Regioselective synthesis of 3-endo-hydroxymethyl-5-exo-phenylbicyclo[2.2.1]heptane-2-endo-amine and its transformation to saturated or partially saturated diendo-fused heterocycles

Aluminium(III)-chloride-catalysed addition of benzene to diendo-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (1) and subsequent treatment with acetic anhydride yields 5-exo-phenyl-diendo-bicyclo[2.2.1] heptane-2,3-dicarboxylic anhydride (2). 3-endo-Hydroxymethyl-5-exo-phenylbicyclo[2.2.1] heptane-2-endo-amine (4) was prepared by LAH reduction of the beta-amino acid 3, obtained by Hofmann degradation of the carboxamide prepared from 2. Reaction of 4 with ethyl chloroformate or with CS(2)/NaOH/Pb(2+) furnished the methylene-bridged hexahydro-3,1-b enzoxazin-2(1H)-one (5) or -benzoxazine-2(1H)-thione (6). With ethyl chloroacetate or 2-chloropropionate, 4 gave the tricyclic oxazepinones 7 and 8. The norbornane 1,3-aminoalcohol 4 was transformed with phenyl isothiocyanate to the phenylimino-1,3-oxazine 9 and -thiazine 10. The cyclizations of 4 with 2-(p-methylbenzoyl)benzoic acid or cis-2-p-chlorobenzoyl-1-cyclohexanecarboxylic acid led to the methylene-bridged isoindolo[2,1-a][3,1]benzoxazines 11 and 12. With ethyl p-chlorobenzimidate, the diendo-5,8-methano-4H-3,1-benzoxazine 13 was obtained, which was converted with dichloroacetic acid/triethylamine to the isomeric azetidinones 14 and 15, or with benzonitrile oxide to methano-1,2,4-oxadiazolo[4,5-a][3,1]-benzoxazine (16). The stereostructures of the new compounds were elucidated by NMR spectroscopy and for 13 also by X-ray diffractometry.