Iodine-Catalyzed Radical C-H Amination of Nonaromatic Imidazole Oxides: Access to Cyclic α-Aminonitrones.

A straightforward cross-dehydrogenative coupling approach to incorporate alicyclic amino residues into the structure of model cyclic aldonitrones, 2H-imidazole oxides, is reported. The elaborated C(sp2)-H functionalization is achieved by employing cyclic amines in the presence of the I2-tert-butyl hydroperoxide (TBHP) reagent system. As a result, a series of 19 novel heterocyclic derivatives were obtained in yields of up to 97%. A mechanistic study involving electron paramagnetic resonance spectroscopic experiments allowed the radical nature of the reaction to be confirmed. In particular, the envisioned mechanistic rationale comprises N-iodination of a cyclic amine, followed by N-I bond homolysis of the resulting intermediate and subsequent amination of the nitrone moiety via the newly generated nitrogen-centered radical.

Triazavirin-A Novel Effective Antiviral Drug.

This review outlines the data of numerous studies relating to the broad-spectrum antiviral drug Triazavirin that was launched on the Russian pharmaceutical market in 2014 as an anti-influenza drug (the international non-patented name is Riamilovir). The range of antiviral activity of Triazavirin has been significantly expanded during recent years; in particular, it has been shown that Triazavirin exhibits activity against tick-borne encephalitis, Rift Valley fever, West Nile fever, and other infections of viral etiology. This drug has been approved for treatment of influenza and acute respiratory infections by the Russian Ministry of Health on the basis of comprehensive clinical trials involving over 450 patients. Triazavirin was found to be a highly effective and well-tolerated drug, allowing its over-the-counter sale. The recently published data on the use of Triazavirin in clinical practice for the treatment of patients with COVID-19 are discussed, with special attention paid to potential biological targets for this drug.

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.

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.

C(sp2)-H functionalization in non-aromatic azomethine-based heterocycles.

Direct C(sp2)-H functionalization of the endocyclic azomethine and aldonitrone moieties in non-aromatic azaheterocycles has established itself as a promising methodology over the last decade. Transition metal-catalyzed cross-coupling reactions, α-metalation-electrophile quenching protocols, and (metal-free) nucleophilic substitution of hydrogen reactions (SNH) are the major routes applied on cyclic imines and their derivatives. In this overview, we show the tangible progress made in this area during the period from 2008 to 2020.

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.

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.

Transition metal-free oxidative and deoxygenative C-H/C-Li cross-couplings of 2H-imidazole 1-oxides with carboranyl lithium as an efficient synthetic approach to azaheterocyclic carboranes.

The direct C-H functionalization methodology has first been applied to perform transition metal-free C-H/C-Li cross-couplings of 2H-imidazole 1-oxides with carboranyllithium. This atom- and step-economical approach, based on one-pot reactions of nucleophilic substitution of hydrogen (SN H) in non-aromatic azaheterocycles, affords novel imidazolyl-modified carboranes of two types (N-oxides and their deoxygenative analogues), which are particularly of interest in the design of advanced materials.

Palladium(II)-catalyzed oxidative C-H/C-H coupling and eliminative S(N)(H) reactions in direct functionalization of imidazole oxides with indoles.

Two novel synthetic approaches to realize the direct C(sp(2))-H bond functionalization in cyclic nitrones are reported. Palladium(II)-catalyzed oxidative C-C coupling of 2,2-dialkyl-4-phenyl-2H-imidazole 1-oxides with indoles was shown to result in the formation of 5-indolyl-3-yl derivatives, while nucleophilic substitution of hydrogen (S(N)(H)) at C(5) of the same imidazole system was found to afford the corresponding deoxygenated compounds.

Rapid and sensitive determination of nitrobenzene in solutions and commercial honey samples using a screen-printed electrode modified by 1,3-/1,4-diazines.

In this work, a screen-printed electrode (SPE) modified by 1,3/1,4-diazines was prepared for the rapid and sensitive determination of nitrobenzene (NB). The obtained results indicated enhanced cathodic currents of direct NB reduction into hydroxylaminophenol on the diazine-modified SPEs. The enhanced effect was most likely due to the combination of complexation and collisional processes of diazines towards nitroaromatic compounds and also the diazine-modified electrodes' increased electroconductivity. The best electrochemical responses were obtained in square wave voltammetry mode by using the carbazolyl substituted diazines as a component of the sensitive layer, which was assembled by co-electropolymerization with the unsubstituted carbazole on the electrode during 5 cycles. The low detection limit estimated as 0.107 µM and wide linear range (1-1000 µM) enables NB in water and food samples to be determined. The developed modified electrode was applied in the analysis of commercial honey samples.

2,7-Diazapyrenes: a brief review on synthetic strategies and application opportunities.

2,7-Diazapyrenes are promising azaaromatic scaffolds with a unique structural geometry and supramolecular properties. This core moiety and its derivatives with some N-methyl cations like N-methyl-2,7,-diazapyrenium, and N,N'-dimethyl-2,7-diazapyrenium attract special attention due to their challenging photophysical properties, especially in the context of interactions with DNA and some of its mononucleotides. This review focuses on the analysis of the main synthetic approaches to 2,7-diazapyrene and its functional derivatives employing various strategies under different reaction conditions. The opportunities of applications of 2,7-diazapyrenes, including their remarkable photophysical and supramolecular properties, DNA-bindings, in sensors, molecular electronics, supramolecular systems, and related areas are also 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.

S(N)(H) approach in the synthesis of nitronyl nitroxides.

We show that the S(N)(H) approach opens up new possibilities in the synthesis of hetaryl-substituted nitronyl nitroxides. The reaction of 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl lithium salt with pyridine-, pyrimidine-, pyrazine-, isoquinoline-, phthalazine-, quinoxaline-, and 1,2,4-triazine-N-oxides readily gives rise to the corresponding paramagnetic hetarenes. The reaction of this salt with quinoxaline-1,4-dioxide enabled the synthesis of the first nitronyl nitroxide biradical with two spin-labeled fragments in the vicinal positions of the heteroaromatic cycle; the persistent biradicals of this type were not known earlier. The characterizations of all persistent radicals obtained by S(N)(H) synthetic strategy include X-ray crystal structures, EPR investigation, and static magnetic susceptibility measurements.

Direct Functionalization of C(sp2)-H Bond in Nonaromatic Azaheterocycles: Palladium-Catalyzed Cross-Dehydrogenative Coupling (CDC) of 2H-Imidazole 1-Oxides with Pyrroles and Thiophenes.

The C(sp2)-H bond functionalization methodology was first applied to carry out the palladium-catalyzed oxidative C-H/C-H coupling reactions of 2H-imidazole 1-oxides with pyrroles and thiophenes. As a result, a number of novel 5-heteroarylated 2H-imidazole 1-oxides, which are of particular interest in the design of bioactive molecules and advanced materials, have been synthesized in yields up to 78%. The detailed H/D-exchange experiments have also been performed to elucidate some mechanistic features of this cross-dehydrogenative coupling process.

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.