Novel Heterocycles
245
3-(2-Hydroxy-ethyl)-1H-indole-2-carboxylic Acid [2-(1-Phenyl-1H-pyraz-
2-[2-(1-Methyl-1H-pyrrol-2-yl)-ethyl]-2,3,4,9-tetrahydro-pyrido[3,4-b]-
ol-4-yl)-ethyl]-amide (4)
indol-1-one (11)
Compound 3 (3.7 g, 20 mmol) and the amine 2 (5.6 g, 30 mmol) were
refluxed in toluene (50 mL) for 48 h. After cooling to room temperature,
ethanol (40 mL) was added and the precipitated product was filtered, washed
with cold ethanol and dried. It was crystallized from ethanol as colourless
microcrystals, mp 232–234 °C; yield 3.4 g (55%). IR: ν (cm1) 3237–2910
(NH and OH), 1600 (C=O, amide I band), a band split at 1560 and 1470
(amide II band, C=N, and aromatics). 1H NMR (CDCl3): δ (ppm) 11.27 (s,
1H, indole-NH), 8.85 (s, 1H, amide-NH), 8.6 (s, 1H, pyrazole-C5-H), 8.38
(s, 1H, pyrazole-C3-H), 7.8–7.0 (m, 9H, Ar-H), 5.38 (s, 1H, OH), 3.6 (t, J =
5.3 Hz, 2H, CH2-OH), 3.3 (t, J = 7 Hz, 2H, CH2-NH), 3.08 (t, J = 5.3 Hz,
2H, indole-CH2), and 2.8 (t, J = 7 Hz, 2H, pyrazole-CH2). Anal.
(C22H22N4O2) C, H, N.
Under nitrogen atmosphere, a mixture of 10 (5.9 g, 20 mmol), the amine
8 (3.7 g, 30 mmol), anhydrous potassium carbonate (4.1 g, 30 mmol) and few
crystals of potassium iodide was refluxed in absolute ethanol (120 mL) for
72 h. After removing the solvent to dryness under reduced pressure, the
residue was treated with excess water and extracted several times with
methylene chloride. The organic extract was washed twice with a saturated
solution of sodium chloride, then with water, dried over anhydrous magne-
sium sulphate and filtered. Rotary evaporation of the methylene chloride
afforded a light brown semisolid residue which was crystallized from tolu-
ene/petroleum ether (3:1) as creamy white crystals, slightly hygroscopic, mp
196–198 °C; yield 1.6 g (27%). IR: ν (cm–1) 3250 (NH), 1630 (C=O amide
I band), a band split at 1600 and 1530 (amide II band and aromatics). 1H
NMR (CDCl3): δ (ppm) 9.11 (s, 1H, indole-NH), 7.6–7.07 (m, 4H, Ar-H),
6.5 (d, J = 3.5 Hz, 1H, at pyrrole-C5-H), 6.15–5.65 (m, 2H, pyrrole-C3-H,
-C4-H), 3.54 and 3.38 (two t, J = 7 Hz, 4H, CH2-N-CH2), 3.4 (s, 3H, CH3),
3.07 (t, J = 7 Hz, 2H, indole-CH2), and 2.8 (t, J = 7 Hz, 2H, pyrrole -CH2).
Anal. (C18H19N3O x 1/3 H2O) C, H, N.
1-Methyl-2-(2-nitroethenyl)-1H-pyrrole (7)
A mixture of 6 (10.9 g, 100 mmol), ammonium acetate (4 g, 52 mmol) and
nitromethane (25 mL) was heated under reflux for 30 min and then cooled
to room temperature. Excess nitromethane was removed under reduced
pressure. The remaining solid residue was crystallized from ethanol, afford-
ing shiny yellow needles, mp 104–106 °C; yield 9.2 g (61%). IR: ν (cm1)
1614 (C-NO2), 1560 (C=C). 1H NMR (CDCl3): δ (ppm) 8.1 (d, J = 15 Hz,
1H, =CH-NO2), 7.5 (d, J = 15 Hz, 1H, pyrrole-CH=), 6.9 (d, J = 3.5 Hz, 1H,
C5-H), 6.77 (d, J = 3.5 Hz, 1H, C3-H), 6.26 (t, J = 3.5 Hz, 1H, C4-H), and
3.77 (s, 3H, CH3). Anal. (C7H8N2O2) C, H, N.
3-Methyl-4,5,6,7,12,12b-hexahydro-3H-indolo[2,3-a]pyrrolo[2,3-h]quin-
olizine (12)
Method A: Under anhydrous conditions, the amide 9 (3.5 g, 11 mmol) was
heated under reflux with phosphorus oxychloride (10 mL) for 3 h. After
cooling to room temperature, excess ether was added, and a dark brown oily
residue was separated. The organic layer was decanted, the residue was
treated withether (5× 50 mL) and excess ether was evaporated under reduced
pressure. The remaining residue was dissolved in methanol (100 mL) and
then treated with sodium borohydride (8.0 g) portionwise over a period of 30
min while cooling to 0 °C. Stirring was kept for 18 h at room temperature,
then methanol was evaporated to dryness under reduced pressure. The
remaining light yellow residue was treated with excess water (150 mL) and
extracted thoroughly with ether. The ethereal extract was washed twice with
a saturated solution of sodium chloride then with water, dried over anhydrous
magnesium sulphate, filtered, and evaporated to dryness under reduced
pressure. Crystallization of the residue from ethanol/petroleum ether (4:1)
afforded deep yellow microcrystals, mp 202–204 °C; yield 1.0 g (33%).
Method B: Under anhydrous conditions, the lactam 11 (2.9 g, 10 mmol)
was refluxed with phosphorus oxychloride (10 mL) in toluene (60 mL) for 5
h. The reaction mixture was worked up as described under method A; yield
0.6 g (20%). IR: ν (cm1) 3390 (NH), 1560 (aromatics). 1H NMR (CDCl3): δ
(ppm) 7.98 (s, 1H, indole-NH), 7.5–7.0 (m, 4H, Ar-H), 6.57 (d, J = 3.5 Hz,
1H, C2-H), 6.2 (d, J = 3.5 Hz, 1H, C1-H), 5.13 (s, 1H, C12b-H), 3.46 (s, 3H,
CH3), and 3.7–2.6 (m, 8H, overlapped signals of two CH2-CH2 moieties).
Anal. (C18H19N3 x C2H5OH) C, H, N.
2-(1-Methyl-1H-pyrrol-2-yl)-ethylamine (8)
Under strictly anhydrous conditions, a solution of 7 (9.1 g, 60 mmol) in
freshly distilled THF (50 mL) was added dropwise to a cooled stirred
suspension of lithium aluminium hydride (11.4 g, 300 mmol) in freshly
distilled THF (100 mL) over a period of 45 min. Working up as described
for compound 2 afforded a deep yellow oil (bp[21] 66–68 °C/1.4 Torr), yield
5.8 g (78%). It was used directly in the next reaction step without further
purification. IR (NaCl): ν (cm1) 3290–2890 (NH and CH). 1H NMR
(CDCl3): δ (ppm) 6.6 (d, J= 3.5 Hz, 1H, C5-H), 6.0–5.8 (m, 2H, C3-H, C4-H),
3.5 (s, 3H, CH3), 2.9 (t, J = 7 Hz, 2H, CH2-NH2), 2.65 (t, J = 7 Hz, 2H, pyrrole
-CH2) and 1.77 (s, 2H, NH2).
3-(2-Hydroxyethyl)-1H-indole-2-carboxylic Acid [2-(1-Methyl-1H-pyrrol-
2-yl)-ethyl]-amide (9)
Pyranoindole 3[7] (3.7g, 20mmol)andtheamine 8 were refluxedintoluene
(50 mL) for 48 h. Working up as described for compound 4 gave rise to 9. It
was crystallized from ethanol as white microcrystals, mp 232–234 °C; yield
3.4 g (55%). IR: ν (cm–1) 3448 (NH and OH), 1665 (C=O, amide I band), a
band split at 1600and1530(amide II bandandaromatics). 1H NMR (CDCl3):
δ (ppm) 11.23 (s, 1H, indole-NH), 8.77 (t, J = 7 Hz, 1H, amide-NH),
7.62–6.92 (m, 4H, Ar-H), 6.6 (d, J = 3.5 Hz, 1H, pyrrole-C5-H), 6.1–5.84
(m, 2H, pyrrole-C3-H, -C4-H), 5.3 (s, 1H, OH), 3.62 (t, J = 5.3 Hz, 2H,
CH2-OH), 3.5 (s, 3H, CH3), 3.38 (t, J = 7 Hz, 2H, CH2-NH), 3.07 (t, J = 5.3
Hz, 2H, indole-CH2), and 2.8 (t, J = 7 Hz, 2H, pyrrole-CH2). Anal.
(C18H21N3O2) C, H, N.
3,5a-Dimethyl-4,5,6,7,12,12b-hexahydro-3H-indolo[2,3-a]pyrrolo[2,3-h]
quinolizinium Iodide (13)
Under anhydrous conditions, methyl iodide (7.1 g, 50 mmol) was added to
a stirred solution of 12 (2.7 g, 10 mmol) in dry acetone (30 mL). Stirring was
maintained at room temperature for 18 h and the precipitated deep yellow
solid was separated by centrifugation. It was used directly in the next reaction
without further purification.
3,6-Dimethyl-3,4,5,6,7,8,13,14-octahydro-indolo[3,2-d]pyrrolo[3,2-g]-
azecine (14)
To a suspension of the quaternary ammonium compound 13 in absolute
ethanol (5 mL) in a three-necked flask immersed in a liquefied nitrogen bath
ammonia was condensed (100 mL). To the mixture (maintained at –40 °C
with methanol-dry ice) sodium (1 g, 4.35 mmol) was added and the resulting
dark blue solution was stirred for 45 min. The blue colour was quenched by
adding few crystals of ammonium chloride. Ammonia was allowed to
evaporate and the remaining residue was treated with water (20 mL) and
extracted thoroughly with methylene chloride. The organic layer was washed
twice each with 10 mL of sodium hydroxide solution (w = 5%) and then with
water, dried over anhydrous magnesium sulphate, filtered and evaporated to
dryness under reduced pressure. The resulting dark orange oil (300 mg) was
purified by column chromatography on alumina (Fluka, type 507C neutral),
3-(2-Bromo-ethyl)-1H-indole-2-carboxylic Acid Ethyl Ester 10
A stirred solution of compound 3 (11.2 g, 60 mmol) in absolute ethanol
(150 mL) was saturated with dry hydrogen bromide gas at 0 °C. Cooling and
stirring were maintained for 18 h. The precipitated product was filtered,
washed several times with cold ethanol and crystallized twice from ethanol.
Creamy white shiny needles, mp 153–155 °C; yield 13 g (73%). IR: ν (cm1)
1
3400 (NH), 1705 (C=O ester), 1275 (C-O-C). H NMR (CDCl3): δ (ppm)
9.0 (s, 1H, NH), 7.77–7.08 (m, 4H, Ar-H), 4.42 (q, J = 5.3 Hz, 2H,
COO-CH2), 3.77–3.42 (m, 4H, CH2-CH2), and 1.46 (t, J = 5.3 Hz, 3H,
COO-CH2-CH3). Anal. (C13H14BrNO2) C, H, N.
Arch. Pharm. Pharm. Med. Chem. 334, 241–247 (2001)