All starting materials and reagents were commercially available and used without further purification, unless otherwise stated. All reactions were monitored by thin-layer chromatography (TLC) on a silica gel GF254 (0.25 mm, Qingdao Ocean Chemical, Ltd., China). The melting points of synthesized compounds were recorded on melting point appar-atus. The 1H NMR and 13C NMR spectra were run on a Bruker spectrophotometer at 500 MHz and 125 MHz or 400MHz and 101MHz in DMSO-d6and CDCl3 using tetramethylsilane (TMS) as an internal standard respectively. Column chromatography (CC) was performed on a silica gel 60 (230 − 400 mesh, Qingdao Ocean Chemical, Ltd., China).
General procedure for the synthesis of 3a-3d:
(E)-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid (3a).
Dissolve 3,4,5-trimethoxyphenylacetic acid and p-methoxybenzaldehyde (44.2mmol) in 15mL acetic anhydride (44.2mmol), add 15mL triethylamine, refluxe the mixture at 140 ℃ for 6h, monitor the complete reaction of raw materials by TLC, wait for the reaction solution to cool to room temperature, pour the reaction solution into ice water bath, adjust it to acid with hydrochloric acid, stir for 2h, precipitate yellow solid, filter. Dissolve in 10% sodium hydroxide solution, wash with ethyl acetate, separate the organic layer and retain the aqueous phase. Adjust the aqueous phase to PH 3 ~ 4 with 2mL dilute hydrochloric acid. The solid was precipitated, filtered and recrystallized with ethyl acetate to obtain compound (3a) as yellow solid, yield: 78%. 1H NMR (400 MHz, Chloroform-d) δ 7.07 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 6.55 (s, 2H), 3.85 (s, 9H), 3.79 (s, 3H), 3.34 (dd, J = 13.7, 8.7 Hz, 1H), 2.99 (dd, J = 13.8, 6.7 Hz, 1H).13C NMR (101 MHz, Chloroform-d) δ 178.74, 158.28, 153.29, 137.46, 133.86, 130.81, 129.95, 113.86, 105.26, 60.90, 56.20, 55.27, 54.02, 38.64.
(E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) acrylic acid (3b).
Yellow solid, yield: 66%.1H NMR (501 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.62 (s, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.73–6.62 (m, 1H), 6.59–6.54 (m, 1H), 6.47 (s, 2H), 3.72 (d, J = 16.2 Hz, 12H).13C NMR (126 MHz, DMSO-d6) δ 169.10, 153.59, 149.38, 146.35, 139.64, 137.49, 132.65, 130.83, 127.56, 123.56, 117.61, 111.94, 107.24, 60.59, 56.38 (d, J = 3.5 Hz), 55.89.
(E)-2-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl) acrylic acid. (3c)
Yellow solid, yield: 78%. 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.40 (s, 2H), 3.85 (s, 6H), 3.61 (s, 6H).13C NMR (101 MHz, Chloroform-d) δ 173.29, 159.46, 152.69, 142.16, 139.24, 131.26, 130.47, 129.74, 127.82, 114.41, 108.36, 60.93, 55.74, 55.42.
(E)-2-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl) acrylic acid. (3d)
Yellow solid, yield: 73%. 1H NMR (500 MHz, DMSO-d6) δ 7.64 (s, 1H), 6.99 (d, J = 7.7 Hz, 2H), 6.82 (d, J = 7.8 Hz, 2H), 6.44 (s, 2H), 3.62 (s, 3H), 3.50 (s, 6H), 2.50 (s, 1H).13C NMR (126 MHz, DMSO-d6) δ 169.32, 157.41, 152.70, 139.06, 138.50, 132.97, 131.22, 130.50, 127.34, 115.87, 108.42, 60.43, 55.73.
(E)-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethyl acrylate. (4a)
Dissolve 3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) acrylic acid (14.52mmol) in dry ethanol, add p-toluenesulfonic acid (2.90mmol), the reaction mixture was stired at 90 ℃ for 12h, wait for the reaction solution to cool to room temperature, add ethyl acetate for extraction, dry with anhydrous sodium sulfate. The solvent was removed by filtration and evaporation under reduced pressure. Column chromatography was performed on silica gel (dichloromethane: methanol = 20:1) to obtain white solid with a yield of 62%. 1H NMR (501 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 6.34 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 1.0 Hz, 6H), 3.57 (s, 6H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.99, 159.24, 152.61, 139.80, 138.74, 131.63, 131.18, 130.11, 128.38, 114.22, 108.02, 61.14, 60.85, 55.67, 55.35, 14.34.
(E)-3-(3-hydroxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethyl acrylate. (4b)
Slight yellow solid,yield: 66%. 1H NMR (501 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.63 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.65 (dd, J = 8.4, 2.1 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 6.48 (s, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.74 (d, J = 3.4 Hz, 6H), 3.69 (s, 6H), 1.23 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 167.47, 153.59, 149.53, 146.38, 140.00, 137.61, 131.93, 130.05, 127.32, 123.70, 117.60, 111.90, 107.35, 60.96, 60.57 (d, J = 3.3 Hz), 56.34 (d, J = 3.2 Hz), 55.87 (d, J = 3.6 Hz), 14.63.
ethyl (E)-2-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl) acrylate. (4c)
White solid, yield: 86%. 1H NMR (501 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.02–6.85 (m, 2H), 6.36 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.83 (d, J = 1.4 Hz, 6H), 3.59 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 167.98, 159.23, 152.60, 139.78, 138.74, 131.62, 131.17, 130.09, 128.37, 114.21, 108.03, 61.13, 60.84, 55.67, 55.34, 14.33.
(E) Ethyl 2-(4-hydroxyphenyl)-3-(3,4,5-trimethoxyphenyl) acrylate. (4d)
White solid, yield: 84%. 1H NMR (501 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.07 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.36 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 3.57 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 168.72, 156.12, 152.47, 140.09, 138.42, 131.61, 131.13, 130.20, 127.42, 115.90, 108.03, 61.51, 60.89, 55.66, 14.31.
Ethyl (E)-2-(4-(3-(dimethylamino)propoxy)phenyl)-3-(3,4,5-trimethoxyphenyl) acrylate. (5)
A solution of compound 3 (11.16mmol) in acetone (40mL) was added K2CO3 (44.64mmol), the reaction mixture was stirred at room temperature for 0.5h, then N, N-dimethylchlorpropylamine (1.49g,11.28mmol) was added, and the reaction was refluxed for 5h. The completion of the reaction was monitored by TLC. Then it was concentrated, 50 mL of water was poured into the reaction solution and the pH was adjusted to 4–5 by acetic acid. The mixture was extracted with EA (40 mL×3), and the organic phases were combined and dried with anhydrous Na2SO4. After filtering to remove Na2SO4, the filtrate was evaporated to yield a solid product,. which was recrystallized with EtOH to obtain white solid, yield: 80%. 1H NMR (400 MHz, Chloroform-d) δ 7.71 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.3 Hz, 2H), 6.34 (s, 2H), 4.26 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.81 (s, 3H), 3.58 (s, 6H), 2.52 (t, J = 7.3 Hz, 2H), 2.31 (s, 6H), 2.00 (p, J = 6.6 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, Chloroform-d) δ 167.96, 158.58, 152.53, 139.75, 138.56, 131.59, 131.12, 130.09, 128.24, 114.73, 107.90, 66.10, 61.12, 60.83, 56.24, 55.62, 45.31, 27.25, 14.33. HR-MS(ESI): Calculated for C25H33NO6 [M + H]+: 444.2386, found: 444.2381.
4-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. (6a)
To a solution of 4a and 5 (5.37mmol) in n-butanol, was added hydrazine hydrate (26.85mmol). The reaction mixture was stirred at 125 ℃ for 48h, evaporate under reduced pressure to remove most of the solvent, add 40ml of water, extract with ethyl acetate, dry with anhydrous sodium sulfate, filter, Evaporate the solvent under reduced pressure and perform column chromatography on silica gel (dichloromethane: methanol = 12:1) to obtain brown solid. Recrystallize (dichloromethane: methanol = 10:1) to obtain 0.23g white solid with a yield of 12%. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.72 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H).13C NMR (101 MHz, DMSO-d6) δ 159.75, 158.08, 153.31, 139.50, 137.70, 131.11, 126.39, 125.43, 114.12, 104.98, 102.96, 60.55, 56.11, 55.50. HR-MS(ESI): Calculated for C19H20N2O5 [M + H]+: 357.1445, found: 357.1441.
5-(3-hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. (6b)
White solid, yield: 11%. 1H NMR (400 MHz, DMSO-d6) δ 6.97 (d, J = 8.3 Hz, 1H), 6.90–6.82 (m, 2H), 6.62 (s, 2H), 3.79 (s, 3H), 3.67 (s, 3H), 3.63 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 159.52, 152.95, 148.32, 146.88, 140.36, 135.97, 128.98, 123.88, 119.59, 115.70, 112.65, 106.55, 102.52, 60.54, 56.12, 56.06. HR-MS(ESI): Calculated for C19H20N2O6 [M + H]+: 373.1394, found: 373.1396.
5-(4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. (6c)
White solid, yield: 11%. 1H NMR (501 MHz, DMSO-d6) δ 7.35 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.58 (s, 2H), 3.77 (s, 3H), 3.66 (s, 3H), 3.61 (s,6H).13C NMR (126 MHz, DMSO-d6) δ 159.67, 152.96, 140.09, 136.10, 129.63, 128.92, 123.53, 114.44, 106.69, 102.68, 60.51, 60.48, 56.06, 55.67. HR-MS(ESI): Calculated for C19H20N2O6 [M + H]+: 357.1445, found: 357.1448.
4-(4-(3-(dimethylamino)propoxy)phenyl)-5-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3H-pyrazol-3-one. (6d)
White solid, yield: 9%. 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz,2H), 6.70 (s, 2H), 3.99 (t, J = 6.2 Hz, 2H), 3.69 (s, 3H), 3.64 (s, 6H), 2.37 (t, J = 7.0 Hz, 2H), 2.16 (s, 6H), 1.85 (t, J = 6.8 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 157.33, 153.25, 137.61, 131.03, 128.26, 125.68, 114.67, 106.52, 105.03, 66.27, 60.57, 57.43, 56.16 (d, J = 6.1 Hz), 46.18, 45.66, 27.41, 11.97.HR-MS(ESI): Calculated for C23H29N3O5 [M + H]+: 428.2186, found: 428.2180.
3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) propionic acid. (7a)
Dissolve (E)-3-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)acrylic acid (13.87mmol) in THF, add palladium carbon (0.75g), replace with hydrogen for 3 times, and stir for 6 h at 40 ℃. The reaction was monitored by TLC, after completion of reaction, filtered and evaporate the solvent, and perform column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1) to obtain white solid, yield: 96%.1H NMR (501 MHz, Chloroform-d) δ 7.02 (d, J = 8.1 Hz, 2H), 6.74 (d, J = 8.1 Hz, 2H), 6.52 (s, 2H), 3.80 (s, 3H), 3.77 (s, 6H), 3.74 (s, 3H), 3.72–3.66 (m, 1H), 3.28 (dd, J = 13.9, 8.6 Hz, 1H), 2.93 (dd, J = 13.9, 6.7 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ 178.59, 158.13, 153.12, 137.15, 134.49, 129.89, 113.72, 105.13, 60.85, 56.09, 55.20, 54.49, 38.69.
3-(3-acetoxy-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) propionic acid. (7b)
White solid, yield: 93%. 1H NMR (501 MHz, Chloroform-d) δ 6.91 (dd, J = 8.4, 2.1 Hz, 1H), 6.83–6.78 (m, 2H), 6.49 (s, 2H), 3.81 (s, 4H), 3.80 (s, 6H), 3.76 (s, 3H), 3.71 (t, J = 7.6 Hz, 1H), 3.29 (dd, J = 14.0, 8.2 Hz, 1H), 2.93 (dd, J = 13.8, 7.1 Hz, 1H), 2.27 (s, 3H), 2.04 (s, 1H). 13C NMR (126 MHz, Chloroform-d) δ 178.19, 169.21, 153.23, 149.66, 139.41, 137.31, 133.60, 131.27, 127.26, 123.29, 112.25, 105.09, 60.81, 58.17–54.23 (m), 53.64, 38.50, 20.64.
2-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl) propionic acid. (7c)
White solid, yield: 94%. 1H NMR (501 MHz, Chloroform-d) δ 7.22 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 6.28 (s, 2H), 3.79 (d, J = 4.3 Hz, 6H), 3.76 (s, 1H), 3.72 (s, 6H), 3.30 (dd, J = 13.7, 8.1 Hz, 1H), 2.94 (dd, J = 13.8, 7.2 Hz, 1H). 13C NMR (126 MHz, Chloroform-d) δ 179.63, 159.11, 152.95, 136.42, 134.46, 129.92, 129.20, 114.11, 105.87, 60.84, 55.95, 55.31, 52.65, 39.70.
Tert butyl (2-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl) ethyl) carbamate. (8a)
To the suspension of 7a (8.66mmol) in anhydrous tert butyl alcohol, triethylamine (9.53mmol) and DPPA (9.53mmol) was added to result in a solution, it was stirred at 85 ℃ for 10 h, the reaction was monitored by TLC. The solution was then cooled to room temperature, saturated sodium carbonate solution was added to quench the reaction, Add ethyl acetate for extraction, evaporate the solvent under reduced pressure, and perform column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1) to obtain white solid, yield: 74%. 1H NMR (400 MHz, Chloroform-d) δ 6.98 (d, J = 8.1 Hz, 2H), 6.80 (d, J = 8.2 Hz, 2H), 6.38 (s, 2H), 4.99–4.88 (m, 1H), 3.84 (s, 3H), 3.80 (s, 6H), 3.78 (s, 3H), 2.98 (d, J = 6.8 Hz, 2H), 1.41 (s, 9H).13C NMR (101 MHz, Chloroform-d) δ 158.39, 155.23, 153.18, 138.30, 138.13, 136.96, 130.48, 129.34, 113.77, 103.41, 79.66, 77.36, 60.87, 56.10, 55.28, 42.51, 28.39. HR-MS(ESI): Calculated for C23H31NO6 [M + Na]+: 440.2044, found: 440.2049.
5-(2-((TERT butoxycarbonyl) amino)-2-(3,4,5-trimethoxyphenyl) ethyl)-2-methoxyphenyl acetate. (8b)
white solid, yield: 77%. 1H NMR (501 MHz, Chloroform-d) δ 6.83 (s, 2H), 6.72 (s, 1H), 6.35 (s, 2H), 5.28 (s, 1H), 3.81 (s, 3H), 3.78 (s, 9H), 3.08–2.85 (m, 2H), 2.27 (s, 3H), 1.40 (s, 9H).13C NMR (126 MHz, Chloroform-d) δ 168.82, 155.13, 153.20, 149.85, 139.55, 137.15, 129.93, 127.66, 123.74, 112.22, 103.51, 79.67, 60.74, 56.10 (d, J = 5.0 Hz), 55.93 (d, J = 4.8 Hz), 42.32, 28.32, 20.57. HR-MS(ESI): Calculated for C25H33NO8 [M + Na]+: 498.2098, found: 498.2096.
Tert butyl (1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethyl) carbamate. (8c)
white solid, yield: 77%. 1H NMR (501 MHz, Chloroform-d) δ 7.14 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 6.25 (s, 2H), 3.70 (s, 3H), 3.67 (d, J = 6.6 Hz, 9H), 3.57 (dd, J = 9.1, 6.5 Hz, 1H), 3.17 (dd, J = 13.6, 9.1 Hz, 1H), 2.78 (dd, J = 13.7, 6.5 Hz, 1H), 1.23 (s, 9H). 13C NMR (126 MHz, Chloroform-d) δ 172.88, 158.69, 152.84, 136.21, 135.21, 131.26, 128.85, 113.84, 105.85, 80.60, 60.74, 55.85, 55.10, 53.64, 40.36, 27.88. HR-MS(ESI): Calculated for C23H31NO6 [M + Na]+: 440.2047, found: 440.2044.
2-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl) ethane-1-amine. (9a)
To a solution of 8a (1.2mmol) in DCM, was added TFA (4.79mmol) slowly at ambient temperature, stir it at room temperature for 5 h. The reaction was monitored by TLC (DCM:MeOH: 20:1) after completion of reaction, 15% aqueous solution of NaOH was used to alkaline the mixture to pH 7–8, the ethyl acetate was added, the organic layer was separated, and aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried with Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica (dichloromethane: methanol = 12:1), to obtain light yellow oil, yield: 80%. 1H NMR (501 MHz, Chloroform-d) δ 7.09 (d, J = 7.0 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 6.57 (s, 2H), 4.09 (s, 1H), 3.84 (s, 9H), 3.78 (s, 3H), 2.91 (d, J = 11.2 Hz, 1H), 2.78–2.69 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 158.27, 153.12, 141.40, 136.83, 130.93, 130.29, 113.83, 103.31, 60.85, 57.89, 56.11, 55.26, 45.62. HR-MS(ESI): Calculated for C18H23NO4 [M + H]+: 318.1700, found: 318.1700.
5-(2-amino-2-(3,4,5-trimethoxyphenyl) ethyl)-2-methoxyphenol. (9b)
Light yellow oil, yield: 50%. 1H NMR (501 MHz, Chloroform-d) δ 6.89–6.73 (m, 2H), 6.64 (d, J = 21.7 Hz, 3H), 4.17–4.00 (m, 1H), 3.84 (d, J = 6.9 Hz, 12H), 3.04–2.83 (m, 1H), 2.80–2.58 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 153.16, 145.87, 145.63, 141.04, 136.92, 132.02, 120.70, 115.69, 110.89, 103.43, 60.85, 57.79, 56.15, 55.97, 45.59. HR-MS(ESI): Calculated for C18H23NO5 [M + H]+: 334.1649, found: 334.1654.
1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethane-1-amine. (9c)
Light yellow oil, yield: 60%. 1H NMR (501 MHz, Chloroform-d) δ 7.19–7.02 (m, 2H), 6.89–6.77 (m, 2H), 6.24 (d, J = 2.1 Hz, 2H), 3.79 (d, J = 2.1 Hz, 3H), 3.77 (d, J = 2.0 Hz, 3H), 3.74 (d, J = 2.1 Hz, 6H), 3.05–2.89 (m, 2H), 2.85–2.67 (m, 1H). 13C NMR (126 MHz, Chloroform-d) δ 158.76, 153.10, 137.67, 136.54, 134.85, 127.57, 113.79, 106.30, 60.85, 56.90, 56.07, 55.31, 46.91. HR-MS(ESI): Calculated for C18H23NO4 [2M]+: 635.3327, found: 635.3322.
6,7,8-trimethoxy-3-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline. (10)
To a solution of compound 9 (0.63mmol), 37% formaldehyde (1.89mmol) and formic acid (3.78mmol) was added, the reaction was heated to 80 ℃ and stirred 8 h, The excess of solvent was evaporated under reduced pressure. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1; 1), and oil was obtained with a yield of 62%. 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.38 (s, 1H), 4.06 (d, J = 15.8 Hz, 1H), 3.98–3.70 (m, 12H), 3.35 (d, J = 15.7 Hz, 1H), 3.29 (dd, J = 10.3, 4.1 Hz, 1H), 3.05 (dd, J = 16.7, 10.1 Hz, 1H), 2.85 (dd, J = 16.8, 4.1 Hz, 1H), 2.16 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.95, 152.07, 149.79, 140.06, 134.70, 130.14, 128.94, 120.66, 113.90, 106.70, 65.49, 60.84, 60.49, 55.94, 55.18, 53.72, 43.44, 38.44. HR-MS(ESI): Calculated for C20H25NO4 [M + H]+:344.185635, found:344.186007.
1-(4-methoxyphenyl)-N-methyl-2-(3,4,5-trimethoxy-2-methylphenyl)ethan-1-amine. (11).
The reaction flask was evacuated and flushed with N2 prior to addition of Pd/C. Tetrahydrofuran was added to the flask followed by a solution of substrate (0.58mmol). The reaction flask was evacuated and backfilled with N2 (×2) prior to evacuation and introduction of a H2 balloon (×2). After stirring overnight, the reaction mixture filtered through a bed of Celite. The Celite was washed with ethyl acetate, and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (Dichloromethane: methanol = 12:1) to afford the desired compound 11 as colorless oil, yield: 69%. 1H NMR (400 MHz, Chloroform-d) δ 7.06 (d, J = 7.4 Hz, 2H), 6.81 (d, J = 7.3 Hz, 2H), 6.43 (s, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H), 3.70 (s, 3H), 2.97–2.86 (m, 2H), 2.85–2.76 (m, 2H), 2.43 (s, 1H). 13C NMR (101 MHz, Chloroform-d) δ 158.03, 152.93, 152.54, 140.07, 136.79, 133.51, 129.51, 121.31, 113.85, 108.55, 61.26, 60.85, 55.94, 55.34, 45.84, 37.16, 35.37, 35.01. HR-MS(ESI): Calculated for C20H27NO4 [M + H]+:346.201285, found:346.201546.
2-(4-methoxyphenyl)-N-methyl-1-(3,4,5-trimethoxyphenyl)ethan-1-amine. (12a)
A solution of 8a (1.2mmol) in THF was added to a suspension of LiAlH4 (4.8mmol) in THF at 0°C and the reaction mixture was stirred at room temperature overnight. After quenching with 15% NaOH, the suspension was passed through a pad of Celite, eluting with ethyl acetate. The solvent was then removed in vacuo to give 10a as a white solide,yield: 60%. 1H NMR (500 MHz, Chloroform-d) δ 7.10 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 6.59 (s, 2H), 3.89 (d, J = 4.8 Hz, 9H), 3.82 (s, 3H), 3.68 (d, J = 7.1 Hz, 1H), 2.93 (tt, J = 21.5, 9.1 Hz, 2H), 2.31 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 158.25, 153.16, 138.49, 136.86, 130.46, 130.25, 113.81, 104.05, 67.31, 60.79 (d, J = 5.2 Hz), 56.08 (d, J = 5.0 Hz), 55.19 (d, J = 4.7 Hz), 44.05, 34.43. HR-MS(ESI): Calculated for C19H25NO4 [M + H]+: 332.1856, found: 332.1854.
2-methoxy-5-(2-(methylamino)-2-(3,4,5-trimethoxyphenyl)ethyl)phenol. (12b)
White solide, yield: 45%. 1H NMR (500 MHz, Chloroform-d) δ 6.86–6.74 (m, 2H), 6.61 (d, J = 8.4 Hz, 3H), 3.85 (d, J = 4.1 Hz, 12H), 3.71–3.64 (m, 1H), 3.03–2.96 (m, 1H), 2.89 (dq, J = 21.8, 13.1, 10.6 Hz, 1H), 2.27 (s, 3H). 13C NMR (126 MHz, Chloroform-d) δ 153.26, 145.82, 145.57, 131.51, 120.74, 115.52, 110.81, 104.28, 67.21, 60.80, 56.17, 45.92, 44.01, 34.19, 9.32. HR-MS(ESI): Calculated for C19H25NO5 [M + H]+: 348.1805, found: 348.1807.
1-(4-methoxyphenyl)-N-methyl-2-(3,4,5-trimethoxyphenyl)ethan-1-amine. (12c)
White solide,yield: 58%.1H NMR (400 MHz, Chloroform-d) δ 7.22 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.32 (d, J = 7.5 Hz, 2H), 3.86–3.74 (m, 12H), 3.68 (d, J = 6.5 Hz, 1H), 2.92–2.77 (m, 2H), 2.46 (s, 1H), 2.24 (d, J = 7.5 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 158.91, 153.09, 136.53, 134.65, 134.38, 128.49, 113.83, 106.25, 66.17, 60.84, 56.05, 55.29, 45.36, 34.35. HR-MS(ESI): Calculated for C19H25NO4 [M + H]+: 332.1856, found: 332.1859.