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DOI: 10.1055/s-0029-1218340
Synthesis and Ring Opening of Alkaloid-Type Compounds with a Novel Indolo[2,3-c][2]benzazepine Skeleton
Publication History
Publication Date:
03 November 2009 (online)
Abstract
Alkylation of the magnesium salts of 2,3-disubstituted indoles with 2-bromomethylbenzonitrile gave 3-(2-cyanobenzyl)-3H-indole derivatives. Reduction of the cyano group of N-methyl 3-(2-cyanobenzyl)-3H-indolium salts afforded previously unreported indolo[2,3-c][2]benzazepines, while acid hydrolysis gave the corresponding indolo[2,3-c][2]benzazepinones. The action of strong protonic acids on indolo[2,3-c][2]benzazepines causes opening of the benzazepine ring annelated to the indole system to form 3H-indolium salts.
Key words
alkaloids - indoles - indolo[2,3-c][2]benzazepines - ring closure - ring opening
- Supporting Information for this article is available online:
- Supporting Information
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References and notes
Postdoctoral fellow of the Research Foundation-Flanders (FWO).
13
Analytical and
Spectroscopic
Data
for Compound 12a
Yellow solid, mp >250 ˚C
(from DMSO, with decomp.).
¹H NMR
(500 MHz, DMSO-d
6): δ = 0.78
(3 H, s, CH3), 3.04 (1 H, d, ²
J = 14.2 Hz,
12-H), 3.09 (1 H, d, J = 14.2
Hz, 12-H), 3.40 (1 H, s, C=NH), 5.91 (1 H, s, 6-H), 6.34
(1 H, br s, NH), 6.96 (1 H, m, 2-H), 7.13 (2 H, m, 3-H, 4-H), 7.29
(1 H, d, J = 7.3
Hz, 1-H), 7.38-7.40 (3 H, m, 9-H, 10-H, 11-H), 7.75 (1
H, m, 8-H). ¹³C NMR (125 MHz, DMSO-d
6): δ = 22.3
(CH3), 39.7 (C-12), 51.2 (C-12a), 96.6 (C-6), 117.2 (C-4),
120.9 (C-1), 122.6 (C-2), 127.1 (C-9), 127.6 (C-3), 127.7 (C-8),
129.7 (C-10), 131.8 (C-11), 133.8 (C-7a), 136.4 (C-11a), 144.5 (C-12b),
151.8 (C-7), 155.3 (C-4a), 185.3 (C-5a). IR (KBr): 3430 (NH), 3310
(NH), 1655 (N=C) cm-¹. MS
(ES+): m/z (%) = 262
(50) [M + 2H]+, 261
(100) [M + H]+. Anal.
Calcd for C18H16N2: C, 83.04; H,
6.19; N, 10.76. Found: C, 82.74; H, 5.99; N, 10.44.
Typical Procedure for the Preparation of an Indolo[2,3- c ][2]benzazepine A solution of 3H-indolium salt 13a (0.5 g, 1.24 mmol) in EtOH (15 mL) was poured in a solution of 5% Na2CO3 (50 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with H2O, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was dissolved in dry Et2O (10 mL), LiAlH4 (94 mg, 2.48 mmol) was added, and the mixture was refluxed under argon for 5 h. The reaction mixture was allowed to cool to r.t. and H2O (1 mL) was dropped carefully into reaction flask. A finely suspended solid was filtered off using a fritted glass filter, and the solid material washed with Et2O (20 mL). The filtrate was washed with H2O, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane-EtOAc, 7:1) to yield 14a (0.19 g, 55%) as a viscous oil. ¹H NMR (500 MHz, CDCl3): δ = 0.96 (3 H, s, 5a-CH3), 1.15 (3 H, s, 12a-CH3), 1.68 (1 H, s, NH), 2.36 (1 H d, ² J = 14.3 Hz, 12-H), 2.72 (3 H, s, NCH3), 3.56 (1 H, d, ² J = 15.1 Hz, 7-H), 3.68 (1 H, d, ² J = 14.3 Hz, 12-H), 4.52 (1 H, d, ² J = 15.1 Hz, 7-H), 6.47 (1 H, d, J = 7.6 Hz, 4-H), 6.71 (1 H, t, J = 7.3 Hz, 2-H), 7.00 (1 H, d, J = 7.1 Hz, 1-H), 7.05 (1 H, m, 8-H), 7.11 (1 H, t, J = 7.6 Hz, 3-H), 7.14-7.19 (3 H, m, 9-H, 10-H, 11-H). ¹³C NMR (125 MHz, CDCl3): δ = 18.7 (12a-CH3), 18.9 (5a-CH3), 27.0 (NCH3), 44.7 (C-12), 45.3 (C-7), 46.2 (C-12a), 87.9 (C-5a), 106.5 (C-4), 117.5 (C-2), 121.1 (C-1), 126.3 (C-8, C-9), 126.6 (C-10), 127.4 (C-3), 130.3 (C-11), 137.5 (C-12b), 138.4 (C-11a), 143.0 (C-7a), 149.1 (C-4a). ¹5N NMR (50.7 MHz, CDCl3, ref.: MeNO2): δ = -333.3 (N-6), -305.4 (N-3). IR (KBr): 3365 (NH) cm-¹. MS (ES+): m/z (%) = 280 (50) [M + 2H]+, 279 (100) [M + H]+. Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 81.48; H, 7.60; N, 10.34.
16
Typical Procedure
for the Preparation of an Indolo[2,3-
c
][2]benzazepin-7(5
H
)-one
A
solution of 3H-indolium salt 13a (0.5 g, 1.24 mmol) in concentrated
H2SO4 (12 mL) was heated at 50 ˚C
for 5 h. The mixture was poured onto crushed ice, neutralized with 10% KOH
solution and extracted with Et2O (3 × 15
mL). The combined organic layers were washed with H2O,
dried over Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified by column chromatog-raphy
(hexane-EtOAc, 2:1) to yield 19a (0.195
g, 53%), mp 226-227 ˚C (from
EtOH). ¹H NMR (500 MHz, CDCl3): δ = 1.28
(3 H, s, 5a-CH3), 1.45 (3 H, s, 12a-CH3),
2.30 (3 H, s, NCH3), 2.44 (1 H, br s, 12-H), 3.29 (1
H, d, ²
J = 12.7
Hz, 12-H), 5.85 (1 H, br s, 4-H), 6.54 (1 H, br s, 11-H), 6.66 (1H,
br t, J = 7.4 Hz, 2-H), 6.82
(1 H, br s, NH), 6.94 (1 H, br t, J = 7.6
Hz, 3-H), 7.03 (1 H, br s, 10-H), 7.07 (1 H, d, J = 7.2
Hz, 1-H), 7.16 (1 H, br t, J = 7.3
Hz, 9-H), 7.57 (1 H, br d, J = 7.5
Hz, 8-H). ¹³C NMR (125 MHz, CDCl3): δ = 19.5
(5a-CH3), 21.5 (12a-CH3), 26.1 (NCH3),
47.6 (C-12), 55.1
(C-12a), 84.3 (C-5a), 104.5 (C-4), 117.1
(C-2), 121.9 (C-1), 126.5 (C-8, C-9), 128.1 (C-3), 128.9 (C-11),
130.1 (C-10), 131.8 (C-12b), 134.9 (C-7a), 136.3 (C-11a), 147.5
(C-4a), 172.8 (C=O). IR (KBr): 3180 (NH), 1650 (C=O)
cm-¹. MS (ES+): m/z (%) = 293
(100) [M + H]+. Anal.
Calcd for C19H20N2O: C, 78.05;
H, 6.89; N, 9.58. Found: C, 78.31; H, 6.91; N, 9.65.