Photo-/Electrocatalytic Difunctionalization of Alkenes Enabled by C-H Radical Functionalization.

The difunctionalization of alkenes represents a powerful tool to incorporate two functional groups into the alkene bones for increasing molecular complexity and has been widely utilizations in chemical synthesis. Upon the catalysis of the green, sustainable, mild photo-/electrochemistry technologies, much attentions have been attracted to the development of new tactics for the transformations of the important alkene and alkane feedstocks driven by C-H radical functionalization. Herein, we summarize recent advances in the photo-/electrocatalytic difunctionalization of alkenes enabled by C-H radical functionalization. We detailedly discuss the substrate scope and the mechanisms of the photo-/electrocatalytic alkene difunctionalization reactions by selecting impressive synthetic examples, which are divided into four sections based on the final terminated step, including oxidative radical-polar crossover coupling, reductive radical-polar crossover coupling, radical-radical coupling, and transition-metal-catalyzed coupling.

Ru(II)-Catalyzed C-H Amination of 1,2,3-Benzotriazinones with Azide Compounds.

A Ru(II)-catalyzed directed C-H amination of 1,2,3-benzotriazinones with azide compounds has been reported. The reaction has a wide substrate scope of organic azides with good results and represents a useful pathway to the construction of versatile heterocyclic amino products. In addition, the method can be used for the phthalazinones, highlighting the synthetic practicability of the strategy.

Synthesis of Diarylalkanes by Photoreductive 1,2-Diarylation of Alkenes with Aryl Halides and Cyanoaromatics.

We report a visible light-induced photoreductive strategy for three-component diarylation of alkenes with aryl halides and cyanoaromatics. Upon photoredox catalysis and with tertiary alkyl amines as the electron transfer agent, aryl halides selectively undergo halogen atom transfer to generate the aryl radicals and two C(sp2)-C(sp3) bonds between the cabron atoms are created in a radical addition and radical-radical coupling fashion to rapidly assemble diverse functionalized polyarylalkanes with high regio- and chemoselectivity. This method can be applied to broad feedstocks, including terminal alkenes, internal alkenes, aryl iodides, aryl bromides, aryl chlorides, electron-deficient benzonitriles, and isonicotinonitriles.

Visible-Light-Induced Photoredox 1,2-Dialkylation of Styrenes with α-Carbonyl Alkyl Bromides and Pyridin-1-ium Salts.

A visible-light-driven photoredox dialkylation of styrenes with α-carbonyl alkyl bromides and pyridin-1-ium salts for the synthesis of polysubstituted 1,4-dihydropyridines is reported. This reaction enables the formation of two new C(sp3)-C(sp3) bonds in a single reaction step and provides a strategy that employs pyridin-1-ium salts as the functionalized alkylating reagents via dearomatization to directly trap the resulting alkyl radicals from radical addition of alkenes and then terminate the alkene dialkylation.

Photoredox Ring Opening 1,2-Alkylarylation of Alkenes with Sulfonium Salts Toward Thioether-Substituted Oxindoles.

A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3)-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds. Importantly, this approach can be easily applied to late-stage modification of pharmaceuticals molecules.

Nickel-Catalyzed Reductive Cross-Coupling of Propargylic Acetates with Chloro(vinyl)silanes: Access to Silylallenes.

Because of their various reactivities, propargyl acetates are refined chemical intermediates that are extensively applied in pharmaceutical synthesis. Currently, reactions between propargyl acetates and chlorosilanes may be the most effective method for synthesizing silylallenes. Nevertheless, owing to the adaptability and selectivity of substrates, transition metal catalysis is difficult to achieve. Herein, nickel-catalyzed reductive cross-coupling reactions between propargyl acetates and substituted vinyl chlorosilanes for the synthesis of tetrasubstituted silylallenes are described. Therein, metallic zinc is a crucial reductant that effectively enables two electrophilic reagents to selectively construct C(sp2)-Si bonds. Additionally, a Ni-catalyzed reductive mechanism involving a radical process is proposed on the basis of deuteration-labeled experiments.

Theoretical Insights into the Mechanism and Origin of Solvent-Dependent Selectivity in the Cyclization of Propargyl Alcohols for the Divergent Synthesis of N-Heterocycles.

This study elucidates the mechanisms and principles governing chemoselectivity in synthesizing two distinct N-heterocycles, benzimidazole thiazine and benzothiazole imidazole, through BF3•OEt2-catalyzed cyclization reactions of propargyl alcohols with benzimidazole thiols. Employing density functional theory calculations, we highlight the crucial role of fluorine source in influencing chemoselectivity. In DCM, BF3, as the catalytic center, coordinates with propargyl alcohol's hydroxyl group to form a precursor. Conversely, in DMF, [BF2•DMF]+, formed from DMF and BF3•OEt2, acts as the catalytic center, activating the propargyl alcohol's hydroxyl group. The mechanisms in both solvents involve sequential steps: B-O bond formation, C-O bond cleavage, S-C bond formation, hydrogen atom transfer (HAT), cyclization, and deprotonation. A notable difference is the HAT process: in DCM, it follows a 1,5-HAT process, while in DMF, BF4- formation from DMF and BF3•OEt2 provides a fluorine source and introduces steric hindrance, favoring a 1,6-HAT process and leading to unique chemoselectivity. This pioneering research showcases the impact of DMF on cyclization reactions, offering valuable insights for comprehending and designing reactions driven by fluorine sources. Crucially, our results propose an innovative reaction mechanism featuring lower potential energy surfaces, enhancing our understanding of the intricate interplay among reactants, catalysts, and solvents.

Electro-/photocatalytic alkene-derived radical cation chemistry: recent advances in synthetic applications.

Alkene-derived radical cations are versatile reactive intermediates and have been widely applied in the construction of complex functionalized molecules and cyclic systems for chemical synthesis. Therefore, the synthetic application of these alkene-derived radical cations represents a powerful and green tool that can be used to achieve the functionalization of alkenes partially because the necessity of stoichiometric external chemical oxidants and/or hazardous reaction conditions is eliminated. This review summarizes the recent advances in the synthetic applications of the electro-/photochemical alkene-derived radical cations, emphasizing the key single-electron oxidation steps of the alkenes, the scope and limitations of the substrates, and the related reaction mechanisms. Using electrocatalysis and/or photocatalysis, single electron transfer (SET) oxidation of the CC bonds in the alkenes occurs, generating the alkene-derived radical cations, which sequentially enables the functionalization of translocated radical cations to occur in two ways: the first involves direct reaction with a nucleophile/radical or two molecules of nucleophiles to realize hydrofunctionalization, difunctionalization and cyclization; and the second involves the transformation of the alkene-derived radical cations into carbon-centered radicals using a base followed by radical coupling or oxidative nucleophilic coupling.

Recent Advances in N-O Bond Cleavage of Oximes and Hydroxylamines to Construct N-Heterocycle.

Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods.

Intermolecular 1,2-Difunctionalization of Alkenes Enabled by Fluoroamide-Directed Remote Benzyl C(sp3)-H Functionalization.

A copper-catalyzed remote benzylic C-H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2-methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite site-selectivity, broad substrate scope, and wide utilizations of late-stage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2-methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in two-component alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f][1,2]thiazepine 1,1-dioxides.

A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy.

Existing nanoparticle-mediated drug delivery systems for glioma systemic chemotherapy remain a great challenge due to poor delivery efficiency resulting from the blood brain barrier/blood-(brain tumor) barrier (BBB/BBTB) and insufficient tumor penetration. Here, we demonstrate a distinct design by patching doxorubicin-loaded heparin-based nanoparticles (DNs) onto the surface of natural grapefruit extracellular vesicles (EVs), to fabricate biomimetic EV-DNs, achieving efficient drug delivery and thus significantly enhancing antiglioma efficacy. The patching strategy allows the unprecedented 4-fold drug loading capacity compared to traditional encapsulation for EVs. The biomimetic EV-DNs are enabled to bypass BBB/BBTB and penetrate into glioma tissues by receptor-mediated transcytosis and membrane fusion, greatly promoting cellular internalization and antiproliferation ability as well as extending circulation time. We demonstrate that a high-abundance accumulation of EV-DNs can be detected at glioma tissues, enabling the maximal brain tumor uptake of EV-DNs and great antiglioma efficacy in vivo.

Electrochemical oxygenation of sulfides with molecular oxygen or water: switchable preparation of sulfoxides and sulfones.

A practical and eco-friendly method for the controllable aerobic oxygenation of sulfides by electrochemical catalysis was developed. The switchable preparation of sulfoxides and sulfones was effectively controlled by reaction time, in which both molecular oxygen and water can be used as the oxygen source under catalyst and external oxidant-free conditions. The electrochemical protocol features a broad substrate scope and excellent site selectivity and is successfully applied to the modification of some sulfide-containing pharmaceuticals and their derivatives.

Electrochemical 1,2-Diarylation of Alkenes Enabled by Direct Dual C-H Functionalizations of Electron-Rich Aromatic Hydrocarbons.

A cobalt-promoted electrochemical 1,2-diarylation of alkenes with electron-rich aromatic hydrocarbons via direct dual C-H functionalizations is described, which employs a radical relay strategy to produce polyaryl-functionalized alkanes. Simply by using graphite rod cathode instead of platinum plate cathode, chemoselectivity of this radical relay strategy is shifted to the dehydrogenative [2+2+2] cycloaddition via 1,2-diarylation, annulation, and dehydrogenation cascades leading to complex 11,12-dihydroindolo[2,3-a]carbazoles. Mechanistical studies indicate that a key step for the radical relay processes is transformations of the aromatic hydrocarbons to the aryl sp2 -hybridized carbon-centered radicals via deprotonation of the corresponding aryl radical cation intermediates with bases.

Radical 1,4-Aryl Migration Enabled Remote Cross-Electrophile Coupling of α-Amino-ß-Bromo Acid Esters with Aryl Bromides.

We report an unprecedented, efficient nickel-catalysed radical relay for the remote cross-electrophile coupling of ß-bromo-α-benzylamino acid esters with aryl bromides via 1,4-aryl migration/arylation cascades. ß-Bromo-α-benzylamino acid esters are considered as unique molecular scaffolds allowing for aryl migration reactions, which are conceptually novel variants for the radical Truce-Smiles rearrangement. This reaction enables the formation of two new C(sp3 )-C(sp2 ) bonds using a bench-stable Ni/bipyridine/Zn system featuring a broad substrate scope and excellent diastereoselectivity, which provides an effective platform for the remote aryl group migration and arylation of amino acid esters via redox-neutral C(sp3 )-C(sp2 ) bond cleavage. Mechanistically, this cascade reaction is accomplished by combining two powerful catalytic cycles consisting of a cross-electrophile coupling and radical 1,4-aryl migration through the generation of C(sp3 )-centred radical intermediates from the homolysis of C(sp3 )-Br bonds and the switching of the transient alkyl radical into a robust α-aminoalkyl radical.

Effects of resveratrol on cariogenic virulence properties of Streptococcus mutans.

BACKGROUND: Streptococcus mutans is the principal etiological agent of human dental caries. The major virulence factors of S. mutans are acid production, acid tolerance, extracellular polysaccharide (EPS) synthesis and biofilm formation. The aim of this study is to evaluate the effect of resveratrol, a natural compound, on virulence properties of S. mutans. RESULTS: Resveratrol at sub-MIC levels significantly decreased acid production and acid tolerance, inhibited synthesis of water-soluble polysaccharide and water-insoluble polysaccharide, compromised biofilm formation. Related virulence gene expression (ldh, relA, gtfC, comDE) was down-regulated with increasing concentrations of resveratrol. CONCLUSIONS: Resveratrol has an inhibitory effect on S. mutans cariogenic virulence properties and it represents a promising anticariogenic agent.

Photocatalytic dual decarboxylative alkenylation mediated by triphenylphosphine and sodium iodide.

An efficient photocatalytic dual decarboxylative alkenylation of α,ß-unsaturated carboxylic acids and alkyl N-hydroxyphthalimide (NHP) esters mediated by triphenylphosphine and sodium iodide has been developed. This protocol proceeds under 456-nanometer irradiation by visible blue light in the absence of transition metals or organic dye based photoredox catalysts. The reaction is successfully applied to a wide range of redox-active esters derived from aliphatic carboxylic acids (1°, 2° and 3°) and α-amino acids, enabling transformations of diverse α,ß-unsaturated carboxylic acids to α,ß-alkylated styrenes with high efficiency and excellent selectivity under mild conditions.

Copper-catalyzed C-H [3 + 2] annulation of N-substituted anilines with α-carbonyl alkyl bromides via C(sp3)-Br/C(sp2)-H functionalization.

A copper-catalyzed C-H [3 + 2] annulation of N-substituted anilines with α-carbonyl alkyl bromides for the synthesis of 3,3'-disubstituted oxindoles is developed. Tandem C-H cycloamidation reactions of various α-carbonyl alkyl bromide derivatives including tertiary-α-bromoalkyl ketone esters, malonic esters and cycloalkanes, with N-aryl or alkyl substituted anilines, can be performed using this system, affording a vast array of valuable 3,3'-disubstituted oxindoles in moderate to good yields.

Manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles/2-arylbenzimidazoles with disubstituted phosphine oxides.

A simple and practical method for the synthesis of phosphoryl-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones through manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles or 2-arylbenzimidazoles with disubstituted phosphine oxides was developed. In this transformation, new C-P bond and C-C bond were constructed simultaneously under silver-free conditions, exhibiting a broad substrate scope. It was noted that not only diarylphosphine oxides but also dialkyl and arylalkyl-phosphine oxides were compatible with the conditions.

Recent Advances in the Intermolecular Oxidative Difunctionalization of Alkenes.

Functionalization of alkenes has been well investigated by chemists, thus it has been extensively applied in organic synthesis and industries. In the past few decades, transition-metal, such as palladium, rhodium, gold, iridium, copper and iron, catalyzed functionalization reactions of alkenes have been significantly developed and played vital roles in synthesis. The difunctionalization of alkenes are appealing as an important alternative to the traditional approaches for the construction of useful carbon centers, particularly carbon quaternary centers, which commonly existed as structural motifs in numerous natural products, pharmaceuticals, and biologically active molecules. This account will summarize our recent advances in the intermolecular difunctionalization of alkenes, and also highlight the scope and limitations as well as the mechanisms of these difunctionalization reactions. In general, in this account the difunctionalization of alkenes starting from dicarbofunctionalization will be discussed. Then carboheterofunctionalization of alkenes will be intensively reviewed, and diheterofunctionalization will also be highlighted.

Construction of Covalent-Organic Frameworks (COFs) from Amorphous Covalent Organic Polymers via Linkage Replacement.

Covalent-organic frameworks (COFs) as porous crystalline materials show promising potential applications. However, developing facile strategies for the construction of COFs directly from amorphous covalent organic polymers (COPs) is still a great challenge. To this end, we report a novel approach for easy preparation of COFs from amorphous COPs through the linkage replacement under different types of reactions. Four COFs with high crystallinity and porosity were constructed via the linkage substitution of polyimide-linked COPs to imine-linked COFs as well as imine-linked COPs to polyimide-linked COFs. The realization of the linkage substitution would significantly expand the research scope of COFs.