Fused heterocycles derived from pseudoephedrine and ephedrine

Abstract

). The formation of heterobicycles by condensation of (IR, 2R)-(-)-pseudoephedrine or (lR, 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 I3c satellite coupling constants in the 300 MHz 'H nmr spectra, combined with the evaluation of dihedral angles using a modified Karplus type relationship. Unequivocal 'H and I3c nmr spectral assignments for all new compounds were done using two-dimensional carbon-proton correlation experiments. Syntheses of the known 5a,6,1la,l2-tetrahydro[l,4]benzoxazino[3,2-blbenzoxazine (3a) whose crystal structure has been previously determined, as well as of its N,Nf-diisopropyl derivative 36, allowed us to corroborate the above observations for the six-membered ring heterocycles. Moreover, the structures of 36 and 7 were independently verified by single crystal X-ray diffraction studies, thus validating the structural conclusions deduced from nmr satellite multiplicity measurements.

The standard enthalpies of combustion and formation of bioxazolidine andcis-oxazino-oxazines derived from pseudoephedrine and ephedrine

“…and (2R*,3S*,6R*,7S*)-2,6-diphenyl-3,4,7,8-tetramethyl-cis-perhydro- [1,4] [1,4]-oxazine (referred as C1, C2, and C3, respectively) are reported in this paper. The molecular structures of these compounds, established by n.m.r.…”

“…On the other hand, it has been reported (1) that oxazino-oxazine formation over bioxazolidines is favored thermodynamically, as evidenced by isomerization in solution or during purification by column chromatography. At the beginning of a systematic thermochemical study of such compounds, the standard massic energies of combustion at the temperature T=298.15 K and the derived molar enthalpies of formation D f H°m of (4R*,4'R*,5R*,5'R*)-5,5'diphenyl-3,3',4,4'-tetramethyl-2,2'-bioxazolidine, (2R*,3R*,6R*,7R*)-2,6diphenyl-3,4,7,8-tetramethyl-cis-perhydro- [1,4]…”

“…At the beginning of a systematic thermochemical study of such compounds, the standard massic energies of combustion at the temperature T=298.15 K and the derived molar enthalpies of formation D f H°m of (4R*,4'R*,5R*,5'R*)-5,5'diphenyl-3,3',4,4'-tetramethyl-2,2'-bioxazolidine, (2R*,3R*,6R*,7R*)-2,6diphenyl-3,4,7,8-tetramethyl-cis-perhydro- [1,4]…”

“…The molecular structures of these compounds, established by n.m.r. spectroscopy, (1) are shown in figure 1. Compound C3 presents an additional steric effect, due to the cis-stereochemistry of the phenyl and methyl groups.…”

“…(4R*,4'R*,5R*,5'R*)-5,5'-diphenyl-3,3',4,4'-tetramethyl-2,2'-bioxazolidine; (2R*, 3R*, 6R*,7R*) -2, 6 -diphenyl -3, 4, 7, 8 -tetramethylcis -perhydro - [1,4] -oxazino -[3,2-b]- [1,4]-oxazine; and (2R*,3S*,6R*,7S*)-2,6-diphenyl-3,4,7,8-tetramethyl-cis-perhydro- [1,4]-oxazino-[3,2-b]- [1,4]-oxazine (these compounds will be referred as C1, C2, and C3, respectively, and their formulae are given in figure 1) were determined by oxygen bomb combustion calorimetry. The enthalpies of sublimation were determined by the Knudsen effusion method using a quartz-crystal microbalance.…”