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D. B. Khadka et al. / Bioorg. Med. Chem. 19 (2011) 1924–1929
8.63 (m, 1H), 7.96–7.93 (m, 1H), 7.60–7.30 (m, 6H), 4.17–4.14 (m,
2H), 4.11–4.07 (m, 2H), 2.94–2.91 (m, 4H), 2.67–2.64 (m, 2H), 2.41
(s, 3H). EIMS: m/z 343 (M+, 100).
5.1.12. 11-Methyl-5-(4-methylpiperazin-1-yl)-11H-indeno[1,2-
c]isoquinolin-11-ol (9a)
To a stirred solution of 7a (100 mg, 0.27 mmol) in THF (10 mL),
1 M CH3MgBr in n-butyl ether (0.6 mL, 0.54 mmol) was added at
0 °C and the reaction mixture was continuously stirred while the
temperature increased to room temperature. After 12 h, the reac-
tion was quenched with water and the mixture was filtered
through celite. The filtrate was washed with CH2Cl2 and brine,
dried over anhydrous Na2SO4 and concentrated to dryness. The res-
idue was purified by column chromatography on silica gel with
hexane/ethyl acetate (2:1) to yield 9a (82 mg, 79%) as a yellow so-
lid. mp: 201–202 °C. IR cmÀ1: 3421. 1H NMR (CDCl3): d 8.28 (d,
J = 8.0 Hz, 1H), 7.96–7.35 (m, 7H), 3.13 (m, 4H), 2.46 (m, 4H),
2.21 (s, 3H), 1.87 (s, 3H). EIMS: m/z 345 (M+, 85).
5.1.5. 5-Butylaminoindeno[1,2-c]isoquinolin-11-one (7e)
The procedure described for the preparation of 7a afforded 7e
(98%) as a yellow solid. mp: 215–218 °C. 1H NMR (CDCl3): d
8.72–8.69 (m, 1H), 7.68–7.26 (m, 7H), 5.99 (s, 1H), 3.88–3.82 (m,
2H), 1.83–1.73 (m, 2H), 1.58–1.48 (m, 2H), 1.03 (t, J = 7.3 Hz, 3H).
EIMS: m/z 302 (M+, 55).
5.1.6. 5-Piperazin-1-ylindeno[1,2-c]isoquinolin-11-one (7f)
The procedure described for the preparation of 7a gave 7f (73%)
as a yellow solid. mp: 188–189 °C. 1H NMR (CDCl3): d 8.73–8.70
(m, 1H), 7.89–7.28 (m, 7H), 3.80 (t, J = 4.9 Hz, 4H), 3.14 (t,
J = 4.9 Hz, 4H), 1.98 (s, 1H). EIMS: m/z 315 (M+, 66).
5.1.13. 11-Hexyl-5-(4-methylpiperazin-1-yl)-11H-indeno[1,2-
c]isoquinolin-11-ol (9b)
5.1.7. 5-(4-Methylpiperazin-1-yl)-11H-indeno[1,2-c]isoquinolin
(8a)
The procedure described for the preparation of 9a gave 9b (70%)
as a yellow solid. mp: 83–84 °C. 1H NMR (CDCl3): d 8.27 (d,
J = 8.1 Hz, 1H), 8.00–7.27 (m, 7H), 4.50 (s, 1H), 3.22 (s, 4H), 2.53
(s, 4H), 2.48–2.30 (m, 2H), 2.24 (s, 3H), 1.08–0.96 (m, 6H), 0.71
(t, J = 6.9 Hz, 3H), 0.66–0.61 (m, 2H). EIMS: m/z 415 (M+, 100).
A reaction mixture of compound 7a (475 mg, 1.79 mmol) and
1 M borane–tetrahydrofuran complex (4 mL) in dry THF (10 mL)
was refluxed for 6 h. After cooling to room temperature, the
mixture was concentrated in vacuo and the residue was diluted
with EtOAc (100 mL). Glacial acetic acid was added dropwise to
the reaction mixture until pH 5. The organic layer was washed
with saturated sodium bicarbonate (100 mL) and brine, dried
over Na2SO4 and concentrated to give the residue which was
purified by short silica gel column with CH2Cl2/methanol
(15:1) to yield the dehydrogenated compound 8a (315 mg,
56%) as a yellow solid. mp: 178–180 °C. 1H NMR (CDCl3): d
8.01 (d, J = 8.4 Hz, 1H), 8.02–7.99 (m, 1H), 7.91 (d, J = 8.3 Hz,
1H), 7.68–7.34 (m, 5H), 4.03 (s, 2H), 3.86–3.83 (m, 2H), 3.68–
3.65 (m, 2H), 3.36–3.33 (m, 2H), 3.12–3.05 (m, 2H), 2.77 (s,
3H). EIMS: m/z 315 (M+, 92).
5.1.14.5-(4-Methylpiperazin-1-yl)-11H-indeno[1,2-c]isoquinolin-
11-ol (10a)
To a stirred solution of 7a (100 mg, 0.27 mmol) in 10 mL MeOH
was added NaBH4 (31 mg, 0.82 mmol) at 0 °C and the reaction mix-
ture was stirred at room temperature for 4 h. The reaction was
quenched with water and extracted with CH2Cl2. The CH2Cl2 layer
was washed with brine, dried over anhydrous Na2SO4 and concen-
trated to dryness. The residue was purified by column chromatog-
raphy on silica gel with hexane/ethyl acetate (2:1) to yield the
alcohol 10a (68 mg, 77%) as a white solid. mp: 195–197 °C. 1H NMR
(CDCl3): d 8.21–8.18 (m, 1H), 7.91 (t, J = 8.2 Hz, 2H), 7.68–7.60 (m,
2H), 7.45–7.27 (m, 3H), 5.75 (s, 1H), 3.16 (m, 4H), 2.53–2.38 (m,
4H), 2.31 (s, 3H). EIMS: m/z 331 (M+, 78).
5.1.8. 5-Morpholin-4-yl-11H-indeno[1,2-c]isoquinolin (8b)
The procedure described for the preparation of 8a yielded 8b
(91%) as a yellow solid. mp: 159–160 °C. 1H NMR (CDCl3): d
8.17–8.14 (m, 1H), 8.03–8.00 (m, 1H), 7.87–7.84 (m, 1H),
7.64–7.31 (m, 5H), 4.04–3.99 (m, 4H), 3.97 (s, 2H), 3.52–3.48 (m,
4H). EIMS: m/z 302 (M+, 100).
5.1.15. 5-Morpholin-4-yl-11H-indeno[1,2-c]isoquinolin-11-ol
(10b)
The procedure described for the preparation of 10a afforded
10b (78%) as a white solid. mp: 149–151 °C. IR cmÀ1: 3382.
1H NMR (CDCl3): d 8.23–7.34 (m, 8H), 5.82 (d, J = 5.8 Hz, 1H),
3.95 (t, J = 4.7 Hz, 4H), 3.50–3.45 (m, 4H). EIMS: m/z 318 (M+, 67).
5.1.9. 5-(4-Ethylpiperazin-1-yl)-11H-indeno[1,2-c]isoquinolin
(8c)
The procedure described for the preparation of 8a gave 8c (69%)
as a yellow solid. mp: 176–179 °C. 1H NMR (CDCl3): d 8.11–8.08
(m, 1H), 8.02–7.99 (m, 1H), 7.92–7.89 (m, 1H), 7.68–7.34 (m,
5H), 4.02 (s, 2H), 3.91–3.87 (m, 2H), 3.69–3.67 (m, 2H), 3.29–
3.27 (m, 2H), 3.14–3.09 (m, 2H), 3.07–3.00 (m, 2H), 1.36 (t,
J = 7.3 Hz, 3H). EIMS: m/z 329 (M+, 87).
5.1.16. 5-(4-Ethylpiperazin-1-yl)-11H-indeno[1,2-c]isoquinolin-
11-ol (10c)
The procedure described for the preparation of 9a gave 9c (87%)
as a white solid. mp: 203–207 °C. 1H NMR (CDCl3): d 8.22–8.19 (m,
1H), 7.99–7.35 (m, 7H), 5.79 (s, 1H), 3.32 (m, 2H), 3.21 (m, 2H),
2.68–2.62 (m, 4H), 2.52–2.45 (m, 2H), 1.59 (t, J = 7.2 Hz, 3H). EIMS:
m/z 345 (M+, 100).
5.1.10. 5-(4-Methyl-[1,4]diazepan-1-yl)-11H-indeno[1,2-
c]isoquinolin (8d)
5.1.17. Acetic acid 5-morpholin-4-yl-11H-indeno[1,2-
The procedure described for the preparation of 8a gave 8d (82%)
as a yellow solid. mp: 147–149 °C. 1H NMR (CDCl3): d 8.07 (d,
J = 8.5 Hz, 1H), 7.99–7.96 (m, 1H), 7.90–7.87 (m, 1H), 7.66–7.35
(m, 5H), 4.00 (s, 2H), 3.99–3.92 (m, 2H), 3.81–3.76 (m, 2H),
3.50–3.35 (m, 3H), 3.15–3.07 (m, 1H), 3.12 (s, 3H), 2.34–2.32 (m,
1H), 2.21–2.13 (m, 1H). EIMS: m/z 329 (M+, 54).
c]isoquinolin-11-yl ester (11)
To a solution of 10b (331 mg, 1.04 mmol) in 10 mL CH2Cl2, pyr-
idine (107 mg, 1.35 mmol) and 4-dimethylaminopyridine (40 mg)
was added anhydride acetic acid (127 mg, 1.25 mmol) at 0 °C un-
der nitrogen. The reaction mixture was stirred overnight and then
poured into water followed by extraction with ether and the ether
layer was washed with brine, dried over Na2SO4 and concentrated
in vacuo. The residue was purified by column chromatography
with n-hexane/ethyl acetate (6:1) on silica gel to afford 11
(278 mg, 74%) as a yellow solid. mp: 164–166 °C. IR cmÀ1: 1726.
1H NMR (CDCl3): d 8.14 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H),
7.78–7.75 (m, 1H), 7.68–7.33 (m, 5H), 7.14 (s, 1H), 4.02–3.99 (m,
4H), 3.58–3.55 (m, 4H), 2.23 (s, 3H). EIMS: m/z 360 (M+, 57).
5.1.11. n-Butyl(11H-indeno[1,2-c]isoquinolin-5-yl)amine(8e)
The procedure described for the preparation of 8a gave 8e (55%)
as a yellow solid. 1H NMR (CDCl3): d 8.00 (d, J = 7.4 Hz, 1H),
7.81–7.77 (m, 2H), 7.62–7.55 (m, 2H), 7.42–7.31 (m, 3H), 5.27 (s,
1H), 3.93 (s, 2H), 3.78 (q, J = 6.5 Hz, 2H), 1.77 (m, 2H), 1.53 (m,
2H), 1.03 (t, J = 7.3 Hz, 3H). EIMS: m/z 288 (M+, 100).