Microwave Assisted Synthesis of Some Biologically Active Benzothiazolotriazine Derivatives

Synthesis of some biologically active benzothiazolotriazine derivatives by microwave irradiation is reported. 2-Amino-6-substituted benzothiazoles 1 on treatment with benzaldehyde in anhydrous ethanol afforded 2benzylidenoimino-6-substitutedbenzothiazoles 2 which underwent cyclisation with ammoniumthiocyanate in dioxane to give 2-phenyl benzothiazolo [3,2-α]-striazine-4-[3H] thiones 3.These both steps were carried out in microwave. Compound 3 with benzoyl chloride in anhydrous pyridine gave 2-phenyl-3(benzoyl) benzothiazolo [3,2-α]-s-triazine-4-thiones 4 in good yields. The structure of all these compounds have been supported by their elemental analysis and their spectral data. All synthesized compounds were tested for their antibacterial activity using standard drug.


Introduction
Heterocyclic compounds containing nitrogen and sulphur possess potential pharmacological activities [1][2][3][4] .Benzothiazole moiety constitute an important class of heterocyclic compounds possessing diverse type of biological activities viz.antibacterial 5 , fungicidal 6 , antituberculotic 7 ,antiallergic 8 ,anticancer 9 etc.Triazine derivatives are also associated with broad spectrum antibacterial 10 ,antifungal 11 , antiviral activity [12][13][14] against numerous viruses viz.Rauscher viruses, Leukemia Moloney viruses, Leukemia Rhinovirus type-2,influenza virus type-2,Vaccinia viruses, Vasicular stomatitis and Measules viruses.In view of the activities exhibit by benzothiazoles and triazines, we have reported synthesis of some new benzothiazolotriazine derivatives by conventional method in our earlier paper 15 .As a part of our continuing interest in biologically active benzothiazolotriazine derivatives, we are reporting a route for synthesis of these compounds by microwave irradiation.Traditional synthesis of compounds suffered from the disadvantages such as long reaction time, low yield and inconvenience of handling.In recent years the use of microwave technology in organic synthesis has received considerable attention.This technology can increase the purity of products, enhance the chemical yield and shorten the reaction time 16 .All synthesized compounds were tested for their antibacterial activity using standard drug.

Experimental
All the melting points are uncorrected.The purity of synthesized compounds has been checked by thin layer chromatography.IR spectra are recorded on FT-IR Perkin-Elmer (Spectrum RX1) spectrophotometer(ν max in cm -1 ) using KBr disc. 1 H NMR spectra are recorded in CDCl 3 on a Bruker DRX-300 MHz using TMS as internal standard.The chemical shifts are reported as parts per million (ppm).Microwave synthesis was carried out in a domestic microwave oven model L.G. MS-194W, 230-50 Hz., 800W.

Microwave synthesis of 2-benzylidenoimino-6-substitutedbenzothiazoles 2
A mixture of 2-amino-6-substitutedbenzothiazole 1 (0.001mol) and benzaldehyde (0.001 mol) in minimum quantity of anhydrous ethanol were taken in Erlen Meyer flask capped with a funnel placed in a microwave oven and irradiated at 160 Watt for 1 to 1.5 minutes.The reaction was monitered by silica gel TLC.(Benzene : Acetone 70 : 30).After completion the reaction , the reaction mixture was allowed to attain room temperature and solid separated was filtered.The crude product was recrystallized from redistilled ethanol.

Results and Discussion
The required 2-amino-6-substitutedbenzothiazoles 1 were prepared by methods reported in literature 17,18 .The synthesis of compounds 3 starting from 2-amino-6-substituted benzothiazoles 1 from conventional method was reported earlier 15 by us.The same reaction scheme was carried out under microwave conditions.It is noteworthy that the reaction which required 4 to 6 hours in conventional methods, was completed within 1 to 2 minutes under microwave conditions and yields have also been improved.Finally compounds 3 on treatment with benzoyl chloride in presence of anhydrous pyridine in acidified cold conditions gave compounds 4(Figure 1).All the synthesized compounds have been characterized on the basis of their physico-chemical data (Table 1) and spectral analysis.Compounds 3 and 4 contain chiral centre and thus exhibit optical activity.The products obtained after purification are dextrorotatory as observed by their optical activity in acetone solution.It seems that the laevo products are obtained in minor quantities and are removed during purification and crystallization.

Antibacterial Activity
All the synthesized compounds were screened for their antibacterial activity against E.Coli, Pseudomonas aeruginosa and Staphylococcus aureus using Muller Hinton Agar media (Hi Media).The activity was carried out using paper disc method.The zone of inhibition measured in mm.The results of antibacterial activity were tabulated (Table 2) in the form of activity index.

Activity index Zone of inhibition of compound in mm Zone of inhibition of standard drug in mm =
DMF was used as a solvent.Standard drug Ceftazidime(Ca)(30µg/ml) was used for comparison.The compounds were tested at 500µg/ml concentration.The observations show that activity index of compound 4c is maximum against E.Coli, activity index of compound 4b is maximum against Pseudomonas aeruginosa, activity index of compound 4c is maximum against Staphylococcus aureus.

Conclusion
In above synthetic scheme we use microwave irradiation technique, this leads to considerable saving in the reaction time and energetically profitable .The smaller volume of solvent required contributes to saving in cost and diminishes the waste disposal problem.Compounds 4b and 4c show potential antibacterial activity.

Table 2 .
Antibacterial activity of synthesized compounds