A research team led by Ji-Min Yang from the College of Chemical Sciences, University of Chinese Academy of Sciences, reported a novel class of monophosphine ligands based on the norbornene skeleton. This work introduces the design concept of "three-dimensional (3D) isosteric benzene rings" from medicinal chemistry into phosphine ligand development, using rigid norbornene to simulate the benzene ring core in traditional biarylphosphines. While maintaining key geometric features, this approach endows the ligand with superior stereo and electronic properties. The catalytic system based on this ligand achieves highly efficient C–N coupling with extremely low palladium loadings (down to 2 ppm), achieving a maximum conversion number (TON) of 490,000, the highest reported to date for this type of reaction. The article was published as an open access Research Article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.
Background information:
The Buchwald–Hartwig coupling reaction is an important method for constructing C–N bonds and has wide applications in pharmaceuticals, pesticides, and functional materials. Over the past thirty years, monodentate biarylphosphine ligands, represented by Buchwald-type biphenyldialkylphosphine, have become one of the most successful ligand systems for this reaction due to their moderate steric hindrance and good electron-donating ability.
Meanwhile, the "escape the plane" strategy (i.e., replacing the planar aromatic ring with a saturated three-dimensional framework) has been widely applied in medicinal chemistry and materials science. Inspired by this, the team proposed the following question: Can this concept be applied to phosphine ligand design? That is, to use a rigid three-dimensional saturated framework to simulate the structure and function of the benzene ring in biarylphosphine, thereby further enhancing the spatial regulation ability and electronic properties of the ligand while retaining its advantageous geometric features.
Highlights of this article:
1. Modular synthesis, flexible and adjustable structure. The research team used brominated or iodobornene as starting materials to efficiently construct a series of norbornene skeleton monophosphine ligands (L1 – L8) in two to three steps. This synthetic route is highly modular: by changing the substituents (Cy, Ph, iPr) on the phosphine atom and the aryl substituents on the norbornene skeleton, the electronic and steric properties of the ligands can be easily controlled, facilitating subsequent performance optimization.
2. Structural verification: Key geometric features of biarylphosphine were successfully simulated. Using single-crystal X-ray diffraction and DFT theoretical calculations, the authors systematically compared the structural parameters of the norcamphene ligand and the classical ligand Cy-JohnPhos. The results show that although the norcamphene skeleton elongates the interatomic spacing of the skeleton carbon atoms, the dihedral angle effect allows the aryl substituents to be spatially compressed, successfully simulating the "P-aromatic ring" spatial relationship in biarylphosphine. More importantly, the buried volume percentage (%Vbur = 61.7%) of the norcamphene ligand L1 is significantly greater than that of Cy-JohnPhos (56.4%), while L7, containing a tert-butyl group, reaches 67.3%, exhibiting a stronger spatial shielding effect. Furthermore, detailed DFT conformational analysis revealed significant differences in the conformational behavior of the norcamphene skeleton ligand and the biaryl ligand during catalytic cycling, providing a theoretical basis for understanding their superior performance (see full article for details).
3. Catalytic performance: Record-breaking TON of 490,000. The ligand L7 (containing a tert-butyl substituted aromatic ring at the 3,5-position) exhibits exceptional performance in palladium-catalyzed C–N coupling to triarylamines, achieving a TON of 490,000, the highest reported value for this transformation to date. This ligand system can also be used for the efficient synthesis of various commercially available triarylamine OLED molecules, maintaining extremely low palladium loading even in 10-gram scale-up experiments, demonstrating promising prospects for practical applications.
4. Highly efficient coupling under room temperature and mild conditions. This catalytic system not only performs excellently under high-temperature reflux conditions but also demonstrates remarkable performance under milder conditions. When the temperature drops to 70°C, only 0.01 mol% Pd is needed to quantitatively convert diphenylamine and bromobenzene to triphenylamine within 2 hours; even at room temperature, the same conversion can be achieved within 8 hours using 2.5 mol %Pd , and it is equally effective for chlorobenzene. Based on this, various substrates (such as N-methylaniline, indole, sterically hindered diarylamines, and the commercially available OLED molecule p-TPD) can all yield the target products in high yields at room temperature.
5. Broad substrate scope, compatible with complex drug molecules. Catalytic systems based on this type of ligand have extremely broad substrate versatility, applicable not only to secondary amines, sterically hindered anilines, aryl chlorides and heteroaryl substrates, but also successfully applied to the late-stage modification of various drug molecules such as paroxetine, clopidogrel, amoxapine, and duloxetine, demonstrating excellent functional group compatibility and practical application potential.
Summary and Outlook:
In summary, this work, based on a "three-dimensional benzene ring simulation" strategy, introduced the norbornene skeleton into phosphine ligand design, modularly constructing a novel class of single phosphine ligands. These ligands effectively simulate the key geometric features of biarylphosphines structurally, while providing stronger and more tunable steric hindrance and superior electron-donating ability. In palladium-catalyzed C–N coupling reactions, this ligand system achieved excellent catalytic efficiency, reaching 490,000 TON in the synthesis of triarylamines. The system maintained excellent catalytic activity even under various challenging substrates and room temperature reaction conditions.
The design concept of norcamphene skeleton is expected to be extended to other rigid three-dimensional skeletons. The different bond lengths and bond angles provided by different skeletons will open up more possibilities for the design of new ligands and catalysts in the future.
This work was published as a Research Article in CCS Chemistry, with Associate Professor Ji-Min Yang from the University of Chinese Academy of Sciences as the corresponding author and postdoctoral researcher Yi-Xiong Dong as the first author. This work was supported by the National Natural Science Foundation of China.
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About the journal: CCS Chemistry is the Chinese Chemical Society's flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem .
About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman's Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/ .
