An efficient procedure for the synthesis of benzimidazole derivatives using Yb(OTf)3 as catalyst under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200039340

o-Diaminobenzene derivatives react smoothly with ortho-esters in the presence of 0.5 mol% of Yb(OTf)₃ under solvent-free conditions to afford the corresponding benzimidazole derivatives in good to excellent yields. In addition, Yb(OTf)₃ can be easily recovered almost quantitatively from the aqueous layer after the reaction was completed, and it could be reused with no loss of activity.

Full text of DOI:10.1081/SCC-200039340

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An Efficient Procedure for the
Synthesis of Benzimidazole
Derivatives Using Yb(OTf)3 as
Catalyst Under Solvent‐Free
Conditions
Limin Wang a , Jia Sheng a , He Tian a & Changtao
Qian b
a Institute of Fine Chemicals, East China University
of Science and Technology, 130 Meilong Lu,
Shanghai, 200237, P. R. China
b Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai, P. R. China
Version of record first published: 10 Jan 2011.
To cite this article: Limin Wang, Jia Sheng, He Tian & Changtao Qian (2004): An
Efficient Procedure for the Synthesis of Benzimidazole Derivatives Using Yb(OTf)3 as
Catalyst Under Solvent‐Free Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:23, 4265-4272
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4265–4272, 2004
An Efficient Procedure for the Synthesis of
Benzimidazole Derivatives Using Yb(OTf)3
as Catalyst Under Solvent-Free Conditions
1
1
2
Limin Wang,1, Jia Sheng, He Tian, and Changtao Qian
*
1Institute of Fine Chemicals, East China University of Science and
Technology, Shanghai, P. R. China
2Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, P. R. China
ABSTRACT
o-Diaminobenzene derivatives react smoothly with ortho-esters in the
presence of 0.5 mol% of Yb(OTf)3 under solvent-free conditions to
afford the corresponding benzimidazole derivatives in good to excellent
yields. In addition, Yb(OTf)3 can be easily recovered almost quantita-
tively from the aqueous layer after the reaction was completed, and it
could be reused with no loss of activity.
Key Words: Yb(OTf)3; Benzimidazole; Solvent-free reaction.
*
Correspondence: Limin Wang, Institute of Fine Chemicals, East China University of
Science and Technology, 130 Meilong Lu, Shanghai 200237, P. R. China; Tel. (fax): 86-
21-64252288, 64252758; E-mail: wanglimin@ecust.edu.cn or wcathy@china.com.
4265
DOI: 10.1081/SCC-200039340
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Wang et al.
INTRODUCTION
It is well known that benzimidazole is an important structural element in
medicinal chemistry, with a wide spectrum of pharmacological activities.[1]
Recently, bisbenzimidazoles are being developed as DNA minor-groove
binding agents with antitumor activity[2] and can act as ligands to transition
metals for modeling biological systems.[3] Conventional synthesis of benzimida-
zoles involved refluxing the reactants in aqueous hydrochloric acid for 30min[4a]
or in a slurry of the dehydrating agent, such as polyphosphoric acid, at 2508C
for 4 h,[4b] as the result of which generating abundant harmful waste to the
environment. New research has recently been applied to the preparation of this
sort of compound, including solid-phase[5] methods, a rapid microwave-assisted
liquid-phase combinatorial approach,[6] the strategy of palladium-catalyzed
intramolecular aryl-amination chemistry,[7,8] using high-temperature water[9]
as the medium and Montmorillonite KSF or K10[10] as the catalyst.
Over the past decade, many efforts have gone into developing rare
earth metal triflate, especially the Yb(OTf)3 and Sc(OTf)3 catalyzed organic
synthesis. As a new type of strong water-compatible Lewis acid, they have
been applied in a wide variety of reactions.[11] Only catalytic amounts of
them are effective enough to complete the reactions in most cases. Further-
more, RE(OTf)3 can be easily recovered and reused without any loss of
activity. As a continuation of our interest in lanthanide triflates catalyzed
reactions,[12] we wish to describe here a simple and convenient method
for the synthesis of benzimidazole derivatives from o-diaminobenzene
derivatives and ortho-esters using Yb(OTf)3 under solvent-free conditions.
RESULTS AND DISCUSSION
Initially, the mixture of 4-methylorthophenylenediamine (1b) and
triethyl orthoformate (2b), producing the 2,5-dimethylbenzimidazole (3b) in
solvent-free conditions (Scheme 1) were chosen as the model reaction to
determine whether the use of ytterbium triflate was efficient and to investigate
Scheme 1.

Benzimidazole
4267
the optimized conditions. The results are summarized in Table 1. Typical Lewis
acids, such as ZnCl2, AlCl3, SnCl2, and FeCl3, did not efficiently catalyze the
reaction, giving low yields at first use in a long-time-reaction. On the other
hand, to our delight, 1 mol% Yb(OTf)3 was found to effectively catalyze the
reaction. The expected product 2,5-dimethylbenzimidazole (3b) was obtained
in 92% yield (entry 7) after 1 h of stirring at 908C. We also examined other rare
earth metals salts [YbCl3, La(OTf)3], using them as potential catalysts, which
were also not as good as Yb(OTf)3. Considering that the amount of catalyst
can affect the reaction, we tried to change it from 0.1 mol% to 5 mol% and
found that 0.5 mol% was sufficient (entry 9). In addition, the catalyst could
be reused three times without showing any loss of activity (entry 12).
Establishing the advantages of Yb(OTf)3 as the catalyst, we continued
to optimize the condition by varying the solvent effect (Table 2). Although
C2H5OH was the best solvent among those tested, the best results were
obtained under solvent-free conditions.
To explore the generality of this reaction, we applied Yb(OTf)3 in
the reaction of various o-diaminobenzene derivatives (1) with several ortho-
esters (2) under optimized conditions (Scheme 2, Table 3). In general, when
the R represented the electron-withdrawing group such as nitro (entries 10,
11), the yield and purity of the product were obviously worse. In the case of
SO3H, no desired products were detected even after heating for 6 h (entry 13).
Table 1. The reaction of 4-methyl-1,2-phenylenediamine (1b) and triethyl ortho-
formate (2b) by various Lewis acids under solvent-free conditions.a
Amount of
catalyst (mol%)
Yield of
3b (%)b
Entry
Catalystc
Time (h)
1
2
ZnCl2
AlCl3
25
25
25
25
25
1.5
1
4
4
4
4
2
1
1
1
1
1
1
1
20
50
3
SnCl2
FeCl3
YbCl3
30
50
4
5
80
83
6
La(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
7
92
8
5
92
92
9
0.5
0.25
0.1
1
10
11
12
85
75
92, 90, 88
aRefluxed at 908C for 1–4 h under solvent-free conditions.
bIsolated yield.
cCatalyst was reused three times.

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Wang et al.
Table 2. Solvent effect on the reaction of 4-methyl-1,2-phenylene-
diamine (1b) and triethyl orthoformate (2b).
Entry
Solventa
Reaction time (h)
Yield of 3b (%)c
1
2
3
4
5
6
7
C2H5OH
CH3CN
EtOAc
2
2
2
2
2
2
1
80
70
40
30
C2H5OC2H5
CH2Cl2
THF
Noneb
20
Trace
92
aRefluxed for 2 h.
b908C for 1 h.
cIsolated yield.
The substituents R1 and R2 in ortho-ester had no influence on the reaction
course. We also found that the reaction of o-aminophenol with triethyl ortho-
formate proceeded rapidly under the same reaction conditions to afford the
corresponding benzoxazole (3k) in good yield (entry 14).
In summary, it can be concluded that Yb(OTf)3 is an efficient catalyst in the
reactions of o-diaminobenzene derivatives and ortho-esters to afford the benzi-
midazole derivates in good to excellent yields under solvent-free conditions
in short reaction times. In contrast to the existing methods using many acidic
catalysts, this method is general, simple, high yielding and environmentally
friendly, avoiding the discharge of toxic volatile solvents and protic acids.
EXPERIMENTAL
1H NMR spectra were recorded at 500 MHz in CDCl3 or DMSO-d6 using
TMS as internal reference. Mass spectra were determined on Finigan 8230
mass spectrometer.
Scheme 2.

Benzimidazole
4269
Table 3. Yb(OTf)3-catalyzed synthesis of benzimidazole and other heterocycle
derivatives under solvent-free conditions.a
Time
(h)
Entry
R
R1
R2
Product
Yield (%)b
1
2
H
H
H
H
C2H5
C2H5
C2H5
CH3
1
3a
3b
3c
80
40
88
92
92
90
90
88
80
75
75
90
CH3
C2H5
H
1
3
1
4
CH3
CH3
CH3
CH3
CH3
Cl
1
3d
3d
3e
5
H
C2H5
CH3
1
6
CH3
CH3
C2H5
H
1
7
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
1
3e
3f
8
1
9
2
3g
3h
3i
10
11
12
13
14
NO2
NO2
OCH3
SO3H
H
H
2
CH3
H
2
1
3j
H
6
1.5
None
3k
H
80
a908C for 1 h.
bIsolated yield.
Yb(OTf)3 Catalyzed Synthesis of Benzimidazole Derivates
Under Solventless Conditions
o-Diaminobenzene derivatives (1 mmol), ortho-esters (1.2 mmol), and
Yb(OTf)3 (0.005 mmol, 0.5 mol%) were mixed. The mixture was stirred for
1 h at 908C. Thin-layer chromatography (TLC) showed that the initial
materials almost disappeared. Then, water was added, and the product was
extracted with ethyl acetate. The organic layer was dried (Na2SO4) and eva-
porated, and the crude was recrystallized from diethyl ether to obtain products
3. The catalyst remaining in the aqueous phase can be recovered by removing
the H2O by evaporation and then drying under reduced pressure at 1008C for
2 h. The following compounds were obtained:
Benzimidazole (3a): m.p. 171–1728C (lit.[1] 172–1738C); 1H NMR
(CDCl3): d ¼ 8.10 (s, 1H), 7.67–7.70 (m, 2H), 7.29–7.32 (m, 2H).
1
2-Methylbenzimidazole (3b): m.p. 176–1778C (lit.[1] 176–1788C); H
NMR (CDCl3): d ¼ 7.53–7.55 (m, 2H), 7.19–7.22 (m, 2H), 2.62
(s, 3H).

4270
Wang et al.
1
2-Ethylbenzimidazole (3c): m.p. 175–1768C (lit.[4a] 1778C); H NMR
(CDCl3): d ¼ 7.54–7.56 (m, 2H), 7.19–7.23 (m, 2H), 2.92–2.96
(q, 2H, J ¼ 7.6 Hz), 1.47 (t, 3H, J ¼ 7.6 Hz).
5-Methylbenzimidazole (3d): m.p. 115–1168C (lit.[13] 116–1188C);
1H NMR (CDCl3): d ¼ 12.49 (s, 1H), 8.12 (s, 1H), 7.58 (d, 1H,
J ¼ 8.2 Hz), 7.48 (s, 1H), 7.12 (d, 2H, J ¼ 8.2 Hz), 2.46 (s, 3H).
2,5-Dimethylbenzimidazole (3e): m.p. 201–2038C (lit.[14] 203–2048C);
1H NMR (CDCl3): d ¼ 7.43 (d, 1H, J ¼ 8.1 Hz), 7.33 (s, 1H), 7.48
(s, 1H), 7.06 (d, 1H, J ¼ 8.1 Hz), 2.63 (s, 3H), 2.42 (s, 3H). MS-EI:
m/z (%): 146 (M, 98), 131 (10).
2-Ethyl-5-methylbenzimidazole (3f): m.p. 163–1648C (lit.[15] 168–
1698C); 1H NMR (CDCl3): d ¼ 7.44 (d, 1H, J ¼ 8.2 Hz), 7.32
(s, 1H), 7.04 (d, 1H, J ¼ 8.2 Hz), 2.95 (q, 2H, J ¼ 7.6 Hz), 2.45
(s, 3H), 1.14 (t, 3H, J ¼ 7.6 Hz); MS-EI: m/z (%): 159 (M, 100),
145 (18).
1
5-Chlorobenzimidazole (3g): m.p. 124–1258C (lit.[1] 125–1268C); H
NMR (CDCl3): d ¼ 8.47 (s, 1H), 7.76 (s, 1H), 7.67 (d, 1H,
J ¼ 8.7 Hz), 7.29 (d, 1H, J ¼ 8.7 Hz).
1
5-Nitrobenzimidazole (3h): m.p. 206–2088C (lit.[16] 203–2058C); H
NMR (DMSO-d6): d ¼ 8.56 (s, 1H), 8.51 (s, 1H), 8.11 (d, 1H,
J ¼ 8.9 Hz), 7.76 (d, 1H, J ¼ 8.9 Hz).
2-Methyl-5-nitrobenzimidazole (3i): m.p. 218–2218C (lit.[16] 220–
2218C); 1H NMR (DMSO-d6): d ¼ 8.38 (s, 1H), 8.08 (d, 1H,
J ¼ 8.9 Hz), 7.65 (d, 1H, J ¼ 8.9 Hz), 2.58 (s, 3H).
5-Methoxybenzimidazole (3j): m.p. 123–1248C (lit.[13] 123–1248C);
1H NMR (CDCl3): d ¼ 8.26 (s, 1H), 7.58 (d, 1H, J ¼ 8.3 Hz), 7.22
(s, 1H), 6.91 (d, 1H, J ¼ 8.3 Hz), 3.80 (s, 3H).
Benzoxazole (3k): m.p. 30–318C (lit.[17] 308C); 1H NMR (CDCl3):
d ¼ 8.42 (s, 1H), 7.77 (d, 1H, J ¼ 8.2 Hz), 7.70 (d, 1H, J ¼ 8.3 Hz),
7.41 (m, 2H).
ACKNOWLEDGMENT
We thank the National Nature Science Foundation of China and the
Science Foundation of East China University of Science and Technology
for their financial support.

Benzimidazole
4271
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