Meta-selective C–H functionalization

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.

The widely used approach to achieve ortho-selectivity involves metal-chelating directing groups, which forms a relatively stable 6- or 7-membered cyclic pre-transition state to bring the metal catalyst to the proximity of the ortho-hydrogen.

[1][2][3][4][5] However, applying the same strategy to meta- or para- C-H functionalization does not work because the corresponding cyclophane-like cyclic pre-transition state is highly strained.

For example, before the development of the C–H activation involving one-pot synthetic route to meta-substituted phenol derivatives by Maleczka and co-workers, the traditional synthesis requires 10 steps from TNT.

[17] 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.

[14][21] The intermediate then rearomatizes with base and undergoes reductive elimination to afford the meta-arylated product and regenerate the active Cu(I) catalyst.

[14] Alternatively, Li and Wu, based on DFT calculations, proposed a mechanism involving a "Heck-like four-membered-ring transition state".

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.

[22] 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.

In their subsequent works, Yu and co-workers report the application of the same strategy in meta-selective C-H cross-coupling,[23] meta-C-H acetoxylation and meta-C–H olefination[24] in a broad substrate scope.

[24] 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.

Originally discovered by Frost and co-workers, the meta selective sulfonation of 2-phenylpyridine using a sulfonyl chloride coupling partner,[26] utilising a ruthenium(II) catalyst.

[18] Meta-olefinated biologically important biphenyl, amino acid and Baclofen derivatives have been accessed by remote C–H activation assisted by the "end-on" template.