Practical N-alkylation via homogeneous iridium-catalyzed direct reductive amination

Abstract

Direct reductive amination (DRA) is one of the most efficient methods for amine synthesis. Herein we report a practical homogeneous DRA procedure utilizing iridium catalysis. Applying simple, readily available and inexpensive PPh3 and alike ligands along with iridium at a low loading, aldehydes and ketones reductively coupled with primary and secondary amines to efficiently form structurally and functionally diverse amine products, including a set of drugs and compounds from late-stage manipulation. The reaction conditions were exceptionally mild and additive-free, in which oxygen, moisture, polar protic groups and multiple other functional groups were tolerated. For targeted products, this methodology is especially versatile for offering multiple possible synthetic options. The 10 gram-scale synthesis further demonstrated the potential and promise of this procedure in practical amine synthesis. DFT studies reveal an “outer-sphere” H-addition pathway, in which π−π interactions and H-bonding play important roles.