Microflow, Sequential Coupling and Cyclization Approach for Synthesis of Cyclic Phosphotriesters from PCl₃

An approach for the synthesis of cyclic phosphotriesters with various ring sizes (5‐ to 8‐membered rings) from phosphorus trichloride and diols was developed. The major challenge in developing this approach is the suppression of the undesired reactions caused by substrates containing multiple highly reactive sites. These undesired reactions were successfully suppressed by microflow technology, which can precisely control the reaction time and temperature. Two optimal conditions were developed, depending on the speed of cyclization. Fifteen cyclic phosphotriesters and their analogs were synthesized. A plausible mechanism for suppressing undesired reactions is proposed.