The methodology developed by Larrosa and co-workers towards the meta-selective arylation of phenols is a great example of combination of knowledge and creativity. Ortho-carboxylation of phenols with CO2 (Kolbe-Schmitt reaction) is a well known process that is used to synthesise salycilic acid, the precursor of aspirin. In addition, CO2 is a smart choice as directing group as it is abundant, inexpensive, non-toxic and non-flammable.
The direct meta-functionalization of phenols is quite a challenge due to the ortho/para directing ability of the hydroxyl group. Previous methodologies to achieve meta-functionalization require the use of protection-deprotection strategies with the consequent additional synthetic and purification steps.
Larrosa an co-workers approach the problem by in-situ introducing an ortho carboxyl group through direct reaction of phenol with CO2. The carboxyl function acts as a transient ortho-directing group that facilitates a palladium mediated metha-selective (to the hydroxyl group) cross coupling before being removed. An important drawback of the methodology is the requirement of high temperatures which could be a limitation for its scope in synthesis.
Do you want to know more? Go directly to the source:
Junfei Luo , Sara Preciado , and Igor Larrosa. Overriding Ortho–Para Selectivity via a Traceless Directing Group Relay Strategy: The Meta-Selective Arylation of Phenols. J. Am. Chem. Soc., 2014, 136, 4109–4112.