Benzalacetone-Based β-Isothiocyanatoketones: Synthesis and Transformation to Diaryl-Substituted 14-Membered Cyclic Thiosemicarbazones and Related Heterocycles

A synthesis of novel 4-aryl-4-isothiocyanatobutan-2-ones based on addition of thiocyanic acid to benzalacetones has been developed. The prepared isothiocyanates react with equimolar amount of hydrazine to give the corresponding 4-(3-oxobut-1-yl)thiosemicarbazides which spontaneously cyclize to 1-amino-6-hydroxyhexahydropyrimidine-2-thiones. In solutions, the latter undergo partial ring opening, yielding equilibrium mixtures of diastereomeric pyrimidines with some amounts of their acyclic isomers. Thermodynamic and kinetic parameters of the ring-chain isomerism were calculated by DFT methods. Treatment of 1-amino-6-hydroxyhexahydropyrimidine-2-thiones with excess of hydrazine gives 4-(3-oxobutyl)thiosemicarbazide hydrazones. Both hydrazones and pyrimidines in the presence of acids undergo cyclooligomerization to afford either 14-membered cyclic bis-thiosemicarbazones or their mixtures with 21-membered cyclic tris-thiosemicarbazones depending on the reaction conditions. Thermodynamic parameters for the macrocycle self-assembly were estimated using DFT calculations. 14-Membered cyclic bis-thiosemicarbazones were found to be thermodynamic products of the cyclization. They were also formed from either 21-membered macrocycles or tetrahydro-1,2,4-triazepine-3-thiones. A synthesis of the latter from 1-amino-6-hydroxyhexahydropyrimidine-2-thiones was developed. We demonstrated that 14-membered macrocycles can serve as ligands for nickel(II) cation. The TsOH-promoted cyclooligomerization of 4-(1-aryl-3-oxobutyl)semicarbazide hydrazones was reinvestigated, and the data obtained were compared with those for the corresponding thioxo analogs.