Unconventional Transformations of Difluorocarbene with Amines and Ethers.

ConspectusFluorine-containing compounds are extensively involved in various fields originating from intriguing and unique characteristics of fluorine atom; notably, in pharmaceuticals, the involvement of a fluorine atom or a fluorine-containing group is a chief technique for improving the pesticide effect and developing new drugs. Difluorocarbene, one of the most important and powerful fluorine-containing reagents, is widely employed and studied in many areas mainly to assemble gem-difluoromethyl molecules, including but not limited to the abundant reactions between difluorocarbene with nucleophilic substrates, Wittig reaction with ketones or aldehydes, cascade reaction with both a nucleophile and an electrophile, or [2+1] cycloaddition with alkenes or alkynes. However, its unconventional and intriguing protocols beyond as a difluoromethyl synthon have rarely been studied, and thus, it is highly desired given its abundance, inexpensiveness and peculiar properties. In this Account, we mainly discuss our discovery with unconventional transformations of difluorocarbene, instead of as a sole difluoromethyl source (different from other dihalocarbene), actually can serve as an electron acceptor to activate C-X bonds (X = N and O) and thus promote a myriad of fascinating transformations for the assembly of versatile valuable products with various aza-compounds (primary/secondary/tertiary amines as well as NH3 and NaNH2 and so on) and aliphatic ethers in the absence of transition metals and expensive ligands. Inspired by the electron-deficient characteristics of difluorocarbene, we first found that the isocyanides could be readily formed in situ when the unoccupied orbital of difluorocarbene meets the lone-pair of primary amines; in basic condition, a cascade defluorination and cyclizations could afford plethora of valuable N-containing heterocycles. Meanwhile, we disclosed that cyano anion could be accessible in situ as well when difluorocarbene and NaNH2 or NH3 were mixed up in suitable basic conditions, and thus a series of aryl nitrile compounds were obtained in the presence of Pd catalysis and ArI. Interestingly, when difluorocarbene encountered secondary amines, formamides were rendered under mild reactions. Of note, concomitant functionalizations of C and N moieties via cleavage of the unstrained C(sp3)-N bond in the absence of metal and oxidant are sparce, which indeed significantly add versatility and diversity to products. Gratifyingly, by uitilizing difluorocarbene and cyclic tertiary amines, we achieved difluorocarbene-mediated deconstructive functionalizations for the first time, showing successive C(sp3)-N bond scission of amines and simultaneous functionalization of C and N atoms which would be introduced into the products in the absence of transition metals and oxidants. This method provides a brand-new while very universal synthetic pathway to selectively cleave inert unactivated Csp3-N bonds, in which halodifluoromethyl reagents act as both C1 synthon and halo (Cl, Br, I) sources. Fascinatingly, nitrogen ylides are generated in situ from difluorocarbene and tertiary amines, and an intriguing and universal approach for deaminative arylation or alkenylation of tertiary amines was disclosed for the first time in appropriate basic conditions, which represents an intriguing reaction mode to lead to a formal transition-metal free Suzuki cross coupling. Besides, we also disclosed that difluorocarbene could proceed novel atom recombination to render meaningful 2-fluoroindoles or 3-(2,2-difluoroethyl)-2-fluoroindoles from ortho-vinylanilines, 3-fluorined oxindoles from 2-aminoarylketones, in which difluorocarbene acts as a C1 synthon and F1 source simultaneously. Last but not the least, we recently found that the lone-pair-electron of oxygen could trap difluorocarbene as well to form oxonium ylide, which eventually leads to C-O bond cleavage with the formation of difluoromethyl ethers.

Design, synthesis, and biological activity of novel semicarbazones as potent Ryanodine receptor1 inhibitors of Alzheimer's disease.

Ryanodine receptors (RyRs) are important ligand-gated Ca2+ channels; their excessive activation leads to Ca2+ leakage in the sarcoplasmic reticulum that may cause neurological diseases. In this study, three series of novel potent RyR1 inhibitors based on dantrolene and bearing semicarbazone and imidazolyl moieties were designed and synthesized, and their biological activity was evaluated. Using a single-cell calcium imaging method, the calcium overload inhibitory activities of 26 target compounds were tested in the R614C cell line, using dantrolene as a positive control. The preliminary investigation showed that compound 12a suppressed Ca2+ release as evidenced by store overload-induced Ca2+release (SOICR) (31.5 ± 0.1%, 77.2 ± 0.1%, 93.7 ± 0.2%) at 0.1 µM, 3 µM and 10 µM, respectively. Docking simulation results showed that compound 12a could bind at the active site of the RyR1 protein. The Morris water-maze test showed that compound 12a significantly improved the cognitive behavior of AD-model mice. Further studies on the structural optimization of this series of derivatives are currently underway in our laboratory.

Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents.

Halodifluoromethyl and trifluoromethyl-containing compounds are widely employed in organic chemistry, pharmaceuticals and materials science. Therefore, their applications and transformations have received significant attention during the past few decades. The single, double, triple and quadruple cleavage of halodifluoromethyl compounds and various deconstructive modes of trifluoromethyl-containing compounds could generate a variety of synthons to prepare more valuable products. Herein, we summarize the most significant achievements in this field with an intriguing focus on results from the last decade.

Elemental-Sulfur-Enabled Divergent Synthesis of Disulfides, Diselenides, and Polythiophenes from ß-CF3 -1,3-Enynes.

Divergent synthesis for precise constructions of cyclic unsymmetrical diaryl disulfides or diselenides and polythiophenes from CF3 -containing 1,3-enynes and S8 was developed when the ortho group is F, Cl, Br, and NO2 on aromatic rings. Meanwhile, disulfides (diselenides) were also quickly constructed when the ortho group is H. These transformations undergo cascade thiophene construction/selective C3-position thiolation process, featuring simple operations, divergent synthesis, broad substrate scope, readily available starting materials, and valuable products. A novel plausible radical annulation process was proposed and validated by DFT calculations for the first time. A series of derivatizations about the thiophene (TBT) and disulfides were also well-represented.

Probucol Protects Against Contrast-Induced Acute Kidney Injury via the Extracellular Signal-Regulated Kinases 1 and 2 (ERK1/2)/JNK-Caspase 3 Pathway in Diabetic Rats.

BACKGROUND Contrast-induced acute kidney injury is an important clinical problem, yet its pathogenic mechanisms are incompletely understood. In this study we explored the potential beneficial effects of probucol as treatment of contrast-induced acute kidney injury in diabetic rats. MATERIAL AND METHODS Rats were divided into 3 groups: i) diabetic control, ii) diabetic with contrast, and iii) probucol treatment groups. Probucol was administered by gavage and the contrast diatrizoate (60%) was injected via femoral vein. After 24 h, the rats were sacrificed and samples were taken to measure biochemical indicators. Pathological damage of renal tubules was evaluated by HE staining. Expression of Bcl-2, Bax, p-ERKs, and p-JNK proteins in the kidneys was examined by Western blotting, whereas expression level of caspase-3 in kidneys was detected by immunohistochemistry. RESULTS Compared to the probucol treatment group, the diabetes with contrast group showed higher serum creatinine and lower creatinine clearance. The pathological changes of kidneys in the probucol treatment group were improved compared with the contrast group. Moreover, Western blot analyses revealed that use of contrast agent led to lower p-ERK1/2, higher p-JNK, lower Bcl-2, and higher Bax levels, which were reversed by probucol. Finally, immunohistochemical findings revealed higher caspase-3 after contrast use, which was partially reversed by probucol. CONCLUSIONS Probucol exerts protective effects on contrast-induced acute kidney injury in diabetic rats by inhibition of renal cell apoptosis. This is achieved by reducing mitochondrial caspase-3 expression through increasing and decreasing the expression of the upstream mediators p-ERK1/2 and p-JNK, respectively.

Mapping the interaction sites of Mucin 1 and DNA aptamer by atomic force microscopy.

Mucin 1 (MUC1) is an attractive tumor marker for cancer diagnosis. An advanced atomic force microscopy (AFM) mode, peak-force tapping AFM with an aptamer functionalized tip, was introduced to map the specific interaction sites of an aptamer and MUC1. Single molecular force spectroscopy (SMFS) was used to investigate dynamic parameters of the aptamer-MUC1.

Correction: Mapping the interaction sites of Mucin 1 and DNA aptamer by atomic force microscopy.

Correction for 'Mapping the interaction sites of Mucin 1 and DNA aptamer by atomic force microscopy' by Nan Wang, et al., Analyst, 2017, 142, 3800-3804.

Metal-free methylation of a pyridine N-oxide C-H bond by using peroxides.

Metal-free methylation of a pyridine N-oxide C-H bond was developed using peroxide as a methyl reagent under neat conditions. Pyridine N-oxide derivatives with various groups (e.g., Cl, NO2, and OCH3) were all suitable substrates, and the desired products were obtained in moderate to excellent yields under standard conditions. Moreover, the methylation can be performed with a good yield on the gram-scale experiment. Tentative mechanistic studies show that the methylation is a classical radical process.

Root pH variation of herbaceous plants among plant functional groups in response to climate and soil gradients on the Tibetan alpine grasslands.

Plant pH is an emerging functional trait that plays important roles in physiological processes and nutrient cycling. However, how root pH varies among plant functional groups (PFGs) and the regulatory factors on a large scale remain unclear. Therefore, we quantified root pH variation of herbaceous plants in four PFGs from 20 sites on the Tibetan Plateau along a 1600 km transect and explored the correlations between root pH and different PFGs, climate and soil conditions. The results showed that the root pH of herbaceous plants was slightly acidic (6.46 ± 0.05). Grasses had the highest root pH (6.91 ± 0.10) across all functional groups (p < .05), whereas legumes had the lowest (5.90 ± 0.08; p < .05). The root pH decreased with mean annual precipitation, aridity index, soil water content and soil stress coefficient, whereas the significant positive correlation with soil pH. PFGs, climate and soil explained 5.39, 11.15 and 24.94% of the root pH variance, respectively. This study provided a comprehensive analysis of root pH patterns in herbaceous plants over a large spatial scale. Root pH was controlled by the combined influence of PFGs, climate and soil properties, with moisture status being the main influential factor. In contrast to the leaf pH, the root pH of herbaceous plants is strongly affected by the soil pH along environmental gradients. Our findings provide new insights into root functional traits and survival strategies of herbaceous plants in alpine ecosystems.

1,1-Oxycarbonation of Terminal Alkynes via Sequential Borylation, 1,2-Migration, and Oxidation with Oxone.

Alkynes are readily available and multifunctional synthetic intermediates, but their 1,1-oxofunctionalization remains challenging. Herein, we report a 1,1-oxycarbonation of terminal alkynes to construct ketones through sequential borylation, 1,2-carbon migration, and oxidation with Oxone as the proton source and oxidant. The synthetic potential of this transformation is showcased by the broad functional groups, scale-up synthesis, and diverse product transformations.

Highly Stereoselective Synthesis of Multisubstituted Olefins from Alkynyl Tetracoordinate Borons and Iodonium Ylides via a Cyclic Intermediate.

We developed an intriguing and practical strategy for highly stereoselective assembly of multisubstituted olefins from alkynyl tetracoordinate boron species via a cyclic intermediate with 1,2-phenyl migration. We also developed a general method for the construction of deuterated trisubstituted alkenes from a cheap deuteration source, D2O, and the corresponding deuterated trisubstituted alkenes were obtained with excellent deuteration rates. This transformation features a novel reaction mechanism, exclusive stereoselectivity, and deuterated trisubstituted alkenes with excellent deuteration ratios.

Ni-catalysed assembly of axially chiral alkenes from alkynyl tetracoordinate borons via 1,3-metallate shift.

Asymmetric synthesis based on a metallate shift of tetracoordinate borons is an intriguing and challenging topic. Despite the construction of central chirality from tetracoordinate boron species via a 1,2-metallate shift, catalytic asymmetric synthesis of axially chiral compounds from such boron 'ate' complexes is an ongoing challenge. Axially chiral alkenes have received great attention due to their unique characteristics and intriguing molecular scaffolds. Here we report an enantioselective nickel-catalysed strategy for the construction of axially chiral alkenes via a 1,3-metallate shift of alkynyl tetracoordinate boron species. The chemoselectivity, regioselectivity and atroposelectivity can be regulated and well-controlled from readily accessible starting materials with a cheap transition-metal catalyst. Downstream transformations indicate the powerful conversion ability of such compounds in this protocol, and late-stage elaborations of bioactive compounds can also be achieved. Mechanistic experiments reveal that regioselective syn-addition of an aryl-Ni complex with a carbon-carbon triple bond and subsequent 1,3-phenyl migration are the two key steps for the synthesis of axially chiral alkenes.

Chemo-, regio- and stereoselective access to polysubstituted 1,3-dienes via Nickel-catalyzed four-component reactions.

1,2-Difunctionalization of alkynes offers a straightforward approach to access polysubstituted alkenes. However, simultaneous multi-component cascade transformations including difunctionalization of two alkynes with both syn- and anti-selectivity in one catalyst system is undeveloped and proves to be a significant challenge. Herein, we report a Nickel-catalyzed four-component reaction to access polysubstituted 1,3-dienes using two terminal alkynes, aryl boroxines, and perfluoroalkyl iodides, wherein the reaction forms three new C-C bonds in a single vessel and serve as a modular strategy to access polysubstituted 1,3-dienes with excellent chemoselectivity, good regioselectivity and exclusive stereoselectivity. Control experiments reveal the plausible reaction mechanism and DFT calculations explain the cause for the formation of this unusual four-component reaction. Furthermore, we successfully incorporate two biologically active units into 1,2,3,4-tetrasubstituted 1,3-dienes, which greatly increases the diversity of molecular scaffolds and brings more potential values to medicinal chemistry, the synthetic utility of our protocol is further demonstrated by the late-stage transformations.

Arylation of Terminal Alkynes: Transition-Metal-Free Sonogashira-Type Coupling for the Construction of C(sp)-C(sp2) Bonds.

Alkynes are attractive synthons for organic chemistry. Despite the prevalence of transition-metal-catalyzed Sonogashira reactions, a transition-metal-free version of the arylation of terminal alkynes is elusive. Herein, we report an efficient transition-metal-free Sonogashira-type coupling reaction for the one-pot arylation of alkynes to construct C(sp)-C(sp2) bonds from a tetracoordinate boron intermediate with NIS as a mediator. With its high efficiency, wide substrate range, and good functional group tolerance, this method is further supported by the gram-scale synthesis and subsequent modification of complex molecules.

Difluorocarbene-Enabled Synthesis of 3-Alkenyl-2-oxindoles from ortho-Aminophenylacetylenes.

Herein, we report a transition-metal-free [4 + 1] cyclization pathway from difluorocarbene and ortho-amino aryl alkynone, rendering an effective and universal strategy for the construction of 3-alkenyl-2-oxindoles. Our strategy starts from cheap and accessible ortho-amino aryl alkynone instead of the direct indole skeleton; moreover, in situ generated difluorocarbene from commercially available halogenated difluoroalkylative reagents enables the cleavage of a C-N bond and formation of new C-N bonds and C-C bonds.

Divergent Synthesis of 1,1-Carbonyl Amino Alkyl Borons from Indoles.

α-Boryl carbonyl species and α-boryl amino compounds are valuable and important frameworks in organic synthesis. However, the strategies that could merge the two scaffolds into one compound, named 1,1-carbonyl amino alkyl boron, are elusive and underdeveloped. Herein, we present an efficient method that could address this gap and produce 1,1-carbonyl amino alkyl borons from readily accessible indoles via oxidation by m-CPBA or oxone. This reaction features operational simplicity, divergent synthesis, broad substrate scope, and valuable products.

[Post-stroke dysphagia treated with four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy on post-stroke dysphagia treated with four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation. METHODS: Sixty patients with post-stroke dysphagia were randomly divided into an observation group and a control group, with 30 cases in each group. The neuromuscular electrical stimulation was adopted in the control group. Besides the treatment as the control group, in the observation group, the four-step acupuncture therapy for opening orifices and benefiting throat was supplemented. Step 1: the three areas of scalp acupuncture on the affected side were stimulated. Step 2: pricking method was operated on the posterior pharyngeal wall. Step 3: bleeding technique was operated at Jinjin (EX-HN 12) and Yuye (EX-HN 13). Step 4: deep insertion of needle was operated at three-pharynx points. The needles were retained for 30 min at the three areas of scalp acupuncture and the three-pharynx points. The intervention of each group was delivered once daily, 6 times a week, at the interval of 1 day. One course of treatment was 1 week and 4 successive courses were required. The rating of Kubota water swallow test, the score of standardized swallowing assessment (SSA) and the rating of Rosenbek penetration- aspiration scale (PAS) were observed before and after treatment in patients of the two groups. The incidence of clinical complications and clinical efficacy were compared between the two groups. RESULTS: Compared with those before treatment, the rating of Kubota water swallow test, the scores of SSA and the rating of PAS of patients in the two groups were decreased after treatment (P<0.01), and the values of the observation group were lower than those of the control group after treatment (P<0.05). The incidence of clinical complications in the observation group was 13.3% (4/30), lower than 36.7% (11/30) in the control group (P<0.05). The total effective rate in the observation group was 93.3% (28/30), which was better than 70.0% (21/30) in the control group (P<0.05). CONCLUSION: The four-step acupuncture therapy for opening orifices and benefiting throat combined with neuromuscular electrical stimulation can improve the swallowing function of patients with post-stroke dysphagia and reduce the incidence of clinical complications.

Comparison of Root Ecological Stoichiometry between Non-Growing Season and Growing Season of Grassland on the Chang Tang Plateau.

Root C: N: P stoichiometry affect the geochemical cycles of ecosystems, while a few studies were conducted on it and its relationship with soil nutrients, especially in the non-growing season. In this study, we investigated the root C:N:P stoichiometry of alpine steppe(AS), alpine meadow steppe(AMS), and alpine meadow(AM) in April (non-growing season) and August(growing season) in 2013. The results showed that: (1) There were no differences in root C, N, P, C: N, C:P, and N:P with a depth of AS in April. However, root C and C: N increased with depth, while N and N:P decreased with a depth of AS in August. In both months, the variation of root C, N, P, C: N with depth in AM was consistent with that of AS in August, and root C at deep layer decreased in August, which indicated roots of AM began to grow in April No significant difference of root C, N, C: N and N:P with depth was found, while P and C:P varied between the two months of AMS. Root P content at 20-30 cm was higher than that of other soil layers in April, which was significantly higher than that of AS, while no significant difference was found in August. (2) Grassland types had significant effects on soil nutrients (except TP) at 0-10 cm and 20-30 cm soil layers. (3) No significant correlation between soil nutrients and root C, N, P, C: N, C: P, and N: P was found in April. Soil TN and AN content had a significant positive correlation with root N: P, indicating that soil nitrogen was the primary N source of the root. Soil TP and AP were significantly negatively correlated with root C and C: N in August. This study can provide basic data and provide theoretical support for further understanding the role of grassland roots in nutrient cycling.

Recent Advances in the Construction of Fluorinated Organoboron Compounds.

Fluorinated organoboron compounds are important synthetic building blocks that combine the unique characteristics of a fluorinated motif with the versatile synthetic applications of organoboron moiety. This review article guides the research on fluorinated organoboron compounds mainly from four aspects in recent years: selective monodefluoroborylation of polyfluoroarenes and polyfluoroalkenes, selective borylation of fluorinated substrates, selective fluorination of organoboron compounds, and borofluorination of alkynes/olefins. In addition, this review will provide a necessary guidance and inspiration for the research on the valuable synthetic building block fluorinated organoboron compounds.

Acquisition pattern of nitrogen by microorganisms and plants affected by gravel mulch in a semiarid Tibetan grassland.

As an important coarse inorganic fraction of soil, gravel may regulate the effects of the interaction between above- and belowground communities and affect the relationship between microorganisms and plants in alpine ecosystems. However, comparatively little is known about the effects of gravel on the acquisition pattern of nitrogen (N) by microorganisms and plants in alpine ecosystems. In this study, a 15N-labelling experiment was conducted to investigate the acquisition pattern of organic (15N-glycine) and inorganic N (15N-NO3- and 15N-NH4+) by microorganisms and plants under three particle sizes of gravel mulch (fine: 2-10 mm, medium: 10-20 mm, coarse: 20-40 mm) on a semiarid Tibetan grassland. Gravel mulch significantly improved the 15N recovery of Stipa purpurea, but had no significant impacts on A. nanschanica. Therefore, gravel mulch decreased the ratio of microbial biomass 15N recovery to plant biomass 15N recovery for S. purpurea, but caused little effect on the state of N competition between plants and soil microbes for A. nanschanica. The N absorption preference of plants from both species shifted from an individual preference for 15N-NO3- in the natural (i.e., control) microplots to a common preference for 15N-NO3-and 15N-NH4+ in the fine- and medium-sized gravel mulch microplots, while there were no significant differences in microbial N recovery between 15N-NO3- and 15N-NH4+ across all treatments. The results helped to improve the understanding of the acquisition pattern of N by microorganisms and plants under the influence of gravel mulch in alpine ecosystems, and provide theoretical support for revegetation in alpine ecosystems in the future.