Direct arylation of benzene with aryl bromides using high‐temperature/high‐pressure process windows: Expanding the scope of C-H activation chemistry

A detailed investigation on the direct arylation of benzene with aryl bromides by using first-row transition metals under high-temperature/high-pressure (high-T/p) conditions is described. By employing a parallel reactor platform for rapid reaction screening and discovery at elevated temperatures, various metal/ligand/base combinations were evaluated for their ability to enable biaryl formation through C-H activation. The combination of cobalt(III) acetylacetonate and lithium bis(trimethylsilyl)amide was subjected to further process intensification at 200 °C (15 bar), allowing a significant reduction of the catalyst/base loading and a dramatic increase in catalytic efficiency (turnover frequency) by a factor of 1000 compared to traditional protocols. The high-throughput screening additionally identified novel nickel- and copper-based metal/ligand combinations that favored an amination pathway competing with C-H activation, with the addition of ligands, such as 1,10-phenanthroline, having a profound influence on the selectivity. In addition to metal-based catalysts, high-T/p process windows were also successfully applied to transition-metal-free systems, utilizing 1,10-phenanthroline as organocatalyst.