Aryl Halide Carboxylation via Decarboxylative Metal-Halogen Exchange

Area of Science:

• Organic Chemistry
• Synthetic Methodology

Background:

• Metal-halogen exchange is crucial for functionalizing aromatic halides.
• Traditional methods often rely on hazardous and sensitive organometallic reagents.
• There is a need for safer, more accessible reagents for carboxylation reactions.

Purpose of the Study:

• To report a unique mode of metal-halogen exchange for aromatic halide carboxylation.
• To demonstrate the use of bench-stable carboxylic acid salts as precursors for metalating agents.
• To develop a mild, broadly applicable carboxylation procedure avoiding hazardous reagents and specialized equipment.

Main Methods:

• Utilizing potassium salts of carboxylic acids as both CO2 source and metalating agent.
• Performing metal-halogen exchange and subsequent carboxylation under mild conditions.
• Employing experimental and computational studies to elucidate the reaction mechanism.

Main Results:

• A novel decarboxylative metal-halogen exchange mechanism was proposed and supported by evidence.
• The method successfully carboxylated a range of aromatic halides using readily available carboxylic acid salts.
• The procedure was applied to carbon isotope labeling of biologically relevant molecules, including late-stage labeling.

Conclusions:

• Carboxylic acid salts offer a safe and convenient alternative to traditional organometallic reagents for metal-halogen exchange.
• This method provides a versatile and mild route for the carboxylation of aromatic halides.
• The developed protocol facilitates carbon isotope labeling for applications in chemical biology and medicinal chemistry.