A research team has discovered an electrochemical method that allows highly selective para-position single-carbon insertion into polysubstituted pyrroles. Their approach has important applications in synthetic organic chemistry, especially in the field of pharmaceuticals.
Their work is published in the Journal of the American Chemical Society on July 14.
"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. Transformations that modify aromatic rings are central to pharmaceutical and materials synthesis. However, inserting a single carbon atom into a specific position—especially the para-position—has remained extremely rare. Para position describes the location of substituents, those atoms that replace a hydrogen atom on a molecule. In the single carbon insertion approach, researchers add a single carbon atom into a molecule's carbon framework. This lengthens a carbon chain or expands a ring by one carbon unit.
"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.
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 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.
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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