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Short Communications
1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-5-methoxy-6,7-
methylenedioxy-1,2,3,4-tetrahydroisoquinoline (10)
equivalence of these protons is rather unexpected. Finally,
the benzyl protecting group was removed by catalytic
hydrogenolysis at 35–40 psi to afford (±)-cathaformine, the
1H and 13C n.m.r. spectral data of which were identical in all
respects with those of natural (+)-cathaformine.
Sodium borohydride (0.5 g) was added portionwise to a stirred solu-
tion of the dihydroisoquinoline (9) (4.8 g) in ethanol (100 ml) and the
mixture was refluxed for 1 h. The mixture was then shaken with water
(100 ml) and chloroform (100 ml). The chloroform layer was washed
with brine, then dried. Removal of the solvent gave a white solid which
was recrystallized from ethanol to give the tetrahydroisoquinoline (10)
as colourless prisms (4.27 g, 89.3%), m.p. 154–155o (Found: C, 61.1;
H, 4.9; N, 2.9. C26H26BrNO5 requires C, 61.0; H, 5.1; N, 2.7%). ꢁmax
228sh, 287 nm; logꢂ 3.99, 3.40. ꢃmax 3319 (NH), 1602, 1572, 1506,
1321, 1312, 1257, 1213, 1163, 1131, 1101, 1069, 1044, 983, 934, 915,
Experimental
Melting points were determined on a Stuart MP-2 apparatus and are
uncorrected. Ultraviolet spectra were recorded on methanol solutions
with a Hitachi U-3300 spectrophotometer. Infrared spectra were
recorded on Nujol mulls with a Nicolet Impact 400 spectrophotometer.
1H and 13C magnetic resonance spectra were recorded on (D)chloro-
form solutions at 60 MHz with a Varian EM360A spectrometer or at
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878, 844, 801, 785, 762, 746, 699, 635 cm–1. H n.m.r. (60 MHz) ꢀ
7.50–7.13, m, 5×Ph H; 7.03, s, ArH; 6.71, s, ArH; 6.51, s, ArH; 5.83, s,
OCH2O; 5.11, s, PhCH2; 4.30–4.00, m, H1; 3.96, s, OCH3; 3.85, s,
OCH3; 3.65–2.43, m, 3×CH2; 2.06, br s, NH. Mass spectrum m/z 206
(100), 190 (18), 118 (7), 91 (48).
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400 MHz for H and 100 MHz for 13C with a Varian Inova 400 MHz
spectrometer. Tetramethylsilane was used as the internal standard.
Mass spectra were run on a Hewlett Packard 5989B spectrometer.
Elemental microanalyses were performed with a Perkin–Elmer 2400
elemental analyser.
Methyl 1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-5-methoxy-6,7-
methylenedioxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (11)
5-Benzyloxy-2-bromo-4-methoxyphenylacetic Acid (5)
Methyl chloroformate (4.70 g) was added portionwise to a stirred
mixture of the tetrahydroisoquinoline (10) (4.27 g) in chloroform (25
ml) and sodium hydrogen carbonate (4.16 g) at 0–5o. Stirring was con-
tinued at room temperature for 3 h. Water (60 ml) and chloroform (60
ml) were added and the chloroform layer was washed with brine, then
dried. Removal of the solvent gave a viscous residue (4.78 g) which
was passed through a column of alumina (125 g) packed in benzene.
Elution with benzene followed by crystallization from ethanol gave the
carbamate (11) as pale yellow prisms (1.54 g, 32.4%), m.p. 187–188o
(Found: C, 58.8; H, 4.8; N, 2.6. C28H28BrNO7 requires C, 59.0; H, 5.0;
N, 2.5%). ꢁmax 229sh, 286 nm; logꢂ 4.03, 3.42. ꢃmax 1686 (C=O), 1625,
1601, 1510, 1497, 1325, 1311, 1261, 1215, 1204, 1163, 1117, 1085,
1066, 1049, 1042, 1024, 988, 976, 960, 945, 914, 885, 873, 872, 867,
850, 803, 767, 752, 743, 731, 698 cm–1. 1H n.m.r. (60 MHz) ꢀ
7.56–7.10, s, 5×Ph H; 7.00, s, ArH; 6.56, 6.50, 6.32, 6.18, 4s, 2×ArH of
both conformers; 5.82, s, OCH2O; 5.36–5.03, m, H1; 5.00, s, PhCH2;
3.97, s, OCH3; 3.83, s, OCH3; 3.84, 3.30, 2s, COOCH3 of both con-
formers; 3.76–2.30, m, 3×CH2. Mass spectrum m/z 264 (100), 204 (6),
178 (3), 91 (20).
Bromine (32.4 g) was cautiously added to a solution of 3-benzyl-
oxy-4-methoxyphenylacetic acid (50 g) and anhydrous sodium acetate
(50 g) in acetic acid (500 ml) and the mixture was stirred for 1 h at room
temperature. Water (2 litres) was then added and the yellow precipitate
was filtered off and recrystallized from ethanol to give colourless crys-
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tals (44 g, 68.2%), m.p. 146–147o (lit.5 145o). H n.m.r. (60 MHz) ꢀ
7.47–7.13, m, 5×Ph H; 7.03, s, ArH; 6.80, s, ArH; 5.05, s, CH2; 3.83, s,
OCH3; 3.70, s, CH2.
2-(5-Benzyloxy-2-bromo-4-methoxyphenyl)-N-(2-methoxy-3,4-
methylenedioxyphenethyl)acetamide (8)
A mixture of acid (5) (27 g) and thionyl chloride (25 g) in chloro-
form (210 ml) was refluxed for 1 h, then the solvent and excess thionyl
chloride were removed under vacuum. The resulting crude acid chlo-
ride (7) was dissolved in chloroform (120 ml) and added portionwise to
a mixture of 2-(2-methoxy-3,4-methylenedioxyphenyl)ethylamine (4)
(14 g) in chloroform (125 ml) and 5% NaHCO3 (190 ml) under ice
cooling. The mixture was stirred at room temperature for 5 h. Water
(350 ml) and chloroform (210 ml) were added and the chloroform layer
was washed with 3 M HCl (2×175 ml), water (350 ml), 5% NaHCO3
(350 ml), water and brine, then dried. Removal of the solvent gave a
pale brown solid which was recrystallized from ethanol to give the
amide (8) as colourless prisms (32.0 g, 84.6%), m.p. 141–142o (Found:
C, 59.2; H, 4.7; N, 2.8. C26H26BrNO6 requires C, 59.1; H, 5.0; N, 2.6%).
ꢁmax 228sh, 284 nm; logꢂ 3.98, 3.40. ꢃmax 3325 (NH), 1652 (C=O),
1602, 1541, 1260, 1213, 1164, 1032, 978, 797, 751, 722 cm–1. 1H n.m.r.
(60 MHz) ꢀ 7.46–7.10, m, 5×Ph H; 6.96, s, ArH; 6.73, s, ArH; 6.33, s,
2×ArH; 5.80, s, OCH2O; 5.40, br s, NH; 5.00, s, PhCH2; 3.83, s, OCH3;
3.80, s, OCH3; 3.46, s, CH2; 3.28, t, J 6 Hz, CH2N; 2.58, t, J 6 Hz, CH2.
Mass spectrum m/z 529 (M+, 1%), 527 (M+, 1%), 448 (37), 270 (32),
199 (12), 178 (89), 129 (12), 91 (100), 57 (44).
Methyl 9-Benzyloxy-3,10-dimethoxy-1,2-methylenedioxy-
noraporphine-6-carboxylate (12)
A solution of azobis(isobutyronitrile) (2.32 g) and tributyltin
hydride (9.11 g) in toluene (159 ml) was added dropwise over 3.5 h to
a refluxing solution of the carbamate (11) (9.11 g) in toluene (232 ml)
under nitrogen. The resulting mixture was then refluxed for 24 h. The
solvent was removed under vacuum and the residue was dissolved in
acetonitrile (100 ml) and washed with hexane (3×500 ml), then dried.
Removal of the solvent under vacuum gave a brown residue which
crystallized from ethanol to give the noraporphine (12) as pale brown
prisms (1.35 g, 17.3%), m.p. 204–205o (Found: C. 68.5; H, 5.3; N, 3.0.
C28H27NO7 requires C, 68.7; H, 5.6; N, 2.9%). ꢁmax 233sh, 284, 304,
315 nm; logꢂ 4.08, 3.88, 3.90, 3.87. ꢃmax 1710 (C=O), 1605, 1517,
1280, 1249, 1215, 1203, 1120, 1054, 1026, 998, 983, 962, 940, 917,
1-(5-Benzyloxy-2-bromo-4-methoxybenzyl)-5-methoxy-6,7-
methylenedioxy-3,4-dihydroisoquinoline (9)
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868, 773, 756, 745, 722 cm–1. H n.m.r. (400 MHz) ꢀ 7.68, s, H11;
7.47–7.26, m, 5×Ph H; 6.80, s, H 8; 6.08, d J 1.46 Hz, 1H, OCH2O;
5.93, d J 1.46 Hz, 1H, OCH2O; 5.19, d, J 12.27 Hz, 1H, PhCH2; 5.14,
d, J 12.27 Hz, 1H, PhCH2; 4.80, m, H 6a; 4.40, m, H5ꢄ; 4.00, s,
C 3–OCH3; 3.93, s, C 10–OCH3; 3.76, s, NCOOCH3; 2.90, m, 2H, H5ꢅ
and H7ꢄ; 2.79, m, 2H, H 7ꢅ and H4ꢄ; 2.46, m, H 4ꢅ. Mass spectrum
m/z 489 (M+, 21%), 460 (5), 398 (100), 367 (31), 311 (28), 296 (24),
250 (15), 221 (13), 152 (18), 115 (17), 91 (67).
A solution of the amide (8) (8 g) and phosphorus oxychloride (16 g)
in benzene (100 ml) was refluxed for 3 h, and the excess reagent and
solvent were removed under vacuum. The resulting red residue was
shaken with chloroform (240 ml) and dilute ammonia (100 ml). The
chloroform layer was washed with water (100 ml), brine, then dried.
Removal of the solvent gave a brown viscous residue which crystal-
lized from ethanol to give the dihydroisoquinoline (9) as pale brown
prisms (4.85 g, 62.9%), m.p. 157–158o (Found: C, 61.3 ; H, 4.6 ; N, 2.9.
C26H24BrNO5 requires C, 61.2; H, 4.7; N, 2.7%). ꢁmax 237sh, 283, 322
nm; logꢂ 4.01, 3.67, 3.57. ꢃmax 1664, 1589, 1274, 1223, 1210, 1152,
1086, 1069, 1053, 1023, 961 cm–1. 1H n.m.r. (60 MHz) ꢀ 7.43–7.13, s,
5×Ph H; 7.00, s, ArH; 6.70, s, ArH; 6.56, s, ArH; 5.86, s, OCH2O, 4.98,
s, PhCH2; 3.94, s, OCH3 and CH2; 3.80, s, OCH3; 3.51, t, J 6 Hz, CH2N;
2.59, t, J 6 Hz, CH2.
(±)-Cathaformine (3)
Asolution of the noraporphine (11) (331 mg) in ethanol (170 ml) was
hydrogenolysed in the presence of 10% Pd/C (334 mg) at 35–40 psi for
8 h. The catalyst was filtered off and the solvent removed under vacuum
to give a viscous residue which crystallized from ethanol to give (±)-
cathaformine as pale brown prisms (131 mg, 48.6%), m.p. 241–242o