Direct synthesis of chiral β-arylamines via additive-free asymmetric reductive amination enabled by tunable bulky phosphoramidite ligands.

This report describes an additive-free iridium-catalyzed direct asymmetric reductive amination that enables the efficient synthesis of chiral β-arylamines, which are important pharmacophores present in a wide variety of pharmaceutical drugs. The reaction makes use of bulky and tunable phosphoramidite ligands for high levels of enantiomeric control, even for alkylamino coupling partners which lack secondary coordinating sites. The synthetic value of this succinct procedure is demonstrated by single-step synthesis of multiple drugs, analogs and key intermediates. Mechanistic investigations reveal an enamine-reduction pathway, in which H-bonding, steric repulsion, and CH-π and electrostatic interactions play important roles in defining the spatial environment for the "outer-sphere" hydride addition.