Facile synthesis of 5H-benzo[b]carbazol-6-yl ketones via sequential reaction of Cu-catalyzed Friedel-Crafts alkylation, iodine-promoted cyclization, nucleophilic substitution and aromatization

Article abstract of DOI:10.1039/c4ob00815d

A convenient method to access 5H-benzo[b]carbazol-6-yl ketones via a sequential Cu-catalyzed Friedel-Crafts alkylation reaction of indoles with 2-(2-(alkynyl)benzylidene)malonates and iodine-promoted electrophilic cyclization followed by nucleophilic substitution and aromatization was developed. The products of the functional 5H-benzo[b]carbazol-6-yl ketones were obtained with up to 98% yield. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00815d

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Biomolecular Chemistry
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Facile synthesis of 5H-benzo[b]carbazol-6-yl
ketones via sequential reaction of Cu-catalyzed
Friedel–Crafts alkylation, iodine-promoted
cyclization, nucleophilic substitution and
aromatization†
Cite this: Org. Biomol. Chem., 2014,
12, 6806
Received 21st April 2014,
Accepted 26th June 2014
DOI: 10.1039/c4ob00815d
www.rsc.org/obc
Jing Wu, Dongping Wang, Haolong Wang, Fan Wu, Xincheng Li and Boshun Wan*
A convenient method to access 5H-benzo[b]carbazol-6-yl ketones
via a sequential Cu-catalyzed Friedel–Crafts alkylation reaction of
indoles with 2-(2-(alkynyl)benzylidene)malonates and iodine-
promoted electrophilic cyclization followed by nucleophilic substi-
tution and aromatization was developed. The products of the func-
tional 5H-benzo[b]carbazol-6-yl ketones were obtained with up to
98% yield.
Condensed heterocyclic aromatic compounds are particularly
appealing due to their unique biological activities and out-
standing optoelectronic properties.1,2 Carbazole and its fused
aromatic analogues, which are a class of heterocyclic aromatic
compounds as well as indole alkaloids,3 have recently been the
subject of intense investigation.4 Some of the carbazole alka-
loids showed a range of promising biological activities,5–9 such
as antitumor,6,7 anti-inflammatory,8 and antipsychotic pro-
perties.9 Among all carbazole analogues, the framework of
benzo[b]carbazoles10–13 was most extensively explored because
they are isosteric species of antitumor drugs based on pyrido
[4,3-b]carbazole alkaloids, such as ellipticine.7 Approaches to
the synthesis of benzo[b]carbazoles mainly start from different
substituted naphthalenes10 (Scheme 1, a–c) or indoles11
(Scheme 1, d–f). Another kind of commonly used method
involves a biradical cyclization of ketenimine intermediates12
(Scheme 1, g). Other methods,13 using the Fischer indolization
and the Bradsher reaction as key steps, have also been reported
(Scheme 1, h and i). In addition, a phase tag-assisted synthesis
of the benzo[b]carbazole motif via SmI2-mediated radical
nucleophilic ring closure offered another novel approach.13d,e
However, for most of the procedures derived from substituted
indole substrates,11 the key step to construct phenyl ring A
Scheme 1 Synthetic routes to benzo[b]carbazoles.
(benzo[b]carbazoles in Scheme 1) involved the Diels–Alder
reaction11c,d or metal-catalyzed benzannulation of indoles.11j,k
To the best of our knowledge, no examples have been reported
yet, which show the formation of benzo[b]carbazoles via elec-
trophilic cyclization in the annulation step. Given the great
utility of benzo[b]carbazoles, exploring efficient alternatives to
construct these structures is still highly desirable.
Very recently, we have developed an efficient Cu-catalyzed
asymmetric Friedel–Crafts alkylation reaction14 of indoles with
arylidene malonates, using bis(sulfonamide) diamine
ligands.15a–d As part of our continued interest in the reactions
of indoles, we envision that when diethyl 2-(2-(phenylethynyl)-
benzylidene)malonate, 2a, is employed as a substrate, the
corresponding product 3a,16 including an alkynyl group,
would be a good precursor for the subsequent cyclization,
where the diethyl malonate moiety may act as a leaving group
(LG) (Scheme 1, j). Herein, we describe a convenient way to
synthesize 5H-benzo[b]carbazol-6-yl ketones via the Cu-cata-
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
China. E-mail: bswan@dicp.ac.cn
†Electronic supplementary information (ESI) available: Analytic data (including
NMR spectra and MS spectrum) and crystallographic data for 5. CCDC 992632.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00815d
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lyzed Friedel–Crafts reaction of indoles with 2-(2-(alkynyl)- obtained in 39–73% yield at an elevated temperature (120 °C).
benzylidene)malonates, followed by an iodine-promoted elec- The Diels–Alder reaction or thermal electrocyclization was pro-
trophilic cyclization, nucleophilic substitution and further posed to be the key step in the process of constructing ring A.
aromatization.
Gratifyingly, our findings suggested that 5H-benzo[b]carba-
Indole, 1a, and diethyl 2-(2-(phenylethynyl)benzylidene)- zol-6-yl ketones could be obtained at ambient temperature and
malonate, 2a, were selected as the substrates to optimize the this promising result encouraged us to investigate the reaction
reaction conditions in step 1 (Table 1). The screening of sol- systematically. The continuous evaluation of the solvents in
vents and catalysts revealed that the catalytic system, which step 2 revealed that the solvents played a crucial role in the
showed the best performance in our previously described transformation and that CH3CN was the optimal choice
Friedel–Crafts reaction of indole with arylidene malonates, (Table 1, entries 1–7). When the reaction was performed in the
remained the best choice for substrate 2a.15d,e Subsequently, open air or under oxygen atmosphere, a slight improvement of
we set out to investigate the cyclization step of intermediate the yield was achieved (Table 1, entries 8 and 9). The sequen-
3a. An initial examination of the effect of electrophiles, such tial examination of the function of different additives revealed
as iodine, NIS (N-iodosuccinimide), IPy2BF4 and DIH (1,3- that a base, such as NaHCO3, had a deleterious effect on the
diiodo-5,5-dimethylhydantoin), showed that only iodine could reaction, as hardly any product was found (Table 1, entry 10).
promote cyclization. However, the product was not the tra- Interestingly, a slight increase in the yield was observed when
ditional product derived from electrophilic cyclization. 5H- adding 1 equivalent of H2O (Table 1, entry 11). The careful
Benzo[b]carbazol-6-yl ketone was unexpectedly obtained with regulation of the I2 amount showed that 2 equivalents of I2
40% yield in CH2Cl2 at room temperature (Table 1, entry 1). It provided the best result, with 88% yield (Table 1, entry 12).
is noteworthy that Li and coworkers have reported PdCl2-cata- Raising the temperature to 50 °C greatly accelerated the reac-
lyzed domino reactions of 2-alkynylbenzaldehydes with in- tion with an increase in the yield (within 2 hours, 90% yield,
doles,11j in which 5H-benzo[b]carbazol-6-yl ketones were Table 1, entry 13). Notably, when the reactions were conducted
in one pot without separation of the intermediate 3a, the reac-
tion proceeded smoothly with a comparable yield (Table 1,
Table 1 Optimization of the reaction conditionsa
entry 14). However, changing the solvent from iBuOH (in step 1)
to CH3CN (in step 2) was necessary. It is worth mentioning
that the compatibility of the catalytic system with step 1 and
step 2 is crucial for a one-pot reaction.16 To our delight, our
catalytic system wasn’t affected by this problem. Given the
simple operation, we decided to take advantage of the one-pot
reaction in the following exploration of the substrate scope.
The optimal conditions are: (step 1) 5 mol% Cu(OTf)2, 5.5 mol%
i
6, BuOH, 0 °C, and (step 2) 2.0 equiv. I2, 1.0 equiv. H2O,
CH3CN, 50 °C.
With the suitable reaction conditions in hand, the gen-
erality of the transformation was explored. Firstly, different R2
groups of 2-(2-(alkynyl)benzylidene)malonate were investi-
gated. Generally, the reaction proceeded smoothly to afford
the products with moderate yields. However, for the R2 groups,
substrates with electron-withdrawing substituents provided
slightly higher yields than those with electron-donating substi-
tuents (Scheme 2, entries 4b–4e). Subsequently, the substi-
tuent effect of the internal alkynyl moiety was evaluated. When
the R3 groups on the alkynyl moiety were aryl substituents,
moderate to high yields were achieved (Scheme 2, entries
4f–4h). In contrast, when an aliphatic substituent R3 group
(e.g. nBu and TMS) was involved on the alkynyl moiety,
complex mixtures were observed. It is probable that when the
alkynyl moiety was linked to the aliphatic substituent groups,
Entry
Solvent
Additives
T (°C)
Yieldb (%)
1
2
3
4
5
6
CH2Cl2
DCE
Et2O
—
—
—
—
—
—
—
—
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
50
40
37
21
17
76
41
N.R.
79
80
N.R.
81
88
90
88
THF
CH3CN
Toluene
iBuOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
7
8c
9d
—
10c
11c,e
12c,e, f
13c,e, f
14c,e, f,g
NaHCO3
H2O
H2O
H2O
H2O
50
a Unless otherwise noted, all reactions were performed with 3a the iodonium ion intermediate is not very stable, which may
result in side reactions. Surprisingly, when substituent R3 was
(0.3 mmol) and electrophile I2 (0.5 mmol) in 2 mL solvent under argon
for 6–24 h. b Isolated yields. c The reaction was performed in the open
air. d The reaction was performed under oxygen. e 1.0 equiv. H2O was
a cyclopropyl group, electrophilic cyclization took place in a
added. f 2.0 equiv. I2 (0.6 mmol) was used. g The reaction was carried 7-endo-dig fashion and afforded a tetracyclic indoloazulene
i
out in one pot: when step 1 was finished after 6 h, the solvent BuOH
derivative, 5, with 41% yield (eqn (1)). Product 5, containing
was removed under reduced pressure. Intermediate 3a was
transformed in step 2 without further purification and the reaction
tetracyclic indole with a seven-membered ring, is a useful
was finished in 2 h.
structural motif for a variety of pharmaceuticals, although
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philic cyclization products. In addition, electrophilic
cyclization product 5 was obtained when the cyclopropyl group
was used as the substituent on the alkynyl moiety. These
results reveal that the reaction undergoes an electrophilic cycli-
zation process but in a different cyclization mode. The reaction
was also performed with 3a and 1.0 equiv. H2O18, for which
the corresponding product 4a′ with an 18O label was obtained
as a major product. On the basis of these experiments, a
mechanism is outlined to explain the process of this trans-
formation (Scheme 3). The alkynyl moiety of the Friedel–Crafts
alkylation compound, 3, is activated by iodine and then under-
goes an electrophilic cyclization reaction of indole through two
pathways when the R groups are aryl groups: (1) path a via a
6-exo-dig mode (3–B) or (2) path b via a 5-exo-dig mode fol-
lowed by ring expansion (3–A–B). Intermediate B undergoes
nucleophilic substitution by H2O, which affords intermediate
C, followed by aromatization with the elimination of one mole-
cule of the diethyl malonate11i,j to provide product 4. Recently,
an iodine-promoted cascade reaction of 2-alkynylbenzaldehyde
and indole was reported by Yao’s group.17d In their system,
tetracyclic indoloazulene derivatives were obtained via iodocy-
clization in a 7-endo-dig fashion, while our system showed a
different iodocyclization mode. However, when the R group is
a cyclopropyl group, the electrophilic cyclization reaction pro-
vides tetracyclic indoloazulene derivatives, 5, in a 7-endo-dig
fashion (path c). Without the driving force of aromatization,
the reaction stops at the step of electrophilic cyclization to
afford product 5.
To further demonstrate the application potential of this
synthetic strategy, a gram-scale reaction was conducted. The
reaction of diethyl 2-(2-(phenylethynyl)benzylidene)malonate,
2a, (5 mmol, 1.74 g) with indole, 1a, (5 mmol, 0.59 g) was
carried out with a lower catalyst loading (2.5 mol%) under
Scheme 2 Cu-catalyzed Friedel–Crafts alkylation and I2-promoted
electrophilic cyclization of indoles, 1, with various 2-(2-(alkynyl)benzyli-
dene)malonates, 2.
there are only few ways to synthesise it.17 The molecular struc-
ture of 5 was unambiguously determined by X-ray crystallo-
graphy of its N-Ts derivative (see the ESI†).
Likewise, the electronic properties and steric hindrance
effect on the indole scaffold were examined. Good yields were
acquired regardless of the electron-donating or -withdrawing
groups at position 5, 6 or 7 of the indole ring (Scheme 2,
entries 4j–4n). However, methoxyl-substituted indole at posi-
tion 4 afforded the corresponding product with lower yield
because of the steric hindrance (Scheme 2, entry 4i).
To gain insight into the mechanism, we examined the reac-
tion solution of 3a with iodine under optimal reaction con-
ditions using HPLC-MS, when the reaction was conducted for
30 min. According to the spectrum, five substances with a
molecular weight of 591.1 were detected, which is in accor-
dance with the molecular weight of the corresponding electro-
Scheme 3 Proposed mechanism.
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Scheme 4 A large scale reaction.
standard reaction conditions. The reaction proceeded
smoothly and the corresponding product, 4a, was obtained
with 82% yield (Scheme 4).
Conclusions
In summary, we have developed a facile method to access 5H-
benzo[b]carbazol-6-yl ketones via a sequential reaction of Cu-
catalyzed Friedel–Crafts alkylation of indoles with 2-(2-
(alkynyl)benzylidene)malonates, followed by iodine-promoted
cyclization, nucleophilic substitution and aromatization. Func-
tionalized 5H-benzo[b]carbazol-6-yl ketones were prepared in
moderate to high yields. A product with the structure of tetra-
cyclic indole, including a seven-membered ring, was also
obtained when the substituent on the alkynyl moiety was a
cyclopropyl group. Moreover, a gram-scale experiment was con-
ducted to illustrate its simple operation and practicality.
Acknowledgements
Financial support from the National Basic Research Program
of China (2010CB833300) is gratefully acknowledged.
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