Selective sp³ C-H alkylation via polarity-match-based cross-coupling

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• Carbon-hydrogen (C-H) bond functionalization is crucial for molecular construction.
• There is a significant need for sp³ C-H alkylation to introduce sp³ C-alkyl groups.
• Existing methods often focus on C(sp³)-C(sp²) coupling, leaving a gap for sp³ C-H bond transformations.

Purpose of the Study:

• To develop a selective method for sp³ C-H alkylation.
• To enable the replacement of sp³ C-H bonds with sp³ C-alkyl groups.
• To provide a versatile tool for synthesizing complex organic molecules.

Main Methods:

• A novel polarity-match-based strategy for selective sp³ C-H alkylation.
• Integration of photoredox, nickel, and hydrogen-atom transfer catalysis.
• Simultaneous operation of three catalytic cycles for C-H functionalization and alkyl-alkyl coupling.

Main Results:

• Achieved selective sp³ C-H alkylation via hydridic C-H bond abstraction and alkyl-alkyl fragment coupling.
• Demonstrated high selectivity for the α-C-H bonds of amines, ethers, and sulfides.
• The method is applicable to pharmaceutically relevant molecular architectures.

Conclusions:

• The developed cross-coupling protocol offers a powerful new approach for organic synthesis.
• This methodology facilitates both de novo synthesis and late-stage functionalization.
• The selective sp³ C-H alkylation expands the toolkit for creating complex molecules.