Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage...

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Cyclic secondary amines, particularly piperidines, are crucial scaffolds in pharmaceutical agents.
• Direct functionalization of N-unprotected cyclic amines is challenging, limiting their synthetic utility.

Purpose of the Study:

• To develop a novel catalytic method for the direct conversion of cyclic secondary amines to lactams.
• To enable efficient functionalization of important pharmaceutical building blocks and complex molecules.

Main Methods:

• A copper and nitroxyl co-catalyzed aerobic oxidative coupling reaction with water.
• Dehydrogenation of N-unprotected cyclic secondary amines to form lactams.

Main Results:

• The developed method efficiently converts various cyclic secondary amines to lactams under mild conditions.
• The reaction tolerates a wide range of functional groups, demonstrating broad applicability.
• The method was successfully applied to the late-stage functionalization of complex molecules, including bromodomain inhibitors.

Conclusions:

• This work provides a valuable new synthetic route for accessing lactams from readily available cyclic secondary amines.
• The mild and versatile method expands the toolkit for medicinal chemistry and organic synthesis, particularly for late-stage functionalization.