Electrochemical quinuclidine-mediated Minisci-type acylation of N-heterocycles with aldehydes.

The electro-generation of acyl radicals from both aromatic and aliphatic aldehydes remains an unmet challenge. We provide a solution to this challenge by merging electro-oxidation and a quinuclidine-mediated hydrogen atom transfer strategy. The generation of acyl radicals at decreased applied potentials compared to that of formyl oxidation exhibits excellent functional group compatibility.

Fucoxanthin restructures the gut microbiota and metabolic functions of non-obese individuals in an in vitro fermentation model.

Fucoxanthin, a carotenoid exclusively derived from algae, exerts its bioactivities with the modulation of the gut microbiota in mice. However, mechanisms through which fucoxanthin regulates the gut microbiota and its derived metabolites/metabolism in humans remain unclear. In this study, we investigated the effects of fucoxanthin on the gut microbiota and metabolism of non-obese individuals using an in vitro simulated digestion-fermentation cascade model. The results showed that about half of the fucoxanthin was not absorbed in the intestine, thus reaching the colon. The gut microbiota from fecal samples underwent significant changes after 48 or 72 hours in vitro fermentation. Specifically, fucoxanthin significantly enhanced the relative abundance of Bacteroidota and Parabacteroides, leading to improved functions of the gut microbiota in its development, glycan biosynthesis and metabolism as well as in improving the digestive system, endocrine system and immune system. The recovery of fucoxanthin during fermentation showed a decreasing trend with the slight bio-conversion of fucoxanthinol. Notably, fucoxanthin supplementation significantly altered metabolites, especially bile acids and indoles in the simulated human gut ecosystem. Correlation analysis indicated the involvement of the gut microbiota in the manipulation of these metabolites by fucoxanthin. Moreover, all these altered metabolites revealed the improvement in the capacity of fucoxanthin in manipulating gut metabolism, especially lipid metabolism. Overall, fucoxanthin determinedly reshaped the gut microbiota and metabolism, implying its potential health benefits in non-obese individuals.

Paired Electrolysis Enabled Trifluoromethylheteroaromatization of Alkenes and Alkyne with Trifluoromethyl Thianthrenium Triflate (TT-CF3+OTf-) as a Bifunctional Reagent.

We report a strategic exploitation of trifluoromethyl thianthrenium triflate (TT-CF3+OTf-) as both electromediator and CF3 radical precursors for paired electrolysis. Enabled by this strategy, the three-component trifluoromethylheteroaromatization of alkenes and alkynes was realized. The superiority of TT-CF3+OTf- to other electrophilic CF3 reagents is attributed to the cathodic generation of thianthrene (TT) as a mediator, which shifts the heterogeneous oxidation of interest to a homogeneous one.

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH4I.

The electrochemical preparation of 2-aminothiazoles has been achieved by the reaction of active methylene ketones with thioureas assisted by ᴅʟ-alanine using NH4I as a redox mediator. The electrochemical protocol proceeds in an undivided cell equipped with graphite plate electrodes under constant current conditions. Various active methylene ketones, including ß-keto ester, ß-keto amide, ß-keto nitrile, ß-keto sulfone and 1,3-diketones, can be converted to the corresponding 2-aminothiazoles. Mechanistically, the in situ generated α-iodoketone was proposed to be the key active species.

Electrochemical Organoselenium-Catalyzed Intermolecular Hydroazolylation of Alkenes with Low Catalyst Loadings.

The organoselenium-catalyzed amination of alkenes is a promising way to construct functionalized amines. However, the use of chemical oxidants and the unavoidable formation of allylic amine or enamine are the two main limitations of these methodologies. Against this background, we herein report an electro-selenocatalytic regime for the hydroazolylation of alkenes with azoles under external oxidant-free conditions with low catalyst loadings. Moreover, this protocol enables the generation of amines without vinyl substituents.

Electrophotocatalytic C-H Functionalization of N-Heteroarenes with Unactivated Alkanes under External Oxidant-Free Conditions.

The Minisci alkylation of N-heteroarenes with unactivated alkanes under external oxidant-free conditions provides an economically attractive route to access alkylated N-heteroarenes but remains underdeveloped. Herein, a new electrophotocatalytic strategy to access alkyl radicals from strong C(sp3 )-H bonds was reported for the following Minisci alkylation reactions in the absence of chemical oxidants. This strategy realized the first example of cerium-catalyzed Minisci alkylation reaction directly from abundant unactivated alkanes with excellent atom economy. It is anticipated that the general design principle would enrich catalytic strategies to explore the functionalizations of strong C(sp3 )-H bonds under external oxidant-free conditions with H2 evolution.

N-Hydroxyphthalimide-Mediated Electrochemical Denitrogenation of Aroylhydrazides to Generate Acyl Radicals and Their Applications in the Syntheses of Fluorenones.

N-Hydroxyphthalimide (NHPI)-mediated electrochemical denitrogenation of aroylhydrazides is developed for the first time. The in situ generated acyl radicals could be intramolecularly trapped to give fluorenones with high efficiencies. This electrochemical method features external oxidant- and transition metal-free conditions. In addition, the use of the catalytic amount of 2,4,6-collidine as the base makes this method more attractive for the syntheses of fluorenones.

Indirect Electrosynthesis with Halogen Ions as Mediators.

Organic electrosynthesis has gained increasing research interest as it harvests electric current as redox regents, thereby providing a sustainable alternative to conventional approaches. Compared with direct electrosynthesis, indirect electrosynthesis employs mediator(s) to lower the overpotentials for substrate activation, and enhance the reaction efficiency and functional group compatibility by shifting the heterogenous electron transfer process to be homogenous. As one of the most versatile and cost-efficient mediators, halogen mediators are always combined with an irreversible halogenation reaction. Thus, the electrochemical reaction between halogen mediators and substrates doesn't directly controlled by the two standard potentials difference. In this account, our recent developments in the area of halogen-mediated indirect electrosynthesis are summarized. The anodically generated halogen species from halogenide salts have the abilities to undergo electron-transfer (ET) or hydrogen-atom- transfer (HAT) processes. The reaction features, scopes, limitations, and mechanistic rationalisations are discussed in this account. We hope our studies will contribute to the future developments to broaden the scope of halogen-mediated electrosynthesis.

Recent advances in organic electrosynthesis employing transition metal complexes as electrocatalysts.

Organic electrosynthesis has been widely used as an environmentally conscious alternative to conventional methods for redox reactions because it utilizes electric current as a traceless redox agent instead of chemical redox agents. Indirect electrolysis employing a redox catalyst has received tremendous attention, since it provides various advantages compared to direct electrolysis. With indirect electrolysis, overpotential of electron transfer can be avoided, which is inherently milder, thus wide functional group tolerance can be achieved. Additionally, chemoselectivity, regioselectivity, and stereoselectivity can be tuned by the redox catalysts used in indirect electrolysis. Furthermore, electrode passivation can be avoided by preventing the formation of polymer films on the electrode surface. Common redox catalysts include N-oxyl radicals, hypervalent iodine species, halides, amines, benzoquinones (such as DDQ and tetrachlorobenzoquinone), and transition metals. In recent years, great progress has been made in the field of indirect organic electrosynthesis using transition metals as redox catalysts for reaction classes including C-H functionalization, radical cyclization, and cross-coupling of aryl halides-each owing to the diverse reactivity and accessible oxidation states of transition metals. Although various reviews of organic electrosynthesis are available, there is a lack of articles that focus on recent research progress in the area of indirect electrolysis using transition metals, which is the impetus for this review.

Anodic oxidation triggered divergent 1,2- and 1,4-group transfer reactions of ß-hydroxycarboxylic acids enabled by electrochemical regulation.

We report a set of electrochemically regulated protocols for the divergent synthesis of ketones and ß-keto esters from the same ß-hydroxycarboxylic acid starting materials. Enabled by electrochemical control, the anodic oxidation of carboxylic acids proceeded in either a one-electron or a two-electron pathway, leading to a 1,4-aryl transfer or a semipinacol-type 1,2-group transfer product with excellent chemoselectivity. The 1,4-aryl transfer represents an unprecedented example of carbon-to-oxygen group transfer proceeding via a radical mechanism. In contrast to previously reported radical group transfer reactions, this 1,4-group transfer process features the migration of electron-rich aryl substituents. Furthermore, with these chemoselective electrochemical oxidation protocols, a range of ketones and ß-keto esters including those possessing a challenging-to-access medium-sized ring could be synthesized in excellent yields.

Nickel-catalyzed electrochemical reductive decarboxylative coupling of N-hydroxyphthalimide esters with quinoxalinones.

Herein the first example of electrochemically enabled, NiCl2-catalyzed reductive decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with quinoxalinones is reported. A range of primary, secondary, tertiary aliphatic carboxylic acids and amino acid-derived esters were tolerated well. This decarboxylative coupling allows access to structurally diverse 3-alkylated quinoxalinones in up to 91% yields.

One-Pot Anodic Conversion of Symmetrical Bisamides of Ethylene Diamine to Unsymmetrical gem-Bisamides of Methylene Diamine.

Symmetrical bisamides of ethylene diamine of type ArCONHCH2CH2NHCOAr undergo anodic C-C bond cleavage in acetonitrile-LiClO4 under controlled-potential electrolysis. The electrogenerated carbocation intermediates react with the solvent acetonitrile to afford unsymmetrical gem-bisamides of type ArCONHCH2NHCOMe in a one-pot reaction. The yields of the latter products are moderate (up to 60%). Other minor products involve two symmetrical gem-bisamides of type ArCONHCH2NHCOAr and MeCONHCH2NHCOMe and fragmentation products (e.g., ArCONHCHO, ArCONH2, and ArCN).

Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2.

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC50 values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.

Electrochemical Dehydrogenative Imidation of N-Methyl-Substituted Benzylamines with Phthalimides for the Direct Synthesis of Phthalimide-Protected gem-Diamines.

A general and green electrochemical dehydrogenative method for the imidation of N-methyl benzylamines with phthalimides with excellent regioselectivities is reported for the first time. This operationally simple method offers a valuable tool to obtain structurally diverse phthalimide-protected gem-diamines.

Electrochemical Formation of N-Acyloxy Amidyl Radicals and Their Application: Regioselective Intramolecular Amination of sp2 and sp3 C-H Bonds.

Electrochemical generation of N-acyloxy amidyl radicals via an inner-sphere electron-transfer process is described for the first time. With NaBr as the catalyst and electrolyte, the in situ generated amidyl radicals undergo intramolecular C(sp2/sp3)-H aminations to give lactams with unprecedented regio- and chemoselectivities. Moreover, the synthetic utility of current method is demonstrated by the synthesis of PJ34 and Phenaglaydon.

Ultrasensitive Tyrosinase-Activated Turn-On Near-Infrared Fluorescent Probe with a Rationally Designed Urea Bond for Selective Imaging and Photodamage to Melanoma Cells.

Melanoma is a highly aggressive malignancy and early monitoring and diagnosis are challenging at present. Tyrosinase is overexpressed in melanoma and regarded as an important biological marker for diagnosis and treatment. Thus, the selective and sensitive detection of tyrosinase is of great significance. To date, a few fluorescent probes have been reported for the detection of tyrosinase in vitro or in vivo. However, a highly sensitive near-infrared probe for tyrosinase monitoring is still missing. In this study, the Gibbs free energy change of different urea bonds during spontaneous hydrolysis is analyzed with the aid of chemical thermodynamic computation. On the basis of this analysis, we modified the dye methylene blue with a rationally designed urea bond to specifically create a probe, called MB1, for rapid detection of tyrosinase. Our experimental results demonstrated that MB1 can serve as a highly sensitive near-infrared responsive fluorescent probe for the monitoring and bioimaging of tyrosinase. In addition, the activated MB1 probe can effectively kill melanoma cells by photodynamic therapy. Thus, the near-infrared probe has great potential for monitoring and treating melanoma.

Functionalization of N-arylglycine esters: electrocatalytic access to C-C bonds mediated by n-Bu4NI.

An efficient electrocatalytic functionalization of N-arylglycine esters is reported. The protocol proceeds in an undivided cell under constant current conditions employing the simple, cheap and readily available n-Bu4NI as the mediator. In addition, it is demonstrated that the mediated process is superior to the direct electrochemical functionalization.

A methylene blue-based near-infrared fluorescent probe for rapid detection of hypochlorite in tap water and living cells.

A methylene blue-based near-infrared fluorescent probe was designed for the selective determination of hypochlorite (ClO-), over other reactive oxygen species or interfering agents. Acetylated methylene blue was synthesized by introducing the acetyl group into the methylene blue framework, which can specifically recognize exogenous and endogenous ClO-. The acetylated methylene blue fluorescent probe was characterized by 1H NMR, 13C NMR and HRMS. The response process and possible mechanism were studied using products of the probe. The emission response of the probe to ClO- presented good linear relationship in the 0-60 µM concentration range, with the detection limit of 0.1 µM (measured at 660 nm and 690 nm). The absorption and emission wavelengths of acetylated methylene blue are both in the near-infrared region; in addition, the probe itself and the degradation products were well-dissolved in water and have almost no toxicity. The probe was used for intracellular ClO- imaging and showed a large fluorescence enhancement (about 200-fold increase).

Use of Electrochemistry in the Synthesis of Heterocyclic Structures.

The preparation and transformation of heterocyclic structures have always been of great interest in organic chemistry. Electrochemical technique provides a versatile and powerful approach to the assembly of various heterocyclic structures. In this review, we examine the advance in relation to the electrochemical construction of heterocyclic compounds published since 2000 via intra- and intermolecular cyclization reactions.

Scalable Electrochemical Dehydrogenative Lactonization of C(sp2/sp3)-H Bonds.

A practical, electrochemical method is developed for the direct dehydrogenative lactonization of C(sp2/sp3)-H bonds under external oxidant- and metal-free conditions, delivering diverse lactones, including coumarin derivatives with excellent regioselectivity. The scalable nature of this newly developed electrochemical process was demonstrated on a 40 g scale following an operationally simple protocol. The remote lactonization of C(sp3)-H bonds would constitute an important synthetic advance toward electrochemical C-O bond formation.