'Cut-to-Fuse' Chemistry Turns Hydroxycoumarins Into Useful Coumaranones

Chemists in Japan have developed a new way to restructure a common class of molecules called hydroxycoumarins into a different, pharmaceutically useful scaffold called a coumaranone, using a technique they call "cut-to-fuse." The work, led by Professor Toshifumi Dohi of Ritsumeikan University with Yusuke Yoto, also of Ritsumeikan University, and Dr. Hideyasu China of Doshisha Women's College of Liberal Arts, was published in JACS Au on July 26, 2026.

The technique belongs to a growing field called skeletal editing, which lets chemists restructure a molecule without rebuilding it from scratch — useful for exploring new chemical structures and simplifying the synthesis of molecules with potential pharmaceutical uses. Skeletal editing has been especially difficult for functional groups such as esters, whose carbon-carbon and carbon-oxygen bonds resist breaking under mild conditions.

"We aimed to develop a new way of editing molecular skeletons for esters, one that could break difficult bonds under mild conditions and immediately reconstruct the molecule into a useful framework," Dohi said. The team's approach uses chlorine to trigger a chain reaction: the halogen first "cuts" bonds in the molecule, generating a reactive intermediate, and a follow-up reaction then "fuses" it into a new ring structure — hence the name "cut-to-fuse."

The discovery came partly by accident. The team had originally been testing whether fluorine could cleave carbon-carbon bonds in hydroxycoumarins, but fluorination simply broke the molecule into separate fragments. "Chlorine changed the reaction pathway completely," Dohi said. Treating a hydroxycoumarin with a chlorine-based reagent called N-chlorosuccinimide instead produced a chlorinated intermediate that reconstructed itself into a coumaranone, removing a carbonyl group in the process.

Once optimized, the reaction ran at room temperature under near-neutral conditions, without any metal catalyst, and produced the model coumaranone in more than 99% yield — what the researchers describe as the mildest nonenzymatic conditions reported so far for this type of transformation. The method worked across a wide range of hydroxycoumarins carrying different chemical groups, including methoxy, halogen, azide, phenol, carboxylic acid, and boron-containing substituents, and also worked on a related cyclic compound called a β-keto ester.

The team also demonstrated the reaction on a larger, gram scale, producing the coumaranone in 91% yield, and showed that the resulting scaffold could be further modified, including conversion into a benzofuran and use directly in palladium-catalyzed coupling reactions.