Migrative Reductive Amination of Ketones Enabled by Multitasking Reagents

Secondary amines are key synthetic intermediates and constituents of pharmaceutical agents. They are often prepared by the classical reductive amination of ketones and aldehydes, a staple reaction in organic chemistry. Reductive amination forms products without modifying the carbon framework, which restricts its power and breadth. To expand chemical space and access isomeric amines with a rearranged skeleton, a migrative variant was developed by orchestrating three distinct reactions in a single flask, without solvent changes, using two inexpensive and nontoxic reagents: a Zn(II) salt and a hydrosilane. Mechanistic insights confirmed that both reagents are uniquely multitasking ─ active and synergistic ─ across all reaction stages, lending a practical open-flask procedure that embodies many ideals of green chemistry. This method demonstrates a wide scope of acyclic and cyclic ketones and aldehydes with both aliphatic and aromatic groups, including bioactive molecules and macrocyclic natural products isolated with highly favorable E-factor, process mass intensity, and other established greenness metrics. Furthermore, the efficiency of this migrative reductive amination was highlighted in a one-step synthesis of the marine natural product haliclorensin C from l-muscone.