Effective self-assembly of 21- and 14-membered azamacrocycles via condition-controlled cyclotrimerization or cyclodimerization of different thiosemicarbazide-based precursors

A preparative synthesis of previously unknown 21- and 14-membered azamacrocycles acid-promoted cyclotrimerization or cyclodimerization of three readily available precursors, namely, 1-amino-6-hydroxy-4,6-dimethylhexahydropyrimidine-2-thione, 4-(4-oxopent-2-yl)thiosemicarbazide hydrazone, and 5,7-dimethyl-1,4,5,6-tetrahydro-3 -1,2,4-triazepine-3-thione has been developed. A dramatic dependence of the selectivity of macrocyclization on the reaction conditions is demonstrated. The thermodynamic aspects of the reactions are discussed based on experimental data and DFT calculation results. Plausible pathways for the formation of macrocycles are proposed.