Palladium-Catalyzed Three-Component Synthesis of Phenothiazines

The formation of aromatic carbon-heteroatom bonds has traditionally been achieved by nucleophilic aromatic substitution or via the copper-mediated Ullman reaction. The palladium-catalyzed formation of aromatic C-N bonds extensively developed by Hartwig and Buchwald has provided a powerful alternative. While the aryl amination reaction is applicable even to aryl chlorides and activated phenols, the analogous C-O and C-S bond forming reactions have attracted less attention. In a medicinal chemistry project, we have developed a palladium-catalyzed reaction that enable the formation of one C-S and one CN bond from thiophenols, amines, and and bromo-iodobenzenes in a one-flask operation. Herein, we report the application of this discovery to the synthesis of the promazine family of antipsychotics.