Carbonylative Ring Expansion of Cyclic Carboxylic Acids

Area of Science:

• Organic Chemistry
• Synthetic Methodology
• Photochemistry & Electrochemistry

Background:

• Cyclic carboxylic acids are versatile building blocks in organic synthesis.
• Efficient methods for ring expansion are crucial for accessing diverse heterocyclic scaffolds.
• Existing methods often require harsh conditions or lack broad applicability.

Purpose of the Study:

• To develop a novel synthetic method for the carbonylative ring expansion of cyclic carboxylic acids.
• To enable the efficient synthesis of lactams, lactones, and thiolactones.
• To explore the application of this method to complex molecules and drug synthesis.

Main Methods:

• Photochemical or electrochemical single electron reduction of cyclic α-heterocarboxylic acids.
• Generation of ketyl radicals, followed by spin-center shift and ring opening.
• Radical and anionic pathways involving hydrogen atom transfer, radical coupling, and intramolecular acyl substitution.
• Application to 2-aryl-substituted cyclopropane and cyclobutane carboxylic acids.

Main Results:

• Successful conversion of cyclic α-heterocarboxylic acids into lactams, lactones, and thiolactones.
• Demonstration of ring expansion by incorporating the carboxylic acid's exocyclic carbonyl group.
• Application to substituted cyclopropanes and cyclobutanes, proceeding via C-C bond homolysis and radical-polar crossover.
• Integration with α-amino C-H carboxylation for molecular editing and synthesis of pharmaceutical intermediates.

Conclusions:

• A versatile and efficient method for carbonylative ring expansion of cyclic carboxylic acids has been established.
• The protocol offers a streamlined approach to valuable heterocyclic compounds.
• This methodology serves as a powerful molecular editing platform for complex molecule synthesis.