Dual-catalytic transition metal systems for functionalization of unreactive sites of molecules

Catalytic reactions occur readily at the sites of starting materials that are both innately reactive and sterically accessible, or that are predisposed by a functional group amenable to direct a catalyst. However, selective reactions at unbiased sites of substrates remain challenging and typically require additional preactivation steps or the use of highly reactive reagents. Here we report dual-catalytic transition metal systems that merge a reversible activation cycle with a functionalization cycle, which together enable the functionalization of substrates at their inherently unreactive sites. By engaging the Ru- or Fe-catalysed equilibrium between an alcohol and an aldehyde, methods for Pd-catalysed β-arylation of aliphatic alcohols and Rh-catalysed γ-hydroarylation of allylic alcohols were developed. The mild conditions, functional group tolerance and broad scope (81 examples) demonstrate the synthetic applicability of the dual-catalytic systems. This work highlights the potential of the multicatalytic approach to address challenging transformations to circumvent multistep procedures and the use of highly reactive reagents in organic synthesis. The ability to functionalize normally unreactive sites in molecules opens up tremendous flexibility in synthesis design and structural modification, in addition to reducing the need for multiple steps or highly reactive reagents. Now, a dual-catalytic strategy, demonstrated with the methods for the β-arylation of aliphatic alcohols and for the enantioselective γ-hydroarylation of allylic alcohols, is reported for such reactions.