Microwave-Induced Synthesis of Schiff Bases of Aminothiazolyl Bromocoumarins as Antibacterials

A fast and highly efﬁ cient method for the synthesis of some of the schiff bases of aminothiazolylbromocoumarin (4a-m) has been performed by microwave irradiation of 2'-amino-4'-(6-bromo-3-coumarinyl) thiazole (3) and substituted aromatic aldehydes (a-m). Microwave assisted reactions have resulted in better yields of the desired products than when prepared under conventional conditions. The resulting products were evaluated for their qualitative and quantitative antibacterial activity.

The synthesis of coumarins and their derivatives has attracted the attention of organic and medicinal chemists as these are widely used as fragrances, pharmaceuticals and agrochemicals 1 . Benz-2pyrones and its heterocyclic derivatives, in particular schiff bases and carboxamides of 3-thiazolyl substituted coumarins, display important biological properties such as analgesic, anti-inflammatory 2,3 , anticoagulant 4 , antimicrobial, antiviral 5 and HIV quantitative antibacterial activity by cup plate method and ELISA technique, respectively.
Melting points were determined in open capillaries and are found uncorrected. IR spectra were recorded on Fourier transform IR spectrophotometer Model Shimadzu 8700 using KBr disc method. 1 H-NMR spectra were recorded on AMX-400 liquid state NMR spectrometer in CDCl 3 using tetramethylsilane as an internal standard. Mass spectra were recorded on Jeol JMS DX303 Mass spectrometer with Electron Impact Ionization (EII). The purity of the products was determined by thin layer chromatography using several solvent systems of different polarity. The compounds were analyzed for C, H and N and the values were found within ±0.4% of the calculated values. The microwave oven used was conventional kitchen microwave oven. The yield and reaction time of the products are reported in Table 1.
The synthesis of 2'-amino-4'-(6-bromo-3-coumarinyl) thiazole 2 (3) was achieved by cyclization of 3-bromoacetyl-6-bromocoumarin (2) with thiourea in absolute ethanol medium in the presence of piperidine as catalyst and the resulting compounds (4a-m) were obtained by microwave irradiation of compound (3) and different aromatic aldehydes (a-m) in absolute ethanol with different time intervals. The synthetic route is shown in Scheme 1.
In conventional refluxing method (method A), compound (3) (0.01 mol) and substituted aromatic aldehydes (a-m) (0.01 mol) were taken in absolute alcohol (20 ml) and refluxed for 2 h, cooled and poured into crushed ice. The precipitate obtained was recrystallized using aqueous dimethyl sulfoxide and ethanol. protease inhibitory 6 activities. Potent antibiotics like novobiocin, coumaromycin and charteusin are coumarin derivatives. Consequently, we were involved in the synthesis and chemistry of schiff bases and carboxamides of aminothiazolyl substituted coumarins. As a continuation of our research in this area, the present work was aimed at the synthesis of schiff bases of 2-amino thiazolyl bromocoumarin by microwave-assisted method. Microwave irradiation has become a very useful tool in organic synthesis and has been explored extensively since the last decade. Microwave irradiation often leads to a remarkable decrease in reaction time, increased yields and easier workup matching with green chemistry protocols. The resulting compounds of Scheme 1 were characterized by 1 H-NMR and mass spectral studies. X-ray study was made on parent compound (3) (3)  4a  62  57  88  120  120  105  4b  71  60  89  90  90  66  4c  58  53  73  120  120  110  4d  60  55  77  120  120  110  4e  66  64  82  150  150  108  4f  66  64  83  90  90  70  4g  69  63  89  120  120  100  4h  64  62  80  120  120  103  4i  68  64  87  60  60  65  4j  62  60  89  120  120  100  4k  78  74  91  90  90  68  4l  67  63  85  120  120  113  4m  64  61  81  120  120  watts. On completion of the reaction, followed by TLC examination, the mixture was cooled to room temperature and the product was poured into crushed ice. The crude products (4a-m) were purified by recrystallization from ethanol and dimethyl sulfoxide. The characterization data of the synthesized test compounds (4a-m) are tabulated in Table 2. Antibacterial screening of the synthesized compounds was carried out by cup-plate method 7 using two strains i.e., Bacillus subtilis (ATCC 6633) and Escherichia coli (ATCC 8739). Ampicillin was used as reference sample and antibacterial activity of the test compounds (4a-m) is presented in Table 3.

Comp. No. Yield (%) Reaction period (min) Method A (conven) Method B (conven) Method C (MORE a ) Method A (min) Method B (min) Method C (sec)
The minimum inhibitory concentration of the test compounds showing promising activity was determined using 96-well plate (two fold dilution technique) and an ELISA Reader 8 .