3.1. Chemistry
The melting point was determined on a XT4A microscope melting-point apparatus (Keyi Electron Optical Instrument Factory, Beijing, China) without correction.1H NMR and 13C NMR spectra were recorded on BRUKER AVANCE 300 and 600 spectrometers (Bruker Company, Rheinstetten, Germany), with TMS as an internal standard and CDCl3 as the solvent. ESI mass spectra were performed on an API-3000 LC-MS spectrometer (Applied Biosystems, Toronto, ON, Canada). Flash column chromatography was performed with silica gel 300–400 mesh (Qingdao Haiyang Chemical, Qingdao, China). All solvents and reagents were purchased from commercial suppliers and, when necessary, were purified and dried by standard protocols. Organic solutions were dried over anhydrous sodium sulfate. The purity of the final compounds was assessed with an Agilent 1200 HPLC (Agilent Technologies, Santa Clara, CA, USA), and the results were greater than 95%.
(Z)-3-(Pyridin-4-yl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (4a)
A mixture of 2-(3,4,5-trimethoxyphenyl)acetonitrile 3 (0.52 g, 2.5 mmol) and isonicotinaldehyde (0.54 g, 5.0 mmol) was dissolved in EtOH (10 mL) at 0 °C, and then NaOH (0.10 g, 2.5 mmol) was added to the solution mixture. After stirring for 30 min, the solution was filtrated and the residue was collected under suction filtration and dried to afford compound 4a (0.63 g, 85.04%) as a yellow green crystals. mp 134–135 °C. 1H NMR (300 MHz, CDCl3): δ 3.91 (s, 3H), 3.43 (s, 3H), 3.95 (s, 6H), 6.90 (s, 2H), 7.40 (s, 1H), 7.71 (dd, 2H, J = 1.5, 4.8 Hz), 8.75 (dd, 2H, J = 1.5, 4.5 Hz).
The synthetic methods for the intermediates 4b–d were similar to the synthesis of intermadiate 4a.
3-(Pyridin-4-yl)-2-(3,4,5-trimethoxyphenyl)propanenitrile (5a)
A mixture of 4a (0.62 g, 2.1 mmol), NaBH4 (0.32 g, 8.5 mmol) and 20 mL MeOH was heated under 50 °C for 0.5 h. The mixture was evaporated and the residue diluted with 25 mL EtOAc. The organic layer was dried and filtered and the solvent removed by evaporation. After the solution was cooled and stayed overnight to give the compound 5a (2.18 g, 86.21%) as a white crystals. mp 129–130 °C. 1H NMR (300 MHz, CDCl3): δ 3.10–3.24 (m, 2H), 3.82 (s, 6H), 3.85 (s, 3H), 3.99 (t, 1H), 6.40 (s, 2H), 7.09 (d, 2H, J = 4.5 Hz), 8.56 (d, 2H, J = 4.5 Hz).
The synthetic methods for the intermediates 5b–d were similar to the synthesis of intermadiate 5a.
3-(Pyridin-4-yl)-2-(3,4,5-trimethoxyphenyl)propan-1-amine (6a)
BF3·O(C2H5)2 (7.5 mmol) was slowly added to a stirred solution of 5a (0.76 g, 2.5 mmol) and NaBH4 (10 mmol) in THF (10 mL) at 0 °C. The solution was refluxed for 1 h, poured into water, and extracted with EtOAc (15 mL × 3). The combined extracts were dried over anhydrous Na2SO4 and filtered. The solvents were removed by evaporation to afford 6a (0.72 g, 96.61%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 2.96–2.79 (m, 5H), 3.81 (s, 6H), 3.83 (s, 3H), 6.32 (s, 2H), 6.98 (dd, 2H, J = 1.5, 4.5 Hz), 8.43 (dd, 2H, J = 1.5, 4.5 Hz).
The synthetic methods for the intermediates 6b–d were similar to the synthesis of intermadiate 6a.
3,4-Dimethoxy-N-(3-(pyridin-4-yl)-2-(3,4,5-trimethoxyphenyl)propyl)benzamide (7)
A mixture of 3,4-dimethoxybenzoic acid (2.1 mmol), EDC·HCl (0.54 g, 2.8 mmol), DMAP (0.03 g, 0.28 mmol) and CH2Cl2 (20 mL), was stirred at room temperature for 10 min, Then 6a (0.73 g, 2.4 mmol) dissolved in CH2Cl2 (10 mL) was added through a dropping funnel for about 5 min. After stirring for about 30 min, the mixture was washed by water (30 mL × 2) and saturated aqueous Na2CO3 (30 mL × 2). The organic layer was dried over anhydrous MgSO4 and filtered. Then the filtrate was concentrated by evaporation and 7 (0.59 g, 52.68%) was obtained as white powder. 1H NMR (300 MHz, CDCl3): δ 2.92–3.04 (m, 2H), 3.08–3.21 (m, 1H), 3.38–3.44 (m, 1H), 3.78 (s, 6H), 3.83 (s, 3H), 3.90 (s, 6H), 3.95–4.02 (m, 1H), 5.93–6.01 (m, 1H), 6.35 (s, 2H), 6.81–6.98 (m, 2H), 7.01–7.05 (m, 2H), 7.31 (s, 1H), 8.45 (dd, 2H, J = 1.5, 4.2 Hz).
The synthetic methods for the intermediates 8–19 were similar to the synthesis of intermadiate 7.
1-(3,4-Dimethoxyphenyl)-6,7,8-trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline (20)
A mixture of 7 (0.70 g, 1.5 mmol), POCl3 (0.82 mL, 9 mmol) and CH3CN (15 mL) was stirred and heated under reflux for 4 h, then the solvents were removed by evaporation, and the residue was dissolved in EtOAc (30 mL). Then the solution was neutralied to pH = 7 with saturated aqueous Na2CO3 and washed by water (30 mL × 3). The organic layer was dried over anhydrous MgSO4 and filtered. Then the filtrate was concentrated under reduced pressure, The residue after evaporation was purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH = 100:1 v/v) and crystallized from EtOAc to give 20 (0.13 g, 19.3%) as white powder. mp 121–122 °C. 1H NMR (300 MHz, CDCl3): δ 2.77–2.80 (m, 3H), 3.43 (s, 3H), 3.47 (dd, 1H, J = 4.8, 14.7 Hz), 3.76 (s, 3H), 3.80 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.04 (dd, 1H, J = 3.0, 14.4 Hz), 6.20 (s, 1H), 6.88 (d, 1H, J = 8.4 Hz), 7.02 (dd, 1H, J = 1.8, 5.1 Hz), 7.07 (dd, 2H, J = 1.5, 4.5 Hz), 7.17 (d, 1H, J = 1.8 Hz), 8.51 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 449.3 [M + 1]+.
The synthetic methods for the compounds 21–32 were similar to the synthesis of compound 20.
2-Methoxy-5-(6,7,8-trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1-yl)aniline (21)
Yellow crystal. mp 109–110 °C. 1H NMR (300 MHz, CDCl3): δ 2.74–2.84 (m, 3H), 3.40–3.46 (m, 4H), 3.75 (s, 3H), 3.79 (s, 3H), 3.82 (s, 2H, N–H), 3.89 (s, 3H), 4.03 (dd, 1H, J = 2.4, 14.7 Hz), 6.18 (s, 1H), 6.79 (d, 1H, J = 8.1 Hz), 6.86 (dd, 1H, J = 1.8, 8.1 Hz), 6.97 (d, 1H, J = 1.8 Hz), 7.06 (dd, 2H, J = 1.5, 4.5 Hz), 8.50 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 434.3 [M + 1]+.
N-(2-Methoxy-5-(6,7,8-trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1-yl)phenyl)acetamide (22)
White powder, mp 173–176 °C. 1H NMR (300 MHz, CDCl3): δ 2.18 (s, 3H), 2.75–2.86 (m, 3H), 3.44 (s, 3H), 3.45 (dd, 1H, J = 4.2, 15.0 Hz), 3.76 (s, 3H), 3.80 (s, 3H), 3.94 (s, 3H), 4.04 (dd, 1H, J = 2.4, 15.0 Hz), 6.20 (s, 1H), 6.93 (d, 1H, J = 8.4 Hz), 7.08 (dd, 2H, J = 1.2, 4.5 Hz), 7.32 (d, 1H, J = 9.0 Hz), 7.77 (s, 1H), 8.48 (s, 1H), 8.49 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 476.3 [M + 1]+.
6,7,8-Trimethoxy-1-(4-methoxyphenyl)-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline (23)
White powder, mp 118–119 °C. 1H NMR (300 MHz, CDCl3): δ 2.75–2.87 (m, 3H), 3.40 (s, 3H), 3.47 (dd, 1H, J = 4.5, 14.7 Hz), 3.75 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H), 4.05 (dd, 1H, J = 2.7, 15.0 Hz), 6.19 (s, 1H), 6.90–6.95 (m, 2H), 7.06 (dd, 2H, J = 1.5, 4.2 Hz), 7.45–7.50 (m, 2H), 8.50 (dd, 2H, J = 1.5, 4.2 Hz). ESI-MS (m/z): 419.3 [M + 1]+.
4-(6,7,8-Trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1-yl)phenol (24)
White crystal, mp 140–141 °C. 1H NMR (300 MHz, CDCl3): δ 3.75–3.90 (m, 3H), 3.38 (s, 3H), 3.36 (dd, 1H, J = 4.8, 15.0 Hz), 3.77 (s, 6H), 4.01 (dd, 1H, J = 2.4, 14.7 Hz), 6.24 (s, 1H), 6.65 (d, 2H, J = 8.7 Hz), 7.06 (dd, 2H, J = 1.2, 4.5 Hz), 7.30 (d, 2H, J = 8.4 Hz), 8.46 (dd, 2H, J = 1.2, 4.5 Hz). ESI-MS (m/z): 405.2 [M + 1]+.
4-(6,7,8-Trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1-yl)phenyl acetate (25)
White powder, mp 119–120 °C. 1H NMR (300 MHz, CDCl3): δ 2.32 (s,3H), 2.75–2.89 (m, 3H), 3.40 (s, 3H), 3.48 (dd, 1H, J = 4.5, 15.0 Hz), 3.76 (s, 3H), 3.79 (s, 3H), 4.07 (dd, 1H, J = 2.7, 15.0 Hz), 6.21 (s, 1H), 7.07 (dd, 2H, J = 1.5, 4.5 Hz), 7.11–7.16 (m, 2H), 7.49–7.53 (m, 2H), 8.51 (dd, 2H, J = 1.8, 4.5 Hz). ESI-MS (m/z): 447.2 [M + 1]+.
1-(4-Fluorophenyl)-6,7,8-trimethoxy-4-(pyridin-4-ylmethyl)-3,4-dihydroisoquinoline (26)
White powder, mp 91–92 °C. 1H NMR (300 MHz, CDCl3): δ 2.75–2.90 (m, 3H), 3.39 (s, 3H), 3.48 (dd, 1H, J = 4.8, 15.0 Hz), 3.76 (s, 3H), 3.80 (s, 3H), 4.06 (dd, 1H, J = 3.0, 15.0 Hz), 6.20 (s, 1H), 7.05–7.12 (m, 4H), 7.46–7.53 (m, 2H), 8.51 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 407.2 [M + 1]+.
6,7,8-Trimethoxy-4-(pyridin-4-ylmethyl)-1-p-tolyl-3,4-dihydroisoquinoline (27)
Yellow crystal, mp 142–143 °C. 1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 2.74–2.89 (m, 3H), 3.38 (s, 3H), 3.47 (dd, 1H, J = 4.5, 14.7 Hz), 3.75 (s, 3H), 3.79 (s, 3H), 4.05 (dd, 1H, J = 2.7, 15.0 Hz), 6.19 (s, 1H), 7.06 (dd, 2H, J = 1.5, 4.5 Hz), 7.19–7.22 (m, 2H), 7.39–7.42 (m, 2H), 8.50 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 403.2 [M + 1]+.
6,7,8-Trimethoxy-4-(pyridin-4-ylmethyl)-1-m-tolyl-3,4-dihydroisoquinoline (28)
White powder, mp 138–139 °C. 1H NMR (300 MHz, CDCl3): δ 2.40 (s, 3H), 2.76–2.86 (m, 3H), 3.39 (s, 3H), 3.47 (dd, 1H, J = 4.5, 15.0 Hz), 3.76 (s, 3H), 3.78 (s, 3H), 4.07 (dd, 1H, J = 2.4, 14.7 Hz), 6.19 (s, 1H), 7.07 (dd, 2H, J = 1.5, 4.5 Hz), 7.19–7.31 (m, 3H), 7.33 (s, 1H), 8.50 (dd, 2H, J = 1.5, 4.5 Hz). ESI-MS (m/z): 403.3 [M + 1]+.
5-(4-Benzyl-6,7,8-trimethoxy-3,4-dihydroisoquinolin-1-yl)-2-methoxyaniline (29)
White powder, mp 96–97 °C. 1H NMR (300 MHz, CDCl3): δ 2.73–2.84 (m, 3H,), 3.44 (dd, 1H, J = 4.5, 14.4 Hz), 3.45 (s, 3H), 3.73 (s, 3H), 3.76–3.85 (m, 2H, N–H), 3.79 (s, 3H), 3.89 (s, 3H), 4.03 (dd, 1H, J = 2.4, 14.7 Hz), 6.18 (s, 1H), 6.79 (d, 1H, J = 8.4 Hz), 6.87 (dd, 1H, J = 2.1, 8.1 Hz), 6.99 (d, 1H, J = 2.1 Hz), 7.10–7.15 (m, 2H), 7.17–7.22 (m, 1H), 7.24–7.30 (m, 2H). ESI-MS (m/z): 433.3 [M + 1]+.
4-(6,7,8-Trimethoxy-4-(3-nitrobenzyl)-3,4-dihydroisoquinolin-1-yl)phenol (30)
Yellow powder, mp 201–203 °C. 1H NMR (300 MHz, CDCl3): δ 2.84–2.91 (m, 3H), 3.38 (s, 3H), 3.42–3.46 (m, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 3.99 (d, 1H, J = 14.5 Hz), 6.32 (s, 1H), 6.60 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.5 Hz), 7.36–7.41 (m, 2H), 8.05–8.06 (m, 2H). IR (KBr, cm−1) ν: 2940.81, 2839.79, 1593.73, 1523.77, 1351.70, 1317.11, 1247.45, 1127.89, 837.23. 13C NMR (500 MHz, CDCl3): δ 37.36, 39.66, 49.27, 56.07, 60.95, 61.47, 106.05, 115.18, 121.42, 123.78, 128.69, 129.28, 131.91, 136.03, 139.03, 141.47, 141.61, 148.34, 152.98, 155.99, 158.36, 166.59. ESI-MS (m/z): 449.2 [M + 1]+.
1-(2,4-Difluorophenyl)-6,7,8-trimethoxy-4-(3-nitrobenzyl)-3,4-dihydroisoquinoline (31)
White powder, mp 112–113 °C. 1H NMR (300 MHz, CDCl3): δ 2.85–2.96 (m, 3H), 3.43 (s, 3H), 3.52 (dd, 1H, J = 4.2, 15.0 Hz), 3.73 (s, 3H), 3.78 (s, 3H), 4.14 (d, 1H, J = 14.4 Hz), 6.14 (s, 1H), 6.80–6.87 (m, 1H), 6.94–7.00 (m, 1H), 7.35–7.45 (m, 2H), 7.53 (d, 1H, J = 7.2 Hz), 8.02–8.10 (m, 2H). ESI-MS (m/z): 469.2 [M + 1]+.
1-(2,4-Difluorophenyl)-6,7,8-trimethoxy-4-(4-nitrobenzyl)-3,4-dihydroisoquinoline (32)
Yellow crystal, mp 215–216 °C. 1H NMR (300 MHz, CDCl3): δ 2.85–2.96 (m, 3H), 3.43 (s, 3H), 3.52 (dd, 1H, J = 4.2, 15.3 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 4.09–4.16 (m, 1H), 6.10 (s, 1H), 6.80–6.87 (m, 1H), 6.94–7.00 (m, 1H), 7.24–7.27 (m, 2H), 7.53 (dd, 1H, J = 8.1, 14.7 Hz), 8.14 (d, 2H, J = 8.7 Hz). ESI-MS (m/z): 469.2 [M + 1]+.