Synthesis and antifungal evaluation of hydroxy‐3‐phenyl‐2<i>H</i>‐1,3‐benzoxazine‐2,4(3<i>H</i>)‐diones and their thioanalogs

Abstract

Abstract magnified image A series of substituted 5‐, 6‐, 7‐, and 8‐hydroxy‐3‐phenyl‐2 H ‐1,3‐benzoxazine‐2,4(3 H )‐diones ( 5–8 ) was synthesized by cyclization of corresponding dihydroxy‐ N ‐phenylbenzamides ( 1–4 ) with methyl chloroformate. The starting compounds 1–4 were prepared by the reaction of the respective dihydroxybenzoic acid, aniline and phosphorus trichloride via microwave irradiation. Thionation of compounds 8a , 8b , 8c , 8d employing Lawesson's reagent was used to prepare 5‐hydroxy‐3‐phenyl‐4‐thioxo‐3,4‐dihydro‐2 H ‐1,3‐benzoxazin‐2‐ones ( 10a , 10b , 10c , 10d ) and 5‐hydroxy‐3‐phenyl‐2 H ‐1,3‐benzoxazine‐2,4(3 H )‐dithiones ( 11a , 11b , 11c , 11d ). The position of sulfur in monothionated derivatives 9c and 10a , 10b , 10c , 10d was confirmed by 2D NMR methods. Attempts to prepare dithionated derivatives from the isomeric 6‐, 7‐ or 8‐hydroxy compounds 5–7 failed. All compounds were tested for their in vitro antifungal activity against eight test strains. Compounds 1–4 showed moderate activity and the cyclization to corresponding hydroxy‐3‐phenyl‐2 H ‐1,3‐benzoxazine‐2,4(3 H )‐diones ( 5–8 ) resulted in a decrease in antifungal activity. No antifungal activity was observed in thionated compounds 9c and 10–11 . J. Heterocyclic Chem., (2009).