The method has applications in organic chemistry, particularly within the pharmaceutical industry.
A team of scientists has developed an electrochemical technique that enables precise, para-position single-carbon insertion into polysubstituted pyrroles. This advancement holds significant promise for synthetic organic chemistry, particularly in the development of pharmaceutical compounds.
Their work was recently published in the Journal of the American Chemical Society.
“We set out to address the longstanding challenge of achieving single-carbon insertion into aromatic rings with precise positional control,” said Mahito Atobe, Professor, Faculty of Engineering, Yokohama National University.
Chemical transformations that alter aromatic rings are fundamental to creating pharmaceuticals and advanced materials. However, introducing a single carbon atom at a specific site, especially at the para position, has been extremely difficult to achieve. The para position refers to the specific arrangement of atoms in a molecule, where substituents (atoms that replace a hydrogen atom) are located opposite each other on an aromatic ring.
In this method, a single carbon atom is added directly into the molecular framework. This can extend a carbon chain or increase the size of a ring structure by one carbon atom, offering a powerful new tool for molecular design.
Introducing a Novel Electrochemical Strategy
“Our goal was to develop a new, electrochemically driven method that enables this transformation selectively and efficiently, while gaining mechanistic insights into how the electronic structure of the substrate controls the insertion position,” said Atobe. This study presents a novel concept for single-carbon insertion chemistry and expands a researcher’s chemical toolbox for synthesizing polysubstituted (hetero)aromatic compounds. Polysubstituted pyrroles are organic compounds that have a pyrrole ring and multiple substituents are joined to it. These compounds play a crucial role in diverse fields, such as natural products, pharmaceuticals, and functional materials. They hold particular interest for pharmaceuticals, where they are fundamental to many approved drugs.
“We discovered an electrochemical method that enables highly selective para-position single-carbon insertion into polysubstituted pyrroles—an unprecedented transformation,” said Naoki Shida, Associate Professor, Faculty of Engineering, Yokohama National University. This reaction is enabled with distonic radical cation intermediates and is governed by the electronic properties of nitrogen-protecting groups. “Our findings establish a new strategy for site-selective molecular editing of aromatic rings, expanding the toolkit for synthetic organic chemistry,” said Shida.
Mechanism and Proof of Concept
The team demonstrated the electrochemical ring expansion reaction using α-H diazo esters as a carbynyl anion equivalent. This approach allowed efficient single-carbon insertion into a range of polysubstituted pyrroles, affording structurally diverse pyridine derivatives. They controlled the insertion position through electronic perturbation by the N-protecting group (PG), and achieved unprecedented para-selective insertion by introducing an electron-withdrawing protecting group to the pyrrole derivatives.
The team used in-situ spectroscopy and theoretical calculations to support the reaction mechanism involving a distonic radical cation intermediate. The spectroscopy and calculations suggest distonic radical cation intermediates are involved, facilitating carbon-atom migration on the aromatic ring and enabling insertion at different positions.
Approved drugs like Netupitant, Esomeprazole, Pyridoxine, and Opicapone contain benzene and pyridine rings with more than three substituents. These drugs are important medications for wide-ranging health challenges, such as Parkinson’s disease, stomach ulcers, or the control of chemotherapy-induced nausea. To synthesize these compounds, researchers have used multiple methods, such as coupling reactions, carbon-hydrogen functionalization, and cyclization reactions.
Single-carbon insertion is yet another approach scientists have used to modify polysubstituted (hetero)aromatic compounds. The single-carbon insertion approach significantly alters the structure of the parent skeletons. But up to this point in time, controlling the insertion position had been a significant challenge for researchers. The team’s novel electrochemical method introduces a new concept for single-carbon insertion chemistry.
Looking to the Future
Looking ahead, the team’s next step is to expand the scope of this reaction to a broader range of heteroaromatic compounds and complex molecules, including pharmaceutical intermediates.
“We also aim to integrate this methodology into flow electrolysis systems to improve scalability and efficiency. Ultimately, our goal is to establish a general platform for precise molecular editing of aromatic frameworks using electricity as a clean and controllable driving force,” said Atobe.
Reference: “Electrochemical Single-Carbon Insertion via Distonic Radical Cation Intermediates” by Tatsuya Morimoto, Yoshio Nishimoto, Taku Suzuki-Osborne, Su-Gi Chong, Kazuhiro Okamoto, Tomoki Yoneda, Azusa Kikuchi, Daisuke Yokogawa, Mahito Atobe and Naoki Shida, 14 July 2025, Journal of the American Chemical Society.
DOI: 10.1021/jacs.5c06798
The research team includes Tatsuya Morimoto, Su-Gi Chong, and Azusa Kikuchi from Yokohama National University, Japan; Yoshio Nishimoto from Kyoto University, Japan; Taku Suzuki-Osborne from University of Bath, United Kingdom; Kazuhiro Okamoto from University of Toyama, Japan; Tomoki Yoneda from International University of Health and Welfare, Japan; and Daisuke Yokogawa from The University of Tokyo, Japan.
This work is funded by PRESTO and JSPS KAKENHI grants.
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