Electrochemical Single-Carbon Insertion via Distonic Radical Cation Intermediates

Area of Science:

• Organic Chemistry
• Electrochemistry
• Medicinal Chemistry

Background:

• Polysubstituted (hetero)aromatic compounds are crucial building blocks in pharmaceuticals.
• Efficient synthesis of these compounds is vital for drug discovery and development.
• Existing methods for carbon insertion often lack selectivity or require harsh conditions.

Purpose of the Study:

• To develop a novel electrochemical method for single-carbon insertion into (hetero)aromatic compounds.
• To specifically target the synthesis of polysubstituted pyridine derivatives.
• To investigate the mechanism and control of regioselectivity in the carbon insertion process.

Main Methods:

• Electrochemical oxidation of pyrrole derivatives to generate radical cation intermediates.
• Nucleophilic attack of diazo compounds on the radical cation intermediates.
• Employing *in situ* spectroscopy and theoretical calculations to elucidate reaction mechanisms.
• Modulating *N*-protecting groups to control the position of carbon insertion.

Main Results:

• A novel electrochemical method for single-carbon insertion into pyridines was established.
• Polysubstituted pyridine derivatives were synthesized with high efficiency.
• Unprecedented *para*-selective insertion was achieved by using electron-withdrawing *N*-protecting groups.
• Distonic radical cation intermediates were identified as key species in the reaction mechanism.

Conclusions:

• The developed electrochemical method offers a versatile and efficient route for synthesizing polysubstituted (hetero)aromatic compounds.
• The study provides new mechanistic insights into single-carbon insertion chemistry.
• This work expands the synthetic toolbox for medicinal chemists and organic synthesis.