The research team of Xumu Zhang and Genqiang Chen at Southern University of Science and Technology has achieved a new breakthrough in the synthesis and application of benzoxoxetine ligands. They efficiently and modularly constructed benzoxoxetine ligands through a tandem nucleophilic addition S N Ar reaction. The related findings, titled "Redox-Free and Modular Access to Oxacyclic Phosphines Enabled by a Robust Ambiphilic Phosphine Reagent," were recently published as an open access Reserach Article in CCS Chemistry .
Background information:
The benzoxoxetine skeleton, with its electron-rich, rigid, and air-stable characteristics, is considered a novel and advantageous ligand skeleton. Over the past 15 years, benzoxoxetine ligands have been widely used in transition metal-mediated asymmetric hydrogenation and cross-coupling reactions. Since the development of representative ligands such as BIBOP and BI-DIME by Professor Wenjun Tang's group, chiral cyclic phosphine ligands such as iBu -OxaPhos, WingPhos, and LalithPhos have been widely applied in key reactions such as cross-coupling and asymmetric hydrogenation. However, the synthesis of these ligands still faces many challenges.
Traditional synthetic methods primarily rely on linear, multi-step reactions, obtaining optically pure products through the resolution of phosphine oxide intermediates. This inevitably involves redox steps, which are not only cumbersome but also limit scalability and cost-effectiveness. Another strategy involves the condensation reaction of chiral secondary phosphines with ketals, but this method often suffers from poor diastereoselectivity, requiring additional resolution or redox operations to obtain optically pure ligands. Furthermore, existing methods are mostly limited to single-phosphine or C₂-symmetric bisphosphine structures, making it difficult to achieve modular construction of structurally diverse oxocyclic phosphine ligands. Therefore, an efficient and modular strategy for synthesizing benzoxoxocyclic phosphine ligands is of significant research importance.
Highlights of this article :
1. Development and efficient synthesis of amphiphilic trivalent phosphine reagents ( phosphine click reagents )
To address the aforementioned issues, the team designed and synthesized a series of amphiphilic trivalent phosphine reagents (also known as Phosphine Click Reagents), and plans to synthesize oxoheterocyclic phosphine skeletons through a sequence nucleophilic addition S N Ar cyclization process. First, the team devised a simple two-step, one-pot strategy to achieve gram-scale synthesis of a series of amphiphilic trivalent phosphine reagents.
2. One-step efficient preparation of oxoheterocyclic phosphine ligands
Building upon these foundations, the research team conducted a preliminary exploration of the feasibility of this reaction. Using 1a and benzaldehyde 2a as model substrates and tetrahydrofuran as solvent, only an equivalent amount of potassium tert-butoxide was needed to obtain the oxonocyclic phosphine ligand 3aa in 95% yield and with a dr value greater than 20:1. After establishing the optimal conditions, the authors investigated the applicability of the substrates. The results showed that the amphiphilic trivalent phosphine reagents prepared by the above scheme could react smoothly and maintain excellent diastereoselectivity. In addition, various aromatic aldehydes, heteroaromatic aldehydes, and even alkyl aldehydes could also yield corresponding oxonocyclic phosphine ligands with excellent results.
3. Substrate-inducing strategy for efficient preparation of chiral oxoheterocyclic phosphine ligands
Beyond modular construction of phosphine ligands, the advantages of this strategy are further demonstrated in the synthesis of chiral oxocyclic phosphine ligands. When using optically pure chiral aldehydes as substrates, chiral ligands can be directly synthesized via a chirality-inducible strategy without additional chiral resolution processes. Furthermore, when using epoxides as substrates, benzoxane-6 oxocyclic phosphine ligands can be further synthesized.
4. The product, oxoheterocyclic phosphine ligands, can be prepared on a gram-scale basis and has a wide range of applications.
To further demonstrate the practicality of this strategy, the authors also conducted gram-scale experiments and corresponding synthetic transformations. This modular synthetic method can be scaled up to the gram scale while maintaining good yields and diastereoselectivity. Furthermore, the chiral ligand 3ezp exhibited good reactivity and enantioselectivity control in Rh-catalyzed asymmetric dehydrogenation cross-coupling and palladium-catalyzed asymmetric axial chiral Heck coupling reactions. 3ezs showed excellent results in iridium-catalyzed asymmetric hydrogenation reactions, yielding chiral compound 13 with an er value of 96.9:3.1. In addition, the racemic chiral ligands 3en and 3fn also showed excellent results in palladium-catalyzed cross-coupling reactions, efficiently promoting the cross-coupling of C, CN, and CO bonds.
5. Revealing the reaction pathway through controlled experiments and theoretical calculations.
To verify the reaction pathway, the research team conducted control experiments and theoretical calculations. The results of the control experiments and related calculations show that the addition of a strong base is conducive to the formation of highly nucleophilic phosphine potassium species, promoting nucleophilic addition and subsequent aromatic nucleophilic substitution processes. The high diastereoselectivity originates from the subsequent intramolecular aromatic nucleophilic substitution process with a high energy barrier, rather than the nucleophilic addition process.
Summary and Outlook:
In summary, the team developed an efficient and modular strategy for the synthesis of benzoxyheterocyclic phosphine skeletons. Compared to classical strategies, this strategy is unique in that it avoids the chiral resolution process, and the unique chiral induction strategy also provides a novel approach for the synthesis of novel chiral oxyheterocyclic phosphine ligands.
This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Guangdong Provincial Key Research and Development Program, the Shenzhen Basic Research Key Project, and the China Postdoctoral Science Foundation.
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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/ .
CCS Chemistry
10.31635/ccschem.025.202506531
Experimental study
Not applicable
Redox-Free and Modular Access to Oxacyclic Phosphines Enabled by a Robust Ambiphilic Phosphine Reagent
8-Dec-2025
There is no conflict of interest to report.