An Efficient Synthesis of Thiazolo and Thiadiazolo Quinoxaline Derivatives in Ionic Liquid

A series of 3-substitutedphenyl-1-thia-tetrazopentaleno[1,2-b] naphthalene 4(a-d) and 2-substitutedphenyl-1-thia-pentazopentaleno[1,2-b] naphthalene 5(a-d) were synthesized via., the reaction of 2-aminothiazoles 2(a-d) and 2-aminothiadiazoles 3(a-d) with 2,3-dichloro quinoxaline 1 in ionic liquid without using any catalyst. This protocol has the advantages of easier workup, milder reaction conditions, high yields, and environmentally benign procedure over traditional methods. The synthesized compounds 4(a-d) and 5(a-d) tested for their anti-fungal activity and these compounds were characterized by IR, NMR and Mass spectral analysis.


Introduction
Compounds containing the quinoxaline nucleus exhibit abroad spectrum of biological activity such as, anti-viral 1 , antiinflammatory, antiprotozoal 2 , antihelminthic 3 , anticancer 4 , antimalarial 5 , and antidepressant activities 6 .Some of the antibiotics such as levomycin, actinoleutin, and echinomycin also contain a quinoxaline scaffold and these are known to inhibit the growth of gram positive bacteria 7 and are active against various transplantable tumours 8 .Besides the biological activities, quinoxalines are also used in the synthesis of organic semiconductors, dyes 9 , and electroluminescent materials 10 .Some of quinoxalines exhibit potent central nervous system (CNS) activities such as analgesic and antiinflammatory activities 11 .Few of azolopyrimidoquinaxalines, pyrimidoquinazolines exhibited good antioxidants, anti-inflammatory, and analgesic activities [12][13][14][15] .Furthermore, organic compounds bearing thiazolopyrimidines and pyridothiazolo quinoxaline nuclei were found to possess potent anticancer activities 16 .These biological applications and development of new route to heterocyclic systems in ionic liquid prompted us to synthesize some new heterocyclic derivatives having phenylthiazoles, thiadiazoles, and quinoxaline moieties starting from 2, 3-dichloro quinoxaline in ionic liquid without using any catalyst and search of better anti-fungal activity.(Schemes 1 & 2).

Experimental
Melting points were measured in open capillary on Buchi melting point B-540 apparatus and were uncorrected.IR spectra were recorded on Simadzu FTIR-8400 spectrometer using KBr pellets. 1 H NMR (300 MHz) spectra recorded in DMSO-d 6 on a Bruker AVANCE 300 instrument with the TMS as an internal standard.All the chemical shifts values were recorded as δ ppm.Mass spectra (EI-MS) were taken on Perkin Elmer (SCIEX API-2000, ESI) at 12.5 eV.CHNS analysis was carried out on Carlo Erba E A 1108 automatic analyzer.The progress of each reaction was monitored and purity of the compounds was checked by thin layer chromatography.

Antifungal Activity
The antifungal activity 19 was assayed by sabouraud dextrose agar media plate disc diffusion method at the concentration of 50 μg per disk.All the synthesized compounds were tested in vitro for their antifungal activity against microorganisms such as Candida albicans, Microsporium gypsum and microsporium canis.Each test compound was dissolved in dimethylsulphoxide (DMSO) to get a concentration of 10 mg/mL.The disc (6 mm in diameter was impregnated with 5 μ L of each test solution to get 50 μg/mL; air dried and placed on the sabouraud dextrose agar media, previously seeded with 0.2 mL of broth culture of each organism for 18 h.The plates were incubated at 22 0 C for 48 h and the inhibition zones were measured in mm.Discs impregnated with DMSO were used as a control and flucanazole disc as antifungal reference standard.

Results and Discussion
Choosing an appropriate solvent is of crucial importance for the successful organic synthesis, Room temperature ionic liquids, especially those based on 1-alkyl-3methylimidazoliumcations have shown great promise as an attractive alternative to conventional organic solvents and more attention has been currently focused on organic reactions prompted by ionic liquids 20 .They are nonvolatile, recyclable, non explosive, easily operable, and thermally robust 21 .To search for the optimal reaction solvent, the reaction of 2,3-dichloroquinoxaline 1 with substituted 2-aminothiazoles 2(a-d) and substituted 2-aminothiadiazoles 3(a-d) were examined using ionic liquid such as [bmim]BF 4 and conventional reaction solvent such as acetic acid at different reaction temperatures.The results are summarized Table 1.It can be seen from Table 1 that the best result was obtained when the reaction was carried out in [bmim] BF 4 at 80 o C. It was chosen as solvent for the reactions as it is environmentally friendly and the toxic organic reagents can be avoided, Under these optimized reaction conditions a series of 3-substituted phenyl-1-thia-

Antifungal Activity
The antifungal activity was determined by the disc diffusion method at the concentration of 50 per disk.All the synthesized compounds were tested in vitro for their antifungal activity against microorganisms such as Candida albicans, Microsporium gypsum, and Microsporium canis, using flucanazole as standard antifungal.The compounds 4b and 5b were highly active.Compounds 4a and 5a were inactive, while rest of the compounds showed moderate activity.

Conclusion
We developed an efficient and economical safe and environmentally benign procedure for synthesis of 3-substituted phenyl-1-thia-tetrazopentaleno-

Table 1 .
Results of anti-fungal activity.

Table 1 .
Solvent and temperature optimization for the synthesis of 4(a-d) and 5(a-d).reaction temperature at 80 o C, b reaction temperature at reflux. a