Facile one-pot synthesis of novel 6-monosubstituted 5,11-dihydroindolo[3,2- b]carbazoles and preparation of different derivatives

Article abstract of DOI:10.1055/s-2006-944183

The synthesis of novel 6-monosubstituted 5,11-dihydroindolo[3,2-b] carbazoles was accomplished by a three-stage one-pot procedure involving condensation of indole and an aldehyde affording 3,3′-bis(indolyl) methanes, followed by isomerization to the 2,3′-

Full text of DOI:10.1055/s-2006-944183

LETTER
1535
Facile One-Pot Synthesis of Novel 6-Monosubstituted 5,11-Dihydroindolo[3,2-
b]carbazoles and Preparation of Different Derivatives
S
ynthesis of 6-M
o
onosubstitute
n
d Indolo[3,2
g
-
b
]carbazoles Gu, Ahmed Hameurlaine, Wim Dehaen*
Department of Chemistry, University of Leuven, Celestijnenlaan 200F, 3001 Heverlee, Belgium
Fax +32(16)327990; E-mail: wim.dehaen@chem.kuleuven.be
Received 23 March 2006
cyclodehydrogenation of N,N¢-diphenyl-p-phenylenedi-
Abstract: The synthesis of novel 6-monosubstituted 5,11-dihy-
droindolo[3,2-b]carbazoles was accomplished by a three-stage one-
pot procedure involving condensation of indole and an aldehyde
affording 3,3¢-bis(indolyl)methanes, followed by isomerization to
amine,4a (2) double Fischer indolization of cyclohexane-
1,4-dione bis(phenylhydrazone),4b (3) condensation of
indole and formaldehyde in the presence of strong acid,
the 2,3¢-analogues and acid-catalyzed intramolecular reaction with air and sensitizers,4c (4) Lewis acid catalyzed dimerization
of 1-(1-benzotriazol-1-yl-alkyl)indoles,4d (5) intra-
triethyl orthoformate to give the corresponding 6-monosubstituted
indolo[3,2-b]carbazoles in good overall yield. Different substitution
molecular cyclization of 2-(1H-indol-3-yl-methyl)-1H-in-
patterns, such as N-alkylation, N-arylation, formylation and bromi-
dole-carbaldehyde,4e (6) condensation of indole with
nation, were successfully introduced, leading to the formation of
aliphatic aldehydes under acidic conditions,4f and (7)
novel substituted 5,11-dihydroindolo[3,2-b]carbazole derivatives.
cyclization of 3,3¢-bis(indolyl)methanes4g or 2,3¢-bis(in-
Key words: three-stage one-pot synthesis, 6-monosubstituted 5,11-
dolyl)methanes4h via acid-catalyzed reaction in the
dihydroindolo[3,2-b]carbazole, N-substitution, formylation, bromi-
presence of triethyl orthoformate. However, most of these
nation
methods involve multistep routines starting from indoles
and afford the target ICZs in low total yield.
In the present work, we report the synthesis of novel 6-
monosubstituted 5,11-dihydroindolo[3,2-b]carbazoles in-
volving a three-stage one-pot procedure with moderate
overall yield. Furthermore, several N,N¢-disubstituted,
formylated and brominated compounds have been pre-
pared.
Indolo[3,2-b]carbazole (ICZ) (1a, Figure 1), which is
formed in the acidic environment of the stomach after
intake of indole-3-carbinol, is a molecule with consider-
able biological significance.1 ICZ shares the biological
activity with TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin,
2). It has been demonstrated that 6-formylindolo[3,2-
b]carbazole (1b) has a strong affinity to the TCDD recep-
tor (aryl hydrocarbon receptor, Ah receptor), binding 5–8
times as strong to the receptor as TCDD itself.2 Moreover,
5,11-disubstituted indolo[3,2-b]carbazoles 1c–e are a new
class of high-performance organic semiconductors suit-
able for organic thin film transistor (OTFT) applications.3
In 2003, Bandgar et al. reported fast reactions of indoles
with various aldehydes and ketones using I2 in acetonitrile
to afford the corresponding 3,3¢-bis(indolyl)methanes in
excellent yields.5 3,3¢-Bis(indolyl)hexane (3) was ob-
tained in 70% yield by condensation of indole and hexanal
with a catalytic amount of iodine for 30 minutes at room
temperature. We treated compound 3 with triethyl ortho-
formate in MeOH using sulfuric acid or methanesulfonic
acid as a catalyst (Scheme 1). We observed that 6-pentyl-
5,11-dihydroindolo[3,2-b]carbazole (4c) was formed only
in trace amounts from mass spectral analysis of the reac-
tion mixture.
R1
R2
N
Cl
Cl
O
O
Cl
Cl
N
R1
2
1a R1 = R2 = H
1b R1 = H, R2 = CHO
1c R1 = octyl, R2 = H
1d R1 = 4-octylphenyl, R2 = H
1e R1 = 4-methylphenyl, R2 = H
H
N
Figure 1
i
Several synthetic methods towards the synthesis of sym-
metrical and unsymmetrical indolo[3,2-b]carbazoles have
been developed, showing the great interest in these nitro-
gen-containing heterocycles, such as (1) Pt-mediated
N
HN
NH
H
3
4c
Scheme 1 Reagents and conditions: (i) (EtO)3CH, MeOH, H2SO4
or CH3SO3H (cat.), r.t.
SYNLETT 2006, No. 10, pp 1535–1538
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1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944183; Art ID: G10506ST
© Georg Thieme Verlag Stuttgart · New York

1536
R. Gu et al.
LETTER
We found that if the condensation of indole and commer- ation of compound 4c using sodium hydride in DMF and
cial aldehydes with iodine as a catalyst was carried out for 4 equivalents of bromoethane at 70 °C afforded the corre-
longer time (14 h) the 3,3¢-bis(indolyl)alkanes were sponding N,N¢-diethylated compound 6a in 50% yield.
isomerized to 2,3¢-bis(indolyl)alkanes 5a–d (monitored On the other hand, tosylation of 4c under similar reaction
1
by H NMR spectroscopy). Because of their instability, conditions using 4 equivalents of p-toluenesulfonyl chlo-
we did not purify compounds 5a–d after work-up. The ride was found to occur at only one nitrogen atom to
acid-catalyzed intramolecular cyclization of crude com- produce selectively monotosylated derivative 6b in 60%
pounds 5a–d in the presence of triethyl orthoformate yield. Thus, the protection of 4c with p-toluenesulfonyl
produced the corresponding ICZs in acceptable overall chloride is regioselective. This result is very interesting
yield (45–50%, Scheme 2, Table 1).
and could be employed to prepare the N-monoarylated or
asymmetrically N,N¢-diarylated ICZ derivatives.
Table 1 Three-Stage One-Pot Synthesis of 6-Monosubstituted
Indolo[3,2-b]carbazoles
The Ullmann-type coupling of aryl halides with ICZ is a
straightforward, inexpensive approach to obtain N-arylat-
ed ICZ. Under the conditions of Ullmann coupling we
have previously reported for the synthesis of oligocarba-
zoles,7a–d the desired N-disubstituted products 6c–f were
obtained in good yield (Scheme 3). The results for these
N-substituted derivatives of 6-pentyl indolo[3,2-b]carba-
zole (4c) are summarized in Table 2.
Entry Compound
R
Reaction time (h) Total yield
of the first step
(%)
46
50
20
47
18
36
20
1
2
3
4
5
6a
7
4a
4b
4c
4c
4c
4d
4e
Methyl
Isobutyl
Pentyl
14
14
3
Pentyl
14
48
14
0.5
Pentyl
R
H
Undecyl
Phenyl
N
N
i or ii
a Using CH2Cl2 as the solvent.
N
N
H
R'
The second step of the synthesis was carried out in MeOH
under acidic conditions using a catalytic amount of meth-
anesulfonic acid (0.2 equiv). To optimize the isomeriza-
tion of the 3,3¢-isomer, alternative reaction times of 3
hours (entry 3) and 48 hours (entry 5) were tried but af-
forded much lower yields compared with entry 4 (14 h).
With this optimal condition, the other 6-monoalkylated
ICZs were obtained in comparable yield, except for 4e
(20%). Thus, aromatic aldehydes are less suited for this
formation of ICZs because the corresponding intermedi-
ates of type 3 and 5 are much less stable, quickly forming
an insoluble precipitate which is difficult to characterize
(entry 7).
4c
6a–f
Scheme 3 Reagents and conditions: (i) compounds 6a–b: NaH,
DMF, 70 °C, bromoethane or p-TsCl; (ii) compounds 6c–f: Cu
(bronze), iodoarene, o-dichlorobenzene, 190 °C.
An N-monoarylated derivative of 4c was not obtained
when 1 equivalent of iodobenzene was used under the
same Ullmann coupling conditions as described above.
The reaction gave in all cases only the completely N-aryl-
ated derivative 6c.
To solve this problem, we designed an alternative synthet-
ic route. First, N-arylation of 6b afforded the correspond-
ing monoarylated product 7 in 70% yield. Deprotection
of the p-tosyl group of 7 under basic conditions gave
compound 8 in 95% yield (Scheme 4).
Comparing with the reported symmetrically 6,12-disub-
stituted ICZs,2,4f,6 the better solubility in apolar organic
solvents of these asymmetrical analogues 4 of ICZ allows
for an easy further structural modification. The N-alkyl-
H
R
N
R
H
N
ii
O
i
+
HN
R
H
N
N
H
H
a R = methyl
b R = isobutyl
c R = pentyl
d R = undecyl
e R = phenyl
5a–e
4a–e
Scheme 2 Reagents and conditions: (i) 0.2 equiv I2, MeCN, r.t., 14 h; (ii) (EtO)3CH, MeOH, 0.2 equiv CH3SO3H, r.t., 14 h.
Synlett 2006, No. 10, 1535–1538 © Thieme Stuttgart · New York

LETTER
Synthesis of 6-Monosubstituted Indolo[3,2-b]carbazoles
1537
However, by using 3 equivalents of NBS, we succeeded to
isolate the corresponding 2,6,8-tribrominated compound
10 in 20% yield. Moreover, by using 5 equivalents of bro-
mine in acetic acid and under reflux, the 2,4,6,8,10-penta-
brominated compound 11 was isolated in 40% yield.
Table 2 N-Substituted Derivatives of Compound 4c
Compound
R
R¢
Method Yield (%)
6a
6b
6c
6d
6e
6f
Ethyl
H
Ethyl
i
50
60
70
53
65
70
Tosyl
Phenyl
2-Thienyl
i
On the other hand, the 2,8-dibrominated compound 12
was synthesized with our three-stage one-pot approach
with 5-bromoindole as the starting material, but initially
the reaction failed due to very slow isomerization of the
corresponding 3,3¢-bis(indolyl)hexane to the 2,3¢-isomer.
However, when instead of iodine, the more active hy-
droiodic acid was used as the catalyst for the condensation
reaction, the final dibrominated compound 12 was ob-
tained in 26% overall yield (Scheme 6).
Phenyl
2-Thienyl
ii
ii
4-Nitrophenyl 4-Nitrophenyl ii
4-[3,6-Bis(tert- 4-[3,6-Bis(tert- ii
butyl)carbazol- butyl)carbazol-
9-yl]phenyl
9-yl]phenyl
In summary, an easy and efficient three-stage one-pot
synthetic approach towards various 6-monosubstituted
5,11-dihydroindolo[3,2-b]carbazoles has been developed.
Iodine was found to be a highly convenient catalyst for
promoting the electrophilic reaction, under mild condi-
tion, of indole with aliphatic aldehyde to afford 2,3¢-
bis(indolyl)alkanes, which are used as intermediates to
synthesize the corresponding 6-monosubstituted ICZs
with methanesulfonic acid as a catalyst. Enhanced solubil-
ity and stability towards oxidative degradation allows for
easy modification. Thus, the ICZ 4c was substituted under
different conditions, including N-alkylation, N-tosylation,
copper-catalyzed Ullmann coupling, Vilsmeier reaction
and bromination. In the case of N-tosylation and C-
formylation, monofunctionalized compounds are selec-
tively obtained.
R
R
N
N
i
N
N
R'
R'
6b R = H, R' = p-Ts
7 R = Ph, R' = p-Ts, 70%
8 R = Ph, R' = H, 95%
ii
Scheme 4 Reagents and conditions: (i) iodobenzene, Cu (bronze),
o-dichlorobenzene, 190 °C; (ii) KOH–MeOH, THF, 55 °C.
All synthesized compounds were fully characterized by
The formylation of 4c was accomplished by the well-
known Vilsmeier reaction (POCl3/DMF). By using an
excess of the reagent, the 6-formyl-12-pentyl-5,11-dihy-
droindolo[3,2-b]carbazole (9) was formed selectively and
isolated in 50% yield (Scheme 5), opening an entry to
potential ligands for the Ah receptor.
1
the usual techniques including H NMR, 13C NMR and
mass spectrometry.8
Acknowledgment
The authors thank the University Research Fund of the K. U.
Leuven, and the Ministerie voor Wetenschapsbeleid for their conti-
nuing support.
H
N
H
References and Notes
N
i
(1) Herrmann, S.; Seidelin, M.; Bisgaard, H. C.; Vang, O.
Carcinogenesis 2002, 23, 1861.
(2) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 6243.
(3) Wu, Y. L.; Li, Y.; Gardner, S.; Ong, B. S. J. Am. Chem. Soc.
2005, 127, 614.
N
N
CHO
H
H
4c
9
(4) (a) Grotta, H. M.; Riggle, C. J.; Bearse, A. E. J. Org. Chem.
1961, 26, 1509. (b) Robinson, B. J. Chem. Soc. 1963, 3097.
(c) Bergman, J. Tetrahedron 1970, 26, 3353. (d) Katritzky,
A. R.; Li, J. Q.; Stevens, C. V. J. Org. Chem. 1995, 60,
3401. (e) Wille, G.; Mayser, P.; Thoma, W.; Monsees, T.;
Baumgart, A.; Schmitz, H. J.; Schrenk, D.; Polborn, K.;
Steglich, W. Bioorg. Med. Chem. 2001, 9, 955.
(f) Tholander, J.; Bergman, J. Tetrahedron 1999, 55, 12577.
(g) Pindur, U.; Muller, J. Arch. Pharm. (Weinheim, Ger.)
1987, 320, 280. (h) Wahlstrom, N.; Stensland, B.; Bergman,
J. Synthesis 2004, 1187.
Scheme 5 Reagents and conditions: (i) POCl3, DMF, 1,2-dichlo-
roethane, 85 °C.
In contrast to the formylation, the bromination of com-
pound 4c was not selective and the brominated products
depended on the reaction conditions, such as the amount
of the halogenation reagent and the reaction temperature.
When the reaction was carried out in dichloromethane at
room temperature in the presence of 1–2 equivalents of N-
bromosuccinimide (NBS), a complex product pattern of
mono-, di- and tribrominated compounds was observed.
(5) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1959.
Synlett 2006, No. 10, 1535–1538 © Thieme Stuttgart · New York

1538
R. Gu et al.
LETTER
H
N
Br
Br
N
H
Br
H
10, 20%
N
N
Br
H
4C
H
N
Br
Br
N
H
Br
Br
11, 40%
H
N
Br
O
Br
iii, iv
+
H
Br
N
N
H
H
12, 26%
Scheme 6 Reagents and conditions: (i) 3 equiv NBS, CH2Cl2, r.t.; (ii) 5 equiv Br2, AcOH, reflux; (iii) 0.2 equiv HI, MeCN, 60 °C; (iv)
(EtO)3CH, MeOH, 0.2 equiv CH3SO3H, r.t.
(6) Black, D. S.; Ivory, A. J.; Kumar, N. Tetrahedron 1995, 51,
11801.
formate (2.9 g, 20 mmol) were dissolved in MeOH (4 mL).
After the addition of methanesulfonic acid (0.3 mL, 4
mmol), the reaction was stirred overnight at r.t. The
(7) (a) Schaerlaekens, M.; Hendrickx, E.; Hameurlaine, A.;
Dehaen, W.; Persoons, A. Chem. Phys. 2002, 277, 43.
(b) Hameurlaine, A.; Dehaen, W. Tetrahedron Lett. 2003,
44, 957. (c) McClenaghan, N. D.; Passalacqua, R.; Loiseau,
F.; Campagna, S.; Verheyde, B.; Hameurlaine, A.; Dehaen,
W. J. Am. Chem. Soc. 2003, 125, 5356. (d) Loiseau, F.;
Campagna, S.; Hameurlaine, A.; Dehaen, W. J. Am. Chem.
Soc. 2005, 127, 11352.
precipitate was filtered off and washed with MeOH. After
drying the pure 4c (2.9 g, 45%) was obtained as a light
yellow solid; mp 286–289 °C. IR (KBr): n = 3405 (s), 2923
(m), 2860 (m), 1611 (m), 1527 (s), 1460 (s), 1422 (s) cm–1.
1H NMR (DMSO): d = 0.85 (3 H, t, CH3), 1.39 (2 H, m,
CH2), 1.56 (2 H, m, CH2), 1.82 (2 H, m, CH2), 3.50 (2 H, m,
CH2), 7.12 (2 H, m, 2 ICZ-H), 7.37 (2 H, m, 2 ICZ-H), 7.47
(2 H, m, 2 ICZ-H), 7.95 (1 H, s, H-12), 8.14 (dd, 2 H, 2 ICZ-
H), 10.90 (1 H, s, NH), 11.05 (1 H, s, NH). 13C NMR
(DMSO): d = 14.9, 23.2, 29.3, 29.7, 32.5, 98.8, 111.2, 111.4,
118.4, 118.7, 119.1, 121.0, 121.1, 122.7, 123.1, 123.4,
123.7, 125.6, 126.3, 134.9, 136.4, 142.1. HRMS (EI):
m/z calcd for C23H22N2 [M]+: 326.17833; found: 326.17801.
(8) Synthesis of Compound 4c.
To a solution of indole (4.6 g, 40 mmol) and n-hexanal (2.1
g, 20 mmol) in MeCN (10 mL) was added I2 (1 g, 4 mmol).
The reaction was stirred at r.t. for 14 h. Then, aq sat. Na2SO3
was added until the iodine color disappeared and the solution
was extracted with EtOAc (3 × 20 mL). After concentration
of the organic layers, the crude product and triethyl ortho-
Synlett 2006, No. 10, 1535–1538 © Thieme Stuttgart · New York