Synthesis of enantiomers of 6-substituted 3-methyl-3,4-dihydro-2H-[1,4]benzoxazines

Individual (S)-enantiomers of 6-methoxy-, 6-chloro-, and 6-nitro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazines were synthesized via an acylative kinetic resolution of race-mates using (S)-naproxen acyl chloride as a diastereoselective chiral resolving agent. The acylation of racemic benzoxazines with (S)-naproxen acyl chloride afforded (S,S)-dia-stereomers of amides as the major products, which were isolated in diastereomerically pure form (>99% de) by the recrystallization or flash column chromatography on silica gel. The acidic hydrolysis of (S,S)-amides gave (S)-enantiomers (>99% ee according to chiral HPLC) of 6-substituted 3-methyl-3,4-dihydro-2H-[1,4]benzoxazines. The (R)-enantiomer of 3-methyl-6-nitro-3,4-dihydro-2H-[1,4]benzoxazine (>99% ee) was prepared by the stoichiometric acylation of a scalemic sample with (S)-naproxen acyl chloride followed by the recrystallization of the (R,S)-amide and subsequent acidic hydrolysis. The configuration assignment of the chiral centers in the synthesized benzoxazines was made based on the X-ray diffraction analysis of the corresponding amides. The synthesized enantio-merically pure 6-substituted 3-methylbenzoxazines can be used in the synthesis of biologically active compounds.