Water-Tuned Tautomer-Selective Tandem Synthesis of the 5,6-Dihydropyrimidin-4(3H)-ones, Driven under the Umbrella of Sustainable Chemistry

Abstract

The selective synthesis of 5,6-dihydropyrimidin-4­(3H)-one scaffold (precursor of dihydrouracil) was a very difficult synthetic challenge that, so far, has not been achieved. For the first time, in this paper, green, selective and high-yields approach to 40 novel 5,6-dihydropyrimidin-4­(3H)-ones (DHPMs) by one-pot reaction of aldehydes, Meldrum’s acid and isothioureas under solvent-free conditions, in the presence of water, since an additive is presented. In the majority of cases, introduced methodology gave an unprecedented tautomer-selective fashion toward targeted compounds with excellent tautomeric purity (>99.9%), which reached 100% in few cases. The molecular structure of the five compounds has been determined by X-ray crystallography. In each one of them, very short length for the corresponding N2–C1 bond was noticed, making them especially interesting from a structural standpoint. This experimental fact can imply a highly localized electron π density in this part of each heterocyclic ring. The obtained experimental results, which are determined from NMR and ESI-MS study, indicate that this Biginelli-type reaction smoothly proceeds in a one-pot mode, pointing to the three-step tandem process, proceeding via the Knoevenagel, aza-Michael, and retro-Diels–Alder reactions. The presented strategy also had the following advantages: reduction amount of waste, excellent values of green chemistry metrics (cEF, EcoScale and GCIS), and it is the first eco-friendly strategy toward the DHPMs scaffold.

Acetophenone-Based 3,4-Dihydropyrimidine-2(1H)-Thione as Potential Inhibitor of Tyrosinase and Ribonucleotide Reductase: Facile Synthesis, Crystal Structure, In-Vitro and In-Silico Investigations

“…The crystallographic results of the title compound were acquired using a Rigaku Oxford diffraction Eos, Gemini diffractometer using Cu Kα radiation (λ = 1.5418 Å). SHELX programme packages [ 33 ] were utilized to solve and refine the structure using the multi-scan absorption correction [ 34 ] applied data, and ORTEP-3 [ 35 ] programme was employed in drawings. The locations of hydrogen atoms were calculated geometrically at distances of 0.88 (for NH), 0.95 (for CH), and 0.98 (for CH 3 ), and then refined using a riding model by applying the constraints of Uiso (H) = k × Ueq (C, N), where k = 1.2 for NH and CH hydrogens and k = 1.5 for CH 3 hydrogens.…”

A new class of half-sandwich ruthenium complexes containing Biginelli hybrids: anticancer and anti-SARS-CoV-2 activities

“…There is an burning need to design and synthesis of novel prospective dual-active compounds, especially anticancer-antiviral [ [32] , [33] , [34] ]. Our interest is the design, synthesis, and pharmacological evaluation of the heterocyclic compounds, especially those derived from the Biginelli reaction [ [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] ]. Selected molecules have proven to be excellent ligands for the synthesis of copper and palladium complexes with significant anticancer and antimicrobial activity [ [44] , [45] , [46] , [47] ].…”

The evaluation of the anticancer activity of the Biginelli hybrids and pharmacokinetic profiling based on their retention parameters

“…Considering the significance of THPMs and our previous activity in Biginelli chemistry, [13][14][15][16][17][18] twenty-four compounds were investigated ( Table 1 ) in terms of their anticancer activity and pharmacokinetics.…”