Nucleophilic Attack on Nitrogen in Tetrazines by Silyl-Enol Ethers

Abstract

The nucleophilic addition to nitrogen in 3-monosubstituted s-tetrazines under mild conditions is reported, by using silyl-enol ethers as the nucleophiles and mediated by BF 3 . The preference for this azaphilic addition over the usually observed inverse electron demand Diels-Alder reactions was determined experimentally and evaluated theoretically. In this regard, the influence of the effect of BF 3 -coordination to s-tetrazines was investigated thoroughly. The substrate dependency of this unusual reaction was rationalized by determination of the activation barriers and on the basis of the activation strain model by employing density functional theory. Lastly, the decomposition of the unstable adducts was examined and an interesting rearrangement to a triazine derived structure was observed.

Cross-coupling Reactions of Monosubstituted Tetrazines

“…In accordance with previous reports, electron rich phenylboronic acids reliably underwent cross-coupling in high yields. [25] Along these lines, para-and meta-methoxy substituted variants (12,13) produced the corresponding tetrazines in yields of 82% and 69%, respectively. The ortho-methoxy analog 14 however, showed greatly reduced yield (37%).…”

“…Flash chromatography was performed using silica gel 60 (230-400 mesh) from Sigma-Aldrich with a forced flow eluent at 0.1-0.3 bar pressure. All 1 H NMR, 13 C NMR, 19…”

“…[2,4,[7][8][9][10] With their fast kinetics in inverse electron-demand Diels-Alder (iEDDA) cycloadditions with suitable reaction partners, such as strained alkenes and alkynes, tetrazines have become an invaluable motif in bioorthogonal applications. [2,[11][12][13] Nonetheless, there are multiple parameters crucial for maximizing their potential. Direct incorporation into target molecules should be possible, without the necessity for bulky hydrophobic linkers, which might negatively affect physiochemical properties and the kinetics of subsequent iEDDA reactions.…”

Closer Look at Inverse Electron Demand Diels–Alder and Nucleophilic Addition Reactions on s-Tetrazines Using Enhanced Sampling Methods

“…The investigation performed by our experimental collaborators revealed a surprising discovery in reactivity of 3-monosubstituted s-tetrazines, a small s-tetrazine building block, with silyl-enol ethers for the synthesis of e.g. macromolecules [4]. In this work, we, therefore, focus on chemical competition between [4+2] cycloadditions and azaphilic addition reactions of 3-Br-s-tetrazine and silyl-enol ethers.…”

“…It has been well known that the DA reaction generally occurs as a major outcome when s-tetrazine reacts with common dienophiles. However, our recent work in close collaboration with the Gademann group reported an unprecedented nucleophilic addition reaction of 3-bromosubstituted s-tetrazine (3-Br-s-tetrazine) which is in contrast to [4+2] cycloaddition reactions [4]. Moreover, the direct nucleophilic attack to nitrogen in s-tetrazine has rarely been described in the literature and is generally restricted to 1,2,4,5-tetrazine and other tetrazine derivatives such as 1,2,3,4-tetrazine and 1,2,3,5-tetrazine [5][6][7].…”