Tetrahydro-1,5-benzoxazepines and tetrahydro-1H-1,5-benzodiazepines by a tandem reduction-reductive amination reaction

A tandem reduction-reductive amination reaction has been applied to the synthesis of (+/-)-4-alkyl-2,3,4,5-tetrahydro-1,5-benzoxazepines and ()-4-alkyl-1-benzoyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepines. The nitro aldehydes and ketones required for 1,5-benzoxazepine ring closures were prepared by nucleophilic aromatic substitution of the alkoxides from several 3-buten-1-ol derivatives with 2-fluoro-1-nitrobenzene followed by ozonolysis. Precursors for the 1,5-benzodiazepines were prepared by similar addition of N-(3-butenyl)benzamide anions to 2-fluoro-1-nitrobenzene followed by ozonolysis. Catalytic hydrogenation of the nitro carbonyl compounds using 5% palladium-on-carbon in methanol then gave the target heterocycles by a tandem reduction-reductive amination sequence. The 1,5-benzoxazepines were isolated in high yield following chromatographic purification; the 1,5-benzodiazepines were isolated as solids directly from the hydrogenation mixture and possessed differentiated functionality on the two nitrogen atoms.