Ni/Ti Dual Catalyzed Cross-Electrophile Coupling Between Unactivated Alkyl Chlorides and Aryl Halides

A dual Ni/Ti-catalyzed method for cross-electrophile coupling (XEC) of primary and secondary alkyl chlorides and aryl halides is described. This is a rare example of a thermal XEC reaction that directly couples unactivated alkyl chlorides, which are valuable substrates because of their accessibility and stability. Mechanistic studies indicate that the Ti catalyst, Cp*₂Ti^IVCl₂ (Cp* = pentamethyl-cyclopentadienyl), is crucial for activation of the alkyl chloride. Specifically, Cp*₂Ti^IVCl₂ undergoes reduction to form Cp*₂Ti^IIICl, which was isolated and crystallographically characterized. Control experiments demonstrate that Cp*₂Ti^IIICl reacts with primary, secondary, and tertiary alkyl chlorides to form alkyl radicals. While the Ni catalyst is not reactive enough to form alkyl radicals from alkyl chlorides directly, it is crucial for activating the aryl halide, resulting in the formation of an intermediate of the form (^tBubpy)Ni(Ar)X (^tBubpy = 4,4'-^tBu₂-2,2'-bipyridine; X = halide). Stoichiometric experiments showed that the (^tBubpy)Ni(Ar)X intermediate captures alkyl radicals generated by the Ti catalyst and subsequently forms the organic XEC product. A key feature in the Ni/Ti dual catalyzed reaction is matching the rates of the Ni and Ti catalytic cycles, so that the rates of radical production and trapping are complementary. This can be achieved by varying the relative loadings of the Ni and Ti catalysts. It is expected that the strategy of using a second reactive catalyst to activate previously inert substrates in Ni-catalyzed XEC will be applicable to other challenging substrate classes.