A New Catalytic System for Ru-Catalyzed C–H Arylation Reactions and Its Application in the Practical Syntheses of Pharmaceutical Agents

Biaryls are a significant structural motif found in valuable compounds in materials and the life sciences. Currently, the most reliable and widely used method to synthesize biaryls is through the use of cross-coupling reactions. However, cross-coupling reactions require stoichiometric amounts of reactive organometallics, such as boronic acids, Grignard reagents, or zinc reagents (C-Met; Met = B, Mg, Zn), to enable sp 2 –sp 2 carbon–carbon bond formation. This has generated a large amount of toxic metal waste, some of which is difficult to handle. In the meantime, C–H arylation has aroused a keen interest in the synthesis of biaryls because of its high atom economy. Carbon–carbon bond formation takes place at an unactivated C–H bond in the presence of a transition metal catalyst. Despite such conceptually attractive features, most of the reported protocols require high catalyst loading and often suffer from a lack of reproducibility. During our process development of angiotensin II receptor blockers (ARBs) through C–H arylation, these same types of issues have seriously retarded further development of the methodology for commercial production. To address this challenge, we searched for a better catalytic system with a new cocatalyst that would ensure the robustness of C–H arylation at scale. Various Brønsted acid potassium salts were tested for use in C–H arylation, including dipotassium dicarboxylates, potassium phosphates, and potassium sulfonates. Among such agents, dipotassium glutarate (GLDK), potassium bis(2-ethylhexyl)phosphate (BEHPK) and potassium 2,4,6-trimethylbenzenesulfonate (TMBSK) furnished the desired products with both high activity and high monoarylation selectivity. In particular, TMBSK was found to be the most efficient even for less reactive substrates, such as weakly coordinated azoles and sterically hindered aryl halides. This protocol has a wide range of generality and has been successfully applied to the novel and scalable syntheses of angiotensin II receptor blockers.