Synthesis and ring opening of alkaloid-type compounds with a novel indolo[2,3-c][2]benzazepine skeleton

Article abstract of DOI:10.1055/s-0029-1218340

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

Full text of DOI:10.1055/s-0029-1218340

LETTER
3119
Synthesis and Ring Opening of Alkaloid-Type Compounds
with a Novel Indolo[2,3-c][2]benzazepine Skeleton
Synthesis
o
of Indolo[2,3
a
-
c
][2]benz
n
Algirdas Šačkus*a
a
Institute of Synthetic Chemistry, Kaunas University of Technology, 50270 Kaunas, Lithuania
Fax +370(37)451432; E-mail: algirdas.sackus@ktu.lt
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Department of Drug and Natural Product Synthesis, University of Vienna, Pharmaziezentrum, 1090 Vienna, Austria
b
c
Received 13 August 2009
miline alkaloids, such as echitamine, which is a promising
cytotoxic compound.4 Echibolines, incorporating
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
the
1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carba-
zole structure 2,5 and 2,3,4,4a,9,9a-hexahydro-1H-pyri-
indolo[2,3-c][2]benzazepines, while acid hydrolysis gave the corre- do[2,3-b]indoles,6 for example, compounds 3 and 4 with
anti-inflammatory activity,7 also comprise structurally re-
sponding indolo[2,3-c][2]benzazepinones. The action of strong pro-
tonic acids on indolo[2,3-c][2]benzazepines causes opening of the
lated classes of alkaloids with synthetic and medicinal po-
benzazepine ring annelated to the indole system to form 3H-
tential. Benzo-annulated derivatives of hexahydro-1H-
indolium salts.
pyrido[2,3-b]indoles, that is, 5a,6,10b,11-tetrahydro-5H-
quinindolines, like structure 5,8 are of interest within the
Key words: alkaloids, indoles, indolo[2,3-c][2]benzazepines, ring
closure, ring opening
synthetic study of communesin A (6a) and cytotoxic com-
munesin
B
(6b),9 whereas the homologues of
2,3,4,4a,9,9a-hexahydro-1H-pyrido[2,3-b]indoles with a
1,2,3,4,5,5a,10,10a-octahydroazepino[2,3-b]indole (7) unit,
have received some attention because of their sedative
properties10 and as photodiscoloration prevention
agents.11
The indole nucleus is a key structural feature in (bio)organic
chemistry, as it constitutes the main structural element of
tryptophane and its metabolites such as tryptamine, sero-
tonine, and others. Fused heterocycles, bearing at the b-
edge of the indole nucleus a saturated azaheterocycle, are
found in a wide range of biologically active indole alka-
loids. The chemistry of hexahydropyrrolo[2,3-b]indoles,
as exemplified by the calabar alkaloid (–)-physostigmine
(1, Figure 1) and the analogues phenserine and (–)-esero-
line,2 has received considerable interest in drug research
and for synthetic applications.3 Moreover, the hexahydro-
pyrrolo[2,3-b]indole ring system is also present in akuam-
In the present paper, the straightforward synthesis and
study of the ring–chain transformations of tetracyclic
compounds with a hitherto unreported 5,5a,6,7,12,12a-
hexahydroindolo[2,3-c][2]benzazepine (8) system is de-
scribed. These syntheses, based on a 2-cyanobenzylation
of indoles at C-3, followed by reductive or hydrolytic cy-
clization, can act as a model for the synthesis of alkaloid-
R2
Me
MeHNCOO
Me
N
N
Me
R3
NH
N
H
N
N
R1
NH
H
Me
N
H
Me
3 R1 = Ph, R2 = Me, R3 = H
4 R1 = H, R2 = Ph, R3 = Me
(–)-physostigmine (1)
echiboline (2)
5
R
O
O
N
H
N
N
HN
NH
NH
NH
N
N
H
H
N
H
Me
communesin A (6a) R = Me
communesin B (6b) R = 2,4-pentadienyl
7
8
9
Figure 1
SYNLETT 2009, No. 19, pp 3119–3122
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1218340; Art ID: G26309ST
© Georg Thieme Verlag Stuttgart · New York

3120
J. Solovjova et al.
LETTER
like compounds since the 5,5a,6,7,12,12a-hexahydroindo- dolium salts 15, which in turn form the initial cyclic ad-
lo[2,3-c][2]benzazepine (8) structural element incorpo- ducts 14 under neutral conditions. The transformation of
rates the aforementioned 1,2,3,4,5,5a,10,10a-octahydro- compounds 14a,b to the open form dications 15a,b in
azepino[2,3-b]indole (7) moiety as well as the deuterated trifluoroacetic acid is indicated by the appear-
2,3,3a,4,9,10-hexahydro-1H-pyrrolo[2,3-c][2]benzazepine
ance of the characteristic signal of the indolium N+=C
(9) scaffold which is also present in the structure of com- moiety in the 13C NMR spectrum at d = 197.9 and 199.3
munesins 6.9c
ppm, respectively. The absorption maxima observed in
the UV spectrum of compound 14a in ethanol are specific
for indoline derivatives [lmax (log e): 212 (2.99), 254
(2.86), 304 (2.51) nm]. The UV spectrum of compound
14a in a 100:1 (v/v) mixture of ethanol with concd hydro-
chloric acid, when compared with the corresponding spec-
The starting compounds, 2,3-dimethyl-1H-indole 10a and
2,3,4,9-tetrahydro-1H-carbazole 10b, prepared by Fischer
indole synthesis, were alkylated at C-3 by treatment with
ethylmagnesium iodide and subsequent reaction with 2-
bromomethylbenzonitrile in benzene under reflux to give
the corresponding 2-cyanobenzylated indoles 11a,b in
53% and 76% yield, respectively (Scheme 1).12 When the
alkylation of 2,3-dimethylindole 10a was performed in a
mixture of benzene and diethyl ether, the yield of com-
trum in pure ethanol, showed
a
hypsochromic
displacement of the absorption bands [lmax (log e): 208
(3.05), 232 (2.84), 272 (2.73) nm], indicating that 3H-in-
dolium salt 15 (R = Me, X = Cl) is formed.15
pound 11a decreased (36% yield) and 12a-methyl-12,12a- Hydrolysis of the cyano group of 3H-indole 11a with con-
dihydrobenzo[4,5]cyclohepta[1,2-b]indol-7(5H)-imine (12a) centrated sulfuric acid at 50 °C resulted in the formation
was formed as a minor product (17% yield).13
of 2-(2,3-dimethyl-3H-indol-3-ylmethyl)benzamide (16)
in 65% yield after basic aqueous work up (Scheme 2).
The 3H-indoles 11 were N-methylated in 78–91% yield
upon reflux in iodomethane for 5 hours leading to 3H-in- Applying the former hydrolytic conditions to compound
dolium salts 13 which were crystallized from ethanol. 11b afforded directly the indolo[2,3-c][2]benzazepinone
These salts disclosed a typical N+=C signal at d = ca. 17. The identification of the open amide 16 and the ring-
195.0 ppm in the 13C NMR spectrum (DMSO-d6).
closed lactam 17 was based on their full spectroscopic
analysis with characteristic signals in the 13C NMR spec-
tra at d = 187.3 (C=N) and 172.4 (C=O) ppm for the amide
16 (CDCl3) and at d = 79.5 (aminal C-5a) and 171.5
(C=O) ppm for the lactam 17 (DMSO-d6). In a solution of
deuterated trifluoroacetic acid, the lactam 17 transforms
to the 3H-indolium cation form 18, possessing a charac-
teristic N+=C signal at d = 203.3 ppm in the 13C NMR
spectrum (TFA-d).
The dehydroiodination of compounds 13 with sodium car-
bonate to afford the corresponding enamines, followed by
reduction with LiAlH4 in diethyl ether under reflux, re-
sulted in cyclization of the intermediate amine across the
enamine to afford indolo[2,3-c][2]benzazepines 14
(Scheme 1).14 The structure of 5,5a,12a-trimethylindo-
lo[2,3-c][2]benzazepine 14a was established by full spec-
troscopic investigations and the strong NOE interactions
between the 5a-CH3 and 12a-CH3 groups suggested a cis Acid hydrolysis of the substituted 3H-indolium iodides 13
relative configuration. It is necessary to point out that followed by basic aqueous workup led to the formation of
compounds 14a,b in solution of CDCl3 show a dynamic indolo[2,3-c][2]benzazepinones 19 (Scheme 3), the struc-
behavior, which leads to more or less broadening of most ture of which was fully proved by elemental and spectral
signals in the NMR spectra. The action of strong protonic analysis.16 The NOE between the 5a-CH3 and 12a-CH3
acids on the indolo[2,3-c][2]benzazepines 14 leads to groups is indicative for the cis-configuration of structure
opening of the azepine ring with the formation of 3H-in- 19a.
R
1) EtMgI,
Et2O, Δ, 0.5 h
R
Me
CN
NH
+
R
R
2) 2-CNC6H4CH2Br,
benzene,
(or benzene–Et2O)
Δ, 4 h
N
N
N
H
H
10a R = Me
11a 36–53%
11b 76%
12a 0–17%
10b R–R = (CH2)4
MeI (neat)
Δ, 5 h
R
R
R
CN
+ HX
– HX
1) Na2CO3, H2O
+
NH3
NH
R
R
2X–
N+
N+
2) LiAlH4,
Et2O, Δ, 5 h
N
R
I–
Me
Me
Me
13a 91%
13b 78%
14a 55%
14b 67%
15 X = CF3COO or Cl
Scheme 1
Synlett 2009, No. 19, 3119–3122 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolo[2,3-c][2]benzazepines
3121
were established by full spectroscopic and elemental anal-
ysis.
Me
Me
1) H2SO4,
50 °C, 5 h
CN
Me
CONH2
Me
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
2) KOH,
H2O
N
11a
N
16 65%
Acknowledgment
The authors are indebted to the Research Foundation – Flanders
(FWO) and Ghent University (BOF) for financial support.
1) H2SO4,
CN
50 °C, 5 h
O
NH
2) KOH,
H2O
N
N
H
References and notes
17 52%
11b
+ HX
(1) Postdoctoral fellow of the Research Foundation-Flanders
(FWO).
– HX
CONH2
(2) (a) Brossi, A.; Pei, X. F.; Greig, N. H. Austr. J. Chem. 1996,
49, 171. (b) Greig, N. H.; Pei, X. F.; Soncrant, T. T.; Ingram,
D. K.; Brossi, A. Med. Res. Rev. 1995, 15, 3. (c) Robinson,
B. Heterocycles 2002, 57, 1327. (d) Huang, A.; Kodanko,
J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126, 14043.
(3) (a) Crich, D.; Banerjee, A. Acc. Chem. Res. 2007, 40, 151.
(b) Takano, S.; Ogasawara, K. In The Alkaloids, Vol. 36;
Brossi, A., Ed.; Academic Press: San Diego, 1989, 225–251.
(4) Ramírez, A.; García-Rubio, S. Curr. Med. Chem. 2003, 10,
1891.
N+
X–
H
18 X = CF3COO or Cl
Scheme 2
(5) (a) Fritz, H.; Fischer, O. Tetrahedron 1964, 20, 1737.
(b) Rees, J. M. H.; Cox, B.; Tanzil, S.; Newboult, L.;
Kimber, K.; Robinson, B. Adv. Biosci. 1989, 75, 93.
(c) Lévy, J.; Sapi, J.; Laronze, J. Y.; Royer, D.; Toupet, L.
Synlett 1992, 601. (d) Dounay, A. B.; Humphreys, P. G.;
Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008,
130, 5368. (e) Shen, L.; Zhang, M.; Wu, Y.; Qin, Y. Angew.
Chem. Int. Ed. 2008, 47, 3618.
(6) (a) Sunazuka, T.; Shirahata, T.; Tsuchiya, S.; Hirose, T.;
Mori, R.; Harigaya, Y.; Kuwajima, I.; Omura, S. Org. Lett.
2005, 7, 941. (b) Snider, B. B.; Wu, X. Org. Lett. 2007, 9,
4913.
(7) (a) Okamoto, T.; Akase, T.; Izumi, T.; Inaba, S.; Yamamoto,
H. JP 47020196, 1972 Chem. Abstr. 1972, 77, 152142.
(b) Cañas-Rodriquez, A.; Leeming, P. R. J. Med. Chem.
1972, 15, 762. (c) Matthews, N.; Franklin, R. J.; Kendrick,
D. A. Biochem. Pharmacol. 1995, 50, 1053.
(8) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett.
2003, 44, 1203. (b) May, J. A.; Stoltz, B. Tetrahedron 2006,
62, 5262.
Spectroscopic analysis of lactams 19 in deuterated tri-
fluoroacetic acid, showing characteristic N+=C signals at
d = ca. 200.0 ppm, demonstrated again that treatment with
protonic acids leads to cleavage of the C–N bond of the
azepinone ring of compounds 19 with formation of the
corresponding 3H-indolium salts 20. Typical changes in
the absorption bands of the UV spectra of compound 19a
in ethanol upon addition of concentrated hydrochloric
acid also demonstrated the formation of the correspond-
ing 3H-indolium chloride 20 (R = Me, X = Cl).
1) H2SO4,
50 °C, 5 h
R
R
CN
O
2) KOH,
H2O
R
I–
NH
N+
N
R
Me
Me
+ HX
19a 53%
19b 50%
(9) (a) George, J. H.; Adlington, R. M. Synlett 2008, 2093.
(b) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
5068. (c) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew.
Chem. Int. Ed. 2008, 47, 8170.
(10) (a) Hester, J. B. J. Org. Chem. 1970, 35, 875. (b) Hester,
J. B. US 3595874, 1971; Chem. Abstr. 1971, 75, 98552.
(11) Kaneko, Y. JP 63163347, 1988; Chem. Abstr. 1989, 110,
144847.
13a,b
– HX
R
CONH2
R
N+
X–
Me
20 X = CF3COO or Cl
(12) For some examples on the alkylation of indolylmagnesium
halides, see: (a) Jackson, A. H.; Smith, P. J. Chem. Soc.
1968, 1667. (b) Rodriguez, J. G.; San Andres, A.
J. Heterocycl. Chem. 1991, 28, 1293. (c)Gruda, I.; Leblanc,
R. M. Can. J. Chem. 1976, 54, 576.
(13) Analytical and Spectroscopic Data for Compound 12a
Yellow solid, mp >250 °C (from DMSO, with decomp.).
1H NMR (500 MHz, DMSO-d6): d = 0.78 (3 H, s, CH3), 3.04
(1 H, d, 2J = 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),
Scheme 3
In summary, it was found that alkylation of the magne-
sium salts of 2,3-disubstituted indoles with 2-bromometh-
ylbenzonitrile and subsequent reduction or hydrolysis of
the introduced cyano group resulted in a straightforward
synthesis of a novel type of heterocyclic systems with an
indolo[2,3-c][2]benzazepine and -benzazepinone skele-
ton, respectively. The structure and ring–chain transfor-
mations of the latter polycyclic alkaloid-type compounds
Synlett 2009, No. 19, 3119–3122 © Thieme Stuttgart · New York

3122
J. Solovjova et al.
LETTER
7.75 (1 H, m, 8-H). 13C NMR (125 MHz, DMSO-d6): d =
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.
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): d = –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.
(15) Hinman, R. L.; Whipple, E. B. J. Am. Chem. Soc. 1962, 84,
2534.
(14) Typical Procedure for the Preparation of an Indolo[2,3-
c][2]benzazepine
(16) Typical Procedure for the Preparation of an Indolo[2,3-
c][2]benzazepin-7(5H)-one
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): d = 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, 2J = 14.3 Hz, 12-H), 2.72 (3
H, s, NCH3), 3.56 (1 H, d, 2J = 15.1 Hz, 7-H), 3.68 (1 H, d,
2J = 14.3 Hz, 12-H), 4.52 (1 H, d, 2J = 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): d = 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-
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): d =
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, 2J = 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): d = 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.
Synlett 2009, No. 19, 3119–3122 © Thieme Stuttgart · New York