A dual catalytic system for visible-light-driven decarboxylative arylation of aliphatic carboxylic acids

Background

The field of molecular synthesis is foundational to advancements in pharmaceuticals, materials science, and chemical biology. Central to this field is the ability to efficiently construct complex molecules with precise control over their structure and functionality. Aliphatic carboxylic acids, including amino acids and fatty acids, are abundant and structurally diverse feedstocks, making them attractive starting materials for the synthesis of value-added compounds. However, expanding the accessible chemical space for drug discovery and materials development requires new methods that can reliably and selectively form carbon–carbon bonds from these simple precursors. There is a pressing need for broadly applicable, efficient, and operationally simple synthetic strategies that minimize hazardous byproducts and enable rapid diversification of molecular libraries.

Current approaches to forming carbon–carbon bonds from aliphatic carboxylic acids typically rely on pre-activation steps, such as conversion to organometallic reagents or redox-active esters, which add complexity, cost, and safety concerns to the process. Traditional cross-coupling reactions often require harsh conditions, expensive or toxic reagents, and generate significant waste. Additionally, many methods lack generality, being limited in substrate scope or functional group tolerance, and may not be compatible with sensitive or structurally complex molecules. These limitations hinder the efficient exploration of chemical space and slow the development of new pharmaceuticals and materials, underscoring the need for innovative solutions that address these shortcomings.

Technology

This technology provides a versatile and efficient method for the decarboxylative arylation of aliphatic carboxylic acids, enabling the direct formation of carbon–carbon bonds between a wide range of carboxylic acid substrates and substituted aryl compounds. The process employs a dual catalytic system: a photoredox catalyst (typically an iridium or ruthenium complex) and an organometallic catalyst (most often a nickel complex), in the presence of a suitable ligand, base, and an aprotic polar solvent such as DMF. The reaction mixture, which can include amino acids, fatty acids, or other aliphatic acids as substrates, is irradiated with visible light—commonly blue LEDs or compact fluorescent lamps—at room temperature. This triggers decarboxylation of the acid and subsequent cross-coupling with an aryl partner bearing a leaving group (halide, triflate, phosphonate, or tosylate), resulting in the efficient synthesis of arylated aliphatic products. The method is highly modular, accommodating a broad range of functional groups and substitution patterns, and is supported by extensive optimization data covering catalyst, ligand, base, solvent, and light source selection.

What differentiates this technology is its operational simplicity, broad substrate scope, and mild reaction conditions, which collectively address longstanding limitations in molecular synthesis. Unlike traditional cross-coupling methods that often require pre-activated organometallic reagents, high temperatures, or harsh conditions, this approach uses readily available carboxylic acids and aryl electrophiles, proceeding efficiently at room temperature under visible light. The dual catalytic system leverages the synergistic effects of photoredox and nickel catalysis, enabling decarboxylative activation and cross-coupling in a single step, while minimizing hazardous byproducts. Extensive experimentation demonstrates the method’s compatibility with diverse substrates—including all standard amino acids and a variety of fatty acids—and its ability to deliver high yields (up to 92%) across a wide range of products. This makes the technology particularly valuable for applications in drug discovery, natural product synthesis, and materials science, where rapid and flexible molecular diversification is essential.

Benefits

• Enables efficient formation of carbon-carbon bonds via decarboxylation of aliphatic carboxylic acids under mild conditions.
• Utilizes a dual catalytic system combining visible-light photoredox and nickel organometallic catalysis for high reactivity and selectivity.
• Operates at room temperature with visible light, reducing energy consumption and avoiding harsh reaction conditions.
• Broad substrate scope including amino acids, fatty acids, and various substituted aryl halides or pseudohalides, allowing diverse molecular architectures.
• Avoids the need for pre-activated organometallic reagents, simplifying synthesis and minimizing hazardous byproducts.
• Compatible with a wide range of functional groups and substitution patterns, enhancing applicability in pharmaceuticals and materials science.
• Offers operational simplicity and scalability with well-defined catalyst, ligand, base, and solvent systems.

Applications

• Pharmaceutical intermediate synthesis
• Drug discovery molecular libraries
• Functionalized materials development
• Natural product derivatization
• Fine chemical manufacturing

Additional info

This dual catalytic method achieves decarboxylative arylation of aliphatic carboxylic acids, including amino and fatty acids, by combining iridium or ruthenium photoredox catalysts with nickel-based organometallic catalysts and ligands. Under visible light at room temperature, the reaction couples these acids with aryl halides, triflates, or tosylates using a base in aprotic polar solvents. This process enables carbon-carbon bond formation via carbon dioxide extrusion.