Ali Samarat

Although ferrocene ketones have been known since the early days of ferrocene chemistry, their behavior in deprotometalation has never been studied in detail. Here, we have optimized this reaction using lithium 2,2,6,6-tetramethylpiperidide in tetrahydrofuran containing ZnCl ₂ · N , N , N' , N' -tetramethylethylenediamine as an in-situ trap. Numerous 2-iodoferrocene derivatives were obtained, while a change in regioselectivity was observed for certain aroyl- and heteroaroylferrocenes, in good agreement with our DFT calculations. The development of an enantioselective deprotometalation was also attempted using lithium di[( S )-1-phenylethyl]amide, affording the desired compounds in up to 60% enantiomeric excess ( ee ). A selection of iodinated derivatives was finally subjected to post-functionalizations, leading to original ferrocene-fused heterocycles, including an enantiopure tetracyclic derivative. A selection of compounds was studied in both electrochemical reduction and oxidation, and weak interactions such as halogen–halogen, halogen–oxygen and chalcogen–chalcogen bonds were identified in the solid state for some new derivatives.

Despite their potential in areas such as medicinal chemistry and organic materials, scaffolds in which quinoline and quinoxaline are fused to phosphacycles such as 1,3‐oxaphosphole, 1,3‐azaphosphole, P‐arylated and P‐alkoxylated 2,3‐dihydro‐1,3‐azaphosphole P‐oxides have, to our knowledge, never been reported. In this study we have developed a synthetic approach to [1,3]azaphospholo[4,5‐f]quinolines and ‐quinoxalines from quinolin‐6‐amine and quinoxalin‐6‐amine. These were converted to 5‐phosphanylquino(xa)lin‐6‐amines by regioselective iodination in position 5, cross‐coupling with diethyl phosphite and reduction. Formation of the azaphosphole ring was then achieved by reaction with N,N‐dimethylformamide dimethyl acetal. Attempts at C−H arylation in position 2 did not lead to the desired derivatives but rather to 1‐arylated 2,3‐dihydro‐[1,3]azaphospholo[4,5‐f]quino(xa)line 1‐oxides. Access to 1‐alkoxylated 2,3‐dihydro‐[1,3]azaphospholo[4,5‐f]quinoline 1‐oxides was also developed using as key steps cross‐coupling with ethyl phosphinate formed in situ and the subsequent Kabachnik‐Fields reaction. The resulting tricyclic compounds were finally tested against a panel of disease‐related protein kinases.

Here, we report the intramolecular Heck cross-coupling of 1,3-dienylphosphonates, affording unique and regioselective access to unprecedented benzofused phostone and phostam derivatives. The reactions proceeded under operationally simple and mild conditions with a wide substrate scope.

The functionalization of methylated azines and diazines has aroused the interest of chemists given the structural diversity that it affords. Hindered lithium dialkylamides have been used to deprotometallate these substrates chemoselectively. In contrast, it can be observed that, despite some promising work, lithium diethylamide has been used very little for this purpose. Our objective here is on the one hand to make an inventory of what reagents have been used to deprotometallate methylpyridines, ‐quinolines and ‐quinoxalines, and on the other hand to describe the results obtained by seeking to functionalize a series of substrates with lithium diethylamide (picolines, 2,4‐lutidine, methylquinolines and 2‐methylquinoxaline). Our efforts to take advantage of the use of an in‐situ trap (a zinc chloride chelate) in these reactions are also described.

An efficient and simple approach has been developed for the synthesis of eight dialkyl/aryl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(aryl)methyl]phosphonates through the Pudovik-type reaction of dialkyl/arylphosphite with imines, obtained from 5-phenyl-1,3,4-oxadiazol-2-amine and aromatic aldehydes, under microwave irradiation. Five of them were hydrolyzed to lead to the corresponding phosphonic acids. Selected synthesized compounds were screened for their in vitro antiviral activity against the avian bronchitis virus (IBV). In the MTT cytotoxicity assay, the dose-response curve showed that all test compounds were safe in the range concentration of 540–1599 µM. The direct contact of novel synthesized compounds with IBV showed that the diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethoxyphenyl)methyl]phosphonate (5f) (at 33 µM) and the [(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethylphenyl)methyl] phosphonic acid (6a) (at 1.23 µM) strongly inhibited the IBV infectivity, indicating their high virucidal activity. However, virus titers from IBV-infected Vero cells remained unchanged in response to treatment with the lowest non-cytotoxic concentrations of synthesized compounds suggesting their incapacity to inhibit the virus replication inside the host cell. Lack of antiviral activity might presumably be ascribed to their polarity that hampers their diffusion across the lipophilic cytoplasmic membrane. Therefore, the interactions of 5f and 6a were analyzed against the main coronavirus protease, papain-like protease, and nucleocapsid protein by molecular docking methods. Nevertheless, the novel 1,3,4-oxadiazole-based α-aminophosphonic acids and α-amino-phosphonates hold potential for developing new hygienic virucidal products for domestic, chemical, and medical uses.

Two silver(I) complexes, bis{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN³:κN⁴-amino) (4-trifluoromethylphenyl)methyl]phosphonate-(tetrafluoroborato-κF)}-di-silver(I) and tetrakis-{diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-κN³-amino)(4-trifluoromethylphenyl)methyl]phosphonate} silver(I) tetrafluoroborate, were prepared starting from the diethyl[(5-phenyl-1,3,4-oxadiazol-2-yl-amino)(4-trifluoromethylphenyl)methyl]phosphonate (1) ligand and AgBF₄ salt in Ag/ligand ratios of 1/1 and 1/4, respectively. The structure, stoichiometry, and geometry of the silver complexes were fully characterized by elemental analyses, infrared, single-crystal X-ray diffraction studies, multinuclear NMR, and mass spectroscopies. The binuclear complex ([Ag₂(1)₂(BF₄)₂]; 2) crystallizes in the monoclinic asymmetric space group P2₁/c and contains two silver atoms adopting a {AgN₂F} planar trigonal geometry, which are simultaneously bridged by two oxadiazole rings of two ligands, while the mononuclear complex ([Ag(1)₄]BF₄; 3) crystallizes in the non-usual cubic space group Fd-3c in which the silver atom binds to four distinct electronically enriched nitrogen atoms of the oxadiazole ring, in a slightly distorted {AgN₄} tetrahedral geometry. The α-aminophosphonate and the monomeric silver complex were evaluated in vitro against MCF-7 and PANC-1 cell lines. The silver complex is promising as a drug candidate for breast cancer and the pancreatic duct with half-maximal inhibitory concentration (IC₅₀) values of 8.3 ± 1.0 and 14.4 ± 0.6 μM, respectively. Additionally, the interactions of the ligand and the mononuclear complex with Vascular Endothelial Growth Factor Receptor-2 and DNA were evaluated by molecular docking methods.

The synthesis of a palladium complex bearing two diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-nitrophenyl)methyl]phosphonates as ligands has demonstrated the ability of this type of α -aminophosphonates to coordinate to the palladium(II) ion via their electronically enriched nitrogen atom of the 1,3,4-oxadiazole ring. The complex was fully characterized by elemental analysis, infrared, NMR and mass spectrometry. A solid-state structure revealed the trans coordination of the two nitrogenated ligands. The presence of a hemilabile P(O)(OEt) 2 moiety in the α -aminophosphonates was exploited into palladium-catalyzed Suzuki–Miyaura cross-coupling of aryl halides. The formation of ( N , O )-chelate intermediates may increase the steric hindrance and the electronic density of the metal, which should favor the oxidative addition and the reductive elimination/product decoordination elementary steps. With our catalytic systems, good activities for the formation of ortho -di/trisubstituted biphenyl compounds were observed from aryl bromides using only 0.5 mol% of palladium. Cross-coupling of aryl chlorides required a catalyst loading of 1 mol% to generate ortho -substituted biphenyls.

Three α-aminophosphonates, namely diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethylphenyl) methyl]phosphonate (3a), diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(2-methoxyphenyl)methyl]phosphonate (3b) and diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-nitrophenyl)methyl]phosphonate (3c), were synthetized via the Pudovik-type reaction between diethyl phosphite and imines, obtained from 5-phenyl-1,2,4-oxadiazol-2-amine and aromatic aldehydes, under microwave irradiation. Compounds 3a–c underwent complexation with a ruthenium(II) precursor, selectively at the more basic nitrogen atom of the oxadiazole ring, leading to the corresponding ruthenium complexes 4a–c of the formula [RuCl₂(L)(p-cymene)] (L = α-aminophosphonates 3a–c). Complexes 4a–c proved to be efficient catalysts for the transfer hydrogenation of ketones to alcohols. All new compounds were fully characterised by elemental analysis, infrared, mass and NMR spectroscopy. An X-ray structure of the α-aminophosphonate 3b was obtained and revealed the presence, in the solid state, of an infinite chain of 3b units supramolecularly interlinked. Two X-ray diffraction studies carried out on ruthenium complexes confirm the specific coordination of the electron-enricher nitrogen atom of the oxadiazole ring.

A series of novel symmetrical 2,5‐difunctionalized 1,3,4‐oxadiazole derivatives of pharmacological significance have been synthesized. The obtained compounds were screened for their in vitro antimicrobial activities against Gram‐negative (Escherichia coli and Salmonella typhimurium) and Gram‐positive bacteria (Staphylococcus aureus, Enterococcus faecium, and Streptococcus agalactiae or group B Streptococcus), as well as against the fungus Candida albicans. Although the synthesized compounds showed moderate antifungal activity against C albicans, they exhibited good‐to‐excellent antibacterial activities against several strains, than did standard drugs ampicillin and nystatin. In silico molecular docking in FabI enzyme active site gave information regarding the binding mode of the drug candidate at the molecular level.