Optimization Strategies for the Anodic Phenol-Arene Cross-Coupling Reaction

Dehydrogenative phenol-arene cross-coupling by direct anodic oxidation is a promising alternative to reductive cross-coupling, especially for construction of smaller molecules. The reaction pathway via phenoxyl radicals allows for unusual regioselectivity. Nevertheless, the numerous electrolysis parameters pose a challenge for optimization, as they determine the yield and selectivity of the reaction. Using design of experiments, we present optimization strategies for two example reactions to improve the space-time yield. In particular, coupling reactions with 2,6-dimethoxyphenol (syringol) were found to be very robust in the electrolysis at high current densities of up to 150 mA/cm(2). Cyclic voltammetry was used to classify combinations of phenols and arenes, on the basis of which the various clusters were optimized. Based on this classification, various biaryls were synthesized and isolated in yields of up to 85 %.

Automated summary

Dehydrogenative phenol-arene cross-coupling by direct anodic oxidation is a promising alternative to reductive cross-coupling, offering unusual regioselectivity via phenoxyl radicals. Optimization strategies were presented for two example reactions to improve space-time yield, particularly emphasizing the robustness of coupling reactions with syringol at high current densities. Classification of phenols and arenes using cyclic voltammetry allowed for the optimization of various clusters, leading to the synthesis and isolation of various biaryls with yields up to 85%.