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

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.