25 (m, 2H, overlapping),
7.11 (ddd, J=8.0, 8.0, 1.6 Hz, 1H), 7.03 (ddd, J=8.0, 8.0, 1.2 Hz,
1H), 6.93 (dd, J=8.0, 1.2 Hz, 1H), 3.92 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=164.2, 148.4, 147.2, 146.1, 137.5, 137.3, 133.1,
132.6, 130.6, 128.0, 127.9 (2C), 127.6, 124.6, 124.5, 121.5 (2C), 120.2,
110.2, 56.1 ppm; HRMS (ESI): m/z [M+H]+ calcd for C20H17N2O4S:
381.0909, found: 381.0907.
Typical procedure for the synthesis of analogues 6a–e:
2-((4-Aminophenyl)thio)-N-(2-methoxyphenyl)benzamide (6a): A
solution of compound 5a (0.175 g, 0.5 mmol) and SnCl2·2H2O
(0.56 g, 2.5 mmol) in EtOAc (10 mL) was heated at 808C for 3 h.
The reaction mixture was allowed to reach RT and treated with sa-
turated aq NaHCO3 solution till basic. The aqueous layer was ex-
tracted with EtOAc (3ꢁ25 mL), and the combined organic portion
was washed with saturated aq NaCl solution (25 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography (EtOAc/hexanes, 2:3) to afford prod-
uct 6a as an off-white solid (0.158 g, 90%): 1H NMR (400 MHz,
CDCl3): d=8.58 (d, J=3.2 Hz, 1H), 8.56 (s, 1H), 7.62 (dd, J=7.6,
1.6 Hz, 1H), 7.33–7.29 (m, 2H), 7.24 (ddd, J=7.6, 7.6, 1.6 Hz, 1H),
7.17 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.08 (ddd, J=7.6, 7.6, 1.2 Hz,
1H), 7.02 (ddd, J=8.0, 8.0, 1.2 Hz, 1H), 6.98 (dd, J=7.6, 1.2 Hz, 1H),
6.91 (dd, J=8.0, 1.6 Hz, 1H), 6.69–6.65 (m, 2H), 3.89 (s, 3H),
3.84 ppm (br s, 2H); 13C NMR (100 MHz, CDCl3): d=166.2, 148.4,
146.8, 139.9, 136.8 (2C), 134.6, 131.0, 128.9, 128.8, 128.4, 128.0,
125.4, 124.2, 121.4, 120.8, 120.2, 116.6 (2C), 110.2, 56.0 ppm; HRMS
(ESI): m/z [M+H]+ calcd for C20H19N2O2S: 351.1167, found:
351.1169.
N-(2-(4-Nitrophenylthio)phenyl)-2-methoxybenzamide (5c): Reac-
tion of 1c and 4-nitrothiophenol gave product 5c as a pale yellow
solid (0.20 g, 53%): 1H NMR (400 MHz, CDCl3): d=10.86 (s, 1H),
8.86 (dd, J=8.4, 1.2 Hz, 1H), 8.24 (dd, J=8.2, 1.8 Hz, 1H), 8.07–8.03
(m, 2H), 7.63 (dd, J=7.6, 1.2 Hz, 1H), 7.60 (ddd, J=8.0, 8.0, 1.6 Hz,
1H), 7.46 (ddd, J=8.0, 8.0, 2.0 Hz, 1H), 7.20 (ddd, J=7.6, 7.6,
1.2 Hz, 1H), 7.12–7.07 (m, 3H), 6.93 (d, J=8.4 Hz, 1H), 3.83 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=163.6, 157.3, 146.7, 145.5,
142.2, 137.5, 133.8, 132.6, 132.4, 125.5 (2C), 124.9, 124.4 (2C), 122.2,
121.6, 121.3, 117.1, 111.5, 56.0 ppm; HRMS (ESI): m/z [M+H]+ calcd
for C20H17N2O4S: 381.0909, found: 381.0906.
N-(2-Methoxyphenyl)-2-((4-nitrophenyl)thio)benzenesulfonamide
(5d): Reaction of 1d and 4-nitrothiophenol gave product 5d as an
orange–brown crystalline solid (0.196 g, 47%): 1H NMR (400 MHz,
CDCl3): d=8.21–8.18 (m, 1H), 8.05–8.02 (m, 2H), 7.81 (s, 1H), 7.51–
7.45 (m, 4H), 7.15–7.11 (m, 2H), 6.99 (ddd, J=8.0, 8.0, 2.0 Hz, 1H),
6.85 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 6.65 (dd, J=8.4, 1.2 Hz, 1H),
3.49 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=148.8, 146.3, 141.5,
137.0, 134.0, 132.0, 131.5, 129.4, 129.0 (2C), 125.9, 125.0, 124.3 (2C),
121.4, 119.4, 110.5, 105.0, 55.5 ppm; HRMS (ESI): m/z [M+H]+ calcd
for C19H17N2O5S2: 417.0579, found: 417.0587.
3-(4-Aminophenylthio)-N-(2-methoxyphenyl)benzamide (6b): Re-
duction of the nitro group in 5b gave product 6b as an off-white
1
solid (0.114 g, 65%): H NMR (400 MHz, CDCl3): d=8.48 (dd, J=8.0,
1.6 Hz, 1H), 8.44 (s, 1H), 7.59 (m, 2H), 7.37–7.30 (m, 3H), 7.25 (m,
1H), 7.07 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.00 (ddd, J=7.6, 7.6,
1.2 Hz, 1H), 6.90 (dd, J=8.0, 1.2 Hz, 1H), 6.72–6.69 (m, 2H), 3.90 (s,
3H), 3.87 ppm (s, 2H); 13C NMR (100 MHz, CDCl3): d=165.1, 148.3,
147.8, 141.7, 136.9 (2C), 136.2, 130.0, 129.3, 127.9, 125.3, 124.2,
124.0, 121.4, 120.0, 119.2, 116.2 (2C), 110.1, 56.0 ppm; HRMS (ESI):
m/z [M+H]+ calcd for C20H19N2O2S: 351.1167, found: 351.1170.
2-Methoxy-N-(2-(4-nitrophenylthio)phenyl)benzenesulfonamide
(5e): Reaction of 1e and 4-nitrothiophenol gave product 5e as
a pale yellow crystalline solid (0.105 g, 25%): 1H NMR (400 MHz,
CDCl3): d=8.10 (s, 1H), 7.99 (m, 2H), 7.91 (dd, J=8.0, 1.2 Hz, 1H),
7.81 (d, J=8.4 Hz, 1H), 7.47–7.39 (m, 3H), 7.09 (ddd, J=7.6, 7.6,
1.2 Hz, 1H), 7.01 (ddd, J=8.0, 8.0, 0.8 Hz, 1H), 6.91 (m, 2H), 6.76 (d,
J=8.4 Hz, 1H), 3.72 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
156.5, 146.7, 145.7, 140.7, 138.0, 135.5, 132.6, 131.0, 126.4, 125.8
(2C), 125.3, 124.4 (2C), 120.7, 119.5, 117.2, 112.2, 56.2 ppm; HRMS
N-(2-(4-Aminophenylthio)phenyl)-2-methoxybenzamide (6c): Re-
duction of the nitro group in 5c gave product 6c (0.137 g, 78%):
1H NMR (400 MHz, CDCl3): d=10.96 (s, 1H), 8.67 (dd, J=8.4, 1.2 Hz,
1H), 8.29 (dd, J=8.0, 1.6 Hz, 1H), 7.49 (ddd, J=8.0, 8.0, 2.0 Hz, 2H),
7.38 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (ddd, J=8.0, 8.0, 1.6 Hz, 1H),
7.13–7.09 (m, 3H), 7.02 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.01 (d, J=
1224
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ChemMedChem 2012, 7, 1217 – 1229