Vol 61, No 7 (2025)

Efficient synthesis of 2-arylpropionic acids by Pd-catalyzed carbonylation of vinyl arenes with CO and HCOOH is reported. Excellent regioselectivity to target 2-arylpropionic acids is achieved by the addition of some polyvinylpyrrolidone. Mild reaction conditions, available catalytic system and low Pd loading are the advantages of the proposed protocol. It was used in the total synthesis of rac-naproxen starting from commercially available 6-hydroxy-2-naphthoic acid. Additionally, vinyl acetate hydroxycarbonylation in 2-acetoxypropionic is demonstrated.

The reaction of ortho-carboranillithium with 3,6-di(2-pyridyl)-1,2,4,5-tetrazine, considered as an example of the “from challenging to simple” strategy in the chemistry of carbonanes, leads to the previously unknown 3-ortho-carboranyl-[1,2,3]triazolo[1,5-a]pyridine as a result of cleavage of the tetrazine cycle and subsequent formation of the triazole cycle with nitrogen elimination. The structure of the obtained compound was confirmed by the spectroscopic and X-ray diffraction studies. The reaction mechanism, which was additionally confirmed by quantum-chemical calculations of electron densities and the Fukui function, was proposed.

The synthesis of selectively 3,4’,6’-tri- and 3,4,4’,6’-tetra-O-sulfated derivatives of the aminopropyl glycoside of the disaccharide α-D-GalNAc-(1–2)-α-L-Fuc (1 and 2), structurally related to highly unusual carbohydrate chain fragments of hexosaminoglycans found in the side chains of fucosylated chondroitin sulfates (FCS) from sea cucumbers Holothuria nobilis and Psolus peronii, is described. Spacered disaccharides 1 and 2 were obtained via a common synthetic route involving selectively protected L-fucose and phenyl-1-seleno-2-azido-2-deoxygalactose building blocks, the latter synthesized by azidophenylselenylation of triacetylgalactal. Target compounds 1 and 2 will be used as model structures to identify the pharmacophoric elements within these FCS that are responsible for their biological activity.

A comparative analysis of the catalytic efficiency of various organocatalysts for the carboxylation of epoxides based on ammonium and phosphonium salts was carried out. The results show that among low molecular weight onium salts, the efficiency of epoxide carboxylation is influenced by both the structure of the catalyst and its solubility in the reaction medium. The best efficiency was achieved with tetrabutyl-substituted onium iodides and bromides. The addition of 20 mol.% water together with the onium salt significantly accelerates the reaction with epoxides and leads to quantitative yields of mono- and disubstituted cyclic carbonates. A polystyrene type catalyst modified with an immobilized tributylphosphonium group (cat. 4 mol.%) with an additive of 1 equiv. of water leads to a quantitative yield of butylene carbonate and can be recycled without loss of catalytic activity (tested for 10 cycles), which makes it promising for practical application.

The reaction of N-methylated Nimesulide with Koiser’s reagent based on 4-iodo-3,5-dimethylisoxazole (DMIX-I(OH)OTs) yielded the corresponding iodonium salt. The interaction of this salt with S, O, and N-nucleophiles resulted in the production of functionalized derivatives of Nimesulide.

An approach to the preparation of ipidacrine conjugates with trifluoromethyl pyrazoles containing acetyl, hydrazone or oxime groups as functional substituents has been investigated. The alkylation of 5-acetyl-3-(trifluoromethyl)pyrazole with 2-chloroacetamide of ipidacrine proceeds non-regioselectively on the nitrogen atoms of the pyrazole ring, giving a mixture of 3-/5-CF₃-regioisomeric products. The introduction of a hydrazone/oxime substituent into the structure of CF₃-pyrazoles leads to the preferential formation of 3-CF₃-regioisomeric conjugates. In alkylation reactions, preservation of the arylhydrazone substituent in pyrazolyl-containing ipidacrines is observed, whereas the oxime group undergoes hydrolysis to the acetyl function. Conjugation of 5-(1-hydroxizimylidenethyl)pyrazole with 3-chloropropanamide of ipidacrine was accompanied by partial reduction of the hydrazone substituent. 4-Chlorobutanamide of ipidacrine in MeCN did not react with pyrazoles, and upon heating in DMF 5-(1-hydroxizimylidenethyl)pyrazole underwent transamination to form symmetric ketazine. The conjugate with the N-propanamide spacer showed moderate selective inhibitory activity towards butyrylcholinesterase (IC₅₀ = 14.5 ± 0.8 μM) and towards self-aggregation of β-amyloid (1–42). The introduction of an aryl substituent into the hydrazone fragment led to an increase in the antioxidant activity of pyrazoles and to the appearance of significant antioxidant properties of the conjugates in the ABTS (TEAC = 0.47–0.56) and FRAP (0.44–0.55 TE) tests.

Bacterial resistance to β-lactam antibiotics is one of the key challenges in global healthcare. A major mechanism underlying this resistance is the production of β-lactamases by pathogens. These enzymes are classified into four groups (A–D), with class B metallo-β-lactamases, particularly the NDM family, posing the highest threat. These zinc-dependent enzymes are capable of inactivating nearly all β-lactam antibiotics, and to date, there are no clinically approved inhibitors for this class. Previous studies have shown that certain derivatives of indole-2-carboxylic acid, hydroxamic acids, and glycine-based compounds can inhibit NDM-1 by interacting with Zn²⁺ ions and amino acid residues within the enzyme’s active site. However, the antibacterial potential of indole-2-carboxamide derivatives of the aforementioned compounds has not yet been explored as inhibitors of metallo-β-lactamases. In the search for new candidates to develop specific metallo-β-lactamase inhibitors, a known indole-2-carboxylic acid-based NDM-1 inhibitor was modified to prepared previously undescribed analogues – indole-2-carboxamides bearing fragments derived from hydroxamic acid, glycine, and imino diacetic acid. To accomplish this, a method commonly used in peptide synthesis was adapted, employing the condensing agent PyBOP. The resulting compounds demonstrated the ability to inhibit NDM-1 in the micromolar concentration range (IC₅₀ = 20–60 µM), highlighting the significant role of the substituent at position 2 in binding to the enzyme’s active site. It was shown that modifying the carboxyl group at position 2 of the indole core with functional fragments possessing intrinsic inhibitory activity leads to a reduction in the activity of the parent indole-2-carboxylic acid derivative.

Reactions of difluoroacetyl- and trifluoroacetylpyruvaldehyde dimethyl acetals with methyl and phenylhydrazine in methanol occur regioselectively and make it possible to obtain N-methyl- and N-phenyl-substituted 5-polyfluoromethylpyrazole-3-carbaldehyde and their dimethyl acetals in good yields. Regioisomeric N- methyl- and N-phenyl-substituted 3-polyfluoromethylpyrazole-5-carbaldehyde and their dimethyl acetals were synthesized in moderate yields by reacting the same reagents in trifluoroethanol or acetic acid.

Divergent approach to 5-cyanotriazoles and triazolo[1,5-a]quinolines based on Pd-catalyzed cyanation of 2-(5-iodotriazolyl)phenylacetic acid derivatives has been developed. Chemoselectivity is controlled by the choice of a cyanide source. Thus, CuCN leads only to replacement of iodine by nitrile moiety, while KCN induces further cyclization of the cyanation product via intramolecular condensation. The method is applicable to the preparation of both types of heterocyclic compounds in good yields (63—88%).

Palladium-catalyzed arylation of tris(3-aminopropyl)amine (TRPN) with several halogen-substituted naphthalene, anthracene, phenanthrene, and pyrene was studied. As a result, corresponding N,N,N"-triaryl derivatives were synthesized, and the best yields of the target compounds were obtained in the reactions with 1-chloro- and 9-bromoanthracenes. Fluorescence spectra of these compounds were studied in the presence of metal cations which showed that complete or very strong quenching of emission was observed upon the addition of Cu(II), Al(III), Cr(III) perchlorates in the case of 1-naphthyl-, 2-anthryl-, and 9-phenanthrenyl derivatives of TRPN. For 1-pyrenyl derivative complete quenching of fluorescence took place only in the presence of copper cations. For a number of other metal cations, slight changes in the emission intensity were observed with hypsochromic shifts of the maximum by approximately 10 nm. The characteristic changes in the absorption spectra of compounds 2, 5, 8 were observed in the presence of Cu(II), Al(III), and Cr(III) cations, which make these compounds promising for fluorescent and spectrophotometric detection of Cu(II), Al(III), and Cr(III) cations.

Based on the chalcogenfunctionalization reactions of allylicatic acid with tellurium, selenium, and sulfur halides, methods for the synthesis of new bifunctional chalcogenorganic compounds with yields of 86–99 % have been developed. The reactions of sulfur and selenium dihalides yield chalcogenides containing two butyrolactone rings in 97–99 % yields. Reactions with TeCl₄ and TeBr₄ yield trihalogenetellanes with a methylbutyrolactone group. The interaction of TeBr₄ with allylicatic acid in methanol proceeds as methoxytellurination and is accompanied by the transformation of the carboxyl group into a methoxycarbonyl group. Reduction of the trihalogenetellanes with high yields yielded the corresponding ditellurides.

A regio- and stereoselective synthesis of new vinyl selenocyanates (yields 76–93 %), containing N-alkylamide groups and heterocyclic amide substituents, has been developed based on the reaction of 3-trimethylsilyl-2-propynamides with potassium selenocyanate. The reaction proceeds in the presence of ammonium chloride in aqueous acetonitrile and is accompanied by a desilylation process.