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.

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.

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.

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.

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.

Identification of a 3,3-difluorinated tetrahydropyridinol compound as a novel antitumor agent for hepatocellular carcinoma acting via cell cycle arrest through disturbing CDK7-mediated phosphorylation of Cdc2.

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.

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.

Extraction Behavior of Acidic Phosphorus-Containing Compounds to Some Metal Ions: A Combination Research of Experimental and Theoretical Investigations.

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.

Photocatalyzed Cyanodifluoromethylation of Alkenes.

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.

Ag-Mediated Trifluoromethylthiolation of Inert Csp3-H Bond.

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

Theoretical Study of pKa Values for Trivalent Rare-Earth Metal Cations in Aqueous Solution.

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 extraction process. Our present results should provide needed insights not only for the qualitatively understanding about the extraction and separation between yttrium and lanthanide elements but also for the prediction of novel and more efficient rare-earth metal extractants in the future.

Difluorocarbene for Dehydroxytrifluoromethylthiolation of Alcohols.

Dehydroxytrifluoromethylthiolation of alcohols with a Ph3P+CF2CO2-/S8/F- system is described. Difluorocarbene generated from Ph3P+CF2CO2- would readily combine with elemental sulfur to furnish S═CF2. S═CF2 can be considered as a bifunctional intermediate, activating alcohol and providing scaffold for CF3S- formation, thus allowing for the convenient dehydroxytrifluoromethylthiolation of alcohols.

Diastereoselective Synthesis of CF3-Containing Vicinal Diamines.

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.

Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines.

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.

Trifluoromethylfluorosulfonylation of Unactivated Alkenes Using Readily Available Ag(O2 CCF2 SO2 F) and N-Fluorobenzenesulfonimide.

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).

An Unconventional Mechanistic Insight into SCF3 Formation from Difluorocarbene: Preparation of 18 F-Labeled α-SCF3 Carbonyl Compounds.

Trifluoromethylthiolation by sulfuration of difluorocarbene with elemental sulfur is described for the first time, which overrides long-standing trifluoromethyl anion-based theory. Mechanistic elucidation reveals an unprecedented chemical process for the formation of thiocarbonyl fluoride and also enables transition-metal-mediated trifluoromethylthiolation and [18 F]trifluoromethylthiolation of α-bromo carbonyl compounds with broad substrate scope and compatibility.

pKa prediction for acidic phosphorus-containing compounds using multiple linear regression with computational descriptors.

Ninety-six acidic phosphorus-containing molecules with pKa 1.88 to 6.26 were collected and divided into training and test sets by random sampling. Structural parameters were obtained by density functional theory calculation of the molecules. The relationship between the experimental pKa values and structural parameters was obtained by multiple linear regression fitting for the training set, and tested with the test set; the R(2) values were 0.974 and 0.966 for the training and test sets, respectively. This regression equation, which quantitatively describes the influence of structural parameters on pKa , and can be used to predict pKa values of similar structures, is significant for the design of new acidic phosphorus-containing extractants. © 2016 Wiley Periodicals, Inc.

Nucleophilic 1,1-Difluoroethylation with Fluorinated Phosphonium Salt.

The fluorinated phosphonium salt (Ph3P+CF2CH3 BF4-) was shown to act as a nucleophilic 1,1-difluoroethylation agent to enable difluoroethylation of aldehydes and imines.

Difluorocarbene-Derived Trifluoromethylthiolation and [(18)F]Trifluoromethylthiolation of Aliphatic Electrophiles.

The first trifluoromethylthiolation and [(18)F]trifluoromethylthiolation of alkyl electrophiles with in situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition-metal-free approach is high yielding, compatible with a variety of functional groups, and operated under mild reaction conditions. The conceptual advantage of this exogenous-fluoride-mediated transformation enables unprecedented syntheses of [(18)F]CF3S-labeled molecules from most commonly used [(18)F]fluoride ions. The rapid radiochemical reaction time (≤1 min) and high functional-group tolerance allow access to a variety of aliphatic [(18)F]CF3S compounds in high yields.