Direct C4-H Amination of Pyridines and Quinolines under Benign Conditions

Abstract

Existing methods for the para-C-H amination of pyridines and quinolines are scarce and rely exclusively on indirect approaches. These typically involve initial installation of an amine surrogate or an aryl phosphine at the para position, followed by subsequent conversion to the amine functionality-a process that suffers from low atom economy and generates substantial waste. Herein, we report a straightforward and environmentally benign method for the direct C4-H amination of azines. This transition-metal-free protocol, employing a base and an activating agent in ethyl acetate, enables mild and efficient C4-H amination of a wide range of 2-substituted pyridines and quinolines. Furthermore, we demonstrate that regioselectivity is strongly influenced by both substrate structure and solvent, and provide practical guidelines for optimal substrate selection.