Diastereoselective synthesis of substituted tetrahydroquinoline-4-carboxylic esters by a tandem reduction-reductive amination reaction

A diastereoselective synthesis of 1-methyl-2-alkyl- and 2-alkyl-1,2,3,4-tet rahydroquinoline-4-carboxylic esters has been developed from methyl (2-nitr ophenyl)acetate (1), The method involves alkylation of 1 with an allylic ha lide, ozonolysis of the double bond, and catalytic hydrogenation. The final hydrogenation initiates a tandem sequence involving (1) reduction of the a romatic nitro group, (2) condensation of the aniline or hydroxylamine(8) ni trogen with the side chain carbonyl, (3) reduction of the resulting nitroge n intermediate, and (4) reductive amination of the tetrahydroquinoline with formaldehyde produced in the ozonolysis to give a methyl (+/-)-1-methyl-2- alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylate. Removal of the formaldehyd e prior to hydrogenation gives the simple (+/-)-2-alkyl derivatives. The pr oducts are isolated in high yield as single diastereomers having the C-2 al kyl group cis to the C-4 carboxylic ester. The reaction has been extended t o the synthesis of tricyclic structures with similar high diastereoselectio n.