Vol. 31, No. 2 (2019)
Green Synthesis Approaches of 2-Bromo-4-methyl thiazole-5-carboxamide Derivatives 299
MeOH], 381 [M+Na+MeOH+2]. Anal. Calcd. (found) % for
C13H13N2OSBr: C 48.10 (48.01); H 3.95 (4.03); N 8.55 (8.61);
S 9.78 (9.86).
65 %); m.p. 215-217 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.40-
7.38 (m, 7.39 Hz, 2H), 7.21-7.19 (m, 7.20 Hz, 2H), 2.73 (s,
3H); 13C NMR (101 MHz, DMSO-d6) δ 167.98, 155.09, 152.32,
136.52, 135.17, 129.01, 122.72, 111.35, 16.54; ESI-MS m/z
337 [M+1], 339 [M+3]. Anal. Calcd. (found) % for
C12H9N4OSBr: C 42.50 (42.74); H 2.48 (2.69); N 16.42 (16.62);
S 9.48 (9.51).
2-Bromo-N-(furan-2-ylmethyl)-4-methylthiazole-5-
carboxamide (5n): Off white amorphous solid (Yield: 60 %);
m.p. 176-178 ºC; 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H),
6.34 (dd, 1H), 6.30 (d, 1H), 4.57 (d, 5.50 Hz, 2H), 2.66 (s,
3H); 13C NMR (100.1 MHz, CDCl3) δ 160.25, 154.99, 150.32,
142.57, 136.76, 110.62, 108.08, 37.09, 17.27; ESI-MS m/z
301 [M+1], 303 [M+3], 323 [M+Na], 325 [M+Na+2]. Anal.
Calcd. (found) % for C10H9N2O2SBr: C40.02 (39.88); H 2.89
(3.01); N 9.11 (9.30); S 10.49 (10.65).
2-Bromo-N-(tert-butyl)-4-methylthiazole-5-carboxamide
(5o):Yellow-white amorphous solid (Yield: 85 %); m.p. 140-
143 ºC; 1H NMR (400 MHz, CDCl3) δ 5.27 (br, NH), 2.62 (s, 3H),
1.44 (s, 9H); 13C NMR (100.1 MHz, CDCl3) δ 159.82, 153.41,
136.00, 132.17, 52.61, 28.88, 17.13; ESI-MS m/z 277 [M+1],
279 [M+3].Anal. Calcd. (found) % for C9H13N2OSBr: C 38.85
(39.00); H 4.55 (4.73); N 10.05 (10.11); S 11.60 (11.57).
Antimicrobial evaluation: Antibacterial evaluation was
tested using agar well diffusion method. The activity of tested
samples was tested against Staphylococcus aureus (NCIM
2079) and Bacillis subtilis (NCIM 2063), as Gram positive bacteria
and Pseudomonas aeruginosa (ATCC 10145), Escherichia coli
(ATCC 11775), as Gram negative bacteria and Aspergillus
niger (ATCC 6275) were used to test antifungal activity. The
solution of 10 mg/mL of each compound in DMSO was used
for testing against bacteria. Known antibiotics like norfloxacin,
ciprofloxacin (reference antibacterial drugs) and itraconazol
(reference antifungal drug) were used for comparison. The anti-
bacterial activity of compounds was evaluated by diffusion
method on a nutrient medium (Luria-Bertani Broth agar for
bacteria and potato dextrose agar for fungi). The required incu-
bation periods were 12-16 h at 37 ºC for bacteria and 48-72 h
at 28-30 ºC for fungi. The control disk contained norfloxacin
and ciprofloxacin in the appropriate wells. The tested comp-
ounds were dissolved in DMSO applying the necessary concen-
tration. The exact volume of solution of compounds is brought
into a nutrient medium. 100 µL of tested samples (10 mg/mL)
were loaded into the wells of plates. The results were estimated
according to the presence or absence of microorganism growth.
The activity was determined by measuring the diameter of the
inhibition zone (in mm).
2-Bromo-N-(2,4-dimethylphenyl)-4-methylthiazole-5-
carboxamide (5g): Off white crystalline solid (Yield: 72 %);
m.p. 150-152 ºC; 1H NMR (400 MHz, CDCl3) δ 7.63 (br, NH),
7.22 (s, 1H), 7.05(d, 2H), 2.74(s, 3H), 2.32 (s, 3H), 2.26 (s, 3H);
13C NMR (100.1 MHz, CDCl3)δ158.69, 155.53, 151.45, 143.84,
137.06, 132.27, 131.42, 127.55, 20.94, 17.85, 17.44; ESI-MS
m/z 325 [M+1], 327 [M+3], 347 [M+Na], 349 [M+Na+2], 379
[M+Na+MeOH], 381 [M+Na+MeOH+2]. Anal. Calcd. (found)
% for C13H13N2OSBr: C 48.15 (48.01); H 3.90 (4.03); N 8.58
(8.61); S 9.80 (9.86).
2-Bromo-N-(3,5-dimethylphenyl)-4-methylthiazole-5-
carboxamide (5h): White solid (Yield: 77 %); m.p. 143-147
ºC; 1H NMR (400 MHz, CDCl3) δ 7.39 (br, NH), 7.16 (s, 2H),
6.82 (s, 1H), 2.72 (3H), 2.31 (6H); 13C NMR (100.1 MHz, CDCl3)
δ 159.53, 158.54, 155.19, 139.02, 136.88, 136.78, 130.68,
127.07, 118.21, 21.36, 17.31; ESI-MS m/z 325 [M+1], 327
[M+3], 347 [M+Na], 349 [M+Na+2]. Anal. Calcd. (found) %
for C13H13N2OSBr: C 47.92 (48.01); H 4.10 (4.03); N 8.50
(8.61); S 9.78 (9.86).
2-Bromo-N-(4-methoxybenzyl)-4-methylthiazole-5-
carboxamide (5i): Off white crystalline solid (Yield: 80 %);
m.p. 118-121 ºC; 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J =
9.28 Hz, 2H), 6.90 (d, J = 8.79 Hz, 2H), 4.50 (d, J = 5.52 Hz),
13
3.81 (s, 3H), 2.64 (s, 3H); C NMR (100.1 MHz, CDCl3) δ
160.31, 159.34, 154.71, 136.57, 130.38, 129.43, 129.31, 114.31,
55.35, 43.84, 17.31; ESI-MS m/z 341 [M+1], 343 [M+3], 363
[M+Na], 365 [M+Na+2]. Anal. Calcd. (found) % for
C13H13N2O2SBr: C 45.55 (45.76); H 3.60 (3.84); N 8.11
(8.21); S 9.32 (9.40).
2-Bromo-N-cyclohexyl-4-methylthiazol-5-carbox-
amide (5j): Orange to red crystalline solid (Yield: 75 %); m.p.
1
123-125 ºC; H NMR (400 MHz, CDCl3) δ 5.56 (br, 1NH),
3.91 (m, 1H), 2.64 (s, 3H), 2.01 (m, 4H), 1.76-1.63 (m, 4H),
1.27- 1.16 (m, 4H); 13C NMR (100.1 MHz, CDCl3) δ 159.58,
153.97, 136.26, 49.12, 33.07, 25.42, 24.74, 17.19; ESI-MS
m/z 303 [M+1], 305 [M+3], 325 [M+Na], 327 [M+Na+2].
Anal. Calcd. (found) % for C11H15N2OSBr: C 43.21 (43.57); H
5.01 (4.99); N 9.10 (9.24); S 10.46 (10.57).
2-Bromo-N-cyclopropyl-4-methylthiazol-5-carbox-
amide (5k): White solid (Yield: 80 %); m.p. 95-98 ºC; 1H NMR
(400 MHz, CDCl3) δ 5.92 (br, NH), 2.83 (m, 1H), 2.64 (s, 3H),
0.88 (dd, 19.44 Hz), 0.61 (dd, 16.14 Hz, 2H); 13C NMR (100.1
MHz, CDCl3) δ 161.93, 154.93, 136.40, 23.36, 17.21, 6.95; ESI-
MS m/z 261 [M+1], 263 [M+3], 283 [M+Na], 285 [M+Na+2].
Anal. Calcd. (found) % for C8H9N2OSBr: C 36.55 (36.79); H
3.38 (3.47); N 10.85 (10.73); S 12.30 (12.28).
RESULTS AND DISCUSSION
The amidation is a highly useful synthetic strategy used
by nature as exemplified by proteins, peptides and many other
naturally occurring substances. The reaction also occupies a
prominent position in many fields of chemical industry inclu-
ding material science and drug development. Numerous amidation
protocols have been extensively explored and developed and
in principle, most amides are synthesized by the reaction
between amines with activated carboxylic acid derivatives [24].
Herein, we report an efficient method for the synthesis of title
compounds according to the procedure outlined in Scheme-I.
N-(Benzo[d]thiazol-2-yl)-2-bromo-4-methylthiazole-5-
carboxamide (5l): Off white amorphous solid (Yield: 60 %);
m.p. 190-192 ºC; 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.55
(m, 4H), 2.79 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ167.98,
155.09, 152.32, 136.52, 135.17, 129.01, 122.72, 111.35, 16.54;
ESI-MS m/z 354 [M+1], 355 [M+3], 376 [M+Na], 378 [M+Na
+2]. Anal. Calcd. (found) % for C12H8N3OS2Br: C 40.55
(40.69); H 2.30 (2.28); N 11.80 (11.86); S 18.01 (18.10).
N-(1H-benzo[d]imidazol-2-yl)-2-bromo-4-methylthia-
zole-5-carboxamide (5m): Off white amorphous solid (Yield: