Preparation of chiral amines via catalytic enantioselective indium-mediated allylation

Preparation of optically active amines has become one of the most important methodologies in synthetic chemistry over the last few decades because they serve as essential building blocks for naturally occurring molecules and synthetic therapeutics. The addition of organometallic reagents to the C=N bond offers direct access to the functionality with defined stereochemistry. Among many organometallic reagents available, organoindium species emerged as an attractive alternative to Grignard reagents due to their high chemo- and regioselectivity. While the majority of earlier studies focused on the addition of organoindium reagents in a racemic or diastereoselective fashion, corresponding enantioselective variants have been limited to a few examples. To this end, our effort was directed toward expanding the utility of organoindium reagents in highly stereoselective chiral amine syntheses. We developed enantioselective In-mediated allylation, crotylation, and cyclohexenylation of N-acylhydrazones to provide access to a wide variety of chiral amines in the presence of 3,3'-bistriflone BINOL ligand. The catalytic system exhibited excellent regio- and stereoselectivities to afford the corresponding products in high yield for a diverse range of aromatic aldehyde-derived hydrazones. Further, the same catalytic system demonstrated an outstanding level of enantioselectivities for more challenging aliphatic ketone-derived hydrazones to furnish a-tertiary carbinamines. Alternatively, Pd(0)-catalyzed enantioselective allylation was developed to serve an allylation protocol. This protocol offers an advantage in the preparation of organoindium species from alcohol precursors via transmetallation of pi-allylpalladium species in the presence of indium iodide. An evaluation of the new catalytic system was conducted to compare with the previously developed In(0)-mediated allylation reactions.