Photoredox-Catalyzed Three-Component 1,2-Cyanoalkylpyridylation of Styrenes with Nonredox-Active Cyclic Oximes.

Three-component alkene 1,2-difunctionalizations have emerged as a powerful strategy for rapid buildup of diverse and complex alkylpyridines, but the distal functionalized alkyl radicals for the alkene 1,2-alkylpyridylations were still rare. Herein, we report an example of regioselective three-component 1,2-cyanoalkylpyridylation of feedstock styrenes with accessible nonredox-active cyclic oximes through visible-light photoredox catalysis, providing a series of structurally diverse ß-cyanoalkylated alkylpyridines. This protocol proceeds through a radical relay pathway including the generation of iminyl radicals enabled by phosphoranyl radical-mediated ß-scission, radical transposition through C-C bond cleavage, highly selective radical addition, and precise radical-radical cross-coupling sequence, thus facilitating the regioselective formation of two distinct C-C single bonds in a single-pot operation. This synthetic strategy features mild conditions, broad compatibility of functional groups and substrate scope, diverse product derivatization, and late-stage modification.

Visible light-enabled synthesis of phosphorylated indolizine and pyridoindole derivatives via HAT-mediated radical cascade cyclization.

A visible light-enabled cascade cyclization strategy is disclosed with concomitant phosphorylation and heterocycle construction. It provides a novel and environmentally benign approach for accessing tetrahydroindolizine-containing phosphonates under metal-free conditions. Mechanistic studies revealed that phosphinoyl radicals were generated from H-phosphonates via a HAT process.

NIR squaraine dyes for dual colorimetric and fluorescent determination of Fe3+, Cu2+, and Hg2+ ions.

Four benzoindolenine-based squaraine dyes (SQs), which have the advantages of intense visible and near-infrared (NIR) absorption and emission (λabs/max 663-695 nm, λem/max 686-730 nm) were synthesized and characterized by UV-vis absorption, fluorescent emission spectrophotometry, FTIR, NMR and HRMS analysis. Among them, BBSQ showed excellent performance, which exhibited high selectivity to Fe3+, Cu2+, and Hg2+ in acetonitrile solution even in the presence of other competitive metal ions, accompanied by obvious color change easily detected by the naked eye. The detection limit was 14.17 µM for Fe3+ and 6.06 µM for Cu2+. Most importantly, the response mechanism of BBSQ to Fe3+, Cu2+, and Hg2+ involves the coordination of BBSQ and metal ions through the O atom on the central squarate ring, N atom, and olefin π bond of BBSQ and has been demonstrated by Job's plot, FTIR, and 1H NMR titration analyses. Furthermore, BBSQ was applied successfully to detect Fe3+, Cu2+, and Hg2+ in thin-layer chromatography (TLC) plates with good precision and is quite promising for the quantitative detection of Fe3+ and Cu2+ ions in water samples.

Catalytic C-H alkynylation of benzylamines and aldehydes with aldimine-directing groups generated in situ.

Iridium-catalysed regioselective C-H alkynylation of unprotected primary benzylamines and aliphatic aldehydes has been achieved using in situ-installed aldimine directing groups. This protocol provides a straightforward route for the synthesis of the alkynylated primary benzylamine and aliphatic aldehyde derivatives, featuring good substrate compatibility and high regioselectivity.

Redox-neutral and metal-free synthesis of 3-(arylmethyl)chroman-4-ones via visible-light-driven alkene acylarylation.

A metal- and aldehyde-free visible-light-driven photoredox-neutral alkene acylarylation with readily available cyanoarenes is described. A variety of 3-(arylmethyl)chroman-4-ones (i.e., homoisoflavonoids) and analogs are efficiently synthesized with good functional group tolerance. This mild protocol relies on a phosphoranyl radical-mediated acyl radical-initiated cyclization and selective radical-radical coupling sequence, and is also further highlighted by subsequent derivatization to chromone and 2H-chromene as well as its application in the three-component alkene acylarylation.

Chemodivergent photocatalytic access to 1-pyrrolines and 1-tetralones involving switchable C(sp3)-H functionalization.

A chemodivergent photocatalytic approach to 1-pyrrolines and 1-tetralones from alkyl bromides and vinyl azides has been developed through chemoselectively controllable intermolecular [3 + 2] and [4 + 2] cyclization. This photoredox-neutral two-component protocol involves intermolecular radical addition and switchable distal C(sp3)-H functionalization enabled by iminyl radical-mediated 1,5-hydrogen atom transfer. Meanwhile, chemoselectivity between C(sp3)-N bond formation and C(sp3)-C(sp2) bond formation is precisely switched by photocatalysts (Ru(bpy)3(PF6)2 vs. fac-Ir(ppy)3) and additives (base vs. acid).

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase.

Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine kinase that plays an important role in many carcinomas. Thus, the targeting of FAK by small molecules is considered to be promising for cancer therapy. Some FAK inhibitors have been reported as potential anticancer drugs and have entered into clinical development; for example, VS-4718 is currently undergoing clinical trials. However, the lack of crystal structural data for the binding of VS-4718 with FAK has hindered the optimization of this anticancer agent. In this work, the VS-4718/FAK interaction model was obtained by molecular docking and molecular dynamics simulations. The binding free energies of VS-4718/FAK were also calculated using the molecular mechanics generalized Born surface area method. It was found that the aminopyrimidine group formed hydrogen bonds with the C502 residue of the hinge loop, while the D564 residue of the T-loop interacted with the amide group. In addition, I428, A452, V484, M499, G505, and L553 residues formed hydrophobic interactions with VS-4718. The obtained results therefore provide an improved understanding of the interaction between human FAK and VS-4718. Based on the obtained binding mechanism, 47 novel compounds were designed to target the adenosine 5'-triphosphate-binding pocket of human FAK, and ensemble docking was performed to assess the effects of these modifications on the inhibitor binding affinity. This work is also expected to provide additional insights into potential future target design strategies based on VS-4718.

Indole and Pyrrole Derivatives as Pre-photocatalysts and Substrates in the Sulfonyl Radical-Triggered Relay Cyclization Leading to Sulfonylated Heterocycles.

A visible-light-induced method for the construction of heterocyclic scaffolds such as pyrido[1,2-a]indoles and indolizines via sulfonyl radical-triggered relay cyclization without employing any external photocatalyst has been developed. Preliminary mechanistic investigation indicated that indole and pyrrole derivatives could serve as pre-photocatalysts to promote the sulfonylation/cyclization, thereby providing a facile method to synthesize valuable sulfonylated heterocycles.

Hydrogen bond serving as a protecting group to enable the photocatalytic [2+2] cycloaddition of redox-active aliphatic-amine-containing indole derivatives.

Redox-sensitive functionalities such as aliphatic amines with low oxidation potentials and easily oxidized by photocatalysts are generally not compatible with photocatalytic reactions. We describe a hydrogen-bond-assisted visible-light-mediated [2+2] cycloaddition of redox-sensitive aliphatic-amine-containing indole derivatives providing a range of cyclobutane-fused polycyclic indoline derivatives, especially bridged-cyclic indolines. Mechanistic studies indicated that the success of the reaction was based on on the formation of H-bonds between the N-atom and alcohol proton of TFE or HFIP, with this formation preventing or blocking the single-electron transfer from the aliphatic amine functionality to the excited photocatalyst.

Neodymium oxide (Nd2O3) coupled tubular g-C3N4, an efficient dual-function catalyst for photocatalytic hydrogen production and NO removal.

Graphitic carbon nitride (g-C3N4) has emerged as a most promising photocatalyst, non-toxicity and low density, but it is plagued by low activity due to the small specific surface area and poor quantum efficiency. Morphological engineering and coupling with other materials to form hybrids have proven to be effective strategies for enabling high photocatalytic performances. Here, neodymium oxide (Nd2O3) coupled tubular g-C3N4 composites had been facilely synthesized by a solvent evaporation and high-temperature calcination method to realize efficient photocatalytic activity of hydrogen production and NO removal. A series of characterizations, such as XRD, ESR, in-situ DRIFTS, etc., were used to analyze the physical and chemical properties of the bifunctional photocatalyst, which demonstrated that the composite material had more active sites and a faster electron transfer rate. The optimal sample (1 wt% Nd2O3/CN-T) had a H2 generation rate of 4355.34 µmol·g-1·h-1, which was 9.46 times than that of original g-C3N4 obtained through heating melamine (CN-M). In addition, the NO removal rate was also 32.32% higher than that of original CN-M. On the basis of the above photocatalytic experimental results and characterizations, a possible mechanism or pathway was proposed and illustrated. This work could provide a feasible strategy to fabricate tubular g-C3N4-based composites with rare earth metal oxides (dual-factor regulation) to simultaneously enhance photocatalytic hydrogen production and NO removal efficiently (double application).

Preparation and evaluation of a molybdenum disulfide quantum dots embedded C18 mixed-mode chromatographic stationary phase.

Molybdenum disulfide quantum dots (MoS2 QDs) were chosen as a functional two-dimensional material to improve the separation performance of a traditional C18 column. In this work, MoS2 QDs were synthesized by the combination of sonication and solvothermal treatment of bulk MoS2. The prepared MoS2 QDs were characterized by transmission electron microscope (TEM), Zeta potential measurement, UV-visible absorption and fluorescence spectroscopy. Then, a novel MoS2 QDs embedded C18 (Sil-MoS2-C18) stationary phase was prepared for performing mixed-mode liquid chromatography. The results of elemental analysis (EA), thermogravimetric analysis (TGA), Fourier transform infrared spectrometry (FT-IR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM) and Brunauer-Emmett-Teller (BET) measurements indicated the stationary phase was prepared successfully. Five types of compounds including alkylbenzenes, polycyclic aromatic hydrocarbons (PAHs), nucleosides and nucleobases, anilines and flavonoids were utilized to evaluate reversed phase, weak cation exchange and hydrophilic interaction of the new column. To a certain extent, the column could achieve separation for different properties of samples on one column, with less organic solvent and shorter time than conventional alkyl and amino columns. Furthermore, the mechanism for separation was studied by investigating effects of mobile phase composition and pH on retentions. In summary, the Sil-MoS2-C18 stationary phase was deemed able to serve the performance of various types of phases, which revealed the prepared mixed-mode column could be potentially applied for the analysis of complex samples. Graphical abstract.

Highly Enantioselective Synthesis and Anticancer Activities of Chiral Conjugated Diynols.

A chiral amino alcohol based ligand was found to promote the highly enantioselective addition of terminal conjugated diynes to aromatic and aliphatic aldehydes. The combination of easily available C2 -symmetric (R)- and (S)-BINOL with Ti(OiPr)4 , Zn powder, and EtI was also found to catalyze the asymmetric addition of 1,3-diynes to aldehydes under mild reaction conditions, and thus, both enantiomers of the chiral conjugated diynols could be prepared with high enantioselectivities. The resulting optically active conjugated diynols were found to have potential anticancer activities with significant differences against HepG2 and HeLa cancer cells, and remarkable enantioselective cytotoxicity was observed for the first time.

Enhanced Turnover for the P450 119 Peroxygenase-Catalyzed Asymmetric Epoxidation of Styrenes by Random Mutagenesis.

A randomized library is constructed based on pET30a-CYP119-T214V plasmid. This library of random mutants of CYP119-T214V was screened by means of the reduced CO difference spectra and epoxidation of styrene. By using directed evolution, a new CYP119 quadruple mutant S148P/I161T/K199E/T214V is constructed, expressed, and purified. This quadruple mutant significantly increases the turnover rate and conversion for the asymmetric epoxidation of styrene and its derivatives. The kcat. value of cis-ß-methylstyrene epoxidation catalyzed by the quadruple mutant exhibits an approximately 10-fold increase, relative to the previously reported T213M mutant under the same conditions. This is the first engineered CYP119 peroxygenase for the epoxidation of cis-ß-methylstyrene with a high turnover rate. The proposed mechanism, on the basis of a molecular docking study, for the asymmetric epoxidation suggests that the introduction of an acidic amino acid side chain into the active site and a hydrophobic amino acid into the substrate channels of CYP119 peroxygenase might result in high efficiency for the formation of compound I, and its subsequent peroxygenation by reconstructing the hydrogen-bonding interaction and increasing the substrate affinity and access.

HPLC Determination of Enantiomeric Purity for 1-Styrene-3-Hexyl Propynol.

A rapid and sensitive high performance liquid chromatography method was developed and validated for the determination of enantiomeric purity of 1-styrene-3-hexyl propynol. Baseline separation with resolution greater than 2.0 was achieved within 17 min on a CHIRALCEL OD-H (25 cm × 0.46 cm; particle size 5 µm) column using n-hexane:isopropanol (95:5 v/v) as mobile phase at a flow rate of 1 mL·min-1 and 25°C as column temperature. The analytes were detected by UV absorbance at 210 nm. The effects of column, composition of mobile phase, temperature and flow rate on the chromatography were investigated. The method was extensively validated and proved to be robust. The recoveries were in the range of 99.6-102.6% with relative standard \deviation <0.32%. The limit of detection and limit of quantitation for (S)-1-styrene-3-hexyl propynol were 0.0041 and 0.22 µg·mL-1, and for (R)-1-styrene-3-hexyl propynol were 0.0036 and 0.19 µg·mL-1, respectively. This method was proved to be accurate, stable, rapid and sensitive for the determination of enantiomeric purity of 1-styrene-3-hexyl propynol and its homologs.

Engineering P450 Peroxygenase to Catalyze Highly Enantioselective Epoxidation of cis-ß-Methylstyrenes.

P450 119 peroxygenase and its site-directed mutants are discovered to catalyze the enantioselective epoxidation of methyl-substituted styrenes. Two new site-directed P450 119 mutants, namely T213Y and T213M, which were designed to improve the enantioselectivity and activity for the epoxidation of styrene and its methyl substituted derivatives, were studied. The T213M mutant is found to be the first engineered P450 peroxygenase that shows highly enantioselective epoxidation of cis-ß-methylstyrenes, with up to 91 % ee. Molecular modeling studies provide insights into the different catalytic activity of the T213M mutant and the T213Y mutant in the epoxidation of cis-ß-methylstyrene. The results of the calculations also contribute to a better understanding of the substrate specificity and configuration control for the regio- and stereoselective peroxygenation catalyzed by the T213M mutant.

Total Synthesis of Chiral Falcarindiol Analogues Using BINOL-Promoted Alkyne Addition to Aldehydes.

An enantioselective total synthesis of chiral falcarindiol analogues from buta-1,3-diyn-1-yltriisopropylsilane is reported. The key step in this synthesis is BINOL-promoted asymmetric diacetylene addition to aldehydes. The two chiral centers of the falcarindiol analogues can be produced by using the same kind of catalyst with high selectivity, and the final product can be obtained in only six steps.

Gas chromatography-mass spectrometry/selected ion monitoring for screening asymmetric epoxidation of styrene.

A screening method by gas chromatography-mass spectrometry (GC-MS) with selected ion monitoring (SIM) has been developed for asymmetric epoxidation of styrene. All samples were analyzed by GC-MS with the mode of SIM by using ethylbenzene as the internal standard, by which styrene and styrene epoxide enantiomers were completely separated and their concentrations were accurately determined. Furthermore, this method was used to evaluate the epoxidation reaction of styrene, which was optimized by orthogonal experiment. The advantages of the method are as follows: excellent precision (RSD in the range of 1. 2% - 5. 2%, n= 5), good linearity (the correlation coefficients for styrene, (R)/(S)-styrene oxide were 0. 9997, 0. 9932 and 0. 9963, respectively) , low limits of quantitation (LOQs of styrene, (R)/(S)-styrene oxide were 1. 3, 1. 1 and 0. 7 mg/L, respectively) and reasonable recoveries (98. 2% - 108. 2%). All in all, the method provided a new way to determine the asymmetric epoxidation mixture of styrene and its homologs.

2-Methyl-1,2,4-triazolo[4,3-a]pyridin-2-ium tetra-fluoroborate.

In the title salt, C7H8N3 (+)·BF4 (-), the 1,2,4-triazolo[4,3-a]pyridinium cation is planar [maximum deviation of 0.016 (2) Šfor all non-H atoms]. The cation and anion constitute a tight ionic pair with an F⋯N [2.911 (4) Å] inter-molecular attractive inter-action. The ionic pairs form dimers via stacking inter-actions between inversion-related cations, the normal distance between the cation planes being 3.376 (5) Å. The dimers are packed in stacks along the a axis and linked via C-H⋯F hydrogen bond, forming a three-dimensional network.

Development of an improved rhodium catalyst for z-selective anti-markovnikov addition of carboxylic acids to terminal alkynes.

To develop more active catalysts for the rhodium-catalyzed addition of carboxylic acids to terminal alkynes furnishing anti-Markovnikov Z enol esters, a thorough study of the rhodium complexes involved was performed. A number of rhodium complexes were characterized by NMR, ESI-MS, and X-ray analysis and applied as catalysts for the title reaction. The systematic investigations revealed that the presence of chloride ions decreased the catalyst activity. Conversely, generating and applying a mixture of two rhodium species, namely, [Rh(DPPMP)2][H(benzoate)2] (DPPMP=diphenylphosphinomethylpyridine) and [{Rh(COD)(µ2-benzoate)}2], provided a significantly more active catalyst. Furthermore, the addition of a catalytic amount of base (Cs2CO3) had an additional accelerating effect. This higher catalyst activity allowed the reaction time to be reduced from 16 to 1-4 h while maintaining high selectivity. Studies on the substrate scope revealed that the new catalysts have greater functional-group compatibility.

Novel bisimidazolium pincers as low loading ligands for in situ palladium-catalyzed Suzuki-Miyaura reaction in the ambient atmosphere.

A series of novel triazinonide-bridged bisimidazolium pincers were easily synthesized by quaternization of functionalized N-phenylimidazoles with highly reactive cyanuric chloride under mild conditions. The pincer was proven to be a very efficient ligand for in situ Pd-catalyzed Suzuki-Miyaura reaction with ppm-level catalyst loading.