page_title: Meta-selective C–H functionalization
section_title: Copper catalyzed meta-selective C–H arylation
hierarchical_section_title: Meta-selective C–H functionalization / Recently-developed meta-selective C–H activation strategies / Copper catalyzed meta-selective C–H arylation
caption_attribution_description: English: Alternative mechanism of copper catalyzed meta-selective C-H arylation
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 2009, Gaunt's group reported a copper catalyzed meta-selective C–H arylation reaction on anilide derivatives. Despite the intrinsic ortho-/para- selectivity of the amido group, the arylation occurs exclusively on the meta position on a variety of anilide substrates. Remarkably, the regioselectivity is totally different from the earlier reported Pd catalyzed C-H functionalizations, where the amido group serve as a powerful ortho-directing group. The method is robust under mild reaction conditions. It is compatible with a spectrum of substituted anilide as well as different bisaryliodonium salts. However, the meta-selectivity is lost when highly ortho/para-directing methoxy group substitutes one of the meta-hydrogen of the anilide, which marks the limitation of this method.
   Despite the limitation, the paper was of high impact. It has been highlighted in a number of journals and news and was voted as one of the top 12 papers of 2009 by Chemical and Engineering News.
  In a more recent report from the same group, α-arylcarbonyl compounds were found to be good substrates for the copper catalyzed meta-selective C-H arylation. The power of the meta-selectivity overrides the electronic effect of different substituents, including the strong ortho/para-directing m-methoxy group.
  Although the copper catalyzed meta-selective C–H arylation is quite successful, the mechanism behind the meta-selectivity is not completely understood. There are generally two proposed mechanisms both involving a Cu(I)/Cu(III) catalyst cycle.
  In Gaunt's original paper, he proposed a mechanism involving an anti-oxy-cupration step as the key to the meta-selectivity. First, the Cu(II) salt generates the active Cu(I) species through either disproportionation or reduction by nucleophile. The active Cu(I) species undergoes oxidative addition with diphenyliodonium salt to generate a highly electrophilic Cu(III) species. While the Cu(III) species activates the aromatic ring, the amide oxygen attacks the ortho position, breaking the aromaticity and allowing cupration at the meta position. The intermediate then rearomatizes with base and undergoes reductive elimination to afford the meta-arylated product and regenerate the active Cu(I) catalyst. 
  Alternatively, Li and Wu, based on DFT calculations, proposed a mechanism involving a "Heck-like four-membered-ring transition state". The amide oxygen first coordinates to the Cu(III) species generated from oxidative addition of Cu(I) triflate and diphenyliodonium triflate. Then, the phenyl group bonded to copper interacts with the aromatic ring at the meta-position, forming a four-membered-ring transition state. According to their calculations, the aromaticity is not completely lost during the transformation. In the last step, the Cu(III)-C bond breaks to regenerate the Cu(I) catalyst while the triflate ion abstract the meta-hydrogen to recover the aromaticity and gives the product.
caption: Alternative mechanism of copper catalyzed meta-selective C-H arylation
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