Building Diversity in ortho-Substituted s‑Aryltetrazines By Tuning N‑Directed Palladium C–H Halogenation: Unsymmetrical Polyhalogenated and Biphenyl s‑Aryltetrazines

We report a general route for synthesizing ortho-substituted unsymmetrical biphenyl and polyaromatic s-aryltetrazines. These compounds are inaccessible by classical Pinner hydrazine condensation or by the current s-aryltetrazine aromatic core functionalization methods described up to now. We exploited multiple versatile N-directed palladium C–H activation/halogenation of s-aryltetrazine to form C–X bonds (X = I, Br, Cl, F), which collectively produced polyhalogenated unsymmetrical building blocks. We achieved a sequence of selective C–H halogenation reactions in a specific order to produce reactive aryl halides. Polyhalogenated s-aryltetrazines can then be used for controlled cross-coupling reactions toward ortho-substituted polyaromatic s-aryltetrazines. In general, this C–H functionalization route gives access to a large number of variously halogenated building blocks practical for further synthetic implementation of tetrazines (arylation, cycloaddition, etc.). Herein, we exemplified their potential by using halogen-selective Suzuki–Miyaura reactions for divergent construction of novel biphenyl s-tetrazines. Therefore, we deliver original poly­(hetero)­aromatic tetrazine structures, such as new typically “Z-shaped” and “T-shaped” species. We examined by DFT calculation the origin of the remarkable regioselectivity in some C–H concurrent halogenation reactions. Computations focused at free enthalpy profiles for C–H activation of aryltetrazines to form the intermediate palladacycles by CMD process. We showed that the presence of halogen substituents on aryl groups before further halogenation increases the activation barrier to form the determining C–H activation intermediate palladacycle. XRD studies of functionalized tetrazines evidenced planarity ruptures in the mutual arrangement of aromatic cycles. Finally, this methodology allowed us to deliver a unique tetrahalogenated s‑aryltetrazine holding not less than four different halogens arranged in ortho-aryl positions.