Facile synthesis of 2-(substitutedbenzylsulfanyl)-benzothiazoles and their antimicrobial activity screening

Article abstract of DOI:10.1002/jhet.5570420124

A simple and convenient procedure for the preparation of 2-(substitutedbenzylsulfanyl)benzothiazoles by the reaction of 2-mercaptobenzothiazole and benzyl bromides in acetone/K₂CO ₃ has been reported and the compounds have been scree

Full text of DOI:10.1002/jhet.5570420124

Jan-Feb 2005
Facile Synthesis of 2-(Substitutedbenzylsulfanyl)-
153
benzothiazoles and their Antimicrobial Activity Screening
Ramanatham Vinod Kumar*, Kotha V. S. R. Seshu Kumar
and Kotarkonda Raja Gopal
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 June 14, 2004
A simple and convenient procedure for the preparation of 2-(substitutedbenzylsulfanyl)benzothiazoles by the reaction
of 2-mercaptobenzothiazole and benzyl bromides in acetone/K CO has been reported and the compounds have been
2
3
screened for their potential antimicrobial activities.
J. Heterocyclic Chem., 42, 153 (2005).
Introduction.
ditions. In this paper, we wish to report a simple but effi-
cient methodology for the synthesis of 2-(substitutedben-
zylsulfanyl)benzothiazoles in excellent yields (Figure 1).
Reaction of 2-mercaptobenzothiazole, 1 with benzyl bro-
mide (2a, Ar=Ph) in refluxing acetone in the presence of
anhydrous potassium carbonate as base for 2 hr, gave the
corresponding 2-benzylsulfanylbenzothiazole (3a, Ar-=Ph)
in 98 % yield. The product was identified with the spectral
Benzothiazoles have been shown to exhibit a wide vari-
ety of biological activities. Many compounds containing
this heterocyclic nucleus are of either industrial [1] or bio-
logical [2] importance. Similarly, benzothiazole-2-thiol
and its derivatives have also been reported to have potent
biological activities, such as antimicobacterial activity [3],
cyclooxygenase inhibitors [4] etc. We were interested in
the synthesis of 2-(substituted-benzylsulfanyl)benzothia-
zoles in connection with our work on benzothiazole com-
pounds of probable biological importance.
Table 1
2-(Substitutedbenzylsulfanyl)benzothiazoles Prepared from
2
-Mercaptobenzothiazole
Results and Discussion.
Sr. No.
1
Benzyl
Bromide
Product
Yield (%)
[a]
A perusal of literature revealed that these compounds
can be prepared by the reaction of 2-mercaptobenzothia-
zole with benzyl halides in the presence of a strong base
like sodium in ethanol [5,3]. Although the use of strong
bases such as NaOH gives good yields of the S-benzylated
products, but the disadvantage lies with the formation of
competing side products such as benzyl ethers [6].
Recently an alternative approach has been reported for the
synthesis of title compounds under CsF-Celite [7] condi-
tions. Other approaches include the use of dibenzylcarbon-
ate [8] in the presence of catalytic amounts of DABCO or
DBU for the benzylation. However, the availability of sub-
stituted dibenzyl carbonates limits this method. Use of
Phase Transfer Catalysis (PTC) conditions in the presence
of strong base like NaOH [4,9] have also been employed to
synthesise the title compound although in less yields 32 %
9
9
9
9
9
9
8
6
5
7
4
5
2
3
4
5
6
&
15%, respectively.
It is evident from the literature that though there are
some methods available for the preparation of these title
compounds, yet there is no simple and efficient method for
the synthesis of these important heterocyclics without the
use of either expensive reagents, strong bases or PTC con-
7
8
9
9
8
6
[a] Yields refer to the Isolated yields.

1
54
R. V. Kumar, K. V. S. R. Seshu Kumar and K. R. Gopal
Vol. 42
Table 2
Growth Inhibition Activity [a] of 2-Substituted-benzylsulfanylbenzothiazoles 3a-3h Against B. subtilis, E. coli, M. luteus,
P. aeruginosa,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
a
b
c
d
e
f
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
6.8 6.6
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- - - -
- -
6.2
6.0
- -
6.9
- -
- -
- -
- -
6.0
- -
- -
8.2
- -
7.1
6.3
6.7
- - 6.1
- - 6.9
- -
6.9
- -
- -
7.0
- - 6.4
6.9 7.2
- - - -
7.6 6.2
g
h
7.0
8.0
6.3
6.7
- -
- -
- -
6.0
[a] Diameter (in mm) of inhibition zones; AM1: Antibiotic medium N°1 (pH=6.5); AM11: Antibiotic medium N°11 (pH=7.9).
data and by comparison with the authentic sample [5].
Similary, compound 1 was reacted with other substituted
benzyl bromides (2b-2h) under similar conditions to get the
corresponding 2-(substituted-benzylsulfanyl)-benzothia-
zoles (3b-3h) in almost quantitative yields (Table 1). All
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
Series –II CHN Analyzer 2400. The starting material, 2-mercap-
tobenzothiazole has been obtained from commercial suppliers.
1
13
the new products were characterized by H-, C-NMR,
mass spectra and elemental analysis data. All the com-
pounds synthesized herein were screened for their potential
antimicrobial activities using disk diffusion method. The
results are measured as the diameters of inhibition zones
for each micro-organism and the details are presented in
Table 2. Since, 2-(substituted-benzylsulfanyl)-benzothia-
zoles constitute an important class of heterocyclics found in
bioactive compounds, the methodology described here may
find useful applications in the synthesis of drug intermedi-
ates and other bioactive compounds containing this hetero-
cyclic moiety.
General Procedure.
A mixture of 2-mercaptobenzothiazole 1 (2 mmole), respec-
tive benzyl bromide (2a-2h, 2 mmol), finely grounded anhydrous
K CO (4 mmol) in acetone was refluxed for 2 hr (TLC monitor-
2
3
ing). The reaction mixture was then cooled to room temperature
and filtered. Evaporation of the filtrate yielded the crude products
(
3a-3h). The crude products were purified by recrystallisation
using a mixture of hexane-ethyl acetate.
Physical and Spectral Data of Compounds
2
-Benzylsulfanylbenzothiazole (3a).
This compound was obtained as white crystals (hexane-ethyl
Conclusion.
acetate), mp 38-40 °C (Lit [5] 39-40); ir (potassium bromide):
3
9
092, 3045, 2920, 1495, 1454, 1309, 1240, 1124, 1070, 1019,
98 cm ; H nmr (deuteriochloroform): δ 4.62 (s, 2H), 7.24-7.34
In conclusion, we have reported a convenient and useful
methodology for the synthesis of 2-(substituted-benzylsul-
fanyl)-benzothiazoles in excellent yields. The advantage
of this methodology is the use of very mild reaction condi-
tions, which can tolerate various functional groups that can
be used for further synthetic manipulations. Further, com-
mercial 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 screening. However, only few compounds
exhibited moderate activity against E. coli, C. albicans and
A. niger in a preliminary screening.
-1 1
(
m, 4H), 7.40-7.46 (m, 3H), 7.81(d, J= 8.0Hz, 1H), 7.90 (d, J=
.0Hz, 1H); C nmr (deuteriochloroform): δ 37.73, 121.00,
21.57, 124.29, 126.06, 127.76, 128.70, 129.13, 135.35, 136.19,
13
8
1
153.17, 166.40; ms: m/z(%I) 259 (M++2, 10.9), 258 (M++1,
+
16.6), 257 (M , 100), 225 (7.6), 224 (41.9), 166 (8.4), 122 (4),
108 (5.7), 92 (5.8), 91 (73.4), 69 (7.4), 65 (9.8).
Anal. Calcd. for C14H NS : C, 65.33; H, 4.31; N, 5.44.
11
2
Found: C, 65.26; H, 4.28; N, 5.31.
2
-(2-Bromo-benzylsulfanyl)-benzothiazole (3b).
This compound was obtained as pale yellow prisms (hexane-
ethyl acetate), mp 40-41 °C; ir (potassium bromide): 3060, 1558,
-
1 1
1
456, 1427, 1309, 1264, 1026, 994 cm ; H nmr (deuteriochlo-
roform): δ 4.73 (s, 2H), 7.12 (t, J= 7.6Hz, 1H), 7.21-7.30(m, 2H),
.42 (t, J= 7.6Hz, 1H), 7.58 (dd, J= 11.6 & 8.0Hz, 2H), 7.73(t, J=
EXPERIMENTAL
7
1
3
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
8.0Hz, 1H), 7.90(d, J= 8.0Hz, 1H); C nmr (deuteriochloro-
form): δ 37.89, 121.02, 121.56, 124.30, 124.81, 126.03, 127.63,
129.36, 131.33, 133.02, 135.48, 136.09, 153.09, 166.01; ms:
+
+
+
m/z(%I) 337 (M +2, 55.9), 336 (M +1, 9.5), 335 (M , 53), 258
(10.8), 257 (18.8), 256 (100), 249 (16), 223 (42.5), 181 (6.3), 171
1
13
Spectrum One FT-IR spectrometer. H and C-NMR spectra

Jan-Feb 2005
Facile Synthesis of 2-(Substitutedbenzylsulfanyl)benzothiazoles
155
+
+
+
(
(
71.3), 169 (79.3), 166 (16), 135 (8.6), 122 (8.5), 108 (13), 90
31.5), 89 (25), 69 (17), 63 (11), 59 (11), 43 (12.6).
m/z(%I) 463 (M +2, 12.5), 461 (M +1, 10), 384 (M , 10.7), 383
(16), 382 (100), 349 (16), 336 (4), 298 (18), 297 (15.7), 296
(19.8), 295 (13.9), 255 (10), 171 (4), 170 (6.7), 169 (9.4), 168 (7),
166 (5.7), 108 (4.4), 90 (4.2), 89 (8.7), 86 (8.9), 84 (12.9), 63
Anal. Calcd. for C H BrNS : C, 50.00; H, 3.00; N, 4.17.
1
4
10
2
Found: C, 50.23; H, 3.16; N, 4. 24.
(3.6).
2
-(2-Nitro-benzylsulfanyl)-benzothiazole (3c).
Anal. Calcd. for C H BrINS : C, 36.38; H, 1.96; N, 3.03.
1
4
9
2
This compound was obtained as off-white solid (hexane-ethyl
Found: C, 36.02; H, 1.98; N, 2.98.
acetate), mp 64-66 °C; ir (potassium bromide): 3059, 2875, 1522,
2
-(2-Bromo-3-methyl-benzylsulfanyl)-benzothiazole (3g).
-1 1
1457, 1425, 1357, 1309, 1019, 782 cm ; H nmr (deuteriochloro-
form): δ 4.95 (s, 2H), 7.28 (t, J= 7.6Hz, 1H), 7.38-7.44(m, 2H),
This compound was obtained as a white crystalline solid
7
.53 (t, J= 7.6Hz, 1H), 7.71 (d, J= 8.0Hz, 1H), 7.81(d, J= 8.0Hz,
(hexane-ethyl acetate), mp 77-79 °C; ir (potassium bromide):
13
3059, 2982, 1574, 1460, 1428, 1375, 1310, 1241, 1076, 992 cm-
1H), 7.90(d, J= 8.4Hz, 1H), 8.04(d, J= 8.4Hz, 1H); C nmr (deu-
1
1
teriochloroform): δ 34.20, 121.05, 121.57, 124.40, 125.24,
; H nmr (deuteriochloroform): δ 2.43 (s, 3H), 4.78 (s, 2H), 7.12
1
1
3
1
1
26.08, 128.72, 132.75, 133.34, 133.52, 135.53, 148.37, 152.84,
(t, J= 7.2Hz, 2H), 7.28 (t, J= 8.0Hz, 1H), 7.41(t, J= 7.8Hz, 2H),
+
+
+
7.72(d, J= 8.0Hz, 1H), 7.90(t, J= 6.8Hz, 1H); 13C nmr (deuterio-
65.73; ms: m/z(%I) 304 (M +2, 4.3), 303 (M +1, 5.8), 302 (M ,
1.5), 284 (3.7), 256 (12), 254(11), 252 (7), 237 (10), 223 (7.2),
69 (13.7), 168 (14.2), 167 (100), 166 (17.3), 136 (19), 122 (8.3),
08 (17.3), 105 (6.4), 89 (12), 86 (47.6), 84 (88), 78 (35.3), 77
chloroform): δ 23.84, 38.86, 121.00, 121.54, 124.27, 126.03,
127.04, 127.39, 128.76, 130.28, 135.45, 136.40, 139.09, 153.09,
+
+
166.33; ms: m/z(%I) 351 (M +2, 89), 350 (M +1, 14.5), 349
+
(10), 69 (10.6), 65 (10.5), 63 (7.7), 49 (12), 47 (6.7).
(M , 80.9), 318 (4.9), 281 (3.5), 272 (12.8), 271 (20.8), 270
Anal. Calcd. for C H N O S : C, 55.61; H, 3.33; N, 9.26.
(100), 238 (14.5), 237 (65.2), 219 (4), 186 (5), 185 (49.7), 184
1
4 10 2 2 2
(
1
6), 183 (57.8), 181 (7), 166 (10.5), 135 (4.5), 122 (4), 108 (7),
04 (14.9), 103 (12.2), 102 (3.6), 78 (4.8), 77 (5.8).
Anal. Calcd. for C H BrNS : C, 51.43; H, 3.45; N, 4.00.
Found: C, 55.71; H, 3.11; N, 9.01.
2
-(4-Iodo-benzylsulfanyl)-benzothiazole (3d).
1
5
12
2
This compound was obtained as pale yellow solid (hexane-
Found: C, 51.12; H, 3.18; N, 3.89.
ethyl acetate), mp 60-62 °C; ir (potassium bromide): 3044, 2921,
2
-(2, 5-Dibromo-benzylsulfanyl)-benzothiazole (3h).
-1 1
1
582, 1482, 1455, 1426, 1309, 1076, 1006, 826 cm ; H nmr
This compound was obtained as off-white solid (hexane-ethyl
(
deuteriochloroform): δ 4.53 (s, 2H), 7.20 (d, J= 8.0Hz, 2H),
acetate), mp 76-77 °C; ir (potassium bromide): 3061, 2963, 1552,
1456, 1428, 1264, 1086, 1026, 998 cm ; H nmr (deuteriochlo-
roform): δ 4.68 (s, 2H), 7.25-7.27 (m, 1H), 7.30 (t, J= 7.6Hz,
1
2.4Hz, 1H), 7.92 (d, J= 8.0Hz, 1H); C nmr (deuteriochloro-
form): δ 37.33, 121.07, 121.28, 121.61, 123.43, 124.47, 126.18,
1
7
2
.30(t, J= 7.6Hz, 1H), 7.42 (t, J= 7.6Hz, 1H), 7.64(d, J= 8.0Hz,
H), 7.74(d, J= 8.0Hz, 1H), 7.89(d, J= 8.0Hz, 1H); C nmr (deu-
-1 1
1
3
teriochloroform): δ 37.06, 93.28, 121.06, 121.57, 124.48, 126.18,
30.83, 131.05, 131.82, 135.33, 136.19, 137.80, 152.94, 165.89;
H), 7.44 (t, J= 7.2Hz, 2H), 7.75 (d, J= 8.0Hz, 1H), 7.82 (d, J=
1
1
3
+
+
+
ms: m/z(%I) 385 (M +2, 10.9), 384 (M +1, 17.8), 383 (M ,
1
2
1
00), 350 (20.6), 337 (4), 297 (4.8), 231 (4), 224 (6), 223 (27.5),
18 (6), 217 (67.2), 181 (3.6), 169 (8.6), 166 (5.7), 149 (3.5),
31(5.8), 108 (4.6), 90 (13.5), 89 (10.9), 63 (3.3).
32.32, 134.27, 134.37, 135.45, 138.30, 152.90, 165.47; ms:
+
+
+
m/z(%I) 415 (M +2, 23.4), 413 (M , 11), 355 (M , 9.3), 338
11.2), 337 (18.5), 336 (100), 335 (18.5), 334 (95.6), 303 (26),
01 (7.4), 268 (13.2), 266 (13.2), 255 (12.7), 251 (16.6), 249
(
3
Anal. Calcd. for C14H10INS : C, 43.87; H, 2.63; N, 3.65.
2
Found: C, 43.64; H, 2.74; N, 3.67.
(
(
35.6), 247 (14.8), 223 (4.2), 185 (4), 170 (9.5), 168 (10.4), 149
6.5), 108 (5.2), 89 (4.2).
2
-(4-Bromo-benzylsulfanyl)-benzothiazole (3e).
Anal. Calcd. for C H Br NS : C, 40.50; H, 2.19; N, 3.37.
Found: C, 40.48; H, 2.38; N, 3.40.
This compound was obtained as off-white solid (hexane-ethyl
14
9
2
2
acetate), mp 68-70 °C; ir (potassium bromide): 3075, 2967, 1913,
-1 1
1
582, 1455, 1426, 1309, 1071, 1019, 828 cm ; H nmr (deuteri-
Antimicrobial Activity of Compounds 3a-3h.
ochloroform): δ 4.55 (s, 2H), 7.28-7.40 (m, 3H), 7.41-7.45 (m,
13
Test disks (6 mm in diameter) impregnated with 100 µg of the
appropriate sample were used to test both antibacterial and anti-
fungal activities at pH 6.5 and 7.9 respectively. Disks were
applied on the surface of plates containing each 25 ml of
Antibiotic medium N°1 (pH=6.5) or N°11(pH=7.9), inoculated
3
H), 7.74 (d, J= 8.0, 1H), 7.89 (d, J= 8.0Hz, 1H); C nmr (deu-
teriochloroform): δ 36.96, 94.88, 121.06, 121.59, 121.73, 124.46,
26.16, 130.83, 131.82, 135.54, 152.99, 165.85; ms: m/z(%I) 337
1
(
(
1
+
+
+
M +2, 100), 336 (M +1, 17.2), 335 (M , 89.5), 320 (3.4), 304
24), 303 (5), 302 (21.2), 223 (41.5), 181 (4), 171 (57.7), 169 (64),
6
with 10 CFU/ml of the microorganisms. The following strains
66 (8), 122 (6.4), 108 (7.8), 90 (16), 89 (9), 69 (4.2).
were used to test the activities: Bacillus subtilis 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
Anal. Calcd. for C H BrNS : C, 50.00; H, 3.00; N, 4.17.
1
4
10
2
Found: C, 50.12; H, 2.96; N, 4.19.
2
-(2-Bromo-5-Iodo-benzylsulfanyl)-benzothiazole (3f).
1
0231 and Aspergillus niger ATCC 16404. Growth inhibition
This compound was obtained as a pale yellow crystals
was tested after a 24 hour incubation at 37 °C. All the results are
expressed as the diameter (in mm) of inhibition zones, and are
shown in Table 2.
(
2
1
hexane-ethyl acetate), mp 79-81 °C; ir (potassium bromide):
-
952, 1883, 1566, 1505, 1459, 1420, 1366, 1074, 1020, 981 cm
1
;
H nmr (deuteriochloroform): δ 4.64 (s, 2H), 7.25-7.32 (m,
2
H), 7.42 (dd, J= 8.0 & 2.0Hz, 2H), 7.29-7.52 (m, 1H), 7.92(d,
1
3
J= 8.0Hz, 1H), 8.0(d, J= 2.0Hz, 1H); C nmr (deuteriochloro-
form): δ 37.15, 92.35, 121.04, 121.62, 124.40, 124.63, 126.12,
REFERENCES AND NOTES
1
34.47, 135.48, 138.20, 138.42, 140.32, 152.99, 165.36; ms:
[*] Author to whom all correspondence should be addressed.

156
R. V. Kumar, K. V. S. R. Seshu Kumar and K. R. Gopal
Vol. 42
E-mail: rvinodk@yahoo.com
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