N-Bromosuccinimide as an efficient catalyst for the synthesis of indolo[2,3-b]quinolines

Article abstract of DOI:10.1016/j.tetlet.2012.06.125

The use of N-bromosuccinimide as a catalyst promoted the synthesis of polycyclic indolo[2,3-b]quinoline derivatives in good to high yields in the reactions of various aryl amines with indole-3-carbaldehyde at room temperature under mild conditions.

Full text of DOI:10.1016/j.tetlet.2012.06.125

Tetrahedron Letters 53 (2012) 4751–4753
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Tetrahedron Letters
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N-Bromosuccinimide as an efficient catalyst for the synthesis
of indolo[2,3-b]quinolines
⇑
Ramin Ghorbani-Vaghei , Seyedeh Mina Malaekehpoor
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan 65174, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of N-bromosuccinimide as a catalyst promoted the synthesis of polycyclic indolo[2,3-b]quinoline
derivatives in good to high yields in the reactions of various aryl amines with indole-3-carbaldehyde at
room temperature under mild conditions.
Received 21 February 2012
Revised 31 May 2012
Accepted 27 June 2012
Available online 4 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indolo[2,3-b]quinolines
Aryl amines
Indole-3-carboxaldehyde
N-Bromosuccinimide
Catalyst
0
0
Heterocyclic compounds containing an indole moiety have been
effects of various catalysts including NBS, TBBDA (N,N,N ,N -tetrab-
1
,2
0
found in many biologically important natural products. Indolo-
quinoline alkaloids have received significant attention in recent
romobenzene-1,3-disulfonamide), PBBS [poly (N,N -dibromo-N-
1
2
ethylbenzene-1,3-disulfonamide)], etc., under various conditions.
The results are summarized in Table 1. The best result was achieved
using N-bromosuccinimide (Table 1, entry 2). We next investigated
the scope of this new protocol in reactions of various aryl amines
and indole-3-carbaldehyde using N-bromosuccinimide (0.67
mmol) under optimized conditions (Table 2, entries 1–9). Also,
the products using aniline and 1-aminonaphthalene (Table 2,
entries 1–2) are the same as the products from these two amines
obtained in the previously published work.
Mechanistically, it is likely that N-bromosuccinimide releases
Br in situ, which acts as an electrophilic species and the mecha-
nism shown in Scheme 2 is proposed for the synthesis of the indo-
3
years because they are known to act as DNA intercalating agents
and exhibit antimalarial properties.4 The roots of Cryptolepis
sanguinolenta, which is a rich source of indoloquinoline alkaloids,
have traditionally been used by Ghanaian healers to treat a variety
,5
6
of health disorders. Cryptolepine (5-methyl-5H-indolo[3,2-b]
quinoline) (1), neocryptolepine (cryptotackieine, 5-methyl-5H-
indolo[2,3-b]quinoline) (2), and isocryptolepine (cryptosanguinol-
entine, 5-methyl-5H-indolo[3,2-c]quinoline) (3) are three
examples of the thirteen characterized alkaloids from Cryptolepis
1
0
7
,8
+
sanguinolenta (Fig. 1). Chemically, these compounds are isomeric
indoloquinolines, but more importantly, the two linearly- (1 and 2)
and angularly-fused (3) isomers possess interesting antiplasmodial
1
0,11
lo[2,3-b]quinoline derivatives.
Initially, N-bromosuccinimide
4
,9
activity.
Recently, the synthesis of 6H-indolo[2,3-b]quinoline
catalyzed the formation of an imine and then a 3-bromo-indolini-
um cation as intermediates. After nucleophilic attack by a second
mole of aniline, intramolecular cyclization and oxidation lead to
was accomplished by simple and useful procedures: iodine in
1
0
11
diphenyl ether or RuY in 1,4-dioxane.
Herein, we report a convenient and simple method for the
synthesis of indolo[2,3-b]quinolines from various aryl amines
and indole-3-carbaldehyde in the presence of N-bromosuccinimide
in good to high yields under mild conditions (Scheme 1).
Initially, we decided to examine various catalysts for the
synthesis of 6H-indolo[2,3-b]quinoline as a model compound (see
Table 2, entry 1). In the absence of catalyst no product was ob-
served, even after a prolonged reaction time. We investigated the
N
N
N
N
N
N
CH3
CH3
CH3
1
2
3
⇑
Corresponding author. Tel./fax: +98 811 8380709.
E-mail address: rgvaghei@yahoo.com (R. Ghorbani-Vaghei).
Figure 1. Structures of cryptolepine (1), neocryptolepine (cryptotackieine) (2), and
isocryptolepine (cryptosanguinolentine) (3).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.125

4
752
R. Ghorbani-Vaghei, S. M. Malaekehpoor / Tetrahedron Letters 53 (2012) 4751–4753
CHO
Synthesis of 6H-indolo[2,3-b]quinoline (Table 2, entry 1);
typical procedure
R
NBS
rt
R
NH2
N
H
N
H
N
To a stirred mixture of aniline (0.372 g, 4 mmol) and indole-3-
carbaldehyde (0.290 g, 2 mmol) was added N-bromosuccinimide
(
0.12 g, 0.67 mmol), [for solid aryl amines a few drops (1 mL) of
Scheme 1. Synthesis of indolo[2,3-b]quinoline derivatives.
MeCN were added]. The progress of the reaction was monitored
by TLC (8:4, n-hexane/acetone). After completion of the reaction,
MeCN (10 mL) was added. The solid was filtered off, washed with
MeCN, and dried. The residue was recrystallized from n-hexane/
EtOAc (80:20) to afford the pure product. Evaporation of the MeCN
under reduced pressure returned the catalyst.
the indoloquinoline derivatives. Also, we prepared imine, sepa-
rately by the reaction between indole-3-carbaldehyde (1 mmol)
and aniline (1 mmol) in the presence of NBS in acetonitrile at room
temperature, and applied it to the reaction with the second mole of
aniline. We obtained the corresponding indoloquinoline. But, the
yield of this procedure (step by step) was lower than the one-pot
procedure that we describe in this Letter.
In conclusion, we have developed a simple procedure for the
synthesis of novel polycyclic indolo[2,3-b]quinoline derivatives
from the reaction of various aryl amines and indole-3-carbalde-
hyde in the presence of N-bromosuccinimide as the catalyst at
room temperature under mild conditions.
Spectral data for 3,7-dihydro-2H-[1,4]dioxino[2,3-g]indolo[2,3-
b]quinoline (Table 2, entry 3): White solid (60%); mp 160-162 ꢀC ;
[Found: C, 73.83; H, 4.31; N, 10.10, C17
H, 4.37; N, 10.14%]; IR (KBr) (mmax, cm ) 3395, 3105, 2926, 2871,
12 2 2
H N O requires C, 73.91;
ꢀ1
1600, 1577, 1494, 1456, 1304, 1244, 1115, 1066, 953, 888,
ꢀ
1
1
748 cm
6
; H NMR (400 MHz, DMSO-d ): d 11.71 (s, 1H, NH),
8.68 (s, 1H, Ar-H), 8.37 (d, J = 8 Hz, 1H, Ar-H) 7.96 (s, 1H, Ar-H),
7.48 (d, J = 4 Hz, 1H, Ar-H), 7.25-7.15 (m, 2H, Ar-H), 6.78 (s, 1H,
Table 1
Optimization of the reaction between aniline and indole-3-carbaldehyde
Entry
Catalyst
Amount of catalyst (mol%) (g)
Conditions
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
NBS
NBS
NBS
NBS
0.42
0.67
1.12
0.67
0.56
0.09
0.21
0.01
0.1
1.55
0.18
0.54
—
Solvent-free, rt
Solvent-free, rt
Solvent-free, rt
220
285
94
196
230
67
270
272
53
340
120
120
150
150
40
90
50
54
50
Trace
30
43
55
0
CH
EtOH-H
3
CN, rt
O, rt
NBS
2
TBBDA
TBBDA
TBBDA
PBBS
Oxalic acid
CAN
CuNO
No catalyst
No catalyst
Solvent-free, rt
Solvent-free, 60 °C
CH CN, reflux
3
Solvent-free, rt
Solvent-free, rt
Solvent-free, rt
Solvent-free, rt
Solvent-free, rt
Solvent-free, 60 °C
1
1
1
1
1
0
40
0
3
—
0
a
Isolated yield.
[
O]
R
R
N
H
N
N
H
N
H
O
O
CHO
O
H2N
N-Br
+
R
N
N
H
Ar
Br
O
N
O
R
N
N
N
Br-N
H
H
NH2
H
O
Ar
R
NHAr
Br
N
Br
H
R
R
N
H
H N
2
N
N
H
H
NHAr
H
Ar
H
N
Br
Br
R
R
N
H
N
N
H
N
H
H
Scheme 2. Proposed mechanism for the preparation of indolo[2,3-b]quinoline derivatives.

R. Ghorbani-Vaghei, S. M. Malaekehpoor / Tetrahedron Letters 53 (2012) 4751–4753
4753
Table 2
Synthesis of polycyclic indolo[2,3-b]quinoline derivatives
Entry
Substrate
NH2
Producta
Time (min)
285
Yield (%)
90
Ref.
1
10
10
N
N
H
NH2
2
3
4
180
420
390
56
60
61
N
N
H
O
O
o
—
—
H2N
o
N
N
N
H
NH2
o
o
O
O
N
H
N
5
6
H N
390
150
70
93
—
—
2
N
N
H
N
NH2
H
N
N
H2N
N
N
H
NH2
7
8
555
285
95
50
—
—
N
N
H
NH2
OCH3
H CO
N
3
N
H
O
O
9
135
72
—
H2N
NH2
N
H
N
N
H
N
a
Products were characterized from their physical properties, by comparison with authentic samples, and by spectroscopic methods.
Ar-H), 4.26 (s, 4H, CH
2
–CH
4.4, 64.6, 109.3, 112.4, 114.5, 115.4, 117.6, 121.2, 122.3, 123.2,
25.2, 133.5, 137.5, 141.3, 144.0, 147.3, 154.5; MS m/z (%): 277
2
); 13C NMR (100 MHz, DMSO-d
6
): d
2. Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47,
906.
4
6
1
(
3.
Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; Pascula-Terasa,
B.; Gago, F.; Rodrigo, M. M.; Ballestros, M. J. Org. Chem. 1996, 61, 5587.
+
MH , 32), 249 (31), 221 (260), 193 (100), 167 (36), 142 (40), 128
21), 76 (7).
4. Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger, C. A. J. Nat. Prod.
997, 60, 688.
Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.; Houghton, P. J. Planta Med.
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1
(
5.
2
Acknowledgements
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9.
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1
We are thankful to Bu-Ali Sina University, Center of Excellence
and Development of Chemical Methods (CEDCM) for financial
support.
1
0. Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. J. Org. Chem. 2009, 74, 8369.
11. Khorshidi, A.; Tabatabaeian, K. J. Mol. Catal. A: Chem. 2011, 344, 128.
2. Ghorbani-Vaghei, R.; Jalili, H. Synthesis 2005, 1099.
References and notes
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