2.2. Synthetic work
2.2.1. Synthesis of N–acylindolines 3a–d
To a solution of indoline (2 g, 16.8 mmol) in dry dichloromethane (20 mL) triethylamine (1.74 g, 17.2 mmol) was added. The reaction mixture was cooled to 0–5°C and corresponding acyl chloride (17.6 mmol, 1.05 equiv) was added. The reaction mixture was stirred at RT for 18 h (TLC monitoring). Then the reaction mixture was diluted with water (10 mL). The organic phase was separated and washed with 1% solution of NaHCO3, brine and dried under anhydrous Na2SO4. The organic phase was filtered on the silica gel pad and solvent was removed in vacuo give the product 3 as a white or pale powder. It was further used without any additional purification.
1-(Indolin-1-yl)ethan-1-one(3a)[39]. Yield 95% (2.57 g), beige powder, mp 102–104 °С. 1H NMR (400 MHz, DMSO-d6) δ: 8.05 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 4.04 (t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.6 Hz, 2H), 2.13 (s, 3H).
1-(Indolin-1-yl)propan-1-one(3b) [39]. Yield 91% (2.68 g), beige powder, mp 101–102 °С. 1H NMR (400 MHz, DMSO-d6) δ: 8.08 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 4.03 (t, J = 8.5 Hz, 2H), 3.11 (t, J = 8.5 Hz, 2H), 2.43 (q, J = 7.3 Hz, 2H), 1.05 (t, J = 7.3 Hz, 3H).
Cyclobutyl(indolin-1-yl)methanone(3c). Yield 97% (3.14 g), beige powder, mp 110–113 °С. 1H NMR (400 MHz, DMSO-d6) δ: 8.10 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 3.94 (t, J = 8.5 Hz, 2H), 3.40 (p, J = 8.3 Hz, 1H), 3.09 (t, J = 8.5 Hz, 2H), 2.35–2.07 (m, 4H), 2.04–1.85 (m, 1H), 1.86–1.70 (m, 1H).
Indolin-1-yl(phenyl)methanone(3d)[39]. Yield 93% (3.48 g), beige powder, mp 125–130 °С. 1H NMR (400 MHz, DMSO-d6) δ: 8.06 (s, 1H), 7.61–7.46 (m, 5H), 7.27 (d, J = 7.4 Hz, 1H), 7.16 (s, 1H), 7.03 (t, J = 7.5 Hz,1), 3.99 (t, J = 8.3 Hz, 2H), 3.07 (t, J = 8.3 Hz, 2H).
2.2.2. Synthesis of sulfonyl chlorides 4a–d
To a cooled to 0–5°C chlorosulfonic acid (1 mL, 15 mmol, 3 equiv) N-acylindoline 3 (5 mmol, 1 equiv) was added under vigorous stirring. The reaction mixture was stirred at RT for 30 min and then heated at 80°C for 2 h. Then thionyl chloride (0.47 mL, 6.5 mmol, 1.3 equiv) was added and the reaction mixture was stirred at 80°C for another 3 h. After completion of the reaction (TLC monitoring), the reaction mixture was poured onto ice and extracted with chloroform (2x 15 mL). The organic phase was washed with water (2 x 40 mL) and dried under Na2SO4. The resulting solution was purified by flash chromatography on silica gel using chloroform as an eluent.
1-Acetylindoline-5-sulfonyl chloride(4a) [40].Yield 79% (1.03 g), beige powder, mp 170–172 °С. 1H NMR (400 MHz, CDCl3) δ: 8.36 (d, J = 8.7 Hz, 1H), 7.86 (dd, J = 8.7, 2.2 Hz, 1H), 7.78 (s, 1H), 4.19 (t, J = 8.7 Hz, 2H), 3.30 (t, J = 8.8 Hz, 2H), 2.28 (s, 3H).
1-Propionylindoline-5-sulfonyl chloride(4b)[41]. Yield 80% (1.09 g), beige powder, mp 130–132 °С. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 5.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 4.17 (t, J = 8.5 Hz, 2H), 3.29 (t, J = 8.5 Hz, 2H), 2.50 (q, J = 6.8 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).
1-(Cyclobutanecarbonyl)indoline-5-sulfonyl chloride(4c).Yield 82% (1.22 g), beige powder, mp 130–134 °С. 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 7.3 Hz, 1H), 7.89–7.83 (m, 1H), 7.77 (s, 1H), 4.08 (t, J = 8.6 Hz, 2H), 3.34 (p, J = 9.1 Hz, 1H), 3.26 (t, J = 8.6 Hz, 2H), 2.42 (p, J = 9.2 Hz, 2H), 2.32–2.18 (m, 2H), 2.12–1.96 (m, 1H), 1.98–1.88 (m, 1H).
1-Benzoylindoline-5-sulfonyl chloride(4d).Yield 78% (1.25 g), beige powder, mp 139–143 °С. 1H NMR (400 MHz, CDCl3) δ: 8.11–7.84 (m, 1H), 7.83 (s, 2H), 7.63–7.38 (m, 5H), 4.18 (t, J = 8.5 Hz, 2H), 3.22 (t, J = 8.4 Hz, 2H).
2.2.3. Synthesis of sulfonamides 5a–d
To a cooled to 10°C solution of ethyl 4-aminobenzoate (165 mg, 1 mmol) and pyridine (0.11 mL, 1.3 mmol) in acetonitrile (10 mL) N-acylindoline-5-sulfonyl chloride 3 (1 mmol) was added. The reaction mixture was stirred at RT for 18 h (TLC monitoring). The reaction mixture was filtered; the collected solid was washed twice with water (2 x 5 mL) and dried at 50°C. The residue was purified by recrystallization from ethanol or ethanol/DMF mixture to afford the desired sulfonamide 5.
Ethyl 4-((1-acetylindoline)-5-sulfonamido)benzoate(5a).Yield 85% (331 mg), white powder, mp 257–261 °С. 1H NMR (400 MHz, DMSO-d6) δ: 10.69 (s, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.69–7.59 (m, 2H), 7.21 (d, J = 7.7 Hz, 2H), 4.23 (q, J = 7.0, 6.4 Hz, 2H), 4.09 (t, J = 8.7 Hz, 2H), 3.14 (t, J = 8.7 Hz, 2H), 2.14 (s, 3H), 1.26 (t, J = 6.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 170.2, 165.8, 147.5, 143.1, 134.0, 133.5, 131.2 (2C), 127.9, 125.1, 124.0, 118.6 (2C), 115.9, 61.1, 49.3, 27.6, 24.7, 14.8. HRMS (ESI), calc. for C19H21N2O5S+ ([M + H]+) 389.1166; found m/z 389.1169.
Ethyl 4-((1-propionylindoline)-5-sulfonamido)benzoate(5b).Yield 82% (330 mg), white powder, mp 205–207 °С. 1H NMR (400 MHz, DMSO-d6) δ: 10.72 (s, 1H), 8.12 (d, J = 10.2 Hz, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.70–7.58 (m, J = 8.6 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 4.23 (q, J = 6.2, 4.9 Hz, 2H), 4.08 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.8 Hz, 2H), 2.44 (q, J = 8.2, 7.7 Hz, 2H), 1.26 (t, J = 6.9 Hz, 3H), 1.02 (t, J = 6.9 Hz, 3H).13C NMR (101 MHz, DMSO-d6) δ: 173.3, 165.8, 147.7, 143.1, 133.9, 133.4, 131.2 (2 C), 127.9, 125.1, 124.0, 118.6 (2 C), 115.8, 61.1, 48.4, 28.9, 27.6, 14.8, 9.0. HRMS (ESI), calc. for C20H23N2O5S+ ([M + H]+): 403.1322; found m/z 403.1317.
Ethyl 4-((1-(cyclobutanecarbonyl)indoline)-5-sulfonamido)benzoate(5c).Yield 68% (292 mg), white powder, mp 225–227 °С. 1H NMR (400 MHz, DMSO-d6) δ: 10.71 (s, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.72–7.56 (m, 2H), 7.21 (d, J = 8.5 Hz, 2H), 4.36–4.15 (m, 2H), 3.99 (t, J = 8.5 Hz, 2H), 3.49–3.36 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.28–2.17 (m, 2H), 2.19–2.10 (m, 2H), 1.92 (dq, J = 20.0, 10.5, 9.6 Hz, 1H), 1.83–1.69 (m, 1H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 173.9, 165.8, 147.8, 143.1, 134.0, 133.4, 131.2 (2C), 127.9, 125.0, 123.9, 118.5 (2C), 115.9, 61.1, 47.9, 39.2, 27.7, 24.5 (2C), 17.9, 14.8. HRMS (ESI), calc. for C22H25N2O5S+ ([M + H]+): 429.1479; found m/z 429.1477.
Ethyl 4-((1-benzoylindoline)-5-sulfonamido)benzoate(5d).Yield 70% (316 mg), white powder, mp 215–218 °С. 1H NMR (400 MHz, DMSO-d6) δ: 10.78 (s, 1H), 7.95 (br s, 1H), 7.82 (d, J = 8.3 Hz, 2H), 7.73–7.66 (m, 2H), 7.60–7.45 (m, 5H), 7.23 (d, J = 8.3 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.01 (t, J = 8.4 Hz, 2H), 3.10 (t, J = 8.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 169.5, 165.8, 147.4, 143.1, 137.0, 135.0, 134.2, 131.2 (2С), 131.2, 129.2 (2С), 127.6, 127.6 (2С), 125.1, 124.2, 118.6 (2С), 116.8, 61.8, 51.5, 28.0, 14.8. HRMS (ESI), calc. for C24H23N2O5S+ ([M + H]+): 451.1322; found m/z 451.1321.
2.2.4. Synthesis of acids 6a–dand 7
To the suspension of ester 5 (1 mmol) in 50% EtOH (5 mL) powdered NaOH (80 mg, 2 mmol) was added. The reaction mixture was stirred at RT for 18 h. The reaction mixture was filtered, cooled to 5–7 ᵒC, and acidified by conc. hydrochloric acid. The formed precipitate was collected by filtration and purified by recrystallization from ethanol or ethanol/DMF mixture to afford the desired product 6.
4-((1-Acetylindoline)-5-sulfonamido)benzoic acid(6a).Yield 65% (235 mg), white powder, mp 255–260 °С. 1H NMR (400 MHz, DMSO-d6) δ: 12.70 (s, 1H), 10.70 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.71–7.55 (m, 2H), 7.18 (d, J = 8.7 Hz, 2H), 4.10 (t, J = 8.6 Hz, 2H), 3.15 (t, J = 9.1 Hz, 2H), 2.14 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 170.2, 167.4, 147.4, 142.8, 134.0, 133.6, 131.4 (2С), 127.8, 126.0, 124.0, 118.6 (2С), 115.9, 49.3, 27.6, 24.7. HRMS (ESI), calc. for C17H17N2O5S+ ([M + H]+): 361.0853; found m/z 361.0850.
4-((1-Propionylindoline)-5-sulfonamido)benzoic acid(6b).Yield 67% (251 mg), white powder, mp 254–257 °С. 1H NMR (400 MHz, DMSO-d6) δ: 12.72 (br s, 1H), 10.68 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.69–7.61 (m, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.08 (t, J = 8.6 Hz, 2H), 3.14 (t, J = 8.6 Hz, 2H), 2.44 (q, J = 7.4 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ: 173.3, 167.4, 147.6, 142.8, 133.9, 133.4, 131.4 (2C), 127.9, 125.9, 124.0, 118.5 (2C), 115.8, 48.4, 28.9, 27.6, 9.1. HRMS (ESI), calc. for C18H19N2O5S+ ([M + H]+): 375.1009; found m/z 375.1007.
4-((1-(Cyclobutanecarbonyl)indoline)-5-sulfonamido)benzoic acid(6c).Yield 75% (301 mg), white powder, mp 259–262 °С. 1H NMR (400 MHz, DMSO-d6) δ: 12.73 (s, 1H), 10.70 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 9.2 Hz, 1H), 7.63 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 4.00 (t, J = 8.5 Hz, 2H), 3.40 (p, J = 16.3, 7.7 Hz, 1H), 3.14 (t, J = 8.6 Hz, 2H), 2.28–2.17 (m, 2H), 2.19–2.08 (m, 2H), 2.00–1.84 (m, 1H), 1.85–1.68 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ: 173.8, 167.4, 147.8, 142.8, 134.0, 133.6, 131.4 (2С), 127.8, 126.0, 123.9, 118.5 (2С), 116.0, 47.9, 39.2, 27.7, 24.6 (2С), 17.9. HRMS (ESI), calc. for C20H21N2O5S+ ([M + H]+): 401.1166; found m/z 401.1178.
4-((1-Benzoylindoline)-5-sulfonamido)benzoic acid(6d).Yield 60% (254 mg), white powder, mp 250–255 °С. 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 10.73 (s, 1H), 7.96 (br s, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.75–7.63 (m, 2H), 7.60–7.45 (m, 5H), 7.20 (d, J = 8.0 Hz, 2H), 4.01 (t, J = 8.6 Hz, 2H), 3.11 (t, J = 8.9 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ: 169.4, 167.8, 147.2, 143.0, 137.1, 134.9, 134.7, 131.3 (2C), 131.1, 129.2 (2C), 127.6 (2C), 126.5, 124.5, 124.2, 118.6 (2C), 116.7, 51.5, 28.0. HRMS (ESI), calc. for C22H19N2O5S+ ([M + H]+): 423.1009; found m/z 423.1006.
4-(Indoline-5-sulfonamido)benzoic acid(7).To the suspension of ester 6 (1 mmol) in 50% EtOH (5 mL) powdered NaOH (160 mg, 4 mmol) was added. The reaction mixture was refluxed for 18 h. The reaction mixture as filtered, cooled to 5–7 ᵒC, and acidified by conc. hydrochloric acid. The formed precipitate was collected by filtration and purified by recrystallization from ethanol or ethanol/DMF mixture to afford the desired product 7. Yield 55% (38 mg), beige powder, mp 227–229°С. 1H NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 10.43 (s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.40–7.37 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 8.2 Hz, 1H), 3.49(t, J = 8.7 Hz, 2H), 2.93 (t, J = 8.8 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ: 167.5, 157.3, 143.4, 131.3 (2C), 129.8, 129.0, 125.6, 125.4, 123.5, 118.0 (2C), 106.6, 46.9, 28.7. HRMS (ESI), calc. for C15H15N2O4S+ ([M + H]+): 319.0747; found m/z 319.0744.