Design, Synthesis and Antibacterial studies of 2.6-Benzoxazoles

INTRODUCTION

Benzoxazoles are considered as the unique heterocyclic systems because of the structural similarity with various naturally occurring biological components.¹ Tremendous biological activities of these agents have been reported such as antibacterial , antifungal, antiviral, anti tubercular, anticancer, anti-inflammatory, antioxidant, ant parasitic have been reported.² Many synthetic approaches were developed by treating o-aminophenols with aryl acids³ , aryl alcohols⁴ , aryl aldehydes⁵ , β-diketones⁶ , isocyanides^7-10 utilising various catalysts and varying reaction temperatures and solvent conditions. One pot synthetic procedures have gained importance in the development of biological molecules as they are simple, efficient and low time consuming.¹¹ So an attempt was made to synthesise benzoxazoles (figure.1) from substituted o-aminophenols and hydroxymoyl chlorides in presence of ethyl acetate in a single step which afforded products in good yield. Ethyl acetate served as a good catalyst and solvent in cyclization mechanism and was easily removed from the reaction mixture.¹²

MATERIALS AND METHODS

Chemicals grade AR used in present investigation were procured from Aldrich chemicals, Avra chemicals. Infrared spectra were recorded on Perkin Elmer Model 283B FT-IR instrument and values are given in cm-1. Proton magnetic resonance spectra were recorded on Avance-300 MHz Bruker UX-NMR instrument. The samples were made in CCl4 / chloroform-d (1:1) or DMSO-d6 using tetra methyl silane (Me4Si) as the internal standard and are given in the δ scale. Analytical thin layer chromatographic (TLC) was performed on pre coated silica gel-60 F254 (0.5 mm) glass plates in ethyl acetate and hexane solvent system. Visualization of the spots on TLC plates was achieved by exposing to iodine vapors and ultraviolet light. All solvents used for gel column chromatography were distilled prior to use. Silica gel used was 100-200 mesh & 60- 120 mesh. Cultures of five bacterial strains gram positive (Bacillus cereus, staphylococcus aureus) and gram negative (Eschericia Coli, Salmonella typhi Pseudomonas aeruginosa) were used for antibacterial studies and were sub cultured prior to testing.

Procedure for synthesis of 2,6-disubstituted benzoxazoles:^13-14

To a stirring solution of (0.3 mol) substituted o-aminophenol, (0.5 ml) of substituted hydroxycarbomoylchoride and 1ml of ethyl acetate were added and refluxed at 600 C for 30 m. The completion of reaction was checked by performing TLC. Then the reaction mixture was filtered, made free from impurities, ethyl acetate by multiple washings using water and recrystallised from methyl alcohol and obtained it in its purest form.

RESULTS AND DISCUSSION

Herein we report the one pot synthesis of 2, 6 disubstituted benzisoxazoles 3(a-l) from o-aminophenol and hydroxymoyl chloride in presence of ethyl acetate in a single step procedure (table.1). The reaction conditions were optimised by conducting the reaction conditions using various solvents and varying temperatures (table.2). Among them the usage of ethyl acetate was proved to be efficient in providing reaction products in good yield.¹² Benzoxazole derivatives were prepared by varying substituent groups at 2 and 6 positions. The structural characterisation of the synthesised series of compounds was achieved by using IR and 1 HNMR spectroscopic methods and shown characteristic peaks in the spectrum. The spectral data of the synthesised compounds clearly show that 2,6 disubstituted benzoxazoles can be prepared from condensation of o-aminophenol and hydroxymoyl chlorides in presence of ethyl acetate.

The synthesised derivatives were evaluated for antibacterial activity using different strains of bacterial species. Among them compounds possessing electron withdrawing groups (3d, 3e, 3f, 3g, 3h, 3i) exhibited potent activity than other compounds.

SPECTRAL DATA

3a. 2-phenyl-1,3 benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 1600-1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.5 (4H, m, Ar) 7.2 (5H, m, Ar)

3b. 2 (4-methyl phenyl)-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.5 (4H, m, Ar), 6.0 (2H, d, Ar), 7.0 (2H, m Ar), 1.15 (s, 3H, CH3-Ar)

3c. 2 (4-ethyl phenyl)-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.5 (4H, m, Ar), 6.0 (2H, d, Ar), 7.0 (2H, m Ar), 2.59 (2H, q, CH2) 1.5(3H, t, CH3)

3d. 6-chloro 2-methyl-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 742(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 3.9(s, 3H, CH3)

3e. 2-isopropyl 6-chloro-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 742(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 2.5(s, -CH), 1.2(d, 6H, -2CH3)

3f. 2-ethyl 6-chloro-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 742(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65 (d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar, 2.59 (2H, q, CH2) 1.5(3H, t, CH3)

3g. 2-(4 chlorophenyl) 6-methyl-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 742(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 7.82(d, 2H, Ar) 7.3 (d, 2H-Ar) 23.9(s, 3H, CH3-Ar)

3h. 2-(3.4-dichlorophenyl) 6-methyl -1,3 -benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 1975-1908(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 7.9(d, 1H, Ar), 7.4(d, 1H, Ar), 7.6(s, 1H, Ar) 3.9(s, 3H, -CH3, Ar)

3i.2-(2,3,4 trichlorophenyl) 6-methyl-1,3 benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str), 1975-1908(C-Cl)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 7.3(d, 2H-Ar)

3j. 2-acetyl 6-methyl-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 3.9(s, 3H, CH3-Ar) 2.24(3H, s, COCH3).

3k) 2-acetyl 6-ethyl-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 2.59(2H, q, CH2) 1.5(3H, t, CH3) 2.24(3H, s, COCH3).

3l) 2-acetyl 6-propyl-1,3-benzoxazole

(IR (cm−1): 3066 (Ar-C-H), 2920, (alkyl-C- H), 1600- 1420 (C-C), 1634 (C=N), 1100 (C-N), 1257 (C-O str)

¹ H NMR (DMSO-d6) δ ppm: 7.65(d, 1H, Ar), 7.9 (d, 1H, Ar), 7.4 (m, 1H, Ar), 2.59(2H, q, CH2)1.3(2H, s.CH2)1.5(3H, t, CH3) 2.24(3H, s, COCH3

CONCLUSION

In present investigation, we have developed a simple, short and efficient method for the synthesis of 2,6-disubstituted benzoxazoles from aromatic amines and hydroxymoyl chlorides in presence of ethyl acetate in a single step procedure which afforded reaction mixtures in good yields. 12 benzoxazole derivatives were synthesized and structurally characterized using IR, and 1 H NMR spectroscopic methods. The synthesized compounds were also screened for antibacterial activity and shown satisfactory results.