Migrative Reductive Amination of Ketones Enabled by Multitasking Reagents

Skeletal editing and “single-atom logic” are emerging strategies that accelerate compound synthesis and open new chemical space by modifying organic molecules using unconventional bond forming processes. These new strategies are particularly attractive to access important biologically active classes of compounds, such as secondary amines, which are key synthetic intermediates and components found in numerous pharmaceutical agents. Herein, a practical modification of the classical reductive amination of ketones and aldehydes, a staple reaction in drug discovery research, was developed to provide isomeric amines by way of a migratory reductive amination (MRA). This one-pot method combines three distinct chemical reactions in a single flask, without solvent changes, via the orchestrated addition of two inexpensive and non-toxic multitasking reagents: Zn(II) salts and a hydrosilane. Both reagents display exceptional orthogonality with a synergetic role in all three stages of the process, lending a procedure that embodies many of the ideals of green chemistry. This MRA method demonstrates a wide scope of acyclic and cyclic ketones and aldehydes with aliphatic or aromatic groups, including complex molecules such as drug intermediates and natural products with an exceptionally low E-factor compared to established methods. Remarkably, MRA enables the expeditious preparation of cyclic secondary amines of varying ring size, including a cyclopentanone-to-piperidine ring-edit that provides a direct access to the most common saturated heterocycle in drug discovery.