Facile synthesis and antimicrobial properties of 2-(substituted- benzylsulfanyl)-1H-benzimidazoles

Article abstract of DOI:10.1002/jhet.5570420722

A simple and convenient procedure for the preparation of 2-benzylthiobenzimidazoles by the reaction of 2-mercaptobenzimidazole and benzyl bromides in acetone/potassium carbonate condition has been reported and the compounds were screened for their potenti

Full text of DOI:10.1002/jhet.5570420722

Nov-Dec 2005
Facile Synthesis and Antimicrobial Properties of 2-(Substituted-
1405
benzylsulfanyl)-1H-benzimidazoles
Ramanatham Vinod Kumar*, Kotarkonda Raja Gopal and
Kotha V. S. R. Seshu Kumar
Janus Research Laboratories P. Ltd., Plot No: 5-9-285/1,1st floor, Rajiv Gandhi Nagar,
Prasanthi Nagar Extn., Kukatpally, Hyderabad (A.P.)-500 072, India
Received December 7, 2004
A simple and convenient procedure for the preparation of 2-benzylthiobenzimidazoles by the reaction of
2-mercaptobenzimidazole and benzyl bromides in acetone/potassium carbonate condition has been reported
and the compounds were screened for their potential antimicrobial activities.
J. Heterocyclic Chem., 42, 1405 (2005).
Benzimidazoles have been shown to exhibit a large
In a typical procedure equimolar amounts of 2-mercap-
tobenzimidazole and benzyl bromide (2a, Ar=Ph) are
refluxed in acetone in the presence of anhydrous potas-
sium carbonate as base for 2 hr, giving the corresponding
2-benzylthiobenzimidazole (3a, Ar-=Ph) in 98 % yield.
The product was identified with spectral data and by com-
parision with the authentic sample [7]. Similary, 2-mercap-
tobenzimidazole was reacted with other substituted benzyl
bromides (2b-2i) under similar conditions to give the cor-
responding 2-benzylthiobenzimidazoles (3b-3i) in excel-
number of biological activities. The biological activities of
the compounds containing this basic moiety have been
well documented [1]. Some of them like thiabendazole,
mebendazole and albendazole are widely used as anti-
helmintic drugs [2]. Similarly, benzimidazole-2-thiol and
its derivatives have also been reported to have potent bio-
logical activities, such as proton pump inhibitors [3]
+
+
antiulcer activity [4], inhibitors of H /K ATP ase [5].
We were interested in the synthesis of 2-benzylthiobenz-
imidazoles in connection with our work on drug intermedi-
ates containing benzimidazole moiety. In this regard, litera-
ture survey revealed that these compounds can be prepared
by the reaction of 2-mercaptobenzimidazole with alkyl or
aryl halides in the presence of bases such as NaH/DMF
lent yields (Table 1). All the products were characterized
by IR, 1H, and 13C- NMR spectral and analytical data.
Since, 2-benzylthiobenzimidazoles constitute an important
class of heterocyclics found in bioactive compounds, the
methodology described here may find useful applications
in the synthesis of drug intermediates and other bioactive
compounds.
(
%
8%) [6], K CO /EtOH (20%) [5], DMF/K CO [3b] (35
2 3 2 3
), in low yields. In some instances, the formation of both
the S and N benzyl derivatives have been reported even by
the use of aq. Na CO in isopropyl alcohol [7]. Using
strong bases such as NaOH/EtOH [8] gave good yield of
the S-arylated products, however the disadvantage lies with
the formation of competing side products such as benzyl
ethers and N-alkylated products.
To overcome this problem recently the use of a phase-
transfer catalysis (PTC) has also been reported in the pres-
ence of strong bases like NaOH [9] and KOH [10]. This
indicates that though there are several methods available in
the literature for the synthesis of these title compounds,
there is no simple and convenient method available for the
synthesis of these important heterocyclics without the use
of either strongly basic conditions or PTC.
Conclusion.
2
3
In conclusion, we have reported for the first time a con-
venient and useful method for the synthesis of 2-benzylth-
iobenzimidazoles in excellent yields. The advantage of this
methodology is the use of very mild reaction conditions,
which can tolerate various functional groups that can be
used for further synthetic manipulations. Further, commer-
cial availability of large number of benzyl bromides or
easy methods of their preparation makes this reaction a
more attractive choice. All the compounds were tested for
antimicrobial activity. Only a few compounds exhibited
moderate activity against B. subtilis, E. coli, P. aeruginosa,
C. albicans and A. niger in a preliminary screening.
In this communication, we wish to report a simple but
efficient method for the synthesis of 2-benzylthiobenzimi-
dazoles in excellent yields (Figure 1).
EXPERIMENTAL
Melting points are uncorrected and were recorded on a MRVIS
Series, Lab India Instrument. TLC analysis was done using pre-
coated silica gel plates and visualization was done using
Iodine/UV lamp. IR spectra were recorded on a Perkin-Elmer
1
13
Spectrum One FT-IR spectrometer. H and C-NMR spectra
were recorded in CDCl on a Bruker 400 MHz spectrometer
3
using TMS as internal standard. Mass spectra were recorded on a
Hewlett Packard Model No- 5989A mass spectrometer operating
at 70 eV. Elemental analysis was carried out on a Perkin–Elmer

1
406
R. V. Kumar, K. R. Gopal and K. V. S. R. Seshu Kumar
Vol. 42
Table 1
List of Various 2-Benzylthiobenzimidazoles Prepared
Sr.
No.
Benzyl
Bromide
Product
Yield (%)
M.P. (°C)
189-190
1
2
3
4
98
(
Lit7.
84-85)
1
96
134 –135
Lit11
32-135)
(
.
1
9
9
9
7
7
8
195-198
153-155
160-161
5
6
7
8
9
9
9
6
6
129-130
204-205
9
9
8
7
175-176
206-207
(
Lit11
98-201)
.
1
Series –II CHN Analyzer 2400. The starting material, 2-mercap-
tobenzimidazole has been obtained from commercial suppliers.
(3a-3i). The crude products were purified by recrystallization
using a mixture of hexane-ethyl acetate.
General Procedure.
Spectral Properties of Compounds.
A mixture of 2-mercaptobenzimidazole 1 (2 mmole), respec-
tive benzyl bromide (2a-2i, 2 mmol), finely grounded anhydrous
2
-Benzylsulfanyl-1H-benzimidazole (3a).
K CO (4 mmol) in acetone was refluxed for 2 hr (TLC monitor-
IR (KBr): 3069, 2963, 2811, 1619, 1513, 1496, 1402, 1351,
2
3
-
1 1
ing). The reaction mixture was then cooled to room temperature
and filtered. Evaporation of the filtrate yielded the crude products
1268, 1152, 1071, 1011, 980 cm . H-NMR (CDCl + DMSO-
d6/TMS): δ 4.50 (s, 2H), 7.18-7.48 (m, 9H). C NMR (100
3
1
3

Nov-Dec 2005
Facile Synthesis and Antimicrobial Properties
1407
Table 2
Growth inhibition activity [a] of 2-substituted-benzylsulfanylbenzimidazoles 3a-3i against B. subtilis, E. coli, M. luteus, P. aerugi-
nosa,C. albicans and A. niger in vitro.
Compd. B. subtilis
E. coli
M. Luteus
P. aeruginosa
C. albicans
A. niger
AM1 AM11
AM1
AM11
AM1 AM11
AM1 AM11
AM1
AM11
AM1
AM11
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
—
—
—
6.3
—
—
—
7.0
—
—
—
—
6.8
—
6.5
—
6.1
—
7.0
—
—
6.0
—
6.3
—
6.1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6.4
—
—
7.0
—
6.9
—
—
—
—
—
—
6.2-
—
—
—
—
—
6.2
—
—
7.0
6.1
6.9
—
6.0
6.1
6.6
—
—
—
—
6.0
—
—
6.4
6.0
6.3
6.7
—
—
7.1
—
6.3
—
—
6.4
6.0
—
6.0
—
—
7.0
6.6
—
6.6
—
6.0
6.0
o
[
a] Diameter (in mm) of inhibition zones; AM1: Antibiotic medium N 1 (pH=6.5); AM11: Antibiotic medium N°11 (pH=7.9).
MHz): 37.17, 122.35, 127.73, 128.76, 129.04, 129.30, 129.53,
Anal. Calcd. for C H BrIN S: C, 37.78; H, 2.26; N, 6.29.
14 10 2
Found: C, 37.70; H, 2.19; N, 6.20.
+
1
30.50, 136.81, 150.12. EI-MS (m/z, %I): 242 (M +2, 6.4), 241
+
+
(
(
(
M +1, 18), 240 (M , 100), 239 (7.8), 225 (4), 208 (9.8), 207
58), 206 (8), 163 (5.5), 149 (14), 122 (15), 92 (6.3), 91 (69), 90
4.3), 65 (12.7), 63 (5).
2
-(2,5-Dibromobenzylsulfanyl)-1H-benzimidazole (3e).
IR (KBr): 3065, 2960, 2804, 1577, 1457, 1403, 1352, 1274,
-1 1
1
228, 1198, 1082, 1023, 978 cm . H-NMR (CDCl + DMSO-
3
2
-(2-Nitrobenzylsulfanyl)-1H-benzimidazole(3b).
d /TMS): δ 4.46 (s, 2H), 6.98 (s, 2H), 7.04 (d, J= 8.8Hz, 1H),
6
1
3
IR (KBr): 2790, 1607, 1573, 1534, 1399, 1350, 1271, 1151,
7.23 (d, J= 8.4Hz, 2H), 7.56 (s, 2H). C-NMR (100 MHz):
-
1 1
1
2
3
014, 987 cm . H-NMR (CDCl + DMSO-d /TMS): δ 4.77 (s,
35.98, 110.05, 117.43, 120.78, 122.79, 131.65, 133.62, 133.72,
3
6
+
H), 6.98-7.01 (m, 2H), 7.23 (t, J = 7.6Hz, 1H), 7.31-7.35 (m,
H), 7.62 (d, J= 7.6 Hz, 1H), 7.85 (d, J= 8.4Hz, 1H). C-NMR
138.75, 141.26, 148.79. EI-MS (m/z, %I): 400 (M +4, 9), 398
1
3
+
+
(M +2, 15.6), 396 (M , 7.8), 333 (5), 321 (6.5), 320 (17.4), 319
(100), 318 (22), 317 (96), 316 (4), 286 (16.5), 284 (17.8), 251
(11.2), 249 (22), 247 (11), 238 (8), 237 (7), 205 (5), 170 (7), 168
(7.5), 163(6), 150 (9.3), 149 (17.6), 122 (23), 90 (5.6), 89 (12.6),
63 (5.5).
(
1
(
(
(
100 MHz): 33.68, 114.09, 122.01, 125.12, 128.68, 132.70,
33.69, 133.78, 141.63, 147.97, 149.32. EI-MS (m/z, %I): 286
M +1, 7.55), 285 (M , 41.7), 240 (6), 239 (31), 237 (8), 225
4.8), 220 (7.7), 207 (6), 206 (9), 180 (4), 151(13), 150 (100), 149
20), 136 (21), 122 (23), 105 (4.8), 91 (6), 90 (6), 78 (20), 63 (4),
+
+
Anal. Calcd. for C H Br N S: C, 42.24; H, 2.53; N, 7.04.
1
4
10
2 2
5
1 (4).
Anal. Calcd. for C H N O S: C, 58.93; H, 3.89; N, 14.73.
Found: C, 41.98; H, 2.58; N, 7.22.
1
4 11 3 2
2
-(2-Bromo-5-fluorobenzylsulfanyl)-1H-benzimidazole(3f).
Found: C, 59.01; H, 3.79; N, 14.81.
IR (KBr): 3046, 2957, 2790, 1604, 1581, 1562, 1469, 1400,
2
-(2-Bromobenzylsulfanyl)-1H-benzimidazole (3c).
-
1 1
1
349, 1271, 1234, 1157, 1031, 1012, 984 cm . H-NMR (CDCl
3
IR (KBr): 2736, 1632, 1509, 1402, 1268, 1228, 1044, 1027,
+ DMSO-d /TMS): δ 4.48 (s, 2H), 6.62-6.67 (m, 1H), 6.97 (dd,
6
-1 1
9
7
87 cm . H-NMR (CDCl + DMSO-d /TMS): δ 4.69 (s, 2H),
J= 6.0 & 3.2Hz, 2H), 7.17 (dd, J= 9.2 & 3.2Hz, 1H), 7.28-7.32
3
6
1
3
13
.08-7.20 (m, 4H), 7.43 (s, 3H), 7.49-7.55 (m, 1H). C-NMR
(m, 3H). C-NMR (100 MHz): 36.57, 36.59, 116.21, 116.43,
(
1
2
100 MHz): 36.99, 114.28, 121.66, 124.48, 127.65, 129.16,
31.21, 132.79, 136.79, 149.49. EI-MS (m/z, %I): 318 (M , 4.5),
40 (16), 239 (100), 219 (3), 207 (9.6), 206 (55), 181(6.6), 180
118.17, 118.35, 118.59, 118.62, 122.02, 133.88, 133.96, 139.01,
+
+
139.09, 149.13, 160.37, 162.84. EI-MS (m/z, %I): 338 (M +2,
+
11), 336 (M , 10.8), 259 (6.6), 258 (17.5), 257 (100), 256 (6.6),
(
9
7), 171 (35), 169 (49), 149 (15), 131 (11), 122 (22), 119 (7.4),
0 (32), 89(17), 69 (9.6).
Anal. Calcd. for C H BrN S: C, 52.68; H, 3.47; N, 8.78.
225 (6.9), 224 (26), 198 (5.6), 189 (13), 187 (12.6), 163 (4), 149
(13), 122 (17.5), 108 (13.5), 107 (11.5), 90 (4), 60 (3.5).
Anal. Calcd. for C H BrFN S: C, 49.86; H, 2.99; N, 8.31.
1
4
11
2
14 10
2
Found: C, 52.36; H, 3.49; N, 8.80.
Found: C, 50.02; H, 3.23; N, 8.02.
2
-(2-Bromo-5-iodobenzylsulfanyl)-1H-benzimidazole(3d).
2-(4-Iodobenzylsulfanyl)-1H-benzimidazole (3g).
IR (KBr): 2957, 2790, 1604, 1482, 1402, 1351, 1272, 1058,
IR (KBr): 3070, 1620, 1513, 1457, 1400, 1348, 1274, 1195,
-
1
1
-1 1
1
154, 1076, 1022, 978 cm . H-NMR (CDCl3 + DMSO-
1000, 980 cm . H-NMR (CDCl + DMSO-d /TMS): δ 4.55 (s,
3
6
d /TMS): δ 4.38 (s, 2H), 6.92 (dd, J= 6.0 & 3.2 Hz, 2H), 7.03 (d,
2H), 7.16-7.20 (m, 3H), 7.38 (s, 1H), 7.51 (dd, J= 6.0 & 3.2Hz,
6
1
3
J= 8.4Hz, 1H), 7.18 (dd, J= 8.4 & 2.4Hz, 1H), 7.24 (d, J= 5.6Hz,
2H), 7.60 (d, J= 8.4Hz, 2H). C-NMR (100 MHz): 36.20, 93.08,
1
3
2
1
H), 7.68 (d, J= 2.4Hz, 1H). C-NMR (100 MHz): 36.24, 92.40,
21.85, 124.36, 134.36, 138.00, 139.14, 139.92, 141.64, 149.12.
114.05, 122.18, 125.86, 130.76, 131.00, 136.93, 137.65, 141.60,
+
+
149.41. EI-MS (m/z, %I): 368 (M +2, 6.6), 367 (M +1, 16.55),
366 (100), 333 (11.5), 217 (45), 206 (13.5), 149 (6.3), 122 (7.8),
90 (13.7), 89 (8.3), 63 (3.9).
+
+
EI-MS (m/z, %I): 446 (M +2, 33), 444 (M , 43.8), 366 (19), 365
100), 332 (13.8), 317 (3), 297 (12), 295 (12), 239 (11), 238 (41),
(
2
1
37 (15), 205 (7), 170 (11), 168 (12.8), 150 (6.1), 149 (9),
22(15), 90 (5), 89 (17), 63 (6).
Anal. Calcd. for C14H IN S: C, 45.91; H, 3.03; N, 7.65.
Found: C, 45.96; H, 3.21; N, 7.62.
11 2

1408
R. V. Kumar, K. R. Gopal and K. V. S. R. Seshu Kumar
Vol. 42
2
-(2-Bromo-3-methylbenzylsulfanyl)-1H-benzimidazole (3h).
Growth inhibition was tested after a 24 hour incubation at 37
°
C. All the results are expressed as the diameter (in mm) of
IR (KBr): 2804, 1588, 1506, 1437, 1395, 1361, 1271, 1226,
inhibition zones, and are shown in Table 2. From the activity
studies it can be inferred that compounds containing the halo-
gens on the phenyl ring at 2-position showed good to moderate
activity against both the bacteria and fungal stains tested. For
example compound 3d having both chloro and iodo substituents
showed promising activity both against bacteria and fungus.
Further presence of methyl group along with bromo as in 3h
also showed good activity. However compound with a nitro
substituent as in 3b did not show much activity except against
the fungal stain P. aeruginosa.
-1 1
1
3
7
025, 984 cm . H-NMR (CDCl + DMSO-d /TMS): δ 2.42 (s,
3 6
H), 4.80 (s, 2H), 7.10 (m, 2H), 7.19 (dd, J= 6.0 & 3.2Hz, 2H),
1
3
.39 (d, J= 5.6Hz, 1H), 7.54 (s, 2H). C-NMR (100
MHz):23.82, 38.32, 122.32, 125.35, 127.14, 128.76, 130.20,
31.76, 136.64, 136.98, 138.87, 149.73. EI-MS (m/z, %I): 334
1
(
2
1
+
+
M +2, 22.5), 332 (M , 20.8), 255 (5.6), 254 (18.3), 253 (100),
21 (5.6), 220 (24.8), 185 (17.33), 183 (17), 149 (5.4), 122 (6.5),
04 (9.7), 103 (7.5), 78 (5.7), 77 (5.7).
Anal. Calcd. For C H BrN S: C, 54.06; H, 3.93; N, 8.41.
1
5
13
2
Found: C, 53.91; H, 3.98; N, 8.18.
2
-(4-Bromobenzylsulfanyl)-1H-benzimidazole (3i).
IR (KBr):2952, 1620, 1513, 1487, 1270, 1229, 1069, 983 cm-
REFERENCES AND NOTES
1. 1
1
H-NMR (CDCl + DMSO-d /TMS): δ 4.52 (s, 2H), 7.16 (m,
3 6
[
*] Author to whom all correspondence should be addressed.
E-mail: rvinodk@yahoo.com
1a] J. B. Wright. Chem. Rev., 48, 397 (1951); [b] C. C. Leznoff, B.
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H), 7.29 (d, J= 8.8Hz, 2H), 7.35 (s, 2H), 7.40 (d, J= 8.4Hz, 2H),
1
3
7
.65 (d, J= 8.0Hz, 1H). C-NMR (100 MHz):35.99, 110.38,
17.93, 121.34, 121.53, 122.07, 130.73, 131.64, 136.52, 144.00,
[
1
1
3
+
+
49.54. EI-MS (m/z, %I): 321 (M +3, 14), 320 (M +2, 92.6),
+
+
19 (M +1, 14.6), 318 (M , 86), 287 (14), 285 (16), 239 (3), 206
[2] Kohler, P. Int. J. Parasitol., 31, 336 (2001).
(
9
31), 171 (100), 169 (98), 149 (64.4), 122 (65), 105 (3), 91 (14.8),
0 (73), 89 (46), 78 (7), 63 (33), 51 (7).
Anal. Calcd. For C H BrN S: C, 52.68; H, 3.47; N, 8.78.
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1
4
11
2
Found: C, 52.96; H, 3.62; N, 8.62.
[
4] M. Uchida, M. Chihiro, S. Morita, H. Yamashita, K.
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Antimicrobial Activity of Compounds 3a-3i.
1
All the compounds synthesized herein were screened for
their potential antimicrobial activities using the disk diffusion
method. Test compounds were dissolved in N,N-dimethylfor-
mamide (DMF) (Control). Test discs (6 mm in diameter)
impregnated with 100 µg of the appropriate sample were used
to test both antibacterial and antifungal activities at pH 6.5 and
[
3
Yamasaki, T. Kanbe, Y. Yobuuchi, K. Nakagawa, Chem. Pharm. Bull.,
38, 534 (1990).
[
7] O. P. Suri, R. K. Khajuria, D. B. Saxena, N. S. Rawat, C. K.
7
.9 respectively. Disks were applied on the surface of plates
Atal, J. Heterocyclic Chem., 20, 813 (1983).
containing each 25 ml of Antibiotic medium N°1 (pH=6.5) or
N°11 (pH=7.9), inoculated with 10 CFU/ml of the microorgan-
6
[8] D. Harrison, R. T. Ralph, J. Chem. Soc., 3132 (1965); Xuzhou
Shifan Daxue
9] R. Paramashivappa, P. P. Kumar, P. V. S. Rao, A. S. Rao,
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Xuebao, Ziran Kexueban. 20, 57 (2002).
isms. All the experiments were carried out in duplicates. The
following strains were used to test the activities: Bacillus sub-
tilis ATCC 6633 CCM-A-10, Escherichia coli ATCC 11105
CCM-A-424, Micrococcus luteus ATCC 9341 CCM-A-45,
Pseudomonas aeruginosa ATCC 9027 CCM-A-39, Candida
albicans ATCC 10231 and Aspergillus niger ATCC 16404.
[
[
(