Metallaphotoredox‐Catalyzed Cross‐Electrophile Couplings of Aryl Chlorides and Alkyl Halides: Harnessing the σ‐Donor/π‐Acceptor Synergy of a 2‐(1 <i>H</i> ‐Imidazol‐2‐yl) pyridine Ligand

Abstract Cross‐electrophile coupling (XEC) reactions that forge C(sp 2 )─C(sp 3 ) bonds have received considerable attention due to the vast libraries of commercially available organohalides. However, the incorporation of ubiquitous aryl chlorides remains a challenge due to the slow rate of oxidative addition of metal catalysts to these electrophiles relative to iodide and bromide derivatives. This study reports a simple metallaphotoredox‐catalyzed C(sp 2 )─C(sp 3 ) cross‐electrophile coupling (XEC) method for the selective coupling of a broad range of aryl chlorides and alkyl halides. By design, this methodology exploits the enabling interplay of a bidentate 2‐(1 H ‐imidazol‐2‐yl)pyridine ligand, incorporating the strong σ‐donor capacity of a 1 H ‐imidazole moiety with the moderate π‐acceptor capacity of a pyridine unit. The synergy provided by these modular components allowed for the electronic requirements of elementary steps to be accommodated, such as the synchronous integration of alkyl radical generation (typically relatively fast) and oxidative addition of low valent nickel species to aryl chlorides (often relatively slow). This protocol enabled the efficient late‐stage diversification of the drugs Me ‐fenofibrate, indomethacin, and etoricoxib to enhance their sp 3 ‐rich complexity. Using an equimolar ratio of substrates, this methodology facilitated a decagram XEC in continuous flow, showcasing the applicability of the method for large scale synthesis.