Design, synthesis and biological evaluation of novel hybrid compounds of imidazole scaffold-based 2-benzylbenzofuran as potent anticancer agents

Article abstract of DOI:10.1016/j.ejmech.2012.12.040

A series of novel hybrid compounds between 2-benzylbenzofuran and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl

Full text of DOI:10.1016/j.ejmech.2012.12.040

European Journal of Medicinal Chemistry 62 (2013) 111e121
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and biological evaluation of novel hybrid
compounds of imidazole scaffold-based 2-benzylbenzofuran
as potent anticancer agents
Xue-Quan Wang a, Lan-Xiang Liu a, Yan Li b, Cheng-Jun Sun a, Wen Chen a, Liang Li a,
,
Hong-Bin Zhang a, Xiao-Dong Yang a
*
a Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology,
Yunnan University, Kunming 650091, PR China
b State Key Laboratory for Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science,
Kunming 650204, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel hybrid compounds between 2-benzylbenzofuran and imidazole has been prepared and
evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzi-
midazoleringand substitutionof the imidazolyl-3-positionwitha naphthylacyl or 4-methoxyphenacylgroup
were vital for modulating cytotoxic activity. In particular, hybrid compounds 46 and 47 were found to be the
most potent derivatives against 5 strains human tumor cell lines and more active than cisplatin (DDP), and
exhibited cytotoxic activities selectively against breast carcinoma (MCF-7) and myeloid liver carcinoma
(SMMC-7721), respectively.
Received 7 October 2012
Received in revised form
20 November 2012
Accepted 23 December 2012
Available online 3 January 2013
Keywords:
Ó 2013 Elsevier Masson SAS. All rights reserved.
Hybrid compound
2-Benzylbenzofuran
Imidazole
Cytotoxic activities
Structureeactivity relationships
1. Introduction
reported [10e13], especially antitumor activity [14,15]. For example,
two new imidazolium halides (Scheme 1), Lepidiline A and Lep-
Design and synthesis of new types of pharmacologically interesting
hybrid compounds for drug discovery have received much attention
during the past two decades [1e3]. Substituted-benzofurans are an
important class of biologically active oxygen-containing heterocycles.
Natural and synthetic products possessing the 2-benzylbenzofuran
moiety exhibit a broad range of biological and pharmacological ac-
tivities [4e7]. Recently, 2-benzylbenzofuran derivatives have been
identified to possess antitumor activity [8,9]. As exemplified in
Scheme 1, (2,4-dimethoxyphenyl)-[6-(3-fluorophenyl)-4-hydroxy-
3-methylbenzofuran-2-yl]methanone (DMFBM) [9] was 2-benzy
lbenzofuran derived compound exhibiting potent cytotoxic activities
against human lung carcinoma cells.
idiline B, isolated from the roots of Lepidium meyenii, showed potent
cytotoxic activity against the human cancer cell lines [16]. Recently,
we have reported the synthesis of a series of novel hybrid com-
pounds of benzofurans and imidazols moieties and their potential
antitumor activities [17e21]. Studies on molecular mechanisms
demonstrated that the imidazolium salt hybrids can induce the G1
phase cell cycle arrest and apoptosis in tumor cells [20].
Considering the anticancer activities of natural and synthetic 2-
benzylbenzofuran derivatives, as well as the potent cytotoxic ac-
tivities of imidazole derivatives, we were interested in synthesizing
a number of new hybrid compounds bearing 2-benzylbenzofuran
(as shown pink shadows in Scheme 1) and substituted imidazole
(as shown green shadows in Scheme 1).
Although dihydrobenzofuran-triazole hybrid compounds were
synthesized and found to possess antitubercular activity by Tripathi
[22], and some benzofuran-based hybrid compounds were syn-
thesized and found to exhibit cholinesterase inhibitory activity by
Rampa [23], to the best of our knowledge, no reports concerning
antitumor activity for 2-benzylbenzofuran-based imidazolium salt
hybrids have been reported.
Imidazole and its derivatives have attracted considerable in-
terests in recent years for their versatile properties in chemistry and
pharmacology. Biological activities of imidazolium salts have been
* Corresponding author. Tel.: þ86 871 5031119; fax: þ86 871 5035538.
E-mail addresses: xdyang@ynu.edu.cn, xdyang120@gmail.com (X.-D. Yang).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.12.040

112
X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
a series of 2-benzylbenzofuran-imidazole hybrids 7e47. Thus, the
2-Benzylbenzofuran moieties
Imidazole derivatives
key step in the formation of the phenylbenzofuran backbone was
readily achieved by reacting salicylaldehydes 1 with phenacyl bro-
mide 2 to produce (benzofuran-2-yl)(phenyl)methanone (3, 92%
yield) in base-mediated reaction for 12 h. Then, the (benzofuran-2-
yl)(phenyl)methanone 3 were reduced with NaBH4 to the respec-
tive (benzofuran-2-yl)(phenyl)methanol compound (4, 95% yields).
Subsequently, the (benzofuran-2-yl)(phenyl)methanol 4 was trans-
formed via the mesylate to the respective four 2-benzylbenzofurane
imidazole hybrids 6e9 with various substituted imidazole (imida-
zole, 2-methyl-imidazole, 2-ethyl-imidazole or benzimidazole)
by refluxing under acetonitrile with 60e75% yields (two steps).
Finally, thirty-eight novel 2-benzylbenzofuran-based imidazolium
salts 10e47 were prepared with excellent yields by reaction of 2-
benzylbenzofuraneimidazole hybrids 7e10 with the corresponding
alkyl and phenacyl halides in refluxing acetone (69e99% yields). The
structures and yields of hybrid compounds are shown in Table 1.
OH
Me
O
OMe
OMe
N
N
F
O
Cl
R
lepidiline A R = H
DMFBM
lepidiline B R = CH3
Molecular
hybridization
R
R
N
N
N
N
X
R'
O
O
2.2. Biological evaluation and structureeactivity relationship
analysis
Scheme 1. Design of novel hybrid compounds.
The cytotoxic potential of all newly synthesized hybrid com-
pounds was evaluated in vitro against a panel of human tumor cell
lines according to procedures described in the literature [24,25].
The panel consisted of leukemia (HL-60), lung carcinoma (A549),
colon carcinoma (SW480), breast carcinoma (MCF-7) and myeloid
liver carcinoma (SMMC-7721). Cisplatin (DDP) was used as the
reference drug. The results are summarized in Table 2 (IC50 value,
defined as the concentrations corresponding to 50% growth
inhibition).
In the present research, we designed and synthesized a series of
novel hybrid compounds of imidazole scaffold-based 2-benzylb
enzofurans. The purpose of this study was to investigate the anti-
tumor activity of 2-benzylbenzofuran-imidazole hybrids, with the
ultimate aim of developing novel potent antitumor agents.
2. Results and discussion
As shown in Table 2, the structures of the hybrid compounds have
an obviousinfluenceonthecytotoxicactivities.2-Benzylbenzofurane
imidazole hybrids 7e10 lacked activities against all tumor cell lines
2.1. Chemistry
As shown in Scheme 2, commercially available salicylaldehyde
1 was chosen as the starting material for the preparation of
investigated at the concentration of 40 mM. However, their imidazo-
lium salts 10e47 exhibited some degree of cytotoxic activities or
higher cytotoxic activities. This difference in cytotoxicity between
neutral compounds and imidazolium salts may be due to the changes
of molecular structure, charge distribution and water solubility [26].
In terms of the imidazole ring (imidazole, 2-methyl-imidazole,
or 2-ethyl-imidazole, and benzimidazole), imidazolium salt hy-
brids 10e19 with imidazole ring displayed weak cytotoxic activ-
ities. Only compounds 15 and 18 showed medium cytotoxic
O
O
O
Br
Acetone, K2CO3
rt, 12h, 92%
H
O
OH
1
2
3
rt, 2h
95%
NaBH4
DCM/MeOH
activities with IC50 values of 2.64e8.47
mM against HL-60 and
SMMC-7721 cell lines, and compound 19 with a naphthylacyl
substituent at position-3 of the imidazole ring displayed higher
cytotoxic activity in vitro compared with DDP (except SW480).
Meanwhile, imidazolium salt hybrids 20e28 with 2-methyl-imi-
dazole ring and 29e37 with 2-ethyl-imidazole ring exhibited
medium cytotoxic activities. Among them, compounds 27, 28, 36
and 37, bearing a 4-methoxyphenacyl or naphthylacyl substituent
at position-3 of the 2-substituted imidazole, showed similar or
higher cytotoxic activities in vitro compared with DDP. However,
imidazolium salt hybrids 38e47 with benzimidazole ring exhibi-
ted powerful cytotoxic activities. Most of this kind of derivatives
was found to be much more active than DDP, such as compounds
40, 43, 44, 46 and 47. Among them, compounds 46 and 47, also
bearing a 4-methoxyphenacyl or naphthylacyl substituent at
position-3 of the benzimidazole, showed potent cytotoxic activ-
MsCl, Et3N
DCM
OMs
OH
O
O
rt, 12h
R
MeCN, reflux
24-48h
NH
4
5
N
two steps, 60%-75%
R
R
R'
X
Method A:
N
N
N
N
R'
Acetone, reflux, 8-24h
X
Method B:
O
O
DMF, rt, 12h
69%-99%
ities with IC50 values of 1.02e3.57 mM against five human tumor
6-9
10-47
cell lines investigated.
imidazole ring
imidazole
In terms of the substituent at position-3 of imidazole ring,
imidazolium salt hybrids 10e13, 20e22, 29, 30, and 38 with butyl,
allyl or benzyl substituent, as well as hybrids 17, 26, 35 and 45
with 4-hydroxyphenacyl substituent at position-3 of imidazole
ring showed lacked activities against five tumor cell lines.
6
R' = phenacyl or aklyl
X = Br or I
7
8
9
2-methyl-imidazole
2-ethyl-imidazole
benzimidazole
Scheme 2. Synthesis of hybrid compounds 6e47.

X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
113
Table 1
Structures and yields of hybrid compounds 6e47.
Compound
Imidazole ring
R0
X
e
e
Molecular formula
C18H14N2O
mp (ꢀC)
Oil
Yields (%)
6
7
e
e
70
72
N
N
N
N
C19H16N2O
Oil
N
N
8
9
e
e
e
e
C20H18N2O
Oil
67
75
C22H16N2O
136e138
N
N
10
11
Br
I
C21H19BrN2O
C22H23IN2O
Oil
75
80
N
N
N
N
103e105
12
13
Br
Br
C25H21BrN2O
C25H20BrN3O3
73e75
69
85
N
N
N
N
Oil
NO2
O
14
15
Br
Br
C26H21BrN2O2
Oil
80
75
N
N
N
N
O
C26H20BrFN2O2
67e69
F
O
O
16
Br
C26H20Br2N2O2
82e84
89
N
N
Br
17
18
Br
Br
C26H21BrN2O3
133e134
71
75
N
N
N
N
OH
O
C27H23BrN2O3
Oil
OMe
O
19
20
21
22
Br
Br
I
C30H23BrN2O2
C22H21BrN2O
C23H25IN2O
68e70
Oil
92
90
95
95
N
N
N
N
N
N
N
N
Oil
Br
C26H23BrN2O
Oil
(continued on next page)

114
X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
Table 1 (continued )
Compound
Imidazole ring
R0
X
Molecular formula
C27H23BrN2O2
mp (ꢀC)
Yields (%)
90
O
N
N
N
N
23
24
Br
130e132
O
Br
Br
C27H22Br2FN2O2
207e208
136e139
90
97
F
O
O
N
N
25
C27H22Br2N2O2
Br
N
N
N
N
26
27
Br
Br
C27H23BrN2O3
206e207
204e206
92
92
OH
O
C28H25BrN2O3
OMe
O
N
N
N
N
28
29
Br
Br
C31H25BrN2O2
C23H23BrN2O
108e110
98
99
Oil
N
N
N
N
N
N
N
N
30
31
32
33
I
C24H27IN2O
Oil
99
95
98
92
Br
Br
Br
C27H25BrN2O
C28H25BrN2O2
C28H24BrFN2O2
Oil
O
196e198
133e135
O
F
O
O
N
N
34
Br
C28H24Br2N2O2
139e140
94
Br
N
N
N
N
35
36
Br
Br
C28H25BrN2O3
208e210
128e130
90
92
OH
O
C29H27BrN2O3
OMe
O
N
N
37
Br
C32H27BrN2O2
134e136
98

X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
115
Table 1 (continued )
Compound
Imidazole ring
R0
X
Molecular formula
C25H21BrN2O
mp (ꢀC)
Yields (%)
38
39
40
41
42
43
44
45
46
47
Br
148e151
84
80
98
92
97
80
87
91
84
65
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
I
C26H25IN2O
142e144
228e230
61e63
Br
Br
Br
Br
Br
Br
Br
Br
C29H23BrN2O
C29H22BrN3O3
C30H23BrN2O2
C30H22BrFN2O2
C30H22Br2N2O2
C30H23BrN2O3
C31H25BrN2O3
C34H25BrN2O2
NO2
O
218e220
202e203
139e141
138e140
141e143
134e136
O
F
Br
O
O
OH
O
OMe
O
However, compared with above alkyl substituent (butyl, allyl or
benzyl) imidazolium salt derivatives, hybrid compounds with
substituted phenacyl substituent at position-3 of imidazole ring
exhibited higher cytotoxic activity. Most of this kind of derivatives
showed moderate or potent activity (except 4-hydroxyphenacyl
substituent). Especially, compounds 18, 27, 36 and 46 with
a 4-methoxyphenacyl substituent, as well as compounds 28, 37
and 47 with a naphthylacyl substituent at position-3 of the imi-
dazole ring displayed similar or higher cytotoxic activity in vitro
compared with DDP. Interestingly, hybrid compounds 46 and 47,
bearing a 4-methoxyphenacyl or naphthylacyl substituent at
position-3 of benzimidazole, were found to be the most potent
tumor cell lines investigated and more active than DDP. Notably,
hybrids 46 and 47 exhibited cytotoxic activities selectively against
breast carcinoma (MCF-7) and myeloid liver carcinoma (SMMC-
7721) with IC50 value 4.6-fold and 6.3-fold more sensitive to DDP,
respectively. This finding shows that electronic and steric effects
have an important role in the cytotoxic activity of imidazolium
salt hybrids. Generally, an electron-donating methoxy group at
position-4 of phenacyl substituent, as well as a bulkier naph-
thylacyl substituent at position-3 of imidazole ring exhibit higher
cytotoxic activity against tumor cells [17,19,21].
The results suggest that the existence of benzimidazole ring and
substitution of the imidazolyl-3-position with a naphthylacyl or
4-methoxyphenacyl group were vital for modulating cytotoxic
derivatives with IC50 values of 1.02e3.57 mM against all of human

116
X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
Table 2
R
R
Cytotoxic activities of hybrid compounds 6e47 in vitrob (IC50 Ma).
, m
Compound
HL-60
A549
SW480
MCF-7
SMMC-7721
N
N
R'
N
N
X
5
6
7
8
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
2.64
>40
2.99
1.93
>40
>40
>40
3.17
4.70
3.30
>40
1.65
1.85
>40
>40
2.06
2.64
2.38
2.94
>40
2.17
1.86
>40
2.87
1.05
10.99
2.69
2.10
2.68
>40
1.02
1.12
3.10
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
15.50
>40
14.60
7.77
>40
>40
>40
18.77
21.71
26.10
>40
8.00
8.57
>40
>40
6.52
13.72
7.36
14.05
>40
5.43
3.23
>40
12.30
6.92
>40
14.38
9.15
4.76
>40
3.57
3.43
13.61
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
11.99
>40
16.13
3.12
>40
>40
>40
10.24
10.70
15.19
>40
9.84
2.24
>40
>40
5.24
13.96
13.77
9.50
>40
9.50
4.20
>40
15.43
9.16
16.40
9.59
12.01
3.35
>40
2.29
3.13
10.64
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
>40
5.50
>40
8.47
3.47
>40
>40
>40
14.76
14.51
11.05
>40
5.29
4.29
>40
>40
7.14
10.59
10.88
6.14
>40
7.07
4.48
>40
7.03
3.63
11.51
5.34
3.98
3.99
>40
3.09
2.35
14.75
O
O
9
(B)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
DDP
(A)
hybrids:
>40
>40
benzofuran-imidazolium salts (B) > benzofuran-imidazole hybrids (A)
Better
imidazole ring:
15.53
>40
15.43
14.23
>40
>40
>40
>40
12.68
14.50
>40
14.41
4.48
>40
benzimidazole > 2-methyl-imidazole ≈ 2-ethyl-imidazole > imidazole
Best
benzyl
phenacyl
alkyl
R' =
>
>
O
O
O
phenacyl =
≈
>
OMe
Br
Best
O
O
O
>40
>
>>
3.75
19.14
>40
15.48
>40
17.11
16.38
>40
29.33
6.31
14.00
15.45
13.62
3.75
>40
OH
F
IC50 values
Best Potent Compounds
between 1.02-3.57 µM
O
O
47 R' =
Br
N
N
R'
O
46 R' =
OMe
3.55
3.18
12.32
Scheme 3. Structureeactivity relationship of hybrid compounds.
a
Cytotoxicity as IC50 for each cell line, is the concentration of compound which
reduced by 50% the optical density of treated cells with respect to untreated cells
using the MTT assay.
b
4. Experimental section
Data represent the mean values of three independent determinations.
4.1. Chemistry
activity. The structureeactivity relationship (SAR) results were
summarized in Scheme 3.
4.1.1. General
Melting points were obtained on a XT-4 melting-point apparatus
and were uncorrected. NMR spectra were recorded on a Bruker
1
3. Conclusion
Avance 300 spectrometer (300 MHz for H and 75 M HZ for 13C) in
CDCl3. Chemical shifts are reported as
d values in parts per million
In summary, a number of novel 2-benzylbenzofuran-imidazole
hybrid compounds prepared in this research proved to be potent
antitumor agents. The imidazolium salt hybrids 46, 47, 40 and 44,
bearing benzimidazole ring and a substituted phenacyl substituent at
position-3 of the imidazole ring, were found to be the most potent
compounds. Compounds 46 and 47, bearing a 4-methoxyphenacyl or
naphthylacyl substituent at position-3 of benzimidazole, were found
(ppm) relative to tetramethylsilane (TMS) and J values are expressed
in Hertz. Low-resolution Mass spectra were recorded on a VG Auto
Spec-3000 magnetic sector MS spectrometer. High Resolution Mass
spectra were taken on AB QSTAR Pulsar mass spectrometer. Silica gel
(200e300 mesh) for column chromatography and silica GF254 for TLC
were produced by Qingdao Marine Chemical Company (China). All
air- or moisture-sensitive reactions were conducted under an argon
atmosphere. Starting materials and reagents used in reactions were
obtained commercially from Acros, Aldrich, Fluka and were used
without purification, unless otherwise indicated.
to be the most potent derivatives with IC50 values of 1.02e3.57 mM
against all of human tumor cell lines investigated and exhibited
cytotoxic activities selectively against breast carcinoma (MCF-7) and
myeloid liver carcinoma (SMMC-7721), respectively. The 2-
benzylbenzofuran-based imidazolium salts 46, 47, 40 and 44 can be
considered promising leads for further structural modifications
guided by the valuable information derivable from our detailed SARs.
4.1.2. Synthesis of (benzofuran-2-yl)(phenyl)methanone (3)
A mixture of salicylaldehyde 1 (12.2 g, 0.1 mol), phenacyl
bromides 2 (19.8 g, 0.1 mol) and K2CO3 (20.7 g, 0.15 mol) was

X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
117
stirred in acetone (150 ml) at room temperature for 12 h. After
completion of the reaction as indicated by TLC, the reaction
mixture was filtered and washed with acetone (3 ꢁ 50 ml). The
filtrate was concentrated, and the residue was chromatographed
on silica gel (petroleum ether 60e90 ꢀC:ethyl acetate ¼ 10:1) to
afford the products 3 (20.4 g, 92%). White powder, mp 84e85 ꢀC.
4.1.4.3. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-1H-imidazole
(8). Yield 67%, yellow oil. IR nmax (cmꢂ1): 3420, 3060, 2975,
2929, 1560, 1494, 1450, 1257, 1168, 1126, 1067, 806, 738. 1H NMR
d
: 7.51 (1H, d, J ¼ 7.5), 7.44 (1H, d, J ¼ 8.1), 7.38e7.36 (3H, m),
7.32e7.21 (2H, m), 7.15 (2H, t, J ¼ 3.6), 6.98 (1H, s), 6.76 (1H, s),
6.58 (1H, s), 6.40 (1H, s), 2.80e2.61 (2H, m), 1.31 (3H, t, J ¼ 7.5).
1H NMR
7.59 (2H, m), 7.55e7.46 (4H, m), 7.34e7.29 (1H, m). 13C NMR
d
: 8.05e8.02 (2H, m), 7.73e7.70 (1H, dd, J ¼ 7.8, 1.8), 7.65e
13C NMR
d: 155.3, 154.5, 149.4, 136.9, 129.0, 128.7, 127.6, 127.3,
d
:
127.2, 125.0, 123.2, 121.3, 118.2, 111.5, 107.3, 57.6, 20.4, 11.9. HRMS
(ESI-TOF) m/z Calcd for C20H18N2O [M þ 1]þ 302.1419, found
302.1427.
184.4, 156.0, 152.2, 137.2, 132.9, 129.5, 128.6, 128.4, 127.0, 124.0,
123.3, 116.6, 112.6.
4.1.3. Synthesis of (benzofuran-2-yl)(phenyl)methanol (4)
4.1.4.4. 1-(Benzofuran-2-yl(phenyl)methyl)-1H-benzo[d]imidazole
(9). Yield 75%, yellow powder, mp 136e138 ꢀC. IR nmax (cmꢂ1):
3433, 3118, 3043,1605,1485,1454,1382,1270,1219,1178,1006, 961,
To a stirred solution of (benzofuran-2-yl)(phenyl)methanone 3
(3.33 g, 15 mmol) in dichloromethane/MeOH (30 mL, 1:1) at 0 ꢀC
was added NaBH4 (0.28 g, 7.5 mmol) in small portions over a period
of 20 min, and then at ambient temperature for 2 h. Reaction
progress was monitored by TLC. A small amount of water was
added and the mixture was stirred for 15 min before rotary evap-
oration. The solvent was evaporated under reduced pressure and
the residue was chromatographed on silica gel (petroleum ether
60e90 ꢀC:ethyl acetate ¼ 1:1) to afford the products 4 (3.19 g, 95%).
870, 807, 751. 1H NMR
d
: 7.85 (1H, d, J ¼ 0.9), 7.83 (1H, s), 7.51 (1H,
dd, J ¼ 7.2, 0.9), 7.44 (1H, d, J ¼ 8.4), 7.39e7.37 (3H, m), 7.33e7.30
(1H, m), 7.28 (1H, s), 7.27e7.25 (2H, m), 7.24 (1H, s), 7.23e7.18
(2H, m), 6.85 (1H, s), 6.50 (1H, s). 13C NMR
d: 155.4, 153.3, 144.0,
142.3, 135.9, 133.7, 129.2, 129.1, 127.6, 125.2, 123.4, 123.3, 122.6,
121.4, 120.6, 111.6, 110.4, 107.7, 58.0. HRMS (ESI-TOF) m/z Calcd for
C22H16N2O [M þ 1]þ 324.1263, found 324.1278.
White powder, mp 72e73 ꢀC. 1H NMR
d
: 7.49e7.47 (4H, m), 7.47e
7.37 (3H, m), 7.31e7.15 (2H, m), 6.51 (1H, s), 5.91 (1H, s), 2.91e
2.61 (1H, m). 13C NMR
: 158.6, 155.1, 140.3, 128.6, 128.4, 128.1,
4.1.5. General procedure for the preparation of 2-benzylbenzofuran-
based imidazolium salts (10e47)
d
126.8, 124.3, 122.9, 121.2, 111.4, 104.1, 70.7.
A mixture of 1-(2-benzylbenzofuran)-substituted imidazole 6e
9 (1 mmol) and phenacyl bromides or alkyl halides (1.2 mmol)
was stirred in acetone (10 ml) at reflux or DMF (10 ml) at room
temperature for 8e24 h. An insoluble substance was formed. After
completion of the reaction as indicated by TLC, the precipitate was
filtered through a small pad of Celite, and washed with toluene
(3 ꢁ 10 ml), then dried to afford imidazolium salts 10e47 in 69e
99% yields.
4.1.4. General procedure for the preparation of 1-(2-
benzylbenzofuran)-substituted imidazoles (6e9)
To
a
solution of (benzofuran-2-yl)(phenyl)methanol
4
(224 mg, 1 mmol) in dichloromethane (50 mL) was added
methanesulfonyl chloride (1.2 mmol) and triethylamine (2 mmol)
at 0 ꢀC. The resulting mixture was stirred at room temperature for
12 h. After quenching the reaction with water (50 mL), the layers
were separated. The organic phase was dried over anhydrous
Na2SO4 and concentrated, and used for the next synthetic step. A
mixture of the previous methanesulfonate and imidazole or
substituted imidazole (3 mmol) was stirred in acetonitrile (20 ml)
at reflux for 24e48 h (monitored by TLC). After cooling to room
temperature, the solvent was concentrated, and the residue
was diluted with EtOAc (20 mL). The organic layer was washed
with water (20 mL) and brine (20 mL), dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, petroleum ether 60e90 ꢀC:ethyl
acetate ¼ 3:1/1:1) to afford 6e9 in 60e75% yield (two steps)
as yellow oil or powder.
4.1.5.1. 1-(Benzofuran-2-yl(phenyl)methyl)-3-allyl-1H-imidazol-3-
ium bromide (10). Yield 75%, yellow oil. IR nmax (cmꢂ1): 3423, 3061,
1617, 1548, 1450, 1252, 1143, 949, 839, 752. 1H NMR
d: 10.33 (1H, s),
7.94 (1H, s), 7.70 (1H, s), 7.51 (4H, s), 7.45e7.37 (4H, m), 7.30 (1H, t,
J ¼ 8.1), 7.22 (1H, t, J ¼ 7.2), 6.98 (1H, s), 6.05e5.95 (1H, m), 5.49e
5.38 (2H, m), 4.99 (2H, d, J ¼ 6.0). 13C NMR
d: 155.4, 150.5, 136.6,
134.3, 129.7, 129.5, 129.4, 128.1, 127.2, 125.6, 123.6, 123.0, 122.6,
121.9, 121.6, 111.6, 109.3, 60.7, 52.4. HRMS (ESI-TOF) m/z Calcd for
C21H19N2O [M ꢂ Br]þ 315.1492, found 315.1497.
4.1.5.2. 1-(Benzofuran-2-yl(phenyl)methyl)-3-butyl-1H-imidazol-3-
ium iodide (11). Yield 80%, yellow powder, mp 103e105 ꢀC. IR nmax
(cmꢂ1): 3433, 3044, 2964, 2927, 2872, 1589, 1542, 1450, 1249, 1149,
4.1.4.1. 1-(Benzofuran-2-yl(phenyl)methyl)-1H-imidazole
Yield 70%, yellow oil. IR nmax (cmꢂ1): 3429, 3108, 1613, 1495, 1453,
1244, 1173, 1076, 958, 813, 739. 1H NMR
: 7.44 (1H, s), 7.41 (1H, d,
(6).
941, 835, 736. 1H NMR
d: 10.08 (1H, s), 7.90 (1H, s), 7.83 (1H, s),
7.54e7.52 (3H, m), 7.50 (1H, s), 7.45 (1H, d, J ¼ 8.1), 7.39 (3H, t,
J ¼ 3.0), 7.31 (1H, t, J ¼ 7.2), 7.23 (1H, t, J ¼ 7.2), 7.01 (1H, s), 4.34 (2H,
t, J ¼ 7.5), 1.96e1.86 (2H, m), 1.40e1.31 (2H, m), 0.91 (3H, t, J ¼ 7.5).
d
J ¼ 8.7), 7.33 (1H, d, J ¼ 8.4), 7.28e7.27 (2H, m), 7.21 (1H, dd,
J ¼ 7.2, 1.2), 7.16 (1H, dd, J ¼ 6.0, 1.5), 7.12e7.08 (3H, m), 7.01 (1H,
13C NMR
d: 155.3, 150.3, 135.7, 134.1, 129.8, 129.4, 128.1, 127.1, 125.7,
s), 6.86 (1H, s), 6.48 (1H, s), 6.39 (1H, s). 13C NMR
d
: 155.3, 154.0,
123.6, 123.0, 121.9, 121.6, 111.6, 109.3, 60.5, 50.3, 31.9, 19.4, 13.4.
HRMS (ESI-TOF) m/z Calcd for C22H23N2O [M ꢂ I]þ 331.11810, found
331.11817.
137.1, 136.8, 129.5, 129.0, 128.9, 127.4, 125.1, 123.3, 121.4, 119.0,
111.5, 107.2, 59.4. HRMS (ESI-TOF) m/z Calcd for C18H14N2O
[M þ 1]þ 247.1106, found 247.1118.
4.1.5.3. 1-(Benzofuran-2-yl(phenyl)methyl)-3-benzyl-1H-imidazol-3-
ium bromide (12). Yield 69%, yellow powder, mp 73e75 ꢀC. IR nmax
(cmꢂ1): 3419, 3050,1608, 1547, 1496, 1451, 1251, 1142, 952, 819, 720.
4.1.4.2. 1-(Benzofuran-2-yl(phenyl)methyl)-2-methyl-1H-imidazole
(7). Yield 72%, yellow oil. IR nmax (cmꢂ1): 3426, 3113, 3086, 2904,
1584, 1531, 1489, 1453, 1419, 1261, 1174, 1123, 973, 798, 736. 1H NMR
1H NMR
d
: 10.51 (1H, s), 7.86 (1H, s), 7.59 (1H, d, J ¼ 1.8), 7.51e7.46
d
: 7.52 (1H, d, J ¼ 7.2), 7.45 (1H, d, J ¼ 7.2), 7.39e7.37 (3H, m), 7.33e
7.21 (2H, m), 7.16 (1H, t, J ¼ 3.3), 6.95 (1H, s), 6.75 (1H, s), 6.54 (1H,
s), 6.40 (1H, s), 2.38 (3H, s). 13C NMR
: 155.3, 154.3, 144.8, 136.6,
(5H, m), 7.44e7.42 (1H, m), 7.39 (1H, s), 7.35e7.33 (3H, m), 7.31e
7.25 (4H, m), 7.20 (1H, t, J ¼ 7.2), 6.95 (1H, s), 5.55 (2H, s). 13C
d
NMR d: 155.4, 150.4, 136.6, 134.3, 132.8, 129.7, 129.4, 129.1, 128.0,
129.0, 128.8, 127.5, 127.4, 127.2, 125.1, 123.2, 121.4, 118.4, 111.5, 107.4,
58.1, 13.3. HRMS (ESI-TOF) m/z Calcd for C19H16N2O [M þ 1]þ
288.1263, found 288.1277.
127.1, 125.6, 123.5, 122.4, 121.9, 121.6, 111.6, 109.3, 60.7, 53.5. HRMS
(ESI-TOF) m/z Calcd for C25H21N2O [M ꢂ Br]þ 365.1648, found
365.1655.

118
X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
4.1.5.4. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(4-nitrobenzyl)-1H-
imidazol-3-ium bromide (13). Yield 85%, yellow oil. IR nmax (cmꢂ1):
3419, 3056, 1606, 1523, 1450, 1346, 1252, 1145, 953, 808, 727. 1H
HRMS (ESI-TOF) m/z Calcd for C27H23N2O3 [M ꢂ Br]þ 423.1703,
found 423.1709.
NMR
d
: 10.64 (1H, d, J ¼ 7.2), 8.10 (1H, s), 8.01 (2H, t, J ¼ 6.9), 7.87
4.1.5.10. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(naphthalen-2-yl)-
2-oxoethyl)-1H-imidazol-3-ium bromide (19). Yield 92%, yellow
powder, mp 68e70 ꢀC. IR nmax (cmꢂ1): 3419, 3056, 2962,1690,1623,
(2H, t, J ¼ 3.9 Hz), 7.68 (1H, s), 7.45 (4H, s), 7.40e7.33 (4H, m), 7.26e
7.14 (2H, m), 6.85 (1H, dd, J ¼ 10.5, 5.7), 5.98e5.79 (2H, m). 13C NMR
d: 155.4, 150.1, 148.1, 140.2, 136.8, 134.0, 130.4, 129.9, 129.5, 127.9,
1550, 1452, 1355, 1257, 1152, 1031, 920, 813, 735. 1H NMR
d: 9.98
127.0, 125.8, 124.2, 123.6, 123.2, 121.8, 121.7, 111.6, 109.3, 61.2, 52.0.
HRMS (ESI-TOF) m/z Calcd for C25H20N3O3 [M ꢂ Br]þ 410.1499,
found 410.1510.
(1H, s), 8.66 (1H, s), 7.88 (1H, d, J ¼ 7.2), 7.81 (2H, s), 7.68 (3H, s), 7.46
(2H, d, J ¼ 5.4), 7.40e7.36 (4H, m), 7.33e7.31 (4H, m), 7.24 (1H, d,
J ¼ 7.5), 7.18 (1H, t, J ¼ 7.5), 6.88 (1H, s), 6.39 (2H, s). 13C NMR
d:
190.3, 155.4, 150.4, 137.7, 136.0, 134.2, 132.2, 131.3, 130.5, 130.0,
129.7,129.4,129.2,128.8,127.9,127.6,127.1,127.0,125.7,124.5,123.6,
123.2, 121.9, 120.7, 111.7, 109.3, 61.0, 56.1. HRMS (ESI-TOF) m/z Calcd
for C30H23N2O2 [M ꢂ Br]þ 443.1754, found 443.1760.
4.1.5.5. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-oxo-2-phenylethyl)-
1H-imidazol-3-ium bromide (14). Yield 80%, yellow oil. IR nmax
(cmꢂ1): 3399, 3061, 2961, 1697, 1594, 1552, 1450, 1346, 1238, 1153,
998, 918, 807, 740. 1H NMR
d
: 9.88 (1H, s), 7.84 (2H, d, J ¼ 7.2), 7.78
(1H, s), 7.63 (1H, s), 7.40 (2H, d, J ¼ 6.9), 7.37e7.30 (5H, m), 7.26 (5H,
4.1.5.11. 1-(Bbenzofuran-2-yl(phenyl)methyl)3-allyl–2-methyl-1H-
imidazol-3-ium bromide (20). Yield 90%, yellow oil. IR nmax (cmꢂ1):
s), 7.14 (1H, t, J ¼ 7.2), 6.81 (1H, d, J ¼ 7.5), 6.21 (2H, s). 13C NMR
d:
190.4,155.4,150.4,137.7,134.6,134.2,133.4,129.7,129.4,129.0,128.5,
127.9, 127.1, 125.7, 124.6, 123.6, 121.9, 120.7, 111.7, 109.3, 60.9, 56.1.
HRMS (ESI-TOF) m/z Calcd for C26H21N2O2 [M ꢂ Br]þ 393.1598,
found 393.1605.
3418, 3053, 2887, 1583, 1504, 1450, 1255, 1187, 947, 750. 1H NMR
d:
7.82 (1H, s), 7.77 (1H, s), 7.54 (1H, d, J ¼ 7.2), 7.43e7.38 (6H, m),
7.35e7.28 (1H, m), 7.23 (1H, t, J ¼ 7.2), 7.13 (1H, s), 7.09 (1H, s),
6.00e5.91 (1H, m), 5.36e5.21 (2H, m), 5.01 (2H, s), 2.85 (3H, s). 13C
NMR d: 155.4, 150.2, 145.0, 133.9, 129.7, 129.6, 129.4, 127.9, 127.6,
4.1.5.6. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-fluorophenyl)-2-
oxoethyl)-1H-imidazol-3-ium bromide (15). Yield 75%, white pow-
der. IR nmax (cmꢂ1): 3424, 3061, 1697, 1597, 1552, 1504, 1452, 1346,
127.2, 125.6, 123.6, 122.0, 120.9, 120.3, 111.6, 109.8, 60.0, 51.3, 11.9.
HRMS (ESI-TOF) m/z Calcd for C22H21N2O [M ꢂ Br]þ 329.1648,
found 329.1655.
1234, 1153, 994, 837, 736. 1H NMR
d: 9.90 (1H, s), 8.04e8.01 (2H,
m), 7.87 (1H, s), 7.65 (1H, s), 7.50 (1H, d, J ¼ 7.2), 7.40e7.35 (7H, m),
4.1.5.12. 1-(Benzofuran-2-yl(phenyl)methyl)-3-butyl-2-methyl-1H-
imidazol-3-ium iodide (21). Yield 95%, yellow oil. IR nmax (cmꢂ1):
3416, 3057, 2958, 2872, 1643, 1560, 1503, 1452, 1183, 966, 748. 1H
7.28 (1H, t, J ¼ 8.1), 7.20 (1H, t, J ¼ 7.5), 7.00 (2H, t, J ¼ 8.1), 6.89 (1H,
s), 6.36 (2H, s). 13C NMR
d: 189.1, 168.1, 164.7, 155.4, 150.3, 137.7,
134.1, 131.6, 131.5, 129.9, 129.8, 129.5, 127.9, 127.1, 125.7, 124.6,
123.6, 121.9, 120.7, 116.4, 116.1, 111.7, 109.4, 61.1, 56.2. HRMS (ESI-
TOF) m/z Calcd for C26H20FN2O2 [M ꢂ Br]þ 411.1503, found
411.1509.
NMR
d
: 7.76 (1H, d, J ¼ 2.1), 7.72 (1H, s), 7.55 (1H, d, J ¼ 7.5), 7.45 (2H,
d, J ¼ 5.1), 7.42e7.38 (3H, m), 7.32 (2 H, t, J ¼ 7.2), 7.24 (1H, t, J ¼ 7.5),
7.10 (1H, s), 7.10 (1H, d, J ¼ 2.1), 4.26 (2H, t, J ¼ 7.5), 2.86 (3H, s),
1.88e1.78 (2H, m),1.42e1.35 (2H, m), 0.93 (3H, t, J ¼ 7.5). 13C NMR
d:
155.3, 150.1, 144.3, 133.8, 129.6, 129.5, 128.0, 127.1, 125.7, 123.6,
122.0, 121.9, 120.3, 111.6, 109.8, 60.1, 49.1, 31.7, 19.6, 13.5, 12.6. HRMS
(ESI-TOF) m/z Calcd for C23H25N2O [M ꢂ I]þ 345.1961, found
345.1956.
4.1.5.7. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-bromophenyl)-
2-oxoethyl)-1H-imidazol-3-ium bromide (16). Yield 89%, yellow
powder. IR nmax (cmꢂ1): 3416, 3063, 2954, 1698, 1582, 1492, 1451,
1397, 1345, 1234, 1154, 991, 915, 819, 733. 1H NMR
d: 9.97 (1H, s),
7.94 (1H, s), 7.81 (2H, d, J ¼ 8.4), 7.70 (1H, s), 7.48 (1H, d, J ¼ 7.8),
4.1.5.13. 1-(Benzofuran-2-yl(phenyl)methyl)-3-benzyl-2-methyl-1H-
imidazol-3-ium bromide (22). Yield 95%, yellow oil. IR nmax (cmꢂ1):
3418, 3048, 2880, 1581, 1503, 1451, 1255, 1184, 1081, 927, 815, 733.
7.44e7.39 (6H, m), 7.33e7.31 (3H, m), 7.26 (1H, t, J ¼ 7.2), 7.19 (1H, t,
J ¼ 7.5), 6.86 (1H, s), 6.38 (2H, s). 13C NMR
d: 189.9, 155.4, 150.3,
137.6, 134.1, 132.3, 132.2, 130.1, 129.8, 129.5, 127.8, 127.1, 125.7, 124.6,
123.6, 121.9, 120.6, 111.7, 109.3, 61.0, 56.2. HRMS (ESI-TOF) m/z Calcd
for C26H20BrN2O2 [M ꢂ Br]þ 471.0703, found 471.0700.
1H NMR
d
: 7.81 (2H, d, J ¼ 2.4), 7.51 (1H, d, J ¼ 7.5), 7.41e7.38 (3H,
m), 7.36e7.33 (3H, m), 7.30 (6H, s), 7.22 (1H, t, J ¼ 7.5), 7.08 (2H, s),
5.57 (2H, s), 3.02 (3H, s). 13C NMR
: 155.3, 150.3, 145.0, 133.9, 132.7,
d
129.5, 129.4, 129.3, 129.1, 128.2, 127.9, 127.2, 125.6, 123.6, 122.3,
121.9, 120.2, 111.5, 109.8, 60.0, 52.4, 12.1. HRMS (ESI-TOF) m/z Calcd
for C26H23N2O [M ꢂ Br]þ 379.1805, found 379.1811.
4.1.5.8. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-hydroxyphenyl)-
2-oxoethyl)-1H-imidazol-3-ium bromide (17). Yield 71%, yellow
powder, mp 133e134 ꢀC. IR nmax (cmꢂ1): 3415, 3085, 1682, 1596,
1503, 1447, 1345, 1236, 1157, 980, 837, 746. 1H NMR
d
: 9.34 (1H, s),
4.1.5.14. 1-(Benzofuran-2-yl(phenyl)methyl)-2-methyl-3-(2-oxo-2-
phenylethyl)-1H-imidazol-3-ium bromide (23). Yield 90%, yellow
powder, mp 130e132 ꢀC. IR nmax (cmꢂ1): 3383, 2972, 2919, 1694,
7.88e7.85 (2H, m), 7.64 (1H, s), 7.58 (1H, d, J ¼ 6.9), 7.49e7.40 (7H,
m), 7.38e7.34 (2H, m), 7.28e7.24 (1H, m), 6.92e6.87 (3H, m), 5.97
(2H, s). 13C NMR
d: 188.1, 163.5, 155.4, 150.1, 137.4, 133.9, 130.9,
1560, 1505, 1449, 1235, 1049, 881, 751. 1H NMR
d: 8.12 (2H, d,
129.8,129.4,127.7,127.0,125.7,124.9,124.5,123.6,121.8,121.0,115.9,
111.5, 109.3, 61.3, 55.3. HRMS (ESI-TOF) m/z Calcd for C26H21N2O3
[M ꢂ Br]þ 409.1547, found 409.1559.
J ¼ 6.9), 7.97 (1H, s), 7.56e7.52 (3H, m), 7.45e7.39 (6H, m), 7.36e
7.30 (3H, m), 7.25 (1H, t, J ¼ 7.2), 6.97 (2H, d, J ¼ 8.4), 6.54 (2H, s),
2.70 (3H, s). 13C NMR
d: 190.4, 155.4, 150.3, 146.6, 134.7, 133.7, 133.3,
129.7, 129.5, 129.1, 128.8, 127.6, 127.1, 125.8, 123.7, 123.4, 121.9, 119.5,
111.6, 109.8, 60.2, 56.2, 11.7. HRMS (ESI-TOF) m/z Calcd for
C27H23N2O2 [M ꢂ Br]þ 407.1754, found 407.1759.
4.1.5.9. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-methoxyphenyl)-
2-oxoethyl)-1H-imidazol-3-ium bromide (18). Yield 75%. Yellow oil.
IR nmax (cmꢂ1): 3416, 3056, 2962,1685,1598, 1509, 1451, 1249, 1161,
1025, 807, 743. 1H NMR
d
: 9.85 (1H, s), 7.86 (2H, d, J ¼ 8.7), 7.74 (1H,
4.1.5.15. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-fluorophenyl)-
2-oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (24). Yield 90%.
White powder, mp 207e208 ꢀC. IR nmax (cmꢂ1): 3419, 3055, 2905,
2855, 1694, 1596, 1508, 1450, 1412, 1232, 1163, 996, 840, 753. 1H
s), 7.65 (1H, s), 7.41 (1H, d, J ¼ 7.5), 7.34e7.32 (4H, m), 7.27e7.23
(3H, m), 7.19 (1H, t, J ¼ 7.2), 7.11 (1H, t, J ¼ 7.2), 6.75 (1H, s), 6.74
(2H, d, J ¼ 8.7), 6.21e6.08 (2H, m), 3.67 (3H, s). 13C NMR
d: 187.6,
163.7, 154.4, 149.5, 136.7, 133.3, 130.1, 128.7, 128.4, 126.9, 126.1,
125.3, 124.7, 123.6, 122.6, 120.9, 119.7, 113.3, 110.7, 108.3, 60.0, 54.6.
NMR
d
: 8.23e8.17 (2H, m), 7.77e7.75 (1H, m), 7.59 (1H, t, J ¼ 6.3),
7.46e7.45 (4H, m), 7.34e7.29 (3H, m), 7.26 (2H, d, J ¼ 4.5), 7.21e

X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
119
7.16 (2H, m), 7.04 (1H, d, J ¼ 5.1), 6.86 (1H, d, J ¼ 5.4), 6.37 (2H, s),
2.65 (3H, s). 13C NMR
: 189.0, 168.4, 164.9, 155.5, 150.1, 146.5,
133.4, 131.9, 131.7, 129.8, 129.6, 127.6, 127.0, 125.9, 123.7, 123.4,
121.9, 119.6, 116.5, 116.2, 111.6, 109.8, 60.4, 56.0, 11.4. HRMS
(ESI-TOF) m/z Calcd for C27H22FN2O2 [M ꢂ Br]þ 425.1660, found
425.1668.
4.1.5.21. 1-(Benzofuran-2-yl(phenyl)methyl)-3-butyl-2-ethyl-1H-
imidazol-3-ium iodide (30). Yield 99%, yellow oil. IR nmax (cmꢂ1):
3410, 3051, 2956, 2873, 1580, 1503, 1452, 1383, 1247, 1185, 1099,
d
950, 739. 1H NMR
d
: 7.87 (1H, d, J ¼ 2.1), 7.66 (1H, s), 7.55 (1H, d,
J ¼ 6.9), 7.54 (1H, s), 7.54e7.42 (2H, m), 7.41e7.39 (3H, m), 7.35e7.30
(1H, m), 7.27e7.22 (1H, m), 7.18 (1H, d, J ¼ 2.1), 7.13 (1H, s), 4.32e
4.20 (2H, m), 3.55e3.48 (1H, m), 3.37e3.26 (1H, m), 2.00e1.83
4.1.5.16. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-bromophenyl)-
2-oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (25). Yield 97%,
yellow powder, mp 136e139 ꢀC. IR nmax (cmꢂ1): 3415, 3060, 2907,
1695, 1583, 1506, 1450, 1396, 1230, 1184, 1071, 993, 819, 750. 1H
(2H, m), 1.49e1.37 (2H, m), 1.02e0.93 (6H, m). 13C NMR
d: 155.3,
150.3,148.2,134.4,129.6,129.5,127.7,127.1,125.7,123.6,122.1,122.0,
120.5, 111.6, 110.0, 59.8, 48.7, 32.1, 19.7, 18.7, 13.6, 11.9. HRMS (ESI-
TOF) m/z Calcd for C24H27N2O [M ꢂ I]þ 359.2118, found 359.2125.
NMR
d
: 8.02 (2H, t, J ¼ 6.9), 7.96 (1H, d, J ¼ 1.8), 7.55e7.49 (4H, m),
7.41e7.37 (4H, m), 7.34e7.30 (3H, m), 7.25 (1H, t, J ¼ 6.9), 6.96 (1H,
4.1.5.22. 1-(Benzofuran-2-yl(phenyl)methyl)-3-benzyl-2-ethyl-1H-
imidazol-3-ium bromide (31). Yield 95%, yellow oil. IR nmax (cmꢂ1):
3409, 3042, 2937, 2879,1560,1501,1451,1349,1248,1182,1101, 924,
d, J ¼ 4.5), 6.92 (1H, s), 6.65e6.52 (2H, m), 2.71 (3H, d, J ¼ 5.4). 13C
NMR d: 189.9, 155.5, 150.3, 146.7, 133.7, 132.3, 132.2, 130.5, 130.0,
129.7, 129.5, 127.6, 127.1, 125.8, 123.7, 123.4, 121.9, 119.5, 111.7, 109.8,
60.2, 56.4, 11.9. HRMS (ESI-TOF) m/z Calcd for C27H22BrN2O2
[M ꢂ Br]þ 485.0859, found 485.0861.
727. 1H NMR
d
: 7.83 (1H, d, J ¼ 4.5), 7.73 (1H, s), 7.53 (1H, d, J ¼ 7.2),
7.38e7.34 (6H, m), 7.31e7.28 (6H, m), 7.23 (1H, t, J ¼ 7.2), 7.16 (1H,
s), 7.10 (1H, s), 5.59 (2H, d, J ¼ 7.2), 3.61e3.32 (2H, m), 0.83 (3H, t,
J ¼ 7.2). 13C NMR
d: 155.4, 150.4, 149.0, 134.5, 132.9, 129.6, 129.4,
4.1.5.17. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-hydroxyphenyl)-
2-oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (26). Yield 92%,
white powder, mp 206e207 ꢀC. IR nmax (cmꢂ1): 3104, 2913, 1679,
129.2,128.3,127.7,127.2,125.7,123.6,122.6,122.0,120.3,111.5,101.0,
59.8, 52.4, 18.6, 11.2. HRMS (ESI-TOF) m/z Calcd for C27H25N2O
[M ꢂ Br]þ 393.1961, found 393.1973.
1594, 1508, 1443, 1347, 1233, 1169, 988, 829, 743. 1H NMR (DMSO)
d:
10.72 (1H, s), 7.97 (2H, d, J ¼ 7.8), 7.83e7.71 (3H, m), 7.65 (2H, s),
4.1.5.23. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-(2-oxo-2-
phenylethyl)-1H-imidazol-3-ium bromide (32). Yield 98%, yellow
powder, mp 196e198 ꢀC. IR nmax (cmꢂ1): 3419, 3037, 2942, 2891,
1692, 1591, 1506, 1448, 1346, 1240, 1188, 994, 802, 741, 689. 1H NMR
7.52e7.49 (5H, m), 7.39 (1H, t, J ¼ 7.5), 7.32 (1H, d, J ¼ 7.5), 7.01 (2H,
d, J ¼ 7.5), 6.94 (1H, s), 6.15 (1H, s), 2.69 (3H, s). 13C NMR (DMSO)
d:
188.8, 163.3, 154.9, 151.3, 146.3, 134.4, 131.1, 129.4, 127.7, 127.1, 125.6,
125.1, 123.5, 122.0, 119.9, 115.6, 111.5, 109.1, 58.6, 54.4, 10.1. HRMS
(ESI-TOF) m/z Calcd for C27H23N2O3 [M ꢂ Br]þ 423.1703, found
423.1715.
d
: 8.27e8.22 (2H, m), 7.81 (1H, d, J ¼ 7.2), 7.76e7.58 (3H, m), 7.55e
7.53 (5H, m), 7.45e7.37 (4H, m), 7.35e7.26 (1H, m), 7.25e7.23 (1H,
m), 6.95 (1H, d, J ¼ 7.8), 6.35 (2H, s), 3.33e3.19 (2H, m), 1.14e1.07
(3H, t, J ¼ 7.5). 13C NMR
d: 190.8, 155.5, 150.3, 149.7, 134.9, 133.9,
4.1.5.18. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-methoxyphenyl)-
2-oxoethyl)-2-methyl-1H-imidazol-3-ium bromide (27). Yield 92%,
white powder, mp 204e206 ꢀC. IR nmax (cmꢂ1): 3408, 3105, 3056,
2924, 2835,1687, 1597, 1508,1452,1243, 1175, 999, 832, 749. 1H NMR
133.2, 129.8, 129.6, 129.1, 128.7, 127.3, 127.0, 125.9, 123.8, 123.7,
121.9, 119.8, 111.6, 109.8, 60.0, 55.8, 17.9, 11.2. HRMS (ESI-TOF) m/z
Calcd for C28H25N2O2 [M ꢂ Br]þ 421.1911, found 421.1913.
d
: 8.11 (2H, d, J ¼ 8.7), 7.91 (1H, s), 7.59 (1H, s), 7.54 (1H, d, J ¼ 7.5),
4.1.5.24. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-(2-(4-fluoro-
phenyl)-2-oxoethyl)-1H-imidazol-3-ium bromide (33). Yield 92%,
white powder, mp 133e135 ꢀC. IR nmax (cmꢂ1): 3414, 3055, 2892,
1695, 1596, 1504, 1453, 1410, 1347, 1234, 1164, 999, 838, 744. 1H
7.42e7.38 (6H, m), 7.31e7.28 (1H, m), 7.26 (1H, t, J ¼ 7.2), 7.00 (1H, s),
6.97 (1H, s), 6.89 (2H, d, J ¼ 8.7), 6.42 (2H, s), 3.78 (3H, s), 2.70 (3H, s).
13C NMR
d: 188.5, 164.7, 155.4, 150.4, 146.6, 133.8, 131.4, 129.6, 129.5,
127.6, 127.1, 126.3, 125.7, 123.6, 123.5, 121.9, 119.5, 114.3, 111.6, 109.8,
60.1, 55.8, 55.6, 11.8. HRMS (ESI-TOF) m/z Calcd for C28H25N2O3
[M ꢂ Br]þ 437.1860, found 437.1868.
NMR
d
: 8.31e8.27 (2H, m), 7.95 (1H, s), 7.55 (1H, d, J ¼ 6.9), 7.45e
7.32 (5H, m), 7.34e7.29 (3H, m), 7.27 (1H, t, J ¼ 3.8), 7.12e7.08
(3H, m), 6.95 (1H, s), 6.63e6.51 (2H, m), 3.39e3.32 (2H, m), 0.98
(3H, t, J ¼ 7.5). 13C NMR
d: 189.6, 168.3, 164.9, 155.5, 150.4, 150.0,
4.1.5.19. 1-(Benzofuran-2-yl(phenyl)methyl)-2-methyl-3-(2-(naph-
thalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium bromide (28). Yield
98%, yellow powder, mp 108e110 ꢀC. IR nmax (cmꢂ1): 3386, 3057,
2915,1689,1624,1588,1509,1452,1366,1262,1183, 945, 819, 743. 1H
134.2, 132.1, 132.0, 129.9, 129.8, 129.6, 127.4, 127.0, 125.9, 124.0,
123.7, 121.9, 119.7, 116.4, 116.1, 111.6, 101.0, 60.0, 56.3, 18.3, 11.5.
HRMS (ESI-TOF) m/z Calcd for C28H24FN2O2 [M ꢂ Br]þ 439.1816,
found 439.1834.
NMR
d
: 8.95 (1H, s), 8.02 (1H, d, J ¼ 7.2), 7.94 (2H, t, J ¼ 7.8), 7.73 (2H,
t, J ¼ 8.7), 7.54e7.47 (3H, m), 7.36e7.29 (7H, m), 7.28e7.21 (2H, m),
4.1.5.25. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-(2-(4-bromo-
phenyl)-2-oxoethyl)-1H-imidazol-3-ium bromide (34). Yield 94%,
yellow powder, mp 139e140 ꢀC. IR nmax (cmꢂ1): 3399, 3053, 2887,
1696, 1581, 1503, 1452, 1394, 1345, 1237, 1184, 1068, 994, 820, 748.
6.93 (2H, d, J ¼ 7.8), 6.58 (2H, s), 2.69 (3H, s). 13C NMR
d: 190.4,155.5,
150.3, 146.6, 136.1, 133.7, 132.4, 132.1, 130.6, 130.3, 129.7, 129.5, 129.3,
128.8, 127.7, 127.6, 127.1, 127.0, 125.8, 123.6, 123.4, 122.0, 119.6, 111.7,
109.9, 60.3, 56.5, 12.1. HRMS (ESI-TOF) m/z Calcd for C31H25N2O2
[M ꢂ Br]þ 457.1911, found 457.1914.
1H NMR
d
: 8.09 (2H, t, J ¼ 6.6), 7.96 (1H, d, J ¼ 2.1), 7.55 (3H, t,
J ¼ 6.2), 7.44e7.39 (5H, m), 7.36e7.28 (3H, m), 7.24 (1H, t, J ¼ 6.0),
7.11 (1H, d, J ¼ 2.1), 6.94 (1H, s), 6.65 (1H, dd, J ¼ 18.9, 7.8), 6.53 (1H,
4.1.5.20. 1-(Benzofuran-2-yl(phenyl)methyl)-3-allyl-2-ethyl-1H-imi-
dazol-3-ium bromide (29). Yield 99%, yellow oil. IR nmax (cmꢂ1):
3413, 3054, 2937, 1622, 1503, 1451, 1250, 1186, 1102, 948, 751. 1H
dd, J ¼ 18.9, 4.5), 3.41e3.26 (2H, m), 0.99e0.92 (3H, m). 13C NMR
d:
190.4, 155.4, 150.4, 150.0, 134.2, 132.3, 132.1, 130.6, 130.1, 129.7,
129.6, 127.4, 127.0, 125.9, 124.0, 123.7, 121.9, 119.7, 111.6, 110.0, 59.9,
56.3, 18.2, 11.5. HRMS (ESI-TOF) m/z Calcd for C28H24BrN2O2
[M ꢂ Br]þ 499.1021, found 499.1014.
NMR
d
: 7.74 (1H, s), 7.66 (1H, s), 7.46 (2H, d, J ¼ 7.2), 7.36e7.32 (5H,
m), 7.28e7.24 (1H, m), 7.17 (1H, d, J ¼ 7.2), 7.12 (1H, s), 7.02 (1H, s),
6.02e5.91 (1H, m), 5.35e5.22 (2H, m), 4.93 (2H, s), 3.46e3.24 (2H,
m), 0.90 (3H, t, J ¼ 7.2). 13C NMR
d
: 155.4, 150.4, 148.8, 134.5, 130.2,
4.1.5.26. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-
(2-(4-hydroxyphenyl)-2-oxoethyl)-1H-imidazol-3-ium bromide (35).
Yield 90%, white powder, mp 208e210 ꢀC. IR nmax (cmꢂ1): 3145,
2958, 1678, 1597, 1501, 1445, 1339, 1234, 1168, 1107, 985, 827, 733.
129.6, 129.5, 127.8, 127.2, 125.7, 123.6, 122.3, 122.0, 121.3, 120.4,
111.6, 110.0, 59.8, 51.1, 18.4, 11.6. HRMS (ESI-TOF) m/z Calcd for
C23H23N2O [M ꢂ Br]þ 343.1805, found 343.1812.

120
X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
1H NMR (DMSO)
d
: 10.69 (1H, s), 7.98 (2H, d, J ¼ 7.8), 7.83 (1H, s),
7.37 (2H, dd, J ¼ 10.5, 3.3), 7.31 (1H, d, J ¼ 7.5), 7.07 (1H, s), 5.83 (2H,
s). 13C NMR (DMSO)
: 155.1, 150.6, 142.3, 134.0, 131.1, 130.8, 129.6,
129.4,129.0,128.7,128.0,127.9,127.2,125.7,123.5,122.1,114.4,114.3,
111.6, 109.5, 58.6, 50.3. HRMS (ESI-TOF) m/z Calcd for C29H23N2O
[M ꢂ Br]þ 415.1805, found 415.1808.
7.75e7.71 (3H, m), 7.64 (1H, d, J ¼ 8.1), 7.52e7.50 (5H, m), 7.39 (1H,
d
t, J ¼ 7.5), 7.31 (1H, t, J ¼ 7.5), 7.00 (2H, d, J ¼ 7.8), 6.95 (1H, s), 6.12
(2H, s), 3.36e3.22 (2H, m), 0.93 (3H, t, J ¼ 7.2). 13C NMR (DMSO)
d:
189.3, 163.3, 154.9, 151.6, 149.6, 134.9, 131.1, 129.4, 129.3, 127.5, 127.1,
125.6, 125.1, 124.1, 123.5, 122.0, 120.2, 115.6, 111.5, 109.1, 58.4, 54.3,
16.5, 11.5. HRMS (ESI-TOF) m/z Calcd for C28H25N2O3 [M ꢂ Br]þ
437.1865, found 437.1872.
4.1.5.32. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(4-nitrobenzyl)-1H-
benzo[d]imidazol-3-ium bromide (41). Yield 92%, yellow powder,
mp 61e63 ꢀC. IR nmax (cmꢂ1): 3417, 3097, 3011, 1605, 1524, 1446,
4.1.5.27. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-(2-(4-metho-
xyphenyl)-2-oxoethyl)-1H-imidazol-3-ium bromide (36). Yield 92%,
yellow powder, mp 128e130 ꢀC. IR nmax (cmꢂ1): 3404, 3053, 2933,
2831, 1683, 1594, 1505, 1453, 1317, 1247, 1177, 1016, 837, 735. 1H
1344, 1192, 1017, 950, 855, 810, 751. 1H NMR
d
: 11.00 (1H, d, J ¼ 9.9),
8.32e8.26 (2H, t, J ¼ 8.4), 7.93e7.82 (4H, m), 7.77e7.57 (10H, m),
7.49e7.42 (1H, m), 7.42e7.35 (1H, m), 7.23 (1H, d, J ¼ 9.6), 6.27 (2H,
d, J ¼ 9.0). 13C NMR
d: 157.9, 152.2, 150.6, 145.1, 142.3, 135.6, 133.9,
NMR
d
: 8.18 (2H, d, J ¼ 8.4), 7.88 (1H, s), 7.55 (1H, d, J ¼ 7.5), 7.49e
133.5,132.3,132.0,131.8,130.3,130.1,130.1,129.6,128.2,126.8,126.1,
124.4, 117.6, 116.2, 114.0, 112.6, 63.3, 52.9. HRMS (ESI-TOF) m/z Calcd
for C29H22N3O3 [M ꢂ Br]þ 460.1661, found 460.1678.
7.40 (5H, m), 7.34e7.32 (3H, m), 7.25 (1H, t, J ¼ 7.2), 7.12 (1H, s), 6.97
(1H, s), 6.92 (2H, d, J ¼ 8.4), 6.49 (1H, d, J ¼ 18.3), 6.38 (1H, d,
J ¼ 18.3), 3.80 (3H, s), 3.41e3.24 (2H, m), 0.98 (3H, t, J ¼ 6.9). 13C
NMR
d
: 189.0, 164.8, 155.4, 150.4, 149.9, 134.2, 131.5, 129.7, 129.5,
4.1.5.33. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-oxo-2-phenylethyl)-
1H-benzo[d]imidazol-3-ium bromide (42). Yield 97%, yellow powder,
mp 218e220 ꢀC. IR nmax (cmꢂ1): 3419, 3099, 2978, 1692, 1596, 1552,
127.4, 127.1, 126.3, 125.8, 124.0, 123.8, 121.9, 119.7, 114.4, 111.6, 110.0,
59.9, 55.9, 55.6,18.3,11.5. HRMS (ESI-TOF) m/z Calcd for C29H27N2O3
[M ꢂ Br]þ 451.2016, found 451.2020.
1445, 1343, 1240, 1192, 987, 827, 749, 687. 1H NMR
d: 10.24e10.12
(1H, m), 8.16 (2H, d, J ¼ 7.5), 7.73e7.58 (4H, m), 7.56e7.50 (6H, m),
4.1.5.28. 1-(Benzofuran-2-yl(phenyl)methyl)-2-ethyl-3-(2-(naph-
7.47e7.44 (5H, m), 7.32 (1H, t, J ¼ 7.5), 7.24 (1H, t, J ¼ 7.5), 7.05 (1H, d,
thalen-2-yl)-2-oxoethyl)-1H-imidazol-3-ium
bromide
(37).
J ¼ 6.3), 6.65e6.45 (2H, m). 13C NMR
d: 192.6, 157.9, 152.2, 145.4,
Yield 98%, yellow powder, mp 134e136 ꢀC. IR nmax (cmꢂ1): 3389,
137.3, 135.7, 135.5, 135.0, 133.0, 132.3, 132.0, 131.5, 131.1, 130.2, 129.9,
129.7, 129.6, 128.2, 126.0, 124.3, 117.0, 116.1, 114.2, 112.5, 63.0, 56.5.
HRMS (ESI-TOF) m/z Calcd for C30H23N2O2 [M ꢂ Br]þ 443.1754, found
443.1773.
3053, 2887, 1689, 1625, 1586, 1506, 1453, 1359, 1253, 1182, 940, 819,
736. 1H NMR
d
: 9.08 (1H, s), 8.07 (1H, d, J ¼ 6.9), 8.00 (1H, d, J ¼ 7.8),
7.94 (1H, s), 7.78e7.71 (2H, m), 7.54e7.50 (3H, m), 7.44e7.38 (5H,
m), 7.34e7.31 (2H, m), 7.26e7.21 (2H, m), 7.05 (1H, s), 6.98 (1H, s),
6.61 (2H, s), 3.40e3.25 (2H, m), 0.95 (3H, t, J ¼ 6.9). 13C NMR
d:
4.1.5.34. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-fluorophenyl)-
2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (43). Yield 80%,
white powder, mp 202e203 ꢀC. IR nmax (cmꢂ1): 3420, 3101, 2995,
1696, 1599, 1553, 1496, 1448, 1344, 1236, 1195, 989, 831, 751, 710. 1H
190.9, 155.4, 150.5, 150.0, 136.1, 134.3, 132.4, 132.3, 130.6, 130.4,
129.7,129.6,129.3,128.8,127.6,127.5,127.1,127.0,125.8,124.3,123.7,
123.4, 122.0, 119.8, 111.7, 110.1, 60.0, 56.5, 18.5, 11.7. HRMS (ESI-TOF)
m/z Calcd for C32H27N2O2 [M ꢂ Br]þ 471.2067, found 471.2068.
NMR
d
: 10.57 (1H, s), 8.23e8.19 (2H, m), 7.77 (1H, d, J ¼ 7.8), 7.66
(2H, d, J ¼ 9.3), 7.55e7.39 (9H, m), 7.31e7.25 (1H, m), 7.20 (1H, t,
4.1.5.29. 1-(Benzofuran-2-yl(phenyl)methyl)-3-allyl-1H-benzo[d]
imidazol-3-ium bromide (38). Yield 84%, yellow powder, mp 148e
151 ꢀC. IR nmax (cmꢂ1): 3413, 3102, 3009, 2872, 1612, 1551, 1452,
J ¼ 7.5), 7.10e7.05 (3H, m), 6.79 (1H, d, J ¼ 18.3), 6.67 (1H, d,
J ¼ 18.3). 13C NMR
d: 188.9, 168.3, 164.9, 155.5, 149.8, 143.1, 133.1,
132.6, 131.9,131.8,130.5, 129.9, 129.7, 127.9, 127.5, 127.3,127.2, 125.8,
123.6, 122.0, 116.5, 116.2, 114.5, 113.9, 111.8, 110.2, 60.6, 54.4. HRMS
(ESI-TOF) m/z Calcd for C30H22FN2O2 [M ꢂ Br]þ 461.1660, found
461.1673.
1332, 1251, 1196, 1011, 950, 816, 758, 719. 1H NMR
d: 11.00 (1H, s),
8.05 (1H, s), 7.69 (1H, d, J ¼ 8.4), 7.66 (1H, J ¼ 8.4), 7.61e7.49 (5H, m),
7.46e7.41 (4H, m), 7.30 (1H, t, J ¼ 7.2), 7.23 (1H, t, J ¼ 7.4), 7.16 (1H,
s), 6.19e6.06 (1H, m), 5.48 (2H, dd, J ¼ 15.9, 9.3), 5.34 (2H, d,
J ¼ 5.4 Hz). 13C NMR
d
: 155.4, 150.1, 142.2, 133.4, 131.7, 131.0, 129.7,
4.1.5.35. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-bromophenyl)-
2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (44). Yield 87%,
yellow powder, mp 139e141 ꢀC. IR nmax (cmꢂ1): 3392, 3020, 2918,
1695,1560,1481,1445,1395,1344,1192,1071, 986, 819, 751. 1H NMR
129.5, 129.3, 128.0, 127.4, 127.2, 125.7, 123.6, 122.2, 122.0, 115.4,
113.8, 111.7, 110.2, 60.5, 50.5. HRMS (ESI-TOF) m/z Calcd for
C25H21N2O [M ꢂ Br]þ 365.1648, found 365.1657.
d
: 10.53 (1H, d, J ¼ 3.0), 8.03 (2H, d, J ¼ 8.4), 7.82 (1H, d, J ¼ 7.8),
4.1.5.30. 1-(Benzofuran-2-yl(phenyl)methyl)-3-butyl-1H-benzo[d]
imidazol-3-ium iodide (39). Yield 80%, yellow powder, mp 142e
144 ꢀC. IR nmax (cmꢂ1): 3432, 3103, 3021, 2960, 2872, 1610, 1550,
7.75e7.68 (2H, m), 7.54e7.38 (8H, m), 7.33e7.31 (3H, m), 7.29e7.23
(1H, m), 7.21e7.15 (1H, m), 7.05 (1H, s), 6.78 (1H, d, J ¼ 18.3), 6.70
(1H, d, J ¼ 18.3). 13C NMR
d: 189.7, 155.5, 149.8, 143.0, 133.2, 132.4,
1453, 1249, 1193, 1129, 1013, 944, 813, 753, 705. 1H NMR
d: 10.78
132.1, 130.4, 130.2, 129.9, 129.6, 127.9, 127.5, 127.3, 127.2, 125.8,
123.6, 122.0, 114.5, 114.0, 111.9, 110.1, 60.5, 54.5. HRMS (ESI-TOF) m/z
Calcd for C30H22BrN2O2 [M ꢂ Br]þ 521.0859, found 521.0859.
(1H, s), 8.01 (1H, s), 7.77 (1H, d, J ¼ 8.4), 7.65 (1H, d, J ¼ 8.4), 7.57
(1H, d, J ¼ 8.4), 7.53e7.40 (4H, m), 7.37e7.7.35 (4H, m), 7.26e7.21
(1H, m), 7.17 (2H, s), 4.63e4.58 (2H, m), 2.10e1.90 (2H, m), 1.49e
1.38 (2H, m), 0.92 (3H, t, J ¼ 7.2). 13C NMR
d
: 155.3, 150.0, 141.0,
4.1.5.36. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-hydroxyphenyl)-
2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (45). Yield 91%,
white powder, mp 138e140 ꢀC. IR nmax (cmꢂ1): 3058, 1680, 1595,
133.3,131.6,130.9,129.8,129.5,128.1,127.5,127.2,125.7,123.6, 122.1,
115.5, 113.3, 111.7, 110.3, 60.3, 48.1, 31.1, 19.8, 13.5. HRMS (ESI-TOF)
m/z Calcd for C26H25N2O [M ꢂ I]þ 381.1961, found 381.1969.
1442, 1343, 1238, 1173, 986, 833, 748. 1H NMR
d: 9.94 (1H, s), 7.80e
7.75 (2H, m), 7.65 (1H, d, J ¼ 8.1), 7.57 (2H, dd, J ¼ 7.8, 3.0), 7.49e
7.46 (4H, m), 7.42e7.35 (5H, m), 7.25e7.20 (1H, m), 7.15 (1H, t,
J ¼ 7.5), 6.95 (1H, s), 6.81 (2H, J ¼ 8.7), 6.27 (1H, d, J ¼ 18.0), 6.18 (1H,
4.1.5.31. 1-(Benzofuran-2-yl(phenyl)methyl)-3-benzyl-1H-benzo[d]
imidazol-3-ium bromide (40). Yield 98%, white powder, mp 228e
230 ꢀC. IR nmax (cmꢂ1): 3413, 3100, 3013, 2879, 1604, 1550, 1485,
d, J ¼ 18.0). 13C NMR
d: 185.3, 161.0, 153.0, 147.2, 140.2, 130.7, 130.0,
1432, 1333, 1256, 1194, 1125, 947, 822, 755, 704. 1H NMR (DMSO)
d:
128.6, 127.9, 127.4, 127.1, 125.3, 125.0, 124.8, 124.6, 123.3, 122.4, 121.1,
119.4, 113.5, 111.9, 111.2, 109.3, 107.5, 57.9, 50.8. HRMS (ESI-TOF) m/z
Calcd for C30H23N2O3 [M ꢂ Br]þ 459.1703, found 459.1716.
10.16 (1H, s), 7.97 (2H, d, J ¼ 8.7z), 7.90 (1H, dd, J ¼ 8.7, 3.6), 7.70 (1H,
d, J ¼ 7.5), 7.65e7.60 (5H, m), 7.53e7.51 (5H, m), 7.43 (2H, d, J ¼ 4.2),

X.-Q. Wang et al. / European Journal of Medicinal Chemistry 62 (2013) 111e121
121
4.1.5.37. 1-(Benzofuran-2-yl(phenyl)methyl)-3-(2-(4-methoxyphenyl)-
Appendix A. Supplementary data
2-oxoethyl)-1H-benzo[d]imidazol-3-ium bromide (46). Yield 84%,
yellow powder, mp 141e143 ꢀC. IR nmax (cmꢂ1): 3408, 3015, 2932,
1633, 1599, 1559, 1447, 1341, 1248, 1178, 1022, 986, 830, 752, 715. 1H
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.12.040.
NMR
d
: 10.58 (1H, s), 8.11 (2H, d, J ¼ 9.0), 7.77 (1H, s), 7.72- 7.68 (2H,
m), 7.57e7.54 (2H, m), 7.52e7.44 (4H, m), 7.41e7.38 (3H, m), 7.27 (1H,
t, J ¼ 7.5), 7.19 (1H, t, J ¼ 7.5), 7.09 (1H, s), 6.89 (2H, d, J ¼ 8.7), 6.63 (1H,
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d, J ¼ 18.0), 6.49 (1H, d, J ¼ 18.0), 3.80 (3H, s). 13C NMR
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Acknowledgment
This work was supported by the National Natural Science
Foundation of China (30960460, 20925205 and 21062026), Nat-
ural Science Foundation of Yunnan Province (2010GA014 and
2012FB113) and National Basic Research Program of China (973
Program, 2009CB522300).