N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines with Enamines Promoted by the Lewis Acid ZnCl₂

Abstract

The second example of selective N1/N4 1,4-cycloaddition (vs C3/C6 1,4-cycloaddition) of 1,2,4,5-tetrazines with preformed or in situ generated enamines now promoted by the Lewis acid ZnCl2 and with an expanded scope is described. The reaction constitutes a formal [4 + 2] cycloaddition across two nitrogen atoms (N1/N4 vs C3/C6) of a 1,2,4,5-tetrazine followed by retro [4 + 2] cycloaddition loss of a nitrile and aromatization to provide 1,2,4-triazines. Optimization of reaction parameters, simplification of its implementation through in situ enamine generation from ketones, definition of the enamine reaction scope for 3,6-bis­(thiomethyl)-1,2,4,5-tetrazine, exploration of the 1,2,4,5-tetrazine scope, and representative applications of the product 1,2,4-triazines are detailed. The work establishes and further extends a powerful method for efficient one-step regioselective synthesis of 1,2,4-triazines under mild reaction conditions directly now from easily accessible ketones. It extends the substrate scope of a solvent (hexafluoroisopropanol) hydrogen bonding-promoted reaction that we recently reported with aryl-conjugated enamines, permitting the use of simple ketone-derived enamines and expanding the generality of the remarkable reaction. The reaction is regioselective with respect to the site of reaction with unsymmetrical ketones and provides exclusively a single 1,2,4-triazine regioisomer consistent with our previously established stepwise mechanism of formal N1/N4 1,4-cycloaddition, overcoming the challenges observed in conventional approaches to 1,2,4-triazines.

Aryl Annulation: A Powerful Simplifying Retrosynthetic Disconnection

“…Although this approach typically provides monocyclic aryl groups and such applications have been disclosed, 68,69 tandem cycloadditions involving two consecutive Diels-Alder reactions can be devised that provide larger bi-and tricyclic aryl groups. 66,70,71 Equation 2…”

Acyclic and Heterocyclic Azadiene Diels–Alder Reactions Promoted by Perfluoroalcohol Solvent Hydrogen Bonding: Comprehensive Examination of Scope

“…However, unlike the normal Diels–Alder reaction and largely because of the low basicity of nitrogen atoms found in heterocyclic or acyclic azadienes, efforts to catalyze such reactions with Lewis acids have largely failed due to preferential coordination with and nonproductive consumption of the reactive electron-rich dienophiles. Although there are notable exceptions, including Wegner’s bidentate boron-based Lewis acid-catalyzed cycloaddition reactions of 1,2-diazines, − Rawal’s Ag-catalyzed reaction of phthalazines with siloxyalkynes, , and our recent ZnCl 2 -promoted N1/N4 (vs C3/C6) [4 + 2] formal cycloaddition of selected 1,2,4,5-tetrazines, they are limited in scope, and the latter two examples feature altered mechanisms. Thus, no general approach for catalysis of the inverse electron demand Diels–Alder reactions of azadienes had emerged until we disclosed a potentially powerful solvent H-bonding acceleration of such reactions using perfluoroalcohols, , which are weakly acidic but non-nucleophilic protic solvents.…”