An efficient, uncatalyzed, and rapid synthesis of thiazoles and aminothiazoles under microwave irradiation and investigation of their biological activity

Article abstract of DOI:10.1080/10426500802715163

A convenient method for the synthesis of thiazoles by treatment of -bromoketones with thioamides (Hantzsch synthesis) in the absence of catalysts under microwave irradiation has been developed. The products were formed rapidly in excellent yields. An efficiency comparison of time, yield, and effort clearly proved the microwave technique to be superior. The structures of the newly synthesized compounds were characterized by spectroscopic data and elemental analyses. The synthesized compounds were tested for their biological activity. Depending on the substituents, some of the thiazoles exhibit very good antibacterial or antifungal activity.

Full text of DOI:10.1080/10426500802715163

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Phosphorus, Sulfur, and Silicon and the
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An Efficient, Uncatalyzed, and
Rapid Synthesis of Thiazoles and
Aminothiazoles Under Microwave
Irradiation and Investigation of Their
Biological Activity
Sudhakar A. Gaikwad a , Amol A. Patil a & Madhukar B. Deshmukh a
a Department of Chemistry, Shivaji University, Vidyanagar, Kolhapur,
India
Published online: 28 Dec 2009.
To cite this article: Sudhakar A. Gaikwad , Amol A. Patil & Madhukar B. Deshmukh (2009) An
Efficient, Uncatalyzed, and Rapid Synthesis of Thiazoles and Aminothiazoles Under Microwave
Irradiation and Investigation of Their Biological Activity, Phosphorus, Sulfur, and Silicon and the
Related Elements, 185:1, 103-109
To link to this article: http://dx.doi.org/10.1080/10426500802715163
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Phosphorus, Sulfur, and Silicon, 185:103–109, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802715163
COMMUNICATION
AN EFFICIENT, UNCATALYZED, AND RAPID SYNTHESIS
OF THIAZOLES AND AMINOTHIAZOLES UNDER
MICROWAVE IRRADIATION AND INVESTIGATION OF
THEIR BIOLOGICAL ACTIVITY
Sudhakar A. Gaikwad, Amol A. Patil,
and Madhukar B. Deshmukh
Department of Chemistry, Shivaji University, Vidyanagar, Kolhapur, India
A convenient method for the synthesis of thiazoles by treatment of α-bromoketones with
thioamides (Hantzsch synthesis) in the absence of catalysts under microwave irradiation
has been developed. The products were formed rapidly in excellent yields. An efficiency
comparison of time, yield, and effort clearly proved the microwave technique to be superior.
The structures of the newly synthesized compounds were characterized by spectroscopic
data and elemental analyses. The synthesized compounds were tested for their biological
activity. Depending on the substituents, some of the thiazoles exhibit very good antibacterial
or antifungal activity.
Keywords Aminothiazole; biological activity; microwave irradiation; thiazole; thiourea
INTRODUCTION
The thiazole ring system is a common structural moiety found in numerous biologi-
cally active molecules.1 This heterocyclic moiety has been employed in the preparation of
different important drugs required for the treatment of hypertension.2 Some of the thiazole
analogues are used as fungicides, inhibiting the in vivo growth of Xanthomonas, and as in-
gredient of herbicides or schistosomicidal and anthelmintic drugs.3 Recently they have been
utilized for the treatment of pain,4 as fibrinogen receptor antagonists with antithrombotic
activity,5 and as inhibitors of bacterial DNA gyrase B.6
The application of microwave (MW) irradiation as a nonconventional energy source
for the activation of reactions has now become a very popular and useful technology in
organic chemistry. MW irradiation has led to enhanced reaction rates, higher yields of pure
products, easier workup, and, sometimes, to selective conversions with several advantages
of the ecofriendly approach in the framework of green chemistry. However, in spite of
their potential utility, many of the reported methods suffer from drawbacks such as harsh
Received 9 December 2008; accepted 26 December 2008.
The authors are thankful to the Associate Editor for his constructive suggestions to modify this manuscript.
Address correspondence to Madhukar B. Deshmukh, Department of Chemistry, Shivaji University, Vidyana-
gar, Kolhapur M.S. 416 004, India. E-mail: sudhakar.gaikwad@yahoo.com
103

104
S. A. GAIKWAD ET AL.
Scheme 1
reaction conditions, unsatisfactory yields, prolonged reaction time, cumbersome product
isolation procedures, and use of hazardous organic solvents and often expensive catalysts.
Here, we report the use of MW irradiation to enhance the condensation reaction between
α-bromoketones with thioamides, i.e., the Hantzsch synthesis (Tables I–III).
RESULTS AND DISCUSSION
Syntheses
All the reactions shown in Scheme 1 were carried out at 80◦C, and the products
were formed within 20 min. No catalysts were used. A variety of α-bromoketones and
thioamides or thiourea was applied (Table III). The yields of thiazoles and aminothiazoles
were excellent. The structures of the products were confirmed from their spectroscopic data
1
(IR, H NMR, 13C NMR, and MS) and elemental analyses. The methodical optimization
was carried out at different temperatures (Table I). To optimize the reaction conditions for
the MW-assisted Hantzsch cyclization, the reaction of 1 (R1 = C6H3Cl2) with thiourea 2
(R2 = NH2) was selected (Table I). Using an automated Emrys Optimizer single mode MW
reactor, the thiazole 3b was formed in 20 min at 80◦C (Table III, Entry 2) with an isolated
yield of 97%. As a standard procedure, the α-bromoketone 1 and the thioamide derivative
2 were dissolved in ethanol (3 mL). At higher temperature, the reaction mixture became
darker and the yield dropped slightly. Therefore it was decided to perform the microwave
Table I Optimization of the reaction conditions for 3b with MW Irradiationa
No.
Temp (◦C)
Initial power (W)
Time (min)b
Isolated yield (%)c,d
1
2
3
4
5
6
7
8
50
60
70
100
110
125
150
200
250
250
300
40
30
30
20
20
20
30
20
90
85
90
96
89
79
90
55
80
100
130
150
175
aEmrys Optimizer microwave from Biotage using Emrys process vials (5 mL), α-
bromoketone (1.5 mmol), (NH2)2CS (1 mmol), ethanol (3 mL).
bReaction monitored by TLC.
cAfter chromatographic purification.
dFor exact procedures see the Experimental section.

MICROWAVE-ASSISTED THIAZOLE SYNTHESIS
Table II Variation of solvent for 3b under microwave irradiation (80◦C) and conventional heating (80◦C)
MW Irradiation Conventional Heating
105
Entry
Solvent
Time (min)
Yield (%)
Time (h)
Yield (%)
1
2
3
4
EtOH
20
20
35
40
96
85
78
70
1.5
1.0
2.5
3.0
93
90
82
89
MeOH
CH3CN
H2O
reactions at 80◦C. The corresponding thermal reactions were carried out using identical
reaction conditions (solvent volume, concentration, temperature; Table II). As shown in
Table II, different results were obtained in the presence of different solvents.
Antimicrobial Activities
The antimicrobial activities of the synthesized thiazoles were determined using the
cup plate method.7 This method depends on the diffusion of an antibiotic through a cavity
into the solidified agar layer in a Petri dish. About 15–20 mL of molten nutrient agar
was poured into each of the sterile plates. With the help of a sterile cork borer, the cups
were punched and scooped out of the solidified agar. The agar plates so prepared were
divided into different sets, and each set of the plates was inoculated with the suspension of
a particular organism by the spread plate technique.
The cups of inoculated plates were then filled with 0.1 mL of the test solution, and the
plates were allowed to stay in their upright position for 2 h. Then the plates were incubated
at 37◦C and kept overnight. The zone of inhibition developed was measured for the test
organism for the particular compound. The in vitro antibacterial activity was carried out
Table III Synthesis of thiazoles under MW irradiation
Thioamide 2
R–CS–NH2 R
Thiazole
Timeb
(min)
Yieldc
(%)
α-Bromoketone 1 Ar–CO–CH2–Br Ar
3a
Mp (◦C)
3,4-Dichlorophenyl
2,5-Dichlorophenyl
4-Iodophenyl
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Me
Me
Me
CO–OEt
CO–OEt
CO–OEt
3a
3b
3c
3d
3e
3f
3g
3h
3i
15
20
10
15
25
20
20
10
15
20
10
15
10
90
97
90
93
86
87
89
94
91
88
93
84
90
193—194
152–155
126–128
130–133
198–200
203–204
Oil
126–128
Oil
Oil
3-Bromophenyl
3,4-Dimethoxyphenyl
4-Methoxyphenyl
2-Methoxyphenyl
3,4-Dichlorophenyl
3-Bromophenyl
2-Chlorophenyl
4-Nitrophenyl
3j
3k
3l
Oil
Oil
Oil
Phenyl
3,4-Dichlorophenyl
3m
aAll products were identified by IR, 1H NMR, 13C NMR, and MS data, and elemental analyses (C, H, and
N).
bReaction monitored by TLC.
cIsolated yields.

106
S. A. GAIKWAD ET AL.
Table IV Antimicrobial activity of the thiazoles
Antibacterial activity zone of inhibition (mm) Antifungal activity zone of inhibition (mm)
Compound E. coli
M. luteus
S. aureus
A. flaves
A. niger
C. lunata
3
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
25
22
—
24
18
—
26
12
14
23
—
19
26
27
+ve
32
26
—
29
15
—
30
18
—
26
—
26
30
32
+ve
21
16
—
20
16
—
19
17
12
19
—
14
20
22
+ve
15
22
—
15
24
—
22
16
12
18
—
20
25
25
+ve
—
16
—
12
17
—
18
13
14
11
—
10
14
18
+ve
11
15
—
10
13
—
15
12
10
13
—
—
14
16
+ve
3m
Standarda
DMFb
aStandard for antibacterial activity: Chloramphenicol (0.001 mol/mL). Standard for antifungal activity:
Fluconazole (0.001 mol/mL).
bControl: DMF (0.01% solution in distilled water), +ve indicates growth of microbes.
against 24 old cultures of Escherichia coli, Micrococcus luteus, and Staphylococcus aureus.
The fungi used were Aspergillus flavus, Aspergillus niger, and Curvuliaria lunata. The
compounds were tested at concentrations of 0.001 mol/mL in DMF using Chloramphenicol
and Fluconazole as standards for the antibacterial and antifungal activities, respectively.
All the microbial strains were used as non-invasive species of their genera and thus were
applicable for work. E. coli and S. aureus are common bacteria causing food poisoning;
therefore we have selected these two bacteria for the antimicrobial screening.
The investigation of the antibacterial screening data revealed that the tested com-
pounds exhibit moderate to good bacterial inhibitions. Compounds 3a, 3d, 3g, and 3m
showed very good inhibition against E. coli, M. luteus, and S. aureus at 0.001 mol/mL. The
thiazoles 3c, 3f, and 3k were biologically inactive (antimicrobial study) as compared with
the standard drug. The results are presented in Table IV. The newly prepared compounds
were screened for their antifungal activity against A. flavus, A. niger, and C. lunata in
DMSO by the cup plate method. The inhibition zones were measured and compared with
the controls. The fungal activity of each compound was compared with Fluconazole as the
standard drug. Compounds 3b, 3e, 3g, and 3m showed very good antifungal activity. The
fungal zones of inhibition values are given in Table IV.
CONCLUSION
In conclusion, we have found out a very simple, efficient, and eco-friendly synthesis of
thiazoles under microwave irradiation. In addition, the biological activity results indicated
that several of the obtained compounds exhibit good or excellent antimicrobial activities.

MICROWAVE-ASSISTED THIAZOLE SYNTHESIS
107
EXPERIMENTAL
General
All solvents and chemicals were of research grade and were used as obtained from
Sigma-Aldrich, Alfa Aesar, and Acros Organics. Melting points were determined on an
Electrothermal 9100 apparatus, and are not corrected. Thin layer chromatography (TLC)
on commercial aluminum-blacked plates of silica gel 60PF254 was used to monitor the
progress of the reactions. The spots were visualized by heat staining with anisaldehyde
in ethanol/sulfuric acid. Column chromatography was performed with Merck silica gel
1
60 (0.063–0.200 mm). H and 13C NMR spectra were recorded on a Bruker DPX-400
instrument at 400 and 100 MHz, respectively. The chemical shifts δ were recorded in ppm
using TMS as an internal standard. IR spectra were recorded as KBr pellets or neat on a
Perkin Elmer Paragon 1000 spectrometer. Elemental analyses were obtained using a flash
EA 1112 Thermo Finnigan instrument. The mass spectra were recorded on a VG-S-70
micro mass spectrometer operating at 70 eV.
General Procedure for the Synthesis of Thiazole (3a–m)
A MW vial (5 mL) was charged with the α-bromoketone 1 (1.5 mmol) and
the thioamide or thiourea 2 (1mmol) and ethanol (3 mL). The vial was sealed and
heated at 80◦C (IR temperature detection) for 10 to 20 min under MW irradiation us-
ing an Emrys optimizer (an automated multiuser microwave synthesizer). If the reac-
tion was performed under conventional heating, the MW vial was immersed into a
preheated oil bath. In both cases, the reaction mixture was monitored by TLC. The
MW vial was opened, and the ethanol was evaporated in a Radleys GreenHouse Blow-
down Evaporator. The resulting product was directly charged on a silica gel column and
eluted with 10% ethyl acetate/cyclohexane to afford the pure 2,4-disubstituted thiazoles
3a–m.
Spectroscopic Data of the Thiazoles (3a–m)
2-Amino-4-(3,4-dichlorophenyl)-1,3-thiazole (3a). Faint green solid, mp
193–194◦C, IR: 3456, 3204, 1648, 1549, 1411, 1025 cm−1. 1H NMR (acetone-d6) δ 2.07
(s, 2H, NH2), 7.17 (s, 1H, thiazole), 7.60–7.88 (m, 3H, ArH); 13C NMR (acetone-d6)
δ 109.1, 118.2, 128.8, 130.23, 130.43, 130.95, 137.12, 147.25, 168.16. M+: 245. Anal.
Calcd. for C9H6Cl2N2S: C, 44.12; H, 2.48; N, 11.45; Found: C, 44.05; H, 2.43; N, 11.32.
2-Amino-4-(2,5-dichlorophenyl)-1,3-thiazole (3b). Brown solid, mp
152–155◦C, IR: 3446, 3210, 1630, 1542, 1413, 1035 cm−1. 1H NMR (acetone-d6) δ 2.08
(s, 2H, NH2), 7.10 (s, 1H, thiazole), 7.30–7.54 (m, 3H, ArH); 13C NMR (acetone-d6) δ
106.9, 118.25, 129.11, 130.26, 130.39, 131.33, 136.7, 147.70, 169.51. M+: 245. Anal.
Calcd. for C9H6Cl2N2S: C, 44.10; H, 2.46; N, 11.42; Found: C, 44.12; H, 2.49; N, 11.50.
2-Amino-4-(4-iodophenyl)-1,3-thiazole (3c). Pale yellow colored solid, mp
1
126–128◦C, IR: 3324, 3291, 1518, 1457, 1052 cm−1. H NMR (DMSO-d6) δ 3.64 (s,
2H, NH2), 6.95 (s, 1H, thiazole), 7.26 (d, 2H, ArH), 7.31 (d, 2H, ArH); 13C NMR (DMSO-
d6) δ 103.5, 115.7, 122.4, 127.4, 129.6, 131.3, 140.6, 155.8, 169.3. M+: 304. Anal. Calcd.
for C9H7IN2S: C, 35.78; H, 2.35; N, 9.26; Found: C, 35.71; H, 2.41; N, 9.33.
2-Amino-4-(3-bromophenyl)-1,3-thiazole (3d). Dark green solid, mp
1
130–133◦C, IR: 3325, 3204, 1518, 1464, 1047 cm−1. H NMR (MeOH-d4) δ 4.86 (s,

108
S. A. GAIKWAD ET AL.
2H, NH2), 6.99 (s, 1H, thiazole), 7.30–7.61 (m, 4H, ArH); 13C NMR (MeOH-d4) δ
103.25, 116.95, 117.3, 129.7, 130.2, 134.5, 138.8, 154.1, 170.0. M+: 255. Anal. Calcd. for
C9H7BrN2S: C, 42.37; H, 2.77; N, 10.98; Found: C, 42.31; H, 2.81; N, 11.05.
2-Amino-4-(3,4-dimethoxyphenyl)-1,3-thiazole (3e). Pale yellow colored
1
solid, mp 198–200◦C, IR: 3316, 3273, 1503, 1458, 1049 cm−1. H NMR (DMSO-d6), δ
3.01 (s, 2H, NH2), 3.64 (s, 6H, OCH3), 6.90 (s, 1H, thiazole), 7.09–7.14 (s, 3H, ArH); 13
C
NMR (DMSO-d6) δ 56.3, 56.1, 100.9, 111.9, 116.4, 120.9, 128.5, 149.3, 149.5, 151.4,
170.2. M+: 237. Anal. Calcd. for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.86; Found: C,
55.90; H, 5.14; N, 11.89.
2-Amino-4-(4-methoxyphenyl)-1,3-thiazole (3f). Yellow colored solid, mp
1
203–204◦C, IR: 3313, 3270, 1519, 1461, 1055 cm−1. H NMR (DMSO-d6) δ 3.04 (s,
2H, NH2), 3.68 (s, 3H, OCH3), 6.85 (s, 1H, thiazole), 7.3 (d, 2H, ArH); 13C NMR (DMSO-
d6) δ 56.35, 56.4, 100.1, 112.0, 116.1, 122.1, 128.7, 149.9, 151.0, 152.1, 170.5. M+: 207.
Anal. Calcd. for C10H10N2OS: C, 58.23; H, 4.89; N, 13.58; Found: C, 58.25; H, 4.93; N,
13.63.
2-Amino-4-(2-methoxyphenyl)-1,3-thiazole (3g). Yellow oil, IR: 3335, 3263,
1
1530, 1472, 910 cm−1. H NMR (DMSO-d6) δ 2.10 (s, 2H, NH2), 3.70 (s, 3H, OCH3),
6.96 (s, 1H, thiazole), 7.15–7.55 (m, 4H, ArH); 13C NMR (DMSO-d6) δ 56.75, 100.3,
112.1, 116.3, 122.4, 128.65, 149.96, 151.25, 152.5, 170.75. M+: 207. Anal. Calcd. for
C10H10N2OS: C, 58.23; H, 4.89; N, 13.58; Found: C, 58.30; H, 4.92; N, 13.61.
4-(3,4-Dichlorophenyl)-2-methyl-1,3-thiazole (3h). Pale yellow solid, mp
126–128◦C, IR: 2935, 1655, 1602, 1530, 1419, 1039, 1020 cm−1. 1H NMR (acetone-d6) δ
2.7 (s, 3H, CH3), 7.22 (s, 1H, thiazole), 7.66–7.95 (m, 4H, ArH); 13C NMR (acetone-d6) δ
34.1, 109.6, 118.26, 128.91, 130.2, 130.45, 131.1, 137.2, 147.28, 168.16. M+: 244. Anal.
Calcd. for C10H7Cl2NS: C, 49.20; H, 2.89; N, 5.74; Found: C, 49.25; H, 2.95; N, 5.80.
4-(3-Bromophenyl)-2-methyl-1,3-thiazole (3i). Pale yellow oil, IR: 2950,
1
1600, 1512, 1449, 1033 cm−1. H NMR (MeOH-d4) δ 2.65 (s, 3H, CH3), 7.00 (s, 1H,
thiazole), 7.35–7.67 (m, 4H, ArH); 13C NMR (MeOH-d4) δ 34.3, 103.25, 116.95, 117.3,
129.7, 130.2, 134.5, 138.8, 154.1, 170.0. M+: 255. Anal. Calcd. for C10H8BrNS: C, 47.26;
H, 3.17; N, 5.51; Found: C, 47.21; H, 3.10; N, 5.45.
4-(2-Chlorophenyl)-2-methyl-1,3-thiazole (3j). Brown oil, IR (neat): 2933,
1
1622, 1518, 1444, 1026 cm−1. H NMR (MeOH-d4) δ 2.64 (s, 3H, CH3), 7.02 (s, 1H,
thiazole), 7.30–7.64 (m, 4H, ArH); 13C NMR (MeOH-d4) δ 34.1, 103.3, 117.2, 118.25,
130.1, 130.6, 135.2, 138.9, 155.6, 170.1. M+: 210. Anal. Calcd. for C10H8ClNS: C, 57.28;
H, 3.85; N, 6.68; Found: C, 57.33; H, 3.91; N, 6.63.
Ethyl 4-(4-Nitrophenyl)-1,3-thiazole-2-carboxylate (3k). Yellow solid, mp
214◦C, IR: 1660, 1550, 1532, 1340, 1310, 1166, 834 cm−1. 1H NMR (acetone-d6) δ 1.24
(t, CH3), 4.18 (q, CH2), 7.20 (s, 1H, thiazole), 7.57 (d, 2 H, ArH), 8.10 (d, 2 H, ArH);
13C NMR (acetone-d6) δ 16.2, 62.7, 110.0, 121.1, 128.5, 133.3, 134.2, 135.0, 137.8, 151.2,
169.2. M+: 280. Anal. Calcd. for C12H10N2O4S: C, 51.79; H, 3.62; N, 10.07. Found: C,
51.80; H, 3.59; N, 10.10.
Ethyl 4-Phenyl-1,3-thiazole-2-carboxylate (3l). Yellow colored oil, IR (neat):
1651, 1600, 1523, 1325, 1175, 1088 cm−1. 1H NMR (acetone-d6) δ 1.27 (t, CH3), 4.20 (q,
CH2), 7.18 (s, 1H, thiazole), 7.33–7.43 (m, 3 H, ArH), 7.58–7.68(m, 2 H, ArH); 13C NMR
(acetone-d6) δ 15.1, 60.5, 109.0, 120.0, 129.9, 132.0, 133.2, 133.5, 138.1, 150.1, 169.2.
M+: 234. Anal. Calcd. for C12H11NO2S: C, 61.79; H, 4.75; N, 6.00. Found: C, 61.81; H,
4.79; N, 6.10.

MICROWAVE-ASSISTED THIAZOLE SYNTHESIS
109
Ethyl 4-(3,4-Dichlorophenyl)-1,3-thiazole-2-carboxylate (3m). Pale yellow
1
colored oil, IR (neat): 2850, 1657, 1611, 1516, 1500, 1301, 1168, 890 cm−1. H NMR
(acetone-d6) δ 1.25 (t, CH3), 4.18 (q, CH2), 7.16 (s, 1H, thiazole), 7.58–7.86 (m, 3H, 3H,
ArH); 13C NMR (acetone-d6) δ 14.7, 60.3, 108.9, 117.5, 128.7, 130.19, 130.4, 130.8, 137.2,
147.5, 168.4. M+: 303. Anal. Calcd. for C12H9Cl2NO2S: C, 47.70; H, 3.00; N, 4.64. Found:
C, 47.85; H, 2.94; N, 4.06.
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