Green and Sustainable Chemistry, 2011, 1, 36-40
doi:10.4236/gsc.2011.12007 Published Online May 2011 (
Copyright © 2011 SciRes. GSC
An Efficient and Rapid Synthesis of
2-Amino-4-Arylthiazoles Employing Microwave
Irradiation in Water
Kishor S. Jain,* Jitender B. Bariwal, Muthu K. Kathiravan, Vikas K. Raskar,
Gajanan S. Wankhede, Nitin A. Londhe, Satish N. Dighe
P. G. Research Centre, Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Pune, India
Received March 26, 2011; revised April 26, 2011; accepted May 18, 2011
A facile, high yielding green chemical synthetic protocol adaptable to the parallel synthesis of a library of
potentially bioactive 2-amino-4-arylthiazoles is reported herein. The methodology involves the condensation
of various aracyl bromides with N-arylthioureas under MWI using water as solvent, to yield pure products
(81% - 97%) in very short reaction times (1-20 min).
Keywords: Green Chemical Synthesis, MWI, Water, 2-Amino-4-arylthiazoles
1. Introduction
Molecules containing a thiazole amine-moiety exhibit
interesting biological activities depending on the substi-
tution pattern at the thiazole ring [1]. 2-Aminothiazole
nucleus is a potential pharmacophore for a broad spec-
trum of activities, comprising of antibacterial [2], anti-
fungal [3], antitubercular [4], anti-HIV [5], pesticidal [6],
anti-inflammatory [7], antiprotozoal [8] etc. Several me-
thods reported for the synthesis of 2-aminothiazoles de-
rivatives include Hantzsch reaction [9], solid supported
[10] and solution phase [11] syntheses to generate librar-
ies of these derivatives, as well as, those employing cat-
alysts such as ammonium-molybdophosphate (AMP)
[12], β-cyclodextrin [13], iodine [14], siliyl chloride [15],
in organic as well as inorganic solvents at elevated tem-
peratures [16,17]. However, these methods suffer from
drawbacks like strong reaction conditions, low yields,
cumbersome product isolation procedures as well as the
use of expensive catalysts etc. The development of effi-
cient and eco-friendly chemical processes for the prepa-
ration these thiazole derivatives is still a major need.
In recent times, water has shown great promise as an
attractive alternative to conventional solvents (e.g., VOC’s)
[18]. It possesses the unique advantage of being costless
and environmental friendly. Water not only acts as reac-
tion media but also promotes the rate of reaction due to
its ability to form hydrogen bonding as well as solvation
Microwave Assisted Organic Synthesis (MAOS) has
shown high impact in enhancing the rates of reaction and
to speed up library syntheses for NDDR [19]. In recent
years, synthesis of bioactive heterocycles using micro-
wave irradiation has evolved as an important technique
of green chemistry [20]. Water with the additive effect of
microwave has been recognized as a green chemical com-
ponent in the MAOS.
In continuation to our research work devoted to the
development of green chemical techniques, we herein
report an efficient method for the synthesis of 2-amino-
4-arylthiazoles employing water as a solvent under MW
irradiation. This novel process allows access to a library
of 2-amino-4-arylthiazoles in very short reaction time
without affecting the yield and purity of the target com-
2. Experimental
All reagents and chemicals used were of LR grade and
purchased from standard vendors and used as received.
Microwave synthesizer; (Questron Technologies Corpo-
ration, Canada; model-ProM) having monomode open-
vessel was used for the synthesis. The 1H NMR spectra
were recorded in CDCl3 using NMR Varian Mercury
YH-300 MHz spectrometer and chemical shifts are given
in units as per million, downfield from TMS (tetrame-
thylsilane) as an internal standard. Mass spectra were
obtained on a Shimadzu GCMS-QP2010 spectrometer.
The Ultraviolet absorption spectra were determined in
methanol on JASCO (Japan) V-530, UV-Visible double
beam spectrophotometer. The IR spectra of the synthe-
sized compounds were recorded on Perkin Elmer (USA)
spectrum BX.FT-IR in potassium bromide discs.
2.1. Synthesis of Starting Materials
The substituted phenacyl bromides (1-4) [21] and sub-
stituted N-phenylthioureas (5-14) [22] were prepared by
reported procedures.
2.2. Synthesis of 2-phenylamino-4-phenylthiazole
(Ia-IVe) by Using Water as Solvent under
Microwave Irradiation (General Procedure)
In a 20 ml reaction vessel containing phenacyl bromide
(1 gm, 0.0036 mol) and N-phenyl thiourea (0.29 gm,
0.003 mol) was added water (5 ml). Thereafter, the reac-
tion mixture was irradiated under microwave (40 W) for
appropriate time (Table 1). The completion of reaction
was monitored by TLC, the solid separated was filtered,
washed with water and recrystallised.
3. Results and Discussion
Literature survey revealed that most of the reported con-
ventional routes, afford 2-amino-4-arylthiazoles in 72% -
80% yields in an overall reaction time of 6 - 18 hr. We
aimed at preparing these compounds employing green
chemical synthetic procedures which could be adaptable
to parallel syntheses for making compounds libraries. An
efficient method using water as solvent for the synthesis
of 2-amino-4-arylthiazoles under MWI is reported herein.
Phenacyl bromides carrying different functional groups
such as EDG and EWG were subjected to study their
reaction with various N-aryl thioureas. The results are
presented in Table 1. The reaction protocol affords good
overall yields (81% - 97%) and in very short reaction
time (01-20 min) (Sc heme 1).
Water when used as a solvent under MWI promotes the
Scheme 1. Synthesis of 2-amino-4-aryl-thiazoles.
reaction through hydrogen bond formation with carbonyl
oxygen of the phenacyl bromide in presence of micro-
wave energy. This leads in the enhancement of electro-
philicity of the carbonyl carbon and facilitates the nu-
cleophilic attack by the amino nitrogen of the thioamide.
This is further followed by the intramolecular nucleo-
philic attack by the sulphur on the bromomethyl carbon,
leading to the formation of thiazole through the removal
of an HBr molecule (Scheme 2).
Thus, we have been successful in developing a rapid
Br N
Scheme 2. Proposed mechanism for the synthesis of thiazole.
green chemical synthetic procedure which can be made
adaptable to high throughput parallel synthesis of com-
pound libraries of 2-amino-4-arylthiazoles with an
added advantage of considerable improvement in the
yields of the target compounds without affecting their
4. Conclusions
We have developed a mild, convenient, ecofriendly and
efficient protocol for the rapid synthesis of 2-substitu-
tedarylamino-4-substitutedarylthiazoles. The process
offers excellent yields of 2-substitutedarylamino-4-sub-
Copyright © 2011 SciRes. GSC
38 K. S. JAIN ET AL.
Table 1. Physical data for the 2-arylamino-4-arylthiazoles (Ia-IVe).
No. Ar1 Ar2NH Time (min) M. P. (˚C) Yield (%)
Ia C6H5 C
6H5 10 134-135 88
Ib C6H5 4-ClC6H4 15 148-150 90
Ic C6H5 4-CH3C6H4 15 115-116 87
Id C6H5 4-NO2C6H4 15 202-203 91
Ie C6H5 4-FC6H4 15 90-91 89
If C6H5 2-ClC6H4 10 75-77 96
Ig C6H5 3-ClC6H4 2 85-87 88
Ih C6H5 2-CH3C6H4 2 104-106 85
Ii C6H5 3-CH3C6H4 2 137-140 85
Ij C6H5 4CH3OC6H4 1 147-159 95
IIa 4-ClC6H4 C
6H5 15 137-138 86
IIb 4-ClC6H4 4-ClC6H4 10 231-232 87
IIc 4-ClC6H4 4-CH3C6H4 15 168-170 86
IId 4-ClC6H4 4- NO2C6H4 15 253-255 85
IIe 4-ClC6H4 4-FC6H4 20 169-170 82
IIf 4-ClC6H4 2-ClC6H4 20 132-134 83
IIg 4-ClC6H4 3-ClC6H4 1 144-146 98
IIh 4-ClC6H4 2-CH3C6H4 5 108-110 93
IIi 4-ClC6H4 3-CH3C6H4 1 190-192 97
IIj 4-ClC6H4 4CH3OC6H4 1 160-162 94
IIIa 4-BrC6H4 C
6H5 15 103-104 88
IIIb 4-BrC6H4 4-ClC6H4 15 140-142 84
IIIc 4-BrC6H4 4-CH3C6H4 20 129-130 87
IIId 4-BrC6H4 4-NO2 C6H4 15 244-246 81
IIIe 4-BrC6H4 4-FC6H4 15 107-108 82
IVa 4-CH3C6H4 C
6H5 20 92-93 89
IVb 4-CH3C6H4 4-ClC6H4 20 71-72 84
IVc 4-CH3C6H4 4-CH3C6H4 20 44-45 87
IVd 4-CH3C6H4 4- NO2C6H4 20 73-75 90
IVe 4-CH3C6H4 4-FC6H4 20 103 88
Representative Data of Target Compounds:
2-(2-Chlorophenyl)amino-4-phenylthiazole If: 1HNMR (400 MHz, CDCl3): δ 6.92(1H, s, NH D2O exchangeable); 7.27 - 8.29(10H, m, Ar-H and thia-
zole proton at 5). IR (KBr) cm–1: 3206[NH], 3065[C-H]. m/z 286(M+). Anal. Calcd. for C15H11ClN2S: C, 62.82; H, 3.87; N, 9.77; found C, 62.76; H, 3.71;
N, 9.93;
2-(4-Chlorophenyl)amino-4-(4-chlorophenyl)thiazole IIb: 1HNMR (400 MHz, CDCl3): δ 6.77(1H, s, NH D2O exchangeable); 6.99-7.98(9H, m,
Ar-H and thiazole proton at 5). IR (KBr) cm–1: 3335[NH], 2922[C-H]. m/z 323 (M+2). Anal. Calcd. For C15H10Cl2N2S: C, 56.09; H, 3.14; N, 8.72; found
C, 55.82; H, 3.11; N, 8.86;
2-(4-Fluorophenyl)amino-4-(4-chlorophenyl)thiazole IIe: 1HNMR (400 MHz, CDCl3): δ 6.71(1H, s, NH D2O exchangeable); 7.08-7.99 (9H, m, Ar-H
and thiazole proton at 5). IR (KBr) cm1: 3251[NH], 3065[C-H]. m/z 304 (M+). Anal. Calcd. for C15H10ClFN2S: C, 56.11; H, 3.31; N, 9.19; found C,
56.05; H, 3.24; N, 9.11;
2-(4-Methox ylp h en yl )ami no-4-(4-chlorop henyl)thiazole IIj: 1HNMR (400 MHz, CDCl3): δ 3.85(3H, s, CH3), 6.64(1H, s, NH D2O exchangeable); 6.95 -
7.75 (9H, m, Ar-H and thiazole proton at 5). IR (KBr) cm–1: 3401[NH] 3164[C-H]. m/z 316( M+). Anal. Calcd. for C16H13ClN2OS: C, 60.66; H, 4.14; N,
8.84; found C, 60.36; H, 4.03; N, 8.67;
2-(4-Chlorophenyl)a mino-4-(4-bromophenyl)thiazole IIIb: 1HNMR (400 MHz, CDCl3): δ 6.64(1H, s, NH D2O exchangeable); 7.25-7.71(9H, m, Ar-H
and thiazole proton at 5). IR (KBr) cm–1: 3367[NH], 2935[C-H]. m/z 366 (M+). Anal. Calcd. for C15H10BrClN2S: C, 49.27; H, 2.76; Br, 21.85; N, 7.66;
found C, 49.01; H, 2.48; N, 7.54;
2-(4-Methylphenyl)amino-4-(4-methylphenyl)thiazole IVc: 1HNMR (400 MHz, CDCl3): δ 2.38(6H, s, CH3); 6.57(1H, s, NH); 7.2-7.7(9H, m, Ar-H and
H- of thiazole). IR (KBr) cm–1: 3437[NH], 2923[C-H]. m/z 280(M+). Anal. Calcd. for C17H16N2S: C, 72.82; H, 5.75; N, 9.99 ; found C, 72.76; H, 5.59; N,
2-(4-Fluorophenyl)amino-4-(4-methylphenyl)thiazole IVe: 1HNMR (400 MHz, CDCl3): δ 2.40 (3H, d, CH3); 6.69(1H, s, NH); 6.9 - 8.0 (8H, m, Ar-H);
7.99 (1H, s, thiazole H). IR (KBr) cm1: 3144[NH], 2923[C-H]. m/z 284(M+). Anal. Calcd. for C16H13FN2S: C, 67.58; H, 4.61; N, 9.85; found C, 67.48;
H, 4.56; N, 9.69;
Copyright © 2011 SciRes. GSC
Copyright © 2011 SciRes. GSC
stitutedarylthiazoles under green chemical conditions in
very short reaction times.
5. Acknowledgments
The authors acknowledge the contributions of Professor
M. N. Navale, President, & Dr. (Mrs.) S. M. Navale,
Secretary, Sinhgad Technical Education Society, Pune
for providing facilities to carry out the synthetic work
and basic spectroscopic analysis. The Mass and NMR
were done at Department of Chemistry, Saurashtra Uni-
versity, Rajkot, India and University of Pune, India, re-
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