An expeditious synthesis of methyl 5-(2-amino 4-arylthiazolyl) acetates using microwave irradiation

: 2,4,5-Trisubstituted thiazole derivatives can be prepared conveniently by condensation or methyl 3-bromo-3-aroyl propionates with thiourea and (un)substituted phenyl thiourea under microwave irradiation in good yields. The structures of the newly synthesized compounds are characterized by spectral data and elemental analysis.

Thiazole derivatives are reported to show a broad spectrum of biological activity, which includes antimicrobial 1 , antidiabetic 2 , analgesic and anti-inflammatory 3 activities. The introduction of thiazole ring improved the activity as in meloxicam in the oxicam series of anti-inflammatory drugs 4 . Thiazoles are easily metabolized by routine biochemical reactions and are noncarcinogenic in natureS. In view of their safety and importance, there is a continuing interest in developing versatile synthetic routes. Generally, 2-aminothiazoles are synthesized by the condensation of a halo carbonyl compound with thiourea, known as Hantzsch synthesis6 and has a wide scope, permitting the synthesis of a variety of thiazole derivatives.

Results and discussion
The methyl 3-aroylpropionates le-d were prepared in better yields by irradiating a mixture of 3-aroylpropionic acids la-b, concentrated sulphuric acid and methanol in open glass containers using unmodified household microwave oven in 1.5 min. This procedure considerably reduces the long~r reaction time (7 hours of refluxing 1~ usually encountered in traditional ester synthesis. The acid is then brominated to methyl 3-bromo-3-1276 aroylpropionate 2a-b. The reaction of 3-bromo-3aroylpropionate with (un)substituted phenyl thiourea 3ai in methanol at reflux resulted in the formation of thiazoles acetates 4a-i and 4j-r with 65-78% yield in 60-75 min. However, when the reaction was performed in PEG-400 in microwave oven the reaction time was reduced to 0.5-1.5 min and the yield rose to 85-95%. The reaction mixture was exposed to the microwave irradiation in an open vessel covered with stemless glass funnel at lower power (540 W). The long neck of glass vessel remains cool since glass is transparent to microwaves. A beaker of water was kept near the reaction vessel to serve as "heat sink" to provide fine control of the temperature of the reaction mixture 11 . We have also attempted the above reaction in PEG-200, ethylene glycol, diethylene glycol, DMSO, isopropyl alcohol and without any solvent ( Table 1). The maximum yield of the desired product was obtained when the reaction was performed in PEG-400.
To test the generality of the reaction a variety of phenyl thioureas (3a-i) were condensed with bromo propio-nate& in PEG-400 under microwave irradiation to form the corresponding methyl 4-aroyl-2-arylamino thiazolyl acetates (Table 2). When two electron withdrawing groups were placed in phenyl thiourea 3 the yields of substituted thiazolyl acetates 4g-h and 4p-q were slightly less and the rate of reaction was also slower.

Experimental
Melting points are uncorrected and were recorded in liquid paraffin bath using open end capillaries. Thin layer chromatography was performed on silica gel G. A simple household microwave (BPL Sanyo India) oven (900 W) equipped with a turntable was used for irradiation. The IR spectra were run on Shimadzu FT IR spectrophotometer in KBr pellets. 1H NMR spectra were obtained using Jeol GSX-400 FT NMR 400 MHz in CDC1 3 /DMSO-d6 solvent using TMS as internal reference. Mass spectra were recorded by Jeol-JMS-300 spectrometer at 70 eV.

Note
Methyl 3-(4-ch/orobenzoyl)propionate (lc) : 3-(4-Chlorobenzoyl)propionic acid la (2.1 g, 10 mmol ), dry methanol (20 ml) and concentrated sulphuric acid (0.5 ml) were taken in a long neck conical flask covered with stemless funnel to avoid excessive evaporation. The resulting mixture was irradiated in a domestic microwave oven at 200 W for 1.5 min. After that the reaction mixture was cooled to room temperature and poured into ice cold water. The ester lc was extracted into ether and washed with water, sodium bicarbonate solution and the ether layer was separated, dried and distilled off to get methyl3-(4-chlorobenzoyl)propionate lc (m.p. 62-63 °C, 96%, Jit. 12 m.p. 63 °C, 75%).