We have developed a pyridine C4-amination reaction via phosphonium salt intermediates, where an electronically tuned phosphine is key to successful C─N bond formation. The process accommodates aliphatic amines, (heteroaryl)anilines, hydrazines, and nitrogen heteroaromatics, as well as a variety of pyridine building blocks and late-stage C─N couplings.

Abstract

We describe a strategy for aminating pyridines and other azines via phosphonium salt intermediates. Precisely tuning the electronic properties of the phosphonium ion was key for C─N bond formation via an S _N Ar-halogenation, S _N Ar-amination sequence. The process couples a wide range of amine classes with pyridines and is viable for applications such as late-stage amination of complex pharmaceuticals and fragment–fragment coupling reactions. The capacity to rapidly modify the structure of the phosphine reagent was decisive and is a valuable feature in pseudohalide design.