Proton-Sensitive Free-Radical Dimer Evolution Is a Critical Control Point for the Synthesis of Δ(2,2(′))-Bibenzothiazines

[Image: see text] 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 Δ(2,2(′))-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 Δ(2,2(′))-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.