Site-selective Ru-catalysed saturation of unactivated arenes via directed 6π activation

Directing group-based strategies have proven highly effective for site-selective functionalization of π bonds in alkenes and carbonyls, as well as C–H and C–C bonds, but have yet to be demonstrated for unactivated aromatic π-systems. Meanwhile, catalytic hydrogenation of arenes to their corresponding saturated carbo- or heterocycles offers a straightforward approach to increase molecular three-dimensionality and sp3 carbon content in pharmaceutical compounds; however, it remains challenging to achieve site-selective dearomatization among electronically and sterically unbiased arenes. Here we report a Ru-catalysed directed arene saturation, which selectively reduces the aryl group adjacent to the directing moiety. Remarkably, a number of easily reducible functional groups are compatible with the mild reaction conditions. The preliminary mechanistic study reveals a homogeneous catalysis process and the potential involvement of an η6-arene-ruthenium intermediate. The synthetic utility of this method is demonstrated in the streamlined synthesis of cis-atovaquone, gram-scale reactions and late-stage saturation of complex bioactive compounds. Directing group strategies for selective dearomatization of unactivated aromatic π-systems have remained elusive. Now a homogeneous ruthenium catalyst, aided by a removable directing group, enables the site-selective hydrogenation of less reactive arene moieties in polyaryl compounds.