Dihydrobenzoxazines and tetrahydroquinoxalines by a tandem reduction-reductive amination reaction

ORGN 390

Richard A. Bunce, Lu Y. Hale, and Jason R. Lewis. Department of Chemistry, Oklahoma State University, 107 Physical Sciences 1, Stillwater, OK 74078-3071
A tandem reduction-reductive amination reaction has been applied to the synthesis of 3-alkyl-3,4-dihydro-2H-1,4-benzoxazines and 1-acetyl-3-alkyl-1,2,3,4-tetrahydroquinoxalines. The nitro ketones required for the benzoxazine ring closures were prepared in two steps by alkylation of the anion derived from 2-nitrophenol with an allylic halide or nucleophilic aromatic substitution of 2-fluoro-1-nitrobenzene with an allylic alkoxide followed by ozonolysis. Substrates for the quinoxaline ring closures were prepared by alkylation of the anion of 2-nitroacetanilide with an allylic halide followed by ozonolysis. Catalytic reduction of the nitro ketones using 5% palladium on carbon in methanol then gave the target heterocycles by a reduction-reductive amination sequence. The N-methyl derivatives were easily prepared by adding 5-10 equivalents of aqueous formaldehyde prior to the hydrogenation. The benzoxazines were isolated in high yield following purification by chromatographic methods; quinoxalines were isolated in similar fashion and possessed differentiated functionality on the two nitrogens.