A simple and regioselective synthesis of dihydropyrido[2,3-c]carbazoles via iodocyclization

Article abstract of DOI:10.1055/s-0030-1259530

An efficient and simple method for the synthesis of various iodo-substituted dihydropyridocarbazole derivatives has been developed via iodocyclization of N-propargylated 3-aminocarbazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259530

LETTER
529
A Simple and Regioselective Synthesis of Dihydropyrido[2,3-c]carbazoles via
Iodocyclization
Synthesis of
D
ihy
a
dropyrido[
m
2, 3-
c
]carbazoles a Raju Jella, Rajagopal Nagarajan*
School of Chemistry, University of Hyderabad, Hyderabad 500046, India
Fax +91(40)23012460; E-mail: rnsc@uohyd.ernet.in
Received 29 November 2010
based catalysts for cyclization. In this methodology, we
utilized the well-known Sonogashira coupling reaction to
prepare different aryl-containing propargylated aminocar-
bazoles which have undergone iodocyclization reaction.
The cyclization occurred only at C-4 position of various
substituted propargylic 3-aminocarbazoles giving only
one product selectively.
Abstract: An efficient and simple method for the synthesis of var-
ious iodo-substituted dihydropyridocarbazole derivatives has been
developed via iodocyclization of N-propargylated 3-aminocarba-
zoles.
Key words: iodocyclization, 3-aminocarbazole, dihydropyridocar-
bazole
Initially, we started with the synthesis of propargylated
aminocarbazole 3a by the propargylation of N-tosylated
amino carbazole 1a with propargyl bromide (2a) in the
presence of K2CO3 in THF, and the product was obtained
with good yield. The obtained product 3a was subjected to
Sonogashira coupling reaction with various aryl iodides
4a–i under very mild conditions (25–35 °C, 8 h) in the
presence of Pd(PPh3)2Cl2 (2 mol%) as a catalyst and CuI
(1 mol%) as a co-catalyst in THF solvent with triethyl-
amine as a base. However, when triethylamine was used
as both the solvent and the base, we got much lower yields
due to incomplete solubility of starting materials. DMF
was also used under heating, but it led to unwanted
byproducts. Best results were obtained by using THF as a
solvent. Using these reaction conditions C-arylation of
terminal alkyne 3a took place yielding disubstituted
alkynes 5a–h in good yields (70–80%, Scheme 1 and
Table 1).
Synthesis of various heteroarylcarbazoles has attracted
much attention, because of their biological and pharmaco-
logical activities.1,2 Among them, pyridocarbazole deriva-
tives are very useful in the development of several DNA
intercalating drugs.3 In particular, ellipticine, a pyridocar-
bazole alkaloid exhibits anticancer and anti-HIV activities
due to its strong binding with DNA.4 Its derivatives are
widely used in the treatment of osteolytic breast cancer
metastases, brain tumors, kidney sarcoma, and myeloblas-
tic leukemia. Owing to their limited toxic effects, high ef-
ficiency to act against several types of cancer and
complete lack of hematological toxicity, ellipticine, and
its derivatives are profoundly used in clinical purposes.
Ellipticine displays antineoplastic property which de-
pends upon its DNA intercalation and/or inhibition of to-
poisomerase II.5
In recent years, considerable attention has been drawn for
synthesizing wide variety of interesting carbocyclic and
heterocyclic compounds through iodocyclization of
alkynes.6,7 These reactions involve iodine, which is inex-
pensive, non-toxic, and readily available reagent. These
reactions are also very efficient, clean, and do not require
harsh reaction conditions. Further, the iodo-substituted
pyridocarbazole derivatives are important precursors in
new C–C, C–N, or C–S bond-forming reactions and are,
thereby, efficient synthetic building blocks for the elabo-
ration of molecular complexity. Larock et al.8–10 published
the iodocyclization-based synthesis of various heterocy-
clic compounds. Several methodologies have already
been developed by us for the synthesis of pyridocarbazole
derivatives.11 Here, we report a simple, yet more efficient
method for the synthesis of iodo-substituted dihydropyri-
docarbazole derivatives based on iodocyclization reac-
tion. This methodology is more effective because it does
not involve highly expensive and toxic transition-metal-
Then we attempted the reaction of phenyl-substituted pro-
pargylated aminocarbazole with three equivalents of io-
Ts
N
Br
NHTs
(2a)
K2CO3, THF
reflux, 10 h
90%
N
H
N
Et
Et
1a
3a
Pd(PPh3)2Cl2 (2 mol%)
CuI (1 mol%), Et3N
THF, r.t., 6–8 h, 70–80%..
Ar-I
(4a–h)
I
Ts
N
Ar
N
Ts
I2, NaHCO3
MeCN, r.t.
4–8 h, 70–80%
N
N
Et
Ar
Et
6a–h
SYNLETT 2011, No. 4, pp 0529–0534
x
x.
x
x.
2
0
1
1
5a–h
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259530; Art ID: G36410ST
Scheme 1 Simple route to the synthesis of dihydropyridocarbazoles
© Georg Thieme Verlag Stuttgart · New York

530
R. R. Jella, R. Nagarajan
LETTER
dine and two equivalents of NaHCO3 in acetonitrile at iodo-substituted dihydropyridocarbazole derivatives in 80
room temperature. The reaction went smoothly and pro- and 72% yields, respectively, with only a trace of side
duced the cyclized product. We screened the iodocycliza- products (entries 1 and 2, Table 2). Good results have
tion reaction with bases such as Et3N and K2CO3 in been obtained by introducing 4-nitrophenyl substrate 5d
different solvents by varying the amount of iodine in ev- also. This cyclization was also succeeded when we intro-
ery case. Finally, we observed that the reaction was going duce dichlorophenyl substituent on propargylated ami-
smoothly with three equivalents of iodine and two equiv- nocarbazole. The cyclized product 6a was first confirmed
1
alents of NaHCO3 as base in acetonitrile as solvent with by H NMR spectrum in which a broad singlet was ob-
good yield. After the completion of optimization, we ex- tained at d = 5 ppm for two methylene protons adjacent to
amined the electronic effects of various substituents on tosylated nitrogen atom, and it was further confirmed by
the aryl moiety in this electrophilic cyclization. Both elec- single crystal X-ray analysis (Figure 1).12 According to
tron-rich and electron-poor aryl-substituted alkynes react- Larock’s reports9c,10b on iodocyclization, we proposed the
ed to form the corresponding products in moderate to mechanism for this iodocyclization process (Scheme 2).
good yields (Scheme 1, Table 2). The iodocyclization of
both phenyl- (5a) and 4-methoxyphenyl-substituted prop-
argylic aminocarbazoles (5b) produced the corresponding
Table 1 Synthesis of 9-Ethyl-3-[4-methylphenyl(3-phenylpropyl)sulfonamido]-9H-carbazoles 5a–i (Scheme 1)a
Entry
Aryl iodides 4 Ar
Coupled product
Time (h)
Yield (%)
Ts
N
1
4a Ph
8
76
N
Et
5a
Ts
N
2
3
4
4b 4-MeOC6H4
4c 4-MeC6H4
4d 4-O2NC6H4
8
8
6
73
72
75
N
Et
OMe
5b
Ts
N
N
Et
5c
Ts
N
N
Et
NO2
5d
Synlett 2011, No. 4, 529–534 © Thieme Stuttgart · New York

LETTER
Synthesis of Dihydropyrido[2,3-c]carbazoles
531
Table 1 Synthesis of 9-Ethyl-3-[4-methylphenyl(3-phenylpropyl)sulfonamido]-9H-carbazoles 5a–i (Scheme 1)a (continued)
Entry
Aryl iodides 4 Ar
4e 4-ClC6H4
Coupled product
Time (h)
Yield (%)
Ts
N
5
6
76
N
Et
Cl
5e
Ts
N
6
4f 4-AcC6H4
6
74
N
Et
COMe
5f
Ts
N
7
8
4g 3-MeC6H4
8
8
72
75
N
Et
5g
Ts
N
4h 3-O2NC6H4
N
NO2
Et
5h
Ts
N
9
4i 1,3-Cl2C6H4
6
74
N
Cl
Et
Cl
5i
a In all the cases, Pd(PPh3)2Cl2 (2 mol%) and CuI (1 mol%) were used in the presence of Et3N as a base and THF as a solvent at r.t.
We performed the detosylation followed by aromatization In summary, we have developed a simple and effective
of 6a in the presence of cesium carbonate in the mixture method for the synthesis of iodo-substituted dihydropyri-
of THF and MeOH at 50 °C to give 7-ethyl-2-iodo-1-phe- docarbazole derivatives using iodocyclization process.
nyl-7H-pyrido[2,3-c]carbazole (7a) with moderate yield The reaction conditions are mild and the products are ob-
(Scheme 3). The obtained detosylated product 7a was first tained in good yields. The iodine group present in the
confirmed by 1H NMR in which a singlet had appeared at products is very useful for further functionalization and
d = 9.27 ppm for the proton attached to the carbon adja- preparation of multisubstituted pyridocarbazole deriva-
cent to nitrogen atom, and the broad singlet at d = 5 ppm tives.
in 6a13 had disappeared. In addition, the structure of 7a14
confirmed by single-crystal X-ray analysis (Figure 2).12
Synlett 2011, No. 4, 529–534 © Thieme Stuttgart · New York

532
R. R. Jella, R. Nagarajan
LETTER
Table 2 Synthesis of 7-Ethyl-2-iodo-4-(4-methylphenylsulfonyl)-
1-phenyl-4,7-dihydro[2,3-c]carbazoles 6a–i (Scheme 1)
Table 2 Synthesis of 7-Ethyl-2-iodo-4-(4-methylphenylsulfonyl)-
1-phenyl-4,7-dihydro[2,3-c]carbazoles 6a–i (Scheme 1) (continued)
Entry Reactant Cyclized product
Time (h) Yield (%)
Entry Reactant Cyclized product
Time (h) Yield (%)
I
I
N
Ts
N
Ts
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
4
6
6
4
4
4
80
72
74
71
76
71
7
5g
6
73
N
N
Et
Et
6a
6g
O2N
I
MeO
I
N
Ts
N
Ts
8
5h
8
70
N
Et
N
6b
Et
I
6h
Cl
N
I
Ts
N
Cl
Ts
N
9
5i
6
72
Et
6c
N
I
Et
O2N
6i
N
Ts
I+
I2
N
Ar
Ts
Et
N
Ts
N
6d
I–
I
Cl
N
N
Ar
N
Et
Et
Ts
I
5a–i
H+
Ar
N
N
Ts
Et
6e
I
N
MeOC
Et
6a–i
N
Ts
Scheme 2 Proposed mechanism for the iodocyclization reaction
N
Et
6f
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 4, 529–534 © Thieme Stuttgart · New York

LETTER
Synthesis of Dihydropyrido[2,3-c]carbazoles
533
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Figure 1 ORTEP diagram of 6a
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Figure 2 ORTEP diagram of 7a
Acknowledgment
We gratefully acknowledge DST for financial assistance (Project
number: SR/S1/OC-70/2008) and for providing a single-crystal
X-ray diffractometer facility in our school. R.R.J. thanks CSIR for
Junior Research Fellowship.
References and Notes
(1) (a) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.;
Academic Press: San Diego, 1990, 239–352. (b) Knölker,
H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(c) Cordell, G. A. The Alkaloids 2008, Vol. 65, 1–430.
(d) Gribble, G. W. Synlett 1991, 289. (e) Gribble, G. W.;
Saulnier, M. G.; Sibi, M. P.; Obaza-Nutaitis, J. A. J. Org.
Chem. 1984, 49, 4518.
I
I
O
(12) The CCDC deposition number for compound 6a is 800159.
Formula: C30H25IN2O2S. Unit cell parameters: a = 9.8829
(15), b = 10.3179 (13), c = 14.554 (2), a = 80.103 (11),
b = 72.103 (13), g = 68.283 (13), space group P-1. The
CCDC deposition number for compound 7a is 800160.
Formula: C23H17IN2. Unit cell parameters: a = 11.4798 (19),
b = 10.4089 (15), c = 15.3963 (18), a = 90.00, b = 91.647
(12), g = 90.00, space group P-1.
Cs2CO3 (3 equiv)
THF–MeOH (2:1)
N
N
S
O
reflux, 12 h
60%
N
N
Et
6a
Et
7a
Scheme
3 Synthesis of 7-ethyl-2-iodo-1-phenyl-7H-pyrido[2,3-
c]carbazole
Synlett 2011, No. 4, 529–534 © Thieme Stuttgart · New York

534
R. R. Jella, R. Nagarajan
LETTER
(13) Preparation of 7-Ethyl-2-iodo-(4-methylphenylsulfonyl)-
1-phenyl-4,7-dihydro-3H-pyrido[2,3-c]carbazole (6a)
To a mixture of 9-ethyl-3-[4-methylphenyl(3-phenylpropyl)-
sulfonamido]-9H-carbazole (5a, 0.5 g, 1 mmol), iodine (0.8
g, 3 mmol), and NaHCO3 (0.36 g, 2 mmol) was added MeCN
(20 mL) at r.t. The reaction mixture was stirred for 4 h. The
reaction mixture was then diluted with EtOAc, washed with
sat. aq Na2S2O3 (20 mL). The organic layer was separated,
and the aqueous layer was extracted with EtOAc (25 mL).
The combined organic layers were dried over Na2CO3,
filtered, and concentrated under the reduced pressure.
Product was purified by column chromatography on silica
gel (eluent: hexane–EtOAc) afforded 6a (0.48 g, 80%).
Mp 172–174 °C. IR (KBr): 3043, 2976, 2926, 1608, 1593,
1440, 1346, 1163, 1087, 883 cm–1. 1H NMR (400 MHz,
TMS, CDCl3): d = 8.16 (1 H, d, J = 8.8 Hz, ArCH), 7.55 (4
H, d, J = 7.2 Hz, ArCH), 7.26–7.16 (4 H, m, ArCH), 7.08 (2
H, m, ArCH), 6.95–6.93 (2 H, m, ArCH), 6.60–6.57 (2 H, m,
ArCH), 5.00 (2 H, br s, CH2), 2.15 (3 H, s, CH3), 1.44 (3 H,
t, J = 6.8 Hz, CH3). 13C NMR (100 MHz, TMS, CDCl3): d =
143.5, 141.0, 140.0, 139.8, 139.4, 135.6, 130.6, 129.9,
129.2, 128.1, 127.7, 127.1, 126.1, 125.2, 124.2, 124.0,
121.8, 118.4, 118.3, 109.2, 107.9, 91.7 (arom. C), 59.8, 37.5,
21.3, 13.6 (aliph. C). MS (positive mode): m/z = 604 [M +
H]. Anal. Calcd (%) for C30H25IN2O2S: C, 59.61; H, 4.17; N,
4.63. Found: C, 59.58; H, 4.10; N, 4.56.
In a round-bottom flask equipped with a magnetic stirring
bar, 7-ethyl-2-iodo-(4-methylphenylsulfonyl)-1-phenyl-4,7-
dihydro-3H-pyrido[2,3-c]carbazole (6a, 0.5 mmol) was
dissolved in a mixture of THF (20 mL) and MeOH (10 mL)
at r.t. Cs2CO3 (1.5 mmol) was added to the clear solution.
The resulting mixture was stirred at 50 °C, and the progress
of the reaction was monitored. When the reaction was
complete (12 h), the mixture was evapourated under
vacuum. To the residue was added H2O (20 mL), and the
mixture was stirred at r.t. for 10 min. Then the aqueous layer
was extracted with EtOAc (3 × 20 mL). The combined
organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. Product was purified
by column chromatography on silica gel (eluent: hexane–
EtOAc) afforded 7a (0.2 g, 60%).
Mp 178–180 °C. IR (KBr): 3126, 3055, 2972, 1614, 1591,
1504, 1444, 1379, 1253, 952 cm–1. 1H NMR (400 MHz,
TMS, CDCl3): d = 9.27 (1 H, s, ArCH), 8.21 (1 H, d, J = 8.0
Hz, ArCH), 7.95 (1 H, d, J = 8.0 Hz, ArCH), 7.58–7.40 (6 H,
m, ArCH), 7.27 (1 H, t, J = 8.0 Hz, ArCH), 6.64 (1 H, t,
J = 8.0 Hz, ArCH), 5.78 (1 H, d, J = 8.0 Hz, ArCH), 4.5
(2 H, q, J = 8.0 Hz, CH2), 1.48 (3 H, t, J = 4.0 Hz, CH3).
13C NMR (100 MHz, TMS, CDCl3): d = 153.2, 148.4, 145.5,
144.6, 138.8, 138.7, 131.2, 129.4, 129.0, 128.9, 125.8,
124.6, 124.1, 123.4, 118.9, 114.5, 114.1, 108.2, 100.1 (arom.
C), 37.6, 14.1 (aliph. C). MS (positive mode): m/z = 449
[M + H]. Anal. Calcd (%) for C23H17IN2: C, 61.62; H, 3.82;
N, 6.25. Found: C, 61.31; H, 3.78; N, 6.31.
(14) Preparation of 7-Ethyl-2-iodo-1-phenyl-7H-pyrido[2,3-
c]carbazole (7a)
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