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Microflow Synthesis of Unsymmetrical H-Phosphonates via Sequential and Direct Substitution of Chlorine Atoms in Phosphorus Trichloride with Alkoxy Groups

Yuma Tanaka, Hiroshi Kitamura, Shinichiro Fuse*

*Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya 464-8601, Japan, Email: fuse.shinichiro.z3f.mail.nagoya-u.ac.jp

Y. Tanaka, H. Kitamura, S. Fuse, J. Org. Chem., 2024, 89, 1777-1783.

DOI: 10.1021/acs.joc.3c02467


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Abstract

A rapid (<15 s) and mild (20 °C) alcoholysis of phosphorus trichloride in a microflow reactor enables sequential direct substitution of the chlorine atoms with alkoxyl/aryloxy groups to provide unsymmetrical H-phosphonates. The optimal base concentration differed in each step, presumably attributed to differences in the Brønsted basicity of the electrophilic intermediates.

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Details

The article discusses the microflow synthesis of unsymmetrical H-phosphonates through the sequential and direct substitution of chlorine atoms in phosphorus trichloride (PCl3) with alkoxy groups. This method is notable for its rapid (<15 s) and mild (20 °C) process, using equivalent amounts of PCl3 and alcohols. The study highlights the importance of base concentration, which varies in each step due to differences in the Brønsted basicity of the intermediates. The optimal conditions for the synthesis were determined, including solvent choice, base type, and reaction time. The process avoids the need for excess reagents and intermediate purification, making it more efficient than traditional methods. The study also quantitatively evaluates the structure-hydrolysis relationship of phosphite intermediates. The developed method shows high yields and reproducibility, with the space-time yield of flow synthesis being significantly higher than batch synthesis. The research provides a valuable approach for synthesizing organophosphorus compounds, which are crucial in pharmaceuticals and agricultural chemicals. The findings are expected to accelerate the development of these compounds, offering a more streamlined and efficient synthesis method.


Key Words

phosphonates, flow chemistry


ID: J42-Y2024