Fe-Catalyzed α-C(sp3)−H Amination of N-Heterocycles

Abstract

Nitrogen-heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site-selective intermolecular C(sp3)−H amination of N-heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site-selectively in α-position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover-limiting Fe-nitrene generation followed by fast H atom transfer and radical rebound.