1
Supporting Information
Synthesis and ring opening of alkaloid-type compounds
with a novel indolo[2,3-c][2]benzazepine skeleton
Joana Solovjova,a Vytas Martynaitis,a Sven Mangelinckx,b, † Wolfgang Holzer,c
Norbert De Kimpeb and Algirdas Šačkusa,*
a
Institute of Synthetic Chemistry, Kaunas University of Technology, LT-50270
Kaunas, Lithuania; bDepartment of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium;
c
Department of Drug and Natural Product Synthesis, University of Vienna,
Pharmaziezentrum, A-1090 Vienna, Austria
†
Postdoctoral Fellow of the Research Foundation-Flanders (FWO)
E-mail: algirdas.sackus@ktu.lt
General Methods. The melting points were determined in open capillary tubes on a
Büchi B-540 melting point apparatus and are uncorrected. Infrared spectra were
recorded with a Perkin Elmer Spectrum One spectrometer using potassium bromide
pellets. UV spectra were determined with a Spectronic Genesys 8 spectrophotometer.
1
H NMR spectra were recorded at 300 MHz on a Varian Unity Inova spectrometer
and at 500 MHz on a Bruker Avance 500 spectrometer;
13
C NMR spectra were
2
registered at 75 and 125 MHz, respectively. Chemical shifts, expressed in ppm, were
relative to tetramethylsilane (TMS). 15N-NMR spectra (50.69 MHz) were obtained on
a Bruker Avance 500 spectrometer using a ‘directly’ detecting broadband observe
probe and were referenced against neat, external nitromethane (coaxial capillary). MS
were measured using a Waters ZQ 2000 instrument (ion spray). Elemental analyses
were measured with a CE-440 elemental analyzer, Model 440 CHN/O/S. For thin
layer chromatographic (TLC) analyses, Merck precoated TLC plates (silica gel 60
F254) were used. Separations by flash chromatography were performed on silica gel
Merck, 9385, 230-400 mesh.
2-[(2,3-Dimethyl-3H-indol-3-yl)methyl]benzonitrile (11a). Method A: To a
solution of ethylmagnesium iodide, prepared from magnesium (0.32 g, 13.3 mmol)
and iodoethane (2.07 g, 1.06 ml, 13.3 mmol) in dry Et2O (16 mL) under argon
atmosphere, a solution of 2,3-dimethyl-1H-indole 10a (1.0 g, 6.9 mmol) in dry Et2O
(6 mL) was added dropwise at reflux temperature during 1 h. After stirring for an
additional 30 min, Et2O was distilled off and benzene (10 mL) was added. Then to the
resulting
solution
of
2,3-dimethylindole
magnesium
iodide,
2-
(bromomethyl)benzonitrile (1.61 g, 8.2 mmol) in benzene (10 mL) was added
dropwise at reflux temperature during 1 h. Stirring was continued at the same
temperature for 3 h. Then the reaction mixture was cooled to room temperature,
diluted with Et2O (10 mL), poured onto a mixture of ice (20 g) and acetic acid (30%,
20 mL). The organic layer was separated and extracted with 3N HCl (3×50 mL). The
combined acidic layers were neutralized with saturated potassium hydroxide solution
and extracted with Et2O (3×50 mL). The combined organic layers were washed with
water followed by drying (Na2SO4). The solvent was removed under reduced
3
pressure, and the residue was purified by column chromatography (Hexane/EtOAc,
1/1) to yield 11a (0.95 g, 53%) as an oil. 1H NMR (300 MHz, CDCl3): δ 1.52 (3H, s,
CH3), 2.49 (3H, s, CH3), 3.23 (1H, d, 2J = 14.1 Hz, ½ CH2), 3.55 (1H, d, 2J = 14.1 Hz,
½ CH2), 6.75-7.57 (8H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δ 16.1 (CH3), 22.1
(CH3), 40.0 (CH2), 58.4 (C-3), 113.3, 118.4, 119.9, 122.6, 125.0, 127.2, 128.1, 129.3,
132.1, 132.6, 140.0, 142.0, 153.9 (Ar-C, CN), 185.5 (N=C). IR (KBr, cm-1): CN =
2225. MS (ES+) m/z (%): 262 ([M+2H]+, 50), 261 ([M+H]+, 100). Anal. Calcd for
C18H16N2: C 83.05; H 6.19; N 10.76. Found: C 83.28; H 6.21; N 10.86. Picrate of
11a: mp 168-169 oC (from ethanol). Anal. Calcd for C24H19N5O7: C 58.90; H 3.91; N
14.31. Found: C 58.71; H 4.05; N 14.15.
Method B: To a solution of ethylmagnesium iodide, prepared from magnesium (0.32
g, 13.3 mmol) and iodoethane (2.07 g, 1.06 ml, 13.3 mmol) in dry Et2O (16 mL)
under argon atmosphere, a solution of 2,3-dimethylindole (1.0 g, 6.9 mmol) in dry
Et2O (6 mL) was added dropwise at reflux temperature during 1 h. After stirring for
an additional 30 min, 4/5 parts of Et2O were distilled off and benzene (10 mL) was
added. Then to the resulting solution of indole magnesium iodide, 2bromomethylbenzonitrile (1.6 g, 8.2 mmol) in benzene (10 mL) was added dropwise
under reflux during 1 h. Stirring was continued at reflux temperature for 3 h. Then the
reaction mixture was cooled to room temperature and quenched with water (20 mL).
The pale yellow crystals were removed by filtration, washed with ether, and dried to
give 12a-methyl-12,12a-dihydrobenzo[4,5]cyclohepta[1,2-b]indol-7(5H)-imine (12a)
(0.31 g, 17%). An analytical sample was crystallized from DMSO; Mp > 250 °C
(with decomposition). Workup of the filtrate by a similar method as described in the
previous
experiment,
and purification of the crude product
chromatography furnished 0.65 g of compound 11a with 36% yield.
by column
4
2-(1,2,3,4-Tetrahydrocarbazol-4a-ylmethyl)benzonitrile (11b). To a solution of
ethylmagnesium iodide, prepared from magnesium (0.29 g, 12.14 mmol) and
iodoethane (1.91 g, 0.98 ml, 12.25 mmol) in dry Et2O (16 mL) under argon
atmosphere, a solution of 2,3,4,9-tetrahydro-1H-carbazole 10b (1.18 g, 6.9 mmol) in
dry Et2O (6 mL) was added dropwise at reflux temperature during 1 h. After stirring
for an additional 30 min, Et2O was distilled off and benzene (10 mL) was added.
Then, to the resulting solution of tetrahydrocarbazole magnesium iodide, 2(bromomethyl)benzonitrile (1.61 g, 7.59 mmol) in benzene (10 mL) was added
dropwise at reflux temperature during 1 h. Stirring was continued at the same
temperature for 3 h. Then, the reaction mixture was cooled to room temperature,
diluted with Et2O (10 mL) and poured onto a mixture of ice (20 g) and acetic acid
(30%, 20 ml). The organic layer was separated and extracted with 3N HCl (3×50 mL).
The combined acidic layers were neutralized with saturated potassium hydroxide and
extracted with Et2O (3×50 mL). The combined organic layers were washed with water
followed by drying (Na2SO4). The solvent was removed under reduced pressure, and
the residue was purified by column chromatography (Hexane/EtOAc, 7/3) to yield
11b (1.50 g, 76%), Mp 121-122 °C (from ethanol). 1H NMR (300 MHz, CDCl3): δ
1.17-2.98 (8H, m, CH2CH2CH2CH2), 3.44 (1H, d, 2J = 14.1 Hz, ½ CH2), 3.54 (1H, d,
2
J = 14.1 Hz, ½ CH2), 6.57-7.42 (8H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δ 21.3
(CH2), 29.1 (CH2), 30.5 (CH2), 37.1 (CH2), 38.5 (CH2), 58.7 (C-4a), 112.9, 118.4,
120.0, 122.3, 124.7, 126.9, 127.9, 128.6, 132.0, 132.4, 140.2, 143.1, 154.5 (Ar-C,
CN), 187.4 (N=C). IR (KBr, cm-1): CN = 2221. MS (ES+) m/z (%): 288 ([M+2H]+,
30), 287 ([M+H]+, 100). Anal. Calcd. for C20H18N2: C 83.88; H 6.34; N 9.78. Found:
C 84.28; H 6.23; N 9.49.
5
3-(2-Cyanobenzyl)-1,2,3-trimethyl-3H-indolium iodide (13a). A mixture of
compound 11a (0.85 g, 3.27 mmol) and iodomethane (8 mL) was heated at reflux
temperature for 5 h. The resulting precipitate was collected by filtration, washed with
Et2O and dried to afford iminium iodide 13a (1.20 g, 91%). An analytical sample was
crystallized from ethanol; Mp 183-184 °C (with decomposition). 1H NMR (300 MHz,
DMSO-d6): δ 1.69 (3H, s, 3-CH3), 3.02 (3H, s, 2-CH3), 3.44 (1H, d, 2J = 13.9 Hz, ½
CH2), 3.69 (1H, d, 2J = 13.9 Hz, ½ CH2), 3.99 (3H, s, ≡N+−CH3), 7.21-7.85 (8H, m,
Ar-H). 13C NMR (75 MHz, DMSO-d6): δ 15.2 (CH3), 19.6 (CH3), 34.8 (NCH3), 38.7
(CH2), 58.5 (C-3), 112.8, 115.1, 117.4, 124.3, 128.4, 129.0, 129.3, 130.5, 132.9,
133.0, 137.7, 137.9, 142.2, (Ar-C, CN), 194.7 (N+=C). IR (KBr, cm-1): CN = 2228;
N=C = 1630. MS (ES+) m/z (%): 276 ([M-I+H]+, 50), 275 ([M-I]+, 100). Anal. Calcd
for C19H19IN2: C 56.73; H 4.76; N 6.96. Found: C 56.69; H 4.83; N 7.01.
4a-(2-Cyanobenzyl)-9-methyl-2,3,4,4a-tetrahydro-1H-carbazolium iodide (13b).
A mixture of compound 11b (0.7 g, 2.4 mmol) and iodomethane (6 mL) was heated at
reflux temperature for 5 h. The resulting precipitate was collected by filtration,
washed with Et2O and dried to afford iminium iodide 13b (0.82 g, 78%). An
analytical sample was crystallized from ethanol; Mp 183-184 °C
decomposition).
1
(with
H NMR (300 MHz, DMSO-d6): δ 1.65-3.66 (8H, m,
CH2CH2CH2CH2), 3.82 (1H, d, 2J = 14.2 Hz, ½ CH2), 3.90 (1H, d, 2J = 14.2 Hz, ½
CH2), 4.19 (3H, s, CH3) 7.26-7.99 (8H, m, Ar-H). 13C NMR (75 MHz, DMSO-d6): δ
19.8 (CH2), 27.5 (CH2), 29.0 (CH2), 34.9 (CH3), 36.7 (CH2), 37.6 (CH2), 58.8 (C-4a),
112.5, 115.5, 117.6, 124.0, 128.2, 128.7, 129.2, 130.2, 132.9, 133.0, 138.4, 138.8,
142.7 (Ar-C), 196.0 (N+=C). IR (KBr, cm-1): CN = 2223, N=C = 1638. MS (ES+) m/z
(%): 301 ([M-I]+, 100). Anal. Calcd for C21H21IN2: C 58.89; H 4.94; N 6.54. Found: C
58.45; H 4.72; N 6.40.
6
5-Methyl-5,5a,6,7,12,12a-hexahydro-5a,12a-butanoindolo[2,3-c][2]benzazepine
(14b). A solution of salt 13b (0.53 g, 1.24 mmol) in 15% ethanol (50 mL) was
neutralized with sodium carbonate and extracted with Et2O (3×10 mL). The combined
organic layers were washed with water followed by drying (Na2SO4) and the solvent
was evaporated under reduced pressure. The residue was dissolved in dry Et2O (10
mL), LiAlH4 (94 mg, 2.48 mmol) added and the mixture refluxed under argon for 5 h.
The reaction mixture was allowed to cool to room temperature and water (1 mL) was
dropped carefully into the reaction flask. A finely suspended solid was filtered off
using fritted glass filter, and the solid material washed with ether (20 mL). The
collected filtrate was washed with water, dried over Na2SO4 and concentrated under
reduced
pressure.
The
residue
was
purified
by column
chromatography
(Hexane/EtOAc, 7/1) to yield 14b (0.23 g, 67%) as a viscous oil, Rf
(Hex/EtOAc, 7/1).
1
= 0.73
H NMR (300 MHz, CDCl3): δ 1.13-1.89 (9H, m,
CH2CH2CH2CH2, NH), 2.19 (1H, d, 2J = 14.3 Hz, ½ CH2), 2.71 (3H, s, CH3), 3.56
(1H, d, 2J = 14.8 Hz, ½ CH2), 3.77 (1H, d, 2J = 14.3 Hz, ½ CH2), 4.70 (1H, d, 2J =
14.8 Hz, ½ CH2), 6.54-7.21 (8H, m, Ar-H).
13
C NMR (75 MHz, CDCl3): δ 22.2
(CH2), 22.5 (CH2), 26.4 (CH3), 28.6 (CH2), 33.0 (CH2), 44.9 (CH2), 45.2 (CH2), 46.9
(C-10a), 86.8 (C-5a), 107.7, 117.6, 120.7, 126.2, 126.6, 126.7, 127.3, 130.2, 136.1,
138.9, 143.1, 149.4 (Ar-C). IR (KBr, cm-1): N-H = 3364. MS (ES+) m/z (%): 306
([M+2H]+, 30), 305 ([M+H]+, 100). Anal. Calcd for C21H24N2: C 82.85; H 7.95; N
9.20. Found: C 82.80; H 7.88; N 9.46.
2-(2,3-Dimethyl-3H-indol-3-ylmethyl)benzamide (16). A solution of compound 11a
(0.52 g, 2.0 mmol) in concentrated sulfuric acid (5 mL) was heated at 50 °C for 5 h.
The mixture was poured onto ice, neutralized with saturated potassium hydroxide and
extracted with Et2O (3×15 mL). The combined organic layers were washed with water
7
followed by drying (Na2SO4). The solvent was removed under reduced pressure, and
the residue was crystallized from ethanol to yield 16 (0.36 g, 65%). Mp 147-148 °C .
1
H NMR (CDCl3, 300 MHz): δ 1.40 (3H, s, CH3), 2.36 (3H, s, CH3), 3.35 (1H, d, 2J =
13.8 Hz, ½ CH2), 3.47 (1H, d, 2J = 13.8 Hz, ½ CH2), 5.48 (1H, br s, NH), 5.83 (1H, br
s, NH), 6.86-7.41 (8H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δ 16.7 (CH3), 22.0
(CH3), 37.6 (CH2), 58.4 (C-3), 119.8, 122.9, 124.6, 126.7, 127.0, 127.8, 129.7, 130.9,
135.4, 135.9, 142.9, 154.4 (Ar-C), 172.4 (C=O), 187.3 (N=C). IR (KBr, cm-1): N-H =
3300, N-H = 3140, C=O = 1670. MS (ES+) m/z (%): 279 ([M+H]+, 100). Anal. Calcd
for C18H18N2O: C 77.67; H 6.52; N 10.06. Found: C 77.71; H 6.65; N 9.89.
5a,6,12,12a-Tetrahydro-5a,12a-butanoindolo[2,3-c][2]benzazepin-7(5H)-one (17).
A solution of compound 11b (0.486 g, 1.7 mmol) in concentrated sulfuric acid (5 mL)
was heated at 50 °C for 5 h. The mixture was poured onto ice, neutralized with
saturated aqueous potassium hydroxide and extracted with Et2O (3×15 mL). The
combined organic layers were washed with water followed by drying with Na2SO4.
The solvent was removed under reduced pressure, and the residue was crystallized
from ethanol to yield 17 (0.27 g, 52%). Mp 185-186 °C (from ethanol). 1H NMR (300
MHz, DMSO-d6): δ 1.13-1.92 (8H, m, CH2CH2CH2CH2), 2.60 (1H, d, 2J = 13.2 Hz,
½ CH2), 3.14 (1H, d, 2J = 13.2 Hz, ½ CH2), 5.71 (1H, s, N(5)H), 6.08-7.42 (8H, m,
ArH), 8.03 (1H, s, NHCO).
13
C NMR (75 MHz, DMSO-d6): δ 18.4 (CH2), 18.8
(CH2), 32.0 (CH2), 35.3 (CH2), 45.2 (CH2), 55.9 (C-10a), 79.5 (C-5a), 107.2, 117.1,
122.4, 126.1, 127.1, 127.2, 129.2, 129.4, 136.1, 136.4, 148.5, 148.6 (Ar-C), 171.5
(C=O). IR (KBr, cm-1): N-H = 3351, N-H = 3193, C=O = 1656. MS (ES+) m/z (%):
306 ([M+2H]+, 25), 305 ([M+H]+, 100). Anal. Calcd. for C20H20N2O: C 78.92; H
6.62; N 9.20. Found: C 78.83; H 6.33; N 8.92.
8
5-Methyl-5a,6,12,12a-tetrahydro-5a,12a-butanoindolo[2,3-c][2]benzazepin7(5H)-one (19b). A solution of compound 13b (0.5 g, 1.17 mmol) in concentrated
sulfuric acid (12 mL) was heated at 50 °C for 5 h. The mixture was poured onto ice
(50 g), neutralized with concentrated aqueous potassium hydroxide and extracted with
Et2O (3×20 ml). The combined organic layers were washed with water followed by
drying (Na2SO4). The solvent was removed under reduced pressure, and the residue
was purified by column chromatography (Hexane/EtOAc, 1/1) to yield 19b (0.185 g,
50%), Mp 205-206 °C (from ethanol). 1H NMR (300 MHz, CDCl3): δ 1.22-2.20 (8H,
m, CH2CH2CH2CH2), 2.29 (3H, s, CH3), 2.45 (1H, d, 2J = 12.9 Hz, ½ CH2), 3.27 (1H,
d, 2J = 12.9 Hz, ½ CH2), 5.84-7.58 (8H, m, Ar-H), 6.73 (1H, br s, NH). 13C NMR (75
MHz, CDCl3): δ 19.1 (CH2), 19.8 (CH2), 25.8 (CH3), 31.5 (CH2), 31.7 (CH2), 47.2
(CH2), 55.3 (C-10a), 82.9 (C-5a), 104.5, 117.0, 121.7, 126.3, 126.6, 128.0, 128.8,
130.0, 130.8, 135.0, 136.5, 148.6 (Ar-C), 173.3 (C=O). IR (KBr, cm-1): N-H = 3203,
C=O = 1655. MS (ES+) m/z (%): 320 ([M+2H]+, 25), 319 ([M+H]+, 100). Anal. Calcd
for C21H22N2O: C 79.21; H 6.96; N 8.80. Found: C 78.82; H 6.88; N 8.42.
9
Figure 1. Relevant NOE correlations for compounds 14a (a) and 19a (b).
H
(a)
H
H
H3C
H
H
H
H
H
N
H
H
CH 3
N
H
H
H
CH 3
H
(b)
H
H
H3C
H
H
H
H
H
N
H
H
CH 3
N
H
O
CH 3
Table 1. 1H and 13C NMR spectra of indolo[2,3-c][2]benzazepines (14a, b, 17, 19a,
b) and 3H-indole 16 in trifluoroacetic acid-d
Compound
14a
14b
16
1
H NMR, chemical shifts, ppm
1.35 (3H, s, 3-CH3), 2.58 (3H, s,
2-CH3), 2.81 (1H, d, 2J = 14.1 Hz,
½ CH2), 3.15-3.21 (2H, m, CH2),
3.53 (1H, d, 2J = 14.1 Hz, ½ CH2),
6.44-7.33 (8H, m, Ar-H)
1.31-3.38 (8H, m, (CH2)4), 2.96
(1H, d, 2J = 14.4 Hz, ½ CH2), 3.27
(1H, d, 2J = 14.1 Hz, ½ CH2), 3.57
(1H, d, 2J = 14.4 Hz, ½ CH2), 3.66
(1H, d, 2J = 14.1 Hz, ½ CH2), 3.94
(3H, s, CH3), 6.56-7.56 (8H, m,
Ar-H)
1.72 (3H, s, 3-CH3), 2.62 (3H, s,
2-CH3), 3.55-3.67 (2H, AB-q, 2J =
13.8 Hz, CH2), 7.22-7.52 (8H, m,
13
C NMR, chemical shifts, ppm
16.0, 21.2, 36.3, 40.2, 43.7, 62.0,
117.3, 127.0, 132.5, 132.8, 132.9,
133.1 (2×C), 133.2, 134.4, 134.8,
140.4, 144.6, 197.9
21.4, 29.3, 30.9, 35.2, 36.1, 37.9,
42.9, 61.1, 116.8, 126.0, 131.7
(2×C), 132.2 (2×C), 132.5, (2×C);
133.2, 134.7, 140.7, 144.3, 199.3
17.7, 22.6, 41.5, 61.7, 118.5,
126.4, 131.0, 131.3, 132.3, 132.5,
134.1, 134.4, 135.2, 135.7, 141.2,
10
17
19a
19b
Ar-H)
1.31-3.28 (8H, m, (CH2)4), 3.773.89 (2H, AB-q, 2J = 14.4 Hz,
CH2), 6.91-7.51 (8H, m, Ar-H)
142.7, 178.5, 201.0
22.0, 32.0, 32.7, 37.9, 42.5, 62.1,
114.4, 126.5, 130.7, 130.8, 131.8,
132.0, 133.1, 133.5, 134.7, 135.6,
141.7, 142.9, 178.7, 203.3
1.71 (3H, s, 3-CH3), 2.48 (3H, s, 16.5, 21.8, 35.7, 41.8, 61.5, 116.6,
2-CH3), 3.45-3.57 (2H, AB-q, 2J = 126.2, 131.0, 131.4, 132.3, 132.9,
13.8 Hz, CH2), 3.93 (3H, s, 134.3, 134.6, 135.1, 135.9, 142.3,
NCH3), 7.23-7.62 (8H, m, Ar-H)
144.1, 178.4, 198.1
1.39-3.36 (8H, m, (CH2)4), 3.653.77 (2H, AB-q, 2J = 14.4 Hz,
CH2), 3.92 (3H, s, CH3), 6.72-7.52
(8H, m, Ar-H)
22.1, 30.2, 31.7, 35.5, 38.0, 41.1,
61.9, 116.9, 126.7, 131.0, 131.1,
132.2, 132.4, 133.8, 134.0, 134.9,
136.1, 142.2, 145.1, 178.7, 200.0
Table 2. UV spectra of indolo[2,3-c][2]benzazepines
Compound
Ethanol, max (log )
14a
14b
16
17
19a
19b
212 (2.99), 254 (2.86), 304 (2.51)
214 (2.99), 252 (2.88), 306 (2.53)
212 (3.06), 298 (2.40)
212 (3.06), 300 (2.66)
204 (3.08), 252 (2.67), 310 (2.06)
216 (3.08), 252 (2.99), 312 (2.44)
Ethanol-conc. HCl 100:1 (v/v),
max (log )
208 (3.05), 232 (2.84), 272 (2.73)
208 (3.05), 234 (2.72), 274 (2.80)
210 (3.07), 278 (2.70)
212 (3.07), 280 (2.67)
206 (3.12), 276 (2.66)
212 (3.08), 2.62 (2.73)