Electrochemical Synthesis and Transformation of Heteroaromatic Compounds via Mediated Electrolysis

Heteroaromatic compounds are ubiquitous structural motifs in pharmaceuticals, natural products, and functional materials. Accordingly, the development of efficient methods for their construction, functionalization, and skeletal transformation has attracted considerable attention. Among the available approaches, electrochemical synthesis has emerged as a sustainable platform that enables the generation of highly reactive intermediates through an electrode-driven electron transfer. Despite these advantages, direct electrolysis often provides limited control over reactivity, because electron transfer occurs directly between the substrate and the electrode surface. To address this limitation, indirect electrolysis employing redox mediators has emerged as a versatile strategy for generating reactive intermediates and expanding the scope of the electrochemical synthesis. Building on these principles, we have developed a range of electrochemical transformations of heteroaromatic compounds that exploit the distinctive reactivity of mediator-derived intermediates. Using both halogen-based and non-halogen mediators, these methods enable the efficient synthesis and skeletal transformation of diverse heteroaromatic frameworks under mild conditions. In this Account, we describe our studies on mediator-controlled electrochemical transformations of heteroaromatic compounds, focusing on halogen-mediated oxidative cyclizations and skeletal transformations as well as DABCO-mediated radical processes. Particular emphasis is placed on the design of reactive intermediates and the mechanistic principles that govern their reactivities. The first section focuses on bromide-mediated electrochemical C-S bond formation for the synthesis of thienoacenes. Electrogenerated electrophilic bromenium ion species, represented as [Br+] equivalents, activate sulfur atoms to form a bromosulfonium intermediate, thereby enabling oxidative cyclization. We then discuss halogen-mediated electrochemical transformations of indole derivatives. Electrophilic [Br+] species selectively activate the C3 position of the indole framework. Furthermore, structurally complex natural product frameworks were accessed through mediator-controlled cyclization reactions, in which the choice of mediator dramatically influenced the reaction pathway and product architecture. In the final section, we describe the DABCO-mediated electrochemical synthesis of benzophosphole oxides. Electrochemically generated DABCO radical cations (DABCO•+) promote hydrogen-atom transfer (HAT) from P-H bonds to generate phosphorus-centered radicals. These reactive intermediates subsequently undergo annulation reactions, providing efficient access to phosphorus-containing heteroaromatic compounds. These studies illustrate how redox mediators can control activation modes under electrochemical conditions and, thereby, unlock distinct reaction pathways. A detailed understanding of the structures and reactivities of electrochemically generated intermediates is essential for the rational design of new transformations. We hope that this Account will stimulate further advances in indirect electrolysis and inspire the development of new electrochemical strategies for molecular construction and skeletal transformations.