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Proton-Sensitive Free-Radical Dimer Evolution Is a Critical Control Point for the Synthesis of Δ2,2-Bibenzothiazines

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journal contribution
posted on 26.08.2020, 08:29 by Luca Valgimigli, Maria Laura Alfieri, Riccardo Amorati, Andrea Baschieri, Orlando Crescenzi, Alessandra Napolitano, Marco d’Ischia
The mechanism of the acid-dependent interring dehydrogenation in the conversion of the single-bonded 3-phenyl-2H-1,4-benzothiazine dimer 2 to the Δ2,2-bi­(2H-1,4-benzothiazine) scaffold of red hair pigments is disclosed herein. Integrated chemical oxidation and oxygen consumption experiments, coupled with electron paramagnetic resonance (EPR) analyses and DFT calculations, allowed the identification of a key diprotonated free-radical intermediate, which was implicated in a remarkable oxygen-dependent chain process via peroxyl radical formation and evolution to give the Δ2,2-bi­(2H-1,4-benzothiazine) dimer 3 by interring dehydrogenation. The critical requirement for strongly acidic conditions was rationalized for the first time by the differential evolution channels of isomeric peroxyl radical intermediates at the 2- versus 3-positions. These results offer for the first time a rationale to expand the synthetic scope of the double interring dehydrogenation pathway for the preparation of novel symmetric double-bond bridged captodative heterocycles.