An Unexpected Pathway to Enantiomerization of Hemithioketals in Toluene Involving a Dimeric Transition State: A Combined Experimental and Computational Study

5‐Alkyl‐8‐aryl‐8‐hydroxy‐8 H ‐[1,2,4]oxadiazolo[3,4‐ c ][1,4]thiazin‐3‐ones ( 1 ) and their thioketals ( 2 ) represent interesting hits as LTTC blockers as well as inhibitors of MDR1 activity. Compounds 1 contain an unstable chiral centre which can give rise to an enantiomerization process, because of the possible equilibrium with the open‐chain forms 4 . We have carried out a combined experimental‐computational study on the 1 / 4 equilibrium in toluene by using the 8‐(4‐bromophenyl)‐5‐ethyl‐8‐hydroxy‐8 H ‐[1,2,4]oxadiazolo[3,4‐ c ][1,4]thiazin‐3‐one ( 1a ), containing two diastereotopic hydrogen atoms. 1 H‐NMR techniques have allowed to calculate the relevant energy barriers for the enantiomerization process (ca. 20 kcal mol –1 ). QM computations have individuated a transition state for a concerted asynchronous process occurring on a dimer of 1a with an activation barrier (ca. 23 kcal mol –1 ) in rather good agreement with the 1 H‐NMR experimental value, thus showing how a spontaneous mutarotation process could occur in non‐polar aprotic solvent.