Radicals, atoms or molecules that readily react with other substances to form new bonds, are useful tools for building complex substances such as pharmaceuticals. But even when a radical is generated efficiently, the reaction cannot continue unless the catalyst returns to its original state. A KAIST research team has developed a new strategy that balances radical generation and catalyst regeneration, broadening the possibility of using even substrates that are difficult to activate to synthesize the complex molecules needed for pharmaceuticals and other applications.

KAIST (President Choongsik Bae) announced on September 20 that a research team led by Professor Sarah Yunmi Lee from the Department of Chemistry has developed a method that uses a ligand, a molecule that attaches to a metal catalyst and controls its properties, to effectively regulate the process by which a copper catalyst generates a radical and then returns to its original state.

The team used a cyclopropenimine (CPI)-based ligand to tune the copper catalyst’s redox behavior, helping it generate radicals and return to its active state.

In this study, the team used tertiary alkyl halides, compounds where bromine or chlorine is attached to a tertiary carbon center, as starting materials. When the copper catalyst breaks this bond, a highly reactive radical is generated, and this radical then forms a new carbon–carbon bond with another part of the same molecule, creating a ring-shaped structure. The process is similar to tying the two loose ends of a string together to form a loop. This is called a radical cyclization reaction.

When the team compared several types of ligands, they found that that generating more radicals did not necessarily lead to more of the desired product. Some ligands were very effective at generating radicals but produced almost none of the final product.

The best-performing CPI-based ligand, however, allowed radical generation and catalyst regeneration to proceed in balance. If the catalyst is compared to a worker performing a task repeatedly, the CPI ligand acts as a helper that lets the worker move on to the next task without stopping after finishing one.

As a result, the team synthesized in high yields 3,3-disubstituted oxindoles, compounds with a ring framework relevant to medicinal chemistry used in pharmaceuticals and bioactive substances.

Notably, substrates bearing bromine reacted efficiently even at room temperature. The team also succeeded in reacting substrates with strong carbon-chlorine bonds that do not break easily. This demonstrated that even tertiary alkyl chlorides, which had previously been difficult to handle, can now be used to synthesize a range of oxindole compounds that were difficult to make before.

The key finding of this study is that generating radicals well is not enough on its own. Rather than simply raising the reactivity of a single step, the team showed that balancing the entire catalytic cycle, including both radical generation and catalyst regeneration, makes it possible to design more efficient catalysts and extend the approach to new reactions.

This principle could expand the range of challenging substrates available for chemical synthesis. It may also help researchers develop more efficient methods for constructing complex molecules relevant to pharmaceuticals and other bioactive compounds under milder conditions.

Professor Sarah Yunmi Lee said, " This study shows that efficient radical generation alone is not sufficient and that the different processes within a catalytic cycle must proceed in balance." She added, "We expect this approach can be applied to the development of new radical-based catalytic reactions that make use of challenging substrates that have previously been difficult to activate."

The study, with Sarah Jang, a student in the integrated master’s–PhD program in the Department of Chemistry at KAIST, and Seongryeol Jeung, who earned a master’s degree at Yonsei University, as co-first authors, and with Sumin Kim, an integrated master's and PhD student in the Department of Chemistry at KAIST, also participating, was published online on August 3 in the Journal of the American Chemical Society (JACS), an international journal published by the American Chemical Society (ACS).

※ Paper title: Cyclopropenimine-Enabled Redox Control in Copper-Catalyzed Radical Cyclization to 3,3-Disubstituted Oxindoles
※ DOI: 10.1021/jacs.6c09015
※ Author information: Sarah Jang (KAIST, co-first author), Seongryeol Jeung (Yonsei University, co-first author), Sumin Kim (KAIST, third author), Sarah Yunmi Lee (KAIST, corresponding author)

This research was supported by the Samsung Science and Technology Foundation under Project SSTF-BA2202-06.