An Efficient and Rapid Synthesis of 2-amino-4-arylthiazoles Employing Microwave Irradiation in Water

doi:10.4236/gsc.2011.12007

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Green and Sustainable Chemistry, 2011, 1, 36-40

doi:10.4236/gsc.2011.12007 Published Online May 2011 (http://www.SciRP.org/journal/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

E-mail: [email protected]

Received March 26, 2011; revised April 26, 2011; accepted May 18, 2011

Abstract

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

effect.

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-

pounds.

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-

K. S. JAIN ET AL.

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

Ar1

NH2

Ar2

MWI

Ar1

Br N

Ar2

Ar1

Ar2

-HBr

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

purity.

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-

38 K. S. JAIN ET AL.

Table 1. Physical data for the 2-arylamino-4-arylthiazoles (Ia-IVe).

By MWI-H2O

Com.

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) cm−1: 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,

9.84;

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) cm−1: 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;

K. S. JAIN ET AL.

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-

spectively.

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