Direct C4- and C2 C–H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably small mole-cule pharmaceuticals. While numerous strategies exist to install nitrogen atoms onto azaarenes, most require pre-functionalization and methods for direct C–H amination are almost entirely limited to the C2-position. Herein, we report a method for the direct C2 and C4 C–H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III)-reagent, [(Py)2IPh]2OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no pre-oxidation of the azaarene and it provides unprecedented access to C4-amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration, and the free amine can be liberated under mild Zincke aminolysis, or the amination and cleav-age can be telescoped to a one-pot process. The scope of the method is broad, the conditions are mild and operationally sim-ple, and the aminated products are produced in good to excellent yields. Computational studies provide insights into the mech-anism of activation, which involves an unusual direct nucleophilic functionalization of an I(III)-ligand, as well as a kinetic basis for the observed C2 and C4 amination products.