Reduced Benzimidazo[2,1-a]isoquinolines
533
alumina; ethyl acetate/hexane, 1 : 3) gave partial separation of
diastereomers (12a1), RF 0.2 and (12a2) (main), RF 0.3.
carbonate. The organic layer was dried and the solvent was removed at
reduced pressure to give an oil. Column chromatography (silica; ethyl
acetate/hexane, 1 : 3) gave (14b/c), in a ratio of ca. 1 : 2, as a yellow oil
(0.10 g, 75%) which slowly solidified (Found (EIMS): M+, 336.1839.
C21H24N2O2 requires M+, 336.1838). 1H NMR (CDCl3) δ 0.77–0.83, m,
CH3; 1.20–1.33, m, 2×CH2; 1.57–1.62, m, CH2; 3.00, d, J 15.8 Hz, Ha5;
3.45, dd, J 15.8, 6.4 Hz, Hb5; 3.85–3.86, 2s, 2×OCH3; 4.56, q, J 6.3 Hz,
H6; 6.78–6.80, m, 1H; 6.85–6.93, m, 2H; 7.18, d, J 8.8 Hz, H8 (14c);
7.27, d, J 2.3 Hz, H11 (14c); 7.64, d, J 8.8 Hz, H11 (14b); 8.12–8.17,
m, H1.
1H NMR of (12a1) (CDCl3) δ 0.71, t, J 7.1 Hz, CH3; 1.17–1.28, m,
2×CH2; 1.59–1.64, m, CH2; 4.72, d, J 5.0 Hz, H5; 4.86–4.93, m, H6;
7.24–7.53, m, 6H; 7.77–7.80, m, 1H; 8.25–8.28, m, 1H.
1H NMR of (12a2) (CDCl3) δ 0.71, t, J 7.1 Hz, CH3; 1.17–1.28, m,
2×CH2; 1.59–1.64, m, CH2; 4.22, d, J 1.0 Hz, H5; 4.87–4.93, m, H6;
7.30–7.57, m, 6H; 7.82–7.87, m, 1H; 8.37, d, J 7.5 Hz, 1H.
6-Butyl-3,9-dimethoxy-5,6-dihydrobenzimidazo[2,1-a]isoquinoline-5-
carbonitrile (12b) and 6-Butyl-3,10-dimethoxy-5,6-
dihydrobenzimidazo[2,1-a]isoquinoline-5-carbonitrile (12c)
6-Butyl-3,9-dihydroxy-5,6-dihydrobenzimidazo[2,1-a]isoquinoline
(14d) and 6-Butyl-3,10-dihydroxy-5,6-dihydrobenzimidazo[2,1-
a]isoquinoline (14e)
A mixture of these compounds was obtained from nitriles (11b/c), as for
(12a), as a semi-solid (85% yield) which was used without further
purification.
A mixture of methoxy compounds (14b/c) (0.06 g), 40% aqueous
hydrobromic acid (2 mL) and acetic acid (0.5 mL) was heated under
reflux for 3 h, then poured onto ice/water (20 mL) and taken to pH >10
with 10% sodium hydroxide. The solution was washed three times with
chloroform and the pH was carefully adjusted to 9.4 with 5%
hydrochloric acid. The precipitate that formed was collected by
filtration to give the product as a brown solid (0.05 g, 90%). Preparative
TLC (alumina; ethyl acetate/triethylamine, 20 : 1) gave (14d/e), in a
ratio of ca. 1 : 2, as an off-white solid, m.p. 185°C (darkened >130°C).
1H NMR (CD3OD) δ 0.78–0.84, m, CH3; 1.23–1.36, m, 2×CH2;
1.56–1.61, m, CH2; 3.01, d, J 15.9 Hz, Ha5; 3.39, dd, J 16.1, 6.7 Hz,
Hb5; 4.62–4.70, m, H6; 6.73–6.77, m; 7.00, d, J 2.1 Hz, H11 (14e);
7.24, d, J 8.7 Hz, H8 (14e); 7.39, d, J 8.7 Hz, H11 (14d); 7.84–7.88,
m, H1.
6-Butyl-5,6-dihydrobenzimidazo[2,1-a]isoquinoline-5-carboxylic Acid
(13a)
A mixture of crude nitrile (12a) (2.1 g) and sulfuric acid (57% by
weight, 20 mL) was heated under reflux for 3 h, then poured onto ice/
water (100 mL), basified with sodium hydroxide and the mixture was
filtered. The filtrate was acidified with concentrated hydrochloric acid
and the precipitate which formed was collected by filtration and washed
with water to give a single diastereomer of (13a) as a cream solid (1.25
g, 56%), m.p. >160°C (decomposed with decarboxylation). It was used
in this state in the next step but a small sample was recrystallized from
light petroleum (b.p. 90–120°C)/toluene for microanalysis (Found: C,
74.8; H, 6.5; N, 8.6. C20H20N2O2 requires C, 75.0; H, 6.3; N, 8.7%). 1H
NMR (CDCl3) δ 0.76, t, J 7.0 Hz, CH3; 1.18–1.30, m, 2×CH2;
1.49–1.56, m, CH2; 4.00, s, H5; 5.27, t, J 7.2 Hz, H6; 6.87, t, J 7.5 Hz,
1H; 7.10, t, J 7.8 Hz, 1H; 7.17–7.22, m, 2H; 7.34–7.43, m, 3H; 7.75, d,
J 7.7 Hz, 1H. 13C NMR (CDCl3) δ 13.7, CH3; 22.2, CH2; 28.2, CH2;
33.5, CH2; 49.9, CH; 55.2, CH; 110.2, CH; 117.4, CH; 121.9, C; 123.9,
CH; 124.1, CH; 125.8, CH; 128.1, CH; 130.7, CH; 131.9, CH; 132.6,
C; 133.5, C; 137.4, C; 145.7, C; 173.4, C. Mass spectrum (ESMS) m/z
321 (M + 1).
6-Butyl-12-methyl-5,6-dihydrobenzimidazo[2,1-a]isoquinolinium
Iodide (15a)
Iodomethane (2 mL) was added to a solution of tetracycle (14a) (0.1 g)
in ethyl acetate (5 mL). The mixture was heated at 80°C for 16 h, during
which time a solid separated. This was collected by filtration from the
cooled mixture to give the product as a pale yellow solid (0.1 g, 66%),
m.p. 168°C (from propanol/ethyl acetate) (Found: C, 57.6; H, 5.4; N,
6.7. C20H23IN2 requires C, 57.4; H, 5.5; N, 6.7%). 1H NMR (CDCl3) δ
0.70, t, J 6.9 Hz, CH3; 1.10–1.40, m, 2×CH2; 1.56, q, J 7.3 Hz, CH2;
3.17, d, J 16.4 Hz, Ha5; 3.77, dd, J 16.4, 6.3 Hz, Hb5; 4.41, s, H3CN+;
5.24, q, J 6.9 Hz, H6; 7.47, d, J 7.1 Hz, 1H; 7.52–7.62, m, 4H;
7.79–7.86, m, 2H; 8.24, d, J 7.3 Hz, 1H. 13C NMR (CDCl3) δ 13.5, CH3;
22.1, CH2; 28.0, CH2; 31.5, CH2; 33.0, CH2; 35.9, CH3; 53.5, CH;
112.8, CH; 113.0, CH; 118.5, C; 127.1, CH; 127.2, CH; 127.8, CH;
128.6, CH; 129.9, C; 130.3, CH; 132.7, C; 134.3, CH; 136.0, C;
143.9, C.
6-Butyl-3,9-dimethoxy-5,6-dihydrobenzimidazo[2,1-a]isoquinoline-5-
carboxylic Acid (13b) and 6-Butyl-3,10-dimethoxy-5,6-
dihydrobenzimidazo[2,1-a]isoquinoline-5-carboxylic Acid (13c)
The crude nitrile mixture (12b/c) was hydrolysed as for (13a) to give a
mix of (13b/c), as a cream solid (50%), m.p. >170°C (decomposed with
decarboxylation). 1H NMR (CDCl3/(D6)DMSO) δ 0.73–0.78, m, CH3;
1.19–1.31, m, 2×CH2; 1.54–1.57, m, CH2; 3.79–3.90, m, 7H, 2×OCH3
and H5; 4.98–5.01, m, H6; 6.79–6.94, m, 4H; 7.15–7.25, m, 1H;
8.04–8.08, m, 1H.
6-Butyl-3,9-dimethoxy-12-methyl-5,6-dihydrobenzimidazo[2,1-
a]isoquinolinium Iodide (15b) and 6-Butyl-3,10-dimethoxy-12-methyl-
5,6-dihydrobenzimidazo[2,1-a]isoquinolinium Iodide (15c)
6-Butyl-5,6-dihydrobenzimidazo[2,1-a]isoquinoline (14a)
Acid (13a) (0.1 g) was heated in a covered Petri dish on a thermostatted
hotplate at 165°C for 15 min. The distillate on the cover and the residue
were extracted three times into hot hexane and the combined organic
extracts were evaporated at reduced pressure to give an oil. Column
chromatography (silica; ethyl acetate/hexane, 1 : 3) gave the product as
a yellow oil (0.07 g, 81%) which slowly set to a glass (Found (EIMS):
M+, 276.1632. C19H20N2 requires M+, 276.1626). 1H NMR (CDCl3) δ
0.80, t, J 7.3 Hz, CH3; 1.18–1.35, m, 2×CH2; 1.58–1.65, m, CH2; 3.07,
d, J 15.8 Hz, Ha5; 3.48, dd, J 15.8, 6.4 Hz, Hb5; 4.65, q, J 6.4 Hz, H6;
7.24–7.29, m, 3H; 7.34–7.40, m, 3H; 7.80–7.83, m, 1H; 8.27–8.31, m,
1H. 13C NMR (CDCl3) δ 13.8, CH3; 22.4, CH2; 28.6, CH2; 32.7, CH2;
33.42, CH2; 51.9, CH; 109.3, CH; 119.6, CH; 122.4, CH; 122.7, CH;
125.6, CH; 126.2, C; 127.6, CH; 128.8, CH; 130.5, CH; 133.1, C;
134.2, C; 143.5, C; 148.1, C.
The tetracycle mixture (14b/c) was reacted with iodomethane, as in the
preparation of (15a), and the mixed methiodides (15b/c) (3 : 5) were
obtained as a pale yellow solid (84%), m.p. 186–188°C (Found: C, 55.3;
1
H, 5.7; N, 5.9. C22H27IN2O2 requires C, 55.2; H, 5.7; N, 5.9%). H
NMR [(D6)DMSO] δ 0.74–0.79, m, CH3; 1.09–1.44, m, 2×CH2; 1.52,
q, J 7.9 Hz, CH2; 3.23–3.29, m, Ha5; 3.52, dd, J 16.1, 6.1 Hz, Hb5;
3.90–3.92, m, OCH3; 4.22–4.23, 2s, H3CN+; 5.12–5.20, m, H6;
7.13–7.17, m, 1H; 7.24–7.27, m, 2H; 7.58, d, J 1.8 Hz, H8 (15b); 7.63,
d, J 1.8 Hz, H11 (15c); 7.91, d, J 9.1 Hz, H8 (15c); 7.97, d, J 9.1 Hz,
H11 (15b); 8.17–8.21, m, H1.
6-Butyl-3,9-dihydroxy-12-methyl-5,6-dihydrobenzimidazo[2,1-
a]isoquinolinium Iodide (15d) and 6-Butyl-3,10-dihydroxy-12-methyl-
5,6-dihydrobenzimidazo[2,1-a]isoquinolinium Iodide (15e)
6-Butyl-3,9-dimethoxy-5,6-dihydrobenzimidazo[2,1-a]isoquinoline
(14b) and 6-Butyl-3,10-dimethoxy-5,6-dihydrobenzimidazo[2,1-
a]isoquinoline (14c)
Reaction of (14d/e) with iodomethane in ethyl acetate was carried out
as in the preparation of (15a). The solvent was removed at reduced
pressure and the residue was extracted with hot water. The product
separated from the cooled extract as a cream solid (0.09 g, 62%), m.p.
145–150°C. Microanalysis figures were consistent with C20H23IN2O2
The acid mixture (13b/c) (0.15 g) was heated at 180°C/0.03 mmHg for
90 min and then shaken with a mixture of chloroform and 10% sodium