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521
4.1.8. General procedure for the synthesis of hydrochloride
salts 1a and 6a–e
135.0, 140.3, 153.3, 161.5, 162.6. Anal. Calcd for C19H22ClNO3: C,
65.61; H, 6.38; Cl, 10.19; N, 4.03. Found: C, 65.40; H, 6.39; Cl, 10.17;
N, 4.02.
The crude compound obtained from reduction of the nitro
derivative was dissolved in ethyl acetate and a slight excess of
0.1 N aq hydrochloride acid solution was added at 0 °C. The mix-
ture was stirred at room temperature about 30 min. The solvent
was evaporated in vacuo and the solid residue was washed twice
with few mL of diethyl ether to give the desired hydrochloride salt.
4.1.9. (Z)-5-[2-(1H-Indol-5-yl)-ethenyl]-2-methoxyphenyl-
amine, oxalate salt (6g)
The compound obtained in previous reduction of nitro group
was dissolved in tetrahydrofuran (5 mL) and mixed with a solution
of oxalic acid dihydrate (1 mmol, 126 mg) in tetrahydrofuran
(5 mL). The oxalate salt 6g separates as colorless solid that is fil-
tered, washed with 15 mL of THF (160 mg).
Recrystalized from methanol/diethyl ether. Mp 112–115 °C.
Yield 70%. 1H NMR (CD3OD) d: 3.59 (s, 3H), 6.32 (dd, J = 1.0,
J = 2.2, 1H), 6.41 (d, J = 12.2, 1H), 6.60 (s, 1H), 6.61 (d, J = 12.2,
1H), 6.96–7.02 (m, 3H), 7.15–7.16 (m, 1H), 7.18–7.21 (m, 1H),
7.23–7.25 (m, 1H), 7.44 (s, 1H). Anal. Calcd for C19H18N2O5: C,
64.40; H, 5.12; N, 7.91. Found: C, 64.15; H, 5.14; N, 7.88.
4.1.8.1. (Z)-5-[3,5-Dimethoxyphenyl)-ethenyl]-2-methoxyben-
zenamine hydrochloride (1a). Recrystallized from methanol/
diethyl ether. Mp 150–153 °C: Yield 85%. 1H NMR (CD3OD) d:
3.65 (s, 6H), 3.95 (s, 3H), 6.35–6.36 (m, 3H), 6.54 (d, J = 12.0, 1H),
6.59 (d, J = 12.0, 1H), 7.12 (d, J = 8.4, 1H), 7.24 (d, J = 2.0, 1H), 7.34
(dd, J = 2.0, J = 8.4, 1H). 13C NMR d: 55.6, 56.8, 100.5, 107.7, 113.1,
120.3, 125.1, 129.4, 131.9, 132.2, 140.0, 153.1, 162.3. Anal. Calcd
for C17H20ClNO3: C, 63.45; H, 6.26; Cl, 11.02; N, 4.35. Found: C,
63.42; H, 6.25; Cl, 11.05; N, 4.34.
4.1.10. Synthesis of isocyanate intermediate (7)
4.1.8.2. (Z)-2-{3-[2-(3-Amino-4-methoxyphenyl)-ethenyl]-5-
methoxyphenoxy}ethanol, hydrochloride (6a). Recrystallized
from methanol/diethyl ether. Mp 157–159 °C. Yield 81%. 1H NMR
(CD3OD) d: 3.67 (s, 3H), 3.80–3.82 (m, 2H), 3.88–3.90 (m, 2H), 3.96
(s, 3H), 6.38––6.40 (m, 3H), 6.54 (d, J = 12.4, 1H), 6.60 (d, J = 12.4,
1H), 7.12 (d, J = 8.4, 1H), 7.25 (d, J = 2.4, 1H), 7.35 (dd, J = 2.4, J = 8.4,
1H), 7.76 (d, J = 2.4, 1H). Anal. Calcd for C18H22ClNO4: C, 61.45; H,
6.30; Cl, 10.80; N, 3.98. Found: C, 61.55; H, 6.30; Cl, 10.77; N, 3.97.
To a mixture of amino stilbene 1a, free base (1.8 mmol, 519 mg)
solubilized in dry dioxane (15 mL), trichloromethyl chloroformate
(0.84 mmol, 105 lL), was added in one portion. The mixture was
heated at 60 °C for 2 h. After cooling down to room temperature
the mixture was concentrated in vacuo and the crude residue
was used for the next reaction without any purification.
4.1.11. (Z)-1-{5-[2-(3,5-Dimethoxyphenyl)-ethenyl]-2-
methoxyphenyl}-3-(2-morpholin-4-yl-ethyl)-urea
4.1.8.3. (Z)-5-[2-(3-Ethoxy-5-methoxyphenyl)-ethenyl]-2-methoxy-
phenylamine, hydrochloride (6b). Recrystallized from methanol/
diethyl ether. Mp 127–131 °C. Yield 82%. 1H NMR (CD3OD) d:
1.30 (t, J = 7.2, 3H), 3.66 (s, 3H), 3.88 (q, J = 7.2, 2H), 3.96 (s, 3H),
6.33–6.35 (m, 3H), 6.54 (d, J = 12.0, 1H), 6.60 (d, J = 12.0, 1H),
7.12 (d, J = 8.8, 1H), 7.23 (d, J = 2.2, 1H), 7.33 (dd, J = 2.2, J = 8.8
1H). 13C NMR d: 15.2, 55.7, 56.9, 64.6, 101.2, 107.6, 108.1, 113.2,
125.1, 129.5, 132.0, 132.1, 140.2, 153.1, 161.7, 162.4. Anal. Calcd
for C18H22ClNO3: C, 64.38; H, 6.60; Cl, 10.56; N, 4.17. Found: C,
64.16; H, 6.62; Cl, 10.54; N, 4.17.
hydrochloride salt (8a)
To a solution of crude isocyanate 7 (0.61 mmol, 200 mg) solubi-
lized in dry dioxane (5 mL) 4-(2-aminoethyl) morpholine,
(0.67 mmol, 88 mg) was added portionwise. The mixture was
heated at 60 °C for 12 h. After cooling down to room temperature,
the mixture was concentrated in vacuo and the crude residue was
purified by flash chromatography (3% methanol/dichloromethane)
on silica gel to afford 105 mg of the expected title morpholine
derivative. The compound (0.5 mmol, 220 mg) was dissolved in
ethyl acetate and a slight excess of 0.1 N hydrochloride solution
was added at 0 °C. The mixture was stirred about 30 min at room
temperature. The solvent was evaporated in vacuo and the solid
residue was washed twice with few mL of diethyl ether to give
205 mg of title compound. Yield 70%. 1H NMR (CDCl3) d: 2.83–
3.02 (m, 2H), 3.15–3.30 (m, 2H), 3.46–3.66 (m, 8H), 3.67–3.78
(m, 2H), 3.81 (s, 3H), 3.94–4.10 (m, 2H), 4.16–4.35 (m, 2H), 6.26
(t, J = 2.4, 1H), 6.40 (d, J = 12.6, 1H), 6.42 (d, J = 2.4, 2H), 6.52 (d,
J = 12.6, 1H), 6.63, 6.67 (m, 1H), 6.90 (dd, J = 1.6, J = 8.4, 1H), 7.39
(s, 1H), 8.0 (s, 1H). 13C NMR d: 36.0, 53.8, 55.8, 56.5, 60.2, 65.2,
100.8, 108.0, 111.4, 121.8, 125.1, 129.3, 130.4, 131.4, 131.7,
140.8, 149.5, 159.4, 162.2. Anal. Calcd for C24H32ClN3O5: C, 60.31;
H, 6.75; Cl, 7.42; N, 8.79. Found: C, 60.18; H, 6.74; Cl, 7.40; N, 5.80.
4.1.8.4.
(Z)-5-{2-[3-(1-methylethoxy)-5-methoxyphenyl]-eth-
enyl}-2-methoxyphenylamine, hydrochloride (6c). Recrystal-
lized from methanol/diethyl ether. Mp 120–122 °C. Yield 78%. 1H
NMR (CD3OD) d: 1.20 (d, J = 6.2, 6H), 3.65 (s, 3H), 3.95 (s, 3H),
4.35–4.48 (m, 1H), 6.31–6.35 (m, 3H), 6.53 (d, J = 12.2, 1H), 6.60
(d, J = 12.2, 1H), 7.11 (d, J = 8.6, 1H), 7.22 (d, J = 2.0, 1H), 7.33 (dd,
J = 2.0, J = 8.6 1H). 13C NMR d: 22.5, 55.8, 57.1, 71.2, 102.7, 107.9,
109.8, 112.5, 113.4, 125.3, 129.5, 132.3, 133.3, 140.3, 153.2,
160.1, 162.6. Anal. Calcd for C19H24ClNO3: C, 65.23; H, 6.91; Cl,
10.13; N, 4.00. Found: C, 65.10; H, 6.93; Cl, 10.16; N, 3.98.
4.1.8.5.(Z)-3-[2-(3-Amino-4-methoxyphenyl)-ethenyl]-5-methoxy-
phenol, hydrochloride (6d). Recrystallized from methanol/diethyl
ether. Mp 158–161 °C. Yield 75%. 1H NMR (CD3OD) d: 3.63 (s, 3H),
3.95 (s, 3H), 6.23–6.26 (m, 3H), 6.49 (d, J = 12.2, 1H), 6.56 (d, J = 12.2,
1H), 7.10 (d, J = 8.2, 1H), 7.24 (d, J = 2.2, 1H), 7.34 (dd, J = 8.2, J = 2.2,
1H). Anal. Calcd for C16H18ClNO3: C, 62.44; H, 5.89; Cl, 11.52; N, 4.55.
Found: C, 62.52; H, 5.90; Cl, 11.49; N, 4.53.
4.1.12. (Z)-{5-[2-(3,5-Dimethoxyphenyl)-ethenyl]-2-methoxy-
phenyl}carbamic acid 2-morpholin-4-yl-ethyl ester,
hydrochloride (8b)
To a solution of the crude isocyanate 7 (0.59 mmol, 180 mg) sol-
ubilized in dry dioxane (5 mL) the 4-(2-hydroxylethyl)morpholine,
(0.6 mmol, 74 lL) was added portionwise. The mixture was heated
at 60 °C for 12 h. After cooling down to room temperature the mix-
ture was concentrated in vacuo and the crude residue was purified
by flash chromatography (3% methanol/dichloromethane) on silica
gel to afford 117 mg of the expected desired carbamate. The com-
pound (0.5 mmol, 220 mg) was dissolved in tetrahydrofuran (THF,
7 mL) and mixed with 0.1 N hydrochloride acid solution (a slight
excess) in THF (5 mL). The hydrochloride salt 8b separates as a col-
orless solid that was filtrated and washed with 10 mL of THF to
give 212 mg. Yield 75%. Mp 152–154 °C. 1H NMR (CDCl3) d: 2.86–
4.1.8.6. (Z)-5-{2-[3-(2-Propenyl)oxy-5-methoxyphenyl]-ethenyl}-
2-methoxyphenylamine, hydrochloride (6e). Recrystallized from
methanol/diethyl ether. Mp 122–125 °C; Yield 70%. 1H NMR (CD3OD)
d: 3.65 (s, 3H), 3.96 (s, 3H), 4.40 (dt, J = 1.6, J = 5.2, 2H), 5.18 (dq,
J = 1.4, J = 10.4, 1H), 5.34 (dq, J = 1.4, J = 17.2, 1H), 5.88–6.07 (m, 1H),
6.37 (s, 3H), 6.53 (d, J = 12.2, 1H), 6.60 (d, J = 12.2, 1H), 7.11 (d, J = 8.4,
1H), 7.25 (d, J = 2.0, 1H), 7.34 (dd, J = 2.0, J = 8.4 1H). 13C NMR d: 55.9,
57.1, 70.0, 101.6, 108.1, 108.7, 113.4, 117.6, 125.4, 129.6, 132.1, 132.5,