Bench-Stable 2-Halopyridinium Ketene Hemiaminals as Reagents for the Synthesis of 2-Aminopyridine Derivatives

Org Lett. 2024 Nov 22;26(46):9805-9810. doi: 10.1021/acs.orglett.4c02915. Epub 2024 Sep 20.

Abstract

2-Chloro-1-(1-ethoxyvinyl)pyridinium triflate and several other 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 and ambient atmosphere and without the need for transition metal catalysts, coupling reagents, or 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 other nucleophilic substitutions using oxygen-, sulfur-, and carbon-based nucleophiles are also demonstrated.