Generalizing arene C-H alkylations by radical-radical cross-coupling

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Synthesizing diverse molecular libraries for drug optimization is challenging, especially introducing complex alkyl groups late-stage.
• Direct C(sp2)-H bond alkylation of arenes is desirable but often requires prefunctionalization or harsh conditions.
• Traditional Friedel-Crafts alkylations lack functional group tolerance and selectivity for late-stage applications.

Purpose of the Study:

• To develop a general and modular method for direct C(sp2)-H bond alkylation of arenes.
• To enable late-stage introduction of diverse alkyl fragments into complex molecular scaffolds.
• To overcome limitations of existing alkylation methods in drug discovery.

Main Methods:

• A new strategy termed 'dynamic orbital selection' for selective radical species coupling.
• In situ formation of two distinct radical species.
• Copper-catalyzed differentiation of radical species based on binding properties.

Main Results:

• Demonstrated a general and modular reaction for direct alkylation of native arene C-H bonds.
• Utilized abundant and benign alcohols and carboxylic acids as alkylating agents.
• Successfully introduced complex alkyl groups into sophisticated drug scaffolds late-stage.

Conclusions:

• The 'dynamic orbital selection' strategy overcomes limitations of Friedel-Crafts alkylations.
• This method provides access to vast new chemical space for drug optimization.
• The coupling platform is expected to be broadly applicable for challenging radical transformations.