Site-Selective Catalytic Saturation of Unactivated Arenes via Directed 6π-Activation

The directing group-based strategy has been highly effective for site-selective functionalization of alkenes, carbonyls, C−H bonds, C−C bonds, etc., but not yet known for unactivated aromatic π-systems. On the other hand, catalytic hydrogenation of arenes to the corresponding saturated carbo- or heterocycles provides a straightforward approach to increase three-dimensionality and sp3-carbons in molecules of pharmaceutical interests; however, it remains very challenging to achieve site-selective dearomatization among electronically and sterically unbiased arenes. Here we report an unprecedented, directed Ru-catalyzed arene saturation approach, which selectively reduces the aryl group adjacent to the directing moiety with excellent cis selectivity. The reaction is enabled by a removable directing group, showing broad functional group tolerance and an excellent substrate scope. Remarkably, a number of easily reducible functional groups, such as alkenes, heteroarenes, ketones, and aryl bromides, can survive under the relatively mild conditions. The preliminary mechanistic study reveals a homogeneous catalysis process and the potential involvement of a η6-arene-ruthenium intermediate. The synthetic utility of this method is demonstrated in the streamlined synthesis of cis-Atovaquone, gram-scale preparations, and late-stage saturation of complex bioactive compounds.