Synthesis of pyrido[1,2-a]benzimidazoles through a copper-catalyzed cascade C-N coupling process

Article abstract of DOI:10.1002/ejoc.201100834

A simple and efficient method for the preparation ofpyrido[1,2-a] benzimidazoles by a copper-catalyzed inter-and intramolecular C-N coupling cascade process was designed and carried out, and the products were obtained in moderate to excellent yields (up to 93 %).

Full text of DOI:10.1002/ejoc.201100834

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100834
Synthesis of Pyrido[1,2-a]benzimidazoles through a Copper-Catalyzed Cascade
C–N Coupling Process
Zhiqing Wu,[a] Qing Huang,[a] Xiangge Zhou,*[a] Lintao Yu,[a] Zhengkai Li,[a] and Di Wu*[a]
Keywords: Copper / Cross-coupling / Heterocycles / Domino reactions / Cyclization
A
simple and efficient method for the preparation of
signed and carried out, and the products were obtained in
moderate to excellent yields (up to 93%).
pyrido[1,2-a]benzimidazoles by a copper-catalyzed inter-
and intramolecular C–N coupling cascade process was de-
pyrido[1,2-a]benzimidazole derivatives through a copper-
catalyzed inter- and intramolecular C–N coupling cascade
process starting from readily available 2-haloanilines and 2-
halopyridines.
It is well known that aryl halides with electron-with-
drawing groups usually react faster than those with elec-
tron-donating groups in Ullmann-type reactions. Thus, we
surmise that 2-haloanilines 1 can couple exclusively with 2-
halopyridines 2 due to the electron-deficient nature of the
pyridine ring; subsequent isomerization of intermediate 3
into 4 followed by intramolecular C–N coupling would af-
ford desired product 5 as show in Scheme 1.[9]
Introduction
Pyrido[1,2-a]benzimidazoles are key core structures in a
wide range of bioactive molecules such as antifungal A,[1]
antitumor B,[2] and antiviral agent C (Figure 1).[3] Tradi-
tionally, these types of compounds are synthesized by the
condensation of benzimidazole-2-acetonitrile with β-keto
esters, which usually suffers from a tedious multistep se-
quence and limited variability in the precursor.[1] As an al-
ternative approach, a one-pot, four-component procedure
was developed recently, but its application was limited due
to low selectivity and yield.[4] Very recently, Zhu and co-
workers reported an elegant intramolecular C–H amination
protocol.[5] However, it is still highly desirable to develop
straightforward and general methods to further improve the
synthetic efficiency.
Scheme 1. Proposed procedure for the synthesis of pyrido[1,2-a]-
benzimidazoles.
Figure 1. Biologically active pyrido[1,2-a]benzimidazoles.
Over the past decade, great progress has been made in
copper-catalyzed Ullmann-type cross-coupling reactions,
and this reaction has been successfully extended to the syn-
thesis of various N-heterocycles through the use of tandem
strategies.[6,7] In continuation of our efforts in copper-cata-
lyzed Ullmann-type reactions,[8] herein is reported a simple,
practical, and efficient strategy for the construction of
Results and Discussion
To verify this hypothesis, 2-iodoaniline and 2-iodopyrid-
ine were selected as the model substrates as indicated in
Table 1. Gratifyingly, the substrates were transformed into
the desired product in 27% yield in the presence of CuI
(20 mol-%) at 120 °C (Table 1, Entry 1). Several ligands
were then tested, and 1,10-phenanthroline proved to be the
most effective, affording the product in 58% yield (Table 1,
Entries 2–6). Screening of the bases suggested that Cs2CO3
was optimal (Table 1, Entries 6–8). Solvent is another im-
[a] Institute of Homogeneous Catalysis,
College of Chemistry, Sichuan University,
Chengdu 610064, China
Fax: +86-28-85412026
E-mail: zhouxiangge@scu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100834.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5242–5245

Copper-Catalyzed Synthesis of Pyrido[1,2-a]benzimidazoles
portant factor affecting catalysis. Both xylene and toluene Meanwhile, sterically hindered 4,6-dimethyl-2-iodoaniline
were highly efficient for the catalysis, giving the product in afforded the product in a much lower yield of 39% (Table 2,
91% and 90% yield, respectively (Table 1, Entries 10 & 11). Entry 6). Furthermore, 2-bromoanilines were also found to
Further investigation revealed that 12 h was enough for the be applicable to this reaction, although a longer reaction
reaction to go to completion (Table 1, Entry 12). When the time of 24 h was required to give the products in moderate
reaction time was decreased to 6 h, the yield dropped to to good yields ranging from 53 to 93% (Table 2, Entries 1–
77% (Table 1, Entry 13). Furthermore, a low temperature 4, 7, 8).
slowed the reaction rate. Only 65% yield was obtained when
the reaction was carried out at 100 °C (Table 1, Entry 14).
Reducing the loading of the CuI catalyst to 10 mol-%
Table 2. Copper-catalyzed coupling of various substituted 2-
haloanilines with 2-iodopyridine.[a]
caused the reaction yield to drop to 70% (Table 1, En-
try 15).
Table 1. Copper-catalyzed coupling of 2-iodoaniline with 2-iodo-
pyridine under different reaction conditions.[a]
Entry
Ligand
Base
Solvent
Time [h] % Yield[b]
1
2
3
4
5
6
7
8
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
xylene
xylene
xylene
xylene
xylene
24
24
24
24
24
24
24
24
24
24
24
12
6
27
10
12
13
48
58
24
66
60
90
91
90
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
9
10
11
12
13
14
15
77
12
12
65[c]
70[d]
[a] Reaction conditions: 2-iodoaniline (0.25 mmol), 2-iodopyridine
(0.3 mmol), base (0.75 mmol), CuI (0.05 mmol), ligand (0.1 mmol),
solvent (0.5 mL), N2 atmosphere, 120 °C. [b] Isolated yield.
[c] 100 °C. [d] CuI (0.025 mmol), ligand (0.05 mmol).
[a] Reaction conditions: 2-haloaniline (0.25 mmol), 2-iodopyridine
(0.3 mmol), base (0.75 mmol), CuI (0.05 mmol), 1,10-phen-
anthroline (0.1 mmol), solvent (0.5 mL), N2 atmosphere, 12 h for 2-
iodoaniline and 24 h for 2-bromoaniline, 120 °C. [b] Isolated yield.
With the optimal reaction conditions established, we
tried to investigate the scope of this new protocol. First,
differently substituted 2-iodoanilines were examined and
treated with 2-iodopyridine. As shown in Table 2, steric hin-
drance of the substituents on the phenyl ring exhibited a
Then, various substituted 2-halopyridines were tested in
greater effect than the electronic properties. For example, this copper-catalyzed tandem process as shown in Table 3.
para-substituted 2-iodoanilines containing either electron- To our delight, almost of the 2-bromopyridines and 2-iodo-
rich or electron-deficient substituents worked well to give pyridines bearing electron-withdrawing or electron-donat-
the corresponding products in good to excellent yields rang- ing groups were able to react with 2-bromoaniline smoothly
ing from 85 to 91%. meta-Chloroiodoaniline also reacted to afford the corresponding products (Table 3, Entries 2–
to form the desired product in 89% yield (Table 2, Entry 5). 8). Generally, 2-bromopyridines gave lower yields than 2-
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Z. Wu, Q. Huang, X. Zhou, L. Yu, Z. Li, D. Wu
SHORT COMMUNICATION
iodopyridines, which might be caused by the low reactivity
of 2-bromopyridines in this catalytic system. Sterically hin-
dered 6-methyl-2-bromopyridine was also coupled with 2-
bromoaniline, though only 25% yield was obtained
(Table 3, Entry 6).
Scheme 2. Synthesis of benzimidazo[2,1-b]benzothiazole.
Table 3. Copper-catalyzed coupling of various substituted 2-halo-
pyridines with 2-bromoaniline.[a]
Conclusions
In summary, we have designed a simple and efficient
method for the preparation of pyrido[1,2-a]benzimidazoles
through a copper-catalyzed inter- and intramolecular C–N
coupling cascade process. A wide range of functional
groups were well tolerated under the reaction conditions,
and a series of pyrido[1,2-a]benzimidazoles with substitu-
ents at different positions were generated in moderate to
excellent yields. Considering the low cost of the catalytic
system and the starting materials, this strategy will thus be
highly useful in organic and medicinal chemistry.
Experimental Section
Typical Procedure for the Catalysis: An oven-dried Schlenk tube
was charged with 2-iodoaniline (0.25 mmol, 54.8 mg), Cs2CO3
(0.75 mmol, 244.4 mg), CuI (0.05 mmol, 9.5 mg), and 1,10-phenan-
throline (0.1 mmol, 18 mg). The tube was evacuated and backfilled
with N2, and then 2-iodopyridine (0.3 mmol, 61.5 mg) and xylene
(0.5 mL) was added. The reaction mixture was stirred at 120 °C for
12 h and then allowed to cool to room temperature. The mixture
was diluted with water and extracted with ethyl acetate. The ex-
tracts were combined and then dried with anhydrous Na2SO4. The
solvent was removed under vacuum, and the residue was purified
by silica gel column chromatography to afford the corresponding
product (37.8 mg).
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, characterization
data, and copies of the NMR spectra.
Acknowledgments
We acknowledge the National Natural Science Foundation of
China (Nos. 20901052, 21072132), Sichuan Provincial Foundation
(08ZQ026-041), and Ministry of Education (NCET-10-0581) for
financial support and the Analytical & Testing Centre of Sichuan
University for NMR spectroscopic analysis.
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[a] Reaction conditions: 2-bromoaniline (0.25 mmol), 2-halopyrid-
ine (0.3 mmol), base (0.75 mmol), CuI (0.05 mmol), 1,10-phen-
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reaction of 2-iodobenzothiazole with 2-iodoaniline to af-
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chemical building block in organic and biological chemis-
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ing product could be obtained.
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Eur. J. Org. Chem. 2011, 5242–5245

Copper-Catalyzed Synthesis of Pyrido[1,2-a]benzimidazoles
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Received: June 9, 2011
Published Online: August 18, 2011
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www.eurjoc.org
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