Fused heterocycles derived from pseudoephedrine and ephedrine

Abstract

The formation of heterobicycles by condensation of (1R, 2R)-(−)-pseudoephedrine or (1R, 2S)-(−)-ephedrine with glyoxal is reported. In the case of pseudoephedrine, the nuclear magnetic resonance data of the crude reaction mixture indicate the presence of three isomeric compounds (5, 6, and 7), which were separated by fractional crystallization, while ephedrine afforded the oxazino-oxazine 8 and the known (5S*,6R*)-4,5-dimethyl-6-phenyl-1,4-oxazin-2-one (9). Conclusive spectroscopic evidence for the structures of the new compounds having the cis-[1,4]oxazino[3,2-b]-1,4-oxazine (5 and 8) and the 2,2′-bioxazolidine type structures (6 and 7) was obtained by measurement of the 13C satellite coupling constants in the 300 MHz 1H nmr spectra, combined with the evaluation of dihedral angles using a modified Karplus type relationship. Unequivocal 1H and 13C nmr spectral assignments for all new compounds were done using two-dimensional carbon–proton correlation experiments. Syntheses of the known 5a,6,11a,12-tetrahydro[1,4]benzoxazino[3,2-b]benzoxazine (3a) whose crystal structure has been previously determined, as well as of its N,N′-diisopropyl derivative 3b, allowed us to corroborate the above observations for the six-membered ring heterocycles. Moreover, the structures of 3b and 7 were independently verified by single crystal X-ray diffraction studies, thus validating the structural conclusions deduced from nmr satellite multiplicity measurements.