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

Abstract

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.

C−H Bond Arylation of Pyrazoles at the β‐Position: General Conditions and Computational Elucidation for a High Regioselectivity

“…[8] We thus examined the opportunity to further a-CÀHf unctionalize the 4-arylpyrazoles previously formed, this possibly leading to valuableu nsymmetrically polysubstituted heteroaromatics (Scheme 6). [16,17] Compound 35 b was reactedw ith as et of aryl bromides in the presenceo f2 mol %o fP d(OAc) 2 catalyst,a nd KOAc as the base in DMA. The a,b-diarylated products 44-46 were obtained in 52-87 %y ields using the electron-poor4 -bromobenzonitrile, 4-fluorobromobenzene and the electron-rich 4-tertbutylbromobenzene.…”

Emerging Concepts in Carbon Nitride Organic Photocatalysis

“…Complexes of palladium remain the most commonly used catalysts in different types of cross-coupling reactions. [133] However, due to the high price of palladium, resources of the catalysis community are concentrated on development of catalytic protocols based on more abundant elements, such as Ni. [134] The intrinsic problem of using Ni in catalysis is the inability of Ni(II)-species to undergo efficiently reductive elimination to complete the catalytic cycle, and high stability of Ni(I)species formed upon reductive elimination of the crosscoupling product unless complex ligands and strong bases are employed.…”

Coordination Chemistry of a bis(tetrazine) tweezer: A Case of Host-guest Behavior With Silver Salts

“…The s-tetrazine (Tz) unit (Figure 1, 1) is the object of high interest in photophysics and biomedical applications, in relation with its electron-poor poly(hetero)aromatic nature that is also amenable to click chemistry [1][2][3]. The diversification of synthetic routes to conceive new tetrazine structures has become very useful to expand current applications [3][4][5][6][7][8][9]. We recently reported a copper-catalyzed homocoupling protocol, which allowed the efficient synthesis of constrained bis(tetrazines) with a unique bridge clamp structure (Fig.…”