A simple and efficient method for the synthesis of indolo[3,2-b]carbazoles

Article abstract of DOI:10.1055/s-0029-1218644

3-Alkylated indoles, obtained by three-component reactions of indole, aldehydes, and N,N-dimethylbarbituric acid, afford indolo[3,2-b]carbazoles in excellent yields under thermal conditions in acetic acid. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1218644

PAPER
929
A Simple and Efficient Method for the Synthesis of Indolo[3,2-b]carbazoles
S
M
ynthesis of Indolo[3,2
o
-
b
]carbazole
h
s
it L. Deb, Swarup Mazumder, Biswajita Baruah, Pulak J. Bhuyan*
North East Institute of Science & Technology, Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 13 October 2009; revised 23 November 2009
The 3-alkylated indoles 4 were prepared from the reac-
tions of indole (1), aldehydes 2, and N,N-dimethylbarbitu-
ric acid (3) (Scheme 1) according to our own reported
Abstract: 3-Alkylated indoles, obtained by three-component reac-
tions of indole, aldehydes, and N,N-dimethylbarbituric acid, afford
indolo[3,2-b]carbazoles in excellent yields under thermal condi-
tions in acetic acid.
1
method. In our reaction strategy, treatment of 3-alkylated
indoles 4 in acetic acid under refluxing conditions afford-
ed, after workup, the indolo[3,2-b]carbazoles 5 in 45–
Key words: heterocycles, indoles, aldehydes, indolo[3,2-b]carba-
zole, N,N-dimethylbarbituric acid
8
7% yield. Thus, in a simple experimental procedure,
compound 4a, for example, was refluxed in acetic acid for
5 minutes; after workup, this afforded indolo[3,2-b]car-
1
Recently we synthesized a novel class of 3-alkylated in-
bazole 5a in 80% yield (Scheme 1). The product was iso-
lated simply by filtration followed by recrystallization
from a mixture of N,N-dimethylformamide and chloro-
form. The structure of the compound was determined
from spectroscopic data and elemental analysis. The N,N-
dimethylbarbituric acid (3) that was eliminated during the
reaction was isolated from the filtrate and characterized.
Following the same reaction procedure, we synthesized
and characterized a series of indolo[3,2-b]carbazoles 5b–
j. Our observations are recorded in Table 1.
doles 4 by a three-component reaction of indole (1), alde-
hydes 2, and N,N-dimethylbarbituric acid (3)
1
(
Scheme 1). The 3-alkylated indoles thus obtained were
then utilized for the synthesis of unsymmetrical bis(in-
dolyl)methanes, which also demonstrated the good leav-
2
ing nature of N,N-dimethylbarbituric acid. As a part of
3
our continued work in the area and synthesis of diverse
heterocyclic compounds of biological importance, we
now report here a very simple and efficient method for the
synthesis of indolo[3,2-b]carbazoles from 3-alkylated in-
dole 4 (Scheme 1).
Table 1 Synthesis of Indolo[3,2-b]carbazoles 5 from 3-Alkylated
Indoles 4 Catalyzed by Acetic Acida
O
4
R
Time
min)
Product Yield Mp
Me
N
b
(
5
(%)
80
82
80
87
72
70
75
48
45
62
(°C)
+
RCHO
+
N
O
N
O
H
4a
Ph
15
15
15
15
20
20
20
40
40
40
5a
5b
5c
5d
5e
5f
5g
5h
5i
350–352
2
Me
4
b
4-MeOC H
4
383–385
>400
1
6
3
R
O
O
4c
4-MeC
3,4,5-(MeO) C H
2
H
6 4
Me
4
d
>400
N
3
6
N
4e
4-HOC H
>400
N
O
6
4
4
H
Me
4
4
f
2-HOC H
357–359
392–393
364–366
341–343
375–377
6
AcOH
heat
4g
4h
3-MeO-4-HOC
4-ClC H
H
3
6
O
R
R
6
4
4
H
N
Me
N
4
4
i
2-ClC H
6
+
N
O
N
O
j
4-BzOC H
5j
6
4
H
Me
a
Reaction conditions: 4 (2 mmol), AcOH (5 mL), heat.
Isolated yields.
b
5a–j
3
Scheme 1
The reaction was also studied by utilizing the 3-alkylated
indoles 4 with various Lewis acids, e.g., iodine, indi-
um(III) chloride, cerium(IV) ammonium nitrate, and indi-
um(III) trifluoromethanesulfonate, in solvents such as
acetonitrile and tetrahydrofuran. Unfortunately, we could
not get the desired products in any of these attempts. Next,
SYNTHESIS 2010, No. 6, pp 0929–0932
x
x
.
x
x
.2
0
1
0
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218644; Art ID: P14309SS
Georg Thieme Verlag Stuttgart · New York
©

9
30
M. L. Deb et al.
PAPER
we studied the reaction in refluxing acetonitrile and using dimethylbarbituric acid. In addition, the N,N-dimethyl-
hydrogen chloride as catalyst. Initially the reaction was barbituric acid that can be isolated in almost quantitative
found to proceed, but some blackish compound appeared yield can be used again in the three-component reaction
quickly during the reaction process; this might be due to that leads to the formation of 3-alkylated indoles 4. This
decomposition of the product, and we were not able to iso- very simple, efficient, and cost-effective procedure for the
late the desired compounds.
synthesis of various indolo[3,2-b]-carbazoles is a valuable
addition to the chemistry of indolocarbazoles (ICZ).
In many earlier reported methods for the synthesis of in-
dolo[3,2-b]carbazoles, it was observed that indolo[2,3-
b]carbazoles were also formed during the reaction pro- All chemicals including the solvents were used without prior dry-
cess, but were difficult to separate due to their insolubili- ing. All reagents and solvents were of reagent grade. All IR spectra
1
4
were recorded on a Perkin-Elmer 2000 FTIR spectrometer. H
ty. In the present case, it is not possible for the
1
3
NMR and C NMR spectra (at 300 MHz and 75 MHz, respectively)
were recorded on a Bruker Avance DPX FT spectrometer; DMSO-
d6 was used as solvent, and TMS as an internal standard. Mass spec-
tra were recorded on a Bruker Daltonics ESQUIRE 3000 LC ESI
ion-trap mass spectrometer. Elemental analyses were performed on
a Perkin-Elmer 2400 instrument. Analytical TLC was performed on
aluminum-backed silica gel plates coated with silica gel (0.2 mm
thick layer) (E. Merck). Melting points (uncorrected) were deter-
mined on a Buchi B-540 apparatus. Indole, the aldehydes, and bar-
bituric acid were purchased from Aldrich Chemical Co., and other
indolo[2,3-b]carbazole isomer to form, and that makes the
method more suitable for the preparation of indolo[3,2-
b]carbazoles.
A plausible mechanism for the reaction is outlined in
Scheme 2. The 3-alkylated indoles 4 first give the inter-
mediate X and N,N-dimethylbarbituric acid (3) in the
presence of acetic acid under thermal conditions. Then
two molecules of the intermediate X react; finally, oxida-
tion affords the indolo[3,2-b]carbazoles 5. The isolation commercially available reagents were used without further purifica-
of the N,N-dimethylbarbituric acid (3) eliminated during tion.
the reaction further supports this mechanism.
6
,12-Diphenyl-5,11-dihydroindolo[3,2-b]carbazole (5a); Typi-
cal Procedure
O
Indole 4a (722 mg, 2 mmol) in AcOH (5 mL) was refluxed for 15
min. The solvent was removed under reduced pressure and the res-
idue was poured into EtOH (5 mL). The solid that had appeared was
collected by filtration, dried, and recrystallized from a DMF–CHCl3
mixture. The structure of the compound was determined to be that
of 5a on the basis of spectroscopic data and elemental analysis. The
filtrate was distilled under reduced pressure and the eliminated N,N-
dimethylbarbituric acid (3) was isolated from the residue by column
chromatography (silica gel, EtOAc–hexane,1:3). The structure of 3
was ascertained from spectroscopic data and by comparison with an
H
O
O
R
R
O
N
Me
Me
O
N
Δ
N
+
N
O
H
O
N
O
N
O
H
Me
X
Me
4
heat
3
O
5
authentic sample. Compounds 5b–j were synthesized and charac-
terized similarly.
N
H
R
–
R
N
+
Compound 5a
N
+
N
Yield: 326 mg (80%); white solid; mp 350–352 °C; R = 0.84
f
R
H
–
R
(
EtOAc–PE, 7:93).
IR (KBr): 3394 (NH stretch), 3062 (w), 3019 (w), 1492 (w), 1456
(s), 744 (s), 702 (m) cm .
–
1
H
H
R
R
N
N
1
H NMR (300 MHz, DMSO-d ): d = 6.74 (t, J = 7.41 Hz, 2 H), 6.89
6
oxidation
(
t, J = 7.32 Hz, 2 H), 7.0 (d, J = 7.71 Hz, 4 H), 7.07 (d, J = 7.83 Hz,
2
13
H), 7.17 (t, J = 7.14 Hz, 6 H), 7.58 (s, 2 H), 9.93 (s, 2 H, NH).
N
N
H
R
R
H
C NMR (75 MHz, DMSO-d ): d = 140.02, 136.57, 134.29,
6
5
133.28, 132.44, 130.18, 128.11, 126.96, 124.61, 122.33, 117.64,
1
14.77, 111.47.
Scheme 2
ESI-MS: m/z = 409.3 [M + H]+.
Anal. Calcd for C H N : C, 88.23; H, 4.90; N, 6.86. Found: C,
3
0
20
2
3
-Alkylated indoles 4 prepared from aromatic aldehydes
8
8.07; H, 4.99; N, 6.81.
that have electron-withdrawing substituents do not give
the products, as they cannot stabilize the intermediate. 6,12-Bis(4-methoxyphenyl)-5,11-dihydroindolo[3,2-b]carba-
Similarly, the reaction is not applicable to aliphatic alde- zole (5b)
Yield: 196.5 mg (82%); white solid; mp 383–385 °C.
hydes, due to the instability of the corresponding interme-
diates X.
IR (KBr): 3394 (NH stretch), 3062 (w), 2977 (w), 1456 (s), 744 (s),
–
1
7
02 (m) cm .
In summary, we have developed a very simple and highly
efficient method for the synthesis of indolo[3,2-b]carba-
zoles from 3-alkylated indoles that are available from a
three-component reaction of indole, aldehydes, and N,N-
1
H NMR (300 MHz, DMSO-d ): d = 3.40 (s, 6 H), 6.76 (d, J = 7.88
6
Hz, 2 H), 6.85–6.97 (m, 4 H), 7.0 (d, J = 7.43 Hz, 2 H), 7.08–7.17
(m, 3 H), 7.26 (t, J = 7.42 Hz, 4 H), 7.72 (s, 1 H), 9.98 (s, 2 H, NH).
Synthesis 2010, No. 6, 929–932 © Thieme Stuttgart · New York

PAPER
Synthesis of Indolo[3,2-b]carbazoles
931
1
3
C NMR (75 MHz, DMSO-d ): d = 159.13, 140.08, 138.26,
6,12-Bis(4-hydroxy-3-methoxyphenyl)-5,11-dihydroindolo[3,2-
b]carbazole (5g)
Yield: 188 mg (75%); yellowish powder; mp 392–393 °C.
6
1
1
36.45, 133.33, 130.93, 128.41, 127.11, 124.87, 122.41, 118.49,
13.93, 111.47, 55.19.
ESI-MS: m/z = 469.3 [M + H]+.
IR (KBr): 3418 (br, s), 3062 (w), 1492 (w), 1456 (s), 1224, 744 (s),
–
1
7
02 (m) cm .
6
,12-Bis(4-methylphenyl)-5,11-dihydroindolo[3,2-b]carbazole
1
H NMR (300 MHz, DMSO-d ): d = 3.41 (s, 6 H), 5.44 (s, 2 H), 6.75
6
(
5c)
(
4
t, J = 7.44 Hz, 2 H), 6.87 (q, J = 7.56 Hz, 2 H), 7.0 (t, J = 7.93 Hz,
Yield: 174.5 mg (80%); white powder; mp >400 °C.
H), 7.10 (d, J = 7.43 Hz, 2 H), 7.14–7.27 (m, 3 H), 7.58 (s, 1 H),
IR (KBr): 3397 (NH stretch), 3062 (w), 2951 (w), 1456 (s), 744 (s),
9.93 (s, 2 H, NH).
–1
6
99 (m) cm .
13
C NMR (75 MHz, DMSO-d ): d = 158.08, 155.20, 140.06,
6
1
H NMR (300 MHz, DMSO-d ): d = 2.29 (s, 6 H), 6.78 (t, J = 7.44
138.58, 136.44, 133.98, 132.02, 131.42, 128.56, 126.94, 124.61,
122.31, 118.51, 114.81, 111.53, 55.47.
6
Hz, 2 H), 6.86–6.97 (m, 2 H), 7.01 (d, J = 7.83 Hz, 3 H), 7.08 (d,
J = 7.55 Hz, 2 H), 7.12–7.21 (m, 6 H), 7.61 (s, 1 H), 10.10 (s, 2 H,
NH).
ESI-MS: m/z = 501.3 [M + H]+.
1
3
C NMR (75 MHz, DMSO-d ): d = 141.13, 136.59, 136.31,
6,12-Bis(4-chlorophenyl)-5,11-dihydroindolo[3,2-b]carbazole
(5h)
Yield: 131 mg (48%); white solid; mp 364–366 °C.
6
1
1
34.62, 133.39, 130.23, 128.17, 127.82, 124.68, 121.69, 118.72,
14.91, 111.47, 21.23.
ESI-MS: m/z = 437.4 [M + H]+.
IR (KBr): 3399 (NH stretch), 3062 (w), 1456 (s), 1137 (m), 744 (s),
–
1
7
02 (m) cm .
6
,12-Bis(3,4,5-trimethoxyphenyl)-5,11-dihydroindolo[3,2-
1
H NMR (300 MHz, DMSO-d ): d = 6.80 (t, J = 8.32 Hz, 2 H), 6.90
6
b]carbazole (5d)
Yield: 250 mg (87%); white powder; mp >400 °C.
(
7
d, J = 7.74 Hz, 2 H), 7.02–7.14 (m, 5 H), 7.20 (d, J = 7.19 Hz, 2 H),
.34 (t, J = 7.47 Hz, 4 H), 7.71 (s, 1 H), 10.02 (s, 2 H, NH).
IR (KBr): 3402 (NH stretch), 3061 (w), 1456 (s), 1233 (s), 745 (s),
13
C NMR (75 MHz, DMSO-d ): d = 139.47, 136.50, 134.31,
–1
6
7
02 (m) cm .
1
33.88, 132.49, 130.76, 128.01, 127.46, 124.79, 121.93, 117.13,
1
H NMR (300 MHz, DMSO-d ): d = 3.76–3.78 (m, 18 H), 6.83 (t,
111.47, 109.91.
6
J = 7.48 Hz, 2 H), 6.92 (t, J = 7.18 Hz, 3 H), 7.0 (d, J = 7.56 Hz, 2
H), 7.09–7.17 (m, 2 H), 7.27 (t, J = 7.14 Hz, 2 H), 7.58 (s, 1 H),
35
+
ESI-MS: m/z (%) = 477.6 [M + H (2 × Cl)] (100), 479.6 [M + H
35
37
+
37
+
(
Cl + Cl)] (63), 481.6 [M + H (2 × Cl)] (10).
1
0.02 (s, 2 H, NH).
1
3
C NMR (75 MHz, DMSO-d ): d = 158.0, 157.79, 141.33, 136.34,
6,12-Bis(2-chlorophenyl)-5,11-dihydroindolo[3,2-b]carbazole
(5i)
Yield: 119 mg (45%); yellowish powder; mp 341–343 °C.
6
1
1
34.42, 133.72, 131.57, 128.42, 127.91, 124.08, 122.80, 118.44,
14.63, 111.13, 55.47, 55.26.
ESI-MS: m/z = 589.8 [M + H]+.
IR (KBr): 3397 (NH stretch), 3062 (w), 1456 (s), 1137 (m), 745 (s),
–
1
7
02 (m) cm .
6
,12-Bis(4-hydroxyphenyl)--5,11-dihydroindolo[3,2-b]carba-
1
H NMR (300 MHz, DMSO-d ): d = 6.73–6.87 (m, 3 H), 6.91 (t,
6
zole (5e)
J = 7.49 Hz, 2 H), 7.02 (d, J = 7.31 Hz, 3 H), 7.15 (d, J = 7.41 Hz,
2
Yield: 165 mg (72%); white cotton-like solid; mp >400 °C.
H), 7.34 (t, J = 7.47 Hz, 4 H), 7.72 (s, 2 H), 10.02 (s, 2 H, NH).
IR (KBr): 3414 (br, s), 3019 (w), 1456 (s), 1233 (s), 744 (s), 699 (m)
cm .
13
C NMR (75 MHz, DMSO-d ): d = 139.49, 136.63, 134.80,
–
1
6
1
33.81, 132.49, 130.70, 128.0, 127.33, 124.61, 121.88, 117.22,
1
H NMR (300 MHz, DMSO-d ): d = 5.67 (s, 2 H), 6.75 (t, J = 7.53
111.47, 109.93.
6
Hz, 2 H), 6.87 (t, J = 8.16 Hz, 2 H), 7.0–7.09 (m, 5 H), 7.15 (d,
J = 7.31 Hz, 3 H), 7.18–7.29 (m, 3 H), 7.61 (s, 1 H), 9.98 (s, 2 H,
NH).
35
+
ESI-MS: m/z = 477.4 [M + H (2 × Cl)] (100), 479.4 [M + H
35
37
+
37
+
(
Cl + Cl)] (63), 481.4 [M + H (2 × Cl)] (10).
1
3
C NMR (75 MHz, DMSO-d ): d = 158.08, 140.14, 136.53,
6,12-Bis[4-(benzoyloxy)phenyl]-5,11-dihydroindolo[3,2-b]car-
bazole (5j)
Yield: 220 mg (62%); white solid; mp 375–377 °C.
6
1
1
34.29, 133.69, 131.89, 130.11, 128.64, 126.90, 124.69, 121.37,
18.06, 111.43.
ESI-MS: m/z = 441.2 [M + H]+.
IR (KBr): 3394 (NH stretch), 3062 (w), 1737 (s), 1456 (s), 1271
–
1
(
m), 744 (s), 702 (m) cm .
6
,12-Bis(2-hydroxyphenyl)--5,11-dihydroindolo[3,2-b]carba-
1
H NMR (300 MHz, DMSO-d ): d = 6.73–6.85 (m, 4 H), 6.89 (t,
6
zole (5f)
J = 7.43 Hz, 2 H), 7.05 (t, J = 7.71 Hz, 6 H), 7.14–7.23 (m, 8 H),
7
Yield: 165.5 mg (70%); white solid; mp 357–359 °C.
.28 (d, J = 7.17 Hz, 4 H), 7.70 (s, 2 H), 10.03 (s, 2 H, NH).
IR (KBr): 3418 (br, s), 3019 (w), 1456 (s), 1233 (s), 744 (s), 699 (m)
cm .
13
C NMR (75 MHz, DMSO-d ): d = 166.32, 153.08, 141.21,
–
1
6
1
38.47, 136.07, 134.29, 133.77, 131.49, 130.27, 128.39, 126.93,
1
H NMR (300 MHz, DMSO-d ): d = 6.78 (s, 2 H), 6.74 (t, J = 7.59
124.45, 122.0, 118.13, 113.41, 111.47, 109.46.
6
Hz, 2 H), 6.87 (t, J = 7.47 Hz, 2 H), 7.02–7.10 (m, 4 H), 7.20 (d,
J = 7.74 Hz, 3 H), 7.23–7.29 (m, 3 H), 7.71 (s, 2 H), 10.64 (s, 2 H,
NH).
ESI-MS: m/z = 649.4 [M + H]+.
1
3
Acknowledgment
C NMR (75 MHz, DMSO-d ): d = 158.34, 140.21, 136.53,
6
1
1
34.29, 133.13, 132.22, 130.17, 128.64, 127.17, 124.94, 122.08,
18.06, 111.44.
The authors thank Dr. P. G. Rao, the Director, NEIST, Jorhat, for
providing the facilities to perform the work, and DST, India for fi-
nancial support. M.L.D., S.M., and B.B. thank CSIR (India) for the
award of Research Fellowships.
ESI-MS: m/z = 441.5 [M + H]+.
Synthesis 2010, No. 6, 929–932 © Thieme Stuttgart · New York

9
32
M. L. Deb et al.
PAPER
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(
(
(
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Synthesis 2010, No. 6, 929–932 © Thieme Stuttgart · New York