Synthesis and in vitro antimicrobial activity of some novel substituted benzimidazole derivatives having potent activity against MRSA

Article abstract of DOI:10.1016/j.ejmech.2008.06.026

The novel benzimidazole derivatives (3, 5, 8, 9, 12-14, 18-41) were prepared in this paper and the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA, standard and clinical isolates), Bacillus subtilis, Escherichia coli and Candida albicans were evaluated. Compounds 24-26 which have no substitution of N-1 position displayed better antibacterial activities than those of standards (ciprofloxacin, ampicillin and sultamicillin) against both the drug-resistant bacteria (MRSA, standard and clinical isolates). These derivatives (24-26), 2,5,6-trihalogenobenzimidazole analogues (8, 12), 5,6-dichloro-2-amino derivative (13), and 5-chloro-2-(4-benzyloxyphenyl)benzimidazole (35) exhibited the most potent antibacterial activity with MIC 3.12 μg/ml against S. aureus.

Full text of DOI:10.1016/j.ejmech.2008.06.026

European Journal of Medicinal Chemistry 44 (2009) 1024–1033
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vitro antimicrobial activity of some novel substituted
benzimidazole derivatives having potent activity against MRSA
,
b
c
Meral Tunçbilek a , Tulug˘ Kiper , Nurten Altanlar
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, 06100 Tandog˘an, Ankara, Turkey
b Novagenix Bioanalytical R&D Center, 06970 Akyurt, Ankara, Turkey
c Department of Microbiology, Faculty of Pharmacy, Ankara University, 06100 Tandog˘an, Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The novel benzimidazole derivatives (3, 5, 8, 9, 12–14, 18–41) were prepared in this paper and
the antimicrobial activities of these compounds against Staphylococcus aureus, methicillin-resistant
S. aureus (MRSA, standard and clinical isolates), Bacillus subtilis, Escherichia coli and Candida albicans
were evaluated. Compounds 24–26 which have no substitution of N-1 position displayed better
antibacterial activities than those of standards (ciprofloxacin, ampicillin and sultamicillin) against both
the drug-resistant bacteria (MRSA, standard and clinical isolates). These derivatives (24–26), 2,5,6-
trihalogenobenzimidazole analogues (8, 12), 5,6-dichloro-2-amino derivative (13), and 5-chloro-2-
(4-benzyloxyphenyl)benzimidazole (35) exhibited the most potent antibacterial activity with MIC
Received 27 March 2008
Received in revised form 19 June 2008
Accepted 30 June 2008
Available online 4 July 2008
Keywords:
Benzimidazole derivatives
Antibacterial
3.12 mg/ml against S. aureus.
Antifungal
Ó 2008 Elsevier Masson SAS. All rights reserved.
Methicillin-resistant Staphylococcus aureus
1. Introduction
antimicrobial activity of these compounds are presented here in
this article.
Resistance to number of antimicrobial agents (b-lactam antibi-
otics, macrolides, quinolones, vancomycin) among a variety of
clinically significant species of bacteria is becoming increasingly
important global problem. In particular, increasing drug resistance
among Gram-positive bacteria such as staphylococci, enterococci,
and streptococci is a significant health matter [1–3]. Methicillin-
resistant Staphylococcus aureus (MRSA) is the most disturbing cause
of nosocomial infections in developed countries [4,5]. In view of
these emerging resistance problems, there is an urgent need for
new anti-MRSA compounds.
Benzimidazole ring displays an important heterocyclic phar-
macophore in drug discovery. These compounds carrying different
substituents in the benzimidazole structure are associated with
a wide range of biological activities including anticancer [6–8],
antiviral [9–12], antibacterial [13–19], antifungal [20–22], anti-
helmintic [23,24], anti-inflammatory [25], antihistaminic [26],
proton pump inhibitor [27,28], antioxidant [29–32], antihyperten-
sive [33] and anticoagulant [34] properties.
2. Chemistry
All new target compounds are shown in Table 1, and synthetic
procedures used for their preparation are demonstrated in
Schemes 1–3. 2-Unsubstituted benzimidazole derivatives (3, 5)
were obtained from 4-chloro-N-cyclopentyl-2-nitroaniline (1) as
starting material by nucleophilic substitution of the chlorine atom
of 1,4-dichloro-2-nitrobenzene with cyclopentylamine (Scheme 1).
Reduction of 1 with zinc powder in 2.5 N NaOH gave the amine
derivative 2. Benzimidazoles 3 and 4 were prepared by the Phillips
method [37] from o-phenylenediamines (4,5-dichloro-o-phenyl-
enediamine, 2) and formic acid. Compound 5 was synthesized by
alkylating 4 with cyclopentyl bromide in the presence of sodium
hydroxide.
2-(Amino-/isopropylamino-/chloro-/bromo-)benzimidazole
analogues (8, 9, 12–14) were synthesized as shown in Scheme 2.
Cyclization of commercially available 4,5-dichloro-o-phenylenedi-
amine with urea [38] and halogenation with phosphorous oxy-
chloride in the presence of hydrochloric acid gas [39] and alkylation
with cyclopentyl bromide led to the formation of 8. Compound 9
was obtained by reaction of 8 with isopropyl amine. Ring closure of
4,5-dichloro-o-phenylenediamine and 2 were accomplished with
cyanogen bromide to give the corresponding 2-amino-benzimid-
azoles (10 [40], 14). Diazotization of 10 with sodium nitrite was
As an outgrowth of our investigations of benzimidazole deriv-
atives, which have displayed significant antifungal [35,36] and
antibacterial activity [14,15], we described new series of substituted
benzimidazoles (3, 5, 8, 9, 12–14, 18–41). The synthesis and
* Corresponding author. Tel.: þ90 312 2033071; fax: þ90 312 2131081.
E-mail address: tuncbile@pharmacy.ankara.edu.tr (M. Tunçbilek).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.06.026

M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
1025
Table 1
Antibacterial and antifungal activities of compounds 3, 5, 8, 9, 12–14, 18–41 (MIC minimum inhibitory concentration,
m
g/ml)
R1
N
N
R3
R2
R4
Compound
R1
R2
R3
R4
S. aureus
MRSAb
(431300)
MRSAc
E. coli
(25922)
B. subtilis
(6633)
C. albicans
(10145)
(25923)a
3
5
8
Cl
Cl
Cl
H
H
H
Cl
50
50
50
ꢀ50
50
50
50
Cl
Cl
6.25
3.12
6.25
6.25
6.25
6.25
12.5
25
12.5
50
50
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
NHCH(CH3)2
50
50
50
50
50
50
50
50
50
12
13
14
Br
3.12
3.12
25
6.25
6.25
50
6.25
6.25
50
25
25
NH2
NH2
6.25
25
6.25
25
18
Cl
OC2H5
6.25
6.25
6.25
50
25
50
F
19
20
Cl
Cl
OC2H5
OC2H5
50
50
50
25
50
50
50
25
25
25
Cl
NO2
12.5
6.25
21
22
23
Cl
Cl
Cl
OC2H5
50
25
50
50
25
50
50
25
50
50
50
25
25
50
25
6.25
6.25
12.5
OCOCH3
OCH3
Cl
Cl
OCOCH3
24
25
Cl
Cl
Cl
Cl
H
H
3.12
3.12
3.12
3.12
3.12
3.12
50
50
6.25
6.25
12.5
F
50
Cl
(continued on next page)

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M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
Table 1 (continued )
Compound
R1
Cl
R2
Cl
R3
R4
S. aureus
MRSAb
(431300)
MRSAc
E. coli
(25922)
B. subtilis
(6633)
C. albicans
(10145)
(25923)a
CH3
CH3
26
H
H
3.12
3.12
3.12
50
6.25
12.5
C
H3C
27
28
Cl
Cl
Cl
Cl
50
25
50
50
50
50
50
25
25
50
25
25
F
29
30
Cl
Cl
Cl
Cl
50
50
25
50
25
50
50
25
25
12.5
25
Cl
CH3
CH3
6.25
C
H3C
31
32
Cl
Cl
Cl
H
50
25
25
25
25
50
25
25
12.5
12.5
12.5
12.5
F
33
34
Cl
Cl
H
H
50
50
50
50
50
50
25
25
25
25
25
Cl
12.5
OCH3
35
Cl
H
3.12
6.25
6.25
50
50
25
O
36
37
Cl
Cl
H
H
50
50
50
50
50
50
50
50
50
25
50
OCOCH3
NO2
12.5
CH3
C
38
39
Cl
Cl
H
H
50
50
12.5
6.25
25
50
50
50
12.5
6.25
H3C
CH3
ꢀ50
ꢀ50
CN

M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
1027
Table 1 (continued )
Compound
R1
Cl
Cl
R2
R3
R4
S. aureus
MRSAb
(431300)
MRSAc
E. coli
(25922)
B. subtilis
(6633)
C. albicans
(10145)
(25923)a
40
H
12.5
25
25
50
25
12.5
6.25
N(CH3)2
41
H
25
25
25
50
25
50
25
Sultamicillin
0.39
0.78
Ampicillin
Ciprofloxacin
Fluconazole
0.78
0.78
50
6.25
50
12.5
0.19
0.09
1.56
a
ATCC number.
MRSA: methicillin-resistant S. aureus (standard).
MRSA: methicillin-resistant S. aureus (clinical isolate).
b
c
followed by the displacement of the diazo group by a bromo atom
to afford 2-bromo derivative 11 [40]. The target compounds 12, 13
were prepared by the alkylation of 11, 10 with cyclopentyl bromide
in the presence of sodium hydroxide.
The structures of all compounds were confirmed by 1H NMR mass
spectral data and elemental analysis.
3. Results and discussion
The synthesis of 2-(substituted aryl)benzimidazole derivatives
(18–41) is outlined in Scheme 3. In the first step, 1,2,4-trichloro-5-
nitrobenzene was subjected to a nucleophilic substitution reaction
with cyclopentylamine in good yields, and the obtained nitro
derivative (15) was reduced with zinc powder in 2.5 N NaOH. With
this reduction two different compounds are produced. One of these
compounds, 4,5-dichloro-N-cyclopentylbenzene-1,2-diamine (16),
has occurred 18% and the other compound which is compound 17
has occurred 80%. Compound 17 is created by nucleophilic substi-
tution of ethoxy group in the presence of NaOH with the Cl atom
[41] of 15 in the 5th position.
Condensation of o-phenylenediamines (17, 16, 4,5-dichloro-o-
phenylenediamine, 2) with Na2S2O5 adduct of appropriate substituted
benzaldehydes gave the desired derivatives (18–27, 32–41). In the
last step, compounds 24–27 were put in reaction with cyclopentyl
bromide to afford the corresponding alkalized derivatives (28–31).
The newly obtained derivatives were evaluated for their in vitro
antibacterial activity against Gram-positive S. aureus, methicillin-
resistant S. aureus (MRSA, standard and clinical isolates), Bacillus
subtilis, Gram-negative Escherichia coli and antifungal activity
against Candida albicans by tube dilution methods [42,43] and MIC
values are given in Table 1. The target compounds and standard
drugs were dissolved in DMSO–water (50%) at a concentration of
200 mg/ml. The concentration was adjusted to 50 mg/ml by 4-fold
dilution with media culture and bacteria solution. Data were not
taken for the initial solution because of the high DMSO concen-
tration (12.5%). As it indicated in Table 1 most of the compounds
showed good activity against Gram-positive bacteria and fungus,
low activity on Gram-negative organism. 2,5,6-Trihalogenobenzi-
midazole analogues (8, 12), 5,6-dichloro-2-amino derivative (13),
5,6-dichloro-2-(4-fluoro/chlorophenyl)-1-nonsubstituted (24–26)
Cl
NO2
Cl
NO2
Cl
b
a
NH
1
Cl
NH2
NH
Cl
Cl
NH2
NH2
2
c
Cl
Cl
Cl
Cl
N
N
N
N
N
d
N
H
Cl
3
4
5
Scheme 1. Reagents: (a) cyclopentylamine; (b) Zn powder, NaOH, EtOH; (c) HCOOH, HCl, H2O; (d) cyclopentyl bromide, NaOH, CH3CN.

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M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
Cl
NH2
NH
H
N
Cl
Cl
NH2
NH2
Cl
Cl
Cl
Cl
N
b
a
O
Cl
N
H
N
H
7
6
2
c
Cl
Cl
Cl
Cl
N
CH3
N
N
d
e
Cl
NHCH
N
CH3
8
9
Cl
Cl
Cl
Cl
Cl
N
N
N
N
f
NH2
Br
NH2
N
H
N
H
10
11
14
c
Cl
Cl
Cl
Cl
N
N
N
NH2
Br
N
12
13
Scheme 2. Reagents: (a) urea; (b) POCl3, HCl (gas); (c) cyclopentyl bromide, NaOH, CH3CN; (d) (CH3)2CHNH2, DMF; (e) CNBr, CH3CN, MeOH, H2O; (f) NaNO2, HBr, H2O, CuBr.
and 5-chloro-2-(4-benzyloxyphenyl)benzimidazole (35) exhibited
excellent activity against S. aureus with MIC 3.12 g/ml. Compounds
5. Experimental
m
24–26 which have no substitution at N1 position were slightly
more effective against MRSA standard and MRSA clinical isolate
than compounds 8, 12, 13, 35. These derivatives possessed also
a better activity against both of the drug-resistant bacteria than
standards (ciprofloxacin, ampicillin and sultamicillin). Among them
the dichlorinated compounds 13, 24, 26 displayed moderate
Melting points were recorded with a capillary melting point
apparatus (Electrothermal 9100) and are uncorrected. The 1H NMR
spectra were measured on VARIAN Mercury 400 FT-NMR spectro-
photometers and are referenced to internal tetramethylsilane
(TMS) at 0.0 ppm. The spin multiplicities are indicated by the
symbols s (singlet), d (doublet), dd (doublet of doublets), t (triplet),
q (quartet), m (multiplet), and br (broad). Mass spectra were taken
on Waters Micromass ZQ by using (ESIþ) method. Elemental anal-
yses (C, H, N) were determined on a Leco CHNS 932 instrument and
were within ꢁ0.4% of the theoretical values. All instrumental
analysis was performed at Ankara University, Faculty of Pharmacy.
Column chromatography was accomplished on silica gel 60 (40–
63 mm particle size). The chemical reagents used in synthesis were
purchased from E. Merck, Fluka, Sigma, Acros and Aldrich.
Compounds 4 [24], 6 [38], 7 [39], 10 [40], and 11 [40] were prepared
according to the literature methods.
activity with MIC value 6.25
mg/ml against B. subtilis. Less activity
(25–50 g/ml) was noted against Gram-negative bacteria E. coli.
m
The synthesized compounds were also tested against yeast cell line
C. albicans (Table 1) and 13, 20–22, 24, 39, 41 showed good anti-
fungal activity with MIC value 6.25 mg/ml.
4. Conclusion
Nowadays growing resistance of pathogens against antibacterial
compounds used is a common and important problem, this shows
us that research on new compounds against these pathogens is
needed. We have synthesized 31 novel substituted benzimidazole
derivatives (3, 5, 8, 9, 12–14, 18–41) and screened for their anti-
microbial activities. Compounds 24–26 having the free NH group of
the benzimidazole moiety exhibited excellent activity with MIC
5.1. 4-Chloro-N-cyclopentyl-2-nitroaniline (1)
A mixture of 2,5-dichloronitrobenzene (2 g, 10.4 mmol) and
cyclopentylamine (4 ml, 31.2 mmol) was heated with stirring at
80 ꢂC for 2 h. The reaction mixture was diluted with water, and the
formed precipitate was collected by filtration and purified by
recrystallization from EtOH to give 1 (1.86 g, 75%) as a orange solid:
3.12 mg/ml against S. aureus, methicillin-resistant S. aureus (MRSA)
standard and MRSA clinical isolate. From 5,6-dichloro-1-cyclo-
pentyl-2-substituted benzimidazoles, three compounds having Cl,
Br and NH2 group at position 2 yielded the most active compounds
mp 83–85 ꢂC. 1H NMR (CDCl3)
d: 1.59–1.82 (6H), 2.09 (m, 2H), 3.94
(m, 1H), 6.85 (d, 1H, Jo ¼ 8.8 Hz), 7.35 (dd, 1H, Jo ¼ 8.8 Hz,
(8, 12, 13) with MIC values of 3.12 mg/ml against S. aureus. Also
Jm ¼ 2.8 Hz), 8.08 (br s, 1H), 8.16 (d, 1H, Jm ¼ 2.8 Hz).
compound 35, which is among monochlorobenzimidazole deriva-
tives and carries 4-benzyloxyphenyl substituent at position 2,
exhibited greatest activity. We need to do studies on in vivo and
mode of action mechanisms of these compounds to better deter-
mine the potential of their antibacterial activity.
5.2. 5-Chloro-1-cyclopentyl-1H-benzimidazole (3)
Zn powder (0.26 g, 4 mmol) was added portionwise to a mixture
of 1 (1 g, 0.4 mmol), 2.5 N NaOH (1 ml) and EtOH (10 ml) under

M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
1029
Cl
Cl
NO2
Cl
Cl
Cl
NO2
NH
a
15
b
Cl
NH2
NH
Cl
Cl
NH2
NH2
Cl
Cl
NH2
NH
Cl
NH2
H3CH2CO
17
NH
2
16
Ar-CHO
Na S O
Ar-CH-OH
SO3Na
5
2
2
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
N
N
H
H3CH2CO
Cl
24-27
c
Ar
Ar
Ar
32
33
34
35
p-F-C6H4
p-Cl-C6H4
Cl
Cl
N
N
p-OCH3-C6H4
p-OCOCH3-C6H4
22
23
p-F-C6H4
p-Cl-C6H4
20 m-NO2-C6H4
p-OCOCH3-C6H4
18
19
p-OCH3-C6H4
28-31
Ar
p-(OCH2-C6H5)-C6H4
21
36 p-OCOCH3-C6H4
37 m-NO2-C6H4
24,28
25,29
26,30
p-F-C6H4
p-Cl-C6H4
p-C(CH3)3-C6H4
38
p-C(CH3)3-C6H4
p-CN-C6H4
39
27,31 C10H7
p-N(CH3)2-C6H4
40
C10H7
41
Scheme 3. Reagents: (a) cyclopentylamine; (b) Zn powder, NaOH, EtOH; (c) cyclopentyl bromide, NaOH, CH3CN.
gentle reflux, and the mixture was refluxed until the TLC monitored
the disappearance of the starting material. EtOH was evaporated in
vacuo and diluted with AcOEt (40 ml) and filtered. The filtrate was
dried over Na2SO4 and concentrated to give 2. The residue con-
taining 2 was dissolved in a mixture of HCOOH (85%, 8 ml), HCl (37%,
3 ml) and H2O (3 ml) after this solution was stirred under reflux for
2 h. The reaction mixture was boiled with charcoal, filtered and
adjusted to pH > 9 with saturated K2CO3 solution. The solid was
filtered, washed with water and dried to afford 3 (0.15 g, 68%) as
chromatography (CHCl3–MeOH, 9:1) to give 5 (0.22 g, 53.7%) as
a white solid: mp 68–70 ꢂC. 1H NMR (CDCl3)
d: 1.82–2.05 (6H), 2.30
(m, 2H), 4.67 (m, 1H), 7.54 (s, 1H), 7.89 (s, 1H), 8.04 (s, 1H). MS (ESIþ)
m/z: 255 (100%) (M þ H), 257 (69%) (M þ H þ 2), 259 (10%)
(M þ H þ 4). Anal. Calcd for C12H12Cl2N2: C, 56.49; H, 4.74; N, 10.98.
Found C, 56.74; H, 4.78; N, 10.97.
5.4. 2,5,6-Trichloro-1-cyclopentyl-1H-benzimidazole (8)
a cream-coloured solid: mp 48–50 ꢂC. 1H NMR (CDCl3)
d: 1.83–2.06
This compound was prepared from 2,5,6-trichloro-1H-benz-
imidazole (7) (0.124 g, 0.56 mmol) according to the procedure
described in for 5 and chromatographed (hexanes–EtOAc, 5:1) to
afford 8 (0.06 g, 37%) as a white solid: mp 108–111 ꢂC. 1H NMR
(6H), 2.28 (m, 2H), 4.71 (m,1H), 7.25 (dd,1H, Jo ¼ 9.2 Hz, Jm ¼ 2.4 Hz),
7.35 (d, 1H, Jo ¼ 8.4 Hz), 7.77 (s, 1H), 7.96 (s, 1H). MS (ESIþ) m/z: 221
(100%) (M þ H), 223 (M þ H þ 2). Anal. Calcd for C12H13ClN2$0.4H2O:
C, 63.24; H, 6.10; N, 12.29. Found C, 63.19; H, 5.99; N, 12.17.
(CDCl3) d: 1.83 (m, 2H), 2.02–2.19 (6H), 4.98 (m,1H), 7.49 (s,1H), 7.77
(s, 1H). MS (ESIþ) m/z: 289 (100%) (M þ H), 291 (94%) (M þ H þ 2),
293 (33%) (M þ H þ 4). Anal. Calcd for C12H11Cl3N2$0.05C6H14: C,
50.26; H, 4.01; N, 9.53. Found C, 49.09; H, 3.95; N, 9.49.
5.3. 5,6-Dichloro-1-cyclopentyl-1H-benzimidazole (5)
5,6-Dichloro-1H-benzimidazole (4) (0.3 g, 1.6 mmol) and NaOH
(0.06 g, 1.6 mmol) were dissolved in CH3CN (10 ml). After 1 h stir-
ring, cyclopentyl bromide (0.17 ml, 1.6 mmol) was added and the
mixture was heated at reflux until the TLC monitored the disap-
pearance of the starting material. Next, the reaction mixture was
evaporated to dryness and the residue was purified by column
5.5. 5,6-Dichloro-1-cyclopentyl-2-(isopropylamino)-1H-
benzimidazole (9)
To a solution of 8 (0.1 g, 0.35 mmol) in DMF (2 ml) was added
isopropyl amine (2 ml) and this mixture was stirred at 100–110 ꢂC

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M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
for 7 h. The reaction mixture was cooled to room temperature, H2O
was added and then extracted with CHCl3. The extract was dried
over Na2SO4, the solvent was evaporated in vacuo, and the residue
was purified by column chromatography eluting with hexanes–
EtOAc (1:1) to give 9 (0.05 g, 46%) as a white solid: mp 210 ꢂC. 1H
dried (yield over 90%). The mixture of these salts (2 mmol) and o-
phenylenediamines (17, 16, 4,5-dichloro-o-phenylenediamine, 2) in
DMF (6 ml) were heated at 110 ꢂC for 4–4.5 h. The reaction mixture
was cooled; H2O was added and then extracted with CHCl3. The
extract was dried over Na2SO4, the solvent was evaporated in
vacuo, and the residue was purified by column chromatography.
NMR (CDCl3) d: 1.33 (d, 6H), 1.78 (m, 2H), 1.95–2.08 (6H), 4.22 (m,
1H), 4.47 (m, 1H), 7.17 (s, 1H), 7.52 (s, 1H). MS (ESIþ) m/z: 312 (100%)
(M þ H), 314 (64%) (M þ H þ 2), 316 (12%) (M þ H þ 4). Anal. Calcd
for C15H19Cl2N3$0.2H2O$0.2CH3COOC2H5: C, 56.90; H, 6.34; N,
12.60. Found C, 56.62; H, 6.44; N, 12.35.
5.10.1. 5-Chloro-1-cyclopentyl-6-ethoxy-2-(4-fluorophenyl)-
1H-benzimidazole (18)
This compound was prepared from 17 (0.35 g, 1.5 mmol) and the
Na2S2O5 adduct of 4-fluorobenzaldehyde (0.41 g, 1.5 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 18 (0.15 g, 30%) as a white solid: mp 195–198 ꢂC. 1H
5.6. 2-Bromo-5,6-dichloro-1-cyclopentyl-1H-benzimidazole (12)
This compound was prepared from 2-bromo-5,6-dichloro-1H-
benzimidazole (11) (0.150 g, 0.56 mmol) according to the procedure
described in for 5 and chromatographed (hexanes–EtOAc, 5:1) to
afford 12 (0.09 g, 48%) as cream-coloured solid: mp 106–109 ꢂC. 1H
NMR (CDCl3)
d
: 1.54 (t, 3H, J ¼ 7.2 Hz), 1.79 (m, 2H), 2.00–2.32 (6H),
4.15 (q, 2H, J ¼ 7.2 Hz), 4.87 (m, 1H), 7.00 (s, 1H), 7.21–7.26 (m, 2H),
7.63–7.67 (m, 2H), 7.86 (s, 1H). MS (ESIþ) m/z: 359 (100%) (M þ H),
361 (37%) (M þ H þ 2). Anal. Calcd for C20H20ClFN2O$0.1H2O: C,
66.60; H, 5.64; N, 7.76. Found C, 66.63; H, 5.86; N, 7.87.
NMR (CDCl3) d: 1.84 (m, 2H), 2.00–2.22 (6H), 5.00 (m, 1H), 7.51 (s,
1H), 7.78 (s, 1H). MS (ESIþ) m/z: 333 (65%) (M þ H), 335 (100%)
(M þ H þ 2), 337 (45%) (M þ H þ 4), 339 (8%) (M þ H þ 6). Anal.
Calcd for C12H11BrCl2N2: C, 43.15; H, 3.32; N, 8.39. Found C, 43.53;
H, 3.59; N, 8.39.
5.10.2. 5-Chloro-2-(4-chlorophenyl)-1-cyclopentyl-6-ethoxy-
1H-benzimidazole (19)
This compound was prepared from 17 (0.35 g, 1.5 mmol) and the
Na2S2O5 adduct of 4-chlorobenzaldehyde (0.45 g, 1.5 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(5:1) to give 19 (0.2 g, 37%) as a white solid: mp 203–206 ꢂC. 1H
5.7. 2-Amino-5,6-dichloro-1-cyclopentyl-1H-benzimidazole (13)
This compound was prepared from 2-amino-5,6-dichloro-1H-
benzimidazole (10) (0.1 g, 0.5 mmol) according to the procedure
described in for 5 and chromatographed (EtOAc–hexanes, 6:5) to
afford 13 (0.065 g, 58%) as a white solid: mp 197–200 ꢂC. 1H NMR
NMR (CDCl3)
d: 1.53 (t, 3H, J ¼ 6.8 Hz), 1.77 (m, 2H), 2.00–2.29 (6H),
4.15 (q, 2H, J ¼ 6.4 Hz), 4.84 (m, 1H), 6.99 (s, 1H), 7.49 (d, 2H,
Jo ¼ 8.4 Hz), 7.63–7.67 (m, 2H), 7.86 (s, 1H). MS (ESIþ) m/z: 375
(100%) (M þ H), 377 (72%) (M þ H þ 2), 379 (13%) (M þ H þ 4). Anal.
Calcd for C20H20Cl2N2O$0.2H2O: C, 63.39; H, 5.42; N, 7.39. Found C,
63.34; H, 5.22; N, 7.47.
(CDCl3) d: 1.78 (m, 2H), 1.91–2.20 (6H), 4.55 (m, 1H), 7.23 (s, 2H),
7.26 (s, 1H), 7.43 (s, 1H). MS (ESIþ) m/z: 270 (100%) (M þ H), 272
(M þ H þ 2). Anal. Calcd for C12H13Cl2N3: C, 52.47; H, 4.95; N, 15.29.
Found C, 52.66; H, 5.27; N, 14.91.
5.8. 2-Amino-5-chloro-1-cyclopentyl-1H-benzimidazole (14)
5.10.3. 5-Chloro-1-cyclopentyl-6-ethoxy-2-(3-nitrophenyl)-
1H-benzimidazole (20)
1,2-Diamino-4-chloro-N-cyclopentylbenzene (2) (0.14 g, 0.66 mmol)
was added to a mixture of H2O (2 ml), MeOH (2 ml) and CNBr
(0.15 ml of a 5.0 M solution, 0.75 mmol). After stirring this mixture
overnight, the solvent was evaporated in vacuo, and the residue was
purified by column chromatography eluting with CHCl3–MeOH
(20:1) to give 14 (0.065 g, 58%) as a light brown solid: mp 200 ꢂC. 1H
This compound was prepared from 17 (0.35 g, 1.5 mmol) and the
Na2S2O5 adduct of 3-nitrobenzaldehyde (0.43 g, 1.5 mmol) accord-
ing to the general procedure and was obtained after purification by
column chromatography eluting with hexanes–EtOAc (5:2) to give
20 (0.21 g, 38%) as a light yellow solid: mp 172 ꢂC. 1H NMR (CDCl3)
d
: 1.55 (t, 3H, J ¼ 7.2 Hz), 1.81 (m, 2H), 2.02–2.36 (6H), 4.17 (q, 2H,
0
NMR (CDCl3)
d
: 1.72 (m, 2H), 1.86–2.10 (6H), 4.60 (m, 1H), 5.75 (br s,
J ¼ 7.2 Hz), 4.85 (m, 1H), 7.01 (s, 1H), 7.74 (t, 1H, Jo,o ¼ 8 Hz), 7.84 (s,
2H), 6.95 (dd,1H, Jo ¼ 8.8 Hz, Jm ¼ 2 Hz), 7.03 (d,1H, Jo ¼ 8.4 Hz), 7.29
(d, 1H, Jm ¼ 1.6 Hz). MS (ESIþ) m/z: 236 (100%) (M þ H), 238 (40%)
(M þ H þ 2). Anal. Calcd for C12H14ClN3$0.15H2O: C, 60.45; H, 6.04;
N, 17.62. Found C, 60.48; H, 6.06; N, 17.47.
1H), 8.04 (d,1H, Jo ¼ 8 Hz), 8.38 (dd,1H, Jo ¼ 8, Jm ¼ 2 Hz), 8.51 (t,1H,
þ
0
Jm,m ¼ 1.6 Hz). MS (ESI ) m/z: 386 (100%) (M þ H), 388 (34%)
(M þ H þ 2). Anal. Calcd for C20H20ClN3O3$0.32H2O: C, 61.34; H,
5.31; N, 10.73. Found C, 60.94; H, 5.41; N, 11.18.
5.9. 4,5-Dichloro-N-cyclopentyl-2-nitroaniline (15)
5.10.4. 2-(4-Acetoxyphenyl)-5-chloro-1-cyclopentyl-6-ethoxy-
1H-benzimidazole (21)
This compound was prepared from 1,2,4-trichloro-5-nitroben-
zene (1 g, 4.4 mmol) and cyclopentylamine (2 ml, 13.2 mmol)
according to the procedure described in for 1 as a yellow-orange
This compound was prepared from 17 (0.35 g, 1.5 mmol) and the
Na2S2O5 adduct of 4-acetoxybenzaldehyde (0.38 g, 1.5 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 21 (0.1 g, 18%) as a white solid: mp 184 ꢂC. 1H NMR
solid 15 (0.065 g, 58%): mp 58–61 ꢂC. 1H NMR (CDCl3)
d: 1.58–1.84
(6H), 2.12 (m, 2H), 3.90 (m, 1H), 7.00 (s, 1H), 8.03 (br s, 1H), 8.26
(s, 1H).
(CDCl3) d: 1.52 (t, 3H), 1.77 (m, 2H), 1.96–2.30 (6H), 2.34 (s, 3H), 4.14
(q, 2H, J ¼ 6.8 Hz), 4.90 (m, 1H), 6.99 (s, 1H), 7.24 (dd, 2H, Jo ¼ 8.8,
Jm ¼ 1.6 Hz), 7.64 (dd, 2H, Jo ¼ 8.4, Jm ¼ 1.6 Hz), 7.79 (s, 1H). MS
(ESIþ) m/z: 399 (100%) (M þ H), 401 (32%) (M þ H þ 2). Anal. Calcd
for C22H23ClN2O3: C, 66.24; H, 5.81; N, 7.02. Found C, 66.39; H, 5.82;
N, 6.91.
5.10. General procedure for synthesis of 18–41
Reduction of 15 (1 g, 150 mmol) was done according to the
procedure described in for 2 and two reduction products 16 and 17
were obtained as a dark brown-coloured oil, which was used in the
next steps without purification. Appropriate aromatic aldehydes
(30 mmol) were dissolved in EtOH (50 ml) and Na2S2O5 (3.3 g) in
hot H2O (10 ml) was added in portions. The reaction mixture was
stirred vigorously and was cooled. The precipitate was filtered and
5.10.5. 5,6-Dichloro-1-cyclopentyl-2-(4-methoxyphenyl)-
1H-benzimidazole (22)
This compound was prepared from 16 (0.35 g,1.5 mmol) and the
Na2S2O5 adduct of 4-acetoxybenzaldehyde (0.57 g, 1.5 mmol)

M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
1031
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 22 (0.14 g, 27%) as a cream-coloured solid: mp 198 ꢂC.
procedure and was obtained after purification by column chro-
matography eluting with hexanes–EtOAc (5:3) to give 27 (0.17 g,
24%) as a light pink solid: mp 167–169 ꢂC. 1H NMR (DMSO-d6)
d:
1H NMR (CDCl3)
d
: 1.75 (m, 2H), 1.98–2.30 (6H), 3.88 (s, 3H), 4.89
7.63 (m, 2H), 7.82 (br s, 1H), 7.94–8.08 (m, 3H), 8.10 (d, 1H,
Jo ¼ 8.4 Hz), 8.29 (dd, 1H, Jo ¼ 8.8 Hz, Jm ¼ 1.6 Hz), 8.76 (s, 1H), 13.42
(s, 1H). MS (ESIþ) m/z: 313 (100%) (M þ H), 315 (52%) (M þ H þ 2),
317 (16%) (M þ H þ 4). Anal. Calcd for C17H10Cl2N2$0.6H2O: C, 63.02;
H, 3.48; N, 8.64. Found C, 62.84; H, 3.64; N, 8.70.
(m,1H), 7.04 (d, 2H, Jo ¼ 8.8 Hz), 7.56 (s, 1H), 7.58 (d, 2H, Jo ¼ 9.2 Hz),
7.86 (s, 1H). MS (ESIþ) m/z: 361 (100%) (M þ H), 363 (68%)
(M þ H þ 2),
365
(12%)
(M þ H þ 4).
Anal.
Calcd
for
C19H18Cl2N2O$0.15C6H14: C, 63.87; H, 5.41; N, 7.48. Found C, 63.98;
H, 5.36; N, 7.48.
5.10.11. 5,6-Dichloro-1-cyclopentyl-2-(4-fluorophenyl)-
1H-benzimidazole (28)
5.10.6. 2-(4-Acetoxyphenyl)-5,6-dichloro-1-cyclopentyl-
1H-benzimidazole (23)
This compound was prepared from 24 (0.15 g, 0.4 mmol)
according to the procedure described in for 5 and chromatographed
(hexanes–EtOAc, 2:1) to afford 28 (0.065 g, 43%) as a white solid:
This compound was prepared from 16 (0.35 g, 1.5 mmol) and
the Na2S2O5 adduct of 4-acetoxybenzaldehyde (0.55 g, 1.5 mmol)
according to the general procedure and was obtained after
purification by column chromatography eluting with hexanes–
EtOAc (10:3) to give 23 (0.1 g, 17%) as a white solid: mp 170–
mp 188–190 ꢂC. 1H NMR (CDCl3)
d: 1.76 (m, 2H), 2.03–2.26 (6H),
4.83 (m, 1H), 7.21–7.26 (m, 2H), 7.58–7.65 (m, 3H), 7.87 (s, 1H). MS
(ESIþ) m/z: 349 (100%) (M þ H), 351 (75%) (M þ H þ 2), 353 (12%)
(M þ H þ 4). Anal. Calcd for C18H15Cl2FN2$0.2H2O: C, 61.27; H, 4.39;
N, 7.93. Found C, 61.04; H, 4.53; N, 7.96.
173 ꢂC. 1H NMR (CDCl3)
d: 1.77 (m, 2H), 2.00–2.30 (6H), 2.36 (s, 3H),
4.90 (m, 1H), 7.28 (d, 2H, Jo ¼ 8.4 Hz), 7.58 (s, 1H), 7.66 (d, 2H,
Jo ¼ 8.8 Hz), 7.88 (s, 1H). MS (ESIþ) m/z: 389 (100%) (M þ H), 391
(69%) (M þ H þ 2), 393 (12%) (M þ H þ 4). Anal. Calcd for
C20H18Cl2N2O2: C, 61.71; H, 4.66; N, 7.20. Found C, 61.32; H, 4.72; N,
7.27.
5.10.12. 5,6-Dichloro-2-(4-chlorophenyl)-1-cyclopentyl-
1H-benzimidazole (29)
This compound was prepared from 25 (0.15 g, 0.4 mmol)
according to the procedure described in for 5 and chromatographed
(hexanes–EtOAc, 2:1) to afford 29 (0.06 g, 30%) as a white solid: mp
5.10.7. 5,6-Dichloro-2-(4-fluorophenyl)-1H-benzimidazole (24)
This compound was prepared from 4,5-dichloro-o-phenyl-
enediamine (0.4 g, 2.25 mmol) and the Na2S2O5 adduct of 4-fluo-
robenzaldehyde (0.52 g, 2.25 mmol) according to the general
procedure and was obtained after purification by column chro-
matography eluting with hexanes–EtOAc (5:3) to give 24 (0.21 g,
235–237 ꢂC. 1H NMR (CDCl3)
d: 1.75 (m, 2H), 2.00–2.31 (6H), 4.85
(m, 1H), 7.53 (d, 2H, Jo ¼ 7.6 Hz), 7.60 (d, 3H), 7.91 (s, 1H). MS (ESIþ)
m/z: 365 (92%) (M þ H), 367 (100%) (M þ H þ 2), 369 (36%)
(M þ H þ 4), 371 (2%) (M þ H þ 6). Anal. Calcd for C18H15Cl3N2: C,
58.40; H, 4.22; N, 7.56. Found C, 58.11; H, 4.20; N, 7.57.
33%) as a light pink solid: mp 272–274 ꢂC. 1H NMR (DMSO-d6)
d:
7.32–7.40 (m, 2H), 7.78 (br s, 2H), 8.12–8.22 (m, 2H), 13.19 (s, 1H).
MS (ESIþ) m/z: 281 (100%) (M þ H), 285 (22%) (M þ H þ 4). Anal.
Calcd for C13H7Cl2FN2: C, 55.54; H, 2.51; N, 9.97. Found C, 55.76; H,
2.73; N, 10.35.
5.10.13. 2-(4-tert-Butylphenyl)-5,6-dichloro-1-cyclopentyl-
1H-benzimidazole (30)
This compound was prepared from 26 (0.1 g, 0.3 mmol)
according to the procedure described in for 5 and chromatographed
(hexanes–EtOAc, 2:1) to afford 30 (0.08 g, 68%) as a white solid: mp
5.10.8. 5,6-Dichloro-2-(4-chlorophenyl)-1H-benzimidazole (25)
This compound was prepared from 4,5-dichloro-o-phenyl-
enediamine (0.4 g, 2.25 mmol) and the Na2S2O5 adduct of 4-
chlorobenzaldehyde (0.55 g, 2.25 mmol) according to the general
procedure and was obtained after purification by column chro-
matography eluting with hexanes–EtOAc (5:3) to give 25 (0.16 g,
205–208 ꢂC. 1H NMR (DMSO-d6)
d: 1.35 (s, 9H), 1.66 (m, 2H), 1.90–
2.22 (6H), 4.86 (m, 1H), 7.62 (s, 4H), 7.87 (s, 1H), 7.97 (s, 1H). MS
(ESIþ) m/z: 387 (100%) (M þ H), 389 (68%) (M þ H þ 2), 391 (14%)
(M þ H þ 4). Anal. Calcd for C22H24Cl2N2: C, 68.22; H, 6.25; N, 7.23.
Found C, 67.94; H, 6.49; N, 7.24.
24%) as a cream-coloured solid: mp 287 ꢂC. 1H NMR (DMSO-d6)
d:
5.10.14. 5,6-Dichloro-1-cyclopentyl-2-(2-naphthyl)-
1H-benzimidazole (31)
7.62 (d, 2H, Jo ¼ 8.8 Hz), 7.83 (br s, 2H), 8.14 (d, 2H, Jo ¼ 8.4 Hz),13.31
(br s, 1H). MS (ESIþ) m/z: 297 (86%) (M þ H), 299 (100%)
(M þ H þ 2), 301 (28%) (M þ H þ 4), 303 (2%) (M þ H þ 6). Anal.
Calcd for C13H7Cl3N2: C, 52.47; H, 2.37; N, 9.41. Found C, 52.55; H,
2.25; N, 9.30.
This compound was prepared from 27 (0.15 g, 0.5 mmol)
according to the procedure described in for 5 and chromatographed
(hexanes–EtOAc, 3:1) to afford 31 (0.075 g, 30%) as a white solid:
mp 187 ꢂC. 1H NMR (CDCl3)
d: 1.75 (m, 2H), 2.00–2.34 (6H), 4.99 (m,
1H), 7.58–7.62 (m, 3H), 7.71 (d, 1H, Jo ¼ 8.8 Hz), 7.93–7.96 (m, 3H),
8.01 (d, 1H, Jo ¼ 8.4 Hz), 8.19 (s, 1H). MS (ESIþ) m/z: 381 (100%)
(M þ H), 383 (68%) (M þ H þ 2), 385 (11%) (M þ H þ 4). Anal. Calcd
for C22H18Cl2N2$0.1H2O: C, 68.97; H, 4.78; N, 7.31. Found C, 68.74; H,
4.84; N, 7.34.
5.10.9. 2-(4-tert-Butylphenyl)-5,6-dichloro-1H-benzimidazole (26)
This compound was prepared from 4,5-dichloro-o-phenyl-
enediamine (0.4 g, 2.25 mmol) and the Na2S2O5 adduct of 4-tert-
butylbenzaldehyde (0.35 g, 2.25 mmol) according to the general
procedure and was obtained after purification by column chro-
matography eluting with hexanes–EtOAc (5:3) to give 26 (0.15 g,
28%) as a cream-coloured solid: mp 217–219 ꢂC. 1H NMR (DMSO-d6)
5.10.15. 5-Chloro-1-cyclopentyl-2-(4-fluorophenyl)-
1H-benzimidazole (32)
d
: 1.29 (s, 9H), 7.55 (d, 2H, Jo ¼ 8.8 Hz), 7.72 (br s, 1H), 7.88 (br s,
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-fluorobenzaldehyde (0.4 g, 1.6 mmol) accord-
ing to the general procedure and was obtained after purification by
column chromatography eluting with hexanes–EtOAc (10:3) to give
32 (0.3 g, 53%) as a cream-coloured solid: mp 145–148 ꢂC. 1H NMR
1H), 8.07 (d, 2H, Jo ¼ 8.8 Hz), 13.16 (s, 1H). MS (ESIþ) m/z: 319
(100%) (M þ H), 323 (48%) (M þ H þ 4). Anal. Calcd for
C17H16Cl2N2$0.1H2O: C, 63.60; H, 5.08; N, 8.72. Found C, 63.52; H,
5.07; N, 8.69.
(CDCl3) d: 1.75 (m, 2H), 2.01–2.11 (m, 4H), 2.28 (m, 2H), 4.85 (m,
5.10.10. 5,6-Dichloro-2-(2-naphthyl)-1H-benzimidazole (27)
This compound was prepared from 4,5-dichloro-o-phenyl-
enediamine (0.4 g, 2.25 mmol) and the Na2S2O5 adduct of 2-
naphthaldehyde (0.5 g, 2.25 mmol) according to the general
1H), 7.19–7.24 (m, 3H), 7.41 (d, 1H, Jo ¼ 8.8 Hz), 7.61–7.65 (m, 2H),
7.78 (d, 1H, Jm ¼ 2 Hz). MS (ESIþ) m/z: 315 (100%) (M þ H), 317 (37%)
(M þ H þ 2). Anal. Calcd for C18H16ClFN2: C, 68.68; H, 5.12; N, 8.90.
Found C, 68.41; H, 4.85; N, 8.98.

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M. Tunçbilek et al. / European Journal of Medicinal Chemistry 44 (2009) 1024–1033
þ
0
5.10.16. 5-Chloro-1-cyclopentyl-2-(4-chlorophenyl)-
1H-benzimidazole (33)
Jm ¼ 2.4 Hz), 8.53 (t, 1H, Jm,m ¼ 1.6 Hz). MS (ESI ) m/z: 342 (100%)
(M þ H), 344 (35%) (M þ H þ 2). Anal. Calcd for C18H16ClN3O2: C,
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-chlorobenzaldehyde (0.39 g, 1.6 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 33 (0.25 g, 54%) as a cream-coloured solid: mp 184–
63.25; H, 4.72; N, 12.29. Found C, 63.19; H, 4.71; N, 12.33.
5.10.21. 2-(4-tert-Butylphenyl)-5-chloro-1-cyclopentyl-
1H-benzimidazole (38)
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-tert-butylbenzaldehyde (0.45 g, 1.6 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 38 (0.21 g, 36%) as a white solid: mp 171–174 ꢂC. 1H
187 ꢂC. 1H NMR (CDCl3)
d: 1.75 (m, 2H), 2.01–2.11 (m, 4H), 2.27 (m,
2H), 4.85 (m, 1H), 7.23 (dd, 1H, Jo ¼ 8.4 Hz, Jm ¼ 2 Hz), 7.41 (d, 1H,
Jo ¼ 9.2 Hz), 7.50 (d, 2H, Jo ¼ 8.8 Hz), 7.60 (d, 2H, Jo ¼ 8.4 Hz), 7.78 (d,
1H, Jm ¼ 2.4 Hz). MS (ESIþ) m/z: 331 (100%) (M þ H), 333 (81%)
(M þ H þ 2), 335 (%15) (M þ H þ 4). Anal. Calcd for C18H16Cl2N2: C,
65.09; H, 4.88; N, 8.43. Found C, 64.84; H, 4.50; N, 8.50.
NMR (CDCl3) d: 1.37 (s, 9H), 1.74 (m, 2H), 1.96–2.14 (m, 4H), 2.27 (m,
2H), 4.96 (m,1H), 7.20 (d,1H, Jo ¼ 8.4 Hz), 7.40 (d,1H, Jo ¼ 8 Hz), 7.53
(d, 2H, Jo ¼ 8 Hz), 7.58 (d, 2H, Jo ¼ 7.6 Hz), 7.77 (s,1H). MS (ESIþ) m/z:
353 (100%) (M þ H), 355 (M þ H þ 2). Anal. Calcd for C22H25ClN2: C,
74.88; H, 7.14; N, 7.94. Found C, 74.87; H, 7.41; N, 8.04.
5.10.17. 5-Chloro-1-cyclopentyl-2-(4-methoxyphenyl)-
1H-benzimidazole (34)
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-methoxybenzaldehyde (0.6 g, 1.6 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 34 (0.27 g, 50%) as a cream-coloured solid: mp 173–
5.10.22. 2-(4-Cyanophenyl)-5-chloro-1-cyclopentyl-
1H-benzimidazole (39)
This compound was prepared from 2 (0.26 g, 1.2 mmol) and the
Na2S2O5 adduct of 4-cyanobenzaldehyde (0.3 g, 1.2 mmol) accord-
ing to the general procedure and was obtained after purification by
column chromatography eluting with hexanes–EtOAc (10:3) to give
175 ꢂC. 1H NMR (CDCl3)
d: 1.73 (m, 2H), 2.00–2.11 (m, 4H), 2.26 (m,
2H), 3.88 (s, 3H), 4.90 (m, 1H), 7.03 (d, 2H, Jo ¼ 8 Hz), 7.19 (dd, 1H,
Jo ¼ 8.8 Hz, Jm ¼ 1.6 Hz), 7.39 (d, 1H, Jo ¼ 8.4 Hz), 7.58 (d, 2H,
Jo ¼ 8 Hz), 7.76 (s, 1H). MS (ESIþ) m/z: 327 (100%) (M þ H), 329 (35%)
(M þ H þ 2). Anal. Calcd for C19H19ClN2O: C, 69.83; H, 5.86; N, 8.57.
Found C, 69.93; H, 5.80; N, 8.66.
39 (0.19 g, 50%) as a white solid: mp 187–189 ꢂC. 1H NMR (CDCl3)
d:
1.78 (m, 2H), 2.00–2.18 (m, 4H), 2.30 (m, 2H), 4.84 (m, 1H), 7.27 (dd,
1H, Jo ¼ 8.4 Hz, Jm ¼ 2 Hz), 7.45 (d, 1H, Jo ¼ 8.8 Hz), 7.78–7.85 (m,
5H). MS (ESIþ) m/z: 322 (100%) (M þ H), 324 (35%) (M þ H þ 2).
Anal. Calcd for C19H16ClN3: C, 70.91; H, 5.01; N, 13.06. Found C,
70.81; H, 5.18; N, 13.09.
5.10.18. 2-(4-Benzyloxyphenyl)-5-chloro-1-cyclopentyl-
1H-benzimidazole (35)
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-benzyloxybenzaldehyde (0.6 g, 1.6 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 35 (0.22 g, 33%) as a cream-coloured solid: mp 143–
5.10.23. 5-Chloro-1-cyclopentyl-2-(4-N,N-dimethylaminophenyl)-
1H-benzimidazole (40)
This compound was prepared from 2 (0.26 g,1.22 mmol) and the
Na2S2O5 adduct of 4-(N,N-dimethylamino)benzaldehyde (0.43 g,
1.22 mmol) according to the general procedure and was obtained
after purification by column chromatography eluting with
hexanes–EtOAc (10:3) to give 40 (0.21 g, 43%) as a white solid: mp
144 ꢂC. 1H NMR (CDCl3)
d: 1.74 (m, 2H), 2.01–2.09 (m, 4H), 2.27 (m,
2H), 4.91 (m, 1H), 5.13 (s, 2H), 7.11 (dd, 2H, Jo ¼ 8.4 Hz, Jm ¼ 1.6 Hz),
7.20 (dd, 1H, Jo ¼ 8.4 Hz, Jm ¼ 2 Hz), 7.34–7.46 (m, 6H), 7.58 (dd, 2H,
Jo ¼ 8.8 Hz, Jm ¼ 2 Hz), 7.77 (d, 1H, Jm ¼ 1.6 Hz), MS (ESIþ) m/z: 403
(100%) (M þ H), 405 (40%) (M þ H þ 2). Anal. Calcd for C25H23ClN2O:
C, 74.52; H, 5.75; N, 6.95. Found C, 74.64; H, 6.06; N, 6.81.
216–219 ꢂC. 1H NMR (DMSO-d6)
d: 1.66 (m, 2H),1.91–2.21 (6H), 2.99
(s, 6H), 4.91 (m, 1H), 6.84 (d, 2H, Jo ¼ 8.4 Hz), 7.21 (dd, 1H,
Jo ¼ 8.4 Hz, Jm ¼ 2 Hz), 7.50 (d, 2H, Jo ¼ 8.8 Hz), 7.59 (d, 1H,
Jo ¼ 8.4 Hz), 7.68 (d, 1H, Jm ¼ 1.2 Hz). MS (ESIþ) m/z: 340 (100%)
(M þ H), 342 (43%) (M þ H þ 2). Anal. Calcd for C20H22ClN3: C,
70.68; H, 6.52; N, 12.36. Found C, 70.57; H, 6.56; N, 12.30.
5.10.19. 2-(4-Acetoxyphenyl)-5-chloro-1-cyclopentyl-
1H-benzimidazole (36)
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 4-acetoxybenzaldehyde (0.45 g, 1.6 mmol)
according to the general procedure and was obtained after purifi-
cation by column chromatography eluting with hexanes–EtOAc
(10:3) to give 36 (0.22 g, 38%) as a semi-white solid: mp 111–114 ꢂC.
5.10.24. 5-Chloro-1-cyclopentyl-2-(2-naphthyl)-
1H-benzimidazole (41)
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 2-naphthaldehyde (0.43 g, 1.6 mmol) according
to the general procedure and was obtained after purification by
column chromatography eluting with hexanes–EtOAc (10:3) to give
1H NMR (CDCl3)
d: 1.77 (m, 2H), 2.02–2.12 (m, 4H), 2.30 (m, 2H),
2.35 (s, 3H), 4.93 (m, 1H), 7.23–7.28 (m, 3H), 7.44 (d, 1H, Jo ¼ 8.4 Hz),
7.68 (d, 2H, Jo ¼ 8.4 Hz), 7.79 (d, 1H, Jm ¼ 2 Hz), MS (ESIþ) m/z: 355
(100%) (M þ H), 357 (38%) (M þ H þ 2). Anal. Calcd for
C20H19ClN2O2$0.3CH3COOC2H5: C, 66.78; H, 5.65; N, 7.34. Found C,
66.82; H, 5.65; N, 7.09.
41 (0.22 g, 38%) as a white solid: mp177–179 ꢂC. 1H NMR (CDCl3)
d:
1.72 (m, 2H), 1.96–2.17 (m, 4H), 2.30 (m, 2H), 4.99 (m, 1H), 7.24 (dd,
1H, Jo ¼ 8.4 Hz, Jm ¼ 1.6 Hz), 7.44 (d, 1H, Jo ¼ 8.4 Hz), 7.58 (m, 2H),
7.71 (d, 1H, Jo ¼ 8.8 Hz), 7.83 (d, 1H, Jm ¼ 1.6 Hz), 7.90–7.99 (m, 3H),
8.17 (s, 1H). MS (ESIþ) m/z: 347 (100%) (M þ H), 349 (41%)
(M þ H þ 2). Anal. Calcd for C22H19ClN2$0.2H2O: C, 75.39; H, 5.57; N,
7.99. Found C, 75.39; H, 5.68; N, 8.08.
5.10.20. 2-(3-Nitrophenyl)-5-chloro-1-cyclopentyl-
1H-benzimidazole (37)
References
This compound was prepared from 2 (0.35 g, 1.6 mmol) and the
Na2S2O5 adduct of 3-nitrobenzaldehyde (0.43 g, 1.6 mmol) accord-
ing to the general procedure and was obtained after purification by
column chromatography eluting with hexanes–EtOAc (10:3) to give
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