Synthesis of some new 1H-benzimidazole-2-carboxamido derivatives and their antimicrobial activitiy

Article abstract of DOI:10.1002/jhet.734

5,6-Dichloro-2-hydroxymethyl-1H-benzimidazole (1) was prepared by the cyclization of 4,5-dichloro-o-phenylenediamine with glycolic acid, then, alcohol group of 1 was converted to carboxylic acid (2). The final products 5,6-dichloro-1H-benzimidazole-2-carb

Full text of DOI:10.1002/jhet.734

November 2011
Synthesis of Some New 1H-Benzimidazole-2-carboxamido
Derivatives and Their Antimicrobial Activitiy
1317
a
Sec¸kin Ozden, Figen Usta, Nurten Altanlar, and Hakan Goker *
a
b
a
¨
¨
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University,
06100 Tandogan, Ankara-Turkey
bDepartment of Microbiology, Faculty of Pharmacy, Ankara University, 06100 Tandogan,
Ankara-Turkey
*E-mail: goker@ankara.edu.tr
Received August 8, 2010
DOI 10.1002/jhet.734
Published online 18 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
5,6-Dichloro-2-hydroxymethyl-1H-benzimidazole (1) was prepared by the cyclization of 4,5-dichloro-
o-phenylenediamine with glycolic acid, then, alcohol group of 1 was converted to carboxylic acid (2).
The final products 5,6-dichloro-1H-benzimidazole-2-carboxamides (3–11, 13–14) were prepared by the
amidification of compounds 2 with several amines by using O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethy-
luronium hexafluorophosphate. Compound 12 was prepared by the reaction of compound 6 with metha-
nolic HCl. The relations between the tautomer and nontautomer types of imidazole moiety are
discussed with NMR spectroscopy. The in vitro antibacterial and antifungal activity of the synthesized
compounds against S. aureus, E. coli, B. subtilis, and C. albicans were evaluated with the disc diffusion
techniques. The synthesized compounds were more active against the bacteria than fungi. Compound 3
exhibited best inhibitory activity against S. aureus.
J. Heterocyclic Chem., 48, 1317 (2011).
INTRODUCTION
ylenediamine with glycolic acid and then, alcohol group
of 1 was converted to carboxylic acid (2) by the oxida-
tion with KMnO4 in alkali medium. The final products
5,6-dichloro-1H-benzimidazole-2-carboxamides (3–11,
13–14) were prepared by the amidification of com-
pounds 2 with appropriate amines by using O-(benzo-
triazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluoro-
phosphate (HBTU). Compound 12 was prepared by the
reaction of compound 6 with methanolic HCl (Scheme
1).
Numerous benzimidazole derivatives containing ami-
dine groups on the benzene ring have been synthesized
for their antifungal, insecticidal, herbicidal, antiinflam-
matory, and potential anthelmintic activities [1]. It is
also well known that amides, amidines, and combina-
tions of both are present in a variety of antimicrobial,
antiparasitic, anthelmintic, antiviral, and antitumoral
agents. Furthermore, our previous work and that of
others showed that benzimidazole carboxamidines dis-
play good antibacterial and antimycotic activity [2–4].
In addition, potent antimicrobial activities of a series of
5,6-dichloro-2-piperidin-4-yl-benzimidazoles [5] and 4-
(5,6-dichloro-1H-benzimidazol-2-yl)-N-substituted ben-
zamides [6] were reported. Taking into consideration
these structural features, we planned to prepare a series
of benzimidazoles carrying amide functional group on
the position C-2.
Annular 1,3-tautomerism in imidazole moiety is con-
sidered to be biologically relevant because the signifi-
cance of the imidazole ring tautomerism in histidine, a
naturally occurring amino acid, has been well estab-
lished. In the imidazole ring, tautomerism means that
the hydrogen atom may be bonded either to the N1 or to
the N3 atom (Scheme 2). This tautomeric proton
exchange ratio is dependent on some several factors,
including the nature of the substituents and their sym-
metrical or unsymmetrical substitution on the benzene
moiety or the concentration ratio of the solution and
intermolecular hydrogen bonding properties between the
molecules and solvents. Symmetrical tautomeric forms
of compound 9 are shown in Scheme 2.
RESULTS AND DISCUSSION
5,6-Dichloro-2-hydroxymethyl-1H-benzimidazole (1)
was prepared by the cyclization of 4,5-dichloro-o-phen-
C
V
2011 HeteroCorporation

¨
S. Ozden, F. Usta, N. Altanlar, and H. Goker
¨
1318
Vol 48
Scheme 1. Synthesis of benzimidazoles 1–14.
In particular, if the benzimidazoles bear a substitutent
motion tautomeric effect even though they have simetri-
1
on the benzen ring at unsymmetrical [C-5(6) or C-4(7)]
position, a mixture of two regioisomers are obtained in
different ratio, during the alkylation of nitrogen atoms
of imidazole moiety [7]. There is no enough systematic
investigation on the influence of a substituent at position
C-5(6) on tautomerism of imidazole except than infrared
spectroscopy and there are only few experimental papers
concerning tautomerism of the C-5(6)-substituted imida-
zoles [8]. In this study, we try to show the relations
between the tautomer and nontautomer type of benzimi-
dazoles by their NMR spectra. Because of the mixture
of tautomers in compounds 3–5, 9, 12, 13, their NMR
spectra were not clear enough under standard conditions
as expected. It means that these compounds have slow
cally equal. As it shown in Figures 1 and 2, both H
and 13C NMR spectra (A and B) of compound 9 are not
clear. At low concentration in DMSO-d6, the 1,3-tau-
tomerism was arrested and compound 9 existed as a sin-
gle isomers so the protons H-4,7 appears as two differ-
ent singlets [Fig. 1(A)]. When the concentration of the
solution is increased, exchange rate of the imidazole
proton increased and this time H-4,7 appeared as broad
signals [Fig. 1(B)]. Similar situation was also observed
with the 13C spectra of compound 9. With low concen-
tration, the signals of C-(5,6), C-(4,7), and C-(3a,7a)
belonging the mixture of tautomers were seen as differ-
ent chemical shim values [d ppm; Fig. 2(A)], whereas it
was not possible to see signals belonging to the same
Scheme 2. Symmetrical tautomeric forms of compound 9.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis of Some New 1H-Benzimidazole-2-carboxamido Derivatives and
Their Antimicrobial Activitiy
1319
Figure 1. (A) 1H NMR spectra of 9 in low concentration. (B) 1H NMR spectra of 9 in high concentration. (C) 1H NMR spectra of 9 þ NaH þ D2O.
carbons, when compound 9 was in high concentration in
DMSO-d6 [Fig. 2(B)]. In contrast, after removal of the
tautomeric effects by addition of a tiny amount of dry
NaH, and two to three drops of D2O, all the chemically
equivalent protons and carbons have been observed as
only one sharp singlets, in their NMR spectra [Figs.
1(C) and 2(C)]. Hence, very fine NMR assignments
without tautomerism were made by a combination of 1D
and 2D NMR techniques. Quaternary and methine car-
bons were easily assigned from the HMBC and HSQC
spectra, respectively, with compound 9 (Table 2). Simi-
lar effects were also observed in 1H NMR spectra of
compound 7 and 9 by the addition of one drop
CF3COOH, instead of NaH þ D2O, however no satis-
factory results was obtained with their 13C spectra. We
also performed the same experiments by using one drop
of CH3COOH, but this time there was no changes even
and placed on an agar plate containing bacteria or fungi
cell. Propylene glycol as a control showed no inhibition
zone. The diameter of the growth inhibition zone around
1
in their H NMR spectra.
The in vitro antibacterial and antifungal activities of
the synthesized compounds 3–14 against S. aureus
(ATCC 25923), E. coli (ATCC 25922), B. subtilis
(ATCC 6633), and C. albicans (ATCC 10231) were
evaluated with the disc diffusion techniques [9]. All
compounds (except 11) were solved in 1,2-propylene
glycol (1.5 mg/mL), 0.02 mL (one drop) of these solu-
tion was dropped on to a paper disk (6-mm diameter)
Figure 2. (A) 13C NMR spectra of 9 in low concentration. (B) 13C
NMR spectra of 9 in high concentration. (C) 13C NMR spectra of 9 þ
NaH þ D2O.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Ozden, F. Usta, N. Altanlar, and H. Goker
¨
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Table 1
NMR data (1H, 13C, HSQC, and HMBC) of compound 9.
Compd 9 (Low conc. in DMSO-d6)
Compd 9 þ NaHa þ D2Ob (in DMSO-d6)
No
C¼O
13C
1H
13C
1H
HMBC
158.2
152.8
148.5
142.6
133.5
141.3
123.6
121.5
127.4
125.8
119.1
122.2
114.3
112.6
56.0
166.1
158.7
152.7
145.8
C-2
C-20
C-5 and C-6
H-30,40,50,60
H-4,7
C-10
C-50
C-40
C3a and C7a
141.5
123.7
121.6
120.7
H-30,50,60
H-30,40,60
H-30,50,60
H-4,7
6.86–6.97 (m)
6.86–6.97 (m)
6.9–7.05 (m)
6.9–7.05 (m)
C-30
C-4 and C-7
6.86–6.97 (m)
8.07 (s,1H)
7.73 (s,1H)
6.86–6.97 (m)
3.78 (s, 3H)
3.04 (br.t, 4H)
119.1
118.4
6.9–7.05 (m)
7.65 (s,2H)
H-40,50,60
C-60
112.5
56.0
51.5
50.9
47.4
42.5
6.9–7.05 (m)
3.8 (s, 3H)
2.95 (br.t, 2H)
3.03 (br.t, 2H)
3.89 (br.t, 2H)
3.81 (br.t, 2H)
H-30,40,50
OCH3
CH2(b)
CH2(b0)
CH2(a)
CH2(a0)
NH
51.3
50.9
47.1
43.4
4.49 (t, 2H)
3.84 (t, 2H)
13.45 (br.s)
a Tip of thin spatula.
b Two drops.
Table 2
In vitro antimicrobial activities and formulas of 3–14.
Growth inhibition zone (as mm)
Staphylococcus aureus Escherichia coli
16 14
Comp.
X
R1
R2
Bacillus subtilis
Candida albicans
3
4
5
6
7
8
9
10
11
12
CH2
N
N
H
CH3
CH2CH2OH
COH
–
–
–
–
–
–
–
–
–
–
15
12
14
16
–
14
–
10
–
12
15
15
8
N
8
10
–
–
N
N
COOEt
-Ph
11
13
–
13
10
13
NT
9
15
14
14
NT
13
N
N
2-(MeO)-Ph
4-(F)-Ph
4-(NO2)-Ph
H
11
12
–
–
N
N
NT*
11
NT
11
13
–
–
12
12
16
–
14
Ampicillin
Fluconazole
–
–
12
22
13
23
15
26
–
24
NT: Not tested.
Compound 11 is insoluble in propylene glycol.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Synthesis of Some New 1H-Benzimidazole-2-carboxamido Derivatives and
Their Antimicrobial Activitiy
1321
C14H16Cl2N4O2 0.5 H2O: C, 47.74; H, 4.86; N, 15.91. Found
C, 47.55; H, 4.57; N, 15.97.
4-[(5,6-Dichloro-1H-benzimidazol-2-yl)carbonyl]piperazine-
1-carbaldehyde (6). Purification, crys. dimethylformamide-
the paper disc was measured after incubation period
(Table 1). In general, it was observed that the synthe-
sized compounds were more active against the bacteria
than fungi. Among the synthesized derivatives, com-
pound 3 exhibited best inhibitory activity against S. aur-
eus with 16-mm zone diameter, however the activity
was less than the reference compound Ampicillin. As
the compounds have no comparable results with the
references by the disc diffusion techniques, further test
tube dilution method was not carried out.
EtOH, yield 29%, mp 272–274ꢀC; 1H NMR (DMSO-d6
þ
D2O) d ppm: 3.54 (s,4H, pipe), 3.73 ve 4.35 (d, 4H, pipe),
7.94 (br. s, 2H), 8.1 (s, 1H, CHO); MS: m/z 327(100),
329(70), 331(13). Anal. Calcd for C13H12Cl2N4O2 0.25 H2O:
C, 47.07; H, 3.80; N, 16.9. Found C, 47.06; H, 3.81; N, 16.83.
Ethyl
4-[(5,6-dichloro-1H-benzimidazol-2-yl)carbonyl]pi-
perazine-1-carboxylate (7). Purification, crys. EtOH, yield
35%, mp 239–241ꢀC; 1H NMR (DMSO-d6) d ppm : 1.17
(t,3H), 3.48 (br. s., 4H, pipe), 3.68 (t,2H, pipe), 4.04 (q,2H),
4.36 (t,2H, pipe), 7.7 (s,1H), 8.05(s,1H), 13.5 (s,1H,imidazole
NH); MS: m/z 371(100), 373(63), 375(13). Anal. Calcd for
C15H16Cl2N4O3 .0.5 H2O: C, 47.38; H, 4.51; N, 14.74. Found
C, 47.23; H, 4.37; N, 14.65.
EXPERIMENTAL
Uncorrected melting points were measured on a Bu¨chi B-
1
540 capillary melting point apparatus. H (400 MHz) and 13C
5,6-Dichloro-2-[(4-phenylpiperazin-1-yl)carbonyl]-1H-benz-
imidazole (8). Purification, cc, dichloromethane:isopropano-
l:ammonium hydroxide (10:5:0.1), yield 28%, mp 264–269ꢀC;
1H NMR (DMSO-d6) d ppm: 3.27 (t, 4H, pipe), 3.86 (t, 2H,
pipe), 4.55 (t, 2H, pipe), 6.82 (t, J ¼ 8 Hz, 1H), 7.01 (d, J ¼
8 Hz, 2H), 7.24 (t, J ¼ 8 Hz, 2H), 7.75 (s,1H), 8.11 (s,1H),
13.4 (s,1H,imidazole NH); MS: m/z 375(100), 377(59),
379(13). Anal. Calcd for C18H16Cl2N4O: C, 57.61; H, 4.30; N,
14.93. Found C, 57.44; H, 4.41; N, 15.18.
5,6-Dichloro-2-{[4-(2-methoxyphenyl)piperazin-1-yl]carbonyl}-
1H-benzimidazole (9). Purification, cc, ethyl acetate:n-hexane
(1:1), yield 29%, mp 246–248ꢀC; 1H NMR (DMSO-d6) d
ppm: See Table 1. MS: m/z 405(100), 407(67), 409(15). Anal.
Calcd for C19H18Cl2N4O2 .0.25 H2O: C, 55.69; H, 4.55; N,
13.67. Found C, 55.69; H, 4.54; N, 13.7.
5,6-Dichloro-2-{[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}-
1H-benzimidazole (10). Purification, cc, dichloromethane:iso-
propanol:ammonium hydroxide (10:5:0.1), yield 22%, mp
265–270ꢀC; 1H NMR (DMSO-d6) d ppm: 3.18 (t,4H, pipe),
3.83 (t, 2H, pipe), 4.52 (t,2H, pipe), 6.97–7.08 (m,4H),
7.73(s,1H), 8.08(s,1H), 13.47 (s, 1H, imidazole NH); MS:
m/z 393(100), 395(61), 397(11). Anal. Calcd for
C18H15Cl2FN4O: C, 54.98; H, 3.84; N, 14.25. Found C, 54.54;
H, 3.96; N: 14.1.
5,6-Dichloro-2-{[4-(4-nitrophenyl)piperazin-1-yl]carbonyl}-
1H-benzimidazole (11). Purification, crys. EtOH, yield 31%,
mp 254–258ꢀC; 1H NMR (DMSO-d6) d ppm: 3.66(t, 4H,
pipe), 3.87 (2H, pipe), 4.60 (t, 2H, pipe), 7.04 (d, J ¼ 8 Hz,
2H), 7.75 (s,1H), 8.09 (m,3H), 13.47 (s,1H,imidazole NH). 13C
NMR (DMSO-d6) d ppm: 158.3, 155, 148.3, 142.6, 137.7,
133.5, 127.5, 126.4, 125.9, 122.2, 114.3, 113.3, 47.2, 46.3,
45.9, 42.8; MS: m/z 420(100), 422(62), 424(10). Anal. Calcd
for C18H15Cl2N5O3: C, 51.44; H, 3.60; N, 16.66. Found C,
50.95; H, 3.58; N, 16.47.
(100 MHz) NMR spectra were recorded using a Varian Mer-
cury 400-MHz FT spectrometer, and chemical shifts (d) are in
ppm relative to TMS. J values are given in Hertz. Mass spec-
tra were taken on a Waters Micromass ZQ connected with
Waters Alliance HPLC, using ESI(þ) method, with C-18 col-
umn. Elemental analyses were performed by Leco CHNS-932.
Analyzer and the results were found to be in good agreement
with the calculated values. Compounds 1 [10] and 2 [11] were
prepared by the literature methods. 4,5-Dichloro-o-phenylene-
diamine and glycolic acid were procured from Aldrich.
General synthesis of 3–11, 13–14.. To a solution of 5,6-
dichlorobenzimidazole-2-carboxylic acid (0.231g, 1 mmol) in
dimethylformamide (1.5 mL) was added corresponding amines
(1.1 mmol) and O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethy-
luronium HBTU (0.417g, 1.1 mmol), followed by triethyl-
amine (1.1 mmol). The mixture was stirred at room tempera-
ture for 24 h. The reaction mixture was cooled and poured
into water. Residue was purified by crystallization or column
chromatography (cc).
5,6-Dichloro-2-(piperidin-1-ylcarbonyl)-1H-benzimidazole
(3). Purification, crys. EtOH, yield 44%, mp 208–212ꢀC; 1H
NMR (DMSO-d6 þ D2O þ NaH) d ppm: 1.39 (2H, pipe),
1.51 (4H, pipe), 3.45 and 3.52 (4H, pipe), 7.6 (s,2H); MS: m/z
298(100), 300(60), 302(13). Anal. Calcd for C13H13Cl2N3O: C,
52.37; H, 4.39; N, 14.09. Found C, 52.0; H, 4.56; N, 14.09.
5,6-Dichloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-benz-
imidazole (4). Purification, cc, dichloromethane:isopropano-
l:ammonium hydroxide (10:5:0.1), yield 76%, mp 267–269ꢀC;
1H NMR (CD3OD þ D2O þ NaH) d ppm: 2.32 (s,3H,CH3),
2.46 and 2.56 (s,s, 4H, pipe), 3.68 and 3.82 (s,s, 4H, pipe),
7.63(s, 2H); 13C NMR (CD3OD þ D2O þ NaH) d ppm:
167.1, 156.6, 144.4, 122.6, 117.5, 54.9, 54.2, 46.7, 44.8, 41.5;
MS : m/z 313 (100), 315(66), 317(11). Anal. Calcd for
C13H14Cl2N4O. 0.25 H2O: C, 49.15; H, 4.60; N, 17.64. Found
C, 49.07; H, 4.60; N, 17.48.
2-{4-[(5,6-Dichloro-1H-benzimidazol-2-yl)carbonyl]pipera-
zin-1-yl}ethanol (5). Purification, cc, dichloromethane:isopro-
panol:ammonium hydroxide (10:5:0.2), yield 23%, mp 232–
235ꢀC; 1H NMR (CD3OD þ D2O þ NaH) d ppm: 2.54 (b.t,
2H, pipe), 2.58 (t,2H, NACH2), 2.65 (b.t, 2H, pipe), 3.65
(b.t,2H, pipe), 3.7 (t,2H,OACH2), 3.81 (b.t, 2H, pipe), 7.62
(s,2H); 13C NMR (CD3OD þ D2O þ NaH) d ppm : 167.1,
156.7, 144.4, 122.6, 117.5, 59.7, 58.5, 53.5, 52.8, 46.8, 41.7;
MS: m/z 343(100), 345(65), 347(12). Anal. Calcd for
5,6-Dichloro-2-(piperazin-1-ylcarbonyl)-1H-benzimidazole
(12). Compound 6 (0.135 g, 0.4 mmol) was stirred in metha-
nolic HCl (5 mL) at room temperature for 24 h. The reaction
mixture was basified with dilute K2CO3 solution and the pre-
cipitate was crystallized from EtOH, yield 46%, mp, 303–
1
305ꢀC; H NMR (DMSO-d6 þ D2O) d ppm: 3.25 and 3.29 (t,
4H, pipe), 3.92 (t, 2H, pipe), 4.66 (t, 2H, pipe), 7.97 (s, 2H);
MS: m/z 299 (100), 300(66), 302(14). Anal. Calcd for
C12H12Cl2N4O: C, 48.18; H, 4.04; N, 18.73. Found C, 48.08;
H, 3.96; N,18.67.
Journal of Heterocyclic Chemistry
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S. Ozden, F. Usta, N. Altanlar, and H. Goker
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Vol 48
REFERENCES AND NOTES
[1] Boiani, M.; Gonalez, M. Mini Rev Med Chem 2005, 5,
Ethyl 4-{[(5,6-dichloro-1H-benzimidazol-2-yl)carbonyl]ami-
no}piperidin-1-carboxylate (13). Purification, crys. ethyl ace-
tate, yield 47%, mp 273–275ꢀC; 1H NMR (DMSO-d6 þ D2O
þ NaH) d ppm: 1.19 (t,3H), 1.48 and 1.81 (m,4H, pipe), 3.77
(s, 1H), 3.95 (m,4H, pipe.), 4.09 (q,2H), 7.64 (s,2H). 13C
NMR (DMSO-d6 þ D2O þ NaH) d ppm: 163.9, 158.9, 155.5,
146.4, 121.1, 118.7, 61.5, 46.9, 43.1, 32.1, 15.2; MS: m/z
385(100), 387(59), 389(13). Anal. Calcd for C16H18Cl2N4O3
.0.25 H2O: C, 49.31; H, 4.78; N, 14.38. Found C, 49.22; H,
4.50; N, 14.41.
5,6-Dichloro-N-morpholin-4-yl-1H-benzimidazole-2-carbox-
amide (14). Purification, crys. (ethyl acetate), yield 32%, mp
254–257ꢀC; 1H NMR (DMSO-d6) d ppm: 2.86 (4H, morp),
3.63 (4H, morp), 7.83 (br. s, 2H), 10.19 (s, 1H, NH), 13.59
(br.s, 1H, imidazole NH). 13C NMR (DMSO-d6 þ D2O þ
NaH) d ppm: 166.1, 164.5, 146.7, 119.2, 117.3, 66.5, 55.8;
MS: m/z 315(100), 317(59), 319(10). Anal. Calcd for
C12H12Cl2N4O2: C, 45.73; H, 3.84; N, 17.78. Found C, 45.53;
H, 3.86; N, 17.67.
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Acknowledgment. Central Laboratory of Pharmacy, Faculty of
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Journal of Heterocyclic Chemistry
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