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*2TiIVCl2 (Cp* = pentamethyl-cyclopentadienyl), is crucial for activation
of the alkyl chloride. Specifically, Cp*2TiIVCl2 undergoes reduction to form Cp*2TiIIICl, which was isolated and crystallographically characterized.
Control experiments demonstrate that Cp*2TiIIICl 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.