Recently, a team led by Li Chaozhong at Jiangxi University of Science and Technology (JXUST) and the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, reported in Nature Communications a new class of dialkyl phthalimidyl phosphite reagents featuring a unique N–O–P bonding structure. The work overcomes the long-standing difficulty of Markovnikov-selective hydrophosphonylation of unactivated alkenes. The paper is titled “Cobalt-catalyzed Markovnikov-selective hydrophosphonylation of unactivated alkenes enabled by phthalimidyl phosphite reagents.” JXUST’s School of Rare Earths is both the first author affiliation and the first corresponding affiliation. Li Chaozhong, academic vice president of JXUST, Zhu Lin, associate researcher at SIOC, and Dr. Chai Linxiang are co-corresponding authors.
In olefin hydrophosphonylation, controlling regioselectivity is key. Under the classic Markovnikov rule, hydrogen adds to the carbon bearing more hydrogens, while the phosphonyl group attaches to the more substituted carbon, yielding a branched product. That matters for extractant design, because branched structures often offer better rare-earth separation selectivity. Yet the synthesis has been difficult. Traditional methods mostly work with activated alkenes, not ordinary unactivated ones lacking electron-withdrawing groups. Phosphonyl radical routes are feasible but tend naturally toward anti-Markovnikov products. Even recently reported palladium systems struggle to steer unactivated alkenes down the Markovnikov path.
Rather than focusing solely on the catalyst, the team took a different tack: redesigning the phosphorus reagent. Their phthalimidyl phosphite looks simple but is subtly clever. It is an efficient radical trap. During the reaction, it not only captures the alkyl radical but also generates a phthalimidyl radical with strong oxidizing power (E°red > 2.0 V vs NHE), enough to reoxidize CoII to CoIII—solving the central bottleneck of catalyst regeneration in similar systems.
The catalytic system is highly practical. The reaction proceeds at room temperature, using cheap diphenylsilane as the hydrogen source and a cobalt-salen complex as the catalyst. Within hours, various unactivated alkenes are converted into the target phosphonates with high yields (up to 76%) and exclusive Markovnikov selectivity, while tolerating hydroxyl, ester, halogen, heterocycle and other common functional groups. More strikingly, the method enables late-stage modification of complex molecules. The team converted olefin side chains in derivatives of the anti-inflammatory drug ibuprofen and the lipid-lowering drug gemfibrozil into phosphonates in a single final step, with good yields. This gives chemists considerable flexibility for rapidly building molecular libraries and optimizing molecular structures.
Compared with traditional methods that rely on precious metals, the cobalt catalyst is cheap, Earth-abundant and low in toxicity, in line with green chemistry. The new phosphorus reagent is also easy to prepare and stable, paving the way for future industrial applications. The study not only solves a long-standing synthetic challenge but also demonstrates the power of “reagent design driving reaction innovation.” The strategy could extend to other hydrofunctionalization reactions, offering a new paradigm for deeply integrating radical chemistry and transition-metal catalysis. The work was supported by the National Natural Science Foundation of China, the Chinese Academy of Sciences, the Ministry of Science and Technology, the State Key Laboratory of Coordination Chemistry at Nanjing University, and JXUST.
Paper link: https://doi.org/10.1038/s41467-026-77482-4
