3,4-Dihydroisoquinolines 4a, b
graphed over silica gel (dichloromethane–ethanol 97 : 3) to give
the N-oxides 6a, b.
The crude product 3a or 3b (78 mmol) and phosphorus oxy-
chloride (22 ml, 235 mmol) were refluxed in dry acetonitrile
(300 ml) for 3 hours. The solution was cautiously poured on
600 ml of cold water. The resulting mixture was stirred for one
hour. The solution was made basic with sodium hydroxide
pellets and stirred while cooling. This was extracted with
dichloromethane, the organic phase was washed with water,
dried over magnesium sulfate and concentrated to dryness. The
crude residue was chromatographed over silica gel eluting with
dichloromethane–ethanol 99 : 1 in the case of 4a or heptane–
ethyl acetate 7 : 3 in the case of 4b.
1-(2-Chlorophenyl)isoquinoline N-oxide 6a. Obtained as a
1
wax (82%). νmax (KBr)/cmϪ1 3327, 2361, 1324, 1223; H: 7.31–
7.56 (m, 7H), 7.66 (d, 1H, J = 7.2), 7.76 (d, 1H, J = 8.5), 8.23 (d,
1H, J = 7.2); 13C: 123.7, 124.6, 126.8, 127.1, 128.2, 128.6, 129.2,
129.9 (2 signals ?), 130.3, 130.7, 131.2, 134.3, 137.0, 143.9;
m/z 240.0573 (Mϩ ϩ H Ϫ O, C15H11NCl requires 240.0580, the
molecular peak was too small for an HRMS).
1-(2-Chlorophenyl)-3-methylisoquinoline
N-oxide
6b.
Obtained as an oil (88%). νmax (KBr)/cmϪ1 3056, 2922, 1360,
1334, 1295; 1H: 2.57 (m, 3H, CH3), 7.11 (d, 1H, J = 8.8), 7.25–
7.50 (m, 5H), 7.61 (s, 1H), 7.62 (d, 1H, J = 9.2); 13C: 18.4, 123.4,
124.8, 126.6, 127.7, 128.6, 129.1, 130.3, 131.0, 131.7, 131.8,
134.8, 144.5, 146.4; m/z 270.0690 (Mϩ ϩ H, C16H12NOCl
requires 270.0686).
1-(2-Chlorophenyl)-3,4-dihydroisoquinoline 4a. This com-
pound was obtained in 72% yield (from phenylethylamine) as
1
a wax. νmax (KBr)/cmϪ1 3186, 2897, 2847, 2661, 1615; H: 2.79
(m, 4H, CH2), 6.83 (d, 1H, J = 7.5), 7.14 (m, 2H), 7.30 (m, 5H);
13C: 26.3, 48.1, 127.36, 127.37, 127.9, 129.3, 130.0, 130.3, 130.5,
130.8, 131.4, 133.0, 137.6, 138.6, 166.7; m/z 242.0746 (Mϩ ϩ H,
C15H13NCl requires 242.0737).
1-(2-Chlorophenyl)isoquinoline-3-carboxaldehyde 7
Compound 5b (1.15 g, 4.42 mmol) and selenium oxide (1.62 g,
13.2 mmol) were refluxed in 1,2-dichlorobenzene for 6 hours.
The suspension was concentrated to dryness, dispersed in
dichloromethane and filtered. The filtrate was concentrated
again and the residue chromatographed over silica gel (heptane–
ethyl acetate 2 : 8) to give the aldehyde 7 (1.15 g, 97%) as a solid
which was used without further purification. νmax (KBr)/cmϪ1
3357, 2843, 2363, 1707; 1H: 7.45 (m, 3H), 7.54 (m, 1H), 7.68 (m,
2H), 7.78 (m, 1H), 8.07 (d, 1H, J = 8.1), 8.44 (s, 1H, H-4), 10.24
(s, 1H, CHO); 13C: 121.5, 127.5, 127.9, 129.5, 129.8, 130.4,
130.6, 130.7, 131.6, 131.63, 133.7, 136.2, 137.9, 146.5, 160.1,
194.0; m/z 268.0541 (Mϩ ϩ H, C16H11NOCl requires 268.0529).
1-(2-Chlorophenyl)-3-methyl-3,4-dihydroisoquinoline
4b.
Obtained in 37% yield (from amphetamine) as an oil. The first
chromatography fraction yielded the known 2-chlorobenzo-
nitrile (46%). The NMR spectra of compound 4b indicates the
existence of several conformations with half lives in the range
of NMR time measurement. This does complicate the carbon
spectrum. νmax (KBr)/cmϪ1 3493, 2959, 2937, 1615; H: 1.52
1
(s (br), 3H, CH2), 2.73 (m, 1H, ½ CH2), 2.89 (m, 1H, ½ CH2),
3.7 (m (br), 1H, CH), 6.92 (d, 1H, J = 7.8), 7.14–7.45 (m, 7H);
13C: 23.0 (br), 34.4 (br), 54.2 (br), 127.7, 128.0, 128.2, 128.8,
129.6, 129.8, 129.9, 130.7, 130.8, 130.9, 131.1, 131.3, 131.6,
131.8, 132.1, 132.3, 133.9, 138.0 (br), 139.6, 166.3 (br); m/z
256.0904 (Mϩ ϩ H, C16H15NCl requires 256.0893).
1-(2-Chlorophenyl)-3-hydroxymethylisoquinoline 8
Compound 6b (0.25 g, 0.92 mmol) and trifluoroacetic
anhydride (1.96 ml, 13.9 mmol) were refluxed in 1,2-dichloro-
benzene for 2 hours. This was concentrated to dryness, treated
with a mixture of ethanol (20 ml) and 1 M sodium hydroxide
(20 ml) for 30 minutes. The resulting solution was extracted
with dichloromethane, the organic phase was washed with
water dried over magnesium sulfate and concentrated to dry-
ness. The residue was chromatographed over silica gel
(dichloromethane–ethanol 99 : 1) to give alcohol 8 (0.17 g, 68%)
1-(2-Chlorophenyl)isoquinoline 5a
In a Dean–Stark apparatus, the compound 4a (6 g, 24.8 mmol)
and manganese() oxide (10 g, 124 mmol) were refluxed
in benzene (500 ml) for four days in the course of which
three more portions of manganese oxide were added and reac-
tion samples were monitored by NMR. After removal of the
solvent, the crude residue was chromatographed over silica
gel (dichloromethane–ethanol 98 : 2) yielding compound 5a
(4.32 g, 72%) as an oil. νmax (KBr)/cmϪ1 3051, 1622, 1584, 1558;
1H: 7.32–7.47 (m, 5H), 7.55 (d, 1H, J = 9.0), 7.58–7.64 (m, 2H),
7.81 (d, 1H, J = 8.3), 8.54 (d, 1H, J = 5.9); 13C: 118.9, 125.1,
125.2, 125.5, 125.7, 127.52, 127.9, 128.1, 128.5, 129.5, 131.6,
134.6, 136.5, 140.3, 157.0; m/z 240.0574 (Mϩ ϩ H, C15H11NCl
requires 240.0579).
1
as a wax. νmax (KBr)/cmϪ1 3200, 3058, 1626, 1594, 1562; H:
4.84 (s, 2H, CH2), 7.29–7.45 (m, 5H), 7.51–7.62 (m, 3H), 7.76
(d, 1H, J = 8.2); 13C: 66.7, 118.6, 128.2, 128.6, 128.8, 129.1,
131.7, 132.3, 133.1, 135.1, 138.7, 139.8, 154.0, 160.1; m/z
268.0529 (Mϩ Ϫ H, C16H11NOCl requires 268.0530).
1-(2-Chlorophenyl)isoquinoline-3-carboxylic acid 9
1-(2-Chlorophenyl)-3-methylisoquinoline 5b
Aldehyde 7 (0.6 g, 2.24 mmol), silver nitrate (0.95 g, 5.61 mmol)
and sodium hydroxide (0.72 g, 17.9 mmol) were stirred in a
mixture of ethanol (40 ml) and water (40 ml) for 2 days. The
ethanol was removed in vacuo, the resulting aqueous phase was
made acidic with 1 M hydrochloric acid and extracted with
dichloromethane. The organic layer was washed with water
and concentrated to dryness. The residue was recrystallized in
heptane to yield acid 9 (0.52 g, 82%). Starting from alcohol 8,
using twice the amount of reagents, a similar yield of acid 9
was obtained. This acid was also obtained in 95% yield from
ester 16 which was treated in boiling 50% aqueous ethanol with
4 equivalents of sodium hydroxide for one hour followed by the
work up described above. Mp = 191 ЊC. νmax (KBr)/cmϪ1 3509,
Compound 4b (5.7 g, 22.3 mmol) and sulfur (3.5 g, 111 mmol)
in decalin (150 ml) were refluxed for 8 hours. After removal of
the solvent, the crude residue was chromatographed over silica
gel (dichloromethane) yielding compound 5b (3.71 g, 65%) as a
wax. νmax (KBr)/cmϪ1 3069, 3052, 1766, 1738, 1717; 1H: 2.73 (s,
3H, CH3), 7.36–7.56 (m, 8H), 7.77 (d, 1H, J = 9.1); 13C: 23.9,
118.3, 125.0, 125.9, 126.0, 126.5, 126.7, 129.3, 129.35, 129.7,
130.9, 133.0, 136.6, 138.1, 150.4, 157.8; m/z 254.0745 (Mϩ ϩ H,
C16H13NCl requires 254.0737).
3,4-Dihydroisoquinoline N-oxides 6a, b
To a solution of 3,4-dihydroisoquinolines 5a or 5b (4.2 mmol)
in dichloromethane (150 ml) was added 70% 2-chloroperoxy-
benzoic acid (2.1 g, 8.51 mmol). The solution was stirred over-
night, and washed with a 1 M sodium hydroxide solution and
water. The resulting organic phase was dried over magnesium
sulfate and concentrated to dryness. The residue was chromato-
1
2618, 2364, 1700; H: 7.39–7.78 (m, 7H), 8.05 (d, 1H, J = 8.2),
8.67 (s, 1H); 13C: 123.2, 127.3, 128.1, 129.2, 129.4, 130.4, 130.6,
131.0, 131.7, 132.1, 133.7, 137.0, 137.1, 139.0, 158.3, 165.3;
m/z (C.I.) 284–286; Anal. (C16H10NClO2): Calc: C: 67.74,
H: 3.55, N: 4.94, found: C: 67.77, H: 3.68, N: 4.70%.
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532
531