Conspectus 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.

An electrochemical strategy for the synthesis of carbazole frameworks has been developed. Bromidemediated anodic oxidation generates electrophilic [Br+] species, which selectively oxidize the indole core and trigger a subsequent intramolecular endo-cyclization/aromatization sequence, thereby furnishing carbazole derivatives via a bioinspired pathway. Notably, the electrochemical protocol enables controlled, gradual generation of the reactive species, effectively suppressing overoxidation and preventing the formation of inseparable brominated byproducts that are typically observed under conventional chemical conditions. Mechanistic studies, including cyclic voltammetry, support preferential oxidation of the indole moiety and highlight the key role of bromide as a redox mediator. This operationally simple and efficient method provides a valuable approach to carbazole-containing scaffolds and is expected to facilitate the total synthesis of indolosesquiterpene natural products.

The electrochemical intermolecular annulation of diarylphosphine oxides with alkynes for the synthesis of benzo[b]phosphole oxides has been reported. The reaction proceeded under transition‐metal‐ and oxidant‐free conditions via indirect electrolysis, using 1,4‐diazabicyclo[2.2.2]octane as a mediator. High‐surface‐area carbon electrodes, such as carbon felt and reticulated vitreous carbon, are essential for this reaction. Several diarylphosphine oxides and alkynes were applied to electrochemical annulation, and the corresponding benzo[b]phosphole oxides were obtained. Mechanistic studies suggested that the reaction proceeds via radical intermediates generated through multiple pathways.

Boranils, difluoroboron complexes with imine and phenoxy moieties, were synthesized by iodide-promoted demethylative borylation. The use of appropriate amounts of BF3•OEt2, Bu4NI, and Et3N enabled the highly efficient synthesis of boranils. Boranils containing heteroaromatics and highly π-extended boranils were also readily obtained by this method. Their physical properties were studied and the properties were consistent with those calculated by DFT calculations.

Aziridines are valuable motifs in organic synthesis due to their biological activities and their utility as synthetic intermediates. Although electrochemical methods have been developed for aziridine synthesis, these approaches rely on anodic oxidation. This study reports the first cathodic reduction-promoted aziridine formation using dichloramine-T as a nitrogen source. The reaction conditions were optimized via Gaussian process regression. Overall, this strategy enables aziridine formation with broad substrate scope, providing a practical platform that expands the electrochemical synthesis toolbox.

Electrochemical synthesis has emerged as a powerful platform for environmentally sustainable chemical transformations. When integrated with flow chemistry, electrosynthetic processes exhibit enhanced scalability, making them suitable for industrial applications. Recently, the integration of electrochemical flow systems with informatics techniques has accelerated the optimization of reaction conditions. Data‐driven strategies facilitate rapid exploration of multidimensional parameter spaces, enabling identification of optimal reaction conditions with high efficiency. These advances have enabled the development of automated optimization systems. This review highlights recent progress in combining electrosynthesis, flow chemistry, and computational tools, focusing on representative examples that illustrate efficient optimization protocols and autonomous reaction development. By showcasing these developments, we discuss how the integration of these technologies is driving innovation in electrochemical synthesis.

We report a novel electrochemical oxidation of benzyl alcohols. We found that trifluoroethanol plays a role as a hydrogen atom transfer (HAT) mediator, enabling the oxidation of electron-deficient substrates that are difficult to directly oxidize on electrode surfaces. Density functional theory calculations, cyclic voltammetry measurements, and constant potential electrolysis studies supported the proposed HAT mechanism. Moreover, the obtained carbonyl compounds could be functionalized in an electrochemical one-pot manner, further highlighting their synthetic utility.

Cyanomethylation of carbonyl compounds affords a β-hydroxy nitrile, which is very useful in the field of synthetic organic chemistry. Although several electrochemical methods have also been reported to achieve cyanomethylation of carbonyl compounds, dehydration as a major side reaction is a significant issue that needs to be prevented. An electrochemical flow reactor, free from side reactions through rapid removal of the reaction solution from the electrode surface, enables the electrochemical cyanomethylation of aldehydes in acetonitrile without any dehydrated side products. To find the "best" reaction conditions for each starting material, we used machine learning (ML) models. In addition, comparing the ML models constructed using various molecular descriptors contributed to understanding the critical molecular properties to proceed the electrochemical cyanomethylation. Our cyanomethylation using a flow system went to completion with a semi-catalytic amount of electrical input, which is not consistent with the conventional basic mechanism, and DFT calculations suggest a radical mechanism.

We report a divergent electrochemical strategy for the bioinspired synthesis of mavacurane- and akuammiline-type alkaloid frameworks from a common indole-malonate precursor. By tuning the redox mediator, selective N-C or C-C bond formation was achieved. Iodide-mediated electrolysis promoted iodination of the malonate carbanion, followed by intramolecular nucleophilic cyclization to furnish the mavacurane core. In contrast, ferrocene-mediated oxidation generated a malonate-centered radical that afforded the akuammiline skeleton.

Amidyl radicals and sulfonamidyl radicals are widely used in the field of organic synthesis. In particular, the electrochemical oxidation of amides in the presence of bases is one of the most practical methods for generating amidyl radicals. However, it is often difficult to observe the "true" radical precursor, such as an amide anion and/or a hydrogen bonding complex with an amide and a base. We found that a sulfonamide and Bu4NOAc form a 1:1 hydrogen bonding complex by spectroscopic experiments. Cyclic voltammetry suggested that 1:1 hydrogen bonding complexes should be oxidized predominantly under the optimized conditions to afford a sulfonamidyl radical via the proton-coupled electron transfer (PCET) process by the oxidation of the complex. Thus-generated sulfonamidyl radicals could be used in the electrochemical synthesis of a variety of benzosultams.

Thienoacenes are significant compounds as organic materials. One of the most efficient ways to synthesize thienoacenes is to form multiple C–S bonds in a single step. Because unprotected S–H bonds are easily oxidized to S–S bonds, S-Me protected substrates are commonly used for the purpose. However, their reactivity is insufficient, and one-step construction of multiple C–S bonds is still challenging. We herein report the electrochemical synthesis of thienoacenes from S-methoxymethyl (MOM)-protected diarylacetylenes. In the presence of Bu4NBr as a halogen mediator, electrochemical double C–S cyclization of diarylacetylenes bearing two MOM groups proceeded to afford [1]benzothieno[3,2-b][1]benzothiophene (BTBT) derivatives. While S-Me or S-p-methoxybenzyl (PMB)-protected diarylacetylenes did not afford BTBT, BTBT was selectively obtained when a substrate protected with S-MOM groups was used. The S-MOM protection strategy is also effective for the electrochemical synthesis of a more π-expanded thienoacene such as dibenzo[d,d′]thieno[3,2-b,4,5-b′]dithiophene (DBTDT). Thienoacenes are crucial for organic electronics, yet synthesizing them via one-step C–S bond formation remains challenging. Here, the authors demonstrate an electrochemical approach using S-methoxymethyl protected diarylacetylenes in the presence of Bu4NBr as a halogen mediator, achieving efficient double C–S cyclization and expanding thienoacene synthesis.

An electrochemical method was developed to convert α,β-unsaturated aldehydes into carboxylic acid derivatives via cyanosilylation, isomerization, and nucleophilic addition. This reaction is more sustainable than the usual electrochemical organic reaction because this reaction proceeds catalytically with active species generated by a very small amount of electricity. Furthermore, scale-up synthesis with a flow reactor has been achieved.

N,O-Bidentate difluoroboron complexes were synthesized from (2-methoxyaryl)pyridines by iodide-promoted demethylative borylation. In the presence of Bu4NI and Et3N, (2-methoxylaryl)pyridines smoothly reacted with BF3·OEt2 to afford the N,O-bidentate difluoroboron complexes. The amounts of BF3·OEt2, Bu4NI, and Et3N strongly influenced the reaction efficiency. The optimal conditions were determined through Bayesian optimization, and several N,O-bidentate difluoroboron complexes were obtained efficiently under the reaction conditions. The resulting complexes exhibited fluorescent properties with large Stokes shifts, which were in good agreement with the calculated properties.

Anodic oxidation-promoted SNAr reactions of electron-rich aryl fluoride were developed. The anodic oxidation of 4-fluoroanisole in hexafluoroisopropyl alcohol (HFIP) with K2CO3 led to SNAr-type hexafluoroisopropoxylation, and the reaction was completed with a catalytic electrical input. The results of cyclic voltammetry suggest that the radical cation of 4-fluoroanisole, which would react with the alkoxide of HFIP, is generated. Electron transfer between the intermediate and the starting material constructs the catalytic cycle, and the elimination of fluoride from the Meisenheimer complex produces the desired compound.

Paired electrosynthesis, which utilize both anodic and cathodic events in electrolysis, enables attractive transformations with higher current efficiency than conventional electrosynthesis. The electrochemical flow technique has been widely employed to ensure stable reaction conditions and mitigate issues stemming from mass transfer. In this study, the electrochemical Meinwald rearrangement of styrene oxides was investigated, yielding aldehydes as intermediates, followed by the nitromethylation of aldehydes to produce beta-nitro alcohols. These reactions were achieved with catalytic electrical input, enabling the conversion of various styrene oxides into the corresponding beta-nitro alcohols

The production of cyclic amines, which are vital to the pharmaceutical industry, relies on energy-intensive thermochemical hydrogenation. Herein, we demonstrate the electrocatalytic hydrogenation of nitrogen-containing aromatic compounds, specifically pyridine, at ambient temperature and pressure via a membrane electrode assembly with an anion-exchange membrane. We synthesized piperidine using a carbon-supported rhodium catalyst, achieving a current density of 25 mA cm–2 and a current efficiency of 99% under a circular flow until 5 F mol–1. Quantitative conversion of pyridine into piperidine with 98% yield was observed after passing 9 F mol–1, corresponding to 65% of current efficiency. The reduction of Rh oxides on the catalyst surface was crucial for catalysis. The Rh(0) surface interacts moderately with piperidine, decreasing the energy required for the rate-determining desorption step. The proposed process is applicable to other nitrogen-containing aromatic compounds and could be efficiently scaled up. This method presents clear advantages over traditional high-temperature and high-pressure thermochemical catalytic processes.

Electrochemical synthesis of [1]benzothieno[3,2-b][1]benzothiophene (BTBT) derivatives from S-methoxymethyl (MOM)-protected bis(o-sulfanylphenyl)acetylene derivatives is described. In the presence of Bu4NBr as a halogen mediator, electrochemical double C–S cyclization proceeded smoothly. MOM protection of thiols was essential for the reaction. While S-Me or S-p-methoxybenzyl (PMB)-protected bis(o-sulfanylphenyl)acetylenes did not afford BTBT and bromocyclized products were predominantly obtained, BTBT was selectively obtained when a similar compound protected with an S-MOM group was used in the reaction. Addition of H2O was significant for the reaction as both a sacrificial agent and a trapping agent for the eliminated MOM group. A variety of symmetrical and asymmetrical BTBT derivatives were obtained under the optimal conditions. Control experiments and DFT calculations suggest that the double-cyclization did not proceed concertedly, but rather in a stepwise fashion. The S-MOM protection strategy is also effective for the electrochemical synthesis of a more π-expanded thienoacene such as dibenzo[d,d’]thieno[3,2-b;4,5-b’]dithiophene (DBTDT).

An electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines using a proton-exchange membrane (PEM) reactor was developed. Cyanoarenes were then reduced to the corresponding benzylamines at room temperature in the presence of ethyl phosphate. The reduction of nitroarenes proceeded at room temperature, and a variety of anilines were obtained. The quinoline reduction was efficiently promoted by adding a catalytic amount of p-toluenesulfonic acid (PTSA) or pyridinium p-toluenesulfonate (PPTS). Pyridine was also reduced to piperidine in the presence of PTSA.

Catalysts for Claisen rearrangement have been intensively studied to overcome the need for high temperature. However, previous studies have encountered challenges, such as the need for heating, a long reaction time, and/or the need for equivalent amounts of catalyst. In this study, we introduce an effective electrogenerated boron-based Lewis acid catalyst for the aromatic Claisen rearrangement, which proceeds in a few minutes at ambient temperature. Generation of the electrogenerated Lewis acid catalyst is discussed based on NMR analysis and DFT calculations.

AbstractAlkynylation of aldehydes initiated by cathodic reduction was performed. The cathodic alkynylation required only a semi‐catalytic amount of electricity to consume the starting material completely. Cyclic voltammetry and some control experiments suggest that the electron‐generated base derived from the cathodic reduction of benzaldehyde promotes alkynylation.