Synthesis of 5,7-dibromo-6',7'-dihydroxy-3',4'-dihydro-2'H-spiro[indoline-3,1'-isoquinolin]-2-one (12c). Method A
The compound was synthesized via the phenolic Pictet–Spengler reaction reported by Ngo Hanna et al. [41]. To a solution of 5,7-dibromoisatin (1.5 g, 5.1 mmol) in absolute ethanol (10 ml) was added dopamine (1 g, 5.1 mmol) and triethylamine (1 ml). The reaction mixture was stirred and heated under reflux for 7–10 h, and subsequently concentrated under reduced pressure to remove the solvent. Distilled water was added to the resulting viscous mass and the product which precipitated out was extracted into ethyl acetate (3 × 30 ml). The combined organic extracts were dried over anhydrous sodium sulphate and concentrated to minimum volume. The crude product was further purified by column chromatography (hexane: ethyl acetate—60 : 40). The final product was recrystallized from absolute ethanol. Yield, 1.7 g, 76% (brown solid). M.p. 256–258 o C (HCl salt).
1 H NMR (CD3OD, 700 MHz): δ ppm 2.74 (dt, J = 16.1, 4.6 Hz, 1H, H4’a), 2.90 (ddd, J = 15.9, 5.4 Hz, 1H, H4’b), 3.10–3.15 (m, H3’a), 3.71–3.77 (m, H3’b), 5.91 (s, 1H, H8’), 6.62 (s, 1H, H5’), 7.27 (d, J = 1.8 Hz, 1H, H4), 7.64 (d, J = 1.8 Hz, 1H, H6). 13C NMR (CD3OD, 175 MHz): δ ppm 27.2 (C4’), 38.4 (C3’), 64.7 (C3/C1’), 102.8 (C7), 111.9 (C8’), 114.9 (C5), 115.4 (C5’), 123.5 (C8’a), 126.7 (C4), 127.3 (C4’a), 133.6 (C6), 138.7 (C3a), 140.9 (C7a), 143.8 (C7’), 145.0 (C6’), 180.1 (C2). FTMS + cESI: m/z 440.92 M+.
General method for the synthesis of 6-methoxy- & 6’,7’-dimethoxy-3’,4’-dihydro-2’ H -spiro[indoline-3,1’-isoquinolin]-2-ones (13l &14g - i). Method B.
A mixture of the appropriate isatin (1 equiv), methoxyphenethylamine (1.2 equiv) and polyphosphoric acid (2 g) was heated in an oil bath (bath temperature at 100°C), while stirring mechanically for 5 hours. Upon completion of the reaction, as revealed by TLC, the reaction mixture was allowed to cool to about 50°C and quenched by slow addition of water. To this mixture was added a saturated solution of sodium carbonate to adjust the pH to 11. The floating product obtained was extracted into ethyl acetate (3 × 30 ml). The combined organic extracts were dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain the crude product. The latter was purified by flash chromatography on silica gel using suitable solvent systems. Yields ranged between 60 and 98%.
6'-methoxy-5-methyl-3',4'-dihydro-2' H -spiro[indoline-3,1'-isoquinolin]-2-one (13l)
Method B. Prepared from 5-methylisatin (2.8 g, 17 mmol), 3-dimethoxyphenethylamine (2.6 g 17 mmol) and polyphosphoric acid (3 g). The crude product was purified by flash chromatography (hexane: ethyl acetate—80: 20). Yield, 4.6 g, 92% (brown solid), M.p. 208–209 oC.
1 H NMR (DMSO-d6, 600 MHz): δ ppm 1.46 (s, 3H, 5-CH3), 2.07–2.13 (m, 1H, H4’a), 2.23 (ddd, J = 16.5, 8.7, 5.3 Hz, 1H, H4’b), 2.39 (dt, J = 12.8, 5.2 Hz, 1H, H3’a), 2.96 (d, J = 5.1 Hz, 4H, H3’b, m, 4H, 7’-OCH3), 5.64 (d, J = 8.6 Hz, 1H, H8’), 5.80 (dd, J = 8.6, 2.7 Hz, 1H, H7’), 5.95 (d, J = 2.7 Hz, 1H, H5’), 6.07 (d, J = 7.87 Hz, 1H, H7), 6.14–6.17 (m, 1H, H4), 6.29 (ddd, J = 7.9, 1.7, 0.8 Hz, 1H, H6). 13C NMR (DMSO-d6, 150 MHz): δ ppm 18.9 (5-CH3), 27.6 (C4’), 37.5 (C3’), 53.4 (6’- OCH3), 62.9 (C3/C1’), 108.7 (C7), 111.8 (C7’), 112.6 (C5’), 124.3 (C4), 125.4 (C8’a), 126.4 (C8’), 128.3 (C6), 131.5 (C3a), 134.5 (C7a), 136.4 (C4’a), 138.4 (C5), 158.0 (C6’), 180.3 (C2). FTMS + cESI: m/z 295.14 [M + 1]+.
5,7-dibromo-6',7'-dimethoxy-1-(4-methylbenzyl)-3',4'-dihydro-2' H -spiro[indoline-3,1'-isoquinolin]-2-one (14g)
Method B. Prepared from 5,7-dibromo-1-(4-methylbenzyl)indoline-2,3-dione (1.8 g, 4.4 mmol), 3,4-dimethoxyphenethylamine (0.8 g, 4.4 mmol) and polyphosphoric acid (2 g). The crude product was purified by flash chromatography (hexane : ethyl acetate—60 : 40). Yield, 1.8 g, 71% (yellow oil), M.p. 239–240 oC (HCl salt).
1 H NMR (DMSO-d6, 600 MHz): δ ppm 1.93 (dt, J = 16.2, 4.3 Hz, 1H, H4’a), 2.11 (ddt, J = 15.3, 9.3, 4.9 Hz, 1H, H4’b), 2.27 (ddd, J = 12.7, 5.4, 4.0 Hz, 1H, H3’a), 2.58 (s, 3H, 7’-OCH3), 2.85–2.89 (m, 1H, H3’b), 2.92 (s, 3H, 6’-OCH3), 4.39 (d, J = 16.1 Hz, 1H, CH2-Ar ), 4.51 (d, J = 16.3 Hz, 1H, CH2-Ar ), 5.00 (s, 1H, H8’), 5.91 (s, 1H, H5’), 6.23 (d, J = 7.8 Hz, 2H, H3”, H5”), 6.30 (m, 2H, H2”, H6”), 6.40 (d, J = 2.0 Hz, 1H, H4), 6.77 (d, J = 1.9 Hz, 1H, H6). 13C NMR (DMSO-d6, 150 MHz): δ ppm 18.8 (4”-CH3), 28.6 (C4’), 37.5 (C3’), 43.0 (CH2-Ar ), 54.2 (7’-OCH3), 54.2 (6’-OCH3), 62.0 (C3/C1’), 101.9 (C7), 107.9 (C8’), 111.6 (C5’), 115.0 (C5), 123.8 (C8’a), 125.5 (C2”, C6”), 126.3 (C4), 128.1 (C3”, C5”), 128.3 (C4’a), 133.5 (C1”), 135.8 (C6), 136.0 (C3a), 138.5 (C4”), 139.0 (C7a), 147.1 (C7’), 148.3 (C6’), 178.3 (C2). FTMS + cESI: m/z 573.02 [M + 1]+.
1-(4-fluorobenzyl)-6',7'-dimethoxy-5-methyl-3',4'-dihydro-2' H -spiro[indoline-3,1'-isoquinolin]-2-one (14h)
Method B. Prepared from 5-methyl-1-(4-fluorobenzyl)indoline-2,3-dione (1 g, 3.7 mmol), 3,4 - dimethoxyphenethylamine (0.8 g, 4.4 mmol) and polyphosphoric acid (3 g). The crude product was purified by flash chromatography (hexane: ethyl acetate—60 : 40). Yield, 1.4 g, 90% (brown solid), M.p. 99–101 oC
1 H NMR (DMSO-d6, 600 MHz): δ ppm 2.19 (s, 3H, 5-CH3), 2.71 (dt, J = 15.9, 4.1 Hz, 1H, H4’a), 2.88 (ddd, J = 15.1, 9.3, 5.4 Hz, 1H, H4’b), 3.05 (ddd, J = 12.5, 5.4, 4.1 Hz, 1H, H3’a), 3.29(s, 3H, 7’-OCH3), 3.65 (ddd, J = 12.4, 9.3, 4.3 Hz, 1H, H3’b), 3.74 (s, 3H, 6’-OCH3), 4.76 (d, J = 15.6 Hz, 1H, CH2-Ar ), 4.96 (d, J = 15.6 Hz, 1H, CH2-Ar ), 5.72 (s, 1H, H8’), 6.76 (s, 1H, H5’), 6.92 (dd, J = 4.8, 3.1 Hz, 2H, H4, H7), 7.05 (ddd, J = 8.0, 1.8, 0.9 Hz, 1H, H6), 7.16–7.18 (m, H3”, H5”), 7.42 (dd, J = 8.6, 5.5 Hz, 2H, H2”, H6”). 13C NMR (DMSO-d6, 150 MHz): δ ppm 21.0 (5-CH3), 28.7 (C4’), 38.9 (C3’), 42.2 (CH2-Ar ), 55.8 (7’-OCH3), 56.0 (6’-OCH3), 63.6 (C3/C1’), 109.2 (C7), 109.4 (C8’), 113.0 (C5’), 115.8 (C3”, C5”), 125.5 (C4), 127.2 (C8’a), 129.3 (C6), 129.5 (C4’a), 129.9 (C2”, C6”), 132.2 (C3a), 133.5 (C1”), 135.5 (C5), 140.4 (C7a), 148.5 (C7’), 148.5 (C6’), 161.2 (C4”), 178.8 (C2). FTMS + cESI: m/z 433.19 [M + 1]+.
6',7'-dimethoxy-5-methyl-1-(4-methylbenzyl)-3',4'-dihydro-2' H -spiro[indoline-3,1'-isoquinolin]-2-one (14i)
Method B. Prepared from 5-methyl-1-(4-methylbenzyl)indoline-2,3-dione (1 g, 3.8 mmol), 3,4 - dimethoxyphenethylamine (0.82 g, 4.5 mmol) and polyphosphoric acid (2 g). The crude product was purified by flash chromatography (hexane: ethyl acetate—60 : 40). Yield, 0.9 g, 56% (brown solid), M.p. 111–112 oC
1 H NMR (DMSO-d6, 600 MHz): δ ppm 2.18 (s, 3H, 5-CH3), 2.26 (s, 3H, 4”-CH3), 2.70 (dt, J = 15.9, 4.2 Hz, 1H, H4’a), 2.87 (ddd, J = 15.2, 9.3, 5.4 Hz, 1H, H4’b), 3.04 (dt, J = 12.5, 4.9 Hz, 1H, H3’a), 3.29(s, 3H, 7’-OCH3), 3.64 (m, 1H, H3’b), 3.73 (s, 3H, 6’-OCH3), 4.69 (d, J = 15.5 Hz, 1H, CH2-Ar ), 4.95 (d, J = 15.5 Hz, 1H, CH2-Ar ), 5.73 (s, 1H, H8’), 6.75 (s, 1H, H5’), 6.86 (d, J = 8.0 Hz, 1H, H7), 6.90 (d, J = 1.8 Hz, 1H, H4), 7.03 (ddd, J = 8.0, 1.8, 0.9 Hz, 1H, H6), 7.13 (d, J = 7.7 Hz, 2H, H3”, H5”), 7.23–7.27 (m, 2H, H2”, H6”). 13C NMR (DMSO-d6, 150 MHz): δ ppm 21.0 (5-CH3), 21.1 (4”-CH3), 28.7 (C4’), 38.9 (C3’), 42.8 (CH2-Ar ), 55.7 (7’-OCH3), 55.9 (6’-OCH3), 63.5 (C3/C1’), 109.3 (C7), 109.4 (C8’), 112.9 (C5’), 125.4 (C4), 127.3 (C8’a), 127.9 (C2”, C6”), 129.3 (C6), 129.5 (C4’a), 129.6 (C3”, C5”), 132.1 (C3a), 134.2 (C1”), 135.6 (C5), 137.1 (C4”), 140.6 (C7a), 147.5 (C7’), 148.4 (C6’), 178.7 (C2). FTMS + cESI: m/z 429.21 [M + 1]+.