An efficient and general synthesis of indolo[2,3-a]carbazoles using the Fischer indole synthesis

Article abstract of DOI:10.1055/s-2004-835667

Synthetically important indolo[2,3-a]carbazoles were obtained in a one-pot reaction via Fischer indole synthesis starting from 2-amino-cyclohexanone hydrochloride and substituted arylhydrazines hydrochloride in the presence of acidic media.

Full text of DOI:10.1055/s-2004-835667

4
2
LETTER
An Efficient and General Synthesis of Indolo[2,3-a]carbazoles Using the
Fischer Indole Synthesis
S
Y
ynthesis of Indolo
o
[2,3-
a
]carba
n
zoles g-Zhou Hu,* You-Qin Chen
Zhejiang University, Department of Medicinal Chemistry, School of Pharmaceutical Science, Hangzhou 310031, P. R. China
Fax +86(571)87217412; E-mail: huyz@zjuem.zju.edu.cn
Received 11 September 2004
1
5
nylmaleimide. Despite the number and diversity of these
methods, several research strategies have shown modest
yields, harsh reaction conditions and/or tedious work up
procedures. For this reason, the development of a new and
general method for the synthesis of indolo[2,3-a]carba-
zoles is of scientific interest.
Abstract: Synthetically important indolo[2,3-a]carbazoles were
obtained in a one-pot reaction via Fischer indole synthesis starting
from 2-amino-cyclohexanone hydrochloride and substituted aryl-
hydrazines hydrochloride in the presence of acidic media.
Key words: Fischer indole synthesis, indolo[2,3-a]carbazole alka-
loids, 2-amino-cyclohexanone, arylhydrazine, heterocycle
We now report a novel tandem Fischer indole synthesis
that assembles indolo[2,3-a]carbazoles 1 in one step from
Indolo[2,3-a]carbazole is the heterocyclic core of several 2-amino-cyclohexanone hydrochloride 2 and substituted
important natural products including the Tjipanazoles (T. arylhydrazines hydrochloride 3 (Scheme 1). This method-
1
2
tjipanasensis), Rebeccamycin (S. aerocolonigenes),
ology provides for the rapid construction of a variety of
3
Staurosporine (S. staurosporeus) and their derivatives. highly substituted indolo[2,3-a]carbazoles.
The indolo[2,3-a]carbazole alkaloids are extremely inter-
esting owing to the wide range of biological activities that
they possess, including antifungal, hypotensive, and
antimicrobial activities, as well as inhibition of protein
kinase C (PKC) and platelet aggregation. The great
interest in these compounds, however, has been due to
their potent antitumor activity. Presently, several indo-
lo[2,3-a]carbazole alkaloids are in clinical trials for poten-
tial use in cancer therapy. Many synthetic strategies
At the first attempt, an equimolar mixture of 2-aminocy-
clohexanone hydrochloride 2a and 4-chlorophenylhydra-
zine hydrochloride 3e in glacial HOAc was refluxed for 3
h. This yielded a mixture of two products, which were
1
,4
5
6
3
a,7
3c
1
separated and assigned on the basis of its IR spectra, H
16
NMR, MS data and microanalyses. One product was 1-
4
,8
oxo-6-chloro-1,2,3,4-tetrahydrocarbazole (4e) and the
other product was 3,8-dichloroindolo[2,3-a]carbazole
9
(
1e). To realize our objective of one-pot synthesis of indo-
lo[2,3-a]carbazoles, we examined the reaction of 2a with
equivalents of 3e in glacial HOAc to give a single prod-
uct 1e. Herein, the plausible mechanism of cyclization of
with 3 is considered to be Fischer indole synthesis, plus
toward the synthesis of indolo[2,3-a]carbazole backbone
have already been developed. These include, for example,
condensation of 8-amino-1,2,3,4-tetrahydro-9-methyl-
4
9
H-carbazole with 2-hydroxycyclohexanone,10 cycliza-
2
tion of either 1,2,3,4-tetrahydro-9H-carbazol-1-one or the
monophenylhydrazone of cyclohexane-1,2-dione with
phenylhydrazine via Fischer indole synthesis, cycload-
dition of 1,1¢-dimethyl-2,2¢-bisindolyl with racemic a-
chloro-a-phenylacetyl chloride, electrocyclization of 3-
substituted indol-2(3H)-one or 1-phenylsulfonyl-3-tribu-
tylstannylindole, palladium-catalyzed cross-coupling
reactions of indole, and [4+2]-cycloaddition of 2,2¢-bis-
indolyl with dimethyl acetylenedicarboxylate or N-phe-
hydrolysis to 1-oxo-1,2,3,4-tetrahydrocarbazoles 4, then
through the bis-Fischer indole reaction to give 5,6,11,12-
tetrahydroindolocarbazoles 5, which dehydrogenate to
obtain target compounds 1 (Scheme 2).
1
1
1
2
As discussed above on mechanism, the acid strength of
the solution in many cases determines the yields in
Fischer indole reactions.17 According to this, we investi-
gated the reaction of 2a with 3e by choosing nine different
1
3
1
4
R1
O
NHNH ·HCl
2
NH2·HCl
acidic media
R2
R2
R2
N
H
N
H
R1
2
3
1
Scheme 1
SYNLETT 2005, No. 1, pp 0042–0048
0
5.
0
1.
2
0
0
5
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-835667; Art ID: U25804ST
Georg Thieme Verlag Stuttgart · New York
©

LETTER
Synthesis of Indolo[2,3-a]carbazoles
43
R2
R2
NHNH2·HCl
O
R1
R1
H
H
NH2HCl
H+
H+
N
N
N
N
H
R2
H
H
R1
2
NH2
NH2
3
R1
R1
R2
R1
H
R2
R2
H
H
+
+
H , H2O
N
N
H
O
-H+
O
NH2
H
NH2
NH2
NH
N
H
R2
R1
R1
R1
R2
R2
R2
-
H+
-NH3
NHNH2
O
NH2
N
O
N
O
NH2
NH2
H
H
4
R1
R1
R1
R2
R2
R2
R2
H+
+H+
-H+
N
N
NH
N
H
NH
NH
NH2
H
N
N
H
H
R2
R2
R2
R2
R1
R1
R1
R2
R2
R2
R2
-
H+
H
NH
NH2
N
N
H H2N
N
H
NH2
N
NH2
H
H
R1
R1
R2
R2
R2
R2
-
NH3
-H2
N
H
N
H
N
H
N
H
5
1
Scheme 2 A plausible reaction mechanism for the synthesis of indolo[2,3-a]carbazoles
acidic medium. The results (Table 1) demonstrated that nylhydrazines hydrochloride with 2a under Fischer indole
5% HOAc–TFA or ZnCl –HOAc were more suitable conditions could occur either to the o-unsubstituted side
9
2
conditions for the mentioned reaction and the yield of the of o-halophenylhydrazine to give the ‘normal’ product,
product 1e could be improved up to 87% and 86%, respec- 1,10-dihaloindolo[2,3-a]carbazole, or to the o-substituted
tively. In the presence of 95% HOAc–TFA, the reaction side of o-halophenylhydrazine to give the ‘abnormal’
of 2 with a series of substituted arylhydrazine hydro- products, 1-haloindolo[2,3-a]carbazole and unsubstituted
chlorides 3 proceeded in good yields (Table 2).1
8,19
indolo[2,3-a]carbazole (Scheme 4). To optimize the
However, cyclization of 3-chlorophenylhydrazine hydro- regioselectivity of the reaction of 2a with o-halophenyl-
chloride (3g) with 2a led to a 2.6:1:1 mixture of 4,7- hydrazines hydrochloride 3j–l, we investigated the
dichloroindolo[2,3-a]carbazole (1g), 2,7-dichloroindo- reaction by choosing several different conditions,20 such
lo[2,3-a]carbazole, 2,9-dichloroindolo[2,3-a]carbazole as p-toluenesulfonic acid (TsOH) in ethanol, hydrogen
(
Scheme 3). In addition, cyclization of the ortho-halophe- chloride in ethanol, zinc chloride in acetic acid or poly-
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York

4
4
Y.-Z. Hu, Y.-Q. Chen
LETTER
phosphoric acid (PPA), which gave unsatisfactory results. Table 1 Results of the Fischer Indolization of 2-Aminocyclohex-
anone Hydrochloride (2a) with p-Chlorophenylhydrazine Hydro-
chloride (3e) in Various Acid Catalysts
At last, the Fischer indolization of 2a with o-bromophe-
nylhydrazine hydrochloride 3l was successfully carried
out with PrOH and glacial HOAc to give only the normal
Entry
Acid catalyst
Reaction
temp (°C) time (h)
Reaction Yield
1
1
,10-dibromoindolo[2,3-a]carbazole (1l, Table 2, entry
2), but unfortunately under the same condition, the re-
(%)a
2
1
1
2
3
4
5
6
7
8
95% HOAc–TFA
Glacial HOAc
100
12
14
13
21
5
87
83
72
86
46
69
30
0c
action of 2a with o-chlorophenylhydrazine hydrochloride
3
k gave a 6:1:1 mixture of the normal 1,10-dichloroindo-
Reflux
Reflux
Reflux
Reflux
Reflux
180
lo[2,3-a]carbazole (1k), the abnormal 1-chloroindolo[2,3-
a]carbazole and indolo[2,3-a]carbazole (1a) in 80% over-
all yield (Table 2, entry 11), and the reaction of 2a with o-
fluorophenylhydrazine hydrochloride (3j) obtained the
mixture of 1,10-difluoroindolo[2,3-a]carbazole (1j), 1-
fluoroindolo[2,3-a]carbazole and indolo[2,3-a]carbazole
HCOOH (97%)
ZnCl –HOAc
2
BF ·OEt –HOAc
3 2
p-TsOH–EtOH
[BMIM][Al Cl
PCl –CH Cl
20
(
1a) in 71% overall yield and ca. 3:3:1 ratio (Table 2, en-
]b
0.5
try 10). It was apparent from the results with o-bromo, o-
chloro and o-fluoro groups that the less electron-attractive
halo group resulted in a higher ratio of normal products to
abnormal products.
2
7
Reflux
Reflux
10
12
3
2
2
9
HCl–EtOH
Isolated yield.
12
a
b
A chloroaluminate ionic liquid, [N-butyl-N-methyl-
imidazolium][Al Cl ].
2
7
c
No reaction had occurred.
Table 2 Reaction of 2-Aminocyclohexanone Hydrochlorides 2 with Arylhydrazine Hydrochlorides 3a
b
Entry
1
2
3
Product 1
Yield (%)
O
NHNH ·HCl
94
2
NH2·HCl
NH2·HCl
N
H
N
H
2
2
a
a
3
a
1a
2
3
O
NHNH ·HCl
86
52
2
N
H
N
H
1b
3
3
3
3
b
O
O
O
NHNH ·HCl
2
OMe
MeO
NH2·HCl
NH2·HCl
NH2·HCl
N
H
N
H
2
2
2
a
a
a
1c
OMe
c
d
e
4
5
NHNH ·HCl
65
87
2
F
F
N
N
H
H
1d
F
NHNH ·HCl
2
Cl
Cl
N
N
H
H
1e
Cl
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolo[2,3-a]carbazoles
45
a
Table 2 Reaction of 2-Aminocyclohexanone Hydrochlorides 2 with Arylhydrazine Hydrochlorides 3 (continued)
b
Entry
6
2
3
Product 1
Yield (%)
O
NHNH ·HCl
2
Br
65
Br
NH2·HCl
N
H
N
H
1
f
2
a
a
Br
3
f
7
O
NHNH ·HCl
Cl
82c
2
Cl
NH2·HCl
Cl
N
H
N
H
2
3
g
1
1
g
8
9
O
O
NHNH ·HCl
48
48
2
NH2·HCl
NH2·HCl
N
H
N
H
2
2
a
a
3h
3i
h
NHNH ·HCl
2
OMe
N
H
N
H
OMe
OMe
1
1
1
1
i
1
1
1
1
0
1
2
3
O
O
O
O
NHNH ·HCl
71d
80e
51
2
NH2·HCl
NH2·HCl
NH2·HCl
NH2·HCl
F
N
H
N
H
F
F
2
2
2
a
a
a
3j
3k
3l
j
k
l
NHNH ·HCl
2
Cl
N
H
N
H
Cl
Cl
NHNH ·HCl
2
Br
N
H
N
H
Br
Br
NHNH ·HCl
2
92
N
H
N
H
3
a
1
m
n
2
2
b
b
1
4
O
NHNH ·HCl
86
2
NH2·HCl
Cl
Cl
N
H
N
H
Cl
1
3
e
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York

4
6
Y.-Z. Hu, Y.-Q. Chen
LETTER
a
Table 2 Reaction of 2-Aminocyclohexanone Hydrochlorides 2 with Arylhydrazine Hydrochlorides 3 (continued)
b
Entry
5
2
3
3
Product 1
Yield (%)
1
1
a
88
O
NHNH ·HCl
2
NH2·HCl
a
N
N
H
H
1
o
2
c
6
O
NHNH ·HCl
71
2
NH2·HCl
Cl
Cl
Cl
3
e
N
H
N
H
1
p
2
c
18
All reactions took place in 95% HOAc–TFA (see ref. ), except for entries 10–12, which performed in the presence of PrOH and glacial HOAc
21
(
see ref. ).
Isolated yield.
b
c
d
e
A 2.6:1:1 mixture of 4,7-dichloroindolo[2,3-a]carbazole (1g), 2,7-dichloroindolo[2,3-a]carbazole and 2,9-dichloroindolo[2,3-a]carbazole.
A 3:3:1 mixture of 1,10-difluoroindolo[2,3-a]carbazole (1j), 1-fluoroindolo[2,3-a]carbazole and indolo[2,3-a]carbazole (1a).
A 6:1:1 mixture of 1,10-dichloroindolo[2,3-a]carbazole (1k), 1-chloroindolo[2,3-a]carbazole and indolo[2,3-a]carbazole (1a).
Cl
Cl
O
N
H
N
H
O
NH2·HCl
N
H
N
H
R
R
NH2·HCl
1g
normal product
1,10-disubstituted indolo[2,3-a]carbazole
2a
95%
HOAc–TFA
Cl
2
a
N
H
N
H
N
H
N
H
Cl
NHNH2·HCl
R
"
1
abnormal" product
-substituted indolo[2,3-a]carbazole
NHNH2·HCl
Cl
R
3g
Cl
N
H
N
H
Cl
3
j–l
N
H
N
H
Scheme 3
"
abnormal" product
To our surprise, the reaction of 2-amino-4-tert-butylcy-
clohexanone hydrochloride (2d) with substituted phenyl-
hydrazines hydrochloride in the presence of 95% HOAc–
TFA did not give the desired product, 5-tert-butylindo-
lo[2,3-a]carbazoles, but afforded indolo[2,3-a]carbazoles
which lost tert-butyl group (Scheme 5).
unsubstituted indolo[2,3-a]carbazole
Scheme 4
using Fischer indole synthesis, which proceeds smoothly
under mild conditions. Apart from experimental simplici-
In summary, we have established a novel and one-pot ty, the advantage of this methodology is the insensitivity
route to synthesize several indolo[2,3-a]carbazole deriva- of the reaction mixture towards air and moisture. Synthet-
tives from easily available 2-amino-cyclohexanone hy- ic study aimed at broadening the scope of this potentially
drochloride and substituted arylhydrazines hydrochloride useful reaction is in progress.
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolo[2,3-a]carbazoles
47
O
NHNH ·HCl
2
NH2·HCl
R
R
9
5% HOAc–TFA
reflux 12 h
N
H
N
H
R
2d
3
1
R = H, Cl
R = H: 1a; yield 79%
R = Cl: 1e; yield 70%
Scheme 5
+
References
m/z = 221 [M + 2], 219 [M ]. Anal. Calcd for C12
H
10ClNO:
C, 65.61; H, 4.59; N, 6.38. Found: C, 65.49; H, 4.51; N,
.25. (b) Spectral Data for 3,8-Dichloroindolo[2,3-
a]carbazole (1e): mp >300 °C (lit. mp >300 °C). IR (KBr):
404.88, 3078.94, 1570.63, 1492.32, 875.91, 811.22 cm .
H NMR (400 MHz, DMSO-d ): d = 11.25 (s, 2 H, NH),
.24 (d, J = 1.6 Hz, 2 H, H-4, H-7), 7.95 (s, 2 H, H-5, H-6),
.70 (d, J = 8.4 Hz, 2 H, H-1, H-10), 7.37 (dd, J = 8.4, 2.0
Hz, 2 H, H-2, H-9). MS (EI): m/z = 327 [M + 2], 325 [M ].
Anal. Calcd for C H Cl N : C, 66.48; H, 3.10; N, 8.61.
Found: C, 66.35; H, 3.07; N, 8.42.
(
1) Bonjouklian, R.; Smitka, T. A.; Doolin, L. E.; Molloy, R.
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–1
3
(
1
6
8
7
(
b) Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.;
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(
1
8
10
2
2
1
986, 135, 397. (b) Funato, N.; Takayanagi, H.; Konda, Y.;
(
(
17) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607.
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Toda, Y.; Harigaya, Y.; Iwai, Y.; Omura, S. Tetrahedron
Lett. 1994, 35, 1251. (c) Oka, S.; Kodama, M.; Takada, H.;
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1m–p):
The 2-amino-cyclohexanone hydrochloride 2 (0.334 mmol)
and substituted arylhydrazine hydrochloride 3 (4 equiv)
were dissolved in 1.5 mL 95% HOAc and 0.5 mL TFA. The
mixture was heated to 100 °C until TLC analysis showed
complete consumption of the intermediate 1-oxo-1,2,3,4-
2
723.
4) Moody, C. J.; Rahimtoola, K. F. J. Org. Chem. 1992, 57,
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978, 89, 58348y.
(
(
2
1
tetrahydrocarbazoles 4. The mixture was cooled to r.t., H O
2
was added and the solid was collected by filtration. The
crude products were purified by chromatography on silica
gel using petroleum ether–EtOAc (5:1) as eluant. The yields
in Table 2 represent the average of two or more runs.
19) All new compounds gave satisfactory analytical and spectral
data. Data for selected compounds are as follows:
1
(
6) Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.;
Tsuchiya, H.; Takahashi, Y.; Masuma, R. J. Antibiot. 1977,
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0, 275.
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(
(
9
Compound 1o (Table 2, entry 15): mp >300 °C. IR (KBr):
357.15, 3300.33, 3054.31, 1695.67, 1599.14, 1488.63,
40.66 cm . H NMR (400 MHz, DMSO-d ): d = 11.24 (s,
H, NH), 11.04 (s, 1 H, NH), 8.14 (d, J = 7.6 Hz, 1 H, Ar-
H), 7.73 (s, 1 H, Ar-H), 7.66 (t, J = 7.6 Hz, 2 H, Ar-H), 7.62
d, J = 7.6 Hz, 2 H, Ar-H), 7.54 (t, J = 7.6 Hz, 2 H, Ar-H),
.47 (t, J = 7.2 Hz, 1 H, Ar-H), 7.37 (t, J = 7.6 Hz, 1 H, Ar-
H), 7.28–7.32 (m, 2 H, Ar-H), 7.16 (t, J = 7.6 Hz, 1 H, Ar-
H), 6.90 (t, J = 7.6 Hz, 1 H, Ar-H). MS (EI): m/z = 332 [M ].
E. M.; Elbaum, D.; Stover, D. R. Synthesis 1999, 1529.
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3
7
1
(
(
–1 1
6
12, 365.
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(
7
(10) Brunton, R. J.; Drayson, F. K.; Plant, S. G. P.; Tomlinson,
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(
+
(
London) 1957, 363. (b) Mann, F. G.; Willcox, T. J. J.
Anal. Calcd for C H N : C, 86.72; H, 4.85; N, 8.43. Found:
2
4
16
2
Chem. Soc. 1958, 1525. (c) Royer, H.; Joseph, D.; Prim, D.;
Kirsch, G. Synth. Commun. 1998, 28, 1239.
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C, 86.61; H, 4.78; N, 8.35.
Compound 1p (Table 2, entry 16): mp >300 °C. IR (KBr):
419.72, 3355.40, 1703.65, 1567.85, 1455.51, 806.60,
04.63 cm . H NMR (400 MHz, DMSO-d ): d = 11.53 (s,
H, NH), 11.32 (s, 1 H, NH), 8.31 (s, 1 H, Ar-H), 7.85 (s, 1
H, Ar-H), 7.74–7.78 (m, 2 H, Ar-H), 7.60–7.66 (m, 4 H, Ar-
H), 7.54 (t, J = 6.4 Hz, 7.2 Hz, 1 H, Ar-H), 7.42 (d, J = 8.4
Hz, 1 H, Ar-H), 7.35 (d, J = 8.4 Hz, 1 H, Ar-H), 7.23 (s, 1 H,
Ar-H). MS (EI): m/z = 403 [M + 2], 401 [M ]. Anal. Calcd
for C H Cl N : C, 71.83; H, 3.52; N, 6.98. Found: C,
(
(
3
7
1
–1
1
6
1
993, 49, 4741. (b) Beccalli, E. M.; Gelmi, M. L.;
Marchesini, A. Tetrahedron 1998, 54, 6909.
(
14) Merlic, C. A.; McInnes, D. M. Tetrahedron Lett. 1997, 38,
7661.
(
(
15) Somei, M.; Kodama, A. Heterocycles 1992, 34, 1285.
16) (a) Spectral Data for 1-Oxo-6-chloro-1,2,3,4-
+
2
4
14
2
2
2
2
tetrahydrocarbazole (4e): mp 218 °C (lit. mp 220 °C). IR
71.69; H, 3.45; N, 6.83.
(KBr): 3269.91, 3065.63, 2944.19, 2867.84, 1652.68,
(
20) Murakami, Y.; Watanabe, T.; Yokoyama, Y.; Naomachi, J.;
Iwase, H.; Watanabe, N.; Morihata, M.; Okuyama, N.;
Kamakura, H.; Takahashi, T.; Atoda, H.; Tojo, T.; Morita,
K.; Ishii, H. Chem. Pharm. Bull. 1993, 41, 1910.
–
1 1
1539.99, 1481.58, 810.98, 734.34 cm . H NMR (400 MHz,
CDCl ): d = 2.27–2.32 (m, 2 H, CH ), 2.67 (t, J = 6.0 Hz, 2
3
2
H, CH ), 2.98 (t, J = 5.6 Hz, 2 H, CH ), 7.32–7.38 (m, 2 H,
2
2
ArH), 7.65 (s, 1 H, ArH), 8.97 (s, 1 H, NH). MS (EI):
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York

4
8
Y.-Z. Hu, Y.-Q. Chen
LETTER
(
21) General Procedure for the Synthesis of Compounds
1j–l):
The 2-amino-cyclohexanone hydrochloride 2a (50 mg,
.334 mmol) was added to a solution of ortho-halophenyl-
hydrazines hydrochloride 3j–l (4 equiv) in n-propyl alcohol
2 mL) at r.t., then the reaction mixture was refluxed for 3 h.
12 h. The mixture was cooled to r.t., H O was added and the
2
(
solid was collected by filtration. The crude products were
purified by chromatography on silica gel using petroleum
ether–EtOAc (15:1) as eluant. The results are depicted in
Table 2 (entries 10–12).
0
(
(22) Gazengel, J. M.; Lancelot, J. C.; Rault, S.; Robba, M. J.
Heterocycl. Chem. 1990, 27, 1947.
The solvent was removed in vacuo, glacial HOAc (3 mL)
was added to the residue, and the mixture was refluxed for
Synlett 2005, No. 1, 42–48 © Thieme Stuttgart · New York