3.5. General Procedure for the Synthesis of Compounds 9a–q
Step 1. Nitric acid (1.5 mL, 33.33 mmol, Sinopharm Chemical Reagent Co., Ltd, Shanghai, China) was added to the suspension of alizarin (5 g, 20.8 mmol) in acetic acid (350 mL) at 50 °C. A yellow solid (4.15 g, 70%) of crude product 6 was obtained by filtration [
40].
Step 2. Sn (10.5 g, 341 mmol, Sinopharm Chemical Reagent Co., Ltd, Shanghai, China), SnCl
2·2H
2O (12.5 g, 55.4 mmol) and concentrated HCl (50.4 mL, 604.8 mmol) were added to the suspension of crude product 6 (1.75 g, 6.14 mmol) in ethanol (350 mL, Sinopharm) and the mixture was stirred at room temperature overnight. Then the mixture was poured into water (1 L) and a red solid precipitated. A black solid of crude product 7 (1.41 g, 90%) was obtained after filtration and being dried under vacuum [
40].
Step 3. To the solution of crude product 7 (255 mg, 1 mmol) in dry pyridine (5 mL, Sinopharm), corresponding sulfonyl chloride (1.5 mmol, Energy Chemical, Shanghai, China) was added and the mixture was stirred at room temperature. Then it was added to 10% aqueous HCl (50 mL, Sinopharm) and the suspension was extracted with ethyl acetate (Sinopharm). The organic phase was washed with brine, dried over anhydrous Na2SO4 and filtered. The residue was purified by silica chromatography after removal of ethyl acetate to give compounds 9a–q.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-4-(trifluoromethyl) benzenesulfonamide (9a). Yellow solid, 25% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.90 (brs, 1H), 10.67 (brs, 1H), 8.22–8.12 (m, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.95–7.86 (m, 2H), 7.73 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 187.78, 180.56, 150.37, 144.20, 143.23, 135.02, 134.22, 133.28, 132.79, 132.68 (q, J = 31.7 Hz), 130.34, 127.60 (2C), 126.77, 126.61, 126.59, 126.39, 123.71, 123.38 (q, J = 273.3 Hz), 113.49, 113.35. MS (ESI) (m/z): 462.0 (M − H)−. HRMS (ESI) calcd. for C21H12F3NO6S [M − H]−: 462.0265; found: 462.0284. Purity 99.8% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-4-nitrobenzenesulfonamide (9b). Orange solid, 50% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H), 10.98 (brs, 1H), 10.79 (brs, 1H), 8.41 (d, J = 8.0 Hz, 2H), 8.25–8.06 (m, 4H), 7.97–7.86 (m, 2H), 7.73 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 187.79, 180.53, 150.41, 149.90, 145.71, 143.61, 135.05, 134.24, 133.27, 132.79, 130.11, 128.22(2C), 126.77, 126.41, 124.65(2C), 123.70, 114.04, 113.50. MS (ESI) (m/z): 439.0 (M − H)−. HRMS (ESI) calcd. for C20H12N2O8S [M − H]−: 439.0242; found: 439.0228. Purity 98.4% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-4-(trifluoromethoxy) benzenesulfonamide (9c). Yellow solid, 41% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H), 10.94 (brs, 1H), 10.51 (brs, 1H), 8.22–8.12 (m, 2H), 8.05–7.99 (m, 2H), 7.95–7.85 (m, 2H), 7.74 (s, 1H), 7.61 (dd, J = 1.2, 9.2 Hz, 2H). 13C-NMR (151 MHz, DMSO) δ 187.78, 180.60, 151.20, 150.35, 142.96, 139.19, 135.02, 134.23, 133.30, 132.82, 130.63, 129.29, 126.78, 126.40, 123.74, 121.47, 119.80 (q, J = 259.7 Hz), 113.22, 113.12. MS (ESI) (m/z): 478.0 (M − H)−. HRMS (ESI) calcd. for C21H12F3NO7S [M − H]−: 478.0214; found: 478.0207. Purity 96.8% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-2-(trifluoromethoxy) benzenesulfonamide (9d). Yellow solid, 40% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (brs, 1H), 11.00 (brs, 1H), 10.37 (brs, 1H), 8.24–8.09 (m, 2H), 8.00 (dd, J = 2.0, 8.0 Hz, 1H), 7.96–7.86 (m, 2H), 7.83–7.75 (m, 1H), 7.71 (s, 1H), 7.63–7.51 (m, 2H). 13C-NMR (151 MHz, DMSO) δ 187.81, 180.54, 150.37, 145.18, 143.20, 135.55, 135.05, 134.25, 133.28, 132.82, 132.34, 130.65, 130.41, 127.45, 126.80, 126.43, 123.61, 120.97, 119.81 (q, J = 259.7 Hz), 113.72, 113.26. MS (ESI) (m/z): 477.8 (M − H)−. HRMS (ESI) calcd. for C21H12F3NO7S [M − H]−: 478.0214; found: 478.0225. Purity 95.2% by HPLC.
4-Cyano-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9e). Red solid, 60% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.77 (brs, 2H), 8.22–8.12 (m, 2H), 8.09 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.96–7.87 (m, 2H), 7.70 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 187.81, 180.57, 150.39, 144.34, 143.46, 135.05, 134.25, 133.49, 133.29, 132.81, 130.22, 127.34, 126.81, 126.75, 126.44, 123.71, 117.60, 115.48, 113.78(2C), 113.44. MS (ESI) (m/z): 419.0 (M − H)−. HRMS (ESI) calcd. for C21H12N2O6S [M − H]−: 419.0343; found: 419.0348. Purity 95.1% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-4-fluorobenzenesulfonamide (9f). Yellow solid, 62% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.58 (brs, 1H), 10.84 (brs, 1H), 10.43 (brs, 1H), 8.19–8.11 (m, 2H), 8.01–7.84 (m, 4H), 7.73 (s, 1H), 7.46 (t, J = 8.8 Hz, 2H). 13C-NMR (151 MHz, DMSO) δ 187.75, 180.59, 164.47 (d, J = 250.7 Hz), 150.32, 142.76, 136.58, 134.99, 134.21, 133.28, 132.81, 130.82, 129.75 (d, J = 9.1 Hz,2C), 126.76, 126.38, 123.72, 116.57 (d, J = 22.7 Hz, 2C), 113.10, 112.89. MS (ESI) (m/z): 412.0 (M − H)−. HRMS (ESI) calcd. for C20H12FNO6S [M − H]−: 412.0297; found: 412.0305. Purity 98.7% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-2-fluorobenzenesulfonamide (9g). Yellow solid, 42% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H), 10.95 (brs, 1H), 10.49 (brs, 1H), 8.21–8.09 (m, 2H), 7.95–7.80 (m, 3H), 7.77–7.67 (m, 2H), 7.46 (t, J = 9.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 187.80, 180.56, 158.34 (d, J = 256.7 Hz), 150.40, 143.42, 136.02, 135.01, 134.21, 133.28, 132.81, 130.39, 129.87, 127.94 (d, J = 12.1 Hz), 126.77, 126.41, 124.90, 123.57, 117.44 (d, J = 21.1 Hz), 113.88, 113.32. MS (ESI) (m/z): 412.0 (M − H)−. HRMS (ESI) calcd. for C20H12FNO6S [M − H]−: 412.0297; found: 412.0300. Purity 96.1% by HPLC.
N-(3,4-Dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-2,3-difluorobenzenesulfonamide (9h). Red solid, 52% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.83 (brs, 2H), 8.23–8.11 (m, 2H), 7.96–7.86 (m, 2H), 7.79 (q, J = 8.6 Hz, 1H), 7.69 (s, 1H), 7.62 (t, J = 7.0 Hz, 1H), 7.44–7.34 (m, 1H). 13C-NMR (151 MHz, DMSO) δ 187.86, 180.52, 150.46, 149.96 (dd, J = 249.9 Hz, J = 12.1 Hz), 146.64 (dd, J = 256.7 Hz, J = 13.6 Hz) 144.45, 135.05, 134.22, 133.29, 132.81, 130.25 (d, J = 10.6 Hz), 129.75, 126.78 (d, J = 10.6 Hz), 126.43 d, J = 7.6 Hz), 125.26, 124.95, 123.51, 122.86 (d, J = 16.6 Hz), 115.28 (d, J = 6.0 Hz), 113.72. MS (ESI) (m/z): 430.0 (M − H)−. HRMS (ESI) calcd. for C20H11FNO6S [M − H]−: 430.0202; found: 430.0206. Purity 95.4% by HPLC.
4-Chloro-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9i). Yellow solid, 56% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.61 (brs, 1H), 10.94 (brs, 1H), 10.47 (brs, 1H), 8.22–8.11 (m, 2H), 7.96–7.83 (m, 4H), 7.78–7.63 (m, 3H). 13C-NMR (151 MHz, DMSO) δ 187.76, 180.58, 150.34, 142.90, 139.07, 138.04, 135.00, 134.22, 133.28, 132.80, 130.63, 129.50 (2C), 128.57 (2C), 126.77, 126.39, 123.72, 113.18, 113.08. MS (ESI) (m/z): 427.8 (M − H)−. HRMS (ESI) calcd. for C20H12ClNO6S [M − H]−: 428.0001; found: 428.0005. Purity 99.4% by HPLC.
2,4-Dichloro-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9j). Orange solid, 60% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (brs, 1H), 11.00 (brs, 1H), 10.56 (brs, 1H), 8.20–8.08 (m, 2H), 8.01 (d, J = 8.8 Hz, 1H), 7.95–7.84 (m, 3H), 7.68–7.63 (m, 2H). 13C-NMR (151 MHz, DMSO) δ 187.76, 180.50, 150.44, 143.33, 138.62, 136.55, 134.99, 134.20, 133.24, 132.79, 132.25, 132.12, 131.49, 130.24, 127.85, 126.75, 126.38, 123.63, 113.52, 113.36. MS (ESI) (m/z): 461.8 (M − H)−. HRMS (ESI) calcd. for C20H11Cl2NO6S [M − H]−: 461.9611; found: 461.9614. Purity 99.2% by HPLC.
2,6-Dichloro-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9k). Red solid, 12% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (brs, 1H), 11.00 (brs, 1H), 10.56 (brs, 1H), 8.20–8.09 (m, 2H), 7.94–7.83 (m, 2H), 7.72–7.52 (m, 4H). 13C-NMR (151 MHz, DMSO) δ 187.71, 180.43, 150.40, 142.57, 134.95, 134.80, 134.29, 134.17, 134.13 (2C), 133.22, 132.78, 131.85 (2C), 130.41, 126.75, 126.36, 123.79, 113.20, 112.18. MS (ESI) (m/z): 461.8 (M − H)−. HRMS (ESI) calcd. for C20H11Cl2NO6S [M − H]−: 461.9611; found: 461.9601. Purity 95.7% by HPLC.
2,4,6-Trichloro-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9l). Yellow solid, 10% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (brs, 1H), 10.96 (brs, 1H), 10.73 (brs, 1H), 8.21–8.11 (m, 2H), 7.96–7.86 (m, 4H), 7.66 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 187.77, 180.49, 150.48, 143.28, 137.64, 135.25 (2C), 135.00, 134.43, 134.22, 133.27, 132.83, 131.20 (3C), 126.79, 126.41, 123.78, 113.43, 113.21. MS (ESI) (m/z): 495.8 (M − H)−. HRMS (ESI) calcd. for C20H10Cl3NO6S [M − H]−: 495.9222; found: 495.9220. Purity 99.4% by HPLC.
4-Bromo-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9m). Yellow solid, 65% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.88 (brs, 1H), 10.47 (brs, 1H), 8.22–8.11 (m, 2H), 7.95–7.78 (m, 6H), 7.73 (s, 1H). 13C-NMR (151 MHz, DMSO) δ 187.77, 180.59, 150.33, 142.88, 139.50, 135.01, 134.23, 133.29, 132.81, 132.44 (2C), 130.65, 128.64 (2C), 127.08, 126.78, 126.39, 123.73, 113.18, 113.05. MS (ESI) (m/z): 471.8 (M − H)−. HRMS (ESI) calcd. for C20H12BrNO6S [M − H]−: 471.9496; found: 471.9495. Purity 96.0% by HPLC.
2-Bromo-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9n). Yellow solid, 46% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.63 (brs, 1H), 11.10 (brs, 1H), 10.24 (brs, 1H), 8.20–8.05 (m, 3H), 7.93–7.84 (m, 3H), 7.67–7.53 (m, 3H). 13C-NMR (151 MHz, DMSO) δ 187.72, 180.55, 150.37, 142.31, 138.96, 135.62, 134.97, 134.74, 134.21, 133.23, 132.80, 130.93, 130.76, 128.28, 126.75, 126.38, 123.75, 119.31, 113.07, 112.14. MS (ESI) (m/z): 471.8 (M − H)−. HRMS (ESI) calcd. for C20H12BrNO6S [M − H]−: 417.9496; found: 417.9498. Purity 97.5% by HPLC.
3-Bromo-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9o). Yellow solid, 54% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.99 (brs, 1H), 10.53 (brs, 1H), 8.21–8.11 (m, 2H), 8.10 (s, 1H), 7.94–7.83 (m, 4H), 7.71 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 187.75, 180.55, 150.33, 142.90, 142.23, 136.02, 134.98, 134.19, 133.27, 132.79, 131.56, 130.49, 129.08, 126.76, 126.37, 125.61, 123.71, 122.16, 113.22, 112.97. MS (ESI) (m/z): 473.8 (M − H)−.HRMS (ESI) calcd. for C20H12BrNO6S [M − H]−: 417.9496; found: 417.9500. Purity 96.1% by HPLC.
4-Iodo-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9p). Yellow solid, 70% yield. 1H-NMR (400 MHz, DMSO-d6) δ 12.60 (brs, 1H), 10.87 (brs, 1H), 10.44 (brs, 1H), 8.23–8.10 (m, 2H), 7.99 (d, J = 8.0 Hz, 2H), 7.96–7.85 (m, 2H), 7.73 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H). 13C-NMR (151 MHz, DMSO) δ 187.75, 180.61, 150.31, 142.73, 139.85, 138.23 (2C), 135.00, 134.22, 133.29, 132.82, 130.76, 128.27 (2C), 126.78, 126.39, 123.74, 113.12, 112.85, 101.56. MS (ESI) (m/z): 519.8 (M − H)−. HRMS (ESI) calcd. for C20H12INO6S [M − H]−: 519.9357; found: 519.9334. Purity 99.3% by HPLC.
2-Iodo-N-(3,4-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) benzenesulfonamide (9q). Yellow solid, 48% yield.1H-NMR (400 MHz, DMSO-d6) δ 12.64 (brs, 1H), 11.18 (brs, 1H), 10.02 (brs, 1H), 8.19–8.06 (m, 4H), 7.93–7.85 (m, 2H), 7.65 (s, 1H), 7.61 (td, J = 1.2, 8.0 Hz, 1H), 7.33 (td, J = 1.6, 8.0 Hz, 1H). 13C-NMR (151 MHz, DMSO) δ 187.72, 180.58, 150.30, 142.77, 142.13, 141.83, 134.97, 134.22, 134.21, 133.24, 132.81, 131.01, 130.16, 128.64, 126.76, 126.38, 123.83, 112.96, 111.59, 93.30. MS (ESI) (m/z): 519.8 (M − H)−. HRMS (ESI) calcd. for C20H12INO6S [M − H]−: 519.9357; found: 519.9356. Purity 96.3% by HPLC.