Intramolecular Inverse Electron Demand Diels–Alder Reactions of Tryptamine with Tethered Heteroaromatic Azadienes

Acid-catalyzed reaction of 3-aminopyrrole with s-tetrazines: formation of 1H-1,2,4-(triazol-3-yl)pyrimidines via an unprecedented s-tetrazine-ring contraction and concomitant pyrrole-ring expansion

“…The intramolecular IEDDA reaction of tryptamine, with tethered 1,2,4,5-tetrazines and 1,2,4-triazines, only occurred when the amino group was acetylated. 19 All of the above studies suggested that the reaction of amino groups with reactive 1,2,4,5-tetrazines was stepwise in nature, with the product(s) determined by the stability of the intermediate(s) formed. This is a consequence of the exceptional reactivity of 1,2,4,5-tetrazines with nucleophiles.…”

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…The electron-deficient aromatic ring of tetrazine and its reactivity towards nucleophiles have been utilized in the preparation of non-symmetrically substituted tetrazines by substitution of leaving groups, such as chloro [770,771], methylthio [770,[772][773][774][775] or dimethylpyridazolyl [755,757,776,777] with nitrogen, oxygen or sulfur nucleophiles. The use of carbon nucleophiles, such as organolithium or Grignard reagents, with 3,6-disubstituted 1,2,4,5-tetrazines 368 led to the addition of an organic group onto a ring nitrogen atom to afford 1,4-dihydrotetrazines 369 [778] (Scheme 20.109).…”

The azaphilic addition of organometallic reagents on tetrazines: scope and limitations

“…5 Their basic structural feature, the electrondeficient heterocyclic core, is the key to their most extensively utilized transformation, the 'inverse electrondemand' Diels -Alder reaction, that provides an attractive route to pyridazines, 6 -8 pyrroles, 9 and other condensed 10,11 and strained heterocyclic ring systems. 12 Another characteristic feature of the electron deficient aromatic ring is its reactivity towards nucleophiles that has been utilized in the preparation of non-symmetrically substituted tetrazines through their addition onto the ring 13 or substitution of leaving groups, such as chloro, 14,15 methylthio 16,17 or dimethylpyrazolyl 15,18,19 with nitrogen, oxygen or sulfur nucleophiles. The analogous reactions introducing carbon nucleophiles would also be of synthetic importance, but there are only a few know examples utilizing potassium cyanide 15 or malonates.…”

“…12 Another characteristic feature of the electron deficient aromatic ring is its reactivity towards nucleophiles that has been utilized in the preparation of non-symmetrically substituted tetrazines through their addition onto the ring 13 or substitution of leaving groups, such as chloro, 14,15 methylthio 16,17 or dimethylpyrazolyl 15,18,19 with nitrogen, oxygen or sulfur nucleophiles. The analogous reactions introducing carbon nucleophiles would also be of synthetic importance, but there are only a few know examples utilizing potassium cyanide 15 or malonates. 20,21 The cross-coupling reactions on tetrazines, also recently reported have only a limited scope.…”