A new one-pot microwave-assisted synthesis and structural analysis of 6,N²,N⁴-trisubstituted 1,3,5-triazine-2,4-diamines

The substituted 1,3,5-triazine-2,4-diamine motif is a well-recognised scaffold for the construction of bioactive compounds. To improve the synthetic accessibility of these compounds and expand their molecular diversity, a convenient one-pot, two-step method for the synthesis of 6,N²,N⁴-trisubstituted 1,3,5-triazine-2,4-diamines was developed. The three-component acid-catalysed reaction of arylaldehydes, amines, and N-arylcyanoguanidines under microwave irradiation resulted in the dihydrotriazine ring closure. The subsequent microwave irradiation of the reaction mixture after treatment with a base afforded fully aromatic 6,N²,N⁴-trisubstituted 1,3,5-triazine-2,4-diamines as products of dehydrogenative aromatisation. The method was rather general, tolerated structural variations of all reactants and afforded a high chemical diversity of products. The molecular structure and intermolecular interactions in the crystal of N²-phenyl-4-morpholino-6-(4-methylphenyl)-1,3,5-triazine-2-amine as a representative example were studied using X-ray crystallography and molecular Hirshfeld surface analysis. The crystal packing was stabilised by two one-dimensional motifs: hydrogen bonding between the secondary amino group and morpholine moiety oxygen and π⋅⋅⋅π stacking interactions, common for the electron-deficient 1,3,5-triazine ring.