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

• Published in: Organic letters Vol. 26; no. 46; pp. 9805 - 9810
• Main Authors: Bote, Isabelle C., Krevlin, Zoe A., Crespo, Maria Christina F., Udomphan, Sudchananya, Levin, Carolyn T., Lam, Christie C., Glanzer, Amy M., Hutchinson, Holly L., Blades, Alisha M., McConnell, Danielle L., Lin, Crystal, Frank, John P., Strutton, William R., Merklin, Jordan C., Sinardo, Beau A., Gueye, Khady J., Leiman, Karly V., Thayaparan, Ashley, Adade, Joel K. A., Martinez, Nestor L., Kramer, Wesley W., Majireck, Max M.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20-09-2024
• ISSN: 1523-7060; 1523-7052; 1523-7052
• DOI: 10.1021/acs.orglett.4c02915

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.