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A Ph3P/ICH2CH2I-promoted dehydroxylative cyanation of alcohols has been developed. In contrast to previous dehydroxylative cyanation methods that can suffer from several limitations, such as the use of transition metals or moisture-sensitive Lewis acids, this protocol features convenient operations, mild reaction conditions, and the use of cheap and widely available reagents.

Described herein is an efficient visible light mediated trifluoromethylation of (hetero)arenes using TFSP as a CF3 source. Various aromatic (hetero)cycles could undergo this protocol to give the corresponding trifluoromethylation products.

Despite intensive studies on the synthesis of 3-formylindoles, it is still highly desirable to develop efficient methods for the formylation of indoles, due to the shortcomings of the reported methods, such as inconvenient operations and/or harsh reaction conditions. Here, we describe a Ph3P/ICH2CH2I-promoted formylation of indoles with DMF under mild conditions. A Vilsmeier-type intermediate is readily formed from DMF promoted by the Ph3P/ICH2CH2I system. A one-step formylation process can be applied to various electron-rich indoles, but a hydrolysis needs to be carried out as a second step in the case of electron-deficient indoles. Convenient operations make this protocol attractive.

Herein we describe an efficient construction of HCF2Se and HCF2S groups by tandem substitutions between alkyl bromides and a reagent system consisting of MSeCN (or MSCN) and Ph3P+CF2H Br-. The tandem process occurs via the first nucleophilic substitution of alkyl bromides by -SeCN (or -SCN) and the subsequent nucleophilic difluoromethylation.

Trifluoromethyl substitution is notably popular in pharmaceuticals and agrochemicals; however, trifluoromethylated compounds normally rely on the use of cost-prohibitive or gaseous trifluoromethylating reagents, which diminishes the general applicability of these methods. Herein an efficient trifluoromethylation reagent trifluoromethylsulfonyl-pyridinium salt (TFSP) was reported, which can be readily prepared from cheap and easily available bulk industrial feedstocks. TFSP can generate a trifluoromethyl radical under photocatalysis and realize the effective azido- or cyano-trifluoromethylation reactions of alkenes.

A successful Cu-catalyzed addition of both Cl and SO

Background: The disorders of glucolipid metabolism are prevalent in patients with type-2 diabetes mellitus (T2DM). Palmitic-Acid-Hydroxy-Stearic Acid (PAHSA) had been reported to benefit glucolipid metabolism in diabetic mice. Given the importance of autophagy in T2DM, the aim of the present study was to investigate whether S-9-PAHSA has specific therapeutic effects on diabetics, particularly with regards to autophagy. Methods: 19-week-old male C57BL6 mice were fed with high-fat-diet for 4 months, and administered with 22.5 mg/kg/d or 5.5 mg/kg/d fatty acids or an equivalent volume of vehicle for 35 days. Glucose levels and weight were determined. Insulin, glycosylated serum protein (GSP), glucagon-like peptide-1(GLP-1) and oxidized modified low-density lipoprotein (ox-LDL) were assessed by ELISA kit. Autophagy-related proteins P62 and Beclin-1in cerebral cortex were detected by western blot. SH-SY 5Y cells were incubated under diabetic environment (glucose 100mmol/L, fatty acid 200μmol/L), and then treated with S-9-PAHSA, R-9-PAHSA and 9-PAHSA. Cell viability, cell proliferation, lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production were detected by respective kits. Apoptosis was assessed by the TUNEL assay. The protein levels of apoptosis (Cleaved caspase-3, BAX/Bcl-2), autophagy (Beclin1, p62 and LC3II/I) and PI3K/AKT pathway were determined by western blot. Results: Although S-9-PAHSA did not alter glucose levels, weight, GLP-1 and GSP in mice, high-does S-9-PAHSA improved insulin resistance and lowered ox-LDL. Compared with control group, the up-regulated expression of P62 and down-regulated expression of Beclin1 in diabetic mice were found, and the S-9-PAHSA administration reduced P62. In vitro, S-9-PAHSA increased cell viability and proliferation while reduced LDH release and ROS production, which were better than R-9-PAHSA and 9-PAHSA. S-9-PAHSA could lower the levels of Cleaved caspase-3 and percentage of TUNEL-positive cells. S-9-PAHSA enhanced the expression of LC3II/I under high glucose and fatty acid stimulation. PI3K and p-AKT/AKT ratio under diabetic environment had a downward trend, and S-9-PAHSA might enhance their expression, but there was no statistical difference. Conclusions: S-9-PAHSA could regulate glycolipid metabolism in HFD-induced T2DM mice through autophagy-associated protein, and exerted protective effects on diabetes by the regulation of autophagy, reducing oxidative stress, partially activating PI3K/AKT signaling pathway.

Although transition metal carbenes have found widespread applications and difluorocarbene has served as a versatile intermediate, it is still quite challenging to make use of transition-metal difluorocarbenes in synthetic chemistry due to their unpredictable reactivities. In this Highlight, we review recent developments in the transition-metal-catalyzed or -mediated transfer of difluorocarbene and the reactivies and conversions of transition-metal difluorocarbene complexes. We start with the MCF2 bonding, then provide the progress in the transfer of difluorocarbene, and finally briefly discuss the conversions of MCF2 into other metal complexes. The understanding of the interesting reactivities of MCF2 may help design the catalytic transfer of difluorocarbene for various reactions.

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF3 SO2 OCF3 in the presence of a suitable base at room temperature has been developed. The reaction allows a straightforward access to a variety of acyl fluorides and proves that CF3 SO2 OCF3 is an effective deoxyfluorination reagent for carboxylic acids. The method features simplicity, expeditiousness, high efficiency, ease of handling, good functional group tolerance, a wide range of substrates, excellent yields of products, compatibility of many amine initiators, use of environmentally friendly reagents, and effortless removal of byproducts. This reaction represents the first utilization of trifluoromethyl trifluoromethanesulfonate as a fluorination reagent.

The fluorination of alkenes with electrophilic N-F type reagents usually occurs through a Markovnikov-type addition, and the anti-Markovnikov-type addition may require the use of a transition metal catalyst or an expensive catalyst. Herein we describe a convenient anti-Markovnikov iodofluorination of alkenes with Selectfluor/

A large number of fluorination methods have been developed, but the construction of a tertiary C-F bond remains challenging. Herein, we describe an efficient dehydroxylative fluorination of tertiary alcohols with Selectfluor via the activation of a hydroxyl group by a Ph2PCH2CH2PPh2/ICH2CH2I system. Although the reagents appear to be not compatible (Selectfluor with the phosphine and I- generated in situ), the reactions occur rapidly to give the desired products in moderate to high yields. This work may present a new discovery in fluorination of alcohols since the reported methods are mainly limited to primary and secondary alcohols.

A large number of efficient cyanation methods have been developed because of the wide range of applications of nitriles, but conventional methods usually suffer from the need for a toxic cyanation reagent. Although difluorocarbene chemistry has received increasing attention, the use of difluorocarbene as a sources of the nitrile carbon for nitrile groups remains largely unexplored. We describe a difluorocarbene-based cyanation of aryl iodides promoted by a cheap copper source, Cu(NO3)2·2.5H2O, under an air atmosphere. Ph3P+CF2CO2 –, an easily available and shelf-stable difluorocarbene reagent, and NaNH2 are used as the carbon source and the nitrogen source for the nitrile group, respectively. The cyanation protocol is attractive because no toxic reagent is used and performing the reactions under an air atmosphere is operationally convenient.

For the dehydroxylation of aldoximes with 4-nitro-1-((trifluoromethyl)sulfonyl)-imidazole (NTSI), slight modifications of reaction conditions resulted in significantly different reaction paths to provide either nitriles or isonitriles. The challenging conversion of aldoximes into isonitriles was achieved under mild conditions.

In contrast with unactivated alkenes, the corresponding hydrotrifluoromethylation of styrene has remained challenging due to the strong propensity of styrene for oligomerization and polymerization. On the basis of our newly developed trifluoromethylation reagent, TFSP, herein we present a general method for the hydrotrifluoromethylation of styrene under photoredox catalysis. The substrate scope was further extended to unactivated alkenes, acrylates, acrylamides, and vinyl-heteroatom-substituted alkenes. The tunability of this method was showcased via the relevant deprotonative trifluoromethylation and trifluoromethyltrifluoroethoxylation reactions.

Herein we describe an efficient construction of HCF

Fluorinated molecules have a wide range of applications and are used as medicines, agrochemicals and refrigerants and in smartphone liquid crystal displays, photovoltaic solar cells, Teflon tapes and the coatings of textiles and buildings. Fluorination and fluoroalkylation — incorporation of a trifluoromethyl, difluoromethyl or monofluoromethyl group — are the major strategies used for the construction of carbon–fluorine bonds and fluorinated carbon–carbon bonds, respectively. The past two decades have witnessed a rapid growth in fluorination and fluoroalkylation methods thanks to the development of new reagents and catalysts. This Primer aims to provide an overview of state-of-the-art strategies in fluorination, trifluoromethylation, difluoromethylation and monofluoromethylation, with an emphasis on using C–H functionalization, although other strategies for fluorination and fluoroalkylation are also discussed. Further landmark achievements are expected in the fields of fluorination and fluoroalkylation as organofluorine compounds are used increasingly in everyday applications. This Primer describes contemporary fluorination and fluoroalkylation reactions in chemical synthesis. The authors describe the main fluorination and fluoroalkylation reactions. The many applications of these reactions in pharmaceuticals, imaging agents and agriculture are discussed, along with the history and future of synthetic organofluorine chemistry.

Described herein is a Rh-catalyzed tunable defluorinative borylation of allylic gem-difluorides to provide allylborylated monofluoroalkenes or homoallylborylated monofluoroalkenes with excellent Z/E selectivities. Completely different reaction paths were observed by slightly changing the reaction conditions. Allylborylated monofluoroalkenes were further converted into dihydroxyl-containing monofluoroalkenes.

Tetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21.25 and 29.07 μM, respectively). We also found that this compound mediated cell cycle arrest in the G0/G1 phase at 30–40 μM. Western blot analysis demonstrated that the cell cycle arrest induced by this compound in HepG2 and HMCCLM3 cells was associated with a significant decrease in Cdc2 and cyclin B1, which led to the accumulation of the phosphorylated-Tyr15 (inactive) form of Cdc2 and low expression of M phase-promoting factor (cyclin B1/Cdc2). Moreover, cells treated with this compound exhibited decreased expression of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H). This compound also induced cell apoptosis via activation of caspase-3. A xenograft model in nude mice demonstrated anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the anticancer effect of this compound was partially due to G0/G1 cell cycle arrest via inhibition of CDK7-mediated expression of Cdc2, and this compound may be a promising anticancer candidate for further investigation.

Difluoromethylation is a straightforward and widely applied strategy used to incorporate HCF2 into organic molecules. In contrast, cyanation reagents are typically volatile or highly toxic, or they require harsh reaction conditions. Incorporation of both CN and HCF2 into organic molecules, such as alkenes, is a worthwhile but challenging task. A method for photocatalyzed cyanodifluoromethylation of alkenes has been developed, which employs a Ph3 P+ CF2 CO2- /NaNH2 (or NH3 ) reagent system. Ph3 P+ CF2 CO2- functions as both the HCF2 and CN carbon source. A cyanide anion is generated in situ under mild conditions, thereby avoiding the use of toxic cyanation reagents. The photocatalytic method permits cyanodifluoromethylation of a range of alkenes under mild room temperature conditions. The CN group within the products may be further derivatized by standard methods.

Described here is the radical-mediated hydrodifluoromethylation of alkenes that occurs under transition-metal-free conditions by using the phosphonium salt [Ph3P+CF2H]Br− under the irradiation of 26 W household compact fluorescent light. The reaction lends itself to a convenient protocol for the installation of a C–CF2H bond while maintaining good functional group tolerance.

Ph3P/I–-promoted dichlorination and dibromination of epoxides by using XCH2CH2X (X = Cl or Br) as the halogen source and reaction solvent is described. All reagents are widely available and easy to handle, and mild conditions and operational simplicity make this protocol attractive.

Although CF3SO2Cl is an efficient chlorotrifluoromethylation reagent, an expensive transition metal complex usually has to be used. We found that CuCl2-catalyzed chlorotrifluoromethylation of alkenes with CF3SO2Cl occurred smoothly under mild conditions. A wide substrate scope and good functional group compatibility were observed.

Although cyanofluoroalkylation has received increasing attention, a toxic cyanation reagent is usually required. Herein, a Cu-catalyzed difluorocarbene-based cyanodifluoromethylation of alkenes with BrCF2CO2Et/NH4HCO3 under photocatalytic conditions is described. BrCF2CO2Et and NH4HCO3 serve as a carbon source and a nitrogen source of the nitrile group, respectively, avoiding the use of a stoichiometric toxic cyanation reagent. The Cu-complex plays a dual role. It is not only a photocatalyst, but also a coupling catalyst for the formation of a C-CN bond.

Owing to the special effects of the fluorine element, including high electronegativity and small atomic radius, the incorporation of a fluorinated group into organic molecules may modify their physical, chemical, and biological properties. Fluorine-containing compounds have found widespread application in a variety of areas, and thus, the development of efficient reagents and methods for the incorporation of fluorinated groups has become a subject of significant interest.Described in this Account are our recent discoveries in the chemistry of fluorinated ylides/carbenes and related intermediates generated from phosphonium/sulfonium salts. Initially, we obtained the (triphenylphosphonio) difluoroacetate, Ph

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF

To provide feasible methods for the extraction of valuable metals from spent batteries or low-grade primary ores, the extraction behavior of some representative acidic phosphorus-containing compounds (APCCs) as extractants is evaluated from the perspective of experimental and theoretical investigations in this work. Aqueous solutions containing five metal ions, Ca(II), Co(II), Mg(II), Mn(II), and Ni(II), were made to simulate leaching liquids, and the extraction of these metals was investigated. A simplified calculated model was used to evaluate the interaction between each extractant and metal ions. The calculation results agree well with the experimental tests in trend. This work not only provides potential extractants for the extraction of valuable metals from spent batteries or low-grade primary ores but also demonstrates the practicability of the simplified calculation model.

We report herein a general and practical copper-catalyzed fluorosulfonylation reaction of a wide range of abundant arenediazonium salts to smoothly prepare various arenesulfonyl fluorides using the 1,4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct as a convenient sulfonyl source in combination with KHF

Ag-mediated trifluoromethylthiolation of inert Csp3–H bond with CF3SOCl is described. Widely available reagents and operational simplicity make this protocol attractive.

As a versatile intermediate, difluorocarbene is an electron-deficient transient species, meaning that its oxidation would be challenging. Herein we show that the oxidation of difluorocarbene could occur smoothly to generate carbonyl fluoride. The oxidation process is confirmed by successful trifluoromethoxylation, 18O-trifluoromethoxylation, the observation of AgOCF3 species, and DFT calculations., Difluorocarbene is a versatile and efficient intermediate for fluorine incorporation. Here, the authors show that difluorocarbene can be oxidized to carbonyl fluoride and this process is confirmed in 18O-trifluoromethoxylation reactions, by observation of AgOCF3 species and theory.

Summary: The CF3O functional group is a unique fluorinated group that has received a great deal of attention in medicinal chemistry and agrochemistry. However, trifluoromethoxylation of substrates remains a challenging task. Herein we describe the dehydroxytrifluoromethoxylation of alcohols promoted by a R3P/ICH2CH2I (R3P = Ph3P or Ph2PCH=CH2) system in DMF. P-I halogen bonding drives the reaction of R3P with ICH2CH2I in DMF to generate iodophosphonium salt (R3P+I I−) and a Vilsmeier-Haack-type intermediate, both of which could effectively activate alcohols, thus enabling a fast (15 min) trifluoromethoxylation reaction. A wide substrate scope and a high level of functional group tolerance were observed. : Chemistry; Organic Chemistry; Organic Synthesis Subject Areas: Chemistry, Organic Chemistry, Organic Synthesis

An efficient reagent system, Ph3P/XCH2CH2X (X = Cl, Br, or I), was very effective for the deoxygenative halogenation (including fluorination) of alcohols (including tertiary alcohols) and aldehydes. The easily available 1,2-dihaloethanes were used as key reagents and halogen sources. The use of (EtO)3P instead of Ph3P could also realize deoxy-halogenation, allowing for a convenient purification process, as the byproduct (EtO)3P═O could be removed by aqueous washing. The mild reaction conditions, wide substrate scope, and wide availability of 1,2-dihaloethanes make this protocol attractive for the synthesis of halogenated compounds.

The preparation of highly pure KF-ZrF4 (FKZr) molten salt, a potential secondary coolant in molten salt reactors, was realized simply by heating a mixture of (NH4)2ZrF6 and KF. X-ray diffraction analysis indicated that the FKZr molten salt was mainly composed of KZrF5 and K2ZrF6. The melting point of the prepared FKZr molten salt was 420–422 °C under these conditions. The contents of all metal impurities were lower than 20 ppm, and the content of oxygen was lower than 400 ppm. This one-step protocol avoids the need for a tedious procedure to prepare ZrF4 and for an additional purification process to remove oxide impurities, and is therefore a convenient, efficient and economic preparation method for high-purity FKZr molten salt.

Molecular acidity of trivalent rare-earth metal cations in aqueous solution is an important factor dedicated to the efficiency of their extraction and separation processes. In this work, the aqueous acidity of these metal ions has been quantitatively investigated using a few theoretical approaches. Our computational results expressed in terms of pKa values agree well with the tetrad effect of trivalent rare-earth ions extensively reported in the extraction and separation of these elements. Strong linear relationships have been observed between the acidity and quantum electronic descriptors such as the molecular electrostatic potential on the acidic nucleus and the sum of the valence natural atomic orbitals energies of the dissociating proton. Making use of the predicted pKa values, we have also predicted the major ionic forms of these species in the aqueous environment with different pH values, which can be employed to rationalize the behavior difference of different rare-earth metal cations during the ex...

The tri- and di-fluoroethylation of alkenes with sulfonium salts, (Ph2S+CH2RF TfO−) (RF = CF3 or HCF2), by visible light photoredox catalysis to give tri-/di-fluoroethyl alkenes or methoxytri-/di-fluoroethylation products are described. It was found that varying the reaction solvent led to changes in the reaction path.

As trifluoromethylthiolation has received increasing attention recently, many CF3S-reagents and trifluoromethylthiolation methods have been developed. Herein we describe trifluoromethylthiolation of alkyl halides by using Ph3P+CF2CO2− as a fluoride and difluorocarbene source. Difluorocarbene is a versatile intermediate, but its side reactions are usually ignored and the by-products would therefore be discarded. In this work, a side reaction of difluorocarbene, the generation of a fluoride anion from difluorocarbene, was developed into a synthetic tool. Although the trifluoromethylthiolation reaction involved multi-sequential steps, the cleavage of C–F bond, the formation of CF2=S bond, F-C(S)F2 bond, and C-SCF3 bond, the conversion proceeded fast and was completed within 10 min.

The reaction of thiocarbonyl fluoride, generated from difluorocarbene, with various amines under mild conditions is described. Secondary amines, primary amines, and o-phenylenediamines are converted to thiocarbamoyl fluorides, isothiocyanates, and difluoromethylthiolated heterocycles, respectively. Thiocarbamoyl fluorides were further transformed into trifluoromethylated amines by using a one-pot process. Thiocarbonyl fluoride is generated in situ and is rapidly fully converted in one pot under mild conditions; therefore, no special safety precautions are needed.

Presented is a novel intermolecular radical trifluoromethylfluorosulfonylation of unactivated alkenes under mild reaction conditions with good functional-group tolerance in the most atom-economic manner by using readily available Ag(O2 CCF2 SO2 F) and N-fluorobenzenesulfonimide (NFSI). Both the trifluoromethyl and sulfonyl groups in the products originate from Ag(O2 CCF2 SO2 F).

The highly diastereoselective synthesis of CF3-containing vicinal diamines by a convenient two-step procedure without the need to isolate the intermediate products is described.

The preparation conditions and purification reaction mechanism for H2–HF treatment of molten FLiNaK salt were investigated. The optimal process conditions for preparation of high-purity molten FLiNaK salt were obtained. They are purification temperature of 650 °C, liquid height of 0.9 m, purification time of 48 h, flow ratio of H2/HF = 10, flow volume magnitude of 800 mL/min, and reaction pressure of 0 MPa. The oxygen content of the prepared molten salt was around 80 ppm, corrosion impurity elements (Cr, Fe, and Ni) were less than 20 ppm, and the S and P contents were below 5 ppm. The quality of FLiNaK molten salt prepared by this hydrofluorination process is better than that obtained by adding NH4HF2 as a fluorinating reagent.