Diastereoselective synthesis of substituted 2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters by a tandem reduction-reductive amination reaction

An efficient, diastereoselective synthesis of substituted and unsubstituted 2,3,4,5-tetrahydro- 1H-1-benzazepine-5-carboxylic esters has been developed based on the tandem reduction-reductive amination reaction. Catalytic hydrogenation of a series of 2-(2-nitrophenyl)-5-oxoalkanoic esters initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the N-hydroxylamino (or amino) nitrogen with the side chain carbonyl, and (3) reduction of the seven-membered cyclic imine. Cyclizations that produce 2-alkyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters are diastereoselective for the product having the C2 alkyl and the C5 ester groups cis. In these reactions, the transannular ester group exerts a strong stereodirecting effect on the reduction of the cyclic imine intermediate, though not as strong as that observed in previous closures of 2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters. This decrease in diastereoselectivity is attributed to (1) the greater distance between the ester and the imine double bond and (2) the increased conformational mobility of the larger ring, both of which diminish the stereodirecting effect of the ester. Finally, formation of the seven-membered ring is sufficiently slow that reaction with the side chain ester group competes with heterocycle formation in several of the reactions.