Metal-free selective synthesis of 2-substituted benzimidazoles catalyzed by Br?nsted acidic ionic liquid: Convenient access to one-pot synthesis of N-alkylated 1,2-disubstituted benzimidazoles

Article abstract of DOI:10.1016/j.tet.2019.05.014

A novel efficient method for the selective synthesis of 2-substituted benzimidazoles is described through condensation reaction of o-phenylenediamines with a wide rang of aliphatic, aromatic and heteroaromatic aldehyde substrates using Br?nsted acidic ionic liquid as a reusable catalyst under metal-free conditions at ambient temperature. Notably, Dodecylimidazolium hydrogen sulfate ([DodecIm][HSO₄]) is the most efficient catalyst for good to excellent yields of the corresponding products (up to 98%). Subsequently, this protocol was successfully applied for the preparation of N-alkylated 1,2-disubstituted benzimidazoles in high to excellent yields via sequential one-pot reaction. In addition, catalysts are recycled at least four times without significant loss in activity.

Full text of DOI:10.1016/j.tet.2019.05.014

Accepted Manuscript
Metal-free selective synthesis of 2-substituted benzimidazoles catalyzed by Brønsted
acidic ionic liquid: Convenient access to one-pot synthesis of N-alkylated 1,2-
disubstituted benzimidazoles
Warapong Senapak, Rungnapha Saeeng, Jaray Jaratjaroonphong, Vinich Promarak,
Uthaiwan Sirion
PII:
S0040-4020(19)30533-2
https://doi.org/10.1016/j.tet.2019.05.014
TET 30335
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 January 2019
Revised Date: 1 May 2019
Accepted Date: 8 May 2019
Please cite this article as: Senapak W, Saeeng R, Jaratjaroonphong J, Promarak V, Sirion U, Metal-free
selective synthesis of 2-substituted benzimidazoles catalyzed by Brønsted acidic ionic liquid: Convenient
access to one-pot synthesis of N-alkylated 1,2-disubstituted benzimidazoles, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.05.014.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Metal-free selective synthesis of 2-substituted
benzimidazoles catalyzed by Brönsted acidic
ionic liquid: Convenient access to one-pot
synthesis of N-alkylated 1,2-disubstituted
benzimidazoles
Leave this area blank for abstract info.
Warapong Senapak,a Rungnapha Saeeng,a Jaray Jaratjaroonphong,a Vinich Promarak,b Uthaiwan Siriona,*
aDepartment of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University,
Sangsook, Chonburi, 20131, Thailand
bSchool of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC),
Wangchan Valley, Wangchan, Rayong 21210, Thailand

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Metal-free selective synthesis of 2-substituted benzimidazoles catalyzed by Brönsted
acidic ionic liquid: Convenient access to one-pot synthesis of N-alkylated 1,2-
disubstituted benzimidazoles
Warapong Senapaka , Rungnapha Saeenga , Jaray Jaratjaroonphonga , Vinich Promarakb
and Uthaiwan Siriona,
aDepartment of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Sangsook, Chonburi, 20131, Thailand
bSchool of Molecular Science and Engineering, Vidyasirimedhi Institute of Science and Technology (VISTEC), Wangchan Valley, Wangchan, Rayong 21210,
Thailand
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel efficient method for the selective synthesis of 2-substituted benzimidazoles is described
through condensation reaction of o-phenylenediamines with a wide rang of aliphatic, aromatic
and heteroaromatic aldehyde substrates using Brönsted acidic ionic liquid as a reusable catalyst
under metal-free conditions at ambient temperature. Notably, Dodecylimidazolium hydrogen
sulfate ([DodecIm][HSO4]) is the most efficient catalyst for good to excellent yields of the
corresponding products (up to 98%). Subsequently, this protocol was successfully applied for
the preperation of N-alkylated 1,2-disubstituted benzimidazoles in high to excellent yields via
sequential one-pot reaction. In addition, catalysts are recycled at least four times without
significant loss in activity.
Available online
Keywords:
2-Substituted Benzimidazole
N-Alkylated 1,2-Disubstituted Benzimidazole
Metal-Free Condition
2009 Elsevier Ltd. All rights reserved
.
Acidic Ionic Liquid
Condensation Reaction
———
Corresponding author. Tel.: +66-98-026-2181; fax: +66-3-839-3494; e-mail: uthaiwan@go.buu.ac.th

2
Tetrahedron
presence of oxidative agents (Scheme 1, path a).6h,6j,6r-v Among
1. Introduction
ACCEPTED MANUSCRIPT
these products, 2-substituted benzimidazoles are more useful in
several applications and as intermediates in the preparation of
Benzimidazole is a diverse and important heterocyclic
compound in medicine1,4 and material science2 (Figure 1). It is
also a useful building block in the preparation of versatile
synthetic organic compounds.3,4d,4f,4i Numerous benzimidazole
versatile
N-alkylated
1,2-disubstiuted
benzimidazoles.1-4
Therefore, the search for a novel and efficient strategy for a
highly selective synthesis of 2-substituted benzimidazoles via
simple condensation of o-phenylenediamine with a variety of
aldehydes without harsh oxidants becomes more of a challenge
for chemists.
derivatives contribute to
a pool of inhibitory biological
activities.1,3b,4
Catalytic systems toward condensation of o-phenylenediamine
with various aldehydes for the preparation of 2-substituted
benzimidazoles have been reported often with Brönsted and
Lewis acids, especially, transition-metal (TM) catalysts such as
Fe(HSO4)3,6a
Cu3/2PMo12O40/SiO2,6b
CuO-nanoparticle,6c
Pt@TiO2 nanoparticle,6d SiO2/ZnCl2,6e Zn(OTf)2,6f In(OTf)3,6g
Sc(OTf)3,6h TiCl3OTf,6i CAN,6j Bi(NO3)3,6k VOSO4,6l LaCl3,6m
SDS,6n DBSA,6o K2S2O8-CuSO46p and recently ZnO nanoparticles
using a ball-milling technique.6q Although most of these catalysts
are quite satisfactory, some have serious drawbacks such as
unstable, difficult to use, less selective and expensive. In
particular, they are not reusable and are considered
environmental toxicants. At present, green and metal-free
reactions and reusable catalysts are highly desirable for the
preparation of pharmaceutical and important biological
compounds. Therefore, some attempts have been made to
synthesize selective 2-substituted benzimidazoles without metals
and/or with reusable catalysts.6e,6n,6t,6w,6x,6y,8a,9a,10a,12a However, this
still requires harsh conditions such as toxic oxidizing agents, high
temperature, microwave radiation, strong acid or base and/or
long reaction times.
Brönsted acidic ionic liquids (BAILs)14-23 have received
considerable attention as potential catalysts for acid-promoted
organic reactions, as they have been identified as eco-friendly
compounds as well as being nontoxic and reusable. To date,
many versatile and successful organic reactions have been
reported using BAILs as catalysts such as esterification,15
Mannich reaction,16 nitration,17 Beckmann rearrangement,18
Friedlander reaction,19 Michael addition reaction20 and Fridel-
Crafts reaction21. In 2010, acidic ionic liquid, [MBsIm][HSO4],
was employed as a catalyst for the synthesis of symmetrical 1,2-
disubstituted benzimidazoles (4) through condensation of o-
phenylenediamine with aromatic aldehydes, and 2-substituted
benzimidazole was not formed under this condition.22 Herein, we
present an efficient method for the synthesis of selectively 2-
substituted benzimidazoles (3) via condensation of o-
phenylenediamines (1) with a variety of aliphatic, aromatic and
heteroaromatic aldehydes (2) using Brönsted acidic ionic liquid
(BAIL) as a reusable catalyst under metal-free conditions at
ambient temperature in a short reaction time. Furthermore, this
protocol was utilized for the preparation of N-alkylated 1,2-
disubstituted benzimidazoles (5) in sequential one-pot two-step
process (Scheme 2).
Figure 1 Example of important benzimidazoles.
Synthetic methods of preparing benzimidazoles have
frequently employed two pathways. One includes a coupling
reaction of 2-haloanilides and their derivatives via transition-
metal-catalyzed intramolecular cyclization.5 A second employs a
condensation reaction of o-phenylenediamine with a variety of
carbonyl-containing molecules and their derivatives such as
aldehydes,6 ketones7 acid chlorides,8 carboxylic acids,4e,9 esters,10
β-ketoesters,11a-b β-diketones11c-d, orthoesters12 and alcohols.13
The latter method is a more convenient and easy procedure in
terms of operation and commercial availability of materials and
catalysts. However, this method generally provides products as a
mixture of 2-substituted and symmetrical 1,2-disubstituted
benzimidazoles through different mechanism pathways6e,6h,6k
(Scheme 1) because of non-regioselective of amino groups on a
benzene ring of o-phenylenediamine (1a), whereas 2-substituted
benzimidazole could be obtained as a sole product in the
Scheme 1. General mechanism pathways for formation of 2-
substituted benzimidazole (pathway a) and 1,2-disubstituted
benzimidazole (pathway b).
Scheme 2. Strategies for the synthesis of benzimidazoles.

3
toluene, 1,4-dioxane and THF solvents (entries 11-13)
2. Results and Discussion
ACCEPTED MANUSCRIPT
indicating their influence on the protocol in contrast to 95%
A series of BAILs (I-V) based-alkylimidazonium cation
(Figure 2) was prepared according to our previous report21a (see
supporting information) and explored as reusable catalysts for
this protocol.
EtOH, the best solvent in terms of yield of desired product (3a).
Table 1. Optimization of selective synthesis of 2-substituted
benzimidazole.a
Entry
Catalyst
(mol%)
Solvent
(mL)
Time
(h)
Yield (%)b
3a
4a
1
I (20)
20
20
3.0
3.0
3.0
3.0
3.0
4.0
6.0
5.0
4.0
5.0
5.0
5.0
73
86
98
78
12
98
98
98
83
85
72
68
14
10
0
Figure 2. Brönsted acidic ionic liquids (BAILs).
2
II (20)
III (20)
IV (20)
V (20)
III (10)
III (5)
III (5)
III (5)
III (5)
H2SO4 (5)
-
The synthesis of 2-substituted benzimidazole (3a) from o-
phenylenediamine (1a, 1.2 mmol) and benzaldehyde (2a, 1.0
mmol) was initially investigated using 20 mol% of acidic ionic
liquid-based dodecylimidazolium salts (I, II, and III) in 95%
EtOH (20 mL) at room temperature for 3.0 h (Table 1, entries 1-
3). The highest yield of the desired product (3a) was 98% with
catalyst III, which consists of HSO4 anion (entry 3). Lower
yields were found in the case of pTSA and OTf anions (73 and
86%, respectively) and also generated undesired product (4a) in
amounts of 10 and 14%, respectively (entries 1 and 2). These
results suggest that the counteranion plays the critical role in this
protocol.23 HSO4 anion exhibited excellent catalytic activity,
providing the highest yield of the desired product (3a) and better
than pTSA and OTf anions. Under the same condition, further
imidazolium ionic liquids bearing butylsulfonic acid with HSO4
anion (IV and V) were investigated as catalysts (entries 4 and 5).
Both catalysts IV and V gave lower yields of the desired product
(3a) than catalyst III. This indicated that acidic ionic liquid with
long alkyl-chain on imidazolium cation was a more effective
catalyst in facilitating selectively 2-substituted benzimidazole
formation. Subsequently, the effectiveness of catalyst III was
examined in decreasing amounts (5 and 10 mol%) resulting the
yield of desired product (3a) retained being highest (98%) with
slightly longer reaction times (entries 6-7). Notably, 5 mol% of
catalyst III with highly concentrated reaction volume (5 mL of
95% EtOH) produced desired product (3a) in the same 98% yield
after 5 h (entry 8). While a reduction of 95% EtOH volume to 1.0
mL gave the desired product in lower yield (83%) and generated
undesired product (4a) in 6% (entry 9). Unfortunately, when o-
phenylenediamine (1a) was reduced to 1.0 mmol, desired product
yield (3a) declined to 85% and generated undesired product (4a)
in 9% yield (entry 10). Therefore, the condition for this protocol
was chosen with 5 mol% of catalyst III in 5.0 mL of 95% EtOH
for 5 h (entry 8). In addition, the control reaction was treated with
general H2SO4 acid under the best condition and found to give
lower yields of the desired product (3a) in 72% and undesired
product (4a) in 14% (entry 11). Whereas, the reaction without a
catalyst (entry 12) provided a yield below that with catalyst III,
68% of the desired product (3a) and 5% of undesired product
(4a).
3
20
4
20
6
5
20
0
6
20
0
7
20
0
8
5.0
1.0
5.0
5.0
5.0
0
9
6
10c
11
12
9
13
5
aAll reactions were conducted with o-phenylenediamine (1a, 1.2 mmol),
benzaldehyde (2a, 1.0 mmol), catalyst (5-20 mol%), 95% EtOH (1-20 mL),
room temperature for 3-6 h. bIsolated yield. c1:1 mmol of 1a:2a.
Table 2. Optimization with various solvent.a
Entry
Solvent
Yield (%)b
3a
98
4a
0
1
95% EtOH
99% EtOH
MeOH
2
92
73
0
3
12
4
H2O
27 (50)c
trace (20)c
5
DMF
85
82
30
28
25
26
0
0
6
DMSO
DCM
trace
0
7
8
DCE
0
9
MeCN
0
Under the best condition (Table 1, entry 8), further screening
was conducted with various solvents (Table 2). High yields of
desired product (3a) were obtained with polar and protic solvents
such as EtOH, MeOH, DMF and DMSO (entries 1-6), except
water that gave low yields due to solubility difficulties with
organic molecules (entry 4) due to solubility difficulties with
organic molecules (entry 4). In contrast, less polar solvents such
as DCM, DCE and MeCN, including ionic liquid ([BMIm][Br])
produced unsatisfactory yields (<30%) of the desired product
(3a, entries 7-10). No product (3a) was obtained in the case of
10
11
12
13
[BMIm][Br]
toluene
1,4-Dioxane
THF
11
0
0
0
0
0
aAll reactions were conducted with o-phenylenediamine (1a, 1.2 mmol),
benzaldehyde (2a, 1.0 mmol), 5 mol% of [DodecIm][HSO4] (III) (5 mol%),
solvent (5.0 mL), room temperature for 5 h. bIsolated yield. c1:2 mmol of
1a:2a.

4
Tetrahedron
Compared to previous report,22 when a reaction of diamine (1a)
Table 3. Synthesis of 2-substituted benzimidazoles and
ACCEPTED MANUSCRIPT
and aldehyde (2a) was conducted with a ratio of 1:2 mmol in
water media, yield of undesired product (4a) was increased to
20% and the target product (3a) was obtained in 50% yield (entry
4, in parentheses) which was in contrary to previous method that
compound (4a) was afforded as the sole product. These results
confirmed that the stoichiometry of diamine and aldehyde played
an important role for this reaction; excess aldehyde substrate
could lead to the undesired product (4a) through the formation of
the diimine intermediate (Scheme 1). In addition, trace amount of
the diimine was also observed when the reactions were carried
out in MeOH, DMSO and [BMIm][Br] (entries 3, 6 and 10). It
should be noted that this protocol could prevent the diimine
formation probably due to the crucial structure of BAILs as
proposed in the mechanism (Scheme 3).
benzothiazoles with various substancesa
A plausible mechanism for selective synthesis of 2-substituted
benzimidazole via condensation of o-phenylenediamine with
aldehydes catalyzed by acidic ionic liquid ([DodecIm][HSO4]) is
proposed in Scheme 3. The effect of catalyst III is to force both
hydrophobic substrates to become close to the hydrophobic core
of the catalyst allowing the reaction to take place more easily.
Then hydrophilic imidazolium salt acts as a Brönsted acid to
activate aldehyde substrate by coordination at the oxygen atom.
On the other hand, amino group of o-phenylenediamine is
cooperatively coordinated with 2H-imidazolium salt via
hydrogen bonding,13b,13d this might allow only one side of an
amino group to attack an activated aldehyde to form an
intermediate A, followed by dehydration to form an intermediate
B. Finally, cyclization to form intermediate C and oxidation in
air provide the corresponding 2-substituted benzimidazoles.
Scheme 3. Plausible mechanism for selective synthesis of 2-
substituted benzimidazole using [DodecIm][HSO4] (III) as
catalyst.
Recycling performance of catalyst III was examined with
benzaldehyde as substrate. After the first run (Table 1, entry 8),
95% EtOH solvent was removed by evaporation. Catalyst III was
recovered by simple extraction with water (3×2 mL) and the
combined water layer was removed leaving catalyst III.
Recovered catalyst III was reused, giving similar yields of the
desirable product (3a) in 98, 98, 96 and 93% respectively, even
after four cycles. NMR analysis confirmed reused catalyst III
retained its structure.
aAll reactions were conducted with aniline (1, 1.2 mmol), aldehyde (2, 1.0
mmol), [DodecIm][HSO4] (III) (5 mol%), 95% EtOH (5.0 mL), room
temperature for 5-24 h. bRelative yields were reported as isolated yields.
cImine intermediate (4c, 4d and 4g). dBenzothiazole intermediate (4w). e60oC.
A variety of either aromatic and aliphatic aldehyde substrates
were evaluated employing the best condition (Table 1, entry 8).
Corresponding products were achieved in good to excellent
yields depending on electronic and steric effects of aldehyde
substrates (Table 3). Aromatic aldehyde substrates with electron
withdrawing substituents, including benzaldehyde produced
excellent yields of products 3a (98%), 3b (90%), 3e (97%) and 3f
(96%). While poor solubility groups (-NO2 and -CO2Me) on
aromatic aldehydes gave lower yield of products 3c (26%) 3d
(15%) and 3g (68%) along with imine intermediates (4c, 4d and
4g) and yield of 3c improved to excellent yield (98%) when the
reaction time was increased to 24 h. A sterically hindered group
at ortho-position on benzene ring of benzaldehyde reduced the
yield of 3h to 76%. However 3c, 3d, 3g and 3h improve to
excellent yields (96-98%) at an elevated reaction temperature (60
oC). Aromatic aldehyde substrates with electron donating
substituents provided moderate yields of products 3i (57%) and
3k (54%) and high yields of products 3j (75%) and 3l (83%).
Highest yields of these products 3i-3l were isolated with

5
prolonged reaction times, 12 h for products 3j, 3k and 3l (90-
98%) and 24 h for product 3i (75%). Heteoaromatic aldehyde
substrates were also successfully incorporated using this
protocol. Although N-Boc-pyrrole-2-carbaldehyde and pyrrole-2-
carbaldehyde gave equally low yield (21%) of products 3m and
3n with 5 h of reaction time, but yields were increased to 48% of
product 3m after 12h and 66% of product 3n after 24 h. While
furan-2-carbaldehyde and indole-3-carbaldehyde, which are more
reactive heteroaromatic aldehydes, gave higher in acceptable
yields of products 3o (45%) and 3p (30%) after 5 h, and good
yields were performed after 24 h (3o, 65% and 3p, 82%).
Interestingly, aliphatic aldehyde substrates also work well using
this protocol and gave satisfactory product yields of 3q (60%)
and 3r (69%), and increased to high yields (81 and 72%,
respectively) after 24 h. Indeed, aliphatic aldehyde with a
sterically hindered cyclopentanecarbadehyde provided in slightly
low yield of product 3s (28%) and could enhanced to moderate
yield (53%) after 24 h. For these aliphatic aldehyde substrates,
we found that no any aldol product was observed even long
reaction time (24 h). The reactions proceeded slowly; aliphatic
aldehyde substrates were remained after reaction (5 h) and
observed in trace amount with prolonged reaction time (24 h).
Furthermore, 2-amino-4-fluoroaniline (1c) was employed as
substrate, produced low yields of products 3t (31%) and 3u
(30%) due to low reactivity of substrate that bear electron-
withdrawing fluorine atoms on benzene rings, however yields
could be increased (82 and 71%, respectively) after 24 h. In
addition, the formation of benzothiazoles was also explored using
this protocol, providing high yields of products 3v (70%) and 3x
(76%) after 5 h, while excellent yield of 3v (93%) was obtained
after 24 h. Similar result was observed with para-
nitrobenzaldehyde substrate that provided relatively low yield of
product 3w and generated benzothiazoline intermediate 4w even
prolonged reaction time (24 h) due to poor solubility of substrate
and intermediate. However high reaction temperature could
improve solubility and provided excellent yields of product 3w in
93% yield.
aldehyde substrates. In addition, this method was successfully
ACCEPTED MANUSCRIPT
applied for the preparation of various N-alkylated 1,2-
disubstituted benzimidazoles in sequential one-pot process.
Table 4. Sequential one-pot synthesis of N-alkylated 1,2-
disubstituted benzimidazoles.[a]
Subsequently, synthetic application of this protocol was
investigated for the preparation of N-alkylated 1,2-disubstituted
benzimidazoles (5) via a sequential one-pot two-step procedure
a(i) o-phenylenediamine (1a, 1.2 mmol) or 2-amino-4-fluoroaniline (1c, 1.2
mmol), aldehyde (2, 1.0 mmol), [DodecIm][HSO4] (III, 5 mol%), 95% EtOH
(5 mL), room temperature for 12 h. (ii) alkyl bromide (6, 2.0 mmol), KOH
(Table 4).
A
reactive amino group on 2-substituted
benzimidazoles (3) could be constructed with several functional
groups to generate versatile N-alkylated 1,2-disubstituted
benzimidazole derivatives (5). After condensation reaction of o-
phenylenediamine (1a) or 2-amino-4-fluoroaniline (1c) with
aldehydes (2) in the first step (i), the crude product (3) was
directly transformed to target products (5) via conventional N-
alkylation with various alkyl halide substrates (6) in the second
step (ii). The corresponding products (5a-5z) were obtained in
good to excellent yields. Whereas, 2-amino-4-fluoroaniline (1c)
substrate gave two isomeric products in ratio 1:1 of N-alkylated
1,2-disubstituted 5- and 6-fluorobenzimidazoles with good to
high total yields of products 5ja and 5jb (80%), 5ka and 5kb
(94%) and 5xa and 5xb (69%).
b
(2.0 mmol), MeCN (5 mL), room temperature for 0.5-24 h. Isolated yield.
c(ii) alkyl chloride (6, 2.0 mmol), KOH (2.0 mmol), MeCN (5 mL), TBAI (20
mol%), rt-60oC for 15 h.
4. Experimental Section
4.1. General remarks
All chemicals were purchased from commercial sources and
1
used without further purification. H and 13C NMR spectra were
recorded using a BRUKER AVANCE (400 MHz) spectrometer
from Burapha University and a BRUKER AVANCE III HD (600
MHz) spectrometer from Vidyasirimedhi Institute of Science and
Technology (VISTEC). High-resolution mass spectra (HRMS)
data were recorded using a Bruker Daltonics-micrOTOF-Q at
Mahidol University and a Bruker Compact QTOF at VISTEC.
Infrared spectra were determined on a PERKIN ELMER FT/IR-
2000S spectrophotometer. Analytical thin-layer chromatrography
(TLC) was conducted on pre-coated TLC plates; silica gel 60 F-
254 [E. Merck, Darmstadt, Germany]. Open-column
chromatography was carried out using silica gel 60 (0.063-0.200
mm) [E. Merck, Darmstadt, Germany]. Melting points were
measured using a Melting point apparatus (Griffin) from Burapha
University and a Melting point meter (KRÜSS) from VISTEC.
3. Conclusion
In summary, we have demonstrated an efficient and simple
method for the selective synthesis of 2-substituted benzimidazole
from o-phenylenediamines with aldehydes using Brönsted acidic
ionic liquid as reusable catalyst under metal-free conditions at
ambient temperature. The acidic ionic liquid based-
dodecylimidazolium cation and HSO4 anion, named
[DodecIm][HSO4] showed the most efficient reusable catalyst to
afford the corresponding desirable products in high to excellent
yields with a variety of aliphatic, aromatic and heteroaromatic

6
Tetrahedron
4.2. General procedure for the synthesis of 2-substituted
MHz, DMSO-d ) δ: 5.32 (s, 2H), 6.58 (t, J = 7.2 Hz, 1H), 6.75
ACCEPTED MANUSCRIPT
6
benzimidazoles
(d, J = 7.2 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.8 Hz,
1H), 7.80 (t, J = 7.8 Hz, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.46 (d, J
= 7.2 Hz, 1H), 7.78 (s, 1H), 8.834 (s, 1H); 13C NMR (151 MHz,
DMSO-d6) δ: 114.90, 116.00, 117.13, 122.75, 124.96, 128.31,
130.22, 134.35, 138.28, 144.36, 148.27, 154.01, 160.18; HRMS
(ESI) m/z C13H11N3O2 [M+H]+ calcd 242.0930, found 242.0999.
To a solution of [DodecIm][HSO4]* (5.00 mol%, 16.7 mg) in
95% EtOH (5.00 mL) was added aldehyde (2) (1.00 mmol) and
o-phenylenediamine (1a), 2-aminothiophenol (1b) or 2-amino-4-
fluoroaniline (1c) (1.20 mmol) at room temperature respectively.
The reaction mixture was stirred at room temperature for 5-24 h
and monitored by TLC. After the reaction completed, the ethanol
solvent was removed by using rotary evaporator. The crude
residue was diluted with water (5.00 mL)# and extracted with
ethyl acetate (3×5 mL). The combine organic layer was dried
over sodium sulfate anhydrous and concentrated using rotary
evaporator. The crude product was purified by column
chromatography (SiO2, 5-50% ethyl acetate/n-hexane as eluent
depend on each derivatives) to give the desired products 3a-3x.
*Recycling experiment. After extraction, the water layer# was
removed to give the catalyst III. Recovered catalyst III was
reused directly by adding EtOH and substrates in the next run
without purification.
4.2.5. Imine intermediate (4d)
As a brown solid (204.3 mg, 85%, Table 3, rt, 5 h); m.p. 128-
o
130 C; Rf = 0.45 (20% EtOAc/n-hexane); IR (KBr): νmax 3462,
3371, 1596, 1516, 1342, 851, 755, 688 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ: 5.42 (brs, 2H), 6.57 (t, J = 8.0 Hz, 1H), 6.75 (d, J =
8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H),
8.26 (d, J = 8.8 Hz, 2H), 8.34 (d, J = 8.8 Hz, 2H), 8.84 (s, 1H);
13C NMR (100 MHz, DMSO-d6) δ: 115.07, 116.01, 117.01,
123.81, 123.81, 128.81, 129.36, 129.36, 133.94, 142.34, 144.88,
148.30, 153.41; HRMS (ESI) m/z C13H10N3O2 [M+H]+ calcd
242.0930, found 242.0939.
Spectral data of compounds 3a,5e-h,6a-c,6f-j,6l-s,6u,6z,6aa-ae,7,8a,9a,12a
4a,6e,6h,6n-o,6u,6y,6aa,22 3b,5d,6c,6i,6o,6ab,6ad,7 3c,6a-b,6f,6j-k,6n,6aa,7 3d,5d-e,5g,6a-
c,6i,6k,6m,6o,6r,6aa-ae,7,8a 3e,5h,6l,6ad 3f,6l,7 3g,7 3h,6r,6aa,7 3i,6b-c,6i-j,6m-n,6q-r,6aa,7
3j,5d-e,5g,6a-c,6f,6h-j,6l,6n-o,6r-s,6ab,6ad-ae,7,11b 3k,6r,6ab 3l,6l 3n,6o 3o,5e,6b,6h-i,6m-
4.2.6. Imine intermediate (4g)
As a organge solid (81.3 mg, 32%, Table 3, rt, 5 h); m.p. 198-
o
200 C; Rf = 0.70 (20% EtOAc/n-hexane); IR (KBr): νmax 2925,
1
2844, 1718, 1435, 1279, 1120, 743 cm-1; H NMR (600 MHz,
o,6s,6ab,6ad
3p,6k,6p,6u 3q,3a,6n,6ab,11b,6ae 3r,3a,26 3s,6z 3t,5d,5g,6p,6u
DMSO-d6) δ: 3.89 (s, 3H), 5.28 (brs, 2H), 6.57 (t, J = 7.2 Hz,
1H), 6.74 (d, J = 7.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 7.19 (d, J
= 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 2H), 8.13 (d, J = 7.8 Hz, 2H),
8.76 (s, 1H); 13C NMR (151 MHz, DMSO-d6) δ: 52.27, 114.89,
116.10, 116.99, 128.27, 128.61, 128.61, 129.44, 129.44, 131.09,
134.51, 140.69, 144.39, 154.84, 165.92; HRMS (APCI) m/z
C15H14N2O2 [M+H]+ calcd 255.1134, found 255.1171.
3v,5f,6a,6c,6j,6l,6n,6p-q,6u,6ab,6ac,8a,11b,12a
3w,6a,6c,6j,6n,6ac,8a
and
3x,5f,6a,6c,6j,6l,6n,6ab,11b were previously described in the literature.
4.2.1. 2-Phenylbenzimidazole (3a)
CAS Number 716-79-0; as a white solid (197.3 mg, 98%,
o
Table 3, rt, 5 h); m.p. 276-278 C; Rf = 0.31 (20% EtOAc/n-
hexane); IR (KBr): νmax 3036, 2958, 1463, 1445, 1411, 1276,
968, 739, 703, 498 cm-1; 1H NMR (400 MHz, DMSO-d6)
4.2.7. 2-(4-Nitrophenyl)benzothiazoline (4w)
As a yellow solid (163.1 mg, 63%, Table 3, rt, 24 h); m.p.
δ
7.15-7.25 (m, 2H), 7.47-7.59 (m, 4H), 7.67 (d, J = 7.6 Hz,
o
1H), 8.18 (d, J = 7.2 Hz, 2H), 12.91 (brs, 1H); 13C NMR (151
MHz, DMSO-d6) δ: 122.06, 126.42, 126.42, 128.90, 128.90,
129.79, 130.17, 151.22; HRMS (ESI) m/z C13H10N2 [M+H]+
calcd 195.0922, found 195.0923.
210-212 C; Rf = 0.22 (10% EtOAc/n-hexane); IR (KBr): νmax
1
3345, 1519, 1472, 1346, 1256, 744 cm-1; H NMR (400 MHz,
CDCl3) δ: 6.43 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.81 (t, J = 7.6
Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.69
(d, J = 8.4 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ: 68.19, 110.35, 121.28, 121.68, 123.94, 123.94,
125.75, 125.83, 125.83, 127.11, 145.74, 147.70, 149.25; HRMS
(APCI) m/z C13H11N2O2S [M+H]+ calcd 259.0541, found
259.0552.
4.2.2. 2-(2-Pyrrolyl-N-Boc)benzimidazole (3m)
As a white solid (135.9 mg, 48%, Table 3, rt, 12 h); m.p. 266-
o
268 C; Rf = 0.26 (20% EtOAc/n-hexane); IR (KBr): νmax 3060,
1
2980, 2684, 1743, 1317, 1158, 1097, 735 cm-1; H NMR (400
MHz, DMSO-d6) δ: 1.28 (s, 9H), 6.38 (t, J = 3.2 Hz, 1H), 6.67
(dd, J = 3.2, 1.6 Hz, 1H), 7.14-7.24 (m, 2H), 7.45-7.50 (m, 2H),
7.62 (d, J = 7.6 Hz, 1H), 12.54 (brs, 1H); 13C NMR (100 MHz,
DMSO-d6) δ: 27.05, 27.05, 27.05, 84.03, 110.93, 111.02, 117.26,
118.60, 121.22, 122.25, 123.71, 124.51, 134.13, 143.05, 145.26,
148.29; HRMS (ESI) m/z C16H17N3O2 [M+H]+ calcd 284.1399,
found 284.1414.
4.3. General procedure for the synthesis of N-alkylated 1,2-
disubstituted benzimidazoles
To a solution of [DodecIm][HSO4]* (5.00 mol%, 16.7 mg) in
95% EtOH (5.00 mL) was added aldehyde (2) (1.00 mmol) and
o-phenylenediamine (1a) (1.20 mmol, 129.8 mg) or 2-amino-4-
fluoroaniline (1c) (1.20 mmol, 151.2 mg) at room temperature
respectively. The reaction mixture was stirred at room
temperature for 12 h and then ethanol solvent was removed by
rotary evaporator. The crude residue was diluted with water (5.00
mL)# and extracted with ethyl acetate (3×5 mL). The combine
organic layer was concentrated using rotary evaporator. Then
crude residue was dissolved in acetonitrile (5.00 mL), followed
by adding KOH (2.00 mmol, 112 mg) and alkyl halide (2.00
mmol) at room temperature respectively. The reaction mixture
was stirred at room temperature for 0.5-24 h. After the reaction
completed, the reaction mixture was neutralized with sat. NH4Cl
and extracted with ethyl acetate (3×15 mL). The combine organic
layer was dried over sodium sulfate anhydrous and concentrated
using rotary evaporator. The crude product was purified by
column chromatography (SiO2, 10-50% ethyl acetate/n-hexane as
eluent depend on each derivatives) to give the desired products
5a-5z.
4.2.3. 2-(4-Bromophenyl)-6-fluorobenzimidazole
(3u)
As a yellow solid (206.7 mg, 71%, Table 3, rt, 24 h); m.p.
o
252-254 C; Rf = 0.29 (20% EtOAc/n-hexane); IR (KBr): νmax
1
3449, 1633, 1259, 1138, 1007, 799 cm-1; H NMR (400 MHz,
DMSO-d6) δ: 7.08 (t, J = 8.4 Hz, 1H), 7.39 (brs, 1H), 7.59 (brs,
1H), 7.77 (d, J = 8.8 Hz, 2H), 8.09 (d, J = 8.8 Hz, 2H), 13.13
(brs, 1H); 13C NMR (151 MHz, DMSO-d6) δ: 110.45, 123.41,
128.32, 128.32, 129.08, 131.96, 131.96, 151.64, 158.74 (d, JCF
=
228.0 Hz); HRMS (ESI) m/z C13H8BrFN2 [M+H]+ calcd
290.9933, found 290.9939.
4.2.4. Imine intermediate (4c)
As a orange solid (176.0 mg, 73%, Table 3, rt, 5 h); m.p. 101-
o
102 C; Rf = 0.63 (20% EtOAc/n-hexane); IR (KBr): νmax 3479,
1
3377, 3076, 1606, 1528, 1351, 750, 674 cm-1; H NMR (600

7
*Recycling experiment. After extraction, the water layer# was
Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
ACCEPTED MANUSCRIPT
removed to give the catalyst III. Recovered catalyst III was
reused directly by adding EtOH and substrates in the next run
without purification.
δ: 48.22, 55.15, 110.42, 111.78, 112.87, 117.97, 119.99, 122.83,
123.29, 124.47, 128.92, 130.23, 130.67, 131.95, 136.16, 137.78,
143.02, 152.89, 160.18; HRMS (APCI) m/z [M+H]+ calcd
C21H17BrN2O 393.0603, found 393.0602.
Spectral data of compounds 5b,24 5c,24 5l,3c 5o,26 and 5q,25
were previously described in the literature.
4.3.8. 1-(4-Nitrobenzyl)-2-(3,4-dimethoxyphenyl)benzimidazole
4.3.1. 1-(4-Nitrobenzyl)-2-phenylbenzimidazole
(5h)
o
(5a)
As a yellow solid (299.1 mg, 77%); m.p. 153-155 C. Rf =
0.48 (50% EtOAc/n-hexane); IR (KBr): νmax 3075, 2987, 2934,
o
As a yellow solid (268.8 mg, 82%); m.p. 136-138 C; Rf =
0.13 (20% EtOAc/n-hexane); IR (KBr): νmax 3060, 1602, 1522,
1344, 745, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ: 5.55 (s, 2H),
7.16 (d, J = 8.0 Hz, 1H), 7.24-7.31 (m, 3H), 7.36 (t, J = 7.2 Hz,
1H), 7.44-7.54 (m, 3H), 7.60-7.65 (m, 2H), 7.90 (d, J = 8.0 Hz,
1H), 8.21 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ:
47.77, 109.94, 120.23, 123.06, 123.40, 124.27, 124.27, 126.82,
126.82, 128.87, 128.87, 129.03, 129.03, 129.56, 130.15, 135.53,
143.10, 143.53, 147.53, 153.94; HRMS (APCI) m/z C20H15N3O2
[M+H]+ calcd 330.1243, found 330.1244.
1607, 1588, 1521, 1504, 1453, 1434, 1341, 1143, 1020, 852, 747
1
cm-1; H NMR (400 MHz, CDCl3) δ: 3.80 (s, 3H), 3.91 (s, 3H),
5.56 (s, 2H), 6.88 (d, J = 8.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.0 Hz,
1H), 7.15 (d, J = 8.0 Hz, 1H), 7.24-7.28 (m, 2H), 7.30 (d, J = 8.8
Hz, 2H), 7.35 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.22
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 47.23,
55.39, 55.59, 110.72, 111.69, 112.36, 119.19, 121.56, 122.01,
122.41, 122.73, 124.02, 127.30, 135.92, 142.66, 144.95, 146.85,
148.69, 150.19, 153.31; HRMS (APCI) m/z [M+H]+ calcd
C22H19N3O4 390.1454, found 390.1458.
4.3.2. 1-Benzyl-2-(4-bromophenyl)benzimidazole
(5d)
4.3.9. 1-(3-Methoxybenzyl)-2-(2,4-dichlorophenyl)benzimidazole
(5i)
As a white solid (321.6 mg, 89%); m.p. 141-143 oC; Rf = 0.23
(10% EtOAc/n-hexane); IR (KBr): νmax 3059, 2941, 1612, 1495,
1446, 1409, 1361, 1012, 840, 737, 725 cm-1; 1H NMR (400 MHz,
CDCl3) δ: 5.45 (s, 2H), 7.09 (d, J = 6.4 Hz, 2H), 7.22-7.38 (m,
6H), 7.57 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.89 (d, J
= 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 48.32, 110.46,
120.00, 122.87, 123.31, 124.51, 125.80, 127.88, 128.90, 129.12,
130.68, 131.97, 136.10, 142.98, 152.92; HRMS (APCI) m/z
[M+H]+ calcd C20H15BrN2 363.0497, found 363.0495.
As a colorless oil (378.7 mg, 98%); Rf = 0.43 (20% EtOAc/n-
hexane); IR (KBr): νmax 3055, 2934, 1599, 1586, 1490, 1451,
1262, 1041, 979, 781, 745, 689 cm-1; 1H NMR (400 MHz,
CDCl3) δ: 3.66 (s, 3H), 5.19 (s, 2H), 6.45 (s, 1H), 6.50 (d, J = 7.6
Hz, 1H), 6.73 (dd, J = 8.4, 1.6 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H),
7.23-7.32 (m, 4H), 7.37 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 1.6 Hz,
1H), 7.84 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
48.05, 55.07, 110.61, 112.42, 112.99, 118.72, 120.21, 122.64,
123.38, 127.34, 128.45, 129.70, 129.84, 133.06, 134.84, 135.10,
136.82, 137.14, 142.90, 150.07, 159.83; HRMS (APCI) m/z
[M+H]+ calcd C21H16Cl2N2O 383.0718, found 383.0718.
4.3.3. 1-Benzyl-2-(4-methoxyphenyl)benzimidazole
(5e)
As a white solid (240.2 mg, 77%); m.p. 137-139 oC. Rf = 0.46
4.3.10. 1-(3-Methoxybenzyl)-2-(4-methoxyphenyl)-5-
fluorobenzimidazole (5ja)
(40% EtOAc/n-hexane); IR (KBr): νmax 2971, 1610, 1483, 1452,
1
1363, 1180, 1035, 843, 744, 735, 727 cm-1; H NMR (400 MHz,
As a white solid (148.4 mg, 41%); m.p. 105-107 oC; Rf = 0.28
(20% EtOAc/n-hexane); IR (KBr): νmax 3055, 2942, 1602, 1576,
CDCl3) δ: 3.85 (s, 3H), 5.45 (s, 2H), 6.97 (d, J = 8.8 Hz, 2H),
7.12 (d, J = 7.2 Hz, 2H), 7.18-7.25 (m, 2H), 7.28-7.37 (m, 4H),
7.64 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 48.35, 55.31, 110.31, 114.19, 119.73, 122.41,
122.52, 122.73, 125.93, 127.69, 129.01, 130.66, 136.11, 136.52,
143.17, 154.12, 160.94; HRMS (APCI) m/z [M+H]+ calcd
C21H18N2O 315.1497, found 315.1497.
1478, 1465, 1437, 1386, 1253, 1138, 1028, 838, 789 cm-1; H
1
NMR (400 MHz, CDCl3) δ: 3.74 (s, 3H), 3.85 (s, 3H), 5.41 (s,
2H), 6.64 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.85 (dd, J = 8.0, 1.6
Hz, 1H), 6.95-7.01 (m, 3H), 7.11 (dd, J = 8.8, 4.4 Hz, 1H), 7.27
(t, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.8, 1.6 Hz, 1H), 7.65 (d, J = 7.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 48.47, 55.20, 55.36,
105.43 (d, JCF = 24.0 Hz), 110.67 (d, JCF = 10.0 Hz), 111.02 (d,
JCF = 26.0 Hz), 111.82, 112.91, 114.28, 118.05, 121.90, 130.25,
130.63, 132.57, 137.79, 143.39 (d, JCF = 12.0 Hz), 155.50,
159.63 (d, JCF = 236.0 Hz), 160.22, 161.09; HRMS (APCI) m/z
[M+H]+ calcd C22H19FN2O2 363.1509, found 363.1510.
4.3.4. 1-Benzyl-2-(4-
trifluoromethanephenyl)benzimidazole (5f)
As a white solid (313.1 mg, 89%); m.p. 133-135 oC; Rf = 0.31
(15% EtOAc/n-hexane); IR (KBr): νmax 3033, 2950, 1619, 1495,
1450, 1417, 1127, 854, 742, 732 cm-1; 1H NMR (400 MHz,
CDCl3) δ: 5.47 (s, 2H), 7.10 (d, J = 6.8 Hz, 2H), 7.24-7.30 (m,
2H), 7.31-7.39 (m, 4H), 7.72 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.4
Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ: 48.35, 110.55, 120.20, 123.02, 123.61, 123.78 (q, JCF = 271.0
Hz), 125.67 (q, JCF = 3.0 Hz), 125.76, 127.96, 129.16, 129.56,
131.69 (q, JCF = 33.0 Hz), 133.53, 135.97, 136.17, 143.02,
152.39; HRMS (APCI) m/z [M+H]+ calcd C21H15F3N2 353.1266,
found 353.1267.
4.3.11. 1-(3-Methoxybenzyl)-2-(4-methoxyphenyl)-6-
fluorobenzimidazole (5jb)
As a white solid (141.2 mg, 39%); m.p. 141-143 oC; Rf = 0.23
(20% EtOAc/n-hexane); IR (KBr): νmax 3076, 2970, 1599, 1476,
1458, 1435, 1420, 1387, 1245, 1179, 1028, 993, 849, 807, 785
1
cm-1; H NMR (400 MHz, CDCl3) δ: 3.75 (s, 3H), 3.85 (s, 3H),
5.36 (s, 2H), 6.63 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.82-6.90 (m,
2H), 6.97 (d, J = 8.8 Hz, 2H), 7.00-7.08 (m, 1H), 7.24-7.30 (m,
1H), 7.62 (d, J = 8.4 Hz, 2H), 7.73-7.80 (m, 1H); 13C NMR (100
MHz, CDCl3) δ: 48.46, 55.21, 55.36, 97.14 (d, JCF = 27.0 Hz),
110.91 (d, JCF = 24.0 Hz), 111.87, 112.94, 114.27, 118.08,
120.35 (d, JCF = 10.0 Hz), 121.93, 130.29, 130.59, 136.22 (d, JCF
= 13.0 Hz), 137.55, 139.32, 154.82, 159.64 (d, JCF = 239.0 Hz),
160.24, 161.01; HRMS (APCI) m/z [M+H]+ calcd C22H19FN2O2
363.1509, found 363.1510.
4.3.5. 1-(3-Methoxybenzyl-2-(4-
bromophenyl)benzimidazole (5g)
As a white solid (386.4 mg, 98%); m.p. 127-129 oC; Rf = 0.28
(10% EtOAc/n-hexane); IR (KBr): νmax 3028, 2970,2937, 1609,
1
1583, 1441, 1456, 1048, 831, 738 cm-1; H NMR (400 MHz,
CDCl3) δ: 3.74 (s, 3H), 5.41 (s, 2H), 6.63 (s, 1H), 6.67 (d, J = 7.6
Hz, 1H), 6.84 (dd, J = 8.4, 2.0 Hz, 1H), 7.23-7.30 (m, 3H), 7.33
(td, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.8

8
Tetrahedron
ACCEPTED MANUSCRIPT
4.3.12. 1-Benzyl-2-(4-bromophenyl)-5-fluorobenzimidazole
4.3.20. 1-Octyl-2-(4-bromophenyl)benzimidazole (5r)
(5ka)
As a yellow oil (294.3 mg, 77%); Rf = 0.34 (10% EtOAc/n-
As a white solid (170.9 mg, 45%); m.p. 167-169 oC; Rf = 0.43
hexane); IR (KBr): νmax 2925, 1613, 1599, 1451, 1404, 1365,
1329, 1076, 1010, 832, 742 cm-1; 1H NMR (400 MHz, CDCl3) δ:
0.86 (t, J = 7.2 Hz, 3H), 1.15-1.30 (m, 10H), 1.72-1.85 (m, 2H),
4.20 (t, J = 7.6 Hz, 2H), 7.28-7.35 (m, 2H), 7.39-7.43 (m, 1H),
7.59 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.79-7.84 (m,
1H); 13C NMR (100 MHz, CDCl3) δ: 14.01, 22.52, 26.59, 28.88,
28.99, 29.69, 31.62, 44.70, 110.10, 119.94, 122.46, 122.86,
124.19, 129.57, 130.76, 131.92, 135.54, 142.95, 152.41; HRMS
(APCI) m/z [M+H]+ calcd C21H25BrN2 385.1279, found
385.1279.
(20% EtOAc/n-hexane); IR (KBr): νmax 3032, 1622, 1590, 1464,
1440, 1412, 1362, 1143, 831, 797 cm-1; H NMR (400 MHz,
1
CDCl3) δ: 5.43 (s, 2H), 7.01 (t, J = 9.2 Hz, 1H), 7.08 (d, J = 7.2
Hz, 2H), 7.12 (dd, J = 8.8, 4.4 Hz, 1H), 7.30-7.39 (m, 3H), 7.51-
7.57 (m, 3H), 7.60 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ: 48.49, 105.70 (d, JCF = 24.0 Hz), 110.87 (d, JCF = 10.0
Hz), 111.63 (d, JCF = 26.0 Hz), 124.75, 125.74, 128.02, 128.61,
129.19, 130.59, 132.05, 132.59, 135.77, 143.42 (d, JCF = 13.0
Hz), 154.34, 159.66 (d, JCF = 237.0 Hz); HRMS (APCI) m/z
[M+H]+ calcd C20H14BrFN2 381.0403, found 381.0403.
4.3.21. 1-Octyl-2-(4-methoxyphenyl)benzimidazole (5s).
As a yellow oil (268.5 mg, 80%); Rf = 0.43 (40% EtOAc/n-
hexane); IR (KBr): νmax 2926, 1611, 1534, 1482, 1454, 1386,
4.3.13. 1-Benzyl-2-(4-bromophenyl)-6-fluorobenzimidazole
(5kb).
As a white solid (186.1 mg, 49%); m.p. 149-151 oC; Rf = 0.37
(20% EtOAc/n-hexane); IR (KBr): νmax 3032, 1618, 1513, 1467,
1365, 1249, 1175, 1028, 836, 745 cm-1; H NMR (400 MHz,
1
CDCl3) δ: 0.86 (t, J = 7.2 Hz, 3H), 1.15-1.30 (m, 10H), 1.82
(pentet, J = 7.2 Hz, 2H), 3.89 (s, 3H), 4.20 (t, J = 7.6 Hz, 2H),
7.04 (d, J = 8.4 Hz, 2H), 7.27-7.32 (m, 2H), 7.37-7.42 (m, 1H),
7.65 (d, J = 8.8 Hz, 2H), 7.78-7.83 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 14.01, 22.53, 26.63, 28.91, 29.01, 29.66, 31.65, 44.65,
55.31, 109.94, 114.09, 119.61, 122.18, 122.37, 122.82, 130.66,
135.50, 142.89, 153.58, 160.66; HRMS (APCI) m/z [M+H]+
calcd C22H28N2O 337.2280, found 337.2285.
1451, 1409, 1363, 1011, 797, 824 cm-1; H NMR (400 MHz,
1
CDCl3) δ: 5.39 (s, 2H), 6.89 (dd, J = 8.4, 2.0 Hz, 1H), 7.05-7.10
(m, 3H), 7.30-7.39 (m, 3H), 7.53 (d, J = 8.8 Hz, 2H), 7.59 (d, J =
8.4 Hz, 2H), 7.78 (dd, J = 8.8, 4.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 48.49, 97.21 (d, JCF = 28.0 Hz), 111.30 (d, JCF = 25.0
Hz), 120.79 (d, JCF = 10.0 Hz), 124.62, 125.76, 127.44, 128.06,
128.62, 129.22, 130.56, 132.04, 135.55, 136.26 (d, JCF = 13.0
Hz), 153.64 (d, JCF = 3.0 Hz), 159.84 (d, JCF = 240.0 Hz); HRMS
(APCI) m/z [M+H]+ calcd C20H14BrFN2 381.0403, found
381.0400.
4.3.22. 1-Morpholinopropyl-2-phenylbenzimidazole (5t)
CAS Number 32926-95-7; as a coloress oil (314.9 mg, 98%);
Rf = 0.13 (50% EtOAc/n-hexane); IR (KBr): νmax 2954, 2850,
2805, 2340, 1737, 1601, 1444, 1392, 1272, 1117, 745, 700 cm-1;
1H NMR (400 MHz, CDCl3) δ: 1.91 (pentet, J = 6.8 Hz, 2H),
2.20-2.28 (m, 6H), 3.60 (t, J = 4.0 Hz, 4H), 4.37 (t, J = 7.2 Hz,
2H), 7.29-7.33 (m, 2H), 7.43-7.47 (m, 1H), 7.50-7.54 (m, 3H),
7.71-7.75 (m, 2H), 7.80-7.84 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ: 26.22, 42.27, 53.25, 54.97, 66.63, 109.92, 119.77,
122.17, 122.48, 128.51, 129.12, 129.51, 130.52, 135.48, 142.91,
153.45; HRMS (APCI) m/z [M+H]+ calcd C20H23N3O 322.1919,
found 322.1958.
4.3.15. 1-Chloropropyl-2-(4-bromophenyl)benzimidazole (5m)
As a white solid (289.1 mg, 83%); m.p. 119-121 oC; Rf = 0.31
(10% EtOAc/n-hexane); IR (KBr): νmax 2921, 1612, 1599, 1451,
1435, 1365, 1250, 827, 738 cm-1; 1H NMR (400 MHz, CDCl3) δ:
2.24 (pentet, J = 6.8 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 4.45 (t, J =
7.2 Hz, 2H), 7.30-7.37 (m, 2H), 7.44-7.49 (m, 1H), 7.60 (d, J =
8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.81-7.85 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ: 32.26, 41.46, 41.89, 109.92, 120.12,
122.82, 123.24, 124.49, 129.12, 130.75, 132.09, 135.46, 142.90,
152.38; HRMS (APCI) m/z [M+H]+ calcd C16H14BrClN2
349.0107, found 349.0100.
4.3.23. 1-Morpholinopropyl-2-(2,4-
dichlorophenyl)benzimidazole (5u)
4.3.16. 1-Chloropropyl-2-(4-methoxyphenyl)benzimidazole (5n)
As a yellow solid (285.8 mg, 95%); m.p. 73-75 oC; Rf = 0.57
(40% EtOAc/n-hexane); IR (KBr): νmax 2939, 1608, 1455, 1426,
As a colorless oil (330.2 mg, 85%); Rf = 0.17 (50% EtOAc/n-
hexane); IR (KBr): νmax 2953, 2854, 1598, 1552, 1446, 1400,
1
1371, 1115, 827, 782, 746 cm-1; H NMR (400 MHz, CDCl3) δ:
1
1365, 1251, 1179, 1023, 837, 745 cm-1; H NMR (400 MHz,
1.83 (pentet, J = 7.2 Hz, 2H), 2.20 (t, J = 6.8 Hz, 2H), 2.26 (brt, J
= 4.0 Hz, 4H), 3.61 (t, J = 4.4 Hz, 4H), 4.15 (t, J = 7.6 Hz, 2H),
2.29-2.37 (m, 2H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.45-7.50 (m,
2H), 7.58 (d, J = 2.0 Hz, 1H), 7.81-7.86 (m, 1H); 13C NMR (100
MHz, CDCl3) δ: 26.23, 42.16, 53.33, 55.04, 66.71, 110.10,
120.27, 122.47, 123.10, 127.39, 128.89, 129.77, 132.95, 134.79,
135.10, 136.80, 142.96, 149.69; HRMS (APCI) m/z [M+H]+
calcd C20H21Cl2N3O 390.1140, found 390.1144.
CDCl3) δ: 2.24 (pentet, J = 7.6 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H),
3.88 (s, 3H), 4.44 (t, J = 7.6 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H),
7.28-7.34 (m, 2H), 7.42-7.47 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H),
7.79-7.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 32.28, 41.61,
41.86, 55.35, 109.75, 114.25, 119.75, 122.35, 122.51, 122.74,
130.63, 135.41, 142.81, 153.51, 160.83; HRMS (APCI) m/z
[M+H]+ calcd C17H17ClN2O 301.1108, found 301.1108.
4.3.18. 2-(4-Trifluoromethanephenyl)-1-propargylbenzimidazole
4.3.24. 2-Propyl-1-phenylbenzimidazole (5v)
(5p)
As a colorless oil (182.7 mg, 73%); Rf = 0.48 (20% EtOAc/n-
hexane); IR (KBr): νmax 3032, 2963, 2931, 1615, 1509, 1496,
1454, 1409, 1356, 741, 727 cm-1; 1H NMR (400 MHz, CDCl3) δ:
1.02 (t, J = 7.2 Hz, 3H), 1.88 (sextet, J = 7.2 Hz, 2H), 2.88 (t, J =
7.6 Hz, 2H), 5.37 (s, 2H), 7.02-7.07 (m, 2H), 7.22-7.34 (m, 6H),
7.82 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 13.92,
20.96, 29.39, 46.78, 109.42, 119.13, 121.91, 122.19, 126.02,
127.77, 128.88, 135.25, 135.95, 142.51, 155.24; HRMS (APCI)
m/z [M+H]+ calcd C17H18N2 251.1548, found 251.1550.
o
As a white solid (252.3 mg, 84%); m.p. 121-123 C; Rf = 0.34
(10% EtOAc/n-hexane); IR (KBr): νmax 3175, 2971, 2115, 1615,
1458, 1417, 1314, 1324, 1165, 1109, 848, 733 cm-1; H NMR
1
(400 MHz, CDCl3) δ: 2.52 (brs, 1H), 4.94 (d, J = 2.0 Hz, 2H),
7.36-7.45 (m, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 8.0 Hz,
2H), 7.88 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ: 34.75, 74.35, 77.00, 110.06, 120.26,
123.25, 123.77, 123.78 (q, JCF = 271.0 Hz), 125.85 (q, JCF = 4.0
Hz), 129.68, 131.90 (q, JCF = 33.0 Hz), 133.05, 135.43, 142.77,
151.40; HRMS (APCI) m/z [M+H]+ calcd C17H11F3N2 301.0953,
found 301.0957.
4.3.25. 2-Propyl-1-(4-fluorophenyl)benzimidazole (5w)
As a colorless oil (177.2 mg, 66%); Rf = 0.46 (40% EtOAc/n-
hexane); IR (KBr): νmax 2969, 2932, 1606, 1508, 1460, 1408,

9
1220, 1157, 820, 740 cm-1; 1H NMR (400 MHz, CDCl ) δ: 1.01
(t, J = 7.2 Hz, 3H), 1.86 (sextet, J = 7.6 Hz, 2H), 2.81 (t, J = 7.6
Special thanks to Prof. Dr. Frederick W.H. Beamish, Faculty of
ACCEPTED MANUSCRIPT
3
Science, Burapha University, for his comments and English
correction.
Hz, 2H), 5.31 (s, 2H), 6.96-7.04 (m, 4H), 7.16-7.28 (m, 3H), 7.77
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 13.95, 21.00,
29.42, 46.19, 109.32, 115.90 (d, JCF = 21.0 Hz), 119.26, 122.08,
122.33, 127.76 (d, JCF = 8.0 Hz), 131.71 (d, JCF = 3.0 Hz),
135.10, 142.52, 155.11, 162.22 (d, JCF = 245.0 Hz); HRMS
(APCI) m/z [M+H]+ calcd C17H17FN2 269.1454, found 269.1454.
References and notes
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4.3.26. 1-Chloropropyl-2-isobutyl-5-fluorobenzimidazole (5xa)
As a yellow oil (94.1 mg, 35%); Rf = 0.20 (20% EtOAc/n-
hexane); IR (KBr): νmax 2959, 1625, 1597, 1484, 1445, 1409,
1
1367, 1134, 959, 853, 796 cm-1; H NMR (400 MHz, CDCl3)
δ: 1.04 (d, J = 6.8 Hz, 6H), 2.26 (pentet, J = 6.8 Hz, 2H), 2.28-
2.38 (m, 1H), 2.77 (d, J = 7.2 Hz, 2H), 3.55 (t, J = 6.0 Hz, 2H),
4.32 (t, J = 6.8 Hz, 2H), 6.99 (td, J = 9.2, 2.4 Hz, 1H), 7.24-7.29
(m, 1H), 7.40 (dd, J = 9.2, 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 22.54, 28.03, 32.23, 36.19, 40.52, 41.39, 105.05 (d, JCF
= 24.0 Hz), 109.27 (d, JCF = 10.0 Hz), 110.13 (d, JCF = 26.0 Hz),
131.18, 143.05 (d, JCF = 12.0 Hz), 155.90, 159.20 (d, JCF = 235.0
Hz); HRMS (APCI) m/z [M+H]+ calcd C14H18ClFN2 269.1221,
found 269.1229.
4.3.27. 1-Chloropropyl-2-isobutyl-6-fluorobenzimidazole (5xb)
As a yellow oil (91.4 mg, 34%); Rf = 0.17 (20% EtOAc/n-
hexane); IR (KBr): νmax 2959, 2928, 1624, 1599, 1481, 1467,
1446, 1407, 1367, 1176, 1135, 959, 830, 809 cm-1; 1H NMR (400
MHz, CDCl3) δ: 1.04 (d, J = 6.8 Hz, 6H), 2.25 (pentet, J = 6.4
Hz, 2H), 2.28-2.38 (m, 1H), 2.76 (d, J = 7.6 Hz, 2H), 3.55 (t, J =
6.4 Hz, 2H), 4.28 (t, J = 7.2 Hz, 2H), 6.98 (td, J = 9.6, 2.4 Hz,
1H), 7.04 (dd, J = 8.8, 2.4 Hz, 1H), 7.64 (dd, J = 8.8, 4.8 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ: 22.58, 28.02, 32.10, 36.17,
40.59, 41.40, 95.98 (d, JCF = 27.0 Hz), 110.08 (d, JCF = 25.0 Hz),
110.08 (d, JCF = 25.0 Hz), 134.80 (d, JCF = 13.0 Hz), 138.96,
155.06 (d, JCF = 3.0 Hz), 159.33 (d, JCF = 238.0 Hz); HRMS
(APCI) m/z [M+H]+ calcd C14H18ClFN2 269.1221, found
269.1221.
4. (a) Taha, M.; Ismail, N. H.; Imran, S.; Selvaraj, M.; Rashwan, H.;
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4.3.28. 2-(2-Furyl)-1-propargylbenzimidazole (5y)
As a yellow solid (164.2 mg, 74%); m.p. 79-81 oC; Rf = 0.28
(20% EtOAc/n-hexane); IR (KBr): νmax 3210, 3009, 2919, 2118,
1608, 1511, 1457, 1389, 1335, 1022, 734 cm-1; H NMR (400
1
MHz, CDCl3) δ: 2.37 (t, J = 1.6 Hz, 1H), 5.27 (d, J = 2.0 Hz,
2H), 6.64 (brt, J = 1.2 Hz, 1H), 7.30-7.40 (m, 3H), 7.51 (d, J =
8.0 Hz, 1H), 7.68 (brs, 1H), 7.82 (d, J = 6.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ: 34.54, 73.66, 77.20, 109.78, 112.21,
113.82, 119.64, 123.47, 123.66, 134.65, 141.99, 143.17, 144.42,
144.56; HRMS (APCI) m/z [M+H]+ calcd C14H10N2O 223.0871,
found 223.0871.
4.3.29. 2-(2-Furyl)-1-phenylbenzimidazole (5z)
As a white solid (179.3 mg, 65%); m.p. 131-133 oC; Rf = 0.34
(20% EtOAc/n-hexane); IR (KBr): νmax 3031, 1619, 1514, 1450,
1424, 1227, 1026, 736 cm-1; 1H NMR (400 MHz, CDCl3) δ: 6.56
(dd, J = 3.2, 1.6 Hz, 1H), 7.14 (d, J = 6.8 Hz, 2H), 7.23-7.34 (m,
7H), 7.58 (brs, 1H), 7.84 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ: 48.21, 109.92, 111.99, 112.66, 119.81, 122.84,
123.19, 126.16, 127.66, 128.83, 135.68, 136.29, 143.02, 143.98,
144.37, 145.15; HRMS (APCI) m/z [M+H]+ calcd C18H14N2O
275.1184, found 275.1189.
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Financial support was provided by the Research Grant of
Burapha University through National Research Council of
Thailand (Grant nos. 147/2560 and 162/2561) and the Center of
Excellence for Innovation in Chemistry (PERCH-CIC) and

10
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Supplementary Material