(±)-2,3-Dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters by a tandem reduction-reductive amination reaction

A series of 2-methyl-2-(2-nitrobenzyl)-substituted beta-keto ester derivatives has been subjected to reductive cyclization under hydrogenation conditions to assess the importance of the ester group position on the diastereoselectivity of the process. Hydrogenation over 5% palladium-on -carbon at 4 atmospheres pressure resulted in formation of (+/-)-2,3-dialkyl-1,2,3,4-tetrahydroquinoline-3-carboxylic esters with a preference for the product isomer having the C2 alkyl cis to the C3 ester. The product ratios were synthetically useful (616:1), but less than that observed in cyclizations to prepare (+/-)-2-alkyl-1,2,3,4-tetrahydroquinoline-4carboxylic esters. The reduced selectivity in the current reactions has been rationalized in terms of the greater conformational mobility around the ester bearing carbon, which decreases the ability of the ester to sterically influence the addition of hydrogen to the final imine intermediate.