Regioselective difunctionalization of arenes remains a long-standing challenge in organic chemistry. We report a novel and general Fe/Ti synergistic methodology for regioselective synthesis of various polysubstituted arenes through either E/E′ or Nu/E ortho difunctionalizations of arenes. Preliminary results showed that an unprecedented 1,2-Fe/Ti heterobimetallic arylene intermediate bearing two distinct C–M bonds is essential to the regioselective difunctionalization.

Fe-catalyzed difunctionalization of aryl titanates via double C–H activation has been developed, where aryl titanates were arylated via ortho C–H activation, followed by ipso electrophilic trapping of the C–Ti bond. The ortho C–H arylation should be promoted by a 1,2-Fe/Ti synergistic heterobimetallic arylene intermediate and represents an ortho C–H ferration directed by a readily transformable C–Ti group. Common benzamides, esters, and nitriles function as arylating reagents, which involves another ortho C–H activation directed by these functionalities.

Regioselective ortho difunctionalization of arenes is highly desirable yet challenging in organic synthesis. Here, we briefly discuss various methods for ortho difunctionalization of arenes, and highlight a novel ortho heterobimetallic arylene complex enabled by heterobimetallic synergism, which shows great potential in regioselective ortho difunctionalizations.