- Direct Access to Chiral β-Fluoroamines with Quaternary Stereogenic Center through Cooperative Cation-Binding Catalysis
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A direct route to chiral β-fluoroamines with tetrasubstituted C?F centers through the organocatalytic Mannich reaction of α-fluoro cyclic ketones and α-amidosulfones by using a chiral oligoethylene glycol as a cation-binding catalyst and KF as a base is reported. For most substrates, nearly perfect enantioselectivities were achieved even at very high temperatures (>80 °C). The salient features of this process include a) a transition-metal-free and operationally simple procedure, b) direct use of α-amidosulfones as bench-stable precursors of sensitive imines, c) direct enolization of racemic α-fluoro cyclic ketones, and d) excellent stereoselectivity up to 99 % enantiomeric excess and >20:1 diastereoselectivity (anti/syn). Thus, this protocol is easily scalable and provides a new approach for the synthesis of biologically relevant products with tetrasubstituted C?F centers. Furthermore, this protocol was also successfully extended to generate C?Cl and C?Br quaternary stereogenic centers.
- Vaithiyanathan, Venkataramasubramanian,Kim, Mun Jong,Liu, Yidong,Yan, Hailong,Song, Choong Eui
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Read Online
- Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2] → [CF2CHF] Isosterism
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Saturated, fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF2 (>20 examples, up to >95 %). A range of diverse substituents are tolerated under standard catalysis conditions and this is interrogated by Hammett analysis. X-ray analysis indicates a preference for the CH?F bond to occupy a pseudo-axial orientation, consistent with stabilising σC?H→σC?F* interactions. The replacement of the symmetric [CH2?CH2] motif by [CF2?CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational analysis and is consistent with stereoelectronic theory.
- Daniliuc, Constantin G.,Gilmour, Ryan,Mück-Lichtenfeld, Christian,Neufeld, Jessica,Stünkel, Timo
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supporting information
p. 13647 - 13651
(2021/05/07)
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- Flow electrochemistry: a safe tool for fluorine chemistry
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The heightened activity of compounds containing fluorine, especially in the field of pharmaceuticals, provides major impetus for the development of new fluorination procedures. A scalable, versatile, and safe electrochemical fluorination protocol is conferred. The strategy proceeds through a transient (difluoroiodo)arene, generated by anodic oxidation of an iodoarene mediator. Even the isolation of iodine(iii) difluorides was facile since electrolysis was performed in the absence of other reagents. A broad range of hypervalent iodine mediated reactions were achieved in high yields by coupling the electrolysis step with downstream reactions in flow, surpassing limitations of batch chemistry. (Difluoroiodo)arenes are toxic and suffer from chemical instability, so the uninterrupted generation and immediate use in flow is highly advantageous. High flow rates facilitated productivities of up to 834?mg h?1with vastly reduced reaction times. Integration into a fully automated machine and in-line quenching was key in reducing the hazards surrounding the use of hydrofluoric acid.
- Rennigholtz, Tim,Winterson, Bethan,Wirth, Thomas
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p. 9053 - 9059
(2021/07/12)
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- Method for synthesizing alpha-fluorinated ketone through hydrazone aliphatic chain monoketone
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The invention belongs to the technical field of organic synthesis, and provides a method for synthesizing alpha-ketone fluoride through hydrazone aliphatic chain monoketone, which comprises the following steps of: reacting aliphatic chain monoketone with hydrazine hydrate to obtain hydrazone, and reacting hydrazone with a compound represented by formula 2 under a heating condition to complete hydrazone defluorination. The fluorinated product is widely applied to medicines, the reaction conditions are mild, and the process is simple.
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Paragraph 0086-0088
(2021/02/06)
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- Bench-Stable Electrophilic Fluorinating Reagents for Highly Selective Mono- and Difluorination of Silyl Enol Ethers
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Efficient methods for the synthesis of fluorinated compounds have been intensively studied, recently. Development of practical fluorinating reagents is indispensable for this purpose. Herein, bench-stable electrophilic fluorinating reagents were synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes. Reagents obtained by replacing one of the NFSI sulfonyl groups with an acyl group led to the highly selective monofluorination of silyl enol ethers with suppression of undesired overreaction, that is, difluorination. On the other hand, reagents bearing electron-withdrawing substituents at NFSI benzenesulfonyl groups efficiently facilitated the difluorination of silyl enol ethers under base-free conditions. Thus, both mono- and difluorinated target materials were prepared from the same substrate.
- Adachi, Akiya,Aikawa, Kohsuke,Ishibashi, Yuichiro,Nozaki, Kyoko,Okazoe, Takashi
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supporting information
p. 11919 - 11925
(2021/07/02)
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- Decarboxylative fluorination of β-Ketoacids with N-fluorobenzenesulfonimide (NFSI) for the synthesis of α-fluoroketones: Substrate scope and mechanistic investigation
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Cesium carbonate (Cs2CO3)-mediated decarboxylative fluorination of β-ketoacids using NFSI in the MeCN/H2O mixed solvent system affords α-fluoroketones with a broad scope. Both electron-rich and electron-deficient α-non-substituted β-ketoacids are amenable to this protocol. The mechanistic study indicates that the reaction proceeds through electrophilic fluorination followed by decarboxylation, which is different from the decarboxylative fluorination of normal carboxylic acids.
- Zhang, Rui,Ni, Chuanfa,He, Zhengbiao,Hu, Jinbo
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p. 166 - 172
(2017/09/18)
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- Palladium-Catalyzed Enantioselective α-Arylation of α-Fluoroketones
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The transition-metal-catalyzed α-arylation of carbonyl compounds is a widely practiced method for C-C bond formation. Several enantioselective versions of this process have been reported, but intermolecular, enantioselective coupling reactions of aryl electrophiles with α-fluoro carbonyl compounds have yet to be disclosed. We report enantioselective coupling of aryl and heteroaryl bromides and triflates with α-fluoroindanones catalyzed by palladium complexes of a BINOL-derived monophosphine and Segphos, respectively. The enolates were generated directly from α-fluoroindanones in the presence of potassium phosphate base during the reactions. We also report that reactions of α-fluorotetralones occur in high yields and enantioselectivities when conducted with enolates generated by elimination of trifluoroacetate from trifluoromethyl β-diketone hydrates. These reactions were catalyzed by palladium complexes of the commercially available bisphosphine Difluorphos. Thus, the formation of enantioenriched α-aryl-α-fluoroketones can be readily achieved by C-C bond formation when the appropriate palladium catalyst and α-fluoro enolate precursor were used.
- Jiao, Zhiwei,Beiger, Jason J.,Jin, Yushu,Ge, Shaozhong,Zhou, Jianrong Steve,Hartwig, John F.
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supporting information
p. 15980 - 15986
(2016/12/23)
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- Exploiting a Difference in Leaving Group Ability: An Approach to β-Substituted Monofluoroalkenes Using gem-Chlorofluoropropenes
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The superior nucleofuge character of chlorine over fluorine was taken advantage of in the selective SN2′ substitution reaction of gem-chlorofluoropropenes, allowing for the clean formation of β-substituted monofluoroalkenes under metal-free conditions. Numerous N-, S-, O-, and C-nucleophiles behaved nicely in this system. Further synthetic transformations of selected monofluoroalkenes were also accomplished.
- Hamel, Jean-Denys,Cloutier, Mélissa,Paquin, Jean-Fran?ois
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supporting information
p. 1852 - 1855
(2016/05/19)
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- Mild and selective α-fluorination of carbonyl compounds (ketones, 1,3-diketones, β-ketoesters, α-nitroketones, and β-ketonitriles) with Selectfluor (F-TEDA-BF4) in imidazolium ILs [BMIM/PF6 or BMIM/NTf2] with Br?nsted-acidic IL [PMIM(SO3H)/OTf] as promoter
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Structurally diverse ketones, 1,3-diketones, and β-ketoesters, were selectively monofluorinated with Selectfluor (F-TEDA-BF4) (1 equiv) in [BMIM][PF6] as solvent and [PMIM(SO3H)][OTf] as promoter under mild conditions. In selected cases, the monofluorinated products were transformed to the gem-difluoro derivatives by employing an additional equivalent of Selectfluor, and gem-difluoro-derivatives were synthesized directly from the substrates by employing 2 equiv of Selectfluor. The method was extended to monofluorination of representative α-nitroketones and β-ketonitriles using [BMIM][NTf2] without the need for promoters. The described method offers the added advantage of recycling and reuse of the IL solvent. (Chemical Equation Presented).
- Reddy, A. Srinivas,Laali, Kenneth K.
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supporting information
p. 5495 - 5499
(2015/09/21)
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- Hypervalent iodine-promoted α-fluorination of acetophenone derivatives with a triethylamine·hf complex
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The direct fluorination reaction of acetophenone using iodosylarenes and TEA·5HF was conducted under mild conditions except for use of a HF reagent. The fluorination reaction was applied to acetophenone derivatives, acetonaphthones, benzyl phenyl ketone, propiophenone, butyrophenone, 1-indanone, and phenacyl chloride, giving selectively the corresponding α-fluoroketone derivatives in good yields.
- Kitamura, Tsugio,Muta, Kensuke,Muta, Kazutaka
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p. 5842 - 5846
(2014/07/08)
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- Metal-free, efficient oxyfluorination of olefins for the synthesis of α-fluoroketones
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A novel oxyfluorination of olefin reactions has been developed. The reactions involve a metal-free and green catalytic system for the synthesis of α-fluoroketones which is an important building block for organic synthesis. Moreover, this reaction system exhibits great functional group tolerance.
- Yang, Qiang,Mao, Liu-Liang,Yang, Bin,Yang, Shang-Dong
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supporting information
p. 3460 - 3463
(2014/07/21)
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- Synthesis of α-fluoroketones and α-fluoroenones in aqueous media
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An efficient synthesis of α-fluoroketones via the nucleophilic fluorination of α-bromoketones in water with TBAF·3H2O as the fluorinating agent was developed in this paper. In addition, a simple and efficient synthesis of α-fluoroenones through the condensation of α-fluoroketones with aldehydes promoted by sodium hydroxide in water was also discovered.
- He, Yan,Zhang, Xinying,Shen, Nana,Fan, Xuesen
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- Effect of acid catalysis on the direct electrophilic fluorination of ketones, ketals, and enamides using Selectfluor
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The fluorination of ketones, ketals, and enamides has been achieved using the electrophilic fluorinating reagent Selectfluor (F-TEDA-BF 4). For the reactions of ketones and ketals the use of sulfuric acid (0.1 equiv) as an additive was found to facilitate the reaction leading to more rapid product formation. This behavior is analogous to the known effects of acid catalysis on the bromination of ketones. The reactions were generally quite selective leading to the formation of monofluorinated products, and could be accomplished on reaction scales up to 85 mmol using N-protected piperidone based substrates. Reactions in the presence of MeOH led to the formation of the corresponding fluoroketones or fluoroketals depending upon the substrate. The formation of the fluoroketals in this manner, as well as the fluorination of cyclic enamides are examples of multi-component coupling reactions.
- Liu, Jack,Chan, Johann,Bryant, Craig M.,Duspara, Petar A.,Lee, Ernest E.,Powell, David,Yang, Hua,Liu, Ziping,Walpole, Chris,Roberts, Edward,Batey, Robert A.
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experimental part
p. 2971 - 2975
(2012/07/28)
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- Fluorinated aromatic ketones as nucleophiles in the asymmetric organocatalytic formation of C-C and C-N bonds: A facile route to the construction of fluorinated quaternary stereogenic centers
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Highly enantioselective Mannich and α-amination reactions have been successfully developed using α-fluorinated aromatic ketones as fluorocarbon nucleophiles in the presence of a bicyclic chiral guanidine (see scheme; Ms=methanesulfonyl). This method is a
- Zhao, Yujun,Pan, Yuanhang,Liu, Hongjun,Yang, Yuanyong,Jiang, Zhiyong,Tan, Choon-Hong
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supporting information; experimental part
p. 3571 - 3574
(2011/05/05)
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- Towards greener fluorine organic chemistry: Direct electrophilic fluorination of carbonyl compounds in water and under solvent-free reaction conditions
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Selective and efficient fluorination of organic 1,3-dicarbonyl compounds was achieved using the electrophilic fluorinating reagents Selectfluor TM F-TEDA-BF4 (1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis-tetrafluoroborate) in aqueous medium or AccufluorTM NFSi (N-fluorobenzenesulfonimide) under solvent-free reaction conditions (SFRC). Under both reaction conditions cyclic 1,3-dicarbonyl compounds were transformed into 2-fluoro-substituted derivatives and acyclic analogues into 2,2-difluoro-substituted compounds, while the reactions of 1-trifluoromethyl-substituted 1,3-dicarbonyls in water resulted in the formation of 2,2-difluoro-3,3-dihydroxy-1-one derivatives. The reactivity of the starting material in water was found to be dependent on its enolizability, hydrophobic interactions and aggregate state at the reaction temperature. Reactions under SFRC proceeded in the molten eutectic phase of the reactants. The technique of competitive reactivity was used in order to evaluate and better understand the effects of reaction conditions on the course of these reactions.
- Stavber, Gaj,Stavber, Stojan
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scheme or table
p. 2838 - 2846
(2011/02/21)
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- Micellar-system-mediated direct fluorination of ketones in water
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A micellar system was developed and applied for direct regioselective fluorination of a variety of cyclic and acyclic ketones to α-fluoroketones in water as reaction medium with Selectfluor F-TEDA-BF4 as fluorinating reagent. The inexpensive ionic amphiphile sodium dodecyl sulfate (SDS) was found to be an excellent promoter for fluorofunctionalization of hydrophobic ketones without prior activation or use of acid catalysts. Georg Thieme Verlag Stuttgart.
- Stavber, Gaj,Zupan, Marko,Stavber, Stojan
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scheme or table
p. 589 - 594
(2009/07/09)
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- Solvent-free fluorination of organic compounds using N-F reagents
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Efficient fluorination of 1,3-dicarbonyl compounds, enol acetates of aromatic ketones, and activated aromatic compounds was achieved under solvent-free conditions using Selectfluor F-TEDA-BF4 or Accufluor NFSi.
- Stavber, Gaj,Zupan, Marko,Stavber, Stojan
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p. 2671 - 2673
(2008/02/03)
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- Chelation-controlled diastereoselective reduction of α-fluoroketones
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The effect of Ti-based Lewis acids on the reduction of α-fluoropropiophenone was examined to determine whether chelation control could be used to direct the diastereoselectivity of conversion to an α-fluoro alcohol. Pretreatment of α-fluoropropiophenone with TiCl4 followed by reduction with LiBH4 in diethyl ether or methylene chloride provided the syn diastereomer predominantly, while use of Ti(OiPr)4 under identical conditions provided the anti diastereomer as the major product. The products are consistent with a chelation-controlled mechanistic pathway in the former reduction and a nonchelation pathway in the latter case. Detailed 1H, 13C, and 19F NMR studies were consistent with chelation between TiCl4 and α-fluoropropiophenone under the reaction conditions utilized in this study. Reduction of other α-fluoroketones in the presence of TiCl4 also provided a high degree of diastereoselectivity in the conversion to α-fluoro alcohols, showing the generality of this approach. Copyright
- Mohanta, Pramod K.,Davis, Todd A.,Gooch, Jeremy R.,Flowers II, Robert A.
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p. 11896 - 11897
(2007/10/03)
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- Fluorination of ketones using iodotoluene difluoride
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Fluorination of ketones was achieved by the reaction of silyl enol ethers with iodotoluene difluoride in the presence of BF3·OEt 2 and a Et3N·HF complex. Georg Thieme Verlag Stuttgart.
- Sato, Saeko,Yoshida, Masanori,Hara, Shoji
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p. 2602 - 2605
(2007/10/03)
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- Selective and effective fluorination of organic compounds in water using selectfluor F-TEDA-BF4
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(Chemical Equation Presented) Selective and effective fluorination of various types of organic compounds performed in water as the reaction medium using 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF
- Stavber, Gaj,Zupan, Marko,Jereb, Marjan,Stavber, Stojan
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p. 4973 - 4976
(2007/10/03)
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- Tert-Butyl Hypofluorite - An Electrophilic tert-Butoxylation Agent
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tert-Butyl hypofluorite, t-BuOF, easily synthesized from Z-BuOH and F2, is a unique source of the novel electrophilic tert-butoxylium moiety t-BuO+. It was added to several benzylic double bonds to form vicinal fluoro-tert-butoxide derivatives. Not surprisingly, this bulky reagent is quite sensitive to steric hindrance. The process is electrophilic in nature, but since the reaction is relatively slow (20-60 min) formation of various radical species can take place, forming eventually several distinct byproducts. t-BuOF was also reacted with a number of enols, producing the corresponding α-tert-butoxy ketone derivatives in moderate to good yields. The best results were obtained with benzylic enol derivatives.
- Ben-David, Iris,Mishani, Eyal,Rozen, Shlomo
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p. 4632 - 4635
(2007/10/03)
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- High yield direct fluorofunctionalisation of ketones using accufluor - NFTh fluorinating reagent
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Direct regioselective conversion of a variety of cyclic and acyclic ketones to α-fluoroketones was achieved in high to excellent yield using 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) [Accufluor - NFTh] in acetonitrile solution. Copyright
- Stavber, Stojan,Zupan, Marko
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p. 3591 - 3594
(2007/10/03)
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- Solvent dependence of the synthesis and reactions of acetyl hypofluorite
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Acetyl hypofluorite (AcOF) has been previously prepared using CFCl3 (CFC-11) as a solvent.It was found that acetonitrile can replace trichlorofluoromethane without sacrificing the efficiency and the regio- and stereo-selectivity of the addition of AcOF to olefins.Most other solvents tested proved to be inadequqte for the synthesis of AcOF, despite the fact that fluorine does react with the dispersed sodium acetate present in the solvent.
- Rozen, Shlomo,Bareket, Yifat,Kol, Moshe
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p. 141 - 146
(2007/10/02)
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- Reaction of Xenon Difluoride with Indene in Aqueous 1,2-Dimethoxyethane and Tetrahydrofuran
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Xenon difluoride (XeF2) reacts with indene in 1,2-dimethoxyethane-water (90:10) to give cis- and trans-2-fluoro-1-hydroxyindans.Our data indicate that neither xenon oxide (XeO) nor hydroxyxenon fluoride (HOXeF) is an intermediate in this reaction even though XeO is a suspected intermediate from aqueous hydrolysis of XeF2.
- Shellhamer, Dale F.,Carter, David L.,Chiaco, Michael Chua,Harris, Tyler E.,Henderson, Rodney D.,et al.
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p. 401 - 403
(2007/10/02)
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- CHEMISTRY OF ORGANO HALOGENIC MOLECULES. PART 100. COMPARATIVE BEHAVIOUR OF XENON DIFLUORIDE AND CAESIUM FLUOROXYSULPHATE IN THE FLUORINATION OF ENOL ACETATES AND KETONES
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Xenon difluoride and caesium fluoroxysulphate reacted in methylene chloride or acetonitrile with various enol acetates, diketones, and ketones, yielding mainly α-fluoro ketones, the course of the reaction depending on the reagent and the structure of the organic molecule.Enol acetates from cycloalkanones were converted with caesium fluoroxysulphate to α-fluoroxycycloalkanones in high yield.Xenon difluoride and caesium fluoroxysulphate converted enol acetates of benzocycloalkanones-1 to α-fluorobenzocycloalkanones, while the reactivity of enol acetates of benzocycloalkanones-2 depended on the reagent used. 1,3-Diphenyl-propane-1,3-dione and its enol acetate were converted with XeF2 and CsSO4F to mono and difluoro substituted products, the course of the reaction being dependent on the reagent.Xenon difluoride converted 1-indanone to rearranged 2,2-difluorochromane, while caesium fluoroxysulphate reacted to 1-fluoro-2-indanone with 2-indanone.
- Stavber, Stojan,Sket, Boris,Zajc, Barbara,Zupan, Marko
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p. 6003 - 6010
(2007/10/02)
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- FURTHER STUDIES ON THE SYNTHESIS OF α-FLUORO CARBONYL COMPOUNDS
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The trimethylsilyl enol ethers of cycloalkanones and acid esters are converted in high yields (70-90percent) to the corresponding α-fluoro carbonyl derivative using XeF2 in CH2Cl2.Non-cyclic α-hydroxy ketones such as ethyl mandelate are efficiently transformed to the α-fluoro product by DAST and by Ishikawa's reagent.Nucleophilic displacement of halogen by fluoride failed in cyclic systems, giving instead, α,β-unsaturated ketones in DMF or CH3CN (18-crown-6) and 1,2-diones in DMSO, with KF acting as a base.Attempts at DMSO oxidation of I(Br)F adducts failed to give the α-fluoro ketones, but resulted in dehydrohalogenation to the trans-vinyl fluorides.
- Cantrell, Gary L.,Filler, Robert
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