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

Abstract

Achieving site selectivity in C–H functionalization is a long-standing challenge in organic synthesis. The small differences in intrinsic reactivity of C–H bonds in a given organic molecule often lead to poor discrimination by a catalyst. One solution to this problem is to distinguish C–H bonds based on their location with respect to a particular functional group. In this context, the activation of C–H bonds 5 or 6 bonds away from a functional group via cyclometalation has been extensively studied.1-13 However, directed activation of C–H bonds that are distal (>6 bonds away) from functional groups has remained difficult, especially when the target C–H bonds are geometrically inaccessible through directed metalation due to the ring strain encountered in cyclometalation.14,15 Herein we report a recyclable template that directs the olefination and acetoxyation of distal meta-C–H bonds (as far as 11 bonds away) of anilines and benzylic amines. Remarkably, this template is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via highly strained tricyclic cyclophane-like palladated intermediates. X-ray and NMR studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by a ligand to switch from ortho- to meta-selectivity.