Hexahydro-1H-phenothiazine moieties can be synthesized by domino aziridine ring opening with o-halothiophenols followed by copper-catalyzed Goldberg coupling–cyclization with good to excellent yields. Less reactive o-chlorothiophenols are also successfully utilized for the domino reaction to synthesize phenothiazine derivatives. This methodology is successfully applied in the synthesis of phenothiazine skeletons containing biologically active molecules such as antihistamine agents.