Design and Antioxidant Properties of Bifunctional 2H-Imidazole-Derived Phenolic Compounds-A New Family of Effective Inhibitors for Oxidative Stress-Associated Destructive Processes.

The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2H-imidazole-derived phenolic compounds affording the bifunctional 2H-imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2H-imidazole family of various architectures bearing both electron-donating and electron-withdrawing substituents in the aryl fragment along with the different arrangements of the hydroxy groups in the polyphenol moiety, namely derivatives of phloroglucinol, pyrogallol, hydroxyquinol, including previously unknown water-soluble molecules, were studied. The structural and antioxidant properties of these bifunctional 5-aryl-2H-imidazoles were comprehensively studied. The redox transformations of the synthesized compounds were carried out. The integrated approach based on single and mixed mechanisms of antioxidant action, namely the AOC, ARC, Folin, and DPPH assays, were applied to estimate antioxidant activities. The relationship "structure-antioxidant properties" was established for each of the antioxidant action mechanisms. The conjugation effect was shown to result in a decrease in the mobility of the hydrogen atom, thus complicating the process of electron transfer in nearly all cases. On the contrary, the conjugation in imidazolyl substituted phloroglucinols was found to enhance their activity through the hydrogen transfer mechanism. Imidazole-derived polyphenolic compounds bearing the most electron-withdrawing functionality, namely the nitro group, were established to possess the higher values for both antioxidant and antiradical capacities. It was demonstrated that in the case of phloroglucinol derivatives, the conjugation effect resulted in a significant increase in the antiradical capacity (ARC) for a whole family of the considered 2H-imidazole-derived phenolic compounds in comparison with the corresponding unsubstituted phenols. Particularly, conjugation of the polyphenolic subunit with 2,2-dimethyl-5-(4-nitrophenyl)-2H-imidazol-4-yl fragment was shown to increase ARC from 2.26 to 5.16 (104 mol-eq/L). This means that the considered family of compounds is capable of exhibiting an antioxidant activity via transferring a hydrogen atom, exceeding the activity of known natural polyphenolic compounds.

Metal-Free C-H/C-H Coupling of 2H-Imidazole 1-Oxides with Polyphenols toward Imidazole-Linked Polyphenolic Compounds.

The methodology of nucleophilic substitution of hydrogen (SNH) was successfully applied as a convenient synthetic tool to afford azaheterocyclic derivatives of phenols of various architectures. A series of 26 novel imidazole-linked polyphenolic compounds were first prepared in 72-95% yields through the direct metal-free C-H/C-H coupling of polyphenols with 2H-imidazole 1-oxides. Comprehensive studies on the reaction condition optimization, scope, and limitations enabled the development of a straightforward method toward novel bifunctional derivatives bearing both phenolic and imidazole scaffolds of particular interest in the design of challenging molecules for versatile applications in medicinal chemistry and materials science.

Recent advances in the functionalization of polyfluoro(aza)aromatics via C-C coupling strategies.

Polyfluoro(aza)aromatic compounds are of interest in various fields of practical applications, such as medicinal and agrochemistry, materials science and advanced technologies. The C-C coupling reactions are known to be a promising synthetic tool to create challenging fluorinated molecules of diverse architectures. In this review, we have summarized the recent advances in the functionalization of polyfluoro(aza)aromatics via both transition metal-catalyzed and metal-free C-C coupling reactions for the period from 2006 to the beginning of 2021. Also, mechanistic features for chemical transformations of fluoroarene scaffolds and new opportunities for practical applications of the designed fluorinated molecules have been highlighted.

Meso-functionalization of calix[4]arene with 1,3,7-triazapyrene in the design of novel fluorophores with the dual target detection of Al3+ and Fe3+ cations.

A meso-functionalization strategy has successfully been applied to the synthesis of novel 1,3,7-triazapyrene derivatives of calixarenes. The key synthetic step in these transformations providing the direct C-C bond formation is nucleophilic substitution of hydrogen (SN H) in 1,3,7-triazapyrene. General photophysical characteristics for these macrocyclic compounds, as well as features in emission properties upon addition of various metal cations have been elaborated. Studies using NMR spectroscopy have also shown a mutual effect of both calix[4]arene and 1,3,7-triazapyrene moieties on the coordination process. The complex stoichiometry and binding constants for Al3+ and Fe3+ guests have been explored with titration experiments.

Transition-Metal-Free C-H/C-Li Coupling of Nonaromatic 2H-Imidazole 1-Oxides with Pentafluorophenyl Lithium in the Design of Novel Fluorophores with Intramolecular Charge Transfer Effect.

Methodology of nucleophilic substitution of hydrogen (SNH) was first applied for the direct modification of nonaromatic 2H-imidazoles to afford novel polyfluoroarylated azaheterocycles. Scope, tolerance for these transition-metal-free C-H/C-Li coupling reactions, and photophysical properties for the novel 4-(perfluorophenyl)-5-aryl-2H-imidazoles were comprehensively studied. In particular, some of the obtained perfluoroaryl-substituted 2H-imidazoles were found to be of particular interest as promising push-pull fluorophore systems in the design of fluorometric sensor materials due to the effect of intramolecular charge transfer.

Synthesis of Functionalized Pyrazin-2(1 H)-ones via Tele-Nucleophilic Substitution of Hydrogen Involving Grignard Reactants and Electrophiles.

The reaction of 6-chloro-1-methylpyrazin-2(1 H)-one with Grignard reactants followed by quenching with different electrophiles gave access to a variety of 3,6-difunctionalized 1-methylpyrazin-2(1 H)-ones. This regioselective three-component reaction represents the first example of a tele-nucleophilic substitution of hydrogen (SNH) in which the anionic σH adduct is quenched by electrophiles (other than a proton) before elimination takes place. Quenching the reaction with iodine (I2) or bromine (Br2) provides an alternative reaction pathway, yielding a 3-functionalized 6-chloro-1-methylpyrazin-2(1 H)-one or 5-bromo-6-chloro-1-methylpyrazin-2(1 H)-one, respectively. The halogens present offer opportunities for further selective transformations.