Combined C-H amination and intermolecular alkyne insertion for a three-component cyclization

In the past two decades, palladium and norbornene (Pd/NBE) co-catalyzed cyclization has become an important method for the synthesis of natural products, drugs, and other materials. Herein, we disclose a Pd/NBE co-catalyzed three-component ipso intermolecular alkyne insertion and cyclization reaction. The reaction pathway first undergoes C-H amination, which results in substituents on both ortho-sites of the aryl palladium intermediate. Its huge steric hindrance poses a challenge for the subsequent alkyne insertion. Mechanistic studies through density functional theory calculations reveal that aryl-norbornyl-palladacycle intermediates do not react with alkynes, and migration insertion is the rate-determining step in the ipso cyclization. In addition, we determine the key role of cesium carbonate in the cyclization process.