Ni-Catalyzed Carbon-Carbon Bond-Forming Reductive Amination

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Tertiary benzhydryl amines are valuable pharmaceutical building blocks.
• Traditional synthetic routes often face limitations in efficiency and scope.
• Developing novel catalytic methods is crucial for accessing these compounds.

Purpose of the Study:

• To develop a novel three-component, Ni-catalyzed reductive coupling reaction.
• To enable the convergent synthesis of tertiary benzhydryl amines.
• To provide a more efficient alternative to traditional reductive amination.

Main Methods:

• Utilizing in situ generated iminium ions from secondary N-trimethylsilyl amines and benzaldehydes.
• Employing a three-component, Ni-catalyzed reductive coupling strategy.
• Investigating the reaction mechanism through mechanistic studies.

Main Results:

• Successfully synthesized diverse tertiary benzhydryl amines.
• Demonstrated a single-step synthesis of the antimigraine drug flunarizine.
• Achieved high-yielding derivatization of pharmaceuticals like paroxetine and metoprolol.
• Mechanistic studies supported a sequential oxidative addition pathway.

Conclusions:

• The developed Ni-catalyzed coupling offers a powerful and convergent approach for synthesizing tertiary benzhydryl amines.
• This methodology provides a valuable tool for medicinal chemistry and drug discovery.
• The reaction is applicable to both intermolecular and intramolecular couplings for diverse benzhydryl amine synthesis.