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

Unsymmetrical H-phosphonates were synthesized by a rapid (<15 s) and mild (20 °C) process in a microflow reactor as the first example of the sequential direct substitution of the chlorine atoms in PCl₃ with alkoxyl/aryloxy groups using equivalent amounts of PCl₃ and alcohols. The optimal base concentration differed in each step, presumably attributed to differences in the Brønsted basicity of the electrophilic intermediates. Phosphite hydrolysis was observed, and the structure-hydrolysis relationship was quantitatively evaluated.