Synthesis of oxazolidinones via acid- and halo-induced intramolecular cyclization

Abstract

Two novel synthetic pathways toward 2-oxazolidinone derivatives were developed. The first pathway is the acid-induced intramolecular cyclization of β-(N-arylcarbamyl) epoxides. Simple treatment of a β-(N-arylcarbamyl)epoxide with trifluoroacetic acid exclusively gave the corresponding N-aryl-2-oxazolidinone in excellent yield. Mechanistically, the Boc carbonyl oxygen intramolecularly attacks the acid-activated epoxide ring in 5-exo-tet fashion to form the desired oxazolidin-2-ones. Toloxatone, a well known antidepressant, and Linezolid (Zyvox®) antibacterial medicine were successfully synthesized from this cyclization method. The second synthetic pathway involves halo-induced cyclization of tert-butyl allyl(phenyl)carbamate. Various halogenated reagents were evaluated for reaction optimization. The synthesis of oxazolidinone derivatives containing one or two halogen atoms were successfully established for all chloro, bromo and iodo compounds. Either unsubstituted-aryl oxazolidinone or p-halo-substituted-aryl oxazolidinone were selectively produced with appropriate choice of halogenated reagents.