Team discovers electrochemical method for highly selective single-carbon insertion in aromatic rings

A research team discovered an electrochemical method which allows highly selective para-position insertion in polysubstitated pyrroles. Their approach has important applications in synthetic organic chemistry, especially in the field of pharmaceutical products.

Their work is published in the Journal of the American Chemical Society July 14.

“We have decided to take up the long -standing challenge to carry out the insertion of a single carbon in aromatic rings with precise positional control,” said Mahito Atobe, professor, engineering faculty of the National University of Yokohama.

The transformations that modify the aromatic rings are at the heart of pharmaceutical synthesis and materials. However, the insertion of a single carbon atom in a specific position – in particular the position of para – has remained extremely rare. The para position describes the location of the substituents, the atoms which replace a hydrogen atom on a molecule. In the single carbon insertion approach, researchers add a single carbon atom in the carbon frame of a molecule. This extends a carbon chain or widens a ring of a carbon unit.

“Our objective was to develop a new electrochemical method which allows this transformation selectively and efficiently, while obtaining mechanistic information on how the electronic structure of the substrate controls the insertion position,” said Atobe.

This study presents a new concept for the chemistry of the insertion of a carbon and extends the chemical toolbox of a researcher to synthesize the Aromatic Polysubstités (hetero) compounds. The polysubstituted pyrrolas are organic compounds which have a pyrrole ring and several substituents are attached to it. These compounds play a crucial role in various fields, such as natural products, pharmaceutical products and functional materials. They are of particular interest in pharmaceutical products, where they are fundamental for many approved drugs.

“We discovered an electrochemical method which allows a very selective para -plaque insertion in polysubstituted pyrroles – an unprecedented transformation,” said Naoki Shida, associate professor, engineering faculty, Yokohama National University.

This reaction is activated by intermediaries of radical discs and is governed by the electronic properties of nitrogen protection groups.

“Our results establish a new strategy for selective molecular editing of the site of the aromatic rings, expanding the toolbox for synthetic organic chemistry,” said Shida.

The team has demonstrated the reaction of the expansion of the electrochemical ring using Diazo α-H esters as an equivalent of anion carbynyl. This approach allowed an effective insertion of a single carbon in a range of polysubstituted pyrroles, offering structurally diverse pyridine derivatives. They checked the position of insertion by electronic disruption by the N (PG) protection group, and have reached unprecedented paralyard insertion by introducing an electronic transplant protection group into pyrrole derivatives.

The team used in situ spectroscopy and theoretical calculations to support the reaction mechanism involving a radical cation intermediary by distance. Spectroscopy and calculations suggest that discomfort radical cation intermediaries are involved, facilitating the migration of carbon atoms on the aromatic ring and allowing insertion in different positions.

Approved drugs such as the Netuperant, Esoméprazole, Pyridoxine and Opicapone contain rings of benzene and pyridine with more than three substituents. These drugs are important drugs for large -scale health challenges, such as Parkinson’s disease, stomach ulcers or the control of nausea induced by chemotherapy.

To synthesize these compounds, the researchers used several methods, such as coupling reactions, carbon-hydrogen functionalization and cyclization reactions. The unique carbon insertion is still another approach that scientists have used to modify the Aromatic Polysubstités (hetero) compounds. The unique carbon insertion approach considerably modifies the structure of parent skeletons. But until this moment, control of the insertion position had been an important challenge for researchers. The new electrochemical method of the team has a new concept for the chemistry of the insertion of a carbon.

For the future, the next stage of the team is to extend the scope of this reaction to a wider range of heteraromatic compounds and complex molecules, including pharmaceutical intermediaries.

“We also aim to integrate this methodology into flow electrolysis systems to improve scalability and efficiency. In the end, our objective is to establish a general platform for precise molecular editing of aromatic frames using electricity as a clean and controllable motor force,” said Atobe.

The research team includes Tatsuya Morimoto, Su-Gi Chong and Azusa Kikuchi from the National University of Yokohama, Japan; Yoshio Nishimoto from the University of Kyoto, Japan; Taku Suzuki-Osborne from the University of Bath, United Kingdom; Kazuhiro Okamoto from the University of Toyama, Japan; Tomoki Yoneda from the International University of Health and Well-Being, Japan; And Daisuke Yokogawa from the University of Tokyo, Japan.