100 years of the biginelli dihydropyrimidine synthesis

In the present study, synthesis of material supported [ZeoDABCO-SO₃H]Cl Bronsted acid heterogeneous catalyst was synthesized and investigated in the reaction between aryl aldehydes, ethyl acetoacetate, and urea/thiourea for the synthesis of Dihydro pyrimidines-2-ones/ thiones in excellent yields. The synthesized [ZeoDABCO-SO₃H]Cl is reusable for six runs without suffering a significant loss of catalytic activity, according to reusability research. The existing technology has a variety of advantages, involving ambient reaction conditions, use of ethanol as green solvent, high yield, less time, and simple workup processes. Additionally, we have investigated the promising cytotoxicity against normal kidney cell lines, with the latter validated by a study of molecular docking.

In this report, we synthesized some pyrimidine derivatives by multi-component reaction of urea, benzaldehydes, and 1,3-indandione in the presence of ZIF-8/ZnFe₂O₄/GO-OSO₃H nanocomposite under reflux conditions. Initially, graphene oxide was prepared from graphite, and then it was sulfonated using ClOSO₃H. Next, GO-OSO₃H nanosheets were used to support ZIF-8/ZnFe₂O₄ nanostructure. The construction of the synthesized structure was established using different spectral techniques such as X-ray crystallography (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX/Mapping), Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), vibrating sample magnetometer (VSM), and Brunauer-Emmett-Teller (BET). The present method provides various benefits including the efficiency of outcomes, easy separation of the catalyst, and excellent yield of the products within short reaction times. Moreover, the antibacterial activities of pyrimidine derivatives were investigated via the agar-well diffusion method on gram-negative (Escherichia coli) and gram-positive (Staphylococcus aureus) bacteria and the obtained results illustrated reasonable effects.

The novel coumarinyldihydropyrimidin-2-thiones (coumarinyl-DHPM) have been synthesized by Knoevenagel condensation of 4-formylcoumarins with different β-keto esters in the presence of aluminum chloride (AlCl₃) as Lewis acid catalyst leading to coumarinylenones followed by cyclization with protected thiourea and subsequent deprotection of protected sulfur intermediate by trifluoroacetic acid. The structures of coumarinylenones, protected intermediate and the desired coumarinyl-DHPM were confirmed by their NMR and X-ray diffraction analysis.

The Biginelli reaction, a conventional three‐component reaction provides 3,4‐dihydropyrimidin‐2(1H)‐ones/thiones via one‐pot acid catalyzed cyclocondensation of an aldehyde, a β‐keto ester, and urea or thiourea. Dihydropyrimidones are well‐known scaffolds having a wide range of pharmacological activities. So far classical Biginelli reaction has witnessed several modification and studies are still continuing in this field to develop greener and efficient methodologies. In this review, we summarize the recent advances in Biginelli reaction covering literature from 2020 to 2023.

A visible‐light induced multicomponent reaction of aromatic aldehydes, amines and sodium difluoromethanesulfinate for the synthesis of fluorinated secondary amines has been investigated. The protocol affords a convenient pathway for the introduction of difluoromethyl group into imines, which generated in situ by the reaction of aldehydes and amines. A diverse range of fluorinated secondary amines were synthesized in 43%–79% yields under room temperature. In addition, a plausible mechanism was proposed based on several control experiments.

In this work, we report an efficient synthesis of pyrimidine fused novel 4-phenyl-2-thioxo-3,4-dihydro-1H-pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5(2H)-one. The chemical structure of the title compound was ascertained by spectral techniques including UV–Visible, FT-IR, ¹H NMR, ¹³C NMR and HRMS. The molecule was further subjected to quantum chemical calculations at the level of Density Functional Theory method employing B3LYP (Becke 3-parameter, Lee-Yang-Parr) level with 6–311++G(d,p) basis set. The computed characteristics of the molecule were investigated and interpreted comparing with the experimental values. Furthermore, Frontier Molecular Orbital (FMO) analysis was used to predict the energy properties and model the possible charge transfer within the molecule. The reactivity sites were identified by mapping the electron density into Molecular Electrostatic Potential (MEP). The stability of the molecule arising from hyper-conjugative interactions and charge delocalization were analyzed using Natural Bond Orbital (NBO) analysis. All the theoretical values were in good agreement with experimental studies. Docking studies was performed to examine binding sites of the title molecule and bioactivity scores indicated that the ligand's pharmacokinetic and pharmacological properties are sufficiently additive and shows the drug-likeness of the synthesized molecule. The study was validated by i) re-docking the N3-peptide inhibitor and superimposing them onto co-crystallized complex and ii) protein ligand complex. Molecular dynamics simulations were performed for 50 ns to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation.