4.1. General Experimental Details
Chemicals were purchased from Sigma-Aldrich or Lancaster. Yields refer to purified products and were not optimized. The structures of the compounds were confirmed by routine spectrometric and spectroscopic analyses. Only spectra for compounds not previously described are given. Purity of compounds was assessed by GC analysis. Melting points were determined on a Gallenkamp apparatus in open glass capillary tubes and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer (Norwalk, CT) Spectrum One FT spectrophotometer, and band positions are given in reciprocal centimeters cm−1. 1H NMR spectra were recorded on a Varian VX Mercury spectrometer operating at 300 MHz using CDCl3 and DMSO-d6 as solvents. Chemical shifts are reported in parts per million (ppm) relative to the residual nondeuterated solvent resonance: CDCl3, δ 7.26 and DMSO-d6, δ 2.48. J values are given in Hz. GC-MS was performed on a Hewlett-Packard 6890-5973 MSD at low resolution. Chromatographic separations were performed on silica gel columns by flash chromatography (Kieselgel 60, 0.040–0.063 mm, Merck, Darmstadt, Germany) as previously reported [38–41]. TLC analyses were performed on precoated silica gel on aluminum sheets (Kieselgel 60 F254, Merck). GC analyses were performed on a Varian 3800 gas chromatograph equipped with a flame ionization detector and a Jew Scientific DB-5 capillary column (30 m length × 0.25 mm ID, 0.25 μm film thickness) [42].
4.1.1. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-2,3 difluorobenzamide (3a)
A mixture of 5a (0.61 g, 3.0 mmol) and triethylamine (0.30 g, 3.0 mmol) in dry dioxane (30 mL) was stirred for 30 min at 50–60°C. A solution of 2,3-difluorobenzoyl chloride (0.53 g, 3.0 mmol) in dry dioxane (30 mL) was added dropwise. The mixture was stirred for 2 h and then poured into crushed ice. The resulting solid, so separated, was collected by filtration and washed with 1% potassium bicarbonate aqueous solution. The crude residue was purified by column chromatography on silica gel (EtOAc/petroleum ether 3 : 7) to give 0.32 g (31%) of 3a as a white solid: mp 240–242°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 38), 141 (100); 1H NMR: δ 7.18–7.25 (m, 1H, Ar HC-5), 7.26–7.35 (m, 1H, Ar HC-3′), 7.42–7.55 (m, 1H, Ar HC-4′), 7.63 (s, 1H, Ar HC-5′), 7.96 (t, J = 6.3 Hz, 1H, Ar HC-7), 10.08 (br s, 1H, NH, exch D2O); IR (KBr): 3405 (NH), 1686 (C=O) cm−1.
4.1.2. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-2,4-difluorobenzamide (3b)
Prepared as reported previously for 3a starting from 5a and 2,4-difluorobenzoyl chloride. Yield: 33%; white solid: mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 18), 141 (100); 1H NMR (DMSO-d6): δ 7.12–7.55 (m, 3H, Ar HC-5 + Ar HC-3′,5′), 7.85–8.05 ppm (m, 2H, Ar HC-7 +Ar HC-6′); IR (KBr): 3418 (NH), 1673 (C=O) cm−1.
4.1.3. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-2,5-difluorobenzamide (3c)
Prepared as reported previously for 3a starting from 5a and 2,5-difluorobenzoyl chloride. Yield: 24%; white solid: mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 17), 141 (100); 1H NMR: δ 7.00–7.25 (m, 2H, Ar HC-5 + HC-4′), 7.50–7.65 (m, 1H, Ar HC-6′), 7.70–7.85 (m, 1H, Ar HC-3′), 8.02 (d, J = 5.2 Hz, 1H, Ar HC-7), 10.22 ppm (br s, 1H, NH); IR (KBr): 3410 (NH), 1677 (C=O) cm−1.
4.1.4. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-2,6-difluorobenzamide (3d)
Prepared as reported previously for 3a starting from 5a and 2,6-difluorobenzoyl chloride. Yield: 12%; white solid: mp 245–247°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 18), 141 (100); 1H NMR: δ 7.01 (t, J = 8.5 Hz, 2H, Ar HC-3′,5′), 7.14 (dd, J = 10.1, 1.8 Hz, 1H, Ar HC-5), 7.44–7.58 (m, 1H, Ar, HC-4′), 7.63 (s, 1H Ar HC-7), 10.37 ppm (br s, 1H, NH); IR (KBr): 3409 (NH), 1694 (C=O) cm−1.
4.1.5. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-3,4-difluorobenzamide (3e)
Prepared as reported previously for 3a starting from 5a and 3,4-difluorobenzoyl chloride. Yield: 14%; slightly yellowish solid: mp 226–228°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 26), 141 (100); 1H NMR: δ 7.19 (dd, J = 9.9, 1.6 Hz, 1H, Ar HC-5), 7.25–7.40 (m, 1H, Ar HC-5′), 7.62 (s, 1H Ar HC-7), 7.80–7.88 (m, 1H, Ar HC-2′), 7.90–8.02 ppm (m, 1H, Ar HC-6′); IR (KBr): 3410 (NH), 1679 (C=O) cm−1.
4.1.6. N-(6-Chloro-4-fluoro-1,3-benzothiazol-2-yl)-3,5-difluorobenzamide (3f)
Prepared as reported previously for 3a starting from 5a and 3,5-difluorobenzoyl chloride. Yield: 34%; white solid: mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 36), 141 (100); 1H NMR: δ 7.10 (tt, J = 8.2, 2.2 Hz, 1H, Ar HC-4′), 7.21 (dd, J = 9.9, 1.9 Hz, 1H, Ar HC-5), 7.47–7.57 (m, 2H, Ar HC-2′,6′), 7.62–7.66 ppm (m, 1H, Ar HC-7); IR (KBr): 3414 (NH), 1681 (C=O) cm−1.
4.1.7. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-2,3-difluorobenzamide (3g)
Prepared as reported previously for 3a starting from 5b and 2,3-difluorobenzoyl chloride. Yield: 64%; white solid: mp 241–243°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 25), 141 (100); 1H NMR: δ 7.25–7.38 (m, 1H, Ar HC-4′), 7.42–7.52 (m, 1H, Ar HC-5′), 7.59 (d, J = 9.3 Hz, 1H, Ar HC-4), 7.86 (d, J = 7.1 Hz, 1H, Ar HC-7), 7.93–8.02 ppm (m, 1H, Ar HC-6′); IR (KBr): 3414 (NH), 1673 (C=O) cm−1.
4.1.8. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-2,4-difluorobenzamide (3h)
Prepared as reported previously for 3a starting from 5b and 2,4-difluorobenzoyl chloride. Yield: 64%; beige solid, mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 17), 141 (100); 1H NMR (DMSO-d6): δ 7.16–7.32 (m, 1H, Ar HC-3′), 7.40–7.56 (m, 1H, Ar HC-5′), 7.80–7.96 (m overlapping d at 7.84 ppm, 1H, Ar HC-6′), 7.84 (d overlapping m at 7.80–7.96 ppm, J = 10.2 Hz, 1H, Ar HC-4), 8.32 (d, J = 7.7 Hz, 1H, Ar HC-7), 13.04 ppm (br s, 1H, NH); IR (KBr): 3420 (NH), 1671 (C=O) cm−1.
4.1.9. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-2,5-difluorobenzamide (3i)
Prepared as reported previously for 3a starting from 5b and 2,5-difluorobenzoyl chloride. Yield: 64%; white solid, mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 15), 141 (100); 1H NMR: δ 7.15–7.40 (m, 2H, Ar HC-3′,5′), 7.59 (d, J = 9.3 Hz, 1H, Ar HC-4), 7.87 (d, J = 6.9 Hz, 1H, Ar HC-7), 7.90–7.98 (m, 1H, Ar HC-6′), 10.05 ppm (br s, 1H, NH); IR (KBr): 3496 (NH), 1682 (C=O) cm−1.
4.1.10. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-2,6-difluorobenzamide (3j)
Prepared as reported previously for 3a starting from 5b and 2,6-difluorobenzoyl chloride. Yield: 70%; white solid, mp 247–249°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 18), 141 (100); 1H NMR: δ 7.03 (t, J = 9.0 Hz, 1H, Ar HC-3′,5′), 7.34 (d, J = 9.3 Hz, 1H, Ar HC-4), 7.45–7.58 (m, 1H, Ar HC-4′), 7.85 ppm (d, J = 6.9 Hz, 1H, Ar HC-7); IR (KBr): 3430 (NH), 1687 (C=O) cm−1.
4.1.11. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-3,4-difluorobenzamide (3k)
Prepared as reported previously for 3a starting from 5b and 3,4-difluorobenzoyl chloride. Yield: 62%; white solid, mp > 250°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 33), 141 (100); 1H NMR: δ 7.25–7.40 (m, 1H, Ar HC-5), 7.48 (d, J = 9.3 Hz, 1H, Ar HC-4), 7.76–7.85 (m, 1H, Ar HC-2′), 7.86 (d, J = 6.9 Hz, 1H, Ar HC-7), 7.87–7.98 ppm (m, 1H, Ar HC-6′); IR (KBr): 3408 (NH), 1682 (C=O) cm−1.
4.1.12. N-(6-Chloro-5-fluoro-1,3-benzothiazol-2-yl)-3,5-difluorobenzamide (3l)
Prepared as reported previously for 3a starting from 5b and 3,5-difluorobenzoyl chloride. Yield: 55%; white solid, mp 235–237°C; GC-MS (70 eV, electron impact) m/z (%) 342 (M+, 39), 141 (100); 1H NMR (DMSO-d6): δ 7.55–7.65 (m, 1H, Ar HC-4′), 7.70–7.90 (m, 3H, HC-4,-2′,6′), 8.33 (d, J = 7.4 Hz, 1H, Ar HC-7), 13.2 ppm (br s, 1H, NH); IR (KBr): 3401 (NH), 1679 (C=O) cm−1.
4.1.13. 6-Chloro-4-fluoro-1,3-benzothiazol-2-amine (5a)
A mixture of 4a (15 g, 103 mmol) and potassium thiocyanate (20 g, 206 mmol) in glacial acetic acid (250 mL) was stirred for 5 min. Bromine (24 g, 150 mmol) in glacial acetic acid (250 mL) was added dropwise to this mixture, with the temperature being kept below 30–35°C throughout the addition. Stirring was continued for an additional 1 h after addition of bromine. After cooling, the residue was removed by filtration. The filtered solution was made alkaline with 28% ammonium hydroxide, and the solid precipitate was collected and washed with water. The combined water layers were made alkaline with 28% ammonium hydroxide, and the resulting precipitate was combined with that previously collected. The combined precipitates were extracted with EtOAc. The organic layers were separated, dried (Na2SO4), and evaporated under vacuum. The crude residue was purified by column chromatography on silica gel (hexane/EtOAc 3 : 7) to give 14.6 g (70%) of 5a as a slight green solid: mp 243–245°C; GC-MS (70 eV, electron impact) m/z (%) 202 (M+, 100); 1H NMR: δ 7.08 (dd, J = 10.2, 1.9 Hz, 1H, Ar HC-7), 7.30–7.40 (m, 1H, HC-5), 5.63 ppm (br s, 1H, NH2); IR (KBr): 3461, 3074 (NH2) cm−1.
4.1.14. 6-Chloro-5-fluoro-1,3-benzothiazol-2-amine (5b)
Prepared as reported previously for 5a starting from 4b. Yield: 65%; white solid: mp 234–236°C; GC-MS (70 eV, electron impact) m/z (%) 202 (M+, 100); 1H NMR: δ 7.30 (d, J = 9.9 Hz, 1H, Ar HC-4), 7.56 (d, J = 6.9 Hz, 1H, Ar HC-7), 5.45 ppm (br s, 1H, NH2); IR (KBr): 3473, 3083 (NH2) cm−1.