Inverting Conventional Chemoselectivity in Pd-Catalyzed Amine Arylations with Multiply Halogenated Pyridines

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Palladium-catalyzed amination is crucial for C-N bond formation.
• Selective functionalization of mixed halides (Br/Cl) remains a synthetic challenge.
• Developing efficient ligands is key to improving catalytic reactions.

Purpose of the Study:

• To report a new catalyst system for selective chloride functionalization.
• To optimize Pd-catalyzed amination of 3,2- and 5,2- Br/Cl-pyridines.
• To identify an effective ligand for this transformation.

Main Methods:

• Screening of diphosphine ligands for Pd-catalyzed amination.
• Ligand parametrization for reaction optimization.
• Synthesis and characterization of pyridine derivatives.

Main Results:

• Identification of 1,1'-bis[bis(dimethylamino)phosphino]ferrocene (DMAPF) as a highly effective ligand.
• Selective functionalization of the chloride in 3,2- and 5,2- Br/Cl-pyridines was achieved.
• DMAPF enabled efficient palladium-catalyzed amination under optimized conditions.

Conclusions:

• DMAPF is a novel and uniquely effective ligand for selective chloride functionalization in Pd-catalyzed amination.
• The developed catalyst system offers a new synthetic route for functionalizing challenging pyridine substrates.
• This work expands the scope of selective cross-coupling reactions.