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B. Vilhanová et al. / Tetrahedron: Asymmetry 24 (2013) 50–55
4.3.2. Synthesis of 6,7-dimethoxy-1-(30,40,50-trimethoxybenzyl)-
3,4-dihydroisoquinoline 2
was stirred at room temperature for 5 min. Imine 2 (3.71 g,
10 mmol) dissolved in acetonitrile (15 mL) was then added and
the mixture was stirred for 6 h. The reaction mixture was evapo-
rated to dryness to give a viscous substance, which was subse-
quently dissolved in water (100 mL) and acidified with
concentrated hydrochloric acid (15 mL). The acidic aqueous phase
was extracted with dichloromethane (6 ꢁ 20 mL) to remove the
catalyst. The solution was rendered strongly alkaline by the addi-
tion of a concentrated aqueous solution of NaOH and the amine
was extracted with diethyl ether (5 ꢁ 30 mL), washed with brine
(30 mL), dried over anhydrous magnesium sulfate, and concen-
trated on a rotary evaporator to give the target product. Yield of
(R)-3: 3.67 g, 98.4%. 1H NMR (399.89 MHz, CDCl3, 303.2 K): 2.62
(1H, ddd, J = 15.9, 5.8, 4.9 Hz, H-4u), 2.72 (1H, ddd, J = 15.9, 7.1,
5.3 Hz, H-4d), 2.78 (1H, dd, J = 13.5, 9.1 Hz, H-1-CH2-u), 2.86 (1H,
ddd, J = 11.9, 7.1, 4.9 Hz, H-3u), 3.11 (1H, dd, J = 13.5, 4.5 Hz, H-1-
CH2-d), 3.16 (1H, d, J = 11.9, 5.8, 5.3 Hz, H-3d), 3.77 (3H, s, 7-
OCH3), 3.78 (9H, s, 30,40,50-OCH3), 3.79 (3H, s, 6-OCH3), 4.09 (1H,
dd, J = 9.1, 4.5 Hz, H-1), 6.41 (2H, s, H-20,60), 6.54 (1H, s, H-5),
6.59 (1H, s, H-8). 13C NMR (100.58 MHz, CDCl3, 303.2 K): 29.22
(C-4), 40.76 (C-3), 42.81 (1-CH2), 55.52 (6-OCH3), 55.67 (7-OCH3),
55.77 (30,50-OCH3), 60.50 (40-OCH3), 105.85 (C-20,60), 109.05 (C-8),
111.56 (C-5), 127.17 (C-4a), 130.00 (C-8a), 134.41 (C-10), 136.19
(C-40), 146.67 (C-7), 147.15 (C-6), 152.92 (C-30,50). HRMS (HESI+)
m/z calculated for [M+H]+: 374.1962; found: 374.19579. Further
characterization can be found in the literature.21
At first, N-[2-(3,4-dimethoxyphenyl)ethyl]-3,4,5-trimethoxyph-
enylacetamide 1 (39.1 g, 100 mmol) was dissolved in dry acetoni-
trile (250 mL) under an argon atmosphere. Phosphorus
oxychloride (47 mL, 500 mmol) was then added gradually over
30 min. The mixture was stirred at 100 °C for 4 h. The volatiles were
removed on a rotary evaporator and a yellow solid was obtained,
which was hydrolyzed with water (100 mL). The solution was alk-
alized with a concentrated solution of sodium hydroxide (120 g)
in water. After reaching pH = 12, a concentrated solution of sodium
sulfite (1.3 g, 10 mmol) was added to minimize the oxidation of the
product. The slurry was cooled down to 35 °C and extracted with
chloroform (4 ꢁ 60 mL). The combined organic extracts were
washed with water (2 ꢁ 30 mL), dried over anhydrous magnesium
sulfate, and concentrated on a rotary evaporator (10 torr, bath tem-
perature 50 °C). The crude product (35 g) was obtained as a yellow
solid, which was recrystallized from methanol (150 mL). Yield of 2:
22.0 g, 59.0%. 1H NMR (400.00 MHz, CDCl3, 293.2 K): d 2.64 (2H, m,
H-4), 3.72 (2H, m, H-3), 3.75 (3H, s, 7-OCH3), 3.78 (3H, s, 40-OCH3),
3.79 (6H, s, 30,50-OCH3), 3.87 (3H, s, 6-OCH3), 3.95 (2H, s, 1-CH2),
6.53 (2H, s, H-20,60), 6.66 (1H, s, H-5), 6.98 (1H, s, H-8). 13C NMR
(100.58 MHz, CDCl3, 293.2 K): d 25.74 (C-4), 43.76 (1-CH2), 47.22
(C-3), 55.84 (6-OCH3), 55.90 (7-OCH3), 55.96 (30,50-OCH3), 60.75
(40-OCH3), 105.41 (C-20,60), 109.39 (C-8), 110.15 (C-5), 121.56 (C-
8a), 131.74 (C-4a), 133.78 (C-10), 136.42 (C-40), 147.11 (C-7),
150.59 (C-6), 153.20 (C-30,50), 165.20 (C-1). HRMS (HESI+) m/z cal-
culated for [M+H]+: 372.1805; found: 372.18017. Further charac-
terization can be found in the literature.19
4.3.5. Synthesis of (R)-N-Me-6,7-dimethoxy-1-(30,40,50-trimeth-
oxybenzyl)-1,2,3,4-tetrahydroisoquinoline (R)-4 from (R)-3
Amine (R)-3 (740 mg, 2.00 mmol) was dissolved in 1,4-dioxane
(10 mL). The aqueous solution of formaldehyde (10 mL, 30% w/w)
and sodium phosphonate pentahydrate (2.2 g, 10 mmol) dissolved
in water (10 mL) was then added and the mixture was stirred at
60 °C for 40 min and then at 80 °C for 3 h. The reaction mixture
was diluted with an aqueous solution of sodium hydroxide
(150 mL, 10% w/w) and extracted with MTBE (3 ꢁ 150 mL). The
combined organic phase was dried over anhydrous magnesium
sulfate and evaporated to dryness on a rotary evaporator. Yield of
4.3.3. Synthesis of racemic N-Me-6,7-dimethoxy-1-(30,40,50-tri-
methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline rac-4
Imine 2 (765 mg, 2.00 mmol) was dissolved in a mixture of eth-
anol (1 mL) and 1,4-dioxane (5 mL). Next, NaBH4 (55 mg,
1.5 mmol) was added and the reaction mixture was heated at
100 °C. After 3 h, the reaction was close to full conversion. Then
NaBH4 (40 mg, 1.1 mmol) dissolved in ethanol (1.5 mL) was added
and the solution was stirred for 30 min. An aqueous solution of
formaldehyde (2 mL, 30% w/w) and sodium phosphonate pentahy-
drate (1.1 g, 5.1 mmol) dissolved in water (5 mL) were added and
the mixture was stirred for 75 min at 80 °C. The reaction mixture
was diluted with water (100 mL) and brine (20 mL), after which so-
dium hydroxide (300 mg, 7.5 mmol) was then added. The mixture
was extracted with MTBE (3 ꢁ 50 mL), and the organic phase was
dried over anhydrous magnesium sulfate and evaporated to dry-
ness on a rotary evaporator. Yield of rac-4: 774 mg, 97.0%. 1H
NMR (399.89 MHz, CDCl3, 303.2 K): 2.52 (3H, s, 2-CH3), 2.58 (1H,
ddd, J = 15.8, 4.7, 4.0 Hz H-4u), 2.71 (1H, dd, J = 13.5, 8.2, H-1-
CH2-u), 2.75 (1H, m, H-3u), 2.83 (1H, ddd, J = 16.0, 15.8, 5.8 Hz
H-4d), 3.13 (1H, dd, J = 13.5, 4.5, H-1-CH2-d), 3.15 (1H, m, H-3d),
3.54 (3H, s, 7-OCH3), 3.69 (1H, dd, J = 8.2, 4.5, H-1), 3.74 (6H, s,
30,50-OCH3), 3.77 (3H, s, 40-OCH3), 3.80 (3H, s, 6-OCH3), 6.00 (1H,
s, H-8), 6.28 (2H, s, H-20,60), 6.54 (1H, s, H-5). 13C NMR
(100.58 MHz, CDCl3, 303.2 K): 25.23 (C-4), 41.40 (1-CH2), 42.40
(2-CH3), 46.61 (C-3), 55.40 (7-OCH3), 55.67 (6-OCH3), 55.95
(30,50-OCH3), 60.65 (40-OCH3), 64.5 (C-1), 106.76 (C-20,60), 111.14
(C-8), 111.21 (C-5),125.71 (C-4a), 128.83 (C-8a), 135.44 (C-10),
136.23 (C-40), 146.21 (C-7), 147.28 (C-6), 152.76 (C-30,50). HRMS
(HESI+) m/z calculated for [M+H]+: 388.2118; found: 388.21210.
Further characterization can be found in the literature.20
(R)-4: 744 mg, 97.0%. ½a D20
¼ ꢀ46:0 (c 1.26, CHCl3). Further charac-
ꢂ
terization can be found in the literature.20
4.3.6. Synthesis of (R)-N-Me-6,7-dimethoxy-1-(30,40,50-trimeth-
oxybenzyl)-1,2,3,4-tetrahydroisoquinolinium (ꢀ)-2,3-dibenzo-
yl-L-tartarate 5 from rac-4
Amine rac-4 (531 mg, 1.37 mmol) and (ꢀ)-2,3-dibenzoyl-
L-tar-
taric acid (491 mg, 1.37 mmol) were dissolved in 1,4-dioxane
(4 mL) and stirred at 80 °C. The mixture was left to cool down
slowly after being inoculated with a standard of the product. The
crystals formed were filtered on sintered glass, rinsed with a 1:1
mixture of 1,4-dioxane and hexane (10 mL), washed with hexane
(5 mL), and dried in an air stream for 5 min. Finally, the crystals
were dried in vacuo for 2 h (10 torr, bath temperature 50 °C). Yield
of 5: 400 mg, 39.1%. 1H NMR (399.89 MHz, CDCl3, 303.2 K): 2.50
(1H, m, H-1-CH2-u), 2.72 (3H, s, 2-CH3), 2.81 (1H, dd, J = 5.8,
17.7 Hz, H-4u), 2.94 (1H, m, H-4d), 3.27 (1H, m, H-3u), 3.37 (3H,
s, 7-OCH3), 3.52 (1H, m, H-3, H-1-CH2-d), 3.63 (3H, s, 30,50-OCH3),
3.77 (3H, s, 40-OCH3), 3.81 (3H, s, 6-OCH3), 5.60 (1H, s, H-8), 5.97
(2H, s, CHtart), 6.11 (2H, s, H-20,60), 6.54 (1H, s, H-5), 7.30 (4H, m,
H-metatart), 7.43 (2H, m, H-paratart), 8.03 (4H, m, H-orthotart). 13C
NMR (100.58 MHz, CDCl3, 303.2 K): 21.18 (C-4), 38.95 (2-CH3),
41.60 (1-CH2), 43.82 (C-3), 55.34 (7-OCH3), 55.85 (6-OCH3), 56.03
(30,50-OCH3), 60.66 (40-OCH3), 64.51 (C-1), 73.31 (CHtart), 107.02
(C-20,60), 110.94 (C-5), 111.51 (C-8),120.54 (C-4a), 121.48 (C-8a),
128.12 (C-metatart), 129.60 (C-ipsotart), 129.95 (C-orthotart), 131.35
(C-10), 132.89 (C-paratart), 136.71 (C-40), 147.02 (C-7), 148.89 (C-
6), 152.97 (C-30,50), 165.53 (COOtꢀart), 170.62 (COOHtart). HRMS
4.3.4. Synthesis of (R)-6,7-dimethoxy-1-(30,40,50-trimethoxybenz-
yl)-1,2,3,4-tetrahydroisoquinoline (R)-3
At first, [RuCl(g
6-p-cymene)(S,S)-TsDPEN] (31.8 mg, 0.05 mmol)
was dissolved in acetonitrile (5 mL), after which an HCOOH/TEA
complex 5:2 (16.7 mL, 40.0 mmol) was added and the mixture