Mechanistic development of a mild palladium-catalyzed C-S/C-H cross-coupling of thioesters with azoles

The catalytic C-H acylation of heteroarenes utilizing abundant carboxylic acid derivatives is a highly desirable chemical transformation. However, current procedures require unstable electrophiles, harsh reaction conditions or strong bases, limiting their substrate scope and consequently hampering applications in complex, densely functionalized systems. In this work, we describe the development of a mild palladium-catalyzed, copper-mediated C-H acylation of azoles, using stable thioester electrophiles and a weak base. Previously difficult substrates such as imidazole derivatives, base-sensitive groups and aliphatic electrophiles could be used in good yields. Furthermore, the reaction showed potential for orthogonal cross-coupling, tolerating aryl bromides, chlorides and boronic acid esters. Elementary steps were investigated by H/D-exchange, initial rate experiments and in operando X-ray absorption spectroscopy. In situ generated bimetallic Pd-Cu complexes are proposed to be the catalytically active species, operating via a non-canonical thioester activation pathway in conjunction with a rate-limiting Cu-phosphite-mediated C-H deprotonation. The catalytic C–H acylation of heteroarenes is a key transformation in organic chemistry, although traditional methods often rely on unstable electrophiles and harsh conditions. Here, the authors present a mild palladium-catalyzed, copper-mediated strategy that employs stable thioester electrophiles and a weak base, enabling broad substrate tolerance along with mechanistic insights obtained via H/D exchange, kinetic analyses and in situ X-ray absorption spectroscopy.