page_title: Meta-selective C–H functionalization
section_title: Meta-selective C-H functionalization assisted by a remote "end-on" template
hierarchical_section_title: Meta-selective C–H functionalization / Recently-developed meta-selective C–H activation strategies / Meta-selective C-H functionalization assisted by a remote "end-on" template
caption_attribution_description: English: Meta-selective C-H olefination assisted by a remote "end-on" template
context_page_description: Meta-selective C–H functionalization refers to the regioselective reaction of a substituted aromatic ring on the C–H bond meta to the substituent.
  Substituted aromatic ring is an important type of substructure in pharmaceuticals and industrial compounds. Thus, synthetic methods towards substituted aromatic rings are always of great interest to chemists.
  Traditionally, regioselectivity on the aromatic ring is achieved by the electronic effect of substituents. Taking the well-known Friedel–Craft electrophilic aromatic substitution as example, electron donating groups direct the electrophile to ortho-/para-position while electron withdrawing groups direct the electrophile to meta-position. However, with complicated systems, electronic difference between different C–H bonds can be subtle and electronic directing effect alone could become less synthetically useful.
  The fast development of C–H activation in the past few decades provides synthetic chemists with the powerful tools to synthesize functionalized aromatic compounds with high selectivity.
context_section_description: In 2012, Yu and co-workers reported a pioneering meta-selective C-H olefination using nitrile-containing templates to deliver the palladium to the meta-position via a macrocyclic cyclophane-like pre-transition state. The nitrile group is tethered to the aromatic ring by a removable linker. It coordinates weakly to palladium in an "end-on" fashion, which refers to the linear structure of C–CN–Pd bonds. 
  The linear coordination is proposed to help overcome the high strain in the cyclophane-like pre-transition state that brings palladium to the vicinity of the meta-hydrogen. The template is designed as such that the flat arene linker keeps the substrate aromatic ring and the nitrile group coplanar. Bulky substituents on the arene linker "lock" the nitrile tether in the desired position. The delicate design results in high regioselectivity towards the meta-C-H bond. The templates can be removed easily to give toluene derivatives or hydrocinnamic acid derivatives in high yield.
  In their subsequent works, Yu and co-workers report the application of the same strategy in meta-selective C-H cross-coupling, meta-C-H acetoxylation and meta-C–H olefination in a broad substrate scope. It is demonstrated that the "end-on" template not only work with the Pd(0)/Pd(II) catalytic cycle but is also compatible with the Pd(II)/Pd(IV) cycle. In all three works, addition of mono-N-protected amino acid (MPAA) such as N-acetyl glycine improves the reaction yields and enhances the regioselectivity.
caption: Meta-selective C-H olefination assisted by a remote "end-on" template
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