While broadly regarded as privileged pharmacophores due to their remarkable ability to improve the pharmacological properties of biologically active compounds, C-CH3 and C-F bonds can be notoriously difficult to construct from C-H bonds. Herein, a catalytic method for the direct ortho C-H methylation and fluorination of benzaldehydes via Pd catalysis is presented. Central to these transformations was the use of a new type of TDGs, orthanilic acids, which contain sulfonic acids as the X-type ligand. Compared to the traditional anthranilic acids, which have carboxylic acids as the X-type ligand, these new TDGs exhibited unprecendented reactivity in C-H methylation and fluorination reactions. By fine tuning of the F+ oxidants, the TDGs, and the solvents, good yields and functional group compatibility could be achieved for both reactions. A single X-ray crystal structure of the benzaldehyde ortho C-H palladacycle was also obtained by trapping the insertion intermediate with triphenylphosphine.

Orthanilic acids: New transient directing groups for benzaldehyde ortho C-H methylation and fluorination via Pd catalysis

256th National Meeting (2018)

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