Conformation-induced remote meta-C–H activation of amines

In anilines and benzylic amines, a recyclable chemical template can direct the olefination and acetoxylation of meta-C–H bonds as far as 11 bonds away from a functional group; in particular, it is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. To fully realize the synthetic potential of carbon–hydrogen (C–H) bond activation in organic chemistry, it is important to develop new approaches that can activate C–H bonds selectively in various locations with respect to existing functional groups. In this paper, Jin-Quan Yu and colleagues use a recyclable template to direct the olefination and acetoxylation of remote meta-C–H bonds — up to eleven bonds away — of anilines and benzylic amines. This template is able to direct the meta-selective C–H functionalization of tetrahydroquinoline, benzoxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines, all of which are commonly used building blocks in drug discovery. Achieving site selectivity in carbon–hydrogen (C–H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C–H bonds in any given organic molecule can lead to the activation of undesired C–H bonds by a non-selective catalyst. One solution to this problem is to distinguish C–H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C–H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied1,2,3,4,5,6,7,8,9,10,11,12,13. However, the directed activation of C–H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C–H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation14,15. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C–H bonds—as far as 11 bonds away—of anilines and benzylic amines. This template is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.