Copper-catalyzed synthesis of benzocarbazoles via α-C-arylation of ketones

Article abstract of DOI:10.1039/c2cc36403d

A simple and efficient copper-catalyzed method for the synthesis of 11H-benzo[a]carbazoles has been developed. The protocol uses readily available substituted 2-(2-bromophenyl)-1H-indoles and ketones as starting materials and an inexpensive catalyst system. The corresponding 11H-benzo[a]carbazoles were obtained in moderate to excellent yields. The Royal Society of Chemistry 2012..

Full text of DOI:10.1039/c2cc36403d

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COMMUNICATION
Copper-catalyzed synthesis of benzocarbazoles via a-C-arylation
of ketonesw
Ruilong Xie,ab Yun Ling*b and Hua Fu*ac
Received 3rd September 2012, Accepted 2nd November 2012
DOI: 10.1039/c2cc36403d
A simple and efficient copper-catalyzed method for the synthesis
of 11H-benzo[a]carbazoles has been developed. The protocol
uses readily available substituted 2-(2-bromophenyl)-1H-indoles
and ketones as starting materials and an inexpensive catalyst
system. The corresponding 11H-benzo[a]carbazoles were obtained
in moderate to excellent yields.
they exhibit antitumor (leukemia, renal, colon)9 and anti-
inflammatory activities,10 and some benzocarbazoles can bind to
estrogen receptors and inhibit the growth of mammary tumors in
rats.11 In addition, benzocarbazole derivatives have found extensive
application as photographic materials.12 Some methods for the
synthesis of benzocarbazole derivatives have been developed,13 but
these methods usually suffer from the need to synthesize complex
starting materials, harsh reaction conditions and low yields.
Therefore, it is highly desirable to develop a simple, efficient
and practical approach to benzocarbazole derivatives. Herein,
we report a novel and efficient copper-catalyzed synthesis of
benzocarbazoles via a-C-arylation of ketones.
Over the past decades, much attention has been paid to
transition metal-catalyzed arylation reactions of substrates
containing activated sp3-hybridized C–H bonds with aryl
halides and pseudohalides, in which the alkyl–aryl bonds are
formed at the a-position of electron-withdrawing groups
including keto, formyl, alkoxycarbonyl, cyano, nitro, sulfoximino,
and sulfonyl groups.1 Of the previous methods, palladium-catalyzed
a-C-arylations are very efficient and commonly used,2 and this
strategy has been applied to the synthesis of cyclic compounds.3
However, palladium-catalyzed methods need expensive Pd
catalysts, and often employ expensive, patented phosphine
ligands. Although nickel-catalyzed a-C-arylations are also
effective, the high toxicity of Ni catalysts greatly limits their
use in industrial applications.4 Recently copper catalysts have
become popular and widely used due to their low cost and low
toxicity, and great achievements have been made in this area.5
Copper-catalyzed a-C-arylations have been investigated,6 and
some heterocycles have been constructed using this strategy
by us7 and other groups.8 Unfortunately, copper-catalyzed
a-C-arylations were only effective for substrates bearing two
electron-withdrawing moieties linked at a methylene group,
and those containing one electron-withdrawing group did not
work. To the best of our knowledge, the copper-catalyzed
a-C-arylation of simple ketones has not been reported thus far.
Benzocarbazole derivatives show various biological functions
although they are rarely found as natural products. For example,
The reaction of 2-(2-bromophenyl)-1H-indole (1a) with aceto-
phenone (2a), leading to 6-phenyl-11H-benzo[a]carbazole (3a)
was used as the model to optimize conditions including the
catalysts, ligands, bases, solvents and temperature under a
nitrogen atmosphere. As shown in Table 1, six copper catalysts
were tested using L-proline as the ligand, Cs2CO3 as the base and
DMSO as the solvent at 80 1C (entries 1–6). CuBr exhibited the
highest activity (entry 4). No target product was observed in the
absence of a copper catalyst (entry 7). The effect of the solvent
was investigated (compare entries 4, 8–11), and DMSO was
found to be the most suitable (entry 4). Other ligands were
screened (entries 12–14), and they were inferior to L-proline. We
investigated other bases (entries 15–18), and Cs2CO3 provided
the highest yield (entry 4). The effect of reaction temperature was
also explored (compare entries 4, 19 and 20), and 80 1C was the
best choice (entry 4). The ratio of the substrates and Cs2CO3 was
investigated (entries 21–23), and the use of 2 equiv. of 2a and
2 equiv. of Cs2CO3 relative to 1a was optimal (entry 22). The
solvent was removed from the reaction mixture of entry 22 and
the residue was examined using inductively coupled plasma mass
spectroscopy (ICP-MS). Only trace amount of Ni (5 ppm), Pd
(o10 ppm), Rh (o10 ppm) and Ru (o10 ppm) were found,
eliminating the possibility of involvement of other transition
metals in the reaction.
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing, 100084, P. R. China.
E-mail: fuhua@mail.tsinghua.edu.cn; Fax: +86 10-62781695
b Key Laboratory of Pesticide Chemistry and Application, Department
of Applied Chemistry, College of Science, Ministry of Agriculture,
China Agricultural University, Beijing, 100193, P. R. China
c Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University, Shenzhen,
518057, P. R. China
w Electronic supplementary information (ESI) available: General pro-
cedure for synthesis, characterization data, and 1H and 13C NMR
spectra of compounds 3a–z. See DOI: 10.1039/c2cc36403d
As shown in Table 2, the substrate scope of the reaction was
investigated using substituted 2-(2-bromophenyl)-1H-indoles
and ketones under the optimized conditions, i.e. 10 mol%
CuBr as the catalyst, 20 mol% L-proline as the ligand, Cs2CO3
as the base and DMSO as the solvent at 80 1C under a nitrogen
atmosphere (minor changes to the conditions were made for
several substrates), and the examined substrates afforded
the products in moderate to excellent yields. For substituted
c
12210 Chem. Commun., 2012, 48, 12210–12212
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Table 2 Copper-catalyzed synthesis of 11H-benzo[a]carbazolesa
Table 1 Copper-catalyzed synthesis of 6-phenyl-11H-benzo[a]carbazole
(3a) via coupling of 2-(2-bromophenyl)-1H-indole (1a) with acetophenone
(2a): optimization of conditionsa
Entry Cat.
Ligand (mol%) Base
L-Proline
Solvent
Yieldb (%)
1
2
Cu
Cu2O L-Proline
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMF
Cs2CO3 NMP
45
60
61
63
62
60
0
3
4
5
CuCl
CuBr
CuI
L-Proline
L-Proline
L-Proline
3 (Yieldb)
6
CuCl2 L-Proline
7
—
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
DMEDA
1,10-phen
PCA
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
46
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cs2CO3 Toluene 16
Cs2CO3 Dioxane 38
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Na2CO3 DMSO
K2CO3
K3PO4
KOAc
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
44
53
57
12
45
45
Trace
10c
61d
71e
77f
73g
DMSO
DMSO
DMSO
a
Reaction conditions: nitrogen atmosphere, 2-(2-bromophenyl)-
1H-indole (1a) (0.5 mmol), acetophenone (2a) (0.75 mmol), catalyst
(0.05 mmol), ligand (0.1 mmol), base (1.5 mmol), solvent (2.0 mL),
b
c
reaction temperature 80 1C. Isolated yield. Reaction temperature
d
e
60 1C. Reaction temperature 100 1C. 2a (1.0 mmol), base
f
g
(1.5 mmol). 2a (1.0 mmol), base (1.0 mmol). 2a (1.0 mmol), base
(0.75 mmol). NMP = N-methylmorpholine. DMEDA = N,N-
dimethylethylenediamine. 1,10-phen = 1,10-phenanthroline. PCA =
piperidine-2-carboxylic acid.
2-(2-bromophenyl)-1H-indoles, in general, no significant
difference in reactivity was observed for the examined substrates
with varied electronic properties, including electron-rich, electron-
poor and neutral groups. For aromatic ketones, substrates
containing electron-withdrawing groups displayed higher reactivity
than those containing electron-donating and neutral groups.
For aliphatic ketones, cyclohexanone afforded higher yields than
propan-2-one, cyclopentanone and cycloheptanone. Substrates
with various functional groups were tolerated under the reaction
conditions, including ethers (3c, 3q and 3r), C–Cl bonds (3d–f, 3s,
3t, 3x–z), nitro (3g and 3h), CF3 (3i), nitrogen heterocycles (3a–z),
oxygen heterocycles (3j) and sulfur heterocycles (3k). Interestingly,
the indole NH group of 1 was retained in the reactions above.
We explored the mechanism of the copper-catalyzed synthesis
of 11H-benzo[a]carbazoles. Treatment of 2-(2-bromophenyl)-1-
methyl-1H-indole (1f) with acetophenone (2a) was investigated
under the standard conditions, and no reaction was observed
(Scheme 1a). Treatment of 2-phenyl-1H-indole (1g) with
acetophenone (2a) did not lead to 4 (Scheme 1b). In order to
compare the reactivity of aryl bromide (1a) and aryl iodide
(1h), the reaction temperature was decreased from 80 1C to
60 1C, and 1b provided higher yield than 1a (Scheme 1c).
a
Reaction conditions: nitrogen atmosphere,
1 (0.5 mmol), 2
(1.0 mmol), CuI (0.05 mmol) for 3n; CuBr (0.05 mmol) for other
compounds, L-proline (0.1 mmol), K2CO3 (1.0 mmol) for 3g and 3h;
Cs2CO3 (1.0 mmol) for other compounds, DMF (2.0 mL) for 3s;
DMSO (2.0 mL) for other compounds, temperature (90 1C for 3s;
b
80 1C for other compounds), reaction time 24 h. Isolated yield.
This result shows that the domino reaction could start from
C-arylation of ketones in the synthesis of 11H-benzo[a]-
carbazoles. Therefore, a possible mechanism for the copper-
catalyzed synthesis of 11H-benzo[a]carbazoles is proposed in
Scheme 2. Treatment of 1 with CuBr (or CuI) and a ligand in
the presence of Cs2CO3 (or K2CO3) provides I, and oxidative
addition of I leads to II. In the presence of base, coordination
c
This journal is The Royal Society of Chemistry 2012
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Notes and references
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´
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Scheme 1 (a) Treatment of 2-(2-bromophenyl)-1-methyl-1H-indole
(1f) with 2a. (b) Treatment of 2-phenyl-1H-indole (1g) with 2a. (c)
Reaction of 2-(2-bromophenyl)-1H-indole (1a) or 2-(2-iodophenyl)-
1H-indole (1h) with 2a at 60 1C.
Scheme 2 Possible mechanism for the synthesis of 11H-benzo[a]-
carbazoles.
7 Copper-catalyzed synthesis of N-heterocycles, see: (a) F. Wang,
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of II to the ketone affords III, and reductive elimination
of III (C-arylation) gives IV, regenerating the copper catalyst.
Isomerization of IV provides V, and intramolecular nucleophilic
attack leads to VI. Finally, dehydration and isomerization of the
CQN bond to a CQC bond gives the target product (3) in the
presence of CsHCO3.
In conclusion, we have developed a simple and efficient
copper-catalyzed method for the synthesis of 11H-benzo[a]-
carbazoles. The protocol uses readily available substituted
2-(2-bromophenyl)-1H-indoles and ketones as starting materials,
CuBr or CuI as the catalyst, L-proline as the ligand, Cs2CO3 or
K2CO3 as the base, and DMSO or DMF as the solvent,
and 11H-benzo[a]carbazoles were obtained in moderate to
excellent yields. The method could tolerate various functional
groups in the substrates. This is the first example of copper-
catalyzed C-arylation of ketones and construction of cyclic
compounds using this strategy thus far. Therefore, this
method will find many applications in organic chemistry and
medicinal chemistry.
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The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 20972083 and 21172128),
the Ministry of Science and Technology of China (Grant Nos.
2012CB722605, 2010CB126104 and 2011BAE06B05) and the
Chinese Universities Scientific Fund (2012YJ132) for financial
support.
c
12212 Chem. Commun., 2012, 48, 12210–12212
This journal is The Royal Society of Chemistry 2012