Four 7a-methyl octa(or hexa)hydrocyclopenta[d][1,3]oxazines, five 8a-methyl octa(or hexa)hydro[3,1]benzoxazines, two 6-phenyl hexahydro[3,1]benzoxazinones, and 8a-methyl hexahydro[1,3]benzoxazinone, all cis-fused, were prepared and their stereostructures studied by various one- and two-dimensional (1)H, (13)C, and (15)N NMR spectroscopic methods. In solution, the cyclopentane-fused 2-oxo derivatives and the 1,3-benzoxazinone were found to attain exclusively the N-in/O-in conformation, whereas the 6-phenyl 2-oxo/thioxo derivatives were found to be present predominantly in the N-out conformation. The C-2 unsubstituted and the 2-oxo/thioxo 7a/8a-methyl derivatives were all present in solution as a rapidly interconverting equilibrium of the N-in and N-out conformations. The C-2 methyl derivatives were each found to be interconvertable mixtures of epimers (at C-2) with the N-in conformer predominating for one epimer and the N-out conformer predominating for the other, with both predominating conformers having the C-2 methyl group equatorially orientated. The substituent on the nitrogen (H or Me) was found to be always predominantly equatorial with respect to the heteroring, except for the epimeric 2-methyl derivatives with N-out conformations where steric constraints and the generalized anomeric effect resulted in the axial orientation of the C-2 methyl being favored.
Tricyclic oxazines fused with norbornene or norbornane were synthesized for pharmacological and stereochemical purposes. Analogous oxszin-2-0nes and -2-thiones were also obtained. The diendo or diexo anellation of the hetero ring to the norbornene or norbornane skeleton was codhued by 'H and =C spectral data. The assignment of the proton sign& was proved and the proton-proton coupling values were determined by double resonance experiments. With mono-and dichloroacetyl chloride, the oxazines fused to norbornene gave azetidinones which are mixtures of two isomers. The mixtures were separated into homogeneous substances, the configuration and conformation of which were determined via Merentid NOE experiments.
INTRODUCI'IONNumerous partly or fully saturated quinazolines and 1,3-benzoxazines have been previously synthesized and have proved to have anti-inflammatory and analgesic a~t i v i t y . '~ A norbornane derivative was recently found which had beta-adrenergic neuronblocking a~t i v i t y ;~ the fusion of these two structures into tricyclic compounds, therefore, seemed to be very promising as a source of new pharmacologically active substances.
endo-2-Amino-endo-3-hydroxymethylbicyclo[2.2.1]-hept-5-ene(1) and exo-2-amino-exo-3-hydroxymethylbicyclo[2.2.l]heptane (4) were reacted with arylimino ethers (2) to yield fused tricyclic diendo-and diexo-3,l-oxazines 3 and 5, respectively (Scheme 1). Reaction of the amino alcohols 1 and 4 with ethyl chloroformate and sodium methylate, or with CS2-KOH and Pb(NOJ2, leads to the analogous 3,1-oxazin-2-ones (6a, 7a) and oxazine-2-thiones (a, 7b), respectively.Azetidinones were produced on the reaction of 3bwith chloroacetyl chloride or dichloroacetyl chloride. Both products were mixtures of two isomers (8 and 9). The isomeric mixtures were separated into homogeneous substances . 6b
PROTON RESONANCE SPECTRAThe presumed diendo and diexo configurations of the tricyclic compounds 3 and 5, respectively, were proved
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