N. Wang et al.
Bull. Chem. Soc. Jpn. Vol. 86, No. 7 (2013)
867
ation of 6 while heating followed by hydration of the resulting
DMSO-d6): ¤ 159.9, 140.4, 139.8, 138.9, 129.4, 124.5, 123.9,
123.7, 122.0 (2C), 121.8, 121.3, 117.0, 113.1, 110.7, 107.4,
33.9.
5
-methylquinolinium salt 11 provided 5-methyl-5,6-dihydro-
11H-indolo[3,2-c]quinolin-6(5H)-one (3b). Further study of
the resulting 6-alkylaminoindolo[3,2-c]quinoline derivatives
for their antimalarial and anticancer activities is currently
underway in our laboratory.
5,11-Dimethyl-5,6-dihydroindolo[3,2-c]quinolin-6(5H)-one
(5) was prepared by the reaction of 3 (117 mg, 0.5 mmol)
and NaH (36 mg, 1.5 mmol) followed with MeI (0.16 mL,
2
.5 mmol) in DMF (2 mL) at room temperature for 3 h. Usual
Experimental
workup followed by purification by column chromatography
Reactions were monitored by thin layer chromatography
(SiO , hexaneAcOEt 20:1 to 5:1 v/v) afforded 5 as white
2
(
TLC) on silica gel plates (60 F254) and flash chromatog-
solids. Yield: 57 mg (67%). R = 0.57 (hexaneAcOEt 1:2
f
1
raphy was performed on silica gel (230400 mesh) using a
gradient solvent system. The 1H NMR and C NMR spec-
tra were measured on a Varian INOVA-600 spectrometer (600
v/v). H NMR (600 MHz, DMSO-d ): ¤ 8.52 (m, 1H), 8.33
6
13
(m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.66 (m, 2H), 7.43 (dddd,
J = 14.6, 8.2, 6.8, 1.5 Hz, 2H), 7.38 (td, J = 7.5, 0.8 Hz, 1H),
1
3
MHz) with DMSO-d as the solvent. Chemical shifts (¤) were
4.29 (s, 3H), 3.73 (s, 3H); C NMR (151 MHz, DMSO-d6):
¤ 159.2, 140.0, 139.5, 139.2, 129.8, 124.7, 124.1 (2C), 122.1,
121.9, 121.4, 116.4, 114.1, 110.7, 106.9, 34.0, 29.2.
6
determined using tetramethylsilane (TMS) as an internal
standard and the coupling constants (J) are given in hertz.
Melting points were determined on a J-Science RFS-10 hot
stage microscope. MW reaction was performed with ®Reactor
EX, Shikoku Instrumentation Co., Ltd., operated at 2.46 GHz.
Synthesis of 6-Chloro-11H-indolo[3,2-c]quinolone (6). A
mixture of 5,6-dihydro-11H-indolo[3,2-c]quinolin-6(5H)-one
(3a, 234 mg, 1.0 mmol) and POCl (2 mL) was heated at reflux
3
1
-Methylisatin (1b) was prepared by N-methylation of isatin
for 12 h. After cooling to room temperature, the mixture was
1
7
(
1a).
poured into cold aqueous NaHCO . The solids precipitated
3
Synthesis of 5,6-Dihydro-11H-indolo[3,2-c]quinolin-
(5H)-one (3a). A mixture of isatin (1a, 2.94 g, 20 mmol)
were collected by filtration. The crude product was purified by
flash chromatography (SiO2, hexaneAcOEt 20:1 to 10:1 v/v)
6
and 2-aminobenzylamine (2, 4.88 g, 40 mmol) was heated
at reflux in AcOH (50 mL) for 10 h, whereupon the reaction
mixture was poured into water. The solids formed were col-
lected by filtration. The crude product was purified by flash
to give 6 as yellow solids. Yield: 209 mg (83%). R = 0.79
f
1
(hexaneAcOEt = 1:2 v/v). H NMR (600 MHz, DMSO-d ):
6
¤ 13.09 (s, 1H), 8.54 (dd, J = 8.0, 0.9 Hz, 1H), 8.39 (d, J =
8.0 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.77 (m, 2H), 7.71 (m,
1H), 7.587.52 (m, 1H), 7.39 (t, J = 7.5 Hz, 1H), 3.99 (d, J =
chromatography (SiO , hexaneAcOEt = 2:1 v/v) to give 3a
2
1
3
as beige solids. Yield: 4.14 g (88%). R = 0.43 (hexane
7.1 Hz, 1H); C NMR (151 MHz, DMSO-d ): ¤ 144.9, 144.8,
f
6
1
AcOEt = 1:2 v/v). H NMR (600 MHz, DMSO-d ): ¤ 12.53
142.4, 139.2, 129.6, 128.8, 126.7, 126.5, 122.7, 121.7 (2C),
121.2, 117.0, 113.0, 111.8.
6
(s, 1H), 11.40 (s, 1H), 8.17 (d, J = 7.8 Hz, 2H), 7.59 (d, J =
8
7
.1 Hz, 1H), 7.477.43 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.27
.22 (dt, J = 15.3, 7.5 Hz, 2H); 13C NMR (151 MHz, DMSO-
Synthesis of 6-Chloro-11-methyl-11H-indolo[3,2-c]quino-
line (8). 6-Chloro-11H-indolo[3,2-c]quinoline (6, 500 mg, 2.0
mmol) was dried over P O under vacuum and dissolved in
d6): ¤ 160.3, 141.1, 138.4, 138.1, 129.6, 124.8, 124.4, 122.5,
2
5
1
21.9, 121.5, 121.2, 116.5, 112.4, 112.2, 106.9.
The same reaction of 1b and 2 in AcOH afforded 5-methyl-
THF (5 mL). To this solution was added NaH (62.4 mg, 2.6
mmol) with cooling on an ice-bath. After being stirred for
1 h, MeI (0.15 mL, 2.6 mmol) was added and the mixture was
stirred at room temperature for 3 h. The solids precipitated were
collected by filtration and washed with brine and water. The
crude products were purified by column chromatography (SiO2,
hexaneAcOEt 10:1 v/v) to afford 8 as yellow solids; mp 198
5
,6-dihydro-11H-indolo[3,2-c]quinolin-6(5H)-one (3b) in 60%
1
yield; R = 0.5 (hexaneAcOEt = 1:2 v/v). H NMR (600
MHz, DMSO-d6): ¤ 12.55 (s, 1H), 8.288.23 (dd, J = 22.4,
7
f
.8 Hz, 2H), 7.617.60 (m, 3H), 7.397.35 (m, 2H), 7.26 (t,
13
J = 7.5 Hz, 1H), 3.73 (s, 3H); C NMR (151 MHz, DMSO-d6):
¤
1
159.5, 140.1, 139.2, 138.3, 130.1, 125.1, 124.6, 123.1, 122.2,
21.6, 121.3, 116.2, 113.4, 112.2, 106.4, 29.0.
200 °C. Yield: 415 mg (78%). R = 0.81 (hexaneAcOEt = 1:2
f
1
v/v). H NMR (600 MHz, DMSO-d ): ¤ 8.81 (d, J = 8.3 Hz,
6
Synthesis of 11-Methyl-5,6-dihydroindolo[3,2-c]quinolin-
1H), 8.50 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.94 (d,
J = 8.3 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.72 (t, J = 7.5 Hz,
1H), 7.62 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 4.43 (s,
6
6
(5H)-one (4).
5,6-Dihydro-11H-indolo[3,2-c]quinolin-
(5H)-one (3a, 117 mg, 0.5 mmol) was dried over P O under
2
5
1
3
vacuum and dissolved in DMF (2 mL). To this solution was
added NaH (13.2 mg, 0.55 mmol) with cooling on an ice-bath
and stirred for 1 h, and then MeI (0.04 mL, 0.65 mmol) and
the resulting mixture was stirred at room temperature for 3 h.
The mixture was filtered and the solids were washed with brine
and dried over P O under vacuum. The crude product was
3H); C NMR (151 MHz, DMSO-d6): ¤ 145.7, 145.0, 141.7,
140.8, 129.3, 129.3, 126.62 (C), 123.6, 122.1, 121.8, 120.2,
117.7, 111.8, 111.2, 34.1. HRMS (ESI) calcd for C H ClN
2
1
6
12
+
[M + H] Exact Mass: 267.0689, found 267.0697.
1,1-Dimethyl-4-(11-methyl-11H-indolo[3,2-c]quinolin-6-
yl)-1,4-diazepanium Iodide (10). 6-(4-Methyl-1,4-diazepan-
1-yl)-11H-indolo[3,2-c]quinoline (7, 500 mg, 1.5 mmol) was
dried over P O under vacuum and dissolved in THF (5 mL).
2
5
purified by column chromatography (SiO , hexaneAcOEt
2
2
(
0:1 to 5:1 v/v) to afford yellow 4 as solids. Yield: 59 mg
2
5
1
48%). Rf = 0.30 (hexaneAcOEt 1:2 v/v). H NMR (600 MHz,
DMSO-d6): ¤ 11.54 (s, 1H), 8.46 (d, J = 8.2 Hz, 1H), 8.29
d, J = 7.7 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.52 (dt, J = 7.7,
.7 Hz, 2H), 7.42 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.29 (ddd,
To this solution was added NaH (62.4 mg, 2.6 mmol) with
cooling on an ice-bath. After being stirred for 1 h, MeI (0.15
mL, 2.6 mmol) was added and the mixture was stirred at room
temperature for 3 h. The solids precipitated were collected by
filtration and washed with water and CH Cl . White solids, mp
(
3
1
3
J = 8.3, 4.7, 1.6 Hz, 2H), 4.31 (s, 3H); C NMR (151 MHz,
2
2