Cu-Catalyzed Aerobic Oxidative Cyclization of Guanidylpyridines and Derivatives

Abstract

A new method for the straightforward synthesis of 2-amino-[1,2,4]triazolo[1,5-a]pyridines and derivatives is presented. The target products are synthesized in high yields from guanidylpyridines and analogues via copper-catalyzed N-N coupling. The present methodology shows a wide scope, tolerating not only different substituents on the pyridine ring but also different heterocylic rings such as pyrazines, pyrimidines, and pyridazines.

Mechanistic insights into copper-catalyzed aerobic oxidative coupling of N–N bonds

“…A number of related reactions have been reported subsequently by others, 16,17,19,20 including process scale applications in the pharmaceutical industry. 21 The second, reported by Hayashi and coworkers, 22 features the oxidative homocoupling of benzophenone imine to afford the corresponding azine. This reaction is the key step in a multi-step process that has been considered for commercial production of hydrazine.…”

1,2,4-Triazolo[1,5-a]pyrimidines in drug design

“…[20] Finally, substituted TP heterocycles can also be accessed through an oxidative cyclization of corresponding pyrimidin-2-yl-amidines (14, Scheme 1C). [21,22]…”

Synthesis of heterocycles via aerobic oxidation

“…56 This cascade protocol worked efficiently with a variety of aromatic nitriles, but yields were limited when using cyanamides, likely due to difficult addition to the nitrile in such compounds. 57 Given the interest in the 2-amino- [1,2,4]triazolo [1,5-a]pyridine scaffold in medicinal chemistry, researchers at Roche modified Nagasawa's protocol employing guanidinic precursors 71 ( Scheme 12B). 57 This method allowed the efficient synthesis of 2-aminotriazolopyridines 72 and analogues 73-76 from diazaheterocyclic guanidines.…”