Base-Free C-N Cross-Electrophile Coupling

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Metal-catalyzed carbon-nitrogen (C-N) cross-coupling is vital in medicinal chemistry, typically requiring basic conditions.
• Existing methods often involve philicity-matched reactions, limiting substrate scope and functional group tolerance.

Purpose of the Study:

• To develop a novel, base-free C-N cross-coupling method.
• To enable C-N bond formation using electrophilic nitrogen precursors.
• To expand the utility of C-N cross-electrophile coupling (XEC) in complex molecule synthesis.

Main Methods:

• A nickel-catalyzed, philicity-mismatched C-N cross-electrophile coupling (XEC) reaction was developed.
• Electrophilic nitrogen precursors were synthesized from various starting materials, including C-H bonds and olefins.
• Mechanistic studies using Ni(II)-aryl-amido intermediates were performed to understand selectivity.

Main Results:

• The new protocol operates under mild, base-free conditions, accommodating base-sensitive functional groups.
• The reaction demonstrates broad functional group tolerance and is suitable for late-stage functionalization.
• A two-step, one-pot N-phenothiazination, C-N XEC sequence was successfully applied to bioactive molecules.

Conclusions:

• This work establishes a new paradigm for base-free C-N bond construction via philicity-mismatched XEC.
• The method facilitates the synthesis of diverse secondary amines, tertiary amines, and unsymmetrical diamines.
• Understanding the mechanism provides a rationale for controlling C-X XEC selectivity.