Radical Process Research Articles

Visible Light-Induced Three-Component Alkoxyalkylation of Alkenes with α-Halocarbonyls and Alcohols.

A visible-light-induced three-component alkoxyalkylation of alkenes has been developed under the photocatalysis of fac-Ir(ppy)3. The alkene substrate scope included aryl and aliphatic alkenes as well as electron-rich and electron-deficient alkenes, allowing the facile coupling with a diverse array of α-halocarbonyl compounds. The redox potential-guided orchestration of radical processes with precision allows rapid access to highly functionalized products that are useful building blocks in organic synthesis.

In vivo Study of the Anti/Prooxidant Activity of a Metal-Organic Coordination Polymer Modified with Iron Oxides and Ascorbic Acid

Experiments on 39 male Wistar rats were performed. A metal-organic coordination polymer modified with iron oxide and ascorbic acid (composite) was administered intravenously to healthy rats at doses of 25 and 50 mg/kg. The anti/prooxidant activity of the composite was assessed 3 and 24 hours after administration. The composite in both doses was shown to have no significant effect on the homeostasis of prooxidants/antioxidants in the blood serum in healthy animals. In high doses, the composite enhances apoptosis of lymphocytes, which indicates its possible use as a catalyst for free radical processes for further use in biomedicine.

Evaluation of antioxidant activity of 1,2,4-triazole derivatives in the initiation of free radical processes

The activation of lipid free radical oxidation is a key stage in the development of many diseases and can lead to the emergence of related complications. To identify new synthetic compounds with antioxidant properties, it is necessary to conduct studies on various models of experimental free radical oxidation of biomolecules. Literature sources indicate that among the derivatives of 1,2,4-triazole, there is a significant number that possess high antioxidant activity. The aim of the study to assess the antioxidant properties of newly synthesized S-derivatives of 1,2,4-triazole through the inhibition of reactive oxygen species accumulation in the superoxide dismutase system. Materials and methods. To achieve this goal, we used one of the methods for assessing antioxidant activity by initiating free radical processes in vitro, specifically by inhibiting the accumulation of reactive oxygen species. Results. Twenty-three S-derivatives of 5-(thiophene-3-ylmethyl)-4-R-1,2,4-triazole-3-thiols were investigated. The most effective compound was sodium 2-((4-phenyl-5-thiophene-3-ylmethyl)-1,2,4-triazole-3-yl)thio)acetate, which exceeded the activity of both reference drugs. Following in activity was compound 22, 1-phenyl-2-((4-phenyl-5-(thiophene-3-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)ethanol, which demonstrated an effect similar to that of emoxipine, while compound 7, 1-(3-fluorophenyl)-2-((5-thiophene-3-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)ethanone, was slightly less active. Conclusions. It was established that among the new S-derivatives of 1,2,4-triazole, some exhibit significant antioxidant effects that are comparable to or exceed the efficacy of reference drugs.

Anti-Selective Carboacylation of Alkynes via Photoredox/Nickel Dual Catalysis.

Here, we report an intermolecular carboacylation of terminal alkynes with tertiary and secondary alkyltrifluoroborates as well as acyl chlorides via photoredox/nickel dual catalysis, affording a varity of stereodefined trisubstituted enones in good to excellent yields and E stereoselectivity, through a radical relay process. This redox-neutral protocol exhibits excellent functional group tolerance, exclusive regio- and stereoselectivity, and broad compatibility with various acyl chlorides and alkyltrifluoroborates.

Dual NHC/HAT‐Promoted Esterification to Access α‐Aryl Glycines

α‐Aryl glycines are among the more important carbonyl compounds, particularly as nonproteinogenic α‐amino acids present in many pharmacophores. As such, many strategies have been developed to access this motif, but direct carboxylation methods remain underdeveloped. Herein, we employ a dual NHC/HAT catalysis strategy to access 2‐azaallyl radicals, which subsequently couple with in situ generated ester azolium radical intermediates. Base‐mediated collapse of the ensuing tetrahedral intermediate liberates the NHC catalyst and benzophenone protected aryl glycine. This methodology was employed to esterify obtain a variety of aryl substituted glycine derivatives, as well as allylic and benzylic sites. Mechanistic studies reveal that this radical process operates under both oxidative and reductive quenching cycles, while preliminary experiments employing a chiral NHC and Lewis acid additive demonstrate modest enantioselectivity.

Visible-light-promoted direct desulfurization of glycosyl thiols to access C-glycosides

C-Glycosides are essential for the study of biological processes and the development of carbohydrate-based drugs. Despite the tremendous hurdles, glycochemists have often fantasized about the efficient, highly stereoselective synthesis of C-glycosides with the shortest steps under mild conditions. Herein, we report a desulfurative radical protocol to synthesize C-alkyl glycosides and coumarin C-glycosides under visible-light induced conditions without the need of an extra photocatalyst, in which stable and readily available glycosyl thiols that could be readily obtained from native sugars are activated in situ by pentafluoropyridine. The benefits of this procedure include high stereoselectivity, broad substrate scope, and easy handling. Mechanistic studies indicate that the in situ produced tetrafluoropyridyl S-glycosides form key electron donor–acceptor (EDA) complexes with Hantzsch ester (for C-alkyl glycosides) or Et3N (for coumarin C-glycosides), which, upon irradiation with visible light, trigger a cascade of glycosyl radical processes to access C-glycosides smoothly.

De(sulfon)amidative Cyclization: The Synthesis of Dibenzolactams and Dibenzosultams for Organic Light Emitting Diode Materials

This study addresses a challenge in organic synthetic chemistry: the direct cleavage of amide bonds, which is typically hampered by the thermodynamic stability of the C(Ar)–C(acyl) bond. Previous methods often rely on “CO” extrusion‐jointing transition metal‐catalyzed process and require activated tertiary amides, limiting their applicability due to incompatibility with reactive functional groups such as halogens. Herein, we report a transition metal‐free approach for the deamidative cyclization of biaryl diamides via a radical process, yielding dibenzolactam derivatives. Along this line, we have developed the desulfonamidative cyclization of biaryl disulfonamides to produce dibenzosultams through direct nucleophilic aromatic substitution, demonstrating high selectivity for unsymmetrical structures. Additionally, unsymmetrical sulfamoyl biaryl amides, containing both amide and sulfonamide functionalities, can selectively undergo desulfonamidative coupling with the amide to form dibenzolactams, which offers a complementary synthetic pathway to unsymmetric dibenzolactams. These protocols exhibit excellent compatibility with reactive functional groups, including halogens, providing an innovative synthetic toolbox for the development of thermally activated delayed fluorescence (TADF) materials used in organic light emitting diodes (OLEDs). DMAC‐PDO, incorporating a dibenzolactam as the acceptor unit, serves as an efficient blue TADF emitter with a maximum external quantum efficiency (EQEmax) of 23.4%.

De(sulfon)amidative Cyclization: The Synthesis of Dibenzolactams and Dibenzosultams for Organic Light Emitting Diode Materials.

This study addresses a challenge in organic synthetic chemistry: the direct cleavage of amide bonds, which is typically hampered by the thermodynamic stability of the C(Ar)-C(acyl) bond. Previous methods often rely on "CO" extrusion-jointing transition metal-catalyzed process and require activated tertiary amides, limiting their applicability due to incompatibility with reactive functional groups such as halogens. Herein, we report a transition metal-free approach for the deamidative cyclization of biaryl diamides via a radical process, yielding dibenzolactam derivatives. Along this line, we have developed the desulfonamidative cyclization of biaryl disulfonamides to produce dibenzosultams through direct nucleophilic aromatic substitution, demonstrating high selectivity for unsymmetrical structures. Additionally, unsymmetrical sulfamoyl biaryl amides, containing both amide and sulfonamide functionalities, can selectively undergo desulfonamidative coupling with the amide to form dibenzolactams, which offers a complementary synthetic pathway to unsymmetric dibenzolactams. These protocols exhibit excellent compatibility with reactive functional groups, including halogens, providing an innovative synthetic toolbox for the development of thermally activated delayed fluorescence (TADF) materials used in organic light emitting diodes (OLEDs). DMAC-PDO, incorporating a dibenzolactam as the acceptor unit, serves as an efficient blue TADF emitter with a maximum external quantum efficiency (EQEmax) of 23.4%.

Photoredox-Catalyzed [3+2] annulation of Aromatic Amides with Olefins via Iminium Intermediates.

Despite the preliminary success of transition metal-catalyzed [3+2] annulation of amides with olefins, the corresponding radical-type [3+2] annulation remains a laborious challenge. Herein we report the first photoredox-catalyzed radical-type [3+2] annulation of aromatic amides with olefins. We established an approach to generate unprecedented iminium radicals by reducing the oxyiminium intermediates, formed in situ from corresponding amides with Tf2O, via photoredox catalysis. The [3+2] annulation was achieved via stepwise radical process, instead of forming linear products via other pathways as previously reported. This annulation protocol exhibits excellent functional group tolerance, and a diversity of substrates are united under the photoredox conditions, affording iminium products that can be in situ diversified into 1-indanones, enamines and amines. Mechanistic investigations indicate reduction of the oxyiminium intermediate to the iminium radicals by excited-state of the photocatalyst initiates the catalytic cycle.

Photoredox‐Catalyzed [3+2] annulation of Aromatic Amides with Olefins via Iminium Intermediates

Despite the preliminary success of transition metal‐catalyzed [3+2] annulation of amides with olefins, the corresponding radical‐type [3+2] annulation remains a laborious challenge. Herein we report the first photoredox‐catalyzed radical‐type [3+2] annulation of aromatic amides with olefins. We established an approach to generate unprecedented iminium radicals by reducing the oxyiminium intermediates, formed in situ from corresponding amides with Tf2O, via photoredox catalysis. The [3+2] annulation was achieved via stepwise radical process, instead of forming linear products via other pathways as previously reported. This annulation protocol exhibits excellent functional group tolerance, and a diversity of substrates are united under the photoredox conditions, affording iminium products that can be in situ diversified into 1‐indanones, enamines and amines. Mechanistic investigations indicate reduction of the oxyiminium intermediate to the iminium radicals by excited‐state of the photocatalyst initiates the catalytic cycle.

TCCA/RSeSeR-Mediated Selenoalkoxy of Allenamides via a Radical Process: Synthesis of Selanyl-allylic N,O-Aminals.

An efficient TCCA (trichloroisocyanuric acid)/RSeSeR-mediated selenoalkoxy of allenamides for the construction of selanyl-allylic N,OA-aminal derivatives was developed. The reaction exhibits good functional group tolerance and high efficiency, affording the products in good to excellent yields. Mechanistic investigations indicated that a selanyl-allylic radical intermediate was first formed via the RSe radical added to the central carbon of allenamides, which subsequently furnished highly stable selanyl-allylic carbocation intermediate by abstraction of an electron by the chlorine radical. Moreover, this is the first report of using selenium reagent (RSeCl) to activate allenamides via a radical process.

Nickel-Catalyzed Cross-Electrophile Vinylation of α-Chloro Phosphonates.

Herein, we report a general and efficient Ni-catalyzed reductive cross-coupling reaction of substituted vinyl bromides and α-chloro phosphonates to access a set of α-vinyl phosphonates using zinc as the terminal reductant. This reaction exhibits broad substrate adaptability and good functional group tolerance, which allows to afford diverse compounds including structurally complex motifs from natural products and drugs. Furthermore, the practicality was certificated through the gram-scale and transformation experiments. The preliminary mechanistic investigations support a radical chain process. The potential to realize enantiomeric control makes it more valuable for further exploration.

Nitrogen Centered Radicals in Visible-Light Promoted Reactions

Nitrogen Centered Radicals (NCR) are known in literature since the first years of 1900, but only with the spread of photoredox catalysis, and in particular visible light-mediated radical processes, nitrogen radical chemistry became more accessible generating these kinds of radicals in situ employing mild conditions. In fact, unlike their carbon counterpart, nitrogen radicals have not historically spread in academia or industry due to a lack of an efficient strategy to produce them. Nowadays, NCR are more established, and this graphical review illustrates the key publications from the literature categorized them by both the type of NCR and the type of reaction. In fact, nitrogen radicals can be divided in four different categories according to their electronical configuration, orbital structure and chemical behaviour. The reactivity of all these radicals can be summarized into four main classes: they are mostly exploited into intramolecular cyclization; intramolecular hydrogen atom abstraction; Norrish type-I fragmentation and intermolecular addition to π systems.

Self-assembly of decavanadate and Ni(HCO3)2 into nanoparticles anchored on carbon nitride for efficient photocatalytic Minisci-type alkylation

Photocatalysis Minisci-type reactions involving carbon-centered radicals (CCRs) have emerged as a hot and significant topic in the field of organic synthesis chemistry. Herein, we present a nickel-vanadium nanoparticle anchored on carbon nitride catalyst (NiV-CN) and persulfate as a hydrogen atom transfer (HAT) precursor. This catalyst enables the photocatalytic Minisci-type CCR alkylation. The nickel-vanadium nanoparticles are synthesized via electrostatic attraction between [V10O28]6− anions and Ni(HCO3)2, with in situ self-assembly occurring during the hydrothermal process. In the model reaction of 4-methylquinoline with cyclohexane, the NiV-CN catalyst showed high stability, without significant loss its catalytic activity after three cycles. The CCRs was extended to cycloalkanes, adamantanes, and cyclic ethers, which react with quinoline, isoquinoline, and benzothiazole to provide the corresponding products in moderate to excellent yields. Mechanism studies indicate that nickel-vanadium nanoparticles play a crucial role in the formation process of carbon-centered radicals by activating the persulfate precursor into sulfate radicals under visible-light irradiation.

Photoredox-Catalyzed Alkynylation of C(sp3)-H Bonds Adjacent to a Nitrogen Atom of Tertiary Amines with Alkynyl Bromides.

A novel and robust alkynylation of C(sp3)-H bonds adjacent to a nitrogen atom of tertiary amines with alkynyl bromides as radical alkynylating reagents has been realized under visible-light irradiation. A range variety of tertiary amines including N-arylamines and N-alkylamine have been coupled with both aromatic and aliphatic alkynyl bromides to furnish 51 examples of propargylamines in moderate to excellent yields (31-80% yields). The possible mechanism was a radical addition-elimination process based on preliminary mechanistic studies.

Antioxidant activity of extracts of oregano and marsh cinquefoil, growing in the Altai region, in connection with their content of favonoids

Drugs based on medicinal plants have such advantages over synthetic analogues as low toxicity, better tolerability and reduced risk of addiction. Antioxidant agents in medicinal plants include substances from the flavonoid group, due to their ability to inactivate free radical processes, due to the mechanism of electron transfer between reaction components to neutralize free radicals. Among the medicinal plants of Western Siberia and the Altai Territory, oregano and marsh cinquefoil have a high content of flavonoids. The purpose of the study was to evaluate the antioxidant activity of alcohol-free extracts of oregano and marsh cinquefoil growing in the Altai region in connection with the content of flavonoids (flavonols and proanthocyanidins). To conduct the study, alcohol-free extracts of the studied plants were prepared using patented technology. The content of flavonols and proanthocyanidins was studied by arbitration techniques using spectrophotometry. The antioxidant activity of the extracts was measured using cathodic voltammetry method. The results showed that the average flavonol content in oregano extract was 866.5 μg/ml, while only traces were found in the extract of cinquefoil (60.0 μg/ ml). The average content of proanthocyanidins in the extract of cinquefoil was 4.05%, in the extract of oregano content of proanthocyanidins was 0.43%. The average coefficient of antioxidant activity for cinquefoil extract was 11.63 mmol/l×min and 3.81 mmol/l×min for oregano extract. From the results obtained, we can conclude that it is advisable to use extracts of marsh cinquefoil and oregano, growing in the Altai Territory, in the composition of biologically active antioxidant additives.

N-Heterocyclic Carbene Catalysis for Polycyclic Benzazepines Assembly: Regioselective Intramolecular Tandem Radical Cyclization.

A variety of polycyclic benzazepines were rapidly constructed by NHC-catalyzed regioselective redox-neutral intramolecular tandem cyclization. Initial mechanistic studies revealed that a SET radical process was possibly involved.

The effect of a new 3-hydroxypyridine derivative LHT-2-20 on free radical oxidation in experimental periodontitis

Aim. To study the effect of a new complex compound LHT-2-20 (2-ethyl-6-methyl-3-hydroxypyridine-2-(3benzoyl phenyl)-propanoate) on free radical oxidation in experimental periodontitis.Materials and methods. The experimental study was performed on 195 white mongrel mice weighing 19–23 g and 137 white mongrel rats weighing 180–220 g. The effect of a new complex compound LHT-2-20 (2-ethyl-6methyl-3-hydroxypyridine-2-(3-benzoyl phenyl)-propanoate) on the intensity of free radical oxidation and the local state of periodontal tissues during a course of intragastric administration was studied on the experimental model of periodontitis. Statistical processing of the results was carried out using the SPSS Statistics 20.0 software package with the analysis of variance (ANOVA) and the parametric Tukey’s test.Results. The LHT-2-20 compound reduced elevated levels of primary and secondary lipoperoxidation products (conjugated dienes, malondialdehyde in plasma and in erythrocytes during spontaneous and iron-induced oxidation) already at the early stages of the experiment, bringing the studied parameters closer to the reference values by the end of the course of treatment. The use of the compound LHT-2-20 contributed to an increase in the activity of the main antioxidant enzymes (catalase and superoxide dismutase), normalizing them to baseline values by the end of the experiment. With the correction of free radical processes, the use of LHT-2-20 limited the local inflammatory response in periodontal tissues, which was confirmed by a decrease in gingival edema and hyperemia, bleeding, depth of periodontal pockets, and tooth mobility.Conclusion. The results of this study confirm the anti-inflammatory potential of the compound and the multiplicity of its effects due to the impact on the mechanisms of oxidative stress. The expediency of further study of the drug is justified by the prospect of creating a new drug and its subsequent wide clinical application as part of the complex therapy of periodontal inflammation.

A Metal-Free Direct Decarboxylative Fluoroacylation of Indole Carboxylic Acids with Fluorinated Acids.

A straightforward preparation of diversified fluorinated indol-3-yl ketones was developed by the direct decarboxylative fluoroacylation of indole carboxylic acids. The reaction could be performed on a gram scale under net conditions. Neither a metal catalyst nor an additive was employed. This methodology featured simple reaction conditions, high efficiency, exclusive selectivity, a broad substrate scope, and easy operation, which allowed it to meet the green chemistry requirement of the modern pharmaceutical industry. Control experiments confirmed that a radical process might be involved in the tandem decarboxylative fluoroacylation sequence.

Transition-metal-free tandem cyclization by radical NHC catalysis: Rapid access to indolo[2,1‑a]isoquinolines

A diverse array of functionalized indolo[2,1-a]isoquinolines are constructed through an NHC-catalyzed transition-metal-, and oxidant-free radical tandem cyclization from readily accessible 2-aryl N-methacryloyl indoles and α-bromo esters. This redox-neutral protocol exhibits a wide substrate scope, excellent functional group tolerance, and can be scaled up to 2.0 mmol with parallel efficiency. Mechanistic studies suggest that a single electron transfer radical process is likely involved.