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. 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. 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. Thus, while ortho-selectivity has been achieved by numerous catalytic systems, meta- and para-selectivity remains a challenge.
In recent years, new strategies that override the electronic and steric bias have been developed to address meta-C–H functionalization. However, before these discoveries, synthesis of meta-substituted aromatic compounds could be either limited or cumbersome. 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. Some early attempts utilize steric and electronic effects to achieve meta-selectivity. However, they are either limited to certain structure of substrates or are not highly selective. In recent years, several highly selective meta-C-H functionalization strategies have been reported which can override the intrinsic electronic and steric properties of the substrates and can apply to a wide range of substrate derivatives. The development of the modern meta-C-H functionalization strategies “open doors for numerous possibilities” for synthesis and catalyst development.