A Photo- and Electrochemistry-Triggered Redox-Neutral Cyclization Strategy to Access Cyclic N-CF₃ Amides

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• The synthesis of trifluoromethyl (CF3)-containing amides has advanced, but remains restricted to acyclic structures.
• Access to cyclic N-CF3 amides, such as isoindolinones, is limited, hindering their application in various chemical fields.

Purpose of the Study:

• To develop a novel synthetic route for constructing N-CF3 isoindolinones.
• To explore the utility of N-CF3 redox-active esters in cyclization reactions.
• To elucidate the mechanism underlying the N-CF3-enabled cyclization.

Main Methods:

• Redox-neutral cyclization of amino acid-derived N-CF3 redox-active esters.
• Photo- or electrochemical activation strategies.
• Mechanistic investigations including electronic and conformational analyses.

Main Results:

• Successful synthesis of N-CF3 isoindolinones was achieved.
• The N-CF3 group was found to uniquely facilitate the cyclization through electronic effects.
• Enhanced conformational flexibility and reduced overoxidation propensity were observed due to the N-CF3 moiety.

Conclusions:

• A novel and efficient method for synthesizing N-CF3 isoindolinones has been established.
• The unique electronic properties of the N-CF3 group are crucial for enabling this transformation.
• This work expands the synthetic toolbox for accessing valuable trifluoromethylated cyclic compounds.