Cu(II)-catalyzed Friedel-Crafts reaction of 2-thiopyrimidine derivatives with aldehydes utilizing water as cocatalyst in the presence of surfactant: elucidation of the role of water on reaction mechanism and tautomerism.

Here, we reported a Cu(II)-catalyst with a water-tolerant active site for the Friedel-Crafts reaction of 4-amino-6-hydroxy-2-mercaptopyrimidine with various aldehydes in aqueous medium, using a surfactant. A portion of the hydrated homogeneous copper(II) complex remains an effective Lewis acid in this reaction, consistent with the theoretical study (DFT) and various control experiments. The study revealed the involvement of a water-assisted hydrogen atom transfer (HAT), indicating the importance of surrounding water molecules. The influence of explicit water-solvation models (20- and 60-molecule shells) on the structures and energies of selected intermediates and transition states was studied. Furthermore, the gram-scale synthesis, recyclability of the reaction medium, and various green chemistry parameters demonstrated the sustainability of our process. Additionally, the structure and relative energies of the various tautomers of product bis-(2-thiopyrimidine) compounds were investigated at the DFT and SCS-MP2 levels. The water-assisted tautomerization mechanism is described, showing that the keto form is prevalent in neutral solutions. The doubly protonated and quadruple deprotonated forms exist in acidic and basic media, as confirmed by TDDFT-predicted UV-vis spectra and DFT-calculated 1H-NMR shifts, which are supported by the respective experimental spectra.