Synthesis and Antibacterial Activity of 2-( 2-( Cyclopropylmethoxy ) Phenyl )-5-Methyl-1 , 3 , 4-Oxadiazole

Heterocyclic compounds containing the five-membered oxadiazole nucleus possess verity of biological activities. 1,3,4oxadiazole moieties are important because of their versatile biological action. The present study depicts synthesis of some novel 2-(2-(cyclopropylmethoxy)phenyl)-5methyl-1,3,4oxadiazole was prepared from N’-acetyl-2-(cyclopropylmethoxy)benzohydrazide by using triphenylphosphine, triethylamine, carbon tetrachloride and acetonitrile at 100°C for 1h. The final compound was examined for its antibacterial activity.

The common methods used for the synthesis of 1,3,4-oxadiazoles involves the cyclization of the carboxylic acid hydrazides with a variety of dehydrating reagents such as POCl3, concentrated sulfuric acid, phosphonium salts and Burgess-type reagents.

Reagents and Instrumentation
All reagents were purchased from Merck and Aldrich and used without further purification.The NMR spectra were recorded on a Bruker Avance DPX 400 MHz instrument.The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm).Elemental analysis was performed on a Heraeus CHN-O-Rapid analyzer.TlC was performed on silica gel Polygram SIl G/UV 254 plates.

Experimental Procedure Preparation of ethyl 2-hydroxybenzoate
Thionyl chloride (20 ml, 0.275 mmol) was added dropwise to a stirred solution of salicylic acid (10 g, 0.0724 mmol) in ethanol (50 ml) at 0°C and the mixture was stirred for 12h at 80°C.After completion of starting material (TlC monitoring), the reaction mixture was concentrated to remove the unreacted thionyl chloride and ethanol under reduced pressure.
The residue was diluted with water and extracted with MTBE solvent .The organic layer was washed with an aqueous solution of NaHCO3 (10%), dried with sodium sulfate and concentrated under reduced pressure to obtain the pure product as a brown color liquid (Yield: 65%).

Preparation of 2-hydroxybenzohydrazide
Hydrazine monohydrate (20 ml) was added to a solution of ethyl 2-hydroxybenzoate (4 g, 0.024 mmol) in ethanol (100 ml) at room temperature and the reaction mixture was heated to 80°C and and stirred for 2h at same temperature.After completion of the reaction (TlC monitoring), ethanol was concentrated.To that residue ice cold water was added and stirred for 30 min until a white color solid was precipitated.The white solid was filtered and dried under vacuum (Yield 70%).

Preparation of N'-acetyl-2-hydroxy benzo hydrazide
A mixture of 2-hydroxybenzohydrazide (2.5 g, 0.016 mmol) and acetic acid (25 ml) was heated to 80°C and stirred for 2h.After completion of the reaction (TlC monitoring), the mixture was poured into ice cold water and stirred for 15 min until a white color solid was precipitated.The solid was filtered and dried under vacuum (Yield 56%). 1

Preparation of N'-acetyl-2-(cyclopropylmethoxy) benzohydrazide
To a s o l u t i o n o f N ' -a c e t y l -2hydroxybenzohydrazide (1 g, 0.0051 mmol) in acetonitrile: water (9:1) (10 ml) was added potassium carbonate (1.97 g, 0.015 mmol) and stirred for 15 min at room temperature.To this solution (bromomethyl) cyclopropane (0.83 g, 0.0061 mmol) was added dropwise and the reaction mixture heated at 90°C for 12 h.After1 consumption of starting material, acetonitrile was concentrated, then residue was diluted with water and extracted with ethyl acetate.Organic layer was dried over sodium sulphate and concentrated under reduced pressure to get off white semi solid.This crude was treated with hexane at 0°C and precipitated solid was filtered off to obtain the white solid (Yield 42%).
In summary, 2-(2-(cyclopropylmethoxy) phenyl)-5-methyl-1,3,4-oxadiazole was successfully synthesized in five steps in good yield and was used for antibacterial activity against Gram-positive and Gram-negative bacteria.In comparison with Gentamicin, the compounds show relatively a good antibacterial activity.