Electrochemical C-O and C-N Arylation using Alternating Polarity in flow for Compound Libraries

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Electrochemistry

Background:

• Aryl halide etherification and amination are key reactions in medicinal chemistry for structure-activity relationship (SAR) studies.
• Electrochemical methods offer advantages in functional group tolerance and nucleophile scope over traditional synthetic routes.
• Existing electrochemical methods lack robust and scalable workflows for library synthesis.

Purpose of the Study:

• To develop an automated, flow-based electrochemical platform for synthesizing C-X (X=NH, OH) arylation compound libraries.
• To optimize reaction conditions using Design of Experiments (DoE) for broad substrate scope and high yields.
• To establish a reproducible and scalable method for generating diverse chemical libraries.

Main Methods:

• Automated synthesis platform utilizing flow electrochemistry for C-X arylation.
• Comprehensive Design of Experiments (DoE) for protocol optimization.
• Potentiostatic alternating polarity strategy to prevent electrode passivation.
• Utilized commercially available equipment for library generation.

Main Results:

• Achieved high yields across over 30 aryl halide scaffolds, diverse amines, and alcohols (including serine in peptides).
• Successfully generated libraries of anilines and aryl ethers through automated reaction sequences.
• Demonstrated reaction feasibility in air without supporting electrolyte.
• Ensured high reproducibility over consecutive runs.

Conclusions:

• The developed platform provides a powerful and automated method for synthesizing nucleophile-independent C-X arylation compound libraries.
• Flow electrochemistry offers a scalable and robust solution for rapid library generation in drug discovery.
• The use of potentiostatic alternating polarity enhances the efficiency and applicability of electrochemical synthesis in flow.