Synthesis of 2-arylbenzimidazoles in microfluidic chip reactor

Article abstract of DOI:10.3987/COM-12-S(N)61

A simple and efficient continuous flow synthesis of 2-arylbenzimidazoles from phenylenediamines and aromatic aldehydes in the presence of iodobenzene diacetate (IBD) has been developed by using a microfluidic chip reactor system. Various substituted 2-ary

Full text of DOI:10.3987/COM-12-S(N)61

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HETEROCYCLES, Vol. 86, No. 1, 2012
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HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 777 - 783. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2012, Accepted, 3rd August, 2012, Published online, 13th August, 2012
DOI: 10.3987/COM-12-S(N)61
SYNTHESIS OF 2-ARYLBENZIMIDAZOLES IN MICROFLUIDIC CHIP
REACTOR
Ming Lei,1,2* Wei Li,1 Ruijun Hu,1 Wan Tian,1 Yanguang Wang,1 and Hong
Zhang2,3*
1 Department of Chemistry, Zhejiang University, Hangzhou 310027, China. 2 Key
Laboratory of Medical Molecular Imaging of Zhejiang Province, Zhejiang
3
University Medical PET Centre, Hangzhou 310009, China. Department of
Nuclear Medicine, Second Affiliated Hospital of Zhejiang University, School of
Medicine, Hangzhou 310009, China. E-mail: leiming@zju.edu.cn
Abstract
–
A
simple and efficient continuous flow synthesis of
2-arylbenzimidazoles from phenylenediamines and aromatic aldehydes in the
presence of iodobenzene diacetate (IBD) has been developed by using a
microfluidic chip reactor system. Various substituted 2-arylbenzimidazoles were
obtained in high yields within 3 min under mild conditions. Compared with the
classical batch systems, the present smooth procedure is highly selective due to
the enhanced thermal and mass transfer.
Benzimidazole is a very useful building block not only in the pharmaceutical science but also in several
other fields such as agricultural, electronic, and polymer chemistry. Various substituted benzimidazole
derivatives have been shown to exhibit versatile bioactivities and have found applications in diverse
therapeutic and biological areas.1 The widespread interest in benzimidazole-containing structures has
prompted extensive studies of benzimidazole derivative libraries and screen them for their various
biological activities including antiulcer, antihypertensive, antiviral, antifungal, anticancer, anthelmintic,
antiprotozoal, analgesic, anxiolytic, antiallergic, hormone antagonist, antidiabetic and antihistaminic,
coagulant, anticoagulant, as well antioxidant activities.2
Combinatorial chemistry as a high-throughput synthetic technology has become a powerful tool for the
discovery of new drugs and increasing interests have been drawn onto the application of microfluidic
chips in this field.3 Automated microreactor-based (microfluidic chip) continuous flow systems have the
Dedicated with respect to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 1, 2012
potential to greatly accelerate the production of small molecule libraries of drug-like structures (primarily
heterocycles).4 In comparison with the classical batch systems, continuous microfluidic based reactors
need less space, energy and reagents, and can offer many advantages including enhanced reagent mixing,
small reaction volumes, precise parameter control, higher reproducibility, and enhanced selectivity in
short reaction time but produce less wastes because of its short diffusion distance, large specific surface
area, which could increase the thermal and mass transfer.
In general, there are two methods for the synthesis of 2-substituted benzimidazoles. One is the coupling
of phenylenediamines and carboxylic acids5 or their derivatives (nitriles, imidates, or orthoesters),6 which
often under strong acidic conditions, sometimes combined with very high temperatures or the using of
microwave irradiation technique.6c The other method involves a two-step procedure that includes the
oxidative cyclodehydrogenation of aniline Schiff’s bases, which are generated in situ from the
condensation of phenylenediamines and aldehydes. In this transformation, various oxidants such as
oxone,7 Pb(OAc)4,8 benzofuroxan,9 nitrobenzene,10 MnO2,11 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ),12 oxone,13 1,4-benzoquinone,14 Na2S2O5,15 NaHSO3,16 and oxygen17 have been employed. In
recent year, Wang18 and Du19 have developed a one-pot synthesis of 2-arylbenzimidazoles from
phenylenediamines and aromatic aldehydes in the presence of iodobenzene diacetate (IBD) as an oxidant
in which vigorous stirring is crucial for increasing the thermal and mass transfer. We envisaged that in
continuous flow system this exothermic transformation would carry out more efficiently than in batch
system by taking the advantage of excellent mixing. Our group had previously demonstrated the use of
microfluidic chip reactors to achieve selective acylation of ferrocene.20 Compared with the classical batch
systems, the method is rapid and highly selective due to the accurate temperature control and efficient
mixing. More recently, we have developed a three-component 1,4-dipolar cycloaddition cascade approach
for the synthesis of 2-(trifluoromethyl)-2H-[1,3]oxazino[2,3-a]isoquinolines in a continuous flow
microreactor in which excellent mixing associated with microflow technique eliminated the formation of
the corresponding byproduct and ensured the desired tandem transformation with very high selectivity
and efficiency.21 As part of our ongoing research to develop new synthetic methods for the generation of
heterocycle libraries based on microfluidic reactor, we herein report the microfluidic chip synthesis of
2-arylbenzimidazole derivatives.
Our reactor is a microfluidic chip fabricated in soda-lime glass with channels produced by standard
photolithography and wet etching techniques.22 The internal geometry of the microfluidic chip is 500 µm
× 100 µm × 1000 mm. The structure of the chip is illustrated in Scheme 1. PTFE tubing (inner diameter
ID = 0.9 mm) was fitted to the inlet and outlet hole directly. The end of inlet tube was connected to a
Harvard PHD 2000 syringe pump and the end of outlet tube was connected to a sample vial, which was
used to collect the final solution.

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HETEROCYCLES, Vol. 86, No. 1, 2012
779
NH2
NH2
O
+
H
Ph
in EtOH
N
Ph
N
H
IBD in EtOH
Scheme 1
Table 1. Synthesis of 2-Phenylbenzimidazole in microfluidic chip at different flow rates and temperature
Yield(%)b
30 oC
Flow rate
Entry
Residence time (s)a
20 oC
35 oC
(μL/min)
1
2
3
4
5
6
7
8
7.5
10
347
260
209
173
130
105
87
84
85
89
92
87
79
72
63
86
88
92
86
87
89
92
88
12.5
15
20
25
30
40
65
a Average time of three runs; b Isolated yield.
We first investigated adapting the model reaction into a continuous flow process for the synthesis of
2-phenylbenzimidazole using o-phenylenediamine and benzaldehyde in the presence of IBD at different
o
flow rates and temperatures. Preliminary test were performed at 20 C. The ethanol solution of
o-phenylenediamine (0.03 M) mixed with benzaldehyde (0.03 M) and the ethanol solution containing
IBD (0.045 M) were introduced respectively through syringe pump at identical flow rates changed from
7.5 μL/min to 40 μL/min. The results are summarized in Table 1. When the flow rates were respectively
set up at 7.5, 10, 12.5 and 15 μL/min, the yields of 2-arylbenzimidazole increased from 84% to 92% with
the increase of flow rate and reached a peak at 15 L/min flow rate (Table 1, entries 1–4). While further
increasing the flow rate led to decrease of the yields (Table 1, entries 5–8). At 30 oC and 35 oC, when flow
rates set up at 10, 12.5, 15, 20 μL/min respectively, the reactions afforded the yields between 86% and
92% (Table 1, entries 2–5). In general, at 15 μL/min flow rate, the reaction could afford best yield.

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HETEROCYCLES, Vol. 86, No. 1, 2012
Table 2. Synthesis of 2-arylbenzimidazoles in microfluidic chip
microfluidic chip
1.5 equiv IBD
N
NH2
NH2
O
Ar
R
R
+
N
H
H
Ar
EtOH, rt
1a-1l
Entry
R
Ar
Product
Yield(%)a
1
2
H
H
Ph
2-MePh
4-MeOPh
4-EtPh
2-ClPh
4-ClPh
4-BrPh
4-FPh
1a
1b
1c
1d
1e
1f
92
85
87
90
91
92
92
93
91
88
87
88
3
H
4
H
5
H
6
H
7
H
1g
1h
1i
8
H
9
Me
MeO
H
Ph
10
11
12
Ph
1j
2-Furyl
2-thiophene
1k
1l
H
a Isolated yield.
Subsequently, a series of 2-arylbenzimidazole derivatives were synthesized to investigate the scope and
limitation of this reaction using the optimized microfluidic chip procedure.23 As shown in Table 2, both
electron-rich and electron-deficient benzaldehydes could afford 2-arylbenzimidazoles in good to excellent
yields (Table 2, entries 1–10). Heteroaryl aldehydes such as 2-furyl and 2-thiophenecarboxaldehydes also
gave good yields (Table 2, entries 11–12). In comparison, when perform the reaction in batch system,
vigorous stirring is crucial for high yield. Otherwise the exothermic reaction would generate colored
impurity. It is noteworthy that in microfluidic chip the reactions completed smoothly within 3 minutes.
Moreover, by-product was not observed in all cases taking the advantage of enhanced thermal and mass
transfer.
In conclusion, we have successfully developed a rapid and efficient process for the synthesis of
2-arylbenzimidazole derivatives using microfluidic chip as the reactor. Under the optimized conditions, a
series of 2-arylbenzimidazole derivatives were synthesized in 85–93% isolated yields. This process was
also applied to similar reactions using heteroaryl aldehydes as the substrates. Compared with the classical
batch systems, the present smooth procedure afforded highly selective due to the excellent mixing. These