Solvent and substrate dependent regioselective synthesis of 2 and 3 substituted 2,3-dihydro-1,4-benzoxathiine

The 1,4-benzoxathiane scaffold is a common moiety present in several therapeutic agents, acting as adrenoceptor antagonists, or as anticancer agents. Very recently, designing novel antibacterial agents, and aiming to afford 2- and 3- substituted benzoxathiine derivatives, we initially followed an established synthetic scheme we were used to apply for the 1,4-benzodioxane scaffold. We then broaden the reaction conditions, finding an easy and reliable method for the obtainment of both 2,3-dihydro-1,4-benzoxathiine-2-yl derivatives and 2,3-dihydro-1,4-benzoxathiine-3-yl ones. As a result, we observed that the right choice of an appropriate solvent and a correct substrate allow the exclusive formation of one of the two possible regioisomers. The relative solvation of O- and S- anions induced the regioselectivity; specifically, when the 1,2-mercaptophenol is treated with an organic base, in a lipophilic solvent, in the absence of water and in the presence of a lipophilic 2-bromo acryl derivative, the thiolate succeeds as nucleophile and thus the 2-substituted compound is fully accomplished. On the other hand, the treatment in the presence of water and with a polar reactive let the phenoxide to manage the nucleophilic substitution and therefore to afford 3-substituted compounds.