Oxidative Amide Coupling from Functionally Diverse Alcohols and Amines Using Aerobic Copper/Nitroxyl Catalysis

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Amide bond formation is crucial in synthesizing drug molecules.
• Developing efficient and selective catalytic methods for amide synthesis is an ongoing challenge.

Purpose of the Study:

• To develop a robust and scalable aerobic oxidative coupling method for amide bond synthesis.
• To leverage copper and 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO) catalysis for efficient C-N bond formation.

Main Methods:

• Utilizing a Cu/ABNO catalytic system for the oxidative coupling of alcohols and amines.
• Employing aerobic conditions and mild reaction parameters.
• Investigating the reactivity of alcohols with β-heteroatoms (O, F, N, Cl).

Main Results:

• The method successfully synthesized amide bonds in diverse drug-like molecules.
• The reaction demonstrated broad functional group tolerance (>20 groups) and scalability (15 mmol).
• Catalyst's steric properties enabled chemoselective amidation of primary amines over secondary amines.

Conclusions:

• The Cu/ABNO catalyzed reaction provides a mild, efficient, and selective route to amide synthesis.
• The method is suitable for large-scale synthesis with readily available catalysts and water as the only by-product.
• Retention of stereocenters in reactants ensures the integrity of complex molecules.