Carboxylic Acids as Adaptive Functional Groups in Metallaphotoredox Catalysis

Area of Science:

• Organic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Palladium-catalyzed cross-coupling reactions have increased the use of arene-rich molecules in drug discovery.
• There is a growing need for C(sp³)-rich scaffolds to improve drug solubility and stability.
• Classical two-electron chemistry has limitations in accessing challenging molecular motifs.

Purpose of the Study:

• To outline recent progress in developing methodologies for the direct functionalization of aliphatic and (hetero)aromatic carboxylic acids.
• To highlight the use of metallaphotoredox catalysis for transforming carboxylic acids into valuable functional groups.
• To emphasize the potential of these methods for late-stage functionalization in drug discovery.

Main Methods:

• Utilizing metallaphotoredox catalysis with first-row transition metals (nickel, copper).
• Employing native carboxylic acid functionality without preactivation.
• Leveraging photoredox catalysis to enable decarboxylative transformations.

Main Results:

• Bench-stable aliphatic carboxylic acids can be alkylated, arylated, aminated, and trifluoromethylated.
• Aryl carboxylic acids can undergo halogenation and borylation, creating new cross-coupling entry points.
• The developed methods demonstrate broad functional group tolerance, enabling late-stage functionalization.

Conclusions:

• Metallaphotoredox catalysis provides direct access to functionalize diverse carboxylic acids.
• These methods offer powerful tools for late-stage functionalization in drug discovery and synthesis.
• Further development of selective transformations is needed to expand the scope and applicability of these protocols.