Phenylboronic Ester-Activated Aryl Iodide-Selective Buchwald-Hartwig-Type Amination toward Bioactivity Assay

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Buchwald-Hartwig amination is a crucial reaction for forming carbon-nitrogen bonds.
• Developing selective and efficient amination methods, particularly for aryl iodides, remains an active area of research.
• The use of activators to enhance catalytic reactions is a key strategy in synthetic chemistry.

Purpose of the Study:

• To develop a phenylboronic ester-activated Buchwald-Hartwig-type amination reaction.
• To achieve selective amination of aryl iodides in the presence of aryl chlorides and bromides.
• To investigate the mechanism and kinetics of the developed reaction and screen products for bioactivity.

Main Methods:

• Nickel-catalyzed (Ni(acac)₂) amination of aryl iodides with aryl/aliphatic amines.
• Inclusion of phenylboronic ester as a key activator in the reaction system.
• Mechanistic studies involving the formation of an "ate complex" and chemical kinetics analysis.

Main Results:

• The developed reaction smoothly affords corresponding amines in high yields, exclusively functionalizing aryl iodides.
• Phenylboronic ester is essential for the reaction to proceed, acting as an amine activator.
• Kinetic studies reveal first-order kinetics for aryl iodides, base, and Ni(acac)₂, and zero-order kinetics for amines and phenylboronic ester.
• Some amination products exhibited significant antifungal activity upon bioactivity screening.

Conclusions:

• A novel and efficient phenylboronic ester-activated amination protocol has been established for selective aryl iodide functionalization.
• The mechanistic insights suggest a crucial role for phenylboronic ester in activating amines.
• The developed method provides access to potentially bioactive amine compounds, highlighting its utility in medicinal chemistry.