Photocatalytic Keto- and Amino-Trifluoromethylation of Alkenes.

Efforts to develop alternatives to triflic anhydride (Tf2O) as a trifluoromethylation reagent continue due to its limitations, including volatility, corrosiveness, and moisture sensitivity. Described herein is the use of a trifluoromethylsulfonylpyridinium salt (TFSP), easily obtained by a one-step reaction of Tf2O with 4-dimethylaminopyridine, as a reagent for the trifluoromethylative difunctionalization of alkenes by photoredox catalysis. DMSO and CH3CN are suitable solvents for achieving keto- and amino-trifluoromethylation of alkenes, respectively, with good functional group tolerance.

S-9-PAHSA's neuroprotective effect mediated by CAIII suppresses apoptosis and oxidative stress in a mouse model of type 2 diabetes.

BACKGROUND: With the rapidly increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), neuronal complications associated with these diseases have resulted in significant burdens on healthcare systems. Meanwhile, effective therapies have remained insufficient. A novel fatty acid called S-9-PAHSA has been reported to provide metabolic benefits in T2DM by regulating glucose metabolism. However, whether S-9-PAHSA has a neuroprotective effect in mouse models of T2DM remains unclear. METHODS: This in vivo study in mice fed a high-fat diet (HFD) for 5 months used fasting blood glucose, glucose tolerance, and insulin tolerance tests to examine the effect of S-9-PAHSA on glucose metabolism. The Morris water maze test was also used to assess the impact of S-9-PAHSA on cognition in the mice, while the neuroprotective effect of S-9-PAHSA was evaluated by measuring the expression of proteins related to apoptosis and oxidative stress. In addition, an in vitro study in PC12 cells assessed apoptosis, oxidative stress, and mitochondrial membrane potential with or without CAIII knockdown to determine the role of CAIII in the neuroprotective effect of S-9-PAHSA. RESULTS: S-9-PAHSA reduced fasting blood glucose levels significantly, increased insulin sensitivity in the HFD mice and also suppressed apoptosis and oxidative stress in the cortex of the mice and PC12 cells in a diabetic setting. By suppressing oxidative stress and apoptosis, S-9-PAHSA protected both neuronal cells and microvascular endothelial cells in in vivo and in vitro diabetic environments. Interestingly, this protective effect of S-9-PAHSA was reduced significantly when CAIII was knocked down in the PC12 cells, suggesting that CAIII has a major role in the neuroprotective effect of S-9-PAHSA. However, overexpression of CAIII did not significantly enhance the protective effect of S-9-PAHSA. CONCLUSION: S-9-PAHSA mediated by CAIII has the potential to exert a neuroprotective effect by suppressing apoptosis and oxidative stress in neuronal cells exposed to diabetic conditions. Furthermore, S-9-PAHSA has the capability to reduce fasting blood glucose and LDL levels and enhance insulin sensitivity in mice fed with HFD.

Identification of a Difluorinated Alkoxy Sulfonyl Chloride as a Novel Antitumor Agent for Hepatocellular Carcinoma through Activating Fumarate Hydratase Activity.

Fenofibrate is known as a lipid-lowering drug. Although previous studies have reported that fenofibrate exhibits potential antitumor activities, IC50 values of fenofibrate could be as high as 200 µM. Therefore, we investigated the antitumor activities of six synthesized fenofibrate derivatives. We discovered that one compound, SIOC-XJC-SF02, showed significant antiproliferative activity on human hepatocellular carcinoma (HCC) HCCLM3 cells and HepG2 cells (the IC50 values were 4.011 µM and 10.908 µM, respectively). We also found this compound could inhibit the migration of human HCC cells. Transmission electron microscope and flow cytometry assays demonstrated that this compound could induce apoptosis of human HCC cells. The potential binding sites of this compound acting on human HCC cells were identified by mass spectrometry-cellular thermal shift assay (MS-CETSA). Molecular docking, Western blot, and enzyme activity assay-validated binding sites in human HCC cells. The results showed that fumarate hydratase may be a potential binding site of this compound, exerting antitumor effects. A xenograft model in nude mice demonstrated the anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the antitumor effect of this compound may act via activating fumarate hydratase, and this compound may be a promising antitumor candidate for further investigation.

Ph3P/ICH2CH2I-promoted reductive deoxygenation of alcohols.

Owing to the ubiquity of the hydroxyl group, reductive deoxygenation of alcohols has become an active research area. The classic Barton-McCombie reaction suffers from a tedious two-step procedure. New efficient methods have been developed, but they have some limitations, such as a narrow substrate scope and the use of moisture-sensitive Lewis acids. In this work, we describe the Ph3P/ICH2CH2I-promoted reductive deoxygenation of alcohols with NaBH4. The process is applicable to benzyl, allyl and propargyl alcohols, and also to primary and secondary alcohols, demonstrating a wide substrate scope and a good level of functional group tolerance. This protocol features convenient operation and low cost of all reagents.

Dehydroxylative Sulfonylation of Alcohols.

Described here is the R3P/ICH2CH2I-promoted dehydroxylative sulfonylation of alcohols with a variety of sulfinates. In contrast to previous dehydroxylative sulfonylation methods, which are usually limited to active alcohols, such as benzyl, allyl, and propargyl alcohols, our protocol can be extended to both active and inactive alcohols (alkyl alcohols). Various sulfonyl groups can be incorporated, such as CF3SO2 and HCF2SO2, which are fluorinated groups of interest in pharmaceutical chemistry and the installation of which has received increasing attention. Notably, all reagents are cheap and widely available, and moderate to high yields were obtained within 15 min of reaction time.

Tf2O as a CF3 Source for the Synthesis of Trifluoromethoxylation Reagent nC4F9SO3CF3.

Described herein is the convenient synthesis of an efficient trifluoromethoxylation reagent, nC4F9SO3CF3, by using cheap and widely available reagents and without the need of any tedious column chromatography purification procedure.

Difluoromethylsulfonyl Imidazolium Salt for Difluoromethylation of Alkenes.

Herein, we describe the design and synthesis of a difluoromethylsulfonyl imidazolium salt, which can act as a radical difluoromethylation reagent to achieve the challenging amino- and oxy-difluoromethylation of alkenes. Notably, the three steps for the synthesis of the imidazolium salt do not require any tedious distillation or column chromatography purification process, and the amino- and oxy-difluoromethylation paths are simply determined by the selection of reaction solvents.

Synthesis and 18F Labeling of Alkenyl Sulfonyl Fluorides via an Unconventional Elimination Pathway.

A successful Cu-catalyzed addition of both Cl and SO2OCF2H groups into alkenes allows us to discover the unusual reactivity of the SO2OCF2H group. As opposed to common sulfonic esters (RSO2-O-R'), in which the R' group is highly electrophilic, the SO2 moiety demonstrates higher electrophilicity in RSO2-OCF2H. The unexpected reactivity is further developed not only as a synthetic tool for well-functionalized alkenyl sulfonyl fluorides but also for the first 18F labeling of alkenyl sulfonyl fluorides.

anti-Markovnikov Iodofluorination of Alkenes.

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/n Bu4 NI. A wide substrate scope and good functional group tolerance were observed. The process allows for the construction of various C-F bonds, especially tertiary C-F bonds. The remarkable features make this protocol attractive, including convenient operations, simple reaction conditions, and the installation of an iodine atom which provides possibilities for further transformations.

Porphyriynes: 18-π-Conjugated Macrocycles Incorporating a Triple Bond.

Tetraphenylporphyriyne (Pyne1), a novel porphyrin analogue with a C≡C bond incorporated into an 18-π-conjugated system, has been created via cleavage of the N-confused pyrrolic ring in Ag(III) N-confused tetraphenylporphyrin. The structure of Pyne1 was confirmed by X-ray crystallography and 1H NMR, IR, and UV-vis spectroscopy. The mechanism of cleavage of the N-confused pyrrolic ring was investigated by theoretical calculations. The successful synthesis of other Pynes indicated the generality of this protocol.

Starting from Styrene: A Unified Protocol for Hydrotrifluoromethylation of Diversified Alkenes.

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.

HCF2Se/HCF2S Installation by Tandem Substitutions from Alkyl Bromides.

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.

Transition-metal difluorocarbene complexes.

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 MCF2 bonding, then provide the progress in the transfer of difluorocarbene, and finally briefly discuss the conversions of MCF2 into other metal complexes. The understanding of the interesting reactivities of MCF2 may help design the catalytic transfer of difluorocarbene for various reactions.

A Readily Available Trifluoromethylation Reagent and Its Difunctionalization of Alkenes.

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.

Rh-catalyzed tunable defluorinative borylation.

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.

Difluorocarbene-based cyanodifluoromethylation of alkenes induced by a dual-functional Cu-catalyst.

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.

Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3 SO2 OCF3.

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.

Dehydroxylative Fluorination of Tertiary Alcohols.

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.

Fluorinated Ylides/Carbenes and Related Intermediates from Phosphonium/Sulfonium Salts.

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, Ph3P+CF2CO2- (PDFA), which was proposed as a reactive intermediate but had never been successfully synthesized. PDFA, shelf-stable and easy to prepare, is not only a mild ylide (Ph3P+CF2-) reagent, but also an efficient difluorocarbene source. It can directly generate difluorocarbene, via the first generation of ylide Ph3P+CF2-, simply under warming conditions without the need for any additive. Interestingly, difluorocarbene chemistry was then discovered by using PDFA as a reagent. Difluorocarbene can be oxidized to CF2═O, can react with elemental sulfur to afford CF2═S, and can be trapped by NaNH2 or NH3 to give CN-. The development of these processes into synthetic tools allowed us to achieve various reactions, including the challenging 18F-trifluoromethylthiolation and cyanodifluoromethylation. It was found that a substituent on the cation of a phosphonium salt can be directly transferred as a nucleophile despite the cation's high electrophilicity. This transfer process is like an "umpolung" of the cation, which may provide more opportunities for the synthetic utilities of phosphonium salts. The investigation of this transfer process led us to find that iodophosphonium salts, active intermediates which can be easily generated, may efficiently promote deoxygenative functionalizations of aldehydes and alcohols. Dehydroxylative substitution of alcohols by this protocol permits the use of unprotected amines with higher pKa values as nucleophiles, which is an attractive feature compared with the Mitsunobu reaction. On the basis of the ylide-to-carbene process (Ph3P+CF2- → :CF2), we further developed sulfonium salts as precursors of fluorinated ylides and fluorinated methyl carbenes. In particular, the studies on difluoromethylcarbene, remaining largely unexplored, may deserve more attention. The discoveries may find utility in the synthesis of biologically active fluorine-containing molecules.