Decarboxylative C(sp³ )-O Cross-Coupling.

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Alkyl aryl ethers are crucial in medicinal and agricultural applications.
• Existing synthesis methods for alkyl aryl ethers, like C(sp2)-O coupling and SN2 reactions, have limitations.
• Catalytic C(sp3)-O cross-coupling of alkyl electrophiles with phenols is an underexplored synthetic strategy.

Purpose of the Study:

• To develop a novel and efficient method for synthesizing alkyl aryl ethers.
• To explore the potential of a tandem photoredox and copper catalysis for C(sp3)-O cross-coupling.
• To overcome limitations associated with current alkyl aryl ether synthesis techniques.

Main Methods:

• Employed a tandem photoredox and copper catalysis system.
• Utilized N-hydroxyphthalimide (NHPI) esters derived from alkyl carboxylic acids as coupling partners.
• Reacted NHPI esters with phenols under mild reaction conditions.

Main Results:

• Successfully achieved decarboxylative C(sp3)-O coupling of alkyl NHPI esters with phenols.
• Synthesized a diverse range of alkyl aryl ethers, including those derived from natural products and drug molecules.
• Demonstrated broad functional group tolerance and complementarity to existing synthetic methods.

Conclusions:

• The developed tandem catalysis offers a powerful new disconnection strategy for alkyl aryl ether synthesis.
• This method provides access to valuable compounds under mild and efficient conditions.
• The approach expands the synthetic toolbox for medicinal and agricultural chemistry.