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

Abstract

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 studied. 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 cyclometallation. 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.

Figure 1. Design of a versatile template to direct meta-C–H activation

Figure 2. Development of templates to direct meta-C–H olefination

a) Olefination of tetrahydroquinoline derivatives; b) Six representative templates designed to screen the meta-C–H olefination; c) Tetrahydroquinolines with a variety of substitution patterns appended with template T₆ (6a-6h) undergo facile meta-C–H olefination. The yields of 2 and 3 are NMR yields with CH₂Br₂ as internal standard. The selectivity is not determined due to multiple olefinated products detected. The isolated yields of other olefinated products are shown along with the selectivity (combined yields shown in b). See Supplementary Information for experimental details. Selectivity of the olefinated products was determined by ¹H NMR analysis or GCMS analysis using flame ionization detector; the variance is estimated to be within 5%. HFIP = hexafluoroisopropanol.

Figure 3. Template-directed remote C–H olefination of N-methylanilines

a) Anilines with a variety of substitution patterns were found to undergo facile meta-C–H olefination; b) In the box, electron-deficient olefins and various di-and tri-substituted olefins were compatible with this transformation. The isolated yields of the mono-olefinated product (and also the isolated yields of the di-olefinated product, when applicable) are shown along with the selectivity. See Supplementary Information for experimental details. Selectivity of the mono- and di-olefinated products was determined by ¹H NMR analysis and GCMS analysis using a flame ionization detector; the variance is estimated to be less than 5%.

Figure 4. meta-Selective C–H acetoxylation of N-methylanilines and benzylamine derivatives

a) Anilines (8) with a variety of substitution patterns undergo facile meta-C–H acetoxylation; b) The isolated yield of the acetoxylated aniline is shown along with the selectivity; c) Benzylamines derivatives (11a–d) were found to undergo facile meta-C–H acetoxylation; d) The isolated yield of the acetoxylated benzylamine derivative is shown along with the selectivity. See Supplementary Information for experimental details. Selectivity of the acetoxylated products was determined by ¹H NMR analysis and GCMS analysis using a flame ionization detector; the variance is estimated to be less than 5%.