2,2′-Bis-azine biaryls, such as 2,2′-bipyridyls, are prevalent in various biologically active molecules and photocatalysts and serve as ligands in metal-catalyzed transformations. Despite their significance, the synthesis of nonsymmetrical 2,2′-bis-azine biaryls via cross-coupling reactions remains challenging, primarily due to the difficulty in selectively forming heterobiaryl linkages. Addressing this gap, we developed palladium and norbornene cooperatively catalyzed reaction conditions for the synthesis of diverse nonsymmetrical 2,2′-bis-azine biaryls employing electrophilically iodinated pyridine derivatives and 2-chloro-azaarenes. The scope, encompassing twelve different heterocycles pertinent to drug discovery, provided over sixty 2,2′-bis-azine biaryls in total and demonstrated functional group tolerance, chemoselectivity, and scalability. Computational studies revealed overall a lower free energy activation barrier for the formation of a key Pd(IV) intermediate influencing the reactivity and selectivity of the coupling reaction. Notably, this work enriches the toolbox of synthetic methods overcoming the '2-pyridyl problem' by employing more economical 2-chloro-azaarenes.
Karaman et al. (Mon,) studied this question.