A one-pot synthesis of 7-phenylindolo[3,2-a]carbazoles from indoles and β-nitrostyrenes, via an unprecedented reaction sequence

Article abstract of DOI:10.1039/c1ob06108a

A six-step one-pot reaction was designed for synthesizing homodimeric 7-phenylindolo[3,2-a]carbazoles from 1H-indoles and β-nitrostyrenes, in the presence of SnCl₂·2H₂O. The reactions proceeded under very mild conditions and the desi

Full text of DOI:10.1039/c1ob06108a

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PAPER
A one-pot synthesis of 7-phenylindolo[3,2-a]carbazoles from indoles and
b-nitrostyrenes, via an unprecedented reaction sequence†‡
Gre´gory Dupeyre,a Pascale Lemoine,b Nabila Ainseba,a Sylvie Michela and Xavier Cachet*a
Received 7th July 2011, Accepted 16th August 2011
DOI: 10.1039/c1ob06108a
A six-step one-pot reaction was designed for synthesizing homodimeric
7-phenylindolo[3,2-a]carbazoles from 1H-indoles and b-nitrostyrenes, in the presence of SnCl2·2H2O.
The reactions proceeded under very mild conditions and the desired heterocycles were obtained in
moderate to good yields. An unprecedented mechanism involving sequential indole dimerization,
regioselective nucleophilic conjugate addition of the resulting 2,3¢-biindole to b-nitrostyrene and formal
intramolecular [4 + 2]-cycloaddition is proposed.
Introduction
In contrast to extensive studies on the indolo[2,3-a]carbazole ring
system 1, the chemistry of the isomeric indolo[3,2-a]carbazole
skeleton 2 has received only little attention to date (Fig. 1).
This is undoubtedly due to the existence of biologically active
natural indolo[2,3-a]carbazole alkaloids such as rebeccamycin or
staurosporine, whose structure–activity relationships have been
thoroughly investigated.1,2 Instead, ancorinazole 3 is the only
indolo[3,2-a]carbazole reported from a natural source, namely the
marine sponge Ancorina sp.3 On the other hand, in recent times,
there has been a growing interest in the use of indolocarbazoles,
particularly indolo[3,2-b]carbazoles, in the field of materials chem-
istry. Indeed, such compounds could serve as hosts for organic
electroluminescent (EL) devices (organic light emitting diodes or
OLEDs).4 For this purpose, preparation of EL devices based on
7-phenylindolo[3,2-a]carbazoles are currently under investigation
(an example of such a carbazole is given in Fig. 1).5
To the best of our knowledge, only a limited number of methods
(less than ten) allowing access to indolo[3,2-a]carbazoles have
been reported. They generally take place under rather drastic
conditions, particularly by heating in high boiling solvents and/or
require numerous steps.6 However, particular efforts have been
Fig. 1 Structures of indolo[a]-annulated carbazole skeletons. Structural
examples of natural and synthetic indolo[3,2-a]carbazoles.
aLaboratoire de Pharmacognosie, Universite´ Paris Descartes, Faculte´ des
Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS, 4 Av-
enue de l’Observatoire, 75006, Paris, France. E-mail: xavier.cachet@
parisdescartes.fr; Fax: +331-40-46-96-58; Tel: +331-53-73-15-80
devoted to the synthesis of arcyriaflavin A analogues in this series
(4).6a,6b
bLaboratoire de Cristallographie et RMN biologiques, Universite´ Paris
Descartes, Faculte´ des Sciences Pharmaceutiques et Biologiques, UMR 8015
CNRS, 4 Avenue de l’Observatoire, 75006, Paris, France
Such compounds have been synthesized by means of a one-
pot synthesis starting from 1H-indole and different maleimides
(R = H or alkyl substituent), heated in acetic acid.6a In a further
study, the same authors also reported that direct heating of N-
ethylmaleimide with 2,3¢-biindole 5, resulted in the formation of
the corresponding indolo[3,2-a]carbazole through a formal [4 + 2]
cycloaddition. This reaction has been successfully carried out with
† This paper is dedicated to the memory of the late Professor Franc¸ois
Tillequin.
‡ Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of all new compounds, COSY and NOESY spectra of compound
6a. Crystallographic data for compound 6g. CCDC reference number
825605. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ob06108a
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Scheme 1 Retrosynthesis of the 7-phenylindolo[3,2-a]carbazole 6a.
Scheme 2 Preliminary studies toward the synthesis of the indolo[3,2-a]carbazole 6a.
a small number of other dienophiles, including dialkyl acetylene
dicarboxylates.6b Finally, a one-pot method for the synthesis of
6,7-diphenylindolo[3,2-a]carbazoles starting from 1H-indoles and
symmetrical diaryl 1,2-diones has been recently published.6d
None of the aforementioned methods allowed an efficient access
to 7-phenylindolo[3,2-a]carbazoles. In view of the increasing
interest in these compounds, particularly in the field of materials
chemistry, and in continuation of our own interest in ring-fused
carbazoles,7 we report herein an expeditious one-pot sequential
synthesis of such compounds through an unusual reaction involv-
ing both a b-nitrostyrene and an indole unit.
this compound would undergo subsequent cyclization upon
heating. Finally, 2,3¢-biindole 5 would be directly obtained from
1H-indole 9a.
To test the feasibility of this retrosynthetic strategy, we first
focused on the preparation of the intermediate 7 from 2,3¢-
biindole 5 (Scheme 2). First of all, the latter compound 5 was
synthesized in two steps from 1H-indole 9a. The dimerization of
1H-indole8 was thus achieved by treatment with one equivalent
of SnCl4 in CH2Cl2. Basic treatment of the resulting tin salt
precipitate afforded 3-(indolin-2-yl)-1H-indole 10 in 87% yield.
This procedure constitutes a convenient alternative to those
previously reported in the literature which involve the precipitation
of 10 as the HCl salt, avoiding therefore problems associated with
the handling of gaseous HCl.9 Thereafter, aromatization of 10 to
the desired 5 was performed in 80% yield according to a literature
procedure using Pd/C.9b
Secondly, we decided to investigate the reactivity of 5 toward
the b-nitrostyrene 8a. Michael-type Friedel–Crafts alkylation of
indoles with a b-nitrostyrene always proceeds sluggishly without a
catalyst.10,11 We were therefore surprised to observe that, probably
due to the higher nucleophilicity of the dimer 5, a spontaneous
reaction occurred at room temperature and without a catalyst
Results and discussion
The retrosynthetic analysis is outlined in Scheme 1 and is
exemplified for the synthesis of 6a from 1H-indole 9a. 7-(3,4,5-
Trimethoxyphenyl)indolo[3,2-a]carbazole 6a was chosen as the
1
initial target because of the relative simplicity of its H NMR
spectrum. The key intermediate nitroalkane, 7, would be prepared
by a regioselective nucleophilic conjugate addition of homodimer
2,3¢-biindole 5 to 3,4,5-trimethoxy-b-nitrostyrene 8a. It might be
expected that after oxidation into the corresponding nitroalkene,
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between 5 and 8a, resulting in conversion to the desired adduct 7
in 91% yield. As expected, reaction of 1H-indole 9a with 8a under
similar conditions failed to afford the corresponding nitroalkane
12. Finally, this compound could be prepared in 72% yield under
thermal conditions12 (neat, 125 ◦C).
During studies directed toward the synthesis of adduct 7, we
also found that treatment of 1H-indole 9a with one equivalent
of SnCl2·2H2O in CH2Cl2 resulted in the formation of the
well known trimer 11 in quantitative yield.13 According to the
generally accepted mechanism, compound 11 is supposed to be
derived from the intermediate 3-(indolin-2-yl)-1H-indole 10.9c,15
We therefore postulated that although the weak and heterogeneous
Lewis acid SnCl2·2H2O enables indole dimerization into 10, this
reaction may proceed without any concomitant precipitation of
the corresponding tin salts in CH2Cl2, thereby allowing further
polymerization of 10 into 11.
These observations prompted us to investigate the possibility
of a one-pot synthesis of 7 from 9a, via a tandem dimerization–
oxidation–addition reaction. Thus, we hypothesized that, if the
dimer 5 could be conveniently formed in situ from 1H-indole 9a,
it would be subsequently trapped by the b-nitrostyrene 8a.
We therefore decided to attempt the reaction using the reagent
combination SnCl2·2H2O/oxidant/8a. We initially tried the reac-
tion in CH2Cl2 at room temperature, with stoichiometric amounts
of both 8a and SnCl2·2H2O and air as the oxidant. We were
surprised to find that neither the desired compound 7 nor the
trimer 11 could be isolated from the reaction mixture. Instead,
a blue fluorescent compound was formed as the major product
in 27% yield, which was unambiguously identified by NMR
spectroscopy and mass spectrometry as the target carbazole 6a
and probably arising from the cyclization of 7 (See ESI).‡16
The formation of 6a was also accompanied by a trace amount17
of the monoindole adduct 12. This pleasant result was totally
unexpected in regard to the previous syntheses of the indolo[3,2-
a]carbazole skeleton always achieved under drastic conditions.
Furthermore, the isolated yield of this one-pot reaction was
acceptable considering the number of steps necessary to convert
1H-indole 9a into a complex pentacyclic compound. Therefore,
we decided to optimize the reaction conditions before further
exploration of its scope.
A number of conditions, including appropriate molar ratios
of reactants, different solvents and oxidants, were screened to
optimize the reaction and especially to limit the formation of
Michael adduct 12. The pertinent results are summarized in Table
1.18 More polar solvents such as CH3CN and EtOAc were not
suitable and no conversion was observed, most probably because
they complex preferentially to the Lewis acid. Increasing the
amount of 8a to 2 equiv led only to traces of Michael adduct
12 and slightly decreased the yield of 6a to 20% (Table 1, entry
4). If the reaction was carried out with a catalytic amount (10
mol%) of SnCl2·2H2O (Table 1, entry 5),19,20 the yield was similar
(28%) albeit a longer reaction time was required. However, the
reaction was cleaner, thus allowing facile separation of a non-
negligible amount of 12 (52% yield). We were surprised to observe
that the yield of this reaction decreased significantly to 12% when
anhydrous SnCl2 was used as the Lewis acid (Table 1, entry 6).
Combinations of catalytic SnCl2·2H2O with other oxidants were
also attempted without success (Table 1, entries 7 and 8). Finally,
the best yields (41–59%) were obtained by employing equimolar
amounts of SnCl2·2H2O, 8a and 9a, and by replacing air (Table
1, entry 4) with either an oxygen atmosphere in the presence
of catalytic amount of salcomine21 (Table 1, entry 11) or the
21,22
heterogeneous oxidant MnO2
(1 equiv or excess) (Table 1,
entries 9 and 10), which are both versatile reagents often used
Table 1 Optimization of one-pot indolo[3,2-a]carbazole 6a formationa
Entry
Lewis acid (equiv)
Oxidant (equiv)
Reaction time (h)
Yield 6a (%)b
Yield 12 (%)b
1
2
/
/
/
/
48
4c
0
0
0
72
3
4
5
6
7
8
9
10
11
12
A (1.0)
A (1.0)
A (0.1)
B (0.1)
A (0.1)
A (0.1)
A (1.0)
A (1.0)
A (1.0)
/
(air)
(air)
(air)
(air)
48
20e
72
72
72
72
48
48
48
48
27
20f
28
12
27
17
59
53
41
0
NId
Traces
52
NId
23
g
O2
MnO2 (1.0)
MnO2 (1.0)
MnO2 (3.0)
O2g+Salc.h
MnO2 (1.0)
29
10
16
NId
0
a Reaction conditions: 9a (0.43 mmol, 1.0 equiv), 8a (0.43 mmol, 1.0 equiv), DCM (10 mL), room temperature. b Isolated yield based on indole. c Without
solvent, temperature: 125 ◦C. d Not isolated (inseparable mixture of several products). e 8a (0.86 mmol, 2.0 equiv). f 62% of 8a is recovered. g O2 atmosphere.
h Salcomine (0.1 equiv). LA: SnCl2·2H2O (A), SnCl2 (B).
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for oxidation of indolines into indoles. The best conditions found
were, therefore, employing one equivalent of MnO2 as oxidant
(Table 1, entry 9). In this case the yield of 6a was increased from
27 to 59% (it is also interesting to note that MnO2 alone did not
induce any observable reaction (Table 1, entry 12). From these
results, MnO2 (1 equiv) emerged as the reagent of choice.
To illustrate the scope of this reaction, other 1H-indoles (9b–9i)
were tested under the same reaction conditions optimized above
(equimolar amounts of SnCl2·2H2O, MnO2 and 8a) (Table 2,
entries 2–9). We next examined the scope of this reaction with
a variety of b-nitrostyrenes (8b–8e) under the same conditions,
but using 9a as the reaction partner (Table 2, entries 10–14). The
reaction generally proceeded in modest to good yields (18–66%),
depending both on the nature of the substituents and on the
solubility of the corresponding carbazole in common solvents.
However, both reactions of 8a with poor electron nitroindoles 9h
and 9i failed to afford the desired products (Table 2, entries 8 and
9), and starting indoles were recovered unchanged. Furthermore,
the 5,6-dimethoxy-1H-indole (9e) seems to be sensitive to the
reaction conditions since its quantitative conversion into 5,6-
dimethoxy-anthranilic acid23 was observed (Table 2, entry 5).
Compounds 6b–k were characterized on the basis of their
spectroscopic data. Particularly, in the 1H NMR spectra of these
compounds, besides thetwo D2O-exchangeableNHsignals (except
for 6b which bears two N-methyl groups) the most deshielded
proton always appears in the range of 8.10–8.70 ppm, depending
both on substituents and NMR solvent. This signal was assigned
to H1. Additionally, the structure of 6g was confirmed by single
crystal X-ray analysis (Fig. 2) (ESI).‡
Scheme 3 Reaction of 2,3¢-biindole 5 with 8a.
conditions afforded the carbazole 6a in near quantitative yield.
Examination of the reaction course by TLC monitoring showed
the rapid formation and subsequent total disappearance of 7.
Interestingly, the use of SnCl2·2H2O/air combination led to a
decreased yield of 27% and a small amount (in about 1% yield) of
7 was also isolated.
A proposed mechanism to account for the unexpected smooth
cyclization of 7 to 6a is shown in Scheme 4. Heterogeneous
oxidation of 7 with MnO2 into the corresponding nitroalkene
13, followed by tin(II) mediated two-electron reduction afford a
highly reactive nitrosoalkene25 14 that undergoes further formal
intramolecular [4 + 2]-cycloaddition (Scheme 4, pathway A).26,27
Fig. 2 SHELXTL Plot of X-ray crystal structure of 6g (Atomic dis-
placement parameters at 50% probability levels) with lattice ethyl acetate
molecule included.
Mechanism
Evidence for the formation of the key intermediate 7 proposed in
our retrosynthetic analysis for compound 6a (Scheme 1) was pro-
vided by the following experiment (Scheme 3).24 Direct treatment
of 2,3¢-biindole 5 with 8a under the aforementioned optimized
Scheme 4 Plausible mechanism accounting for the cyclization of 7 to 6a.
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Table 2 Synthesis of indolo[3,2-a]carbazoles from various substituted indoles
Entry
1
R1, R2
R3
Product
Yielda (%)
59
R1 = R2 = H 9a
3,4,5- trimethoxy 8a
2
R1 = H, R2 = Me 9b
3,4,5- trimethoxy 8a
30b
3
4
R1 = 5-OMe, R2 = H 9c
3,4,5- trimethoxy 8a
41
52
R1 = 6-OMe, R2 = H 9d
3,4,5- trimethoxy 8a
5
6
R1 = 5,6-OMe, R2 = H 9e
3,4,5- trimethoxy 8a
3,4,5- trimethoxy 8a
/
0c
66
R1 = 5-OMe, 6-Br, R2 = H 9f
7
R1 = 5-Br, R2 = H 9g
3,4,5- trimethoxy 8a
18c
8
9
R1 = 5-NO2, R2 = H 9h
R1 = 6-NO2, R2 = H 9i
3,4,5- trimethoxy 8a
3,4,5- trimethoxy 8a
/
/
0
0
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Table 2 (Contd.)
Entry
10
R1, R2
R3
Product
Yielda (%)
53
R1 = R2 = H 9a
H 8b
11
12
13
R1 = R2 = H 9a
R1 = R2 = H 9a
R1 = R2 = H 9a
4-Me 8c
4-OMe 8d
4-Br 8e
31
40
33
14
R1 = R2 = H 9a
4-NO2 8f
20d
a Isolated yields. b Compound with a poor solubility in many solvents. c Indole non-stable in the reaction conditions. d Difficult purification.
An alternative mechanism, involving a direct Lewis-acid promoted
cyclization of 16 cannot be discarded since the one-pot reaction
also succeeds with a catalytic amount of SnCl2·2H2O (Scheme
4, pathway B). However, in both pathways, coordination of
the Lewis acid to the oxygen of the nitroso or nitro group,
as well as to the lone pair of the nitrogen atom N(1) likely
favours the cycloaddition. Finally, the cycloadduct may undergo
aromatization through the formal loss of HNO or HNO2.
In contrast to previous indolo[3,2-a]carbazole syntheses, our
reaction proceeds under very mild conditions. Moreover, although
the nucleophilic conjugate addition of indoles to nitroolefins in
the presence of Lewis acid catalysts has received considerable
attention, to the best of our knowledge, this is the first report of
such a reaction. In this context, our results underline the crucial
role of SnCl2·2H2O in nonpolar solvents such as CH2Cl2, in this
one-pot reaction.
Furthermore, the first step of the mechanism for the formation
of indolo[3,2-a]carbazoles involves indole dimerization. The ef-
ficiency of this dimerization depends on indole reactivity, which
limits the scope of the method. However, independent syntheses of
2,3¢-biindoles may well overcome this limitation. Further studies
on the synthetic applications of this one-pot reaction, for example
Conclusions
In summary, we have developed an efficient and expeditious
synthesis of homodimeric 7-phenylindolo[3,2-a]carbazoles from
1H-indoles and b-nitrostyrenes, via a six-step one-pot reaction.
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in the preparation of electroactive carbazoles, are currently under
investigation in our laboratory.
Hz, 1H, H8), 7.57 (d, J = 8.0 Hz, 1H, H4), 7.61 (d, J = 8.0 Hz,
1H, H11), 8.22 (d, J = 7.7 Hz, 1H, H1), 8.37 (br s, D2O exch.,
1H, NH5), 8.78 (br s, D2O exch., 1H, NH12). 13C NMR (CDCl3)
d 56.2 (3¢–5¢OCH3), 61.1 (4¢OCH3), 104.9 (C6), 106.3 (C12b), 106.6
(C2¢–6¢), 110.6 (C11), 110.8 (C4), 113.9 (C7a), 119.6 (C9), 119.9 (C2),
120.5 (C1), 121.5 (C8), 122.0 (C12c), 123.8 (C7b), 124.0 (C10), 124.7
(C3), 134.5 (C12a), 136.4 (C1¢), 137.2 (C5a), 137.6 (C4¢), 138.8 (C7),
139.0 (C4a), 139.2 (C11a), 153.2 (C3¢–5¢). MS (ZQ2000/ESI+) m/z
445 [M + Na]+; Anal. (C27H22N2O3). Found: C, 68.26%; H, 5.08%;
N, 5.11%; Calc: C, 68.29%; H, 5.05%; N, 5.13%.
Experimental
General methods
All reagents were used as purchased without further treatment
unless otherwise stated. All solvents were dried according to
standard procedures. b-Nitrostyrenes 8a–8f were readily prepared
according to literature procedures. Reactions were monitored
by thin layer chromatography (TLC) using Merck Kieselgel 60
F254 silica gel; zones were detected visually under ultraviolet
irradiation (254 and 366 nm) and by spraying with sulfuric vanillin
followed by heating. All indolo[3,2-a]carbazoles exhibited brilliant
fluorescence (from blue to yellow, depending on the substitution
pattern) under UV light (366 nm). Flash column chromatography
was performed with silica gel (SDS 60 ACC 35–70 mM). NMR
spectra were recorded at 300 or 400 MHz (1H) and at 75 or 100
MHz (13C) with AC 300 and Avance 400 BRUKER spectrometers.
Chemical shifts are given in parts per million (ppm, d) relative to
solvent peaks as internal standards (d: CDCl3: 7.27 ppm (1H), 77.0
ppm (13C); DMSO-d6: 2.50 ppm (1H), 40.6 ppm (13C); acetone-d6:
2.05 ppm (1H), 29.8 and 206.0 ppm (13C); DMF-d7: 2.05 ppm
(1H), 29.8 and 206.0 ppm (13C)); coupling constants are given in
hertz (Hz, J). IR spectra were recorded on a NICOLET 500 FT-
IR spectrophotometer. The UV spectrum of 6a was recorded on
a BECKMAN DU 640 spectrophotometer. Melting points were
measured on a LEICA VM microscope equipped with a heating
stage and are uncorrected. Mass spectra (MS) were measured
with a Nermag R10-10C mass spectrometer (CI/NH3) or with
a ZQ 2000 Waters mass spectrometer (ESI). High-resolution mass
spectrometry (HRMS) spectra were performed at the Laboratoire
de Spectrome´trie de Masse (I.C.S.N./C.N.R.S., Gif sur Yvette,
France).
5,12-Dimethyl-7-(3¢,4¢,5¢-trimethoxyphenyl)-5H,12H-indolo[3,
2-a]carbazole (6b). The title compound 6b was prepared accord-
ing to the typical procedure using indole 9b (50 mg, 0.38 mmol) and
b-nitrostyrene 8a. Purification was carried out by chromatography
with 20–45 mm silica gel (cyclohexane/diethyl ether 9 : 1) to afford
6b (25 mg, 29%) as a colorless solid. Mp: 272–273 ◦C (from
acetone). IR (KBr) n¢ (cm-1) 3042, 2949, 2932, 2827, 1654, 1618,
1581, 1560, 1508, 1460, 1429, 1406, 1355, 1327, 1230, 1127, 1095,
1
1024, 1007, 974, 835, 723, 742. H NMR (CDCl3) d 3.90 (s, 6H,
OCH3 ¥ 2), 3.99 (s, 3H, NCH3), 4.04 (s, 3H, OCH3), 4.58 (s, 3H,
NCH3), 6.92 (s, 2H), 7.07 (dd, J = 7.2 Hz, J = 1.0 Hz, 1H), 7.22 (s,
1H), 7.34 (ddd, J = 8.2 Hz, J = 5.5 Hz, J = 2.7 Hz, 1H), 7.39–7.45
(m, 2H), 7.50–7.57 (m, 3H), 8.64 (dl, J = 8.1 Hz, 1H). 13C NMR
(CDCl3) d 29.6 (NCH3), 35.0 (NCH3), 56.2 (OCH3 ¥ 2), 61.2
(OCH3), 103.0 (CH), 106.0 (Cq), 106.4 (CH), 108.8 (CH), 114.0
(Cq), 119.1 (CH), 119.2 (CH), 121.1 (Cq), 121.3 (CH), 122.7 (CH),
123.8 (CH), 124.3 (CH), 136.2 (Cq), 137.4 (Cq), 138.0 (Cq), 140.7
(Cq), 141.1 (Cq), 141.4 (Cq), 153.2 (Cq ¥ 2). MS (ZQ2000/ES+)
m/z 923 [2M + Na]+, 473 [M + Na]+. HRMS (QTOF/ESI+) calcd
for C29H27N2O3, m/z 451.2022, found 451.2032.
2,9-Dimethoxy-7-(3¢,4¢,5¢-trimethoxyphenyl)-5H,12H-indolo[3,
2-a]carbazole (6c). The title compound 6c was prepared accord-
ing to the typical procedure using indole 9c (50 mg, 0.34 mmol) and
b-nitrostyrene 8a. Purification was carried out by chromatography
with 20–45 mm silica gel (cyclohexane/ethyl acetate 7 : 3) to afford
6c (33 mg, 41%) as a colorless solid. Mp: 281–283 ◦C (from
acetone). IR (NaCl film) n¢ (cm-1) 3378, 2936, 1695, 1634, 1583,
Typical procedure for the synthesis of indolocarbazoles 6 from
1H-indoles 9. To a solution of indolic compound (9, 50 or
100 mg) and b-nitrostyrene (8, 1.0 equiv) in anhydrous DCM
(10 or 20 mL) was added equimolar amounts of SnCl2·2H2O and
MnO2. After 48 h of stirring at room temperature, the reaction
mixture was filtered through a Celite pad and the residue was
washed thoroughly with ethyl acetate. Solvents were evaporated
under reduced pressure and the residue was then purified by
chromatography on silica gel.
1
1557, 1510, 1487, 1357, 1291, 1219, 1125, 1158, 1033. H NMR
(acetone-d6) d 3.64 (OCH3), 3.81 (OCH3), 3.89 (s, 6H, OCH3 ¥ 2),
3.95 (s, 3H, OCH3), 6.92 (dd, J = 8.6 Hz, J = 2.5 Hz, 1H), 6.95 (s,
2H), 6.97 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 8.8 Hz, J = 2.5 Hz, 1H),
7.24 (s, 1H), 7.47 (dd, J = 8.6 Hz, J = 0.5 Hz, 1H), 7.53 (dd, J = 8.7
Hz, J = 0.4 Hz, 1H), 8.10 (d, J = 2.5 Hz, 1H), 10.48 (br s, D2O exch.,
1H, NH), 10.93 (br s, D2O exch., 1H, NH). 13C NMR (acetone-
d6) d 54.7 (OCH3), 55.5 (OCH3), 55.7 (OCH3 ¥ 2), 59.9 (OCH3),
103.8 (CH), 104.2 (CH), 104.5 (CH), 106.3 (Cq), 106.8 (CH ¥ 2),
111.2 (CH), 111.3 (CH), 112.1 (CH), 112.8 (Cq), 113.3 (CH), 122.3
(Cq), 124.3 (Cq), 134.3 (Cq), 135.3 (Cq), 136.1 (Cq), 137.5 (Cq),
137.8 (Cq), 140.1 (Cq), 153.4 (Cq ¥ 2), 153.5 (Cq), 154.3 (Cq). MS
(ZQ2000/ES+) m/z 505 [M + Na]+. HRMS (QTOF/ESI+) calcd
for C29H26N2O5Na, m/z 505.1739, found 505.1736.
7-(3¢,4¢,5¢-Trimethoxyphenyl)-5H,12H-indolo[3,2-a]carbazole
(6a). The title compound 6a was prepared according to the
typical procedure using indole 9a (50 mg, 0.43 mmol) and b-
nitrostyrene 8a. Purification was carried out by flash chromatogra-
phy (cyclohexane/ethyl acetate 8 : 2) to afford 6a (53 mg, 59%) as a
colorless solid. Mp 272–274 ◦C (from dichloromethane/methanol
9 : 1). UV (CDCl3) lmax (nm) 209 (loge = 4.54); 212 (loge = 4.55);
241 (loge = 4.51); 269 (loge = 4.51); 283 (loge = 4.55); 352 (loge =
4.01). IR (NaCl film) n¢ (cm-1) 2932, 1631, 1580, 1455, 1429, 1413,
3,10-Dimethoxy-7-(3¢,4¢,5¢-trimethoxyphenyl)-5H,12H-indolo-
[3,2-a]carbazole (6d). The title compound 6d was prepared
according to the typical procedure using indole 9d (50 mg,
0.34 mmol) and b-nitrostyrene 8a. Purification was carried out
by chromatography with 20–45 mm silica gel (cyclohexane/ethyl
acetate 7 : 3) to afford 6d (43 mg, 52%) as a white solid. Mp:
1
1375, 1305, 1266, 1227, 1123. H NMR (CDCl3) d 3.88 (s, 6H,
3¢–5¢OCH3), 4.03 (s, 3H, 4¢OCH3), 6.93 (s, 2H, H2¢–6¢), 7.08 (td, J =
7.6 Hz, J = 1.0 Hz, 1H, H9), 7.24 (s, 1H, H6), 7.37 (td, J = 8.0
Hz, J = 1.0 Hz, 1H, H10), 7.39 (td, J = 7.3 Hz, J = 1.0 Hz, 1H,
H2), 7.49 (td, J = 7.5 Hz, J = 1.0 Hz, 1H, H3), 7.55 (d, J = 7.8
7786 | Org. Biomol. Chem., 2011, 9, 7780–7790
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162–163 ◦C (from acetone). IR (NaCl film) n¢ (cm-1) 3385, 2933,
1620, 1580, 1503, 1452, 1366, 1234, 1198, 1161, 1125, 822. H
7-Phenyl-5H,12H-indolo[3,2-a]carbazole (6g). The title com-
pound 6g was prepared according to the typical procedure using
indole 9a (100 mg, 0.86 mmol) and b-nitrostyrene 8b. Purification
was carried out by flash chromatography (cyclohexane/ethyl
acetate 8 : 1) to afford 6g (76 mg, 53%) as a colorless solid. Mp:
230–232 ◦C (colorless prisms from ethyl acetate). IR (KBr) n¢
(cm-1) 3373, 3334, 3046, 2999, 2960, 2935, 1638, 1584, 1512, 1459,
1416, 1322, 1270, 1122, 1039, 836, 732. 1H NMR (CDCl3) d 7.05
(ddd, J = 7.9 Hz, J = 7.2 Hz, J = 1.0 Hz, 1H), 7.19 (s, 1H), 7.33–
7.44 (m, 3H), 7.49 (ddd, J = 7.4 Hz, J = 6.9 Hz, J = 1.0 Hz, 1H),
7.53–7.61 (m, 5H), 7.71 (dd, J = 8.0 Hz, J = 1.8 Hz, 1H), 8.21
(d, J = 7.7 Hz, 1H), 8.29 (br s, D2O exch., 1H, NH), 8.74 (br
s, D2O exch., 1H, NH). 13C NMR (CDCl3) d 105.2 (CH), 106.2
(Cq), 110.6 (CH), 110.8 (CH), 114.0 (Cq), 119.5 (CH), 119.9 (CH),
120.5 (CH), 121.4 (CH), 122.0 (Cq), 123.9 (Cq, CH), 124.6 (CH),
127.5 (CH), 128.4 (CH ¥ 2), 129.5 (CH ¥ 2), 134.4 (Cq), 136.5
(Cq ¥ 2), 138.8 (CH), 138.9 (Cq), 139.2 (Cq), 141.7 (Cq). MS
(ZQ2000/ESI+) m/z 355 [M+Na]+. HRMS (QTOF/ESI+) calcd
for C24H16N2Na ([M + Na]+), m/z 355.1211, found 355.1220.
1
NMR (acetone-d6) d 3.85 (OCH3), 3.86 (OCH3), 3.87 (s, 6H,
OCH3 ¥ 2), 3.91 (s, 3H, OCH3), 6.66 (dd, J = 8.8 Hz, J = 2.4
Hz, 1H), 6.93 (dd, J = 8.6 Hz, J = 2.3 Hz, 1H), 6.95 (s, 2H); 7.14
(d, J = 2.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 7.22 (s, 1H), 7.43 (d,
J = 8.7 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 10.44 (br s, D2O exch.,
1H, NH), 10.84 (br s, D2O exch., 1H, NH). 13C NMR (acetone-
d6) d 54.7 (OCH3), 54.9 (OCH3), 55.6 (OCH3 ¥ 2), 59.9 (OCH3),
94.7 (CH), 94.9 (CH), 104.6 (CH), 106.8 (CH ¥ 2), 107.2 (CH),
108.0 (CH), 113.3 (Cq), 115.7 (Cq), 117.6 (Cq), 121.3 (CH), 121.6
(CH), 133.8 (Cq), 133.9 (Cq), 137.6 (Cq), 137.7 (Cq), 138.8 (Cq),
141.0 (Cq), 141.2 (Cq), 153.4 (Cq ¥ 2), 157.6 (Cq), 158.3 (Cq). MS
(ZQ2000/ES+) m/z 505 [M + Na]+. HRMS (QTOF/ESI+) calcd
for C29H26N2O5Na, m/z 505.1739, found 505.1737.
3,10-Dibromo-2,9-dimethoxy-7-(3¢,4¢,5¢-trimethoxyphenyl)-5H,
12H-indolo[3,2-a]carbazole (6e). The title compound 6e was pre-
pared according to the typical procedure using indole 9f (100 mg,
0.44 mmol) and b-nitrostyrene 8a. Purification was carried-out by
flash chromatography (cyclohexane/ethyl acetate 7 : 3) to afford 6e
(93 mg, 66%) as a colorless solid. Mp: 142–144 ◦C (from acetone).
IR (NaCl film) n¢ (cm-1) 2924, 1592, 1560, 1508, 1459, 1425, 1381,
1359, 1322, 1237, 1205, 1158, 1127, 999. 1H NMR (DMSO-d6) d
3.58 (OCH3), 3.77 (OCH3), 3.82 (s, 6H, OCH3 ¥ 2), 4.08 (s, 3H,
OCH3), 6.88 (s, 1H), 6.91 (s, 2H), 7.22 (s, 1H), 7.79 (s, 1H), 7.80
(s, 1H), 8.29 (s, 1H), 11.52 (br s, D2O exch., 1H, NH), 11.91 (br s,
D2O exch., 1H, NH). 13C NMR (DMSO-d6) d 56.2 (OCH3), 56.5
(OCH3 ¥ 2), 57.7 (OCH3), 60.6 (OCH3), 104.0, 104.9, 105.4, 105.9,
106.9 (CH ¥ 2), 107.1, 108.6, 112.3, 115.1 (CH), 115.3 (CH), 121.4,
123.5 (CH/q), 134.6 (Cq), 134.9 (Cq), 135.0 (Cq), 136.2 (Cq),
136.9 (Cq), 137.4 (Cq), 140.4 (Cq), 148.9 (Cq), 149.8 (Cq), 153.3
(Cq ¥ 2). MS (ZQ2000/ESI+) m/z 665 [C29H2481Br2N2O5Na]+,
663 [C29H2479Br81BrN2O5Na]+, 661 [C29H2479Br2N2O5Na]+. HRMS
(QTOF/ESI+) calcd for C29H2479Br81Br N2O5Na, m/z 662.9929,
found 662.9925.
7-(4¢-Methyl)-5H,12H-indolo[3,2-a]carbazole (6h). The title
compound 6h was prepared according to the typical procedure
using indole 9a (50 mg, 0.43 mmol) and b-nitrostyrene 8c. Purifica-
tion was carried out by flash chromatography (cyclohexane/ethyl
acetate 9◦: 1) to afford 6h (23 mg, 31%) as a colorless solid. Mp:
256–258 C (from acetone). IR (KBr) n¢ (cm-1) 3461, 3378, 3016,
2916, 1637, 1611, 1758, 1518, 1455, 1374, 1353, 1263, 1180, 1155,
1
1020, 821, 802, 747. H NMR (acetone-d6) d 2.50 (s, 3H, CH3),
6.96 (ddd, J = 7.5 Hz, J = 1.1 Hz, 1H), 7.25 (s, 1H), 7.31 (ddd,
J = 7.5 Hz, J = 1.1 Hz, 2H), 7.38–7.47 (m, 4H), 7.58 (d, J = 9.0
Hz, 2H), 7.63 (dd, J = 9.0 Hz, J = 3.0 Hz, 2H), 8.57 (dd, J = 9.0
Hz, J = 3.0 Hz, 1H, H1), 10.65 (br s, D2O exch., 1H, NH), 11.04
(br s, D2O exch., 1H, NH). 13C NMR (acetone-d6) d 20.5 (CH3),
105.0 (CH), 106.0 (Cq), 110.8 (CH), 110.9 (CH), 113.2 (Cq), 118.7
(CH), 119.1 (CH), 120.7 (CH), 120.8 (CH), 121.9 (Cq), 123.3
(CH), 123.9 (Cq), 124.2 (CH), 128.9 (CH ¥ 2), 129.2 (CH ¥ 2),
134.6 (Cq), 136.2 (Cq), 136.9 (Cq), 139.3 (Cq), 139.5 (Cq ¥ 2),
139.9 (Cq). MS (ZQ2000/ESI+) m/z 369 [M + Na]+, 347 [M +
H]+. HRMS (QTOF/ESI+) calcd for C25H19N2 ([M + H]+), m/z
347.1524, found 347.1531.
2,9-Dibromo-7-(3¢,4¢,5¢-trimethoxyphenyl)-5H,12H-indolo[3,2-
a]carbazole (6f). The title compound 6f was prepared according
to the typical procedure using indole 9g (100 mg, 0.86 mmol)
and b-nitrostyrene 8a. Purification was carried out by flash
chromatography (cyclohexane/ethyl acetate 8 : 2) to afford 6f
7-(4¢-Methoxyphenyl)-5H,12H-indolo[3,2-a]carbazole
(6i).
◦
(26 mg, 18%) as a colorless solid. Mp: >350 C (from acetone).
The title compound 6i was prepared according to the typical
procedure using indole 9a (50 mg, 0.43 mmol) and b-nitrostyrene
8d. Purification was carried out by flash chromatography
(cyclohexane/dichloromethane 7 : 3) to afford 6i (31 mg, 40%) as
a colorless solid. Mp: 314–316 ◦C (from dichloromethane/acetone
9 : 1). IR (KBr) n¢ (cm-1) 3417, 3011, 2918, 1708, 1642, 1607, 1516,
1456, 1378, 1321, 1285, 1266, 1182, 1149, 1126, 1023, 841, 819,
IR (KBr) n¢ (cm-1) 3442, 3384, 2999, 2960, 2933, 2834, 1638,
1577, 1509, 1457, 1413, 1372, 1368, 1310, 1284, 1235, 1121, 1083,
1053, 1003, 901, 850, 797, 760, 736, 685, 658, 571, 434. 1H NMR
(acetone-d6) d 3.89 (s, 3H, OCH3), 3.92 (s, 6H, OCH3 ¥ 2), 6.99
(s, 2H), 7.37 (s, 1H), 7.43 (dd, J = 8.5 Hz, J = 2.0 Hz, 1H), 7.56
(dd, J = 8.6 Hz, J = 1.8 Hz, 1H), 7.59–7.66 (m, 2H), 7.70 (d, J =
2.0 Hz, 1H), 8.70 (d, J = 1.8 Hz, 1H), 10.96 (br s, D2O exch., 1H,
NH), 11.38 (br s, D2O exch., 1H, NH). 13C NMR (acetone-d6) d
55.7 (OCH3 ¥ 2), 59.9 (OCH3), 105.5 (CH), 106.8 (CH ¥ 2), 111.3
(Cq), 111.7 (Cq), 112.4 (Cq), 112.7 (CH ¥ 2), 123.1 (CH), 123.4
(Cq), 123.5 (CH), 125.5 (Cq), 126.0 (CH), 127.0 (CH), 134.9 (Cq),
136.6 (Cq), 137.1 (Cq), 138.2 (Cq), 138.6 (Cq), 140.3 (Cq), 153.6
(Cq ¥ 2). MS (ZQ2000/ES+) m/z 605 [C27H2081Br2N2O3Na]+,
603 [C27H2079Br81BrN2O3Na]+, 601 [C27H2079Br2N2O3Na]+. HRMS
(QTOF/ESI+) calcd for C27H20Br2N2O3Na, m/z 602.9718, found
602.9706.
1
749, 734. H NMR (acetone-d6) d 3.98 (s, 3H, OCH3), 6.97 (dd,
J = 7.5 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H) 7.24 (s, 1H), 7.25–7.33
(m, 2H), 7.40–7.46 (m, 2H), 7.60–7.65 (m, 4H), 8.56 (d, J = 7.7
Hz, 1H), 10.65 (br s, D2O exch., 1H, NH), 11.01 (br s, D2O exch.,
1H, NH). 13C NMR (acetone-d6, 75 MHz) d 54,7 (OCH3), 105.0
(CH), 105.9 (Cq), 110.7 (CH), 110.8 (CH), 113.3 (Cq), 113.7
(CH ¥ 2), 118.7 (CH), 119.1 (CH), 120.7 (CH), 120.8 (CH),
121.9 (Cq), 123.2 (CH), 123.9 (Cq), 124.1 (CH), 130.4 (CH ¥ 2),
134.4 (Cq), 134.5 (Cq), 135.9 (Cq), 139.4 (Cq), 139.5 (Cq), 139.9
(Cq), 159.3 (Cq). MS (ZQ2000/ESI-) m/z 361 [M - H]-. HRMS
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(QTOF/ESI-) calcd for C25H17N2O ([M - H]-), m/z 361.1341,
found 361.1357.
7.72 Hz, 1H, H7¢), 6.76 (d, J = 7.22 Hz, J¢ = 7.36 Hz, 1H, H5¢), 7.09
(m, 1H, H5), 7.08 (m, 1H, H6¢), 7.15 (d, J = 7.22 Hz, 1H, H4¢), 7.19
(br s, 1H, H2), 7.21 (t, J = 7.81 Hz, J¢ = 7.72 Hz, 1H, H6), 7.38 (d,
J = 8.12 Hz, 1H, H7), 7.60 (d, J = 7.96 Hz, 1H, H4), 8.02 (br s, D2O
exch., 1H, NH1). 13C NMR (CDCl3) d 37.7 (C3¢), 56.4 (C2¢), 109.2
(C7¢), 111.3 (C7), 118.7 (C5¢), 119.5 (Cq), 119.5 (C4), 119.6 (C6¢),
121.1 (C2), 122.3 (C5), 124.7 (C6), 125.8 (Cq), 127.4 (C4¢), 128.9
(Cq), 136.76 (C7a, C7¢a). MS (DIC/NH3) m/z 235 [M + H]+, 118.
7-(4¢-Bromophenyl)-5H,12H-indolo[3,2-a]carbazole (6j). The
title compound 6j was prepared according to the typical procedure
using indole 9a (50 mg, 0.43 mmol) and b-nitrostyrene 8e.
Purification was carried out by flash chromatography (cyclohex-
ane/dichloromethane 7 : 3) to afford 6j (29 mg, 33%) as a colorless
solid. Mp: 304–306 ◦C (from dichloromethane/acetone 9 : 1). IR
(KBr) n¢ (cm-1) 3350, 3280, 3065, 2995, 1697, 1636, 1456, 1355,
1268, 827, 752, 735. 1H NMR (acetone-d6) d 7.00 (dd, J = 8,3 Hz,
J¢ = 7.5 Hz, 1H), 7.28 (s, 1H), 7.29–7.33 (m, 2H), 7.39 (br d, J =
8.0 Hz, 1H), 7.45 (dd, J = 8.3 Hz, J¢ = 7.5 Hz, 1H), 7.63–7.68 (m,
4H), 7.79 (br d, J = 8.3 Hz, 2H), 8.58 (br d, J = 7.9 Hz, 1H), 10.71
3-(1H-Indol-2-yl)-1H-indole (5)9b. To a solution of 3-(indolin-
2-yl)-1H-indole 10 (170 mg, 0.7 mmol) in toluene (30 mL)
was added 10% Pd/C (30 mg) under argon atmosphere. The
mixture was refluxed for 10 h and filtered on a Celite pad. The
suspension was washed with warm ethyl acetate (50 mL). The
subsequent brownyfiltrate was evaporated under reduced pressure.
Crude product was purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 8 : 2) affording the title compound 5 as
a white powder in 80% yield (135 mg). 1H NMR (dmso-d6) (lit.,29)
d 6.76 (br s, 1H, H3), 6.96 (t, J = 7.89 Hz, J¢ = 6.99 Hz, 1H, H5),
7.03 (t, J = 7.69 Hz, J¢ = 7.57 Hz, 1H, H6), 7.15 (m, 1H, H5¢), 7.19
(m, 1H, H6¢), 7.35 (d, J = 7.69 Hz, 1H, H7), 7.47 (d, J = 8.37 Hz,
1H, H7¢), 7.50 (d, J = 7.89 Hz, 1H, H4), 7.86 (d, 1H, H2¢), 8.00 (d,
J = 6.97 Hz, 1H, H4¢), 11.21 (br s, D2O exch., 1H, NH1), 11.40
(br s, D2O exch., 1H, NH1¢). 13C NMR (75 MHz, dmso-d6) (lit.29)
d 97.3 (C3), 110.9 (C3¢), 112.4 (C7¢), 119.3 (C5), 119.5 (C4), 120.1
(C4¢), 120.3 (C5¢), 120.8 (C6), 122.2 (C6¢), 123.6 (C2¢), 125.1 (C3¢a),
129.7 (C3a), 134.6 (C2), 136.4 (C7a), 137.1(C7¢a).
(br s, D2O exch., 1H, NH), 11.09 (br s, D2O exch., 1H, NH). 13
C
NMR (acetone-d6) d 105.0 (CH), 106.4 (Cq), 110.8 (CH), 111.0
(CH), 112.8 (Cq), 118.9 (CH), 119.2 (CH), 120.5 (CH), 120.8
(CH), 121.0 (Cq), 121.8 (Cq), 123.5 (CH + Cq), 124.4 (CH), 131.4
(CH ¥ 4), 134.5 (Cq), 134.6 (Cq), 139.4 (Cq), 139.5 (Cq), 139.9
(Cq), 141.5 (Cq). MS (ZQ2000/ESI-) m/z 411 [M - H]-. HRMS
(QTOF/ESI-) calcd for C24H1479BrN2 ([M - H]-), m/z 409.0340,
found 409.0343.
7-(4¢-Nitrophenyl)-5H,12H-indolo[3,2-a]carbazole (6k). The
title compound 6k was prepared according to the typical procedure
using indole 9a (50 mg, 0.43 mmol) and b-nitrostyrene 8f.
Purification was carried out by successive flash chromatographies
(cyclohexane/ethyl acetate 8 : 2) to afford 6k (16 mg, 20%) as a
yellow solid. Mp: 246–248 ◦C (from ethyl acetate). IR (KBr) n¢
(cm-1) 3395, 3048, 2961, 2917, 1637, 1610, 1591, 1514, 1458, 1380,
1340, 1267, 1153, 1099, 833, 747, 733, 705, 699. 1H NMR (acetone-
d6) d 6.96 (dd, J = 8.4 Hz, J¢ = 7.4 Hz, 1H), 7.28–7.34 (m, 3H
including a singlet (1H) at 7.34 ppm), 7.39 (br d, J = 8.2 Hz, 1H),
7.45 (dd, J = 8.3 Hz, J¢ = 7,1 Hz, 1H), 7.65 (br d, J = 8.2 Hz,
1H), 7.99 (br d, J = 8.8 Hz, 2H), 8.47 (br d, J = 8.8 Hz, 2H), 8.58
(d, J = 7.7 Hz, 1H), 10.78 (br s, D2O exch., 1H, NH), 11.15 (br s,
D2O exch., 1H, NH). 13C NMR (acetone-d6) d 106.2 (CH), 107.9
(Cq), 111.9 (CH), 112.0 (CH), 113.3 (Cq), 119.9 (CH), 120.3 (CH),
121.4 (CH), 121.9 (CH), 122.5 (Cq), 124.0 (Cq), 124.5 (CH ¥ 2),
124.7 (CH), 125.6 (CH), 131.5 (CH ¥ 2), 134.3 (Cq), 135.6 (Cq),
140.2 (Cq), 140.6 (Cq), 140.9 (Cq), 148.3 (Cq), 150.0 (Cq). MS
(QTOF/ESI-) m/z 376 [M - H]-. HRMS (QTOF/ESI-) calcd for
C24H14N3O2 ([M - H]-), m/z 376.1086, found 376.1085.
Procedure for synthesis of indolocarbazole 6a from 2,3¢-biindole 5.
To a solution of 2,3¢-biindole (5, 20 mg, 0.086 mmol, 1.0 equiv) and
trans-nitrostyrene (8a, 21 mg, 0.086 mmol, 1.0 equiv) in anhydrous
dichloromethane (10 mL) was added SnCl2·2H2O (19.4 mg, 0.086
mmol, 1 equiv) and MnO2 (7.5 mg, 0.086 mmol, 1.0 equiv). After
24 h of stirring at room temperature, the reaction mixture was
filtered and the precipitate washed with ethyl acetate. Solvents were
evaporated under reduced pressure and the residue was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate
8 : 2 to 7 : 3) affording the indolocarbazole derivative 6a in a pure
state in 97% yield (35 mg).
3-[1-(3¢,4¢,5¢-Trimethoxyphenyl)-2¢¢-nitroethyl]-1H-indole (12).
A mixture of 1H-indole 9a (50 mg, 0.43 mmol) and 3,4,5-
trimethoxynitrostyrene 8a (102.1 mg, 0.43 mmol) was heated for 4
h at 125 ◦C. Crude product was purified by flash chromatography
on silica gel (cyclohexane/ethyl acetate 6 : 4) affording the title
compound 12◦as a colorless amorphous powder in 72% (110 mg).
Mp: 136–138 C (from ethyl acetate). IR (NaCl) n¢ (cm-1) 3056,
2994, 2963, 2939, 2838, 1593, 1551, 1506, 1460, 1423, 1379, 1332,
3-(Indolin-2-yl)-1H-indole (10). To a stirred solution of 1H-
indole 9a (1.0 g, 8.5 mmol) in anhydrous DCM (200 mL), SnCl4
(4.25 mL, 0.5 eq) was added dropwise at 0 ◦C under argon.
After stirring at 0 ◦C for 6 h, the mixture was allowed to reach
room temperature and stirred for another 8 h. The subsequent
precipitate was filtered on a Bu¨chner funnel and washed three
times with DCM (10 mL), then was taken-up in deionized water
(10 mL). After adjustment of pH to 11–12 with a saturated solution
of NaHCO3, the aqueous layer was extracted four times with
ethyl acetate (60 mL). Combined organic layers were dried on
MgSO4, filtered and evaporated under reduced pressure. The title
compound 10 was obtained as an amorphous white powder in
87% yield (867 mg) and engaged in the next step without further
1
1236, 1184, 1126, 1000, 910, 835, 744. H NMR (CDCl3) d 3.80
4¢
(s, 6H, 3¢–5¢OCH3), 3.84 (s, 3H, OCH3), 4.94 (dd, Ja–b = 12,4 Hz,
J
a-1¢¢ = 8,5 Hz, 1H, Ha), 5.06 (dd, Jb-a = 12,4 Hz, Jb-1¢¢ = 7,5 Hz, 1H,
Hb), 5.15 (dd, J1¢¢-a = 8,5 Hz, J1¢¢-b = 7,5 Hz, 1H, H1¢¢), 6.58 (s, 2H,
2¢–6¢), 7.02 (s, 1H, H2), 7.11 (t, J = 7,5 Hz, 1H, H5), 7.21 (t, J =
H
7,5 Hz, 1H, H6), 7.35 (d, J = 8 Hz, 1H, H7), 7.52 (d, J = 7,9 Hz,
1H, H4), 8.22 (br s, D2O exch., 1H, NH). 13C NMR (CDCl3) d
42.0 (C1¢¢), 56.2 (3¢–5¢OCH3), 60.9 (4¢OCH3), 79.6 (C2¢¢), 105.0 (C2¢–6¢),
111.6 (C7), 114.4 (C3), 119.0 (C4), 120.1 (C5), 121.8 (C2), 122.9 (C6),
126.2 (C3a), 135.0 (C1¢), 136.6 (C7a), 137.4 (C4¢), 153.6 (C3¢–5¢). MS
(ZQ2000/ES+) m/z 379 [M + Na]+; Anal. (C19H20N2O5). Found:
1
2
purification. H NMR (CDCl3) (lit.,9c) d 3.23 (dd, J = 15.6 Hz,
J
3¢–2¢ = 8.3 Hz, 1H, H3¢b), 3.47 (dd, 2J = 15.6 Hz, J3¢a–2¢ = 9.1 Hz, 1H,
H3¢a), 5.26 (dd, J3¢a–2¢ = 9.1 Hz, J3¢b–2¢ = 8.3 Hz, 1H, H2¢), 6.68 (d, J =
7788 | Org. Biomol. Chem., 2011, 9, 7780–7790
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C, 63.65%; H, 5.82%; N, 7.59%; Calc: C, 63.84; H, 5.76%; N,
7.76%.
Notes and references
1 (a) U. Pindur, Y.-S. Kim and F. Mehrabani, Curr. Med. Chem., 1999, 6,
29; (b) M. Prudhomme, Curr. Med. Chem., 2000, 7, 1189.
2 H. J. Kno¨lker and K. R. Reddy, Chem. Rev., 2002, 102(11), 4303.
3 K. M. Meragelman, L. M. West, P. T. Northcote, L. K. Pannell, T. C.
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4 A. Pron, P. Gawrys, M. Zagorska, D. Djurado and R. Demadrille,
Chem. Soc. Rev., 2010, 39, 2577.
5 (a) J. T. Je, G. U. Ryu, B. G. Song, Kor. Pat., 016047, 2011; (b) J. T. Je,
G. U. Ryu, R. G. Kang, Kor. Pat., 016044, 2011; (c) J. T. Je and H. J.
Kwon, Kor. Pat., 011578, 2011.
6 (a) J. Bergman, E. Desarbre and E. Koch, Tetrahedron, 1999, 55, 2363;
(b) T. Janosik and J. Bergman, Tetrahedron, 1999, 55, 2371; (c) N.
Wahlstro¨m and J. J. Bergman, Tetrahedron Lett., 2004, 45, 7273; (d) V.
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130(47), 15823.
7 N. Ty, G. Dupeyre, G. G. Chabot, J. Seguin, L. Quentin, A. Chiaroni, F.
Tillequin, D. Scherman, S. Michel and X. Cachet, Eur. J. Med. Chem.,
2010, 45, 3726.
8 Indoles are prone to polymerization under various acidic conditions.
For reviews, see: (a) G. F. Smith, Adv. Heterocycl. Chem., 1963, 2,
287; (b) R. J. Sundberg, The Chemistry of Indoles, Academic Press,
New York, 1970, p. 6; (c) R. J. Sundberg, Top Heterocycl Chem.,
vol. 26, Electrophilic Substitution Reaction of Indoles, Springer-Verlag,
Heildeberg, 2011, p. 51.
9 (a) O. Schmitz-Dumont and B. Nicolojannis, Chem. Ber., 1930, 63, 323;
(b) N. Wahlstro¨m, J. Sa¨tt, B. Stensland, A. Ertan, J. Bergman and T.
Janosik, J. Org. Chem., 2007, 72, 5886; (c) H. Ishii, K. Murakami, E.
Sakurada, K. Hosoya and Y. Murakami, J. Chem. Soc., Perkin Trans.
1, 1988, 2377.
2-(1H-Indol-3-yl)-3-(1-(3,4,5-trimethoxyphenyl)-2-nitroethyl)-
1H-indole (7). A mixture of 3-(1H-indol-2-yl)-1H-indole 5
(179 mg, 0.77 mmol) and 3,4,5-trimethoxynitrostyrene 8a (185 mg,
0.77 mmol) in dichloromethane (25 mL) was stirred for 24 h at
room temperature. Solvent was evaporated under reduced pressure
and the residue was then purified by flash chromatography on silica
gel (cyclohexane/ethyl acetate 7 : 3) affording the title compound
7 in 91% yield (331 mg). Mp: 211–213 ◦C (from dichloromethane).
IR (KBr) n¢ (cm-1) 3385, 3351, 3055, 2971, 2938, 2839, 1702, 1594,
1551, 1508, 1459, 1425, 1378, 1332, 1232, 1124, 1010, 993, 826,
770, 725. 1H NMR (CDCl3) d 3.67 (s, 6H, OCH3 ¥ 2), 3.81 (s, 3H,
OCH3), 5.10–5.21 (m, 2H), 5.27 (dd, J = 15.8 Hz, J = 7.8 Hz, 1H),
6.53 (s, 2H), 7.13–7.31 (m, 5H), 7.42 (d, J = 8.0 Hz, 1H), 7.46 (d,
J = 8.2 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H),
8.34 (br s, D2O exch., 1H, NH), 8.54 (br s, D2O exch., 1H, NH).
13C NMR (CDCl3) d 41.5 (CH), 56.2 (OCH3 ¥ 2), 60.8 (OCH3),
79.3 (CH2), 104.7 (CH ¥ 2), 107.6 (Cq), 110.0 (Cq), 111.3 (CH),
111.7 (CH), 119.2 (CH), 119.4 (CH), 120.0 (CH), 120.7 (CH),
122.0 (CH), 123.0 (CH), 124.4 (CH), 126.9 (Cq), 127.0 (Cq), 131.1
(Cq), 135.9 (Cq), 136.0 (Cq), 136.1 (Cq), 136.7 (Cq), 153.2 (Cq ¥
2). MS (ZQ2000/ESI+) m/z 494 [M + Na]+, 965 [2M + Na]+.
HRMS (QTOF/ESI+) calcd for C27H25N3O5Na ([M + Na]+) m/z
494.1692, found 494.1694.
10 M. Bandini and A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608.
11 See ref. 8c p. 85.
12 J. Lehmann, N. Jiang and A. Behncke, Arch. Pharm., 1993, 326, 813.
13 3,3¢-Trimer can be conveniently prepared by treatment of 1H-indole 9a
with dilute aqueous HCl (See ref. 9c and 14).
14 O. Schmitz-Dumont, B. Nicolojannis, E. Schonrrenberg and H. H.
Saenger, J. Prakt. Chem., 1931, 131, 146.
15 G. F. Smith, Chem. Ind. (London), 1954, 1451.
16 This hypothesis has been subsequently confirmed. A plausible mecha-
nism for the formation of 6a will be discussed later in this paper.
17 Compound 12 is obtained as a chromatographically inseparable
mixture with unidentified by-products.
18 Data for preliminary studies are also included in this table to facilitate
comparison (entries 1–3).
19 A recent report described the use of catalytic amounts (10 mol%)
of metal halide hydrates such as SnCl2·2H2O and MnCl2·4H2O in
the conjugated Friedel–Crafts reaction between 1H-indole 9a and
nitrostyrene 8b. Reactions were carried out either at room temperature
in various solvents or in refluxing dichloromethane and always failed to
proceed. These findings are consistent with our own observations. The
best results were achieved either in polar protic solvents under refluxing
conditions or under solventless conditions at 100 ◦C. However, under
these conditions, the use of SnCl2·2H2O led to poor yields of conversion
(54 and 57%, respectively). In our hands, treatment at room temperature
of a dichloromethane solution of equimolar amounts of both 9a and
8a with catalytic or stoichiometric amount of MnCl2·4H2O gave no
reaction (See ref. 20).
2-(2,2-Di(1H-indol-3-yl)ethyl)benzenamine (the 3,3¢-trimer)
(11). To a solution of 1H-indole 9a (1 g, 8.55 mmol) in CH2Cl2
(15 mL), SnCl2·2H2O (1.93 g, 8.55 mmol) was added and the
reaction mixture was stirred at room temperature for 72 h.
The organic layer was washed with water and brine, dried over
MgSO4, and concentrated in vacuo. Crude product was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate
1 : 1) affording the title compound 11 as a lacquer in 96% yield
(0.96 g). IR (KBr) n¢ (cm-1) 3385, 3351, 3055, 2971, 2938, 2839,
1702, 1594, 1551, 1508, 1459, 1425, 1378, 1332, 1232, 1124, 1010,
993, 826, 770, 725. 1H NMR (CDCl3)13 d 3.44 (d, J = 7.2 Hz, 2H,
CH2), 4,87 (t, J = 7,2 Hz, 1H, CH), 5.30 (br s, D2O exch., 2H,
NH2), 6.55 (d, J = 8.0 Hz, 1H), 6.62 (m, 1H), 6.95–7.05 (m, 6H),
7.14 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H),
7.84 (br s, D2O exch., 2H, NH ¥ 2). 13C NMR (CDCl3)13 d 34.3
(CH), 37.0 (CH2), 111.1 (CH ¥ 2), 115.7 (C3¢), 118.8, 119.0 (CH ¥
2), 119.3 (CH), 119.5 (CH ¥ 2), 121.7 (CH ¥ 2), 121.9 (CH ¥ 2),
126.0, 126.8 (CH), 130.2 (CH), 136.5 (Cq ¥ 2), 144.6 (Cq). MS
(ZQ2000/ESI+) m/z 390 [M + K]+, 374 [M + Na]+.
2-Amino-4,5-dimethoxybenzoic acid. ◦ Orange crystals. Mp:
◦
175–177 C (from ethanol) (lit.30 172 C). IR (KBr) n¢ (cm-1)
20 C. Schwalm, M. A. Ceshi and D. Russowsky, J. Braz. Chem. Soc., 2011,
1
22, 623.
3453, 3326, 1648, 1593, 1509, 1397, 1236, 850. H NMR (dmso-
21 A. Inada, Y. Nakamura and Y. Morita, Chem. Lett., 1980, 1287.
22 R. J. K. Taylor, M. Reid, J. Foot and S. A. Raw, Acc. Chem. Res., 2005,
38(11), 851.
d6) d 3.72 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 6.51 (s, 1H, H3),
7.32 (s, 1H, H6), 7.48 (br s, D2O exch., 2H), 7.32 (s, 1H). 13C NMR
(CDCl3) d 56.3 (OCH3 ¥ 2), 99.0 (C1 + C3), 106.5 (C6), 141.5 (C5),
142.5 (C2), 156.8 (C4), 169.1 (CO2H). MS (ZQ2000/ESI-) m/z 197
[M - H]-.
23 All spectroscopic data were in full agreement with those obtained for a
commercial sample (Sigma-Aldrich). MS spectrum was in accordance
with the assigned structure (See the Supporting Information for
details‡).
24 Monoindole adduct 12 can be considered as the main undesired by-
product in the one-pot synthesis of 6a. Indeed, direct treatment of 12
with 1 equiv of both SnCl2·2H2O and 1H-indole 9a in CH2Cl2, neither
leads to 6a nor gives back the starting 1H-indole.
25 P. Li, M. M. Majireck, J. A. Witek and S. M. Weinreb, Tetrahedron
Lett., 2010, 51, 2032.
Acknowledgements
The authors are grateful to Dr Christine Cachet-Vivier (ICMPE
– UMR 7182 University of East Paris) for helpful discussions.
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26 Excess SnCl2·2H2O (at least two molar equivalents) is known to reduce
nitroolefins into the corresponding oxime. In the commonly accepted
mechanism, the first step involves a two-electron reduction of the
nitro olefin into the nitroso olefin. When the reaction is performed in
nucleophilic solvents such as alcohols and thiols, and in the presence of
stoichiometric amount of the reducing agent, the highly reactive nitroso
olefin intermediate could be trapped leading to the corresponding a-
alkoxy (or thioalkoxy) oxime (See ref. 27). For a detailed description of
the mechanism for the reduction of nitroolefin into oxime, see ref. 28.
27 (a) R. S. Varma and G. W. Kabalka, Synth. Commun., 1985, 15(5), 443;
(b) R. S. Varma and G. W. Kabalka, Chem. Lett., 1985, 243; (c) A.
Hassner, K. M. L. Rai and W. Dehaen, Synth. Commun., 1994, 24(12),
1669.
28 A. Sera, S. Fukumoto, M. Tamura, K. Takabatake, H. Yamada and K.
Itoh, Bull. Chem. Soc. Jpn., 1991, 64, 1787.
29 V. Bocchi and G. Palla, Tetrahedron, 1986, 42(18), 5019.
30 B. A. Merritt, N. M. Sashikumar and S. Chun, J. Org. Chem., 2002,
67(23), 8284.
7790 | Org. Biomol. Chem., 2011, 9, 7780–7790
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The Royal Society of Chemistry 2011
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