Reaction pathway of POCl3-mediated Knoevenagel condensation of bisulfite adducts with 2,4-thiazolidinedione

We investigated the POCl3-mediated transformation of aromatic bisulfite adducts to the corresponding 5-arylidenethiazolidine-2,4-diones. The in situ transformation of an aromatic bisulfite adduct to the parent aldehyde in a non-aqueous non-polar solvent (toluene) was demonstrated using DoE (Design of experiment), offline H-1 NMR, online ReactIR, HPLC, LC-MS, and GC-MS. By means of these analytical tools, we determined, for the first time, the structure of the intermediate species (aldehyde) prior to the carbon-carbon double-bond formation. The carbon-sulfur bond undergoes a fast cleavage, immediately after the addition of POCl3, which finally affords the corresponding 5-arylidenethiazolidine-2,4-diones.