Development of New N,N-Ligands for the Enantioselective Copper(II)-Catalyzed Henry Reaction

Abstract

This account shows our efforts towards the development of new N,N-ligands and their application in the asymmetric Henry reaction. Iminopyridine ligands were prepared by the condensation of chiral monoterpene ketones and pyridinylalkylamines. The complexes of these ligands with copper(II) ions catalyzed the enantio­selective addition of nitromethane to aldehydes with generally high yields and moderate enantioselectivities. The same reaction with other nitroalkanes gave racemic products. Stereoselective reduction of the imino group allowed us to obtain new aminopyridine ligands. The new ligands were shown to be more efficient, and they catalyzed the addition of nitromethane and also larger nitroalkanes to aldehydes to give the corresponding products in generally very high yields and excellent enantiomeric excesses. We have used this aminopyridine catalytic system in the first catalytic enantioselective Henry reactions with bromo(nitro)methane and methyl 4-nitrobutanoate. The reaction involving the latter substrate gave multifunctional chiral building blocks that were transformed into γ-lactams and δ-lactones. The application of the reaction to the synthesis of known amino(aryl)ethanol pharmaceuticals is also reported. Im­inopyridine ligands, however, were more efficient in the addition of nitromethane to α-keto esters.