Visible-light-induced C(sp3)-H bromination of 4-methylthiophene derivatives with HBr/H2O2.

A convenient method to synthesize ethyl 4-(bromomethyl)thiophene-3-carboxylate derivatives has been developed via a visible-light-induced radical process in good yields and with wide functional group tolerance under air conditions and at ambient temperature. The present protocol has the advantages of a high atom economy, easy purification, and environmental friendliness as it employs HBr as the bromine source and the cheap and low-toxic H2O2 as the oxidant. The synthetic utility of this method is demonstrated by a gram scale reaction and its application in the innovative synthesis of the clinical drug relugolix.

Lewis Acid Catalyzed [4 + 2] Annulation of Propargylic Alcohols with 2-Vinylanilines.

An elegant Lewis acid catalyzed, protection-free, and straightforward synthetic strategy for the assembly of a series of sophisticated polycyclic quinoline skeletons employing propargylic alcohols and 2-vinylanilines as the substrates in the presence of Yb(OTf)3 (10 mol %) and AgOTf (10 mol %) in tetrahydrofuran has been described. This annulation protocol, which proceeds through a sequential Meyer-Schuster rearrangement/nucleophilic substitution/deprotonation sequence, provides a versatile, practical, and atom-economical approach for accessing quinoline derivatives in moderate-to-good yields.

Palladium-Catalyzed Intramolecular Heck Dearomative Alkenylation of Indoles with N-Tosylhydrazones.

An elegant Pd-catalyzed intramolecular Heck dearomative alkenylation of aryl iodides with functionalized N-tosylhydrazones proceeded through a sequential dearomative carbopalladation, migratory insertion, and ß-hydride elimination in the presence of Pd(CF3COO)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (2.0 equiv) in 1,4-dioxane (2.0 mL) at 120 °C for 14 h under an argon atmosphere. This cascade cycloaddition protocol provided a reliable and versatile approach to a sequence of structurally diverse indolines in moderate to good yields with good functional group compatibility. In addition, the synthetic robustness of the methodology is highlighted by a scaled-up experiment and derivatization of products via epoxidation and reduction reactions.

Visible-Light-Induced Oxyalkylation of 1,2,4-Triazine-3,5(2H, 4H)-diones with Ethers via Oxidative Cross-Dehydrogenative Coupling.

An efficient and convenient method to synthesize 6-oxyalkylated 1,2,4-triazine-3,5(2H, 4H)-diones has been developed via visible-light-induced cross-dehydrogenative coupling reaction between 1,2,4-triazine-3,5(2H, 4H)-diones and ethers with a wide range of functional group tolerance. The present transformation employs the cheap and low-toxic 2-tert-butylanthraquinone as a metal-free photocatalyst and air as a green oxidant at room temperature. Moreover, this reaction can also be driven by sunlight as a clean energy resource. The synthetic utility of this method is further demonstrated by gram-scale reaction and application in the preparation of key intermediates of bioactive molecules.

KLF4 Affects Acute Renal Allograft Injury via Binding to MicroRNA-155-5p Promoter to Regulate ERRFI1.

Kruppel-like factor 4 (KLF4) owns the promising potential in treating kidney injury, which inevitably occurs during renal allograft. Given that, this research targets to unveil KLF4-oriented mechanism from microRNA-155-5p/ERBB receptor feedback inhibitor 1 (miR-155-5p/ERRFI1) axis in acute renal allograft injury. Mice were injected with miR-155-5p-related sequences before acute renal allograft modeling. Afterwards, serum inflammation, along with oxidative stress, renal tubular injury, and apoptosis in renal tissues were detected. HK-2 cells were processed by hypoxia/reoxygenation (H/R) and transfected with miR-155-5p- or ERRFI1-related sequences, after which cell proliferation and apoptosis were measured. KLF4, miR-155-5p, and ERRFI1 expressions and their interaction were tested. KLF4 and miR-155-5p levels were enhanced, and ERRFI1 level was repressed in mice after acute renal allograft and in H/R-treated HK-2 cells. KLF4 bound to the promoter of miR-155-5p. Depleting miR-155-5p reduced serum inflammation and attenuated oxidative stress, renal tubular injury, and apoptosis in mice with acute renal allograft injury. Downregulating miR-155-5p facilitated proliferation and repressed apoptosis of H/R-treated HK-2 cells. miR-155-5p targeted ERRFI1. Knocking down ERRFI1 antagonized the effects of downregulated miR-155-5p on acute renal allograft injury, as well as on H/R-treated HK-2 cell proliferation and apoptosis. A summary displays that silencing KLF4 suppresses miR-155-5p to attenuate acute renal allograft injury by upregulating ERRFI1, which provides a way to control acute renal allograft injury.

Photocatalytic Oxidative Bromination of 2,6-Dichlorotoluene to 2,6-Dichlorobenzyl Bromide in a Microchannel Reactor.

Photocatalytic oxidative benzylic bromination with hydrobromic acid (HBr) and hydrogen peroxide (H2O2) is a green process for the synthesis of benzyl bromides, but suffers from the risk of explosion when performing it in a batch reactor. This disadvantage could be overcome by running the reaction in a microchannel reactor. In this work, a green and safe process for the synthesis of 2,6-dichlorobenzyl bromide (DCBB) was developed by conducting selective benzylic bromination of 2,6-dichlorotoluene (DCT) with H2O2 as an oxidant and HBr as a bromine source in a microchannel reactor under light irradiation. The reaction parameters were optimized, and the conversion of DCT reached up to 98.1% with a DCBB yield of 91.4% under the optimal reaction conditions.

Primary Amination of Ar2P(O)-H with (NH4)2CO3 as an Ammonia Source under Simple and Mild Conditions and Its Extension to the Construction of Various P-N or P-O Bonds.

A facile and efficient method for the synthesis of primary phosphinamides from Ar2P(O)-H reagents with stable and readily available ammonium carbonate as an ammonia source is disclosed herein for the first time. This ethyl bromoacetate-mediated primary amination proceeds smoothly under mild and simple conditions, without any metal catalyst or oxidant. Moreover, this method is also appropriate for the reaction of Ar2P(O)-H with a variety of amines, alcohols, and phenols to construct P-N or P-O bonds, with features of handy operation, good functional group tolerance, and broad substrate scope.

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.

Visible-Light-Induced C(sp2)-C(sp3) Cross-Dehydrogenative-Coupling Reaction of N-Heterocycles with N-Alkyl-N-methylanilines under Mild Conditions.

Disclosed herein is a cross-dehydrogenative-coupling reaction of N-heterocycles including 1,2,4-triazine-3,5(2H, 4H)-diones and quinoxaline-2(1H)-ones with N-methylanilines to form C(sp2)-C(sp3) under visible-light illumination and ambient air at room temperature. In this process, easily available Ru(bpy)3Cl2·6H2O serves as the catalyst, and air acts as the green oxidant. This method features high atom economy, environmental friendliness, and convenient operation and provides an efficient and practical access to aminomethyl-substituted N-heterocycles with extensive functional group compatibility in 40-86% yields.

The tumour microenvironment and metabolism in renal cell carcinoma targeted or immune therapy.

Renal cell carcinoma (RCC) is one of the most common tumours of the urinary system, and is insidious and not susceptible to chemoradiotherapy. As the most common subtype of RCC (70-80% of cases), clear cell renal cell carcinoma (ccRCC) is characterized by the loss of von Hippel-Lindau and the accumulation of robust lipid and glycogen. For advanced RCC, molecular-targeted drugs, tyrosine kinase inhibitors (TKIs) and the immune checkpoint inhibitors (ICIs) have been increasingly recommended and investigated. Due to the existence of a highly dynamic, adaptive and heterogeneous tumour microenvironment (TME), and due to the glucose and lipid metabolism in RCC, this cancer may be accompanied by various types of resistance to TKIs and ICIs. With the increased production of lactate, nitric oxide, and other new by-products of metabolism, novel findings of the TME and key metabolic enzymes drived by HIF and other factors have been increasingly clarified in RCC carcinogenesis and therapy. However, there are few summaries of the TME and tumour metabolism for RCC progression and therapy. Here, we summarize and discuss the relationship of the important implicated characteristics of the TME as well as metabolic molecules and RCC carcinogenesis to provide prospects for future treatment strategies to overcome TME-related resistance in RCC.

The C3-H Bond Functionalization of Quinoxalin-2(1H)-Ones With Hypervalent Iodine(III) Reagents.

The modification of quinoxalin-2(1H)-ones via direct C-H bond functionalization has begun to receive widespread attention, due to quinoxalin-2(1H)-one derivatives' various biological activities and pharmaceutical properties. This mini review concentrates on the accomplishments of arylation, trifluoromethylation, alkylation, and alkoxylation of quinoxalin-2(1H)-ones with hypervalent iodine(III) reagents as reaction partners or oxidants. The reaction conditions and mechanisms are compared and discussed in detail.

Direct Introduction of Sulfonamide Groups into Quinoxalin-2(1H)-ones by Cu-Catalyzed C3-H Functionalization.

Direct sulfonamidation of quinoxalin-2(1H)-one derivatives has been developed using a readily available Cu salt as the catalyst and inexpensive ammonium persulfate as the oxidant in moderate conditions. Owing to the feature of handy operation and good functional group tolerance, this method provides a convenient and efficient access to curative 3-sulfonamidated quinoxalin-2(1H)-one scaffolds.

Synthesis of 1,6-Dihydropyridine-3-carbonitrile Derivatives via Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with (E)-3-Amino-3-phenylacrylonitriles.

A novel Lewis acid-catalyzed, highly efficient, practical, and atom-economical protocol for the synthesis of functionalized 1,2-dihydropyridine-3-carbonitrile derivatives in the presence of Bi(OTf)3 (10 mol %) in tetrahydrofuran (2.0 mL) at 80 °C for 8 h in air is described, starting from readily accessed propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles. This cycloaddition protocol, which is scalable and proceeds under mild conditions, is amenable to the gram-scale construction of valuable 1,2-dihydropyridine-3-carbonitriles. Furthermore, the good functional group compatibility and broad scope of this strategy were demonstrated by a broad range of propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles, with yields ranging from 34 to 96%.

Direct C3 Alkoxylation of Quinoxalin-2(1H)-ones with Alcohols via Cross-Dehydrogenative Coupling under Catalyst-Free Conditions.

A facile and effective alkoxylation protocol of quinoxalin-2(1H)-ones with primary or secondary alcohols via cross-dehydrogenative coupling under catalyst-free conditions has been disclosed. This method provides a powerful and convenient access to 3-alkoxylquinoxalin-2(1H)-ones in good to excellent yields by utilizing PhI(OTFA)2 as an oxidant and allows to easily obtain potential drug molecules containing 3-alkoxylquinoxalin-2(1H)-one skeletons.

Dicyanovinyl substituted push-pull chromophores: effects of central C[double bond, length as m-dash]C/phenyl spacers, crystal structures and application in hydrazine sensing.

To discern the distinctive effect of the C[double bond, length as m-dash]C bond and the phenyl bridge on the photophysical and chemical properties of D-π-A molecular systems, three new dicyanovinyl substituted push-pull chromophores 1-3 containing either a C[double bond, length as m-dash]C bond or a phenyl ring as the central π-linker were synthesized by the Suzuki-Miyaura and Knoevenagel reactions. Together with the counterpart of 1 developed by Zhang's group (TPE-z), their optical properties and single crystal structures were systematically and comparatively investigated. Notably, the simple π-extension of a C[double bond, length as m-dash]C linker to a phenyl ring between electron donor and electron acceptor moieties could greatly affect the photophysical properties of chromophores, particularly leading to significant hypsochromic shifts in both absorption and emission spectra. Meanwhile, as a node of twisted sections in chromophores, the C[double bond, length as m-dash]C bond was demonstrated to play an important role in the nonradiative relaxation of excited states, as compared to the rigid phenyl spacer. Moreover, the three chromophores were found to display spectral responses to hydrazine with slightly different sensitivities, and visual detection of hydrazine in the gaseous state was achieved via using readily fabricated paper test strips.

Ru/UiO-66 Catalyst for the Reduction of Nitroarenes and Tandem Reaction of Alcohol Oxidation/Knoevenagel Condensation.

A 3.1% Ru/UiO-66 material was prepared by adsorption of RuCl3 from ethyl acetate on to MOF UiO-66, followed by reduction with NaBH4. The presence of acid-base and ox-red sites allows this 3.1% Ru/UiO-66 material acting as a bifunctional catalyst for the reduction of nitroarenes and tandem reaction of alcohol oxidation/Knoevenagel condensation. The high efficiency of 3.1% Ru/UiO-66 was demonstrated in the reduction of nitroarenes to amines. This system can be applied as a catalyst for at least six successive cycles without loss of activity. The 3.1% Ru/UiO-66 catalyst also was active in the tandem aerobic oxidation of alcohols/Knoevenagel condensation with malononitrile. However, the activity of this catalyst strongly decreased in the second cycle. A combination of physicochemical and catalytic experimental data indicated that Ru nanoparticles are the active sites both for the catalytic reduction of nitro compounds and the aerobic oxidation of alcohols. The activity for the Knoevenagel condensation reaction was from the existence of the "Zr n+-O2- Lewis acid-base" pair in the framework of UiO-66.

Cobalt-Catalyzed Trifluoromethylation-Peroxidation of Unactivated Alkenes with Sodium Trifluoromethanesulfinate and Hydroperoxide.

Disclosed herein is an unprecedented cobalt-catalyzed trifluoromethylation-peroxidation of unactivated alkenes. In this process the hydroperoxide acts as a radical initiator as well as a coupling partner. The cheap and readily available sodium trifluoromethanesulfinate serves as the CF3 source in the reaction. Various alkenes are transformed into vicinal trifluoromethyl-peroxide compounds in moderate to good yields.

Geminal Brønsted acid ionic liquids as catalysts for the Mannich reaction in water.

Quaternary ammonium geminal Brønsted acid ionic liquids (GBAILs) based on zwitterionic 1,2-bis[N-methyl-N-(3-sulfopropyl)-alkylammonium]ethane (where the carbon number of the alkyl chain is 4, 8, 10, 12, 14, 16, or 18) and p-toluenesulfonic acid monohydrate were synthesized. The catalytic ionic liquids were applied in three-component Mannich reactions with an aldehyde, ketone, and amine at 25 °C in water. The effects of the type and amount of catalyst and reaction time as well as the scope of the reaction were investigated. Results showed that GBAIL-C14 has excellent catalytic activity and fair reusability. The catalytic procedure was simple, and the catalyst could be recycled seven times via a simple separation process without noticeable decreases in catalytic activity.

Transurethral bipolar plasma kinetic resection of ejaculatory duct for treatment of ejaculatory duct obstruction.

To evaluate the efficacy of transurethral bipolar plasma kinetic resection of ejaculatory duct for ejaculatory duct obstruction. The clinical information of 42 cases of ejaculatory duct obstruction was analyzed between July 2008 and June 2012. The diagnostic criteria included semen analysis, fructose and neutral α-glucosidase measurement in seminal plasma, transrectal ultrasonography, magnetic resonance imaging and vasography necessarily. Endoscopic procedure with bipolar plasma kinetic resection of ejaculatory duct was performed in all patients. Among these cases followed up 6 ≈ 24 months after operation, 38 patients (90.5%) had improved semen parameters, 23 azoospermic patients (60.5%) had sperm in the semen and 13 patients' wife (31%) achieved pregnancies in 42 cases of bipolar plasma kinetic resection of ejaculatory duct. Postoperative complications ensued as epididymitis in 1 case, watery ejaculate in 1, but no serious complication was observed. Bipolar plasma kinetic resection of ejaculatory duct appears to represent a promising endoscopic treatment alternative for ejaculatory duct obstruction patients, with high efficacy, less complications, quicker recovery and satisfactory follow-up parameters.