Simple and convenient synthesis of 2-(substituted-benzylsulfanyl)-4,5- dihydrothiazoles and their antimicrobial activity studies

Article abstract of DOI:10.1002/jhet.5570420624

A simple and convenient procedure for the preparation of 2-(substitutedbenzylsulfanyl)-4,5-dihydrothiazoles by the reaction of 4,5-dihydro-thiazole-2-thiol and benzyl bromides in acetone/K₂CO ₃ condition has been reported.

Full text of DOI:10.1002/jhet.5570420624

Simple and Convenient Synthesis of 2-(Substituted-benzylsulfanyl)-
4,5-dihydrothiazoles and their Antimicrobial Activity Studies
Ramanatham Vinod Kumar* and Kotha V. S. R. Seshu Kumar
Sep-Oct 2005
1191
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.
E-mail: rvinodk@yahoo.com
Received November 8, 2004
A simple and convenient procedure for the preparation of 2-(substitutedbenzylsulfanyl)-4,5-dihydrothia-
zoles by the reaction of 4,5-dihydro-thiazole-2-thiol and benzyl bromides in acetone/K CO condition has
2
3
been reported.
J. Heterocyclic Chem., 42, 1191 (2005).
Introduction.
of anhydrous potassium carbonate as a base for 2 hr, gave
the corresponding 2-benzylsulfanyl-4,5-dihydrothiazole
(3a, Ar-=Ph) in 98 % yield (Figure 1). The product was
identified with the spectral data and by comparison with
the authentic sample [21]. Similary, compound 1 was
reacted with other substituted benzyl bromides (2b-2h)
under similar conditions to obtain the corresponding 2-
(substituted-benzylsulfanyl)-4,5-dihydrothiazoles (3b-3h)
in almost quantitative yields. (Table 1). All the new prod-
ucts were characterized by IR, H-, C-NMR spectral and
analytical data. All the compounds 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-(substi-
tuted-benzylsulfanyl)-4,5-dihydrothiazoles constitute an
important class of heterocyclics found in bioactive com-
pounds, the methodology described here may find useful
applications in the synthesis of drug intermediates and
other bioactive compounds containing this heterocyclic
moiety.
Thiazoles are an important group of heterocyclic systems
found in many bioactive molecules, specifically in Vitamin-
B1 [1]. Compounds containing this heterocyclic nucleus are
also found in many bioactive substrates such as thiazole nat-
ural products [2], thiazole based amino acids [3] and peptide
antibiotics [4] etc. Similarly, 4,5-dihydrothiazoles and their
derivatives were also found to be potent antithrombotic [5],
nematocidal [6] and thiopenam [7] agents and oligo thiazo-
line and polyazole natural products [8,9]. We have previ-
ously reported the synthesis of 2-benzylsulfanylbenzo-
thiazoles and their antimicrobial activities [10]. In continua-
tion of our work on thiazole compounds, we now wish to
report the synthesis of 2-benzylsulfanyl-4,5-dihydrothia-
zoles and their microbial activity studies.
1
13
Results and Discussion.
A perusal of literature revealed that these compounds
can be prepared by the reaction of 2-mercapto-4,5-dihy-
drothiazole with benzyl halides in the presence of a base
[11]. The yield of reactions depends on the solvent, basic
catalyst and acidity of thiol. Generally these reactions
require very long refluxing time and yields obtained are
often very low [12]. Several other methods employed for
preparing thioethers include Pd(0) mediated alkylation
[13], phase-transfer catalysis [14], bis(diphenylstannyl)tel-
luride [15], tin sulfides with aryl halides [16], ligand trans-
fer reactions [17], clay catalysis [18], trifluoroacetic acid
[19] and the use of strong base like n-BuLi has also been
reported [20]. Recently use of CsF-Celite condition has
also been reported for the S-alkylation [21]. Thus, it is evi-
dent from the literature that though there are several meth-
ods reported for the preparation of 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 conditions. In this
paper, we wish to report a simple but efficient methodol-
ogy for the synthesis of 2-(substitutedbenzylsulfanyl)-4,5-
dihydrothiazoles in excellent yields.
Conclusion.
In conclusion, we have reported a convenient and useful
methodology for the synthesis of 2-(substituted-benzylsul-
fanyl)-4,5-dihydrothiazoles in excellent yields. The
advantage of this methodology is the use of very mild reac-
tion conditions, which can tolerate various functional
groups that can be used for further synthetic manipula-
tions. Further, commercial availability of large number of
benzyl bromides or easy methods of their preparation
makes this reaction a more attractive choice. All the com-
pounds were tested for antimicrobial screening. However,
only few compounds exhibited moderate activity against
Reaction of 4,5-dihydro-thiazole-2-thiol, 1 with benzyl
bromide (2a, Ar=Ph) at reflux in acetone, in the presence

1192
R. V. Kumar and K. V. S. R. Seshu Kumar
Vol. 42
Table 1
List of Various 2-(Substitutedbenzylsulfanyl)-4,5-dihydro-thiazoles Sythesized
Sr.
No.
Starting
Material
Aryl halide
Used (2)
Product
Obtained (3)
Yield
(%)
M.P.
(°C)
1
1
2a, Ar = C H -
3a, Ar = C H -
98
47- 48 (Lit
[20]-48)
35 - 36
83 - 84
-
43 – 44
48 - 49
-
6
5
6 5
2
3
4
5
6
7
8
1
1
1
1
1
1
1
2b, Ar = 2-Br-C H -
3b, Ar = 2-Br-C H -
95
96
96
95
97
96
97
6
4
6 4
2c, Ar = 2-NO -C H -
3c, Ar = 2-NO -C H -
2
6
4
2 6 4
2d, Ar = 4-Br-C H -
3d, Ar = 4-Br-C H -
6 4
6
4
2e, Ar = 4-I-C H -
3e, Ar = 4-I-C H -
6
4
6 4
2f, Ar = 2,5-Br -C H -
3f, Ar = 2,5-Br -C H -
2
6
3
2 6 3
2g, Ar = 2-Br-3-Me-C H -
2h, Ar = 2-Br-5-I-C H -
3g, Ar = 2-Br-3-Me-C H -
6 3
3h, Ar = 2-Br-5-I-C H -
6
3
57 - 58
6
3
6 3
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
3a
3b
3c
3d
3e
3f
7.1
—
6.0
—
—
6.0
—
—
6.9
—
6.3
—
—
7.2
—
6.8
—
—
6.3
—
6.9
—
7.6
—
—
6.8
6.4
7.1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
6.2
—
—
7.2
—
6.3
—
—
6.6
—
—
8.2
—
—
—
—
—
6.2
6.0
—
7.0
6.1
6.9
6.3
6.7
6.7 6.9
7.1
6.3
6.7
—
—
7.0
8.0
—
—
—
—
7.3
—
—
—
7.2
—
—
—
3g
3h
7.0
7.6
6.6
7.6 6.0
o
o
[a] Diameter (in mm) of inhibition zones; AM1: Antibiotic medium N 1 (pH=6.5); AM11: Antibiotic medium N 11 (pH=7.9).
-1
E. subtilis, E. coli, P. aeruginosa, C. albicans and A. niger
in a preliminary screening.
2967, 1575, 1465, 1402, 1302, 1275, 1203, 1053, 999, 925 cm ;
1
H-NMR (CDCl /TMS): δ 3.39 (t, J= 8.0 Hz, 2H), 4.22 (t, J = 8.0
Hz, 2H), 4.48 (s, 2H), 7.11 (t, J=7.6Hz, 1H), 7.25 (d, J=7.6Hz,
1H), 7.52 (m, 2H); C-NMR (100MHz/CDCl ): 35.77, 37.18,
64.11, 124.68, 127.51, 129.12, 131.28, 132.89, 136.41, 164.94.
3
13
3
EXPERIMENTAL
Anal. Calcd. for C H BrNS : C, 41.67; H, 3.50; N, 4.86.
Found: C, 41.68; H, 3.52; N, 4. 89.
10 10
2
Melting points are uncorrected and were recorded on a MRVIS
Series, Lab India Instrument.IR spectra were recorded on a
1
13
2-(2-Nitrobenzylsulfanyl)-4,5-dihydrothiazole (3c).
This compound has the following properties: IR (KBr): 3012,
Perkin-Elmer Spectrum One FT-IR spectrometer. H- and C-
NMR spectra were recorded in CDCl on a JEOL 400 MHz spec-
3
trometer using TMS as internal standard. Elemental analysis was
carried out on a Perkin–Elmer Series –II CHN Analyzer 2400.
The starting material, 4,5-dihydro-thiazole-2-thiol has been
obtained from commercial suppliers.
-1
1
2848, 1608, 1574, 1444, 1350, 1249, 1170, 1060, 968 cm ; H-
NMR (CDCl /TMS): δ 3.38 (t, J= 8.0 Hz, 2H), 4.20 (t, J = 8.0
3
Hz, 2H), 4.67 (s, 2H), 7.43 (t, J = 6.8Hz, 1H), 7.55 (t, J = 7.0Hz,
13
1H), 7.69 (d, J = 8.0Hz, 1H), 8.02 (d, J = 8.0Hz, 1H); C-NMR
(100MHz/CDCl ): 33.68, 35.87, 63.96, 125.10, 128.50, 132.78,
133.42, 133.56, 148.24, 164.68.
General Procedure.
3
A mixture of 4,5-dihydro-thiazole-2-thiol 1 (2 mmole), respec-
tive benzyl bromide (2 mmol), finely grounded anhydrous
Anal. Calcd. for C H N O S : C, 47.22; H, 3.96; N, 11.01.
10 10
2 2 2
Found: C, 46.96; H, 4.02; N, 11.04.
K CO (4 mmol) in acetone was refluxed for 2 hr and the reac-
2
3
2-(4-Bromobenzylsulfanyl)-4,5-dihydrothiazole (3d).
tions were followed by method of tlc. The reaction mixture was
then cooled to room temperature and filtered. Evaporation of the
filtrate yielded the crude product. The crude products were puri-
fied by silica-gel flash column chromatography.
This compound has the following properties: IR (CHCl ):
3
3042, 2936, 2848, 1899, 1570, 1485, 1432, 1408, 1303, 1244,
-1
1
1193, 1102, 1070, 995 cm ; H-NMR (CDCl /TMS): δ 3.39 (t,
3
J= 8.0 Hz, 2H), 4.21 (t, J = 8.0 Hz, 2H), 4.28 (s, 2H), 7.23 (d, J =
Spectral Data of Compounds.
13
8.4Hz, 2H), 7.42 (d,
J
=
8.4Hz, 2H);
C-NMR
2-(2-Bromobenzylsulfanyl)-4,5-dihydro-thiazole (3b).
This compound has the following properties: IR (KBr): 3060,
(100MHz/CDCl ): 35.71, 36.16, 64.11, 121.38, 130.71, 131.65,
3
135.95, 164.89.

Sep-Oct 2005
Synthesis of 2-(Substituted-benzylsulfanyl)-4,5-dihydrothiazoles
1193
Anal. Calcd. for C H BrNS : C, 41.67; H, 3.50; N, 4.86.
Found: C, 41.69; H, 3.48; N, 4.84.
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. Growth inhibition
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.
10 10
2
2-(4-Iodobenzylsulfanyl)-4,5-dihydro-thiazole (3e).
This compound has the following properties: IR (KBr): 2933,
-1
1
1908, 1573, 1483, 1396, 1303, 1192, 1056, 968 cm ; H-NMR
(CDCl /TMS): δ 3.39 (t, J= 8.0 Hz, 2H), 4.20 (t, J = 8.0 Hz, 2H),
3
4.27 (s, 2H), 7.10 (d, J = 8.4Hz, 2H), 7.61 (d, J = 8.0Hz, 2H);
13
C-NMR (100MHz/CDCl ): 35.70, 36.23, 64.09, 92.92, 130.93,
3
REFERENCES AND NOTES
136.58, 137.59, 164.79.
Anal. Calcd. for C
Found: C, 35.96; H, 3.12; N, 4.01.
H INS : C, 35.83; H, 3.01; N, 4.18.
10 10 2
[1a] J. V. Metzger (Ed.), Thiazole and its Derivatives, Wiley-
Interscience, New York, 1979; [b] J. V. Metzger in A. R. Katritzky and
C. W. Rees (Eds.), Comprehensive Heterocyclic Chemistry, Pergamon
Press, Oxford, 1984,Vol. 6, 235; [c] R. Tanaka and I. Shinkai in H.
Suschitzky and E. F. V. Scriven (Eds.), Progress in Heterocyclic
Chemistry, Pergamon Press, Oxford, 1989-1994, Vols. 1-6; J. V. Metzger,
Chem. Heterocycl. Compds., 34, 1 (1979).
[2a] Z. Jin, Z. Li and R. Huang, Natural Product Reports, 19, 454
(2002); [b] P. Catsoulacos and Ch. Camoutsis, J. Heterocyclic Chem.,
18, 1485 (1981).
[3] A. Bertram and G. Pattenden, Synlett, 12, 1873 (2001).
[4] Y-M. Li, J. C. Milne, L.L. Madison, R. Kolter and C. T.
Walsh, Science, 274, 1188 (1996).
[5] A. K. Saxena, S. K. Pandey, P. Seth, M. P. Singh, M. Dixit, A.
Carpy, Bioorg & Med. Chem., 9, 2025 (2001).
[6] A. J. Martinez,U S Pat., 4584306, 1986; Chem. Abstr., 105:
60598x (1986).
[7] E. Schaumann, W. R. Foerster and G. Adiwidjaja, Angew.
Chemie., 96, 429 (1984).
[8] S. Hoppen and U. Koert, Organic Synthesis Highlights IV,
218 (2000).
[9] P. Wipf and S. Venkatraman, Synlett, 1, 1 (1997).
[10] R. Vinod Kumar, K. V. S. R. Seshu Kumar and K. Raja Gopal,
J. Heterocyclic Chem., 42, 153 (2005).
2-(2, 5-Dibromobenzylsulfanyl)-4,5-dihydrothiazole (3f).
This compound has the following properties: IR (KBr): 3086,
-
2847, 1567, 1456, 1405, 1304, 1238, 1198, 1084, 1029, 993 cm
1
1
; H-NMR (CDCl /TMS): δ 3.42 (t, J= 8.0 Hz, 2H), 4.24 (t, J =
3
8.0 Hz, 2H), 4.42 (s, 2H), 7.25 (dd, J = 10.4 & 2.4Hz, 1H), 7.40
13
(d, J = 8.4Hz, 1H), 7.67 (d, J = 2.0Hz, 1H); C-NMR
(100MHz/CDCl ): 35.87, 36.59, 64.02, 121.18, 123.29, 132.06,
3
134.09, 134.14, 138.75, 164.54.
Anal. Calcd. for C H Br NS : C, 32.72; H, 2.47; N, 3.82;
10
9
2
2
Found: C, 32.86; H, 2.18; N, 3.76.
2-(2-Bromo-3-methylbenzylsulfanyl)-4,5-dihydrothiazole (3g).
This compound has the following properties: IR (CHCl ):
3
3050, 2944, 2848, 1935, 1571, 1461, 1379, 1261, 1190, 1025,
-1 1
964 cm ; H-NMR (CDCl /TMS): δ 2.41 (s, 3H), 3.38 (t, J= 8.0
3
Hz, 2H), 4.23 (t, J = 8.0 Hz, 2H),4.52 (s, 2H), 7.13 (d, J=4.8Hz,
13
2H), 7.32 (t, J=4.6Hz, 1H); C-NMR(100MHz/CDCl ): 23.83,
35.70, 38.10, 64.13, 126.92, 127.26, 128.68, 130.02, 136.69,
138.91, 165.08.
3
Anal. Calcd. for C H BrNS : C, 43.71; H, 4.00; N, 4.63.
[11] For a review, see: M. E. Peach in The Chemistry of Thiol
Groups, S. Patai (Ed.), Thiols as nucleophiles; John Wiley & Sons,
London, 721 (1974).
[12] S.-I. Yunoki, K. Takimiya, Y. Aso and T. Otsubo, Tetrahedron.
Lett., 38, 3017 (1997).
11 12
2
Found: C, 43.82; H, 4.08; N, 4.44.
2-(2-Bromo-5-Iodobenzylsulfanyl)-4,5-dihydro-thiazole (3h).
This compound has the following properties: IR (KBr): 3077,
[13] C. Goux, P. Lhoste and D. Sinou, Tetrahedron.Lett., 33, 8099
(1992).
-
1904, 1559, 1456, 1404, 1375, 1306, 1235, 1198, 1075, 996 cm
1
1
; H-NMR (CDCl /TMS): δ 3.42 (t, J= 8.0 Hz, 2H), 4.25 (t, J =
3
[14]
(1975).
A. W. Herriott and D. Picker, J. Am. Chem.Soc., 97, 2345
8.0 Hz, 2H), 4.40 (s, 2H), 7.26 (d, J=3.6Hz, 1H), 7.42 (dd, J=8.0
13
&
2.0Hz, 1H), 7.85 (d, J=2.0Hz, 1H);
NMR(100MHz/CDCl ): 35.81, 36.52, 63.85, 92.33, 124.51,
134.40, 138.02, 138.79, 139.99, 165.01.
C-
[15] C.-J. Li and D. N. Harpp, Tetrahedron.Lett., 33, 7293 (1992).
[16] M. Kosugi, T. Ogata, M. Terada, H. Sano and T. Migata, Bull.
Chem. Soc. Jpn, 58, 3657 (1985).
3
Anal. Calcd. for C H BrINS : C, 29.00; H, 2.19; N, 3.38.
Found: C, 28.86; H, 2.31; N, 3.20.
[17a] F. D. Toste and I. W. J. Still, Tetrahedron.Lett., 36, 4361
(1995); [b] F. D. Toste F. Laronde and I. W. J. Still, Tetrahedron.Lett., 36,
2949 (1995).
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(1998).
[19] L. S. Richter, J. C. Marsters and T. R. Gadek,
Tetrahedron.Lett., 35, 1631 (1994).
[20a] E. Fujita, Y. Nagao, K. Seno, S. Takeo and T. Miyasaka, J.
Chem. Soc., Perkin Trans. 1, ,914 (1981); [b] J. Yin and C. Pidgeon,
Tetrahedron. Lett., 38, 5953 (1997).
10
9
2
Antimicrobial Activity of Compounds 3a-3h.
Test disks (6mm in diameter) impregnated with 100µg 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
6
with 10 CFU/ml of the microorganisms. The following strains
[21] S. T. A. Shah, K. M. Khan, A. M. Heinrich and W. Voelter,
Tetrahedron. Lett., 43, 8281 (2002).
were used to test the activities: Bacillus subtilis ATCC 6633