Bench-stable 2-halopyridinium ketene hemiaminals as new reagents for the synthesis of 2-aminopyridines via mild nucleophilic aromatic substitutions with amine nucleophiles

Bench-stable N-(1-alkoxyvinyl) 2-halopyridinium triflates have been developed as reagents for the synthesis of valuable 2-aminopyridine scaffolds via unusually mild SNAr substitutions with amine nucleophiles. Advantages of this approach include an operationally simple mix-and-stir procedure at room temperature or mild heat, ambient atmosphere, and without need of transition metal catalysts, coupling reagents, and high-boiling solvents. The stable N-(1-ethoxyvinyl) moiety serves as a dual SNAr-activating group and pyridine N-protecting group that can be cleaved under thermal, acidic, or oxidative conditions. Preliminary results of nucleophilic aromatic substitutions using alcohol, thiol, indole, and silyl enol ether nucleophiles are also demonstrated.