Activation of remote meta-C-H bonds assisted by an end-on template

Abstract

Functionalization of unactivated carbon-hydrogen (C-H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C-H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C-H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C-H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C-H activation to a weak 'end-on' interaction between the linear nitrile group and the metal centre. The 'end-on' coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C-H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

Figure 1

A removable template for activation of distal meta-C–H bonds (10 bonds away).

Figure 2. Template-directed meta-selective C–H olefination of toluene derivatives

Arenes (8a–p) with a variety of substitution pattern undergo facile olefination. In the highlighted box, a myriad of election-deficient olefins, including vinyl ketones, vinyl phosphonate, α-imidoacrylate and various 1,2-disubstituted olefins were used. The isolated yield after purification by silica gel column chromatography is shown along with the selectivity. (The isolated yield of the di-olefinated product is also shown, when applicable). See Supplementary Information for experimental details. Selectivity of the mono product was determined by ¹H NMR analysis and confirmed by NOESY experiments. Products 17b₁₀ and 17b₁₁ were prepared from diethyl maleate and diethyl fumerate respectively. Abbreviations: PhthN, N-phthaloyl.

Figure 3. Template-directed meta-selective C–H olefination of hydrocinnamic acid derivatives

Four representative hydrocinnamic acid derivatives (top box). Regardless of electronic or steric factors, C–H olefination occurs at the meta position with high selectivity. Bottom box: (A) Use of the template allows meta-C–H olefination in the presence of ortho,ortho-disubstituents. (B) Out of the seven possible C–H bonds, only the meta C–H bond at the most remote position is activated using the template. (C) Biologically-active natural amino acid, N-protected phenylalanine, is olefinated at the meta position of the phenyl ring. (D) Baclofen, a blockbuster drug molecule, is directly modified using this methodology. Isolated yields after purification by silica gel column chromatography and selectivities are shown below each entry. (The isolated yield of the di-olefinated product is also shown, when applicable). See Supplementary Information for experimental details. Selectivity of the mono product was determined by ¹H NMR analysis and confirmed by NOESY experiments.