Unanticipated Reactivity toward Nucleophilic Attack in the Synthesis of Saccharyl-1,3,4-Thiadiazolyl Conjugates: Structure and Mechanistic Insights

Along with the synthetic process optimization of 3-[(5-methyl-1,3,4-thiadiazole-2-yl)sulfanyl]-1,2-benzothiazole 1,1-dioxide (MTSB), a selective copper chelator with potential interest in cancer chemotherapy, the unprecedented isolation of a novel compound, 3-(1,1-dioxidobenzo[d]isothiazol-3-yl)-5-methyl-1,3,4-thiadiazole-2(3H)-thione (BMTT), evidenced an unexpected reactivity of the starting 5-methyl-1,3,4-thiadiazole-2-thiol. To shed light into the reaction mechanisms, quantum chemical calculations were conducted at the M06-2X/def2-TZVPP/PCM(THF)//M06-2X/6-31++G(d,p) level of theory. The results conjecture the formation of BMTT from nucleophilic attack of the nitrogen at position 3 of the thiadiazole ring, involved in an S-to-N delocalized thiadiazole-2-thiolate structure, which is thermodynamically more favorable in the presence of Na⁺. Experimental assays refute a plausible concerted 1,3-sigmatropic S- to N-rearrangement of MTSB that would lead to BMTT. Hence, contradicting the nucleophilicity indices of sulfur (from thiol) and nitrogen atoms of 5-methyl-1,3,4-thiadiazole-2-thiol, it is believed that an exotic nucleophilic attack by the nitrogen at 3-position of this reagent to the sp² carbon in position 3 of pseudo-saccharyl chloride should take place. Besides, the crystal structures of the MTSB and BMTT hybrids were investigated in detail by X-ray crystallography.