Synthesis and Antibacterial Activity of Novel 1,3-Oxazine Derivatives

In modern synthetic organic chemistry, heterocycles are vital for the development of pharmaceuticals, industrial chemicals and natural products.'-" Among heterocycles, oxazines are of particular interest for their unique applications in drug discovery!? and natural products chemistry.' Oxazines play important roles as antihyperglyce- mic, " antileishmanial, 15 antitubercular, 16.17 anti-ulcer, 18 anticancer 19,20 and antibac- terial?' agents. In recent examples demonstrating the applicability of oxazines to drug discovery, Patil and his coworkers synthesized oxazines and found compounds with activity against E. coli, S. aureus, and strains of Micrococcus and B. subtilis.?2 Kategaonkar and colleagues successfully prepared oxazines bearing naphthalene moi- eties and tested them against Gram positive (B. subtilis) and Gram negative (E. coli) organisms. The oxazines displayed strong inhibitory activity? Oxazine derivatives were prepared by Chernov and coworkers and were found to have inhibitory activ- ities against S. aureus and E. coli? Recent developments in the preparation of oxa- zines have included green methods," eco-friendly synthesis? and other up-to-date approaches."-30 These reports spurred our own interest, and we now report our pre- liminary findings on the preparation of some novel 1,3-oxazine derivatives and their antibacterial activities. We were especially interested in preparing amide and mor- pholino derivatives because of their good druggability. In addition many heterocyclic systems having these functionalities possess antimicrobial, anti-inflammatory, and central nervous system activities. In the event, the multicomponent reaction of benzaldehyde, phenylacetylene and urea in the presence of trifluoroacetic acid and acetic acid resulted in compound 1 (Scheme 1, 59%). Compound 1 was successfully acylated with 4-chlorobenzoyl chloride under an
inert atmosphere to yield compound 2 (83%). In a similar vein.