Med Chem Res (2012) 21:2644–2651
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4-Acetylamino-N-(6-methoxybenzothiazol-2-yl)benzamide
(1e) Yield: 37%. Mp 225–228°C. Rf = 0.26 (c-hexane/
EtOAc 5:5). H NMR (CDCl3): 2.23 (s, 3H), 3.82 (s, 3H),
2,6-Difluoro-N-(6-trifluoromethoxybenzothiazol-2-yl)benz-
amide (2d) Yield: 43%. Mp 250–251°C. Rf = 0.78 (c-
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hexane/EtOAc 5:5). H NMR (CDCl3): 7.16 (m, H-40),
7.05 (dd, 1H, Jo = 8.8 Hz, Jm = 2.5 Hz, H-5), 7.32 (d, 1H,
Jm = 2.5 Hz, H-7), 7.58 (d, 1H, Jo = 8.8 Hz, H-4), 7.82
(d, 2H, Jo = 8.8 Hz, H-30,50), 8.17 (d, 2H, Jo = 8.8 Hz,
H-20,60), 10.28 (br s, 1H, NH). Anal. Calcd. for
C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31. Found: C,
60.08; H, 4.21; N, 12.51.
7.38 (dd, 1H, Jo = 8.8 Hz, Jm = 1.1 Hz, H-5), 7.48 (d, 1H,
Jo = 8.8 Hz, H-4), 7.52 (d, 1H, Jm = 1.1 Hz, H-7), 7.75
(m, H-30,50), 11.15 (br s, 1H, NH). Anal. Calcd for
C15H7F5N2O2S: C, 48.14; H, 1.89; N, 7.48. Found: C,
48.37; H, 1.76; N, 7.66.
4-Acetylamino-N-(6-trifluoromethoxybenzothiazol-2-yl)benz-
amide (2e) Yield 41%. Mp 297–298°C. Rf = 0.17 (c-
hexane/EtOAc 5:5). 1H NMR (DMSO-d6): 2.23 (s, 3H), 6.63
(br s, 1H, NH), 7.58 (dd, 1H, Jo = 8.8 Hz, Jm = 1.1 Hz,
H-5), 7.65 (d, 2H, J = 8.22 Hz, H-20,60), 7.93 (d, 1H,
Jo = 8.8 Hz, H-4), 8.25 (m, H-7, 30,50), 10.28 (br s, 1H, NH);
Anal. Calcd for C17H12F3N3O3S: C, 51.65, H, 3.06, N, 10.63.
Found: C, 51.88, H, 2.93, N, 10.86.
General procedures for the synthesis of compounds 2a–e
To a solution of 2-amino-6-trifluoromethoxybenzothiazole
6 (100 mg, 0.42 mmol) in DMF (4 ml), NaH (13 mg,
0.42 mmol) was slowly added and the reaction mixture was
stirred vigorously for further 10 min at room temperature.
To the resulting suspension, the appropriate benzoyl chlo-
ride (0.64 mmol, 1.5 equiv) in DMF (0.5 ml) was added,
and the mixture was stirred for 6 h at room temperature.
The reaction mixture was quenched by addition of water
and diluted with ethyl acetate (40 ml). The organic layer
was washed with water (3 9 40 ml) and dried over MgSO4.
After filtration and concentration, the crude product was
purified by flash chromatography (c-hexane/EtOAc 5:5) to
afford the desired amide in 35–70% yield.
General procedures for the synthesis of compounds 3a–d
2-Amino-6-methoxybenzothiazole 5 (100 mg, 0.55 mmol)
was dissolved in dry CH2Cl2 (5 ml) and reacted with the
appropriate aryl-isocyanates (0.83 mmol, 1.5 equiv) at
room temperature under stirring. After 3 h, the desired
product was obtained as a precipitate which was collected
by filtration under vacuum, purified by washing with ethyl
ether, and air-dried to give a white powder.
4-Fluoro-N-(6-trifluoromethoxybenzothiazol-2-yl)benzamide
(2a) Yield: 35%. Mp 199–200°C. Rf = 0.77 (c-hexane/
EtOAc 5:5). 1H NMR (CDCl3): 7.23 (dd, 2H,
JH–H = 8.8 Hz, JH–F = 8.2 Hz, H-20,60), 7.28 (dd, 1H,
Jo = 8.8 Hz, Jm = 1.1 Hz, H-5), 7.56 (d, 1H, Jo = 8.8 Hz,
H-4), 7.74 (d, 1H, Jm = 1.1 Hz, H-7), 8.20 (dd, 2H,
JH–H = 9.1 Hz, JH–F = 5.1 Hz, H-30,50), 10.15 (br s, 1H,
NH). Anal. Calcd for C15H8F4N2O2S: C, 50.57; H, 2.26; N,
7.86. Found C, 50.67; H, 2.04; N, 7.98.
1-(4-Fluorophenyl)-3-(6-methoxybenzothiazol-2-yl)urea
(3a) Yield: 60%. Mp [ 300°C. Rf = 0.41 (Et2O). 1H
NMR (DMSO-d6): 7.15 (d, 1H, Jm = 1.1 Hz, H-7), 7.33
(m, 2H, H-30,50), 7.68 (m, 4H, H-4, H-5, H-20,60), 9.32 (br
s, 1H, NH), 10.80 (br s, 1H, NH). Anal. Calcd for
C15H12FN3O2S: C, 56.77; H, 3.81; N, 13.24. Found: C,
57.09; H, 3.68; N, 13.42.
4-Methoxy-N-(6-trifluoromethoxybenzothiazol-2-yl)benz-
amide (2b) Yield: 51%. Mp 270–271°C. Rf = 0.66 (c-
1-(4-Methoxyphenyl)-3-(6-methoxybenzothiazol-2-yl)urea
(3b) Yield: 73%. Mp [300°C. Rf = 0.32 (Et2O). 1H
NMR (DMSO-d6): 3.80 (s, 3H), 3.85 (s, 3H), 7.10 (d, 2H,
J = 6.75, H-30,50), 7.54 (dd, 1H, Jo = 8.24 Hz,
Jm = 1.1 Hz, H-5), 7.71 (d, 2H, J = 6.75, H-20,60), 7.98 (d,
1H, J = 8.25, H-4), 8.05 (d, 1H, Jm = 1.1 Hz, H-7), 9.25
(br s, 1H, NH), 10.90 (br s, 1H, NH). Anal. Calcd for
C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76. Found: C,
58.61; H, 4.32; N, 12.98.
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hexane/EtOAc 5:5). H NMR (CDCl3): 3.81 (s, 1H) 6.85
(d, 2H, J = 8.2 Hz, H-30,50), 7.30 (dd, 1H, Jo = 8.8 Hz,
Jm = 1.1 Hz, H-5), 7.65 (d, 1H, Jo = 8.8 Hz, H-4), 7.54
(d, 1H, Jm = 1.1 Hz, H-7), 7.95 (d, 2H, J = 8.22 Hz,
H-20,60), 11.35 (br s, 1H, NH). Anal. Calcd for
C16H11F3N2O3S: C, 52.17; H, 3.01; N, 7.61. Found C,
52.39; H, 2.83; N, 7.85.
4-Cyano-N-(6-trifluoromethoxybenzothiazol-2-yl)benzam-
ide (2c) Yield: 58%. Mp 259–260°C. Rf = 0.72 (c-hex-
ane/EtOAc 5:5). H NMR (CDCl3): 7.24 (dd, 1H, Jo =
1-(4-Cyanophenyl)-3-(6-methoxybenzothiazol-2-yl)urea (3c)
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Yield: 85%. Mp 275–276°C. Rf = 0.48 (Et2O). H NMR
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(DMSO-d6): 3.80 (s, 3H), 7.45 (dd, 1H, Jo = 8.24 Hz,
Jm = 1.1 Hz, H-5) 8.0 (m, 5-H, H-30,50, H-20,60, H-4), 8.15
(d, 1H Jm = 1.1 Hz, H-7), 9.59 (br s, 1H, NH), 10.20 (br s,
1H, NH). Anal. Calcd for C16H12N4O2S: C, 59.25; H, 3.73;
N, 17.27. Found: C, 59.49; H, 3.59; N, 17.42.
8.8 Hz, Jm = 1.1 Hz, H-5), 7.30 (d, 1H, Jo = 8.8 Hz, H-4),
7.78 (m, 3H, H-7, 30,50), 8.13 (d, 2H, J = 8.22 Hz, H-20,60),
11.35 (br s, 1H, NH). Anal. Calcd for C16H8F3N3O2S: C,
52.90; H, 2.22; N, 11.57. Found: C, 52.73; H, 2.55; N, 11.31.
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