Dihydrobenzoxazines and tetrahydroquinoxalines by a tandem reduction-reductive amination reaction

A tandem reduction-reductive amination reaction has been applied to the synthesis of 3,4-dihydro-2H-1,4-benzoxazines and 1-acetyl-1,2,3,4-tetrahydroquinoxalines. The nitroketones required for the benzoxazine ring closures were prepared by (A) alkylation of the anion derived from 2-nitrophenol with an allylic halide or (B) nucleophilic aromatic substitution of an allylic alkoxide on 2-fluoro-1-nitrobenzene followed by ozonolysis. Precursors for the quinoxalines were prepared by alkylation of the anion of 2-nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic hydrogenation of the nitroketones using 5% palladium-on-carbon in methanol then gave the target heterocycles by a reduction-reductive amination sequence. The N-methyl derivatives for both ring systems were easily prepared by adding 5-10 equivalents of aqueous formaldehyde prior to the reduction. The dihydrobenzoxazines were isolated in high yield following purification by chromatographic methods; tetrahydroquinoxalines were isolated in a similar manner and possessed differentiated functionality on the two nitrogens.