Copper-catalyzed N-arylation and aerobic oxidative C-H/C-H coupling: One-pot synthesis of indoloimidazoquinoline derivatives

Article abstract of DOI:10.1039/c3ra40999f

A novel and efficient copper-catalyzed one-pot synthesis of indoloimidazoquinoline derivatives has been developed. The protocol uses the readily available substituted 2-(2-bromophenyl)-1H-indoles, imidazole and benzoimidazoles as the starting materials, inexpensive CuBr as the catalyst, air as the terminal oxidant, and the procedure underwent a sequential copper-catalyzed intermolecular N-arylation and an aerobic oxidative intramolecular C-H/C-H coupling.

Full text of DOI:10.1039/c3ra40999f

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Copper-catalyzed N-arylation and aerobic oxidative C–
H/C–H coupling: one-pot synthesis of
Cite this: DOI: 10.1039/c3ra40999f
indoloimidazoquinoline derivatives3
Meng Wang,ab Yunhe Jin,a Haijun Yang,a Hua Fu*ac and Liming Hu*b
Received 27th February 2013,
Accepted 10th April 2013
DOI: 10.1039/c3ra40999f
www.rsc.org/advances
A novel and efficient copper-catalyzed one-pot synthesis of
indoloimidazoquinoline derivatives has been developed. The
protocol uses the readily available substituted 2-(2-bromophe-
nyl)-1H-indoles, imidazole and benzoimidazoles as the starting
materials, inexpensive CuBr as the catalyst, air as the terminal
oxidant, and the procedure underwent a sequential copper-
catalyzed intermolecular N-arylation and an aerobic oxidative
intramolecular C–H/C–H coupling.
On the other hand, indole derivatives are used as receptor
antagonists,13a,b antihypertensive13c and antibiotic angents.13d
Imidazoquinoline derivatives also show a wide range of biological
activities.14 For example, they are used as anxiolytic,15a antifungal/
antibacterial,15b antineoplastic,15c anticancer agents,15d and as
DNA intercalators.15e However, the synthesis and biological
function of N-fused heterocycles of indole and imidazoquinoline
motifs and indoloimidazoquinolines (Fig. 1), have not been
reported thus far. In this communication, we report a novel and
efficient method for the synthesis of indoloimidazoquinoline
derivatives through a sequential copper-catalyzed N-arylation and
aerobic oxidative C–H/C–H coupling. As shown in Fig. 1, our
strategy for the copper-catalyzed one-pot synthesis of indoloimi-
dazoquinolines is divided into the following two-step process: the
copper-catalyzed N-arylation of imidazole derivatives with 2-(2-
bromophenyl)-1H-indoles under a nitrogen atmosphere, and an
aerobic oxidative intramolecular C–H/C–H coupling, leading to the
target products.
The synthesis of nitrogen heterocycles is an important goal in
organic synthesis because they occur widely in various natural
products and biologically active molecules,1 and have been
assigned as privileged structures in drug development.2 The
traditional methods for the synthesis of N-heterocycles usually
need precursors with the appropriate functional groups. Recently,
there have been great advances in C–H functionalization3 that
make it possible and economical for the construction of
N-heterocycles through C–H functionalization. For example
carbazoles,4 indazoles,5 N-methoxylactams,6 benzimidazoles,7
and indolines,8 were synthesized by the transition metal-catalyzed
aerobic oxidation of C–H bonds using molecular oxygen as the
oxidant,9 for which expensive palladium-, rhodium-, and ruthe-
nium-based catalysts are usually required. During the past decade,
copper-catalyzed cross-coupling reactions have attracted attention
because of the low cost and the low toxicity of the copper-
catalysts,10 and some efficient syntheses of heterocycles through
copper-catalyzed aerobic oxidation have been developed by us11
and other groups.12 However, the synthesis of N-heterocycles via a
copper-catalyzed C–H/C–H coupling still remains limited.
At first, 2-(2-bromophenyl)-1H-indole (1a) and imidazole (2a)
were chosen as the model substrates to optimize the reaction
conditions including the catalysts, ligands, bases, solvents and
temperature for the N-arylation (the first step) and acids for the C–
H/C–H coupling (the second step). As shown in Table 1, the
N-arylation was performed by using CuBr as the catalyst,
aKey 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
bCollege of Life Sciences and Bioengineering, Beijing University of Technology, Beijing
100124, P. R. China. E-mail: huliming@bjut.edu.cn
cKey Laboratory of Chemical Biology (Guangdong Province), Graduate School of
Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
Electronic supplementary information (ESI) available: General procedure for
3
synthesis, characterization data, and 1H and 13C NMR spectra of compounds 3a–q.
Fig. 1 Our strategy for the copper-catalyzed one-pot synthesis of indoloimidazo-
quinoline derivatives (N-fused heterocycles of indole and imidazoquinoline motifs).
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Table 1 Copper-catalyzed one-pot reaction of 2-(2-bromophenyl)-1H-indole (1a) with imidazole (2a): optimization of conditionsa
Entry
Catalyst
Ligand
Base
Acid
Yield (3a) (%)b
Yield (3a9) (%)b
1
2
3
4
5
6
7
8
CuBr
CuBr
CuI
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
L-Proline
1,10-phen
PA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
—
3
4
9
9
5
15
5
8
Trace
3
4
10
11
3
Trace
7
9
PivOH
PivOH
PivOH
PivOH
PivOH
AcOH
TFA
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
78
54
15
73
44
75
Trace
24
45
77
80
16
Trace
66
73
CuCl
Cu2O
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
K3PO4
Cs2CO3
12
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
13
14c
15d
16e
17f
phen
phen
phen
phen
Trace
Trace
a
Reaction conditions: 2-(2-bromophenyl)-1H-indole (1a) (0.25 mmol), imidazole (2a) (0.5 mmol), catalyst (0.05 mmol), ligand (0.1 mmol), base
(0.5 mmol), DMSO for entries 1–15 (1.5 mL), acid (1.75 mmol), reaction temperature for entries 1–13, 16 and 17 (110 uC) under nitrogen
b
c
d
atmosphere for the first step, under air for the second step. Isolated yield. Reaction temperature (80 uC). Reaction temperature (130 uC).
e
f
Using N,N-dimethylformamide (DMF) (1.5 mL) as the solvent. Using 1,4-dioxane (1.5 mL) as the solvent. PivOH = pivalic acid. AcOH =
acetic acid. TFA = trifluoroacetic acid. DMEDA = dimethylethylenediamine. phen = 1,10-phenanthroline. PA = pipecolic acid.
dimethylethylenediamine (DMEDA) as the ligand and 2 equiva-
lents of Cs2CO3 as the base, in DMSO at 110 uC for 12 h under N2.
The C–H/C–H coupling was carried out at 110 uC for 12 h under air
without the addition of an acid, and the one-pot two-step reactions
provided a small amount of two products 3a and 3a9 (entry 1).
When 7 equivalents of pivalic acid was added for the second step
reaction, the yield of 3a increased to 78% with 3a9 (9% yield) also
isolated (entry 2). Other copper catalysts were tested, and they were
inferior to CuBr (versus entries 3–6). When acetic acid was used in
the second step, instead of pivalic acid, a 75% yield of 3a was
provided (entry 7). Only a trace amount of 3a was observed when
trifluoroacetic acid was added (entry 8). When K2CO3 and K3PO4
were used as the base in the first step N-arylation, lower yields
were observed (entries 9 and 10). L-Proline, 1,10-phenanthroline
and pipecolic acid were used as the ligands (entries 11–13), and
1,10-phenanthroline afforded the highest yield (compare entries 2
and 11–13). We varied the temperature, and 110 uC was suitable
(compare entries 12, 14 and 15). DMF (entry 16) or 1,4-dioxane
(entry 17) replaced DMSO as the solvent, and no better result was
found. Therefore, the optimal conditions for the copper-catalyzed
one-pot synthesis of indoloimidazoquinoline derivatives are as
follows: CuBr as the catalyst, 1,10-phenanthroline as the ligand
and Cs2CO3 as the base, in DMSO at 110 uC for 12 h under N2 for
the N-arylation (the first step); 7 equivalents of pivalic acid was used
in the resulting solution, at 110 uC for 12 h under air for the C–H/
C–H coupling (the second step).
As is shown in Table 2, the scope of the copper-catalyzed one-
pot synthesis of indoloimidazoquinoline derivatives was investi-
gated, and the substrates that were examined provided moderate
to good yields of products. For substituted 2-(2-bromophenyl)-
1H-indoles (1a–1f), their various electronic characteristics did not
obviously affect the product yields. For substituted benzoimida-
zoles, the substrates containing electron-withdrawing groups
provided higher yields than those containing neutral, or
electron-donating groups. The reactions in Table 2 could tolerate
some functional groups, including an ether (3d, 3h, 3l–p), C–Cl
(3e, 3j–l and 3p), C–F bond (3q).
As is shown in Scheme 1, some control experiments were
performed in order to explore the reaction mechanism for the
synthesis of indoloimidazoquinoline derivatives. The copper-
catalyzed coupling of 2-(2-bromophenyl)-1H-indole (1a) with
imidazole (2a) under N2 provided the N-arylation product (Ia) in
a 91% yield (see Scheme 1A). We attempted the copper-catalyzed
aerobic oxidative intramolecular C–H/C–H coupling of isolated Ia
under various conditions (Scheme 1B). Only a trace amount of the
target product was observed in the absence of a copper-catalyst
(condition (I) in Scheme 1B). The copper-catalyzed reaction did not
work in the absence of pivalic acid (condition (II) in Scheme 1B). A
low yield (4%) was provided in the presence of pivalic acid
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Table 2 Copper-catalyzed one-pot synthesis of indoloimidazoquinoline deriva-
tives via a sequential N-arylation and aerobic oxidative C–H/C–H couplingab
Scheme 1 (A) Copper-catalyzed coupling of 2-(2-bromophenyl)-1H-indole (1a)
with imidazole (2a) under N2 leading to the N-arylation product (Ia); (B) copper-
catalyzed aerobic oxidative intramolecular C–H/C–H coupling of Ia under air
providing 3a under various conditions.
3 (Yield)
(condition (III) in Scheme 1B). When 0.4 equivalents of 1,10-phen
were added as the ligand, the yield increased to 45% (condition
(IV) in Scheme 1B). A high yield (80%) was obtained in the
presence of 0.5 equivalents of Cs2CO3 (condition (V) in
Scheme 1B). Therefore, a possible mechanism for the synthesis
of the indoloimidazoquinoline derivatives is suggested in
Scheme 2. The coupling of substituted 2-(2-bromophenyl)-
1H-indole (1) with imidazole derivative (2) initially affords the
N-arylation product (I) under copper catalysis. The coordination of
CuBr with the imidazole moiety in I gives complex II, and the
addition of the 3-CH in the indole group to the 29-C of the
imidazole provides III. The oxidation of III leads to the target
product (3), freeing the Cu(I) catalyst.
In summary, we have developed a novel, efficient and practical
copper-catalyzed one-pot method for the synthesis of indoloimi-
dazoquinoline derivatives. The protocol uses readily available
substituted 2-(2-bromophenyl)-1H-indoles and imidazoles as the
starting materials, cheap CuBr–1,10-phenanthroline as the catalyst
system, and economical and environmentally friendly air as the
terminal oxidant. The corresponding indoloimidazoquinoline
derivatives were prepared in moderate to good yields. The one-
pot two-step reactions underwent a sequential copper-catalyzed
Ullmann-type N-arylation and an aerobic oxidative C–H/C–H
coupling, and this convenient and efficient method for the
a
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), CuBr (0.05
mmol), 1,10-phen (0.1 mmol), Cs2CO3 (0.5 mmol), DMSO (1.5 mL),
pivalic acid (1.75 mmol) and reaction temperature 110 uC, (for both
the two-step reactions). Reaction time 12 h and under nitrogen
atmosphere for the first step; reaction time 12 h and under air for
Scheme 2 Possible mechanism for the copper-catalyzed synthesis of indoloimi-
dazoquinoline derivatives.
b
the second step. Isolated yield.
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Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21172128 and 21272020), the
Ministry of Science and Technology of China (Grant No.
2012CB722605), the National Basic Research Program of China
(Grant No. 2009CB930203) and the Doctoral Program of
Higher Education (No. 20090002110058) for financial support.
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