Aqueous synthesis of 1-H-2-substituted benzimidazoles via transition-metal-free intramolecular amination of aryl iodides

Article abstract of DOI:10.3390/molecules171112506

A straightforward method has been developed for the synthesis of the benzimidazole ring system through a carbon-nitrogen cross-coupling reaction. In the presence of 2.0 equiv. of K₂CO₃ in water at 100 °C for 30 h, the intramolecular cyclization of N-(2-iodoaryl)benzamidine provides benzimidazole derivatives in moderate to high yields. Remarkably, the procedure occurs exclusively in water and doesn't require the use of any additional reagent/catalyst, rendering the methodology highly valuable from both environmental and economical points of view.

Full text of DOI:10.3390/molecules171112506

Molecules 2012, 17, 12506-12520; doi:10.3390/molecules171112506
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Aqueous Synthesis of 1-H-2-Substituted Benzimidazoles via
Transition-Metal-Free Intramolecular Amination of Aryl Iodides
1
,2
1
1,2,
1
1,
Chunxia Chen , Chen Chen , Bin Li *, Jingwei Tao and Jinsong Peng *
1
Department of Chemistry and Chemical Engineering, College of Science,
Northeast Forestry University, Harbin 150040, China
2
Post-Doctoral Mobile Research Station of Forestry Engineering, Northeast Forestry University,
Harbin 150040, China
*
Authors to whom correspondence should be addressed; E-Mails: libinzh62@163.com (B.L.);
jspeng1998@163.com (J.P.); Tel.: +86-451-8219-0679 (B.L.); Fax: +86-451-8219-2699 (B.L.).
Received: 25 September 2012; in revised form: 17 October 2012 / Accepted: 21 October 2012 /
Published: 24 October 2012
Abstract: A straightforward method has been developed for the synthesis of the
benzimidazole ring system through a carbon-nitrogen cross-coupling reaction. In the
2 3
presence of 2.0 equiv. of K CO in water at 100 °C for 30 h, the intramolecular cyclization
of N-(2-iodoaryl)benzamidine provides benzimidazole derivatives in moderate to high
yields. Remarkably, the procedure occurs exclusively in water and doesn’t require the use
of any additional reagent/catalyst, rendering the methodology highly valuable from both
environmental and economical points of view.
Keywords: benzimidazoles; aqueous synthesis; N-arylation; transition-metal-free
conditions; aryl iodides
1
. Introduction
Benzimidazoles are an important class of heterocycles that are frequently used in drug and
agrochemical discovery programs. For examples, the benzimidazole core structure is found in a variety
of commercial drugs such as Atacand, Nexium, Micardis, Protonix, and Vermox (Figure 1).
Recent medicinal chemistry applications of benzimidazole analogs include antibacterial and antifungal
agents [1–3], anthelmintic agents [4], HIV-1-induced cytopathic inhibitor [5], anti-inflammatory and
antiulcer agents [6], cytotoxic and antitumor agents [7,8], DNA binding agents [9], enzyme and

Molecules 2012, 17
12507
receptor agonists or antagonists [10]. Other applications of benzimidazoles include their use as organic
ligands [11,12], fluorescent whitening agent dyes [13] and functional materials [14,15]. Therefore, the
construction of these heterocycles has always been of great interest to organic and medicinal chemists
and has consequently received much attention [16].
Figure 1. Structures of some pharmacologically important benzimidazoles.
The classical and most common methods to assemble benzimidazoles involve the condensation of
benzene-1,2-diamines with aldehydes, carboxylic acids, or their derivatives (Scheme 1, route a) under
strong acid/high temperature conditions or using a stoichiometric oxidant [17–20]. Although these
transformations are widely used owing to their inherent simplicity, this method is restricted to the
available starting materials and involves harsh reaction conditions [17–20]. Furthermore, this
methodology is not suitable for the regioselective synthesis of N-substituted benzimidazoles, as both
syntheses result in regioisomers and disubstituted products from the 1,2-diaminoarene. To circumvent
these restrictions, the transition-metal-catalyzed amination approach is a viable strategy to construct
the benzimidazole ring regiospecifically. Among the different catalysts, palladium- [21–25],
copper- [26–33], nickel- [34], iron- [35], and cobalt-based [36] complexes are generally employed for
this coupling reaction (Scheme 1, routes b–e). Despite these recent advances, transition-metal-
catalyzed methods are often expensive and require especially designed ligands. Another disadvantage
is the need to find ways to remove metal-related impurities from products, an important issue in the
synthesis of pharmaceutical compounds.
Transition-metal-free N-arylation reactions [37–44] are also known to occur either by nucleophilic
aromatic substitutions [45] or aryne-type intermediates [46–50] in the presence of a base. The former
usually requires dipolar aprotic solvents (such as DMF, NMP and DMSO) and sometimes high
reaction temperatures; the latter method requires strongly basic reaction conditions (generally
potassium amide in liquid ammonia or n-BuLi in hexane). Both synthetic procedures have some
drawbacks: harsh reaction conditions, inconvenient handling and workup, or a relatively narrow scope

Molecules 2012, 17
12508
of substrates. Green reaction conditions in synthetic processes have been advocated, and extensive
efforts have been devoted to finding sustainable reaction media. Notably the use of water as solvent
has attracted much attention in recent years [51–54]. In parallel with our efforts to develop metal-free
synthetic protocols for the production of pharmaceutical and agrochemical heterocyclic
compounds [55,56], we envisaged the application of more sustainable protocol to the aqueous
synthesis of the benzimidazole framework under transition metal-free conditions.
Scheme 1. Available methods to assemble benzimidazole derivatives.
As shown in Scheme 2, we propose the synthesis of benzimidazole derivatives 2 through a
direct base-mediated intramolecular N-arylation reaction in water, starting from the corresponding
N-(2-haloaryl) amidine 1.
Scheme 2. Proposed approach to the synthesis of benzimidazoles 2.
N-(2-Halophenyl) benzamidines 1a–a" were selected as model substrates for this N-arylation reaction.
In fact, our recently reported copper-catalyzed amination [28] showed that 2-iodoarylbenzamidine 1a
(with a concentration of 0.67 mol/L on a 1 mmol scale) can be transformed into the corresponding
product in 19% yield with K CO in water at 100 °C for 30 h. The use of Cu O/DMEDA as the
2
3
2
catalyst could efficiently promote this transformation giving 98% yield. Based on the above
observations, we wondered whether this copper-free chemical reaction can be improved by changing
heterogeneity, oil-water interface, and modes of aggregation “on” the surface of water or in water [57,58].

Molecules 2012, 17
12509
Further investigations showed that using a relatively low concentration (about 0.1 mol/L on a
0.25 mmol scale), benzimidazole can be obtained in moderate to high yields with vigorous stirring in water.
2
. Results and Discussion
Optimization of other reaction conditions such as base, temperature and time is shown in Table 1.
At first, the control experiment of 1a was examined in the absence of a base (entry 1, Table 1), and the
desired product was not observed. The intramolecular carbon-nitrogen cross-coupling reaction of
N-(2-iodophenyl)benzamidine (1a) using potassium carbonate (K CO , 2.0 equiv.) as the base in water
2
3
at 100 °C for 30 h was then examined. To our delight, benzimidazole 2a was smoothly obtained in
80% yield (entry 2, Table 1).
Table 1. Optimization of base-mediated intramolecular C–N cross-coupling of
[
a]
benzamidine 1a–c in water .
H
N
X
NH
base, H O
2
N
H
N
temperature, time
2a
1a: X = I; 1a': X = Br; 1a'': X = Cl
[
b]
Entry Substrate
Base
Temperature (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a'
1a''
―
100
100
100
100
100
100
100
100
100
100
80
30
30
30
30
30
30
30
30
30
30
30
30
20
48
30
30
30
30
0
80
63
trace
0
2 3
K CO
KOH
3
K PO4
NaOH
NaHCO3
0
Na CO3
0
2
Cs CO3
84
0
2
Et N
3
1
1
1
1
1
5
6
1
1
0
Pyridine
0
[
c]
1
2
K CO3
trace
60
50
74
78
66
0
2
3
4
K CO3
2
90
K CO3
2
100
100
120
150
100
100
K CO3
2
[d]
1
1
K CO3
2
2
[d]
K CO3
7
8
K CO3
2
2
K CO3
0
[
a]
The reaction was carried out with N-(2-halophenyl)benzamidine (0.25 mmol) and base (0.5 mmol) in water
[
b]
(
[
2.0 mL) with vigorous stirring at 80–150 °C for 20–48 h; Isolated yield after column chromatography;
c]
[d]
Complete recovery of starting material; Decomposition product o-bromoaniline was also obtained under
the given reaction conditions.
Recent research has revealed that metal impurities in commercially available reagents might
2 3
potentially affect their reactions [59–62]. To eliminate this possibility, different sources of K CO and

Molecules 2012, 17
12510
purified K CO with high purities (99.9%) were used with new glassware, and metal reagents were
2
3
avoided in synthetic steps wherever possible, and almost the same yields were obtained. Furthermore,
based on the data from entries 2 to 10 in Table 1, we concluded that the presence of trace metal
impurities weren’t involved in this carbon-nitrogen bond formation reaction [63]. The nature of base
was very important to the reaction outcome. KOH and Cs CO were also effective in promoting
2
3
this C–N bond formation in water, and the following yields were obtained: 63% (KOH) and 84%
Cs CO ). Surprisingly, other bases such as NaOH, NaHCO , K PO , Na CO , Et N and pyridine gave
(
2
3
3
3
4
2
3
3
no product. The reactions performed at 100 °C gave the best result, because at lower temperature
the conversions remained incomplete (entries 11 and 12, Table 1), at higher temperature the
undesired decomposition of substrate to o-iodoaniline happened (entries 15 and 16, Table 1). The
ortho-substituted halogen on the aniline moiety was very important to this intramolecular
carbon-nitrogen cross-coupling reaction. Aryl chloride and aryl bromide, which were expected
to be more reactive than their iodo analogues in a substitution reaction proceeding by the S Ar
N
mechanism [64,65], gave no product. Obviously an aromatic nucleophilic substitution process is
inconsistent with our experimental results (entries 17 and 18, Table 1), so this reaction presumably
occurred by an aryne-type intermediate in the presence of a base.
With the optimized reaction conditions in hand, the generality of the aniline moiety in the amination
process was explored first. As shown in Table 2, (o-iodoaryl)benzamidines can smoothly be converted
to the desired products in moderate to high yields, however, the use of aryl bromides to effect such
transformations afforded none of the desired products (entries 3 and 9, Table 2). For aryl iodides, a
variety of substituents such as F, Cl, Br, Me and MeO can be used. It is worth noting that reaction
conditions compatible with C–Br or C–Cl combinations are particularly appealing, since these
substituents offer great opportunity for further synthetic manipulations (entries 4 and 21, Table 2).
3
-Iodo-2-aminopyridine substrate 1g can be transformed into the corresponding benzimidazole in 44%
yield (entry 8, Table 2), however, 2-iodo-3-aminopyridine substrate 1h gave no product (entry 10,
Table 2) that probably attributed to failure to generate an aryne intermediate by ortho-deprotonations
followed by iodide elimination. These results as well as the order of reactivity of aryl halides (entries 2,
17 and 18. Table 1) further pointed to the involvement of aryne-type intermediates.
The scope and limitation of the nitrile moiety were next studied (Table 3). Obviously, the electronic
nature of the benzonitrile motifs had a great effect on the yields. Substrates bearing various
electron-donating substituents such as Me–, MeO– and Me N– can be converted smoothly into the
2
desired products in moderate to high yields (entries 1–6, Table 3). Furthermore, the steric hindrance
of ortho substituents on the benzonitrile moiety seemed not to hamper N-arylation reaction, the
benzimidazoles could be obtained in similar yields (entries 1–4, Table 2). However, the presence of
relatively electron-withdrawing or stronger electron-withdrawing functional groups completely held
back intramolecular amination process. Other electron-rich aromatic and heteroaromatic substrates
such as 1q, 1r and 1s could be efficiently transformed into the corresponding benzimidazoles in
satisfactory yields (entries 9–11, Table 3). In addition, N′-phenylated alkylamidine substrate 1u could
also be converted to the desired product 2u under these conditions (entry 13, Table 3). In contrast to
electron-rich aromatic substituents, N-(2-iodophenyl)amidine with an aliphatic functional group (Me–)
provided a trace amount of the product (entry 12, Table 3), the most of the starting materials were
unchanged and recovered from the reaction mixture.

Molecules 2012, 17
12511
[
a]
Table 2. Direct weak base-mediated synthesis of 2-phenylbenzimidazole derivatives in water .
R
X
NH
R
H
N
K CO , H O
2
3
2
N
H
1
00℃, 30 h
N
X = Br, I
1
2
[b]
Entry
Substrate
Product
Yield (%)
I
H
NH
N
N
1
80
N
H
2
a
1
a
F
I
F
N
NH
2
77
0
N
H
N
H
2b
2b
1
b
F
Br
F
c
N
NH
3
N
H
N
H
1
b'
Cl
I
Cl
N
NH
4
66
N
H
N
H
2
c
1
c
Br
I
Br
N
NH
5
6
54
67
N
H
N
H
2d
1
d
Me
I
Me
N
NH
N
H
N
H
2
e
1
e
MeO
I
MeO
N
NH
7
8
67
44
N
N
H
H
2f
g
1
f
I
H
N
N
N
NH
N
N
H
N
2
1
g
Br
H
N
[
c]
NH
9
0
0
N
N
H
N
2
g
1
g'
N
I
H
N
[
c]
NH
1
0
N
H
N
N
2
h
1
h
[
a]
Reaction conditions: 1.0 equiv. of N-(2-haloaryl)benzamidine (0.25 mmol) and 2.0 equiv. of K
2
CO
3
in
[
b]
water (2.0 mL) at 100 °C with vigorous stirring for 30 h;
[
Isolated yield after column chromatography;
c]
Complete recovery of starting material.

Molecules 2012, 17
Table 3. Synthesis of 2-arylbenzimidazole derivatives in water .
12512
[
a]
[b]
Entry
Substrate
Product
Yield (%)
I
H
NH
N
N
1
60
Me
N
H
2i
2j
Me 1i
I
H
NH
N
2
63
OMe
N
H
N
OMe 1j
I
Me
NH Me
H
3
4
5
N
58
64
70
N
H
N
2
k
1
k
I
MeO
NH OMe
H
N
N
H
N
2l
1
l
I
H
N
NH
NMe
2
N
H
N
2m
NMe
2
1
m
I
Me
NH
NH
H
6
N
50
0
Me
N
H
N
2n
1
n
I
H
N
[
[
c]
c]
7
8
Cl
N
N
2o
2p
2q
H
Cl 1o
I
H
NH
N
0
CN
N
N
H
CN 1p
I
H
N
NH
9
48
60
48
0
N
H
N
1
q
I
H
NH
NH
N
S
1
0
S
N
N
2r
2s
H
1
r
I
H
N
O
1
2
1
1
O
N
H
N
1
s
I
H
[
c]
NH
Me
N
1
Me
Me
N
H
N
2t
1
t
I
Ph
N
N
HN
3
33
N
Me
1
u
Ph
2
u
[
a]
Reaction conditions: 1.0 equiv. of N-(2-iodophenyl)amidine (0.25 mmol) and 2.0 equiv. of K
2
CO
3
in
[
b]
water (2.0 mL) at 100 °C with vigorous stirring for 30 h;
[
Isolated yield after column chromatography;
c]
Complete recovery of starting material.

Molecules 2012, 17
12513
3. Experimental
3.1. General
Chemicals and solvents were all purchased from commercial supplies and used without further
purification. Amidines were prepared through the addition of an aniline to a nitrile according to known
procedures [20–24]. Silica gel (100 mesh) was used for chromatographic separation. Silica gel G was
used for TLC. Petroleum ether refers to the fraction boiling between 60 °C and 80 °C. All reactions
1
were carried out in dried glassware. H-NMR spectra were recorded on a Bruker-400 MHz
1
3
spectrometer and C-NMR spectra were recorded at 100 MHz using tetramethylsilane (TMS) as the
internal standard in DMSO-d
6
. Chemical shifts (δ) are given in parts per million (ppm) downfield
1
13
relative to TMS ( H-NMR: TMS at 0.00 ppm, DMSO at 2.50 ppm; C-NMR: DMSO at 40.0 ppm).
1
Yields refer to isolated yields of compounds estimated to be >95% pure as determined by H-NMR.
Melting points were determined by use of a Buchi melting point apparatus and not corrected.
High-resolution mass spectra were recorded on a Bruker BIO TOF Q mass spectrometer.
3
.2. Chemistry
3
.2.1. General Procedure for the Preparation of Benzimidazoles 2a–u
A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with the (o-iodoaryl)-
benzamidine substrate (0.25 mmol, 1.0 equiv.) and K CO (69 mg, 0.5 mmol, 2.0 equiv.), then H O
2
3
2
(
2.0 mL) was added via syringe at room temperature. The tube was sealed and put into a pre-heated oil
bath at 100 °C for 30 h. The reaction mixture was cooled to room temperature, quenched with water
3 mL), and diluted with ethyl acetate (5 mL). The layers were separated and the aqueous layer was
(
extracted with (2 × 5 mL) ethyl acetate. The combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The crude product was then purified by flash
chromatography on silica gel (H), eluting with 5–10% ethyl acetate/petroleum ether.
1
2
-Phenyl-1H-benzo[d]imidazole (2a). White solid; m.p. 293–295 °C; yield: 80%. H-NMR: δ 12.92
(
br s, 0.19H), 8.21–8.19 (d, 2H, J = 7.6 Hz), 7.69–7.67 (d, 1H, J = 6.8 Hz), 7.58–7.48 (m, 4H), 7.24–7.22
1
3
(d, 2H, J = 6.8 Hz). C-NMR: δ 151.55, 144.23, 135.30, 130.57, 130.32, 129.42, 126.89, 123.02,
+
1
22.15, 119.34, 111.75. HRMS-ESI (m/z): [M+Na] calcd. for C13
H
10
N
2
Na 217.0742; found 217.0745.
1
5
-Fluoro-2-phenyl-1H-benzo[d]imidazole (2b). White solid; m.p. 243–244 °C; yield: 77%. H-NMR:
1
3
δ 13.06 (br s, 0.14H), 8.18–8.16 (d, 2H, J = 8.0 Hz), 7.69–7.31 (m, 5H), 7.12–7.04 (m, 1H). C-NMR:
δ 160.15, 153.33, 140.91, 130.60, 130.28, 126.95, 120.19, 111.19, 110.44, 104.90, 98.28. HRMS-ESI
+
(
m/z): [M+Na] calcd. for C13
H
9
FN
2
Na 235.0647; found 235.0649.
1
5
-Chloro-2-phenyl-1H-benzo[d]imidazole (2c). White solid; m.p. 209–211 °C; yield: 66%. H-NMR: δ
1
3.13 (br s, 0.18H), 8.20–8.18 (d, 2H, J = 7.2 Hz), 7.74–7.51 (m, 5H), 7.26–7.24 (d, 1H, J = 8.0 Hz).
1
3
C-NMR: δ 152.55, 144.63 (142.48), 135.52 (133.60), 130.15, 129.56, 128.94, 126.50, 122.53
+
(
122.08), 120.02, 118.18, 112.53 (110.92). HRMS-ESI (m/z): [M+Na] calcd. for C13
H
9
ClN
2
Na
2
51.0352; found 251.0356.

Molecules 2012, 17
12514
1
5
1
1
-Bromo-2-phenyl-1H-benzo[d]imidazole (2d). White solid; m.p. 202–203 °C; yield: 54%. H-NMR: δ
1
3
3.09 (br s, 0.26H), 8.18–8.16 (d, 2H, J = 8.0 Hz), 7.87–7.50 (m, 5H), 7.37–7.33 (m, 1H). C-NMR: δ
45.20, 142.82, 130.27, 129.54, 129.01, 126.57, 125.21, 124.70, 114.71, 113.87, 113.07. HRMS-ESI
+
(
m/z): [M+Na] calcd. for C H BrN Na 294.9847; found 294.9849.
1
3
9
2
1
5
1
1
-Methyl-2-phenyl-1H-benzo[d]imidazole (2e). White solid; m.p. 242–243 °C; yield: 67%. H-NMR: δ
13
2.80 (br s, 0.22H), 8.20 (m, 2H), 7.55 (m, 5H), 7.05 (m, 1H), 2.45 (s, 3H). C-NMR: δ 150.80,
41.94, 135.08, 131.53, 130.24, 129.59, 128.84, 128.01, 126.26, 123.51, 118.29, 110.86, 21.27.
+
HRMS-ESI (m/z): [M+Na] calcd. for C H N Na 231.0898; found 231.0896.
1
4
12
2
1
5
-Methoxy-2-phenyl-1H-benzo[d]imidazole (2f). White solid; m.p. 148–150 °C; yield: 67%. H-NMR:
δ 13.07 (br s, 0.13H), 8.29–8.13 (m, 2H), 7.58–7.48 (m, 4H), 7.25–7.08 (m, 1H), 7.02–7.01 (m, 1H),
1
3
3
.83–3.82 (s, 3H). C-NMR: δ 156.8, 151.4, 137.4, 136.2, 130.4 (130.1), 129.4 (129.2), 127.5, 126.8,
+
1
14.2, 112.4, 94.99 (94.94), 56.4. HRMS-ESI (m/z): [M+Na] calcd. for C H N NaO 247.0847;
1
4
12
2
found 247.0849.
1
2
-Phenyl-3H-imidazo[4,5-b]pyridine (2g). White solid; m.p. 283–284 °C; yield: 44%. H-NMR δ
1
3.48 (br s, 1H), 8.34 (dd, J = 4.8, 1.5 Hz, 1H), 8.25−8.21 (m, 2H), 8.02 (d, J = 7.5 Hz, 1H), 7.61−7.51
1
3
(
m, 3H), 7.25 (dd, J = 8.1, 4.8 Hz, 1H). C-NMR: δ 152.32, 143.75, 135.57, 130.52, 129.57, 129.00,
+
1
2
26.70, 126.27, 119.16, 118.09. HRMS-ESI (m/z): [M+Na] calcd. for C12
H
9
N
3
Na 218.0694; found
18.0697.
1
2
-p-Tolyl-1H-benzo[d]imidazole (2i). White solid; m.p. 276–278 °C; yield: 60%. H-NMR: δ 12.83
(
br s, 0.15H), 8.09–8.07 (d, 2H, J = 7.6 Hz), 7.65–7.53 (m, 2H), 7.37–7.35 (d, 2H, J = 8.0 Hz), 7.20
1
3
(
m, 2H), 2.39 (s, 3H). C-NMR: δ 151.17, 143.71, 139.49, 134.74, 129.42, 127.31, 126.30, 122.23,
+
1
2
21.50, 118.62, 111.04, 20.87. HRMS-ESI (m/z): [M+Na] calcd. for C14
H
12
N
2
Na 231.0898; found
31.0895.
1
2
-(4-Methoxyphenyl)-1H-benzo[d]imidazole (2j). White solid; m.p. 221–223 °C; yield: 63%. H-NMR:
δ 12.76 (br s, 0.11H), 8.14–8.12 (d, 2H, J = 8.8 Hz), 7.57 (m, 2H), 7.20–7.17 (m, 2H), 7.13–1.11 (d,
1
3
2
H, J = 8.8 Hz), 3.85 (s, 3H). C-NMR: δ 160.59, 151.25, 143.73, 134.97, 127.98, 122.61, 122.07,
+
1
21.74, 118.43, 114.34, 111.05, 55.29. HRMS-ESI (m/z): [M+Na] calcd. for C H N NaO 247.0847;
1
4
12
2
found 247.0851.
1
2
-o-Tolyl-1H-benzo[d]imidazole (2k). White solid; m.p. 206–208 °C; yield: 58%. H-NMR δ 12.64 (br
s, 0.11H), 7.76–7.74 (d, 1H, J = 6.8 Hz), 7.62 (m, 2H), 7.39–7.37 (m, 3H), 7.23–7.21 (m, 2H), 2.62 (s,
1
3
3
H). C-NMR δ 151.73, 136.91, 131.15, 129.94, 129.33, 129.22, 125.85, 121.78, 20.90. HRMS-ESI
+
(
m/z): [M+Na] calcd. for C14
H
12
N
2
Na 231.0898; found 231.0901.
1
2
-(2-Methoxyphenyl)-1H-benzo[d]imidazole (2l). White solid; m.p. 181–182 °C; yield: 64%. H-NMR
δ 12.13 (br s, 0.22H), 8.35–8.32 (dd, 1H, J = 7.6, 1.6 Hz), 7.66–7.62 (m, 2H), 7.52–7.47 (m, 1H),
1
3
7
1
5
.27–7.25 (d, 1H, J = 8.0 Hz), 7.21–7.19 (m, 2H), 7.15–7.11 (m, 1H), 4.04 (s, 3H). C-NMR δ 156.74,
52.87, 141.72, 141.68, 131.25, 129.70, 122.02, 129.33, 121.50, 120.85, 118.45, 117.93, 112.07,
+
5.74. HRMS-ESI (m/z): [M+Na] calcd. for C14
H
12
N
2
NaO 247.0847; found 247.0849.

Molecules 2012, 17
12515
4
-(1H-Benzo[d]imidazol-2-yl)-N,N-dimethylaniline (2m). White solid; m.p. 272–274 °C; yield: 70%.
1
H-NMR: δ 12.57 (br s, 0.29H), 8.01 (d, 2H, J = 8.0 Hz), 7.57–7.46 (m, 2H), 7.15–7.13 (dd, 2H,
1
3
J = 6.0, 2.8 Hz), 6.85–6.83 (d, 2H, J = 8.0 Hz), 3.00 (s, 6H). C-NMR: δ 152.12, 151.22, 144.01,
+
1
34.78, 127.52, 121.48, 121.16, 117.99, 117.31, 111.81, 110.60, 41.07. HRMS-ESI (m/z): [M+Na]
calcd. for C15 Na 260.1164; found 260.1168.
15 3
H N
1
2
-(m-Tolyl)-1H-benzo[d]imidazole (2n). White solid; m.p. 213–215 °C; yield: 50%. H-NMR: δ 12.88
(
br s, 0.21H), 8.03 (s, 1H), 7.98–7.96 (d, 1H, J = 8.0 Hz), 7.65–7.54 (m, 2H), 7.47–7.43 (t, 1H, J = 8.0 Hz),
1
3
7
.33–7.31 (d, 1H, J = 8.0 Hz), 7.22–7.21 (m, 2H), 2.43 (s, 3H). C-NMR: δ 151.13, 143.26, 138.15,
1
30.47, 129.92, 129.86, 128.83, 126.96, 123.55, 122.46, 121.64, 118.78, 111.22, 21.02. HRMS-ESI
+
(
m/z): [M+Na] calcd. for C H N Na 231.0898; found 231.0899.
1
4
12
2
1
2
-(Naphthalen-2-yl)-1H-benzo[d]imidazole (2q). White solid; m.p. 206–207 °C; yield: 48%. H-NMR:
δ 13.11 (br s, 0.29H), 8.76 (s, 1H), 8.34 (d, 1H, J = 8.0 Hz), 8.11–8.05 (m, 2H), 8.01–7.99 (m, 1H),
1
3
7
1
1
.73–7.71 (m, 1H), 7.64–7.59 (m, 3H), 7.25 (m, 2H). C-NMR: δ 151.23, 143.87, 134.96, 133.45,
32.79, 128.54, 128.42, 127.77, 127.53, 127.10, 126.91, 125.79, 123.91, 122.67, 121.76, 118.88,
+
11.31. HRMS-ESI (m/z): [M+Na] calcd. for C17
H
12
N
2
Na 267.0898; found 267.0899.
1
2
1
7
1
-(Thiophen-2-yl)-1H-benzo[d]imidazole (2r). White solid; m.p. 341–343 °C; yield: 60%. H-NMR: δ
2.94 (br s, 0.24H), 7.83 (dd, J = 3.6, 0.8 Hz, 1H), 7.72 (dd, J = 4.8, 0.8 Hz, 1H), 7.62−7.60 (m, 1H),
1
3
.50 (dd, J = 6.9, 2.1 Hz, 1H), 7.25−7.16 (m, 3H). C-NMR: δ 146.86, 143.54, 134.49, 133.59,
+
28.73, 128.25, 126.67, 122.61, 121.74, 118.51, 111.02. HRMS-ESI (m/z): [M+Na] calcd. for
11 8 2
C H N NaS 223.0306; found 223.0304.
1
2
1
1
-(Furan-2-yl)-1H-benzo[d]imidazole (2s). White solid; m.p. 285–286 °C; yield: 48%. H-NMR: δ
2.92 (br s, 0.26H), 7.95 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 (br s, 2H), 7.24−7.20 (m, 3H), 6.73 (dd, J = 3.3,
1
3
.8 Hz, 1H). C-NMR: δ 145.5, 144.6, 143.5, 134.3, 122.3, 121.6, 118.7, 112.3, 111.4, 110.5.
+
HRMS-ESI (m/z): [M+Na] calcd. for C H N NaO 207.0534; found 207.0536.
1
1
8
2
1
2
-Methyl-1-phenyl-1H-benzo[d]imidazole (2u). White solid; m.p. 127–129 °C; yield: 33%. H-NMR:
1
3
δ 7.67–7.63 (m, 3H), 7.59–7.53 (m, 3H), 7.24–7.12 (m, 3H), 2.43 (s, 3H). C-NMR δ 143.2, 136.1,
+
1
34.3, 130.4, 129.2, 127.3, 124.5, 122.8, 122.4, 118.9, 110.3, 14.6. HRMS-ESI (m/z): [M+Na] calcd.
for C14
H
12
N
2
Na 231.0898; found 231.0896.
. Conclusions
In summary, a straightforward weak base-mediated protocol had been developed for the
4
intramolecular C–N bond formation to provide benzimidazole derivatives in moderate to high yields.
Particularly interesting, the use of water as a benign and accessible solvent should render the
methodology described herein economical and environmentally attractive, providing an alternative
synthetic protocol for potential industrial applications without the addition of any exogenous transition
metal catalysts.

Molecules 2012, 17
12516
Acknowledgments
We are grateful for the funding support from the Fundamental Research Funds for the Central
Universities (DL12DB03), China Postdoctoral Science Foundation (20110491013, 2012T50319) and
Heilongjiang Postdoctoral Grant (LBH-Z11251).
References and Notes
1.
2.
3.
4.
5.
6.
7.
Desai, K.G.; Desai, K.R. Green route for the heterocyclization of 2-mercaptobenzimidazole into
β-lactum segment derivatives containing –CONH– bridge with benzimidazole: Screening in vitro
antimicrobial activity with various microorganisms. Bioorg. Med. Chem. 2006, 14, 8271–8279.
Güven, Ö.Ö.; Erdoğan, T.; Göker, H.; Ylidiz, S. Synthesis and antimicrobial activity of some
novel phenyl and benzimidazole substituted benzyl ethers. Bioorg. Med. Chem. Lett. 2007, 17,
2
233–2236.
Igual-Adell, R.; Oltra-Alcaraz, C.; Soler-Company, E.; Sánchez-Sánchez, P.; Matogo-Oyany, J.;
Rodríguez-Dalabuig, D. Efficacy and safety of ivermectin and thiabendazole in the treatment of
strongyloidiasis. Expert Opin. Pharmacother. 2004, 5, 2615–2619.
Mavrova, A.T.; Anichina, K.K.; Vuchev, D.I.; Tsenov, J.A.; Denkova, P.S.; Kondeva, M.S.;
Micheva, M.K. Antihelminthic activity of some newly synthesized 5(6)-(un)substituted-1H-
benzimidazol-2-ylthioacetylpiperazine derivatives. Eur. J. Med. Chem. 2006, 41, 1412–1420.
Barreca, M.L.; Chimirri, A.; de Clercq, E.; de Luca, L.; Monforte, A.-M.; Monforte, P.; Rao, A.;
Zappala, M. Anti-HIV agents: Design and discovery of new potent RT inhibitors. Il Farmaco
2
003, 58, 259–263.
Leonard, J.T.; Rajesh, O.S.; Jeyaseeli, L.; Murugesh, K.; Sivakumar, R.; Gunasekaran, V.
Synthesis, Antiinflammatory and Antibacterial Activities of Substituted Phenyl Benzimidazoles.
Asian J. Chem. 2007, 19, 116–120.
Baraldi, P.G.; Bovero, A.; Fruttarolo, F.; Preti, D.; Tabrizi, M.A.; Pavani, M.G.; Romagnoli, R.
DNA minor groove binders as potential antitumor and antimicrobial agents. Med. Res. Rev. 2004,
2
4, 475–528.
8
.
.
Singh, A.K.; Lown, J.W. Design, synthesis and antitumor cytotoxicity of novel
bis-benzimidazoles. Anticancer Drug Des. 2000, 15, 265–275.
9
Chaudhuri, P.; Ganguly, B.; Bhattacharya, S. An Experimental and Computational Analysis on
the Differential Role of the Positional Isomers of Symmetric Bis-2-(pyridyl)-1H-benzimidazoles
as DNA Binding Agents. J. Org. Chem. 2007, 72, 1912–1923.
1
0. Alamgir, M.; Black, D.St.C.; Kumar, N. Synthesis, Reactivity and Biological Activity of
Benzimidazoles. In Topics in Heterocyclic Chemistry; Khan, M.T.H., Ed.; Springer: Berlin,
Germany, 2007; Volume 9, pp. 87–118.
1
1. Pal, S.; Hwang, W.-S.; Lin, I.J.B.; Lee, C.-S. Benzene benzimidazole containing Pd(II)
metallacycle: Synthesis, X-ray crystallographic characterization and its use as an efficient Suzuki
coupling catalyst. J. Mol. Catal. A: Chem. 2007, 269, 197–203.

Molecules 2012, 17
12517
1
1
1
1
2. Hao, P.; Zhang, S.; Sun, W.-H.; Shi, Q.; Adewuyi, S.; Lu, X.; Li, P. Synthesis, Characterization
and Ethylene Oligomerization Studies of Nickel Complexes Bearing 2-Benzimidazolylpyridine
Derivatives. Organometallics 2007, 26, 2439–2446.
3. Rajadhyaksha, D.D.; Rangnekar, D.W. Synthesis of pyrazolo[4′,3′:5,6]pyrido[1,2-a]benzimidazole
derivatives and study of their fluorescence properties. J. Chem. Technol. Biotechnol. 1986, 36,
3
00–304.
4. Asensio, J.A.; Gomez-Romero, P. Recent Developments on Proton Conduc-ting
Poly(2,5-benzimidazole) (ABPBI) Membranes for High Temperature Poly-mer Electrolyte
Membrane Fuel Cells. Fuel Cells 2005, 5, 336–343.
5. Schwartz, G.; Fehse, K.; Pfeiffer, M.; Walzer, K.; Leo, K. Highly efficient white organic light
emitting diodes comprising an interlayer to separate fluorescent and phosphorescent regions.
Appl. Phys. Lett. 2006, 89, doi:10.1063/1.2338588.
1
6. Carvalho, L.C.R.; Fernandes, E.; Marques, M.M.B. Developments Towards Regioselective
Synthesis of 1,2-Disubstituted Benzimidazoles. Chem. Eur. J. 2011, 17, 12544–12555.
7. Grimmett, M.R. Ring Syntheses Involving Formation of Two Bonds: [4+1] Fragments. In
Imidazole and Benzimidazole Synthesis; Meth-Cohn, O., Ed.; Academic: London, UK, 1997;
pp. 63–102.
1
1
8. Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C.M. A Versatile Method for the Synthesis of
Benzimidazoles from o-Nitroanilines and Aldehydes in One Step via a Reductive Cyclization.
Synthesis 2005, 47–56.
1
2
2
2
2
9. Bahrami, K.; Khodaei, M.M.; Naali, F. Mild and Highly Efficient Method for the Synthesis of
2
-Arylbenzimidazoles and 2-Arylbenzothiazoles. J. Org. Chem. 2008, 73, 6835–6837.
0. Goossen, L.J.; Knauber, T. Concise Synthesis of Telmisartan via Decarboxylative Cross-Coupling.
J. Org. Chem. 2008, 73, 8631–8634.
1. Brain, C.T.; Brunton, S.A. An intramolecular palladium-catalysed aryl amination reaction to
produce benzimidazoles. Tetrahedron Lett. 2002, 43, 1893–1895.
2. Brain, C.T.; Brunton, S.A. An Improved Procedure for the Synthesis of Benzimidazoles, Using
Palladium-Catalyzed Aryl-Amination Chemistry. J. Org. Chem. 2003, 68, 6814–6816.
3. Zhao, D.; Hu, J.; Wu, N.; Huang, X.; Qin, X.; Lan, J.; You, J. Regiospecific Synthesis of
1
,2-Disubstituted (Hetero)aryl Fused Imidazoles with Tunable Fluorescent Emission. Org. Lett.
011, 13, 6516–6519.
2
2
2
4. Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Direct Imidation to
II
Construct 1H-Benzo[d]imidazole through Pd -Catalyzed C-H Activation Promoted by Thiourea.
Chem. Eur. J. 2009, 15, 7292–7296.
5. Zheng, N.; Anderson, K.W.; Huang, X.H.; Nguyen, H.N.; Buchwald, S.L. A Palladium-Catalyzed
Regiospecific Synthesis of N-Aryl Benzimidazoles. Angew. Chem. 2007, 119, 7653–7656;
Angew. Chem. Int. Ed. Engl. 2007, 46, 7509–7512.
2
6. Evindar, G.; Batey, R.A. Copper- and Palladium-Catalyzed Intramolecular Aryl Guanidinylation:
An Efficient Method for the Synthesis of 2-Aminobenzimidazoles. Org. Lett. 2003, 5, 133–136.
7. Szczepankiewicz, B.G.; Rohde, J.J.; Kurukulasuriyz, R. Synthesis of Purines and Other Fused
Imidazoles from Acyclic Amidines and Guanidines. Org. Lett. 2005, 7, 1833–1835.
2

Molecules 2012, 17
12518
2
2
3
3
8. Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, X.; Wang, Y.; Chen, C. Copper-Catalyzed
Intramolecular C−N Bond Formation: A Straightforward Synthesis of Benzimidazole Derivatives
in Water. J. Org. Chem. 2011, 76, 716–719.
9. Brasche, G.; Buchwald, S.L. C–H Functionalization/C–N Bond Formation: Copper-Catalyzed
Synthesis of Benzimidazoles from Amidines. Angew. Chem. 2008, 120, 1958–1960;
Angew. Chem. Int. Ed. Engl. 2008, 47, 1932–1934.
0. Zou, B.L.; Yuan, Q.L.; Ma, D.-W. Synthesis of 1,2-Disubstituted Benzimidazoles by a
Cu-Catalyzed Cascade Aryl Amination/Condensation Process. Angew. Chem. 2007, 119,
2
652–2655; Angew. Chem. Int. Ed. Engl. 2007, 46, 2598–2601.
1. Kim, Y.; Kumar, M.R.; Park, N.; Heo, Y.; Lee, S. Copper-Catalyzed, One-Pot, Three-Component
Synthesis of Benzimidazoles by Condensation and C–N Bond Formation. J. Org. Chem. 2011, 76,
9
577–9583.
2. Deng, X.; Mani, N.S. Reactivity-Controlled Regioselectivity: A Regiospecific Synthesis of
,2-Disubstituted Benzimidazoles. Eur. J. Org. Chem. 2010, 680–686.
3
3
1
3. Deng, X.; McAllister, H.; Mani, N.S. CuI-Catalyzed Amination of Arylhalides with Guanidines
or Amidines: A Facile Synthesis of 1-H-2-Substituted Benzimidazoles. J. Org. Chem. 2009, 74,
5
742–5745.
3
3
3
4. Amrani, R.O.; Thomas, A.; Brenner, E.; Schneider, R.; Fort, Y. Efficient Nickel-Mediated
Intramolecular Amination of Aryl Chlorides. Org. Lett. 2003, 5, 2311–2314.
5. Shen, M.; Driver, T.G. Iron(II) Bromide-Catalyzed Synthesis of Benzimidazoles from Aryl
Azides. Org. Lett. 2008, 10, 3367–3370.
6. Saha, P.; Ali, M.A.; Ghosh, P.; Punniyamurthy, T. Cobalt-catalyzed intramolecular C–N and C–O
cross-coupling reactions: Synthesis of benzimidazoles and benzoxazoles. Org. Biomol. Chem.
2
010, 8, 5692–5699.
3
7. Roberts, J.D.; Semenow, D.A.; Simmons, H.E., Jr.; Carlsmith, L.A. The Mechanism of
Aminations of Halobenzenes. J. Am. Chem. Soc. 1956, 78, 601–611.
3
8. Ross, S.D. Nucleophilic Displacement Reactions in Aromatic Systems. IV. Rates of Reaction
of 1-Halo-2,4-dinitrobenzene with n-Butylamine in Chloroform and with n-Butylamine and
t-Butylamine in Dimethylformamide. J. Am. Chem. Soc. 1959, 81, 2113–2115.
3
9. Beller, M.; Breindl, C.; Riermeier, R.H.; Tillack, A. Synthesis of 2,3-Dihydroindoles, Indoles, and
Anilines by Transition Metal-Free Amination of Aryl Chlorides. J. Org. Chem. 2001, 66, 1403–1412.
0. Shi, L.; Wang, M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Rapid and Efficient Microwave-Assisted
Amination of Electron-Rich Aryl Halides without a Transition-Metal Catalyst. Org. Lett. 2003, 5,
4
3
515–3517.
4
4
1. Varala, R.; Ramu, E.; Alam, M.M.; Adapa, S.R. Scope and Utility of CsOH·H O in Amination
2
Reactions via Direct Coupling of Aryl Halides and sec-Alicyclic Amines. Synlett 2004, 1747–1750.
2. Bolliger, J.L.; Frech, C.M. Transition metal-free amination of aryl halides—A simple and reliable
method for the efficient and high-yielding synthesis of N-arylated amines. Tetrahedron 2009, 65,
1
180–1187.
4
3. Poirier, M.; Goudreau, S.; Poulin, J.; Savole, J.; Beaulieu, P.L. Metal-Free Coupling of Azoles
with 2- and 3-Haloindoles Providing Access to Novel 2- or 3-(Azol-1-yl)indole Derivatives.
Org. Lett. 2010, 12, 2334–2337.

Molecules 2012, 17
12519
4
4. Yuan, Y.; Thomé, I.; Kim, S.H.; Chen, D.; Beyer, A.; Bonnamour, J.; Zuidema, E.; Chang, S.;
Bolm, C. Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase for the Transition Metal-Free
Preparation of Cross-Coupling Products. Adv. Synth. Catal. 2010, 352, 2892–2898.
4
4
4
4
4
5
5. March, J. Aromatic Nucleophilic Substitution. In Advanced Organic Chemistry, Reactions,
Mechanisms and Structure, 4th ed.; John Wiley & Sons: New York, NY, USA, 1992; p. 641.
6. Huisgen, R.; König, H. Erweitertes Makromolekulares Kolloquium, Freiburg. Angew. Chem.
1
957, 69, 268–272.
7. Huisgen, R.; Sauer, J. Nucleophile aromatische Substitutionen über Arine. Angew. Chem. 1960,
2, 91–108.
7
8. Hrutford, B.F.; Bunnett, J.F. A General Principle for the Synthesis of Heterocyclic and
Homocyclic Compounds. J. Am. Chem. Soc. 1958, 80, 2021–2022.
9. Bunnett, J.F.; Hrutford, B.F. Ring Closure via Aryne Intermediates: A General Principle of
Synthesis. J. Am. Chem. Soc. 1961, 83, 1691–1697.
0. Sielecki, T.M.; Meyers, A.I. Formamidines in synthesis. An efficient one-pot synthesis of
7
-substituted indolines via intramolecular cyclization of (2-phenethyl)formamidines. An
asymmetric route to benzopyrrocoline alkaloids. J. Org. Chem. 1992, 57, 3673–3676.
1. Grieca, P.A., Ed. Organic Synthesis in Water; Blackie A & P: London, UK, 1998.
2. Chanda, A.; Fokin, V.V. Organic Synthesis “On Water”. Chem. Rev. 2009, 109, 725–748.
3. Butler, R.N.; Coyne, A.G. Water: Nature’s Reaction Enforcer—Comparative Effects for Organic
Synthesis “In-Water” and “On-Water”. Chem. Rev. 2010, 110, 6302–6337.
5
5
5
5
4. Simon, M.-O.; Li, C.-J. Green chemistry oriented organic synthesis in water. Chem. Soc. Rev.
2
012, 41, 1415–1427.
5
5. Peng, J.; Zong, C.; Ye, M.; Chen, T.; Gao, D.; Wang, Y.; Chen, C. Direct transition-metal-free
intramolecular C–O bond formation: Synthesis of benzoxazole derivatives. Org. Biomol. Chem.
2
011, 9, 1225–1230.
5
6. Wang, Y.; Song, Z.; Chen, C.; Peng, J. Pictet-Spengler condensation reactions catalyzed by a
+
recyclable H -montmorillonite as a heterogeneous Brønsted acid. Sci. Chin. Chem. 2010, 53,
5
62–568.
7. Pirrung, M.C. Acceleration of Organic Reactions through Aqueous Solvent Effects. Chem. Eur. J.
006, 12, 1312–1317.
8. Jung, Y.; Marcus, R.A. On the Theory of Organic Catalysis “On Water”. J. Am. Chem. Soc. 2007,
29, 5492–5502.
5
5
5
6
2
1
3
9. Buchwald, S.L.; Bolm, C. On the Role of Metal Contaminants in Catalyses with FeCl .
Angew. Chem. 2009, 121, 5694–5695; Angew. Chem. Int. Ed. Engl. 2009, 48, 5586–5587.
0. Larsson, P.-F.; Correa, A.; Carril, M.; Norrby, P.-O.; Bolm, C. Copper-Catalyzed
Cross-Couplings with Part-per-Million Catalyst Loadings. Angew. Chem. 2009, 121, 5801–5803;
Angew. Chem. Int. Ed. Engl. 2009, 48, 5691–5693.
6
1. Thomé, I.; Nijs, A.; Bolm, C. Trace metal impurities in catalysis. Chem. Soc. Rev. 2012, 41, 979–987.
2. Leadbeater, N.E. When is free really free? Nat. Chem. 2010, 2, 1007–1009.
6

Molecules 2012, 17
12520
6
3. Trace metal amounts in the commercially available bases were analyzed by inductively coupled
plasma atomic emission spectroscopy (ICP-AES): for K CO 2 ppm of Pd, <1 ppm of Cu, 2 ppm
2
3
of Ni, 3 ppm of Fe; for KOH 5 ppm of Pd, <1 ppm of Cu, 2 ppm of Ni, 3 ppm of Fe; for NaOH 4
ppm of Pd, <1 ppm of Cu, 4 ppm of Ni, 3 ppm of Fe; for K PO 6 ppm of Pd, <1 ppm of Cu,
3
4
<
1 ppm of Ni, 3 ppm of Fe; for NaHCO
for Na CO 10 ppm of Pd, <1 ppm of Cu, 3 ppm of Ni, 4 ppm of Fe; for Cs
1 ppm of Cu, 2 ppm of Ni, 5 ppm of Fe.
3
8 ppm of Pd, <1 ppm of Cu, 1 ppm of Ni, 5 ppm of Fe;
2
3
2
CO 6 ppm of Pd,
3
<
6
4. Briner, G.P.; Miller, J.; Liveris, M.; Lutz, P.G. The S mechanism in aromatic compounds. Part VII.
N
J. Chem. Soc. 1954, 1265–1266.
6
5. Bartoli, G.; Todesco, P.E. Nucleophilic substitution. Linear free energy relations between
reactivity and physical properties of leaving groups and substrates. Acc. Chem. Res. 1977, 10,
1
25–132.
Sample Availability: Samples of the compounds are available from the authors.
©
2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
http://creativecommons.org/licenses/by/3.0/).
(