1
166
M. Derudas, N. Pala, V. Sanna, R. Dallocchio, A. Dess `ı , A. M. Roggio, and M. Sechi
Vol 48
by column flash chromatography eluting with petroleum ether/
ethyl acetate (85/15) to give a pale yellow solid, 0.69 g (98%),
1N HCl. The precipitate obtained was filtered to give a pale
brown solid, 0.11 g, (59%); (c) To a solution of 11 (0.60 g,
2.23 mmol) in ethanol (12 mL), 37% HCl (12 mL) was added
and the reaction mixture was stirred at reflux for 1.5 h. After
this period, the reaction mixture was allowed to cool down,
diluted with water, and the precipitate formed was filtered and
purified by column flash chromatography gradient elution of
petroleum ether/ethyl acetate (80/20 then 70/30) to give a
ꢂ
ꢂ
1
mp 142ꢀ144 C (lit [19], 145ꢀ146 C); H NMR (CDCl
3
): d
7
.77 (d, 1H, ArAH), 7.50ꢀ7.30 (m, 2H, ArAH), 7.24ꢀ7.10
(
NCH
m, 1H, ArAH), 7.02 (s, 1H, ArAH), 4.45 (t, 2H, J ¼ 6.4 Hz,
2
CH
2
), 3.23 (t, 2H, J ¼ 6.4 Hz, NCH
2 2
CH ). ms: m/e 171
þ
(
M ). Mol Formula: C11 NO.
-(2-Carboxyethyl)-1H-indole-2-carboxylic acid (9). To a
H
9
1
solution of 8 (0.18 g, 0.74 mmol) in methanol (6 mL), 2N
ꢂ
brown solid, 0.30 g (72%), mp 140ꢀ142 C for products from
ꢂ
1
NaOH (1.5 mL, 3.0 mmol) was added and the mixture was
ꢂ
(a), (b), and (c) (lit. [17], 138ꢀ140 C); H NMR (CDCl ): d
3
stirred at room temperature for 5 h then at 60 C for 15 h. Af-
7.74 (d, 1H, ArAH), 7.47ꢀ7.35 (m, 2H, ArAH), 7.33 (s, 1H,
ter this period, the reaction mixture was allowed to cool down,
diluted with water, and acidified with 1N HCl. The precipitate
formed was filtered to give a white solid, 0.14 g (81%), mp
ArAH), 7.23ꢀ7.13 (m, 1H, ArAH), 4.27 (t, 2H, NCH
2
), 2.76
(t, 2H, CH ), 2.42 (m, 2H, CH CH CH ). ms: m/e 185 (M ).
þ
2
2
2
2
Mol Formula: C H NO.
12 11
ꢂ
ꢂ
1
2
7
15ꢀ217 C ([20], 220 C); H NMR (CDCl /DMSO-d ): d
(E/Z)-1-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)2,3-
dihydro-1H-pyrrolo[1,2-a]indole bromohydrate (12). To a
solution of 5 (0.25 g, 1.46 mmol) in absolute ethanol (13 mL),
2-amine-2-imidazoline bromohydrate (0.53 g, 2.92 mmol) was
added and the reaction mixture was stirred at reflux for 23 h.
After this period, the precipitate formed was filtered to give a
3
6
.65 (d, 1H, ArAH), 7.50 (d, 1H, ArAH), 7.40ꢀ7.11 (m, 2H,
ArAH), 7.12 (t, 1H, ArAH), 4.86 (t, 2H, J ¼ 7.4 Hz, NCH
2
),
þ
2
Formula: C H NO .
.81 (t, 2H, J ¼ 7.4 Hz, CH COOH). ms: m/e 233 (M ). Mol
2
12
11
4
Ethyl 1-(4-ethoxy-4-oxobutyl)-1H-indole-2-carboxylate
10). A solution of 7 (5.00 g, 26.43 mmol) in anhydrous DMF
80 mL) was added, under a nitrogen atmosphere, to a solution
ꢂ
1
(
(
beige solid, 0.29 g (60%), mp 263ꢀ265 C; H NMR (CDCl
3
DMSO-d ): d 11.34 (bs, 1H, NH), 8.05 (bs, 1H, NH), 7.63 (d,
6
of NaH (60% dispersion in mineral oil) (1.10 g, 27.50 mmol)
in anhydrous DMF (10 mL). Then ethyl 4-bromo-butyrate
1H, ArAH), 7.40 (d, 1H, ArAH), 7.33ꢀ7.00 (m, 2H, ArAH),
6.71 (s, 1H, ArAH), 4.42 (t, 2H, NCH CH ), 3.81 (s, 4H, 2 ꢃ
2
2
þ
(
4.50 mL, 31.44 mmol) was added dropwise and the reaction
NCH
2
imidazolic), 3.47 (t, 2H, NCH
2
CH
2
). ms: m/e 253 (M ).
mixture was stirred at room temperature for 18 h. After this
period, the reaction mixture was quenched with water (30 mL)
and 2N HCl (10 mL) and extracted with ethyl acetate. The or-
ganic phase was washed with water (5 times), dried over
5
Anal. Calcd. for C14H16BrN : C, 50.31; H, 4.83; N, 20.95.
Found C, 50.15; H, 4.93; N, 21.07.
(E/Z)-9-(2-(4,5-dihydro-1H-imidazol-2-yl)hydrazono)-6,7,8,9-
tetrahydropyrido[1,2-a]indole bromohydrate (13). To a solu-
tion of 6 (0.20 g, 1.08 mmol) in absolute ethanol (10 mL), 2-
amine-2-imidazoline bromohydrate (0.39 g, 2.16 mmol) was
added and the reaction mixture was stirred at reflux for 48 h.
After this period, the precipitate formed was filtered to give a
NaSO
.97 g (87%); H NMR (CDCl
d, 1H, ArAH), 7.40ꢀ7.28 (m, 2H, ArAH), 7.20ꢀ7.08 (m,
H, ArAH), 4.64 (t, 2H, NCH CH CH ), 4.37 (q, 2H,
4
then concentrated to give a yellow oil (lit [17], oil),
1
6
3
): d 7.67 (d, 1H, ArAH), 7.46
(
1
2
2
2
ꢂ
1
COOCH CH ), 4.12 (q, 2H, COOCH CH ), 2.34 (t, 2H,
dark yellow solid, 0.10 g (27%), mp 295ꢀ297 C dec;
H
2
3
2
3
NCH
3
2
CH
2
CH
H, COOCH
2
), 2.28ꢀ2.08 (m, 2H, NCH
2
CH
2
CH
CH
2
), 1.41 (t,
3 6
NMR (CDCl DMSO-d ): d 11.46 (bs, 1H, NH), 8.35 (bs, 1H,
2
CH
3
), 1.32ꢀ1.15 (m, 3H, COOCH
2
3
). ms: m/
NH), 7.60 (d, 1H, ArAH), 7.47 (d, 1H, ArAH), 7.30ꢀ7.16 (m,
þ
e 303 (M ). Mol Formula: C H NO .
1H, ArAH), 7.15ꢀ7.00 (d, 2H, ArAH), 4.19 (t, 2H, NCH ),
1
7
21
4
2
Ethyl 9-hydroxy-6,7-dihydropyrido[1,2-a]indole-8-carbox-
ylate (11). To a solution of 10 (5.00 g, 16.48 mmol) in anhy-
drous toluene (200 mL), NaH (60% dispersion in mineral oil;
3.39 (s, 4H, 2 x CH imidazolic), 2.79 (t, 2H, CH ), 2.18 (m,
2
2
þ
2H, CH CH CH ). ms: m/e 267 (M ). Anal. Calcd. for
2 2 2
C H BrN : C, 51.73; H, 5.21; N, 20.11. Found C, 51.50; H,
5.03; N, 20.32.
15
18
5
1
.32 g, 32.96 mmol) was added under a nitrogen atmosphere
and the reaction mixture was stirred at reflux for 6 h. After
this period, the reaction mixture was quenched with ethanol
and water, acidified with 1N HCl and extracted with ethyl ace-
tate. The organic phase was washed with brine, dried over
NaSO and concentrated. The residue was triturated with
4
petroleum ether to give a beige solid, 2.97 g (70%), mp
Ethyl 9-(2-(dimethylamino)ethylamino)-6,7-dihydropyr-
ido[1,2-a]indole-8-carboxylate (14). A solution of 11 (0.20 g,
0.78 mmol), N,N-dimethylethylenediamine (0.17 mL, 1.55
mmol) and DMAP (0.03 g, 0.23 mmol) in anhydrous toluene
(4 mL) was stirred at reflux for 22 h under nitrogen atmos-
phere. After this period, the solvent was removed and the resi-
due purified by column flash chromatography eluting with
ꢂ
ꢂ
1
1
(
00ꢀ102 C (lit [21], 101ꢀ103 C); H NMR (CDCl
bs, 1H, enol), 7.80ꢀ7.60 (m, 2H, ArAH), 7.44ꢀ7.08 (m, 2H,
ArAH), 7.03 (s, 1H, ArAH), 4.36ꢀ4.11 (m, 2H, COOCH ),
3
): d 12.17
CHCl /MeOH (95/5) to give a yellow solid, 0.03 g (12%), mp
3
ꢂ
1
2
100ꢀ103 C; H NMR (CDCl ): d 9.06 (bs, 1H, NH), 7.64 (d,
3
4
.08 (t, 2H, J ¼ 6.6 Hz, NCH ), 2.89 (t, 2H, J ¼ 6.6 Hz,
1H, ArAH), 7.38ꢀ7.23 (m, 2H, ArAH), 7.16ꢀ7.05 (m, 1H,
2
þ
CH ), 1.37 (t, 3H, CH ). ms: m/e 257 (M ). Mol Formula:
2
ArAH), 6.93 (s, 1H, ArAH), 4.21 (q, 2H, COOCH CH ), 4.09
3
2
3
C H NO .
15
2 2 2 2
(t, 2H, NCH CH ), 3.76 (q, 2H, NHCH CH ), 2.81 (t, 2H,
15
3
7
,8-Dihydropyrido[1,2-a]indol-9(6H)-one (6a). (a) To a so-
lution of 11 (1.14 g, 4.43 mmol) in dioxane (70 mL), 1N HCl
22.0 mL, 22.15 mmol) was added and the reaction mixture
NCH CH ), 2.59 (t, 2H, CH CH N(CH ) ), 2.31 (s, 6H,
2 2 2 2 3 2
þ
N(CH ) ), 1.32 (t, 3H, COOCH CH ). ms: m/e 327 (M ).
3
3
2
2
(
Anal. Calcd. for C H N O : C, 69.70; H, 7.70; N, 12.83.
19 25 3 2
was stirred at reflux for 12 h. After this period, the solvent
was removed and the residue triturated with water to give a
pale brown solid, 0.75 g (91%); (b) A solution of 11 (0.25 g,
Found C, 69.99; H, 7.58; N, 12.57.
Ethyl 9-(3-(dimethylamino)propylamino)-6,7-dihydropyr-
ido[1,2-a]indole-8-carboxylate (15). A solution of 11 (0.20 g,
0.78 mmol), N ,N -dimethylpropane-1,3-diamine (0.20 mL,
1.55 mmol) and DMAP (0.03 g, 0.23 mmol) in anhydrous tol-
uene (4 mL) was stirred at reflux for 14 h under nitrogen
1
1
0
.97 mmol) in 12% KOH aqueous solution (10 mL) was
stirred at reflux for 2.5 h. Then, the reaction mixture was
allowed to cool down, diluted with water, and acidified with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet