Restructuring a molecule without rebuilding it from scratch is an increasingly important goal in modern organic chemistry. Skeletal editing is an approach that helps chemists explore new chemical structures and simplify the synthesis of molecules with potential pharmaceutical applications. But in case of functional groups such as esters, skeletal editing remains difficult because their carbon–carbon and carbon–oxygen bonds are resistant to cleavage under mild conditions.
Now, a research team led by Professor Toshifumi Dohi of Ritsumeikan University, along with Mr. Yusuke Yoto also of Ritsumeikan University, and Dr. Hideyasu China of Doshisha Women's College of Liberal Arts, developed a unique solution inspired by nature. Their study, made available online in the JACS Au journal on July 26, 2026, demonstrates that introducing chlorine into hydroxycoumarins can trigger a sequence of bond-cleavage and bond-forming events that removes a carbonyl group and reconstructs the molecule as a coumaranone.
"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," says Prof. Dohi.
The idea started from the team's interest in a "cut-to-fuse" strategy. In this concept, halogenation first "cuts" bonds in a cyclic compound, generating a reactive chain, before a subsequent intramolecular reaction "fuses" the chain into a new heterocyclic structure. The researchers projected that a similar process might enable carbonyl deletion—the net removal of a carbonyl unit from hydroxycoumarins.
The initial experiments produced an unexpected result. The team had been investigating fluorine-induced carbon–carbon bond cleavage, but fluorination caused the hydroxycoumarin to fragment into separate products.
"Chlorine changed the reaction pathway completely," says Prof. Dohi. Treating a hydroxycoumarin with N-chlorosuccinimide (NCS) led to formation of a chlorinated intermediate that underwent decarbonylative reconstruction, ultimately producing a coumaranone rather than fragmenting the molecule.
The researchers then optimized the reaction and found that the transformation could proceed at room temperature in near-neutral conditions, without transition-metal catalysis. Under the optimized conditions, hydroxycoumarin was treated with NCS, water, and sodium acetate in ethyl acetate, followed by potassium phosphate. The method produced the model coumaranone in more than 99% yield. According to the researchers, this represents the mildest nonenzymatic conditions reported to date for simultaneous cleavage of the C–C and C–O bonds involved in this type of carbonyl deletion.
This reaction also proved broadly applicable. Hydroxycoumarins containing methoxy, halogen, azide, phenol, carboxylic acid, and boron-containing functionalities were tolerated, as were substrates bearing substituted aromatic rings, naphthalene, pyridine, thiophene, furan, and aliphatic groups. Several products were obtained in good to excellent yields, demonstrating that the method can accommodate considerable structural diversity. A related cyclic β-keto ester also underwent reconstruction, showing that the chemistry is not limited to a single substrate class.
Mechanistic experiments highlighted the importance of selective chlorination. When the chlorinating reagent was omitted, the starting material was recovered unchanged. Stepwise experiments showed that chlorination occurred first, followed by decarboxylation and intramolecular cyclization. The team also demonstrated the method's practical potential. On a gram scale, the model reaction produced the desired coumaranone in 91% yield. The resulting scaffold could then be further modified, including conversion to a benzofuran, introduction of a quaternary carbon center, and transition-metal-catalyzed coupling reactions. In this case, a coumaranone bearing a boron pinacol ester was useful as being directly applicable for palladium-catalyzed coupling without isolation.
Taking inspiration from halogenation-driven transformations found in natural product biosynthesis, researchers developed a new way to rethink carbonyl deletion and molecular scaffold construction. Their "cut-to-fuse" strategy provides an efficient route from hydrocoumarins to coumaranones while avoiding the harsh conditions usually required for ester bond cleavage. This study proves to be useful for future approaches in medicinal chemistry, where streamlined molecular editing is increasingly valuable for rapidly generating structurally diverse compounds.
Reference
Title of original paper: Halogen-Guided Reconstructive Transformation of Hydroxycoumarin to Coumaranone
Journal: JACS Au
DOI: https://doi.org/10.1021/jacsau.6c00801
About Ritsumeikan University, Japan
Ritsumeikan University is one of the most prestigious private universities in Japan. With an unwavering objective to generate social symbiotic values and emergent talents, it aims to emerge as a next-generation research-intensive university. It will enhance researcher potential by providing support best suited to the needs of young and leading researchers, according to their career stage. Ritsumeikan University also endeavors to build a global research network as a "knowledge node" and disseminate achievements internationally, thereby contributing to the resolution of social/humanistic issues through interdisciplinary research and social implementation.
Website: http://en.ritsumei.ac.jp/
Ritsumeikan University Research Report: https://www.ritsumei.ac.jp/research/radiant/eng/
About Professor Toshifumi Dohi from Ritsumeikan University, Japan
Professor Toshifumi Dohi is a Professor in the College of Pharmaceutical Sciences at Ritsumeikan University, Japan. He holds a Ph.D. in Pharmaceutical Sciences from The University of Osaka, which he received in 2005. His research focuses on synthetic organic chemistry, pharmaceutical chemistry, reaction development, environmentally sustainable synthesis, and hypervalent iodine chemistry, with an emphasis on developing innovative methods for synthesizing pharmaceutical and functional molecules. Professor Dohi has authored more than 160 scientific publications, including numerous articles in leading international journals.
Funding information
T.D. and K.K. acknowledge support from JSPS KAKENHI grant number 19K05466 (T.D.) and 23K04827 (K.K.), JST CREST grant number JPMJCR20R1, and the Ritsumeikan Global Innovation Research Organization (R-GIRO) project. H.C. also acknowledges support from JSPS KAKENHI grant number 24K09738. Y.Y. thanks JST the establishment of university fellowships towards the creation of science technology innovation grant number JPMJSP2101.
