Cross-coupling Reactions of Monosubstituted Tetrazines

Abstract

<div><div><div><p>A fast and mild method for the Pd-catalyzed cross-coupling reaction of monosubstituted 3-bromo-1,2,4,5-tetrazine is presented. Investigation of silver-based additives revealed that Ag2CO3 is the optimal mediator, enabling the process without the need for strong bases or high temperatures. Electronic modification of the classical 1,1′- bis(diphenylphosphine)ferrocene (dppf) ligand proved to be a powerful strategy in tailoring the catalytic system to the requirements set by the process. Under the optimized conditions a scope comprising a variety of alkyl-, heteroatom-, and halide substituted aryl- and heteroaryl-tetrazines were prepared in good to excellent yields (29 examples, up to 87% yield). This method constitutes the first example of a direct cross-coupling reaction of monosubstituted tetrazines.</p></div></div></div>

Mechanistic Studies and Data Science-Guided Exploration of Bromotetrazine Cross-Coupling

“…Halogenated tetrazines occupy the electron-poor region of this chemical space. 15,16 While electron-poor aryl halides are generally well tolerated by cross-coupling protocols, the extraordinary electron deficiency of tetrazinyl halides has resulted in their limited application in cross-coupling reactions. 17−20 Recently, our group reported on the development of a Pdcatalyzed Suzuki−Miyaura-type cross-coupling of 3-bromo-1,2,4,5-tetrazine (1).…”

“…17−20 Recently, our group reported on the development of a Pdcatalyzed Suzuki−Miyaura-type cross-coupling of 3-bromo-1,2,4,5-tetrazine (1). 15 The strongly electron-deficient tetrazine proved recalcitrant in classical cross-coupling protocols, especially if reacted with electron-poor boronic acids. Ag 2 CO 3 constitutes a crucial additive for the successful Pd-catalyzed cross-coupling in these reactions, likely by facilitating the transmetalation event.…”

“…A reasonable explanation for the decreased yields is the in situ formation of Ag 2 O, which in prior reports by our group was found to be an inferior mediator for the reaction. 15 On the other hand, conclusive evidence for the involvement of Pd(II) bisaryl complexes in the generation of the Pd(0) species was obtained when exchanging the 4-F-Ph-B(OH) 2 for the less reactive C 6 F 5 -B(OH) 2 . 23 While this substrate was considered unfeasible for cross-coupling, it afforded the Pd(II) bispentafluorophenyl complex 5 as the only isolable product, and its structure was confirmed by X-ray diffraction (XRD) analysis (Scheme 2A).…”

“…34−36 Since reductive elimination rates were shown to be faster for electron-poor complexes, this effect would be in line with the reported success of the electron-poorer ligand dppf-CF 3 over its parent compound dppf. 15,34 Hence, Pd(dba) 2 was established as a viable Pd(0) precursor for the process, which removed the necessity for the reduction of Pd(II) (Scheme 2B). In situ generation of Pd 0 L n (dppf-CF 3 ), followed by cross-coupling of tetrazine 1 with 2 in the presence of 1.0 equiv.…”

“…Previous reports by our group had demonstrated modification of the electron-withdrawing ability of the ancillary ligand to be a powerful strategy to overcome limitations of the catalytic cross-coupling of monosubstituted tetrazines. 15 Exchanging the frequently utilized dppf (11) ligand for the electron-poorer dppf-CF 3 (8) ligand had allowed a considerable expansion of the method scope. 15 To investigate this observation and gain an understanding of how such ligand variations influence the energy landscape of the catalytic cycle, the same calculations on the catalytic cycle steps were also performed with the closely related ligands 11 and 12 for the transmetalation and reductive elimination steps (Scheme 5A,B,E).…”