(5-Methoxy-2,3-dihydro-1 H-indol-1-yl)(5-methoxy-1 H-indol-2-yl)methanone (3)
A solution of 5-methoxyindoline (2) (0.94 g, 6.28 mmol) in dry CH2Cl2 (5 ml) was added to a stirred solution of 5-methoxyindole-2-carboxylic acid (1) (1.2 g, 6.28 mmol) and ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl) (1.80 g, 9.42 mmol) in dry CH2Cl2 (15 ml). The reaction mixture was stirred for 18 h at room temperature, extracted with 5 N hydrochloric acid (3 × 5 ml), washed with water (2 × 10 ml), and dried (Na2SO4). The organic layer was evaporated in vacuo, and the residue was recrystallized from isopropanol to yield 1.76 g (87%) of 3 (1.76 g, 87%) as a pale yellow powder mp 234–236°C. FTIR (ATR) ν = 3270, 2935, 1604, 1576, 1406, 797 cm-1. 1 H NMR (DMSO-d
6
): δ 3.26 (t, 2 H, J = 8.4 Hz, H-3′), 3.79 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.52 (t, 2 H, J = 8.4 Hz, H-2´), 6.83 (dd, 1 H, J = 8.8, 2.5 Hz, H-6), 6.93 (d, 1 H, J = 2.5 Hz, H-4′), 6.95-6.96 (m, 1 H, H-6′), 7.04 (s, 1 H, H-3), 7.15 (d, 1 H, J = 2.5 Hz, H-4), 7.43 (d, 1 H, J = 8.8 Hz, H-7), 8.14 (d, 1 H, J = 8.6 Hz, H-7′), 11.58 (br., 1 H, NH). 13 C NMR (DMSO-d
6): δ 28.4 (C-3′), 49.7 (C-2′), 55.3 (OCH3), 55.4 (OCH3), 102.1 (C-4), 104.9 (C-3), 110.7 (C-6′), 111.9 (C-6), 113.1 (C-7), 115.1 (C-4′), 117.6 (C-7′), 127.6, 131.2, 131.4, 133.9, 136.9 (ArC), 153.8, 156.1 (C-5, C-5′), 159.5 (O = C). MS (EI): m/z (%) = 322 (M+, 27), 174 (10), 149 (100), 134 (29). Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C, 70.41; H, 5.61; N, 8.75.
(5-Methoxy-1 H-indol-1-yl)(5-methoxy-1 H-indol-2-yl)methanone (4)
A mixture of 3 (0.20 g, 0.62 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (0.19 g, 0.68 mmol) was heated at reflux temperature in ethyl acetate (30 ml) for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform/methanol/ammonia, 10:1:0.1) to furnish 0.19 g (96%) of 4 as a light red powder mp 178–179°C and. FTIR (ATR) ν = 3290, 2937, 1625, 1517, 1026, 797 cm-1.1 H NMR (CDCl3): δ 3.85 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 6.63 (d, 1 H, J = 3.8 Hz, H-3′), 6.99 (dd, 1 H, J = 9.1, 2.5 Hz, H-6′), 7.03 (dd, 1 H, J = 8.8, 2.2 Hz,, 7.07 (d, 1 H, J = 2.2 Hz, H-4), 7.08-7.09 (m, 2 H, H-3, H-4′), 7.37 (d, 1 H, J = 8.8 Hz, H-7), 7.90 (d, 1 H, J = 3.8 Hz, H-2′), 8.37 (d, 1 H, J = 9.1 Hz, H-7′), 9.70 (br., 1 H, NH). 13 C NMR (CDCl3): δ 55.7 (2 x OCH3), 102.4 (C-4), 103.7 (C-3′), 108.9 (C-3), 109.6 (C-7), 113.0 (C-6′), 113.4 (C-6), 116.9 (C-7′), 117.7 (C-4′), 127.6 (C-2′), 127.8, 129.2, 130.8, 131.6, 132.5 (ArC), 154.9, 156.7 (C-5, C-5′), 160.8 (O = C). MS (EI): m/z (%) = 320 (M+, 70), 173 (53), 147 (100), 119 (29). Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.75. Found: C, 70.95; H, 5.08; N, 8.68.
5-Methoxy-1-[(5-methoxy-1 H-indol-2-yl)methyl]-1 H-indole (5)
Compound 4 (0.50 g, 156.03 mmol) was dissolved in dry THF (5 ml) and was added dropwise to a cooled (0°C) suspension of LiAlH4/AlCl3 in dry diethyl ether (prepared by a slow addition of AlCl3 (0.32 g, 2.41 mmol) to a suspension LiAlH4 (0.27 g, 7.13 mmol) in dry diethyl ether (15 ml) at 0°C. The resulting reaction mixture was stirred at 0°C for one hour and at room temperature for another one hour. The reaction was quenched by a slow addition of saturated sodium sulphate solution. The solids were removed by filtration, washed with chloroform (20 ml) and the combined organic phase was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol/ammonia, 10:1:0.1) to produce 0.4 g (83%) of 5 as a light red powder mp 173–174°C. FTIR (ATR) ν = 3384, 2956, 1622, 1485, 795 cm-1.1 H NMR (CDCl3): δ 3.83 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 5.26 (s, 2 H, CH2-N), 6.39 (s, 1 H, H-3) 6.49 (d, 1 H, J = 3.3 Hz, H-3′), 6.81 (dd, 1 H, J = 8.8, 2.3 Hz, H-6′), 6.86 (dd, 1 H, J = 8.8, 2.5 Hz, H-6), 7.01 (d, 1 H, J = 8.8 Hz, H-7′), 7.04-7.05 (m, 2 H, H-2′, H-4), 7.15 (d, 1 H, J = 2.3 Hz, H-4′), 7.20 (d, 1 H, J = 8.8 Hz, H-7), 7.74 (br., 1 H, NH). 13 C NMR (CDCl3): δ 44.0 (CH2-N), 55.8 (OCH3), 55.9 (OCH3), 101.3 (C-3), 101.6 (C-3′), 102.3 (C-4), 102.8 (C-4′), 110.1 (C-6′), 111.6 (C-6), 112.2, 112.3 (C-7, C-7′), 128.4, 128.5 (ArC), 129.2 (C-2′), 131.4, 131.6, 134.7 (ArC), 154.2 (C-5, C-5′). MS (EI): m/z (%) = 306 (M+, 35), 160 (100), 147 (23). Anal. Calcd for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.19; H, 5.95; N, 8.89.
2-{[5-Methoxy-3-(2-nitroethyl)-1 H-indol-1-yl]methyl}-5-methoxy-3-(2-nitroethyl)-1 H-indole (8)
A mixture of 5 (0.250 g, 0.82 mmol), 2-nitroethyl acetate (0.350 g, 2.63 mmol), and tert. butyl catechol (6 mg) in xylene (20 ml) was heated at reflux temperature for 18 h. The reaction mixture was evaporated under vacuum and the residue was purified by silica gel chromatography (chloroform/methanol, 9:0.5) to yield 0.17 g (46%) of 8 as brown viscous oil. FTIR (ATR) ν = 3421, 2965, 1548, 1212, 795 cm-1. 1 H NMR (CDCl3): δ 3.39 (t, 2 H, J = 7.1 Hz, CH
2-CH2-N), 3.44 (t, 2 H, J = 6.8 Hz, CH
2-CH2-N), 3.83 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 4.56 (t, 2 H, J = 6.8 Hz, CH2-CH
2-N), 4.61 (t, 2 H, J = 7.1 Hz, CH2-CH
2-N), 5.30 (s, 2 H, CH2-N), 6.81 (dd, 1 H, J = 8.8, 2.3 Hz, ArH), 6.86 (dd, 1 H, J = 8.8, 2.5 Hz, ArH), 6.88 (s, 1 H, H-2′), 6.80 (d, 1 H, J = 2.4 Hz, ArH), 6.98 (d, 1 H, J = 2.4 Hz, ArH), 7.09 (d, 1 H, J = 8.8 Hz, ArH), 7.14 (d, 1 H, J = 8.8 Hz, ArH), 7.66 (br., 1 H, NH). 13 C NMR (CDCl3): δ 22.6 (CH2-CH2-N), 23.5 (CH2-CH2-N), 42.0 (CH2-N), 55.9 (OCH3), 56.0 (OCH3), 74.9 (CH2-CH2-N), 75.7 (CH2-CH2-N), 100.0, 100.6, 110.4, 112.1, 112.6, 112.8 (ArCH), 126.7 (C-2′), 109.5 (C-3, C-3′), 128.9, 130.6, 131.9, 132.0, 133.4 (ArC), 154.5, 154.6 (C-5, C-5′). MS (EI): m/z (%) = 452 (M+, 17), 233 (58), 186 (100). Anal. Calcd for C23H24N4O6: C, 61.06; H, 5.35; N, 12.38. Found: C, 60.86; H, 5.24; N, 12.49.
N-{2-[1-({3-[2-(Acetylamino)ethyl]-5-methoxy-1 H-indol-2-yl}methyl)-5-methoxy-1 H-indol-3-yl]ethyl}acetamide (10)
A mixture of 8 (0.17 g, 0.38 mmol) and 10% Pd/C (70 mg) in absolute ethanol (10 ml) was hydrogenated under 4 mbar pressure in Parr shaker device at ambient temperature for 18 h. The reaction mixture was filtered off and the filtrate was evaporated under reduced pressure to furnish 0.15 g of 9 as pale yellow viscous oil. Crude 9 (0.15 g, 0.38 mmol) was acetylated using acetic anhydride (0.36 ml, 3.82 mmol) and triethylamine (0.38 ml, 2.66 mmol) in dry DCM (10 ml) at room temperature for 18 h. The solvent was evaporated under vacuum and the residue was purified by silica gel chromatography (chloroform/methanol/ammonia, 10:1:0.1) to yield 0.11 g (63%) of 10 as a beige powder mp 88–90°C and was FTIR (ATR) ν = 3286, 2924, 1635, 1216, 794 cm-1.1 H NMR (CDCl3): δ 1.76 (s, 3 H, CH3), 1.80 (s, 3 H, CH3), 2.84 (t, 2 H, J = 6.6 Hz, CH
2-CH2-N), 2.96 (t, 2 H, J = 6.8 Hz, CH
2-CH2-N), 3.39-3.44 (m, 2 H, CH2-CH
2-N), 3.48-3.53 (m, 2 H, CH2-CH
2-N), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 5.25 (s, 2 H, CH2-N), 5.74 (t, 1 H, J = 5.7 Hz, NH), 5.83 (t, 1 H, J = 5.6 Hz, NH), 6.78 (dd, 1 H, J = 8.8, 2.3 Hz, ArH), 6.81 (dd, 1 H, J = 8.8, 2.5 Hz, ArH), 6.87 (s, 1 H, H-2′), 6.99 (d, 2 H, J = 2.3 Hz, ArH), 7.11 (d, 1 H, J = 8.8 Hz, ArH), 7.14 (d, 1 H, J = 8.8 Hz, ArH), 8.24 (br., 1 H, NH). 13 C NMR (CDCl3): δ 23.1 (CH3), 23.2 (CH3), 24.3 (CH2-CH2-N), 25.3 (CH2-CH2-N), 39.8 (CH2-CH2-N), 40.2 (CH2-CH2-N), 41.9 (CH2-N), 55.9 (2 x OCH3), 100.5, 100.9, (ArCH), 110.1, 110.3 (C-3, C-3′), 111.9, 112.3, 112.4, 112.5 (ArCH), 126.2 (C-2′), 128.5, 128.8, 130.9, 131.4, 131.9 (ArC), 154.1, 154.2 (C-5, C-5′), 170.3 (O = C), 170.5 (O = C). MS (EI): m/z (%) = 476 (M+, 31), 417 (16), 245 (100), 203 (41), 186 (64). Anal. Calcd for C27H32N4O4: C, 68.05; H, 6.77; N, 11.76. Found: C, 68.37; H, 6.59; N, 11.66.