- 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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Read Online
- HFIP-catalyzed direct dehydroxydifluoroalkylation of benzylic and allylic alcohols with difluoroenoxysilanes
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Hexafluoroisopropanol (HFIP)-catalyzed direct dehydroxydifluoroalkylation of benzylic and allylic alcohols with difluoroenoxysilanes is developed. This procedure enables the synthesis of a broad range of α,α-difluoroketones, a class of highly valuable intermediates and building blocks in medicinal and organic chemistry. Here, we have demonstrated for the first time that HFIP could act as a powerful catalyst for fluorinated carbon-carbon bond formation. The application of this protocol in late-stage dehydroxydifluoroalkylation of potentially bioactive drugs and natural products has also been carried out.
- Li, Jinshan,Xi, Wenxue,Zhong, Rong,Yang, Jianguo,Wang, Lei,Ding, Hanfeng,Wang, Zhiming
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Read Online
- Palladium-catalyzed one-pot construction of difluorinated 1,3-enynes from α,α,α-iododifluoroacetones and alkynes
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A palladium-catalyzed one-pot difunctionalization of alkynes with α,α,α-iododifluoroacetones is introduced for the synthesis of difluorinated 1,3-enynes. The reaction proceeds through the radical addition of RCOCF2 radical to alkynes and subseq
- Wang, Xing,Hu, Jian,Ren, Jie,Wu, Tianci,Wu, Jingjing,Wu, Fanhong
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Read Online
- Addition of trifluoromethyltrimethylsilane to acyl phosphonates: Synthesis of TMS-protected 1-alkyl-1-trifluoromethyl-1-hydroxy phosphonates and 1-aryldifluoroethenyl phosphates
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(Chemical Equation Presented) Addition reactions of nucleophilic CF 3TMS to acyl phosphonates were investigated. Various acyl phosphonates reacted readily with CF3TMS in the presence of K 2CO3 in DMF at rt to gi
- Demir, Ayhan S.,Eymur, Serkan
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Read Online
- Single electron transfer approaches to the practical synthesis of aromatic and heterocyclic-CF2H derivatives
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Single electron transfer (SET) approaches with organic reductants such as sodium hydroxymethanesulfinate (Rongalite), sodium dithionite (regarded as precursors of sulfoxylate radical anion) and tetrakis(dimethylamino)ethylene (TDAE) were employed for the reductive dehalogenation of a series of halogeno-difluoromethylated aromatics and heterocycles, and for the practical synthesis of the corresponding difluoromethylated derivatives.
- Dolbier Jr., William R,Médebielle, Maurice,Ait-Mohand, Samia
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Read Online
- Difluoromethylation reactions of ethyl pyruvate with the TDAE - A mild approach to the synthesis of 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric ethyl esters derivatives
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New 3,3-difluoro-2-hydroxy-2-methyl-4-oxo-butyric ethyl esters derivatives are easily obtained in moderate to good yields from the tetrakis(dimethylamino)ethylene (TDAE) mediated reduction of a series of RCF2X (X = Cl or Br) starting materials in the presence of ethyl pyruvate.
- Médebielle, Maurice,Kato, Katsuya,Dolbier Jr., William R.
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Read Online
- Direct Synthesis of Tri-/Difluoromethyl Ketones from Carboxylic Acids by Cross-Coupling with Acyloxyphosphonium Ions
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A simple and straightforward approach to the synthesis of trifluoromethyl and difluoromethyl ketones from widely available carboxylic acids is disclosed. The transformation utilizes an acyloxyphosphonium ion as the active electrophile, conveniently generated in situ from the carboxylic acid substrate by using commodity chemicals. The utility of the reaction system is exemplified by its chemoselectivity, with tolerance to a variety of important functional groups. The late-stage functionalization of carboxylic acid active pharmaceutical ingredients and pharmaceutically relevant compounds is also discussed.
- Ispizua-Rodriguez, Xanath,Munoz, Socrates B.,Krishnamurti, Vinayak,Mathew, Thomas,Prakash
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supporting information
p. 15908 - 15913
(2021/10/07)
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- Direct electrochemical hydrodefluorination of trifluoromethylketones enabled by non-protic conditions
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CF2H groups are unique due to the combination of their lipophilic and hydrogen bonding properties. The strength of H-bonding is determined by the group to which it is appended. Several functional groups have been explored in this context includ
- Atkins, Alexander P.,Box, John R.,Lennox, Alastair J. J.
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p. 10252 - 10258
(2021/08/12)
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- Trifluoromethylthiolation, Trifluoromethylation, and Arylation Reactions of Difluoro Enol Silyl Ethers
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This study reports a new application area of difluoro enol silyl ethers, which can be easily obtained from trifluoromethyl ketones. The main focus has been directed to the electrophilic fluoroalkylation and arylation methods. The trifluoromethylthiolation of difluoro enol silyl ethers can be used for the construction of a novel trifluoromethylthio-α,α-difluoroketone (-COCF2SCF3) functionality. The -CF2SCF3 moiety has interesting properties due to the electron-withdrawing, albeit lipophilic, character of the SCF3 group, which can be combined with the high electrophilicity of the difluoroketone motif. The methodology could also be extended to difluoro homologation of the trifluoromethyl ketones using the Togni reagent. In addition, we presented a method for transition-metal-free arylation of difluoro enol silyl ethers based on hypervalent iodines.
- Jiang, Xingguo,Meyer, Denise,Baran, Dominik,Cortés González, Miguel A.,Szabó, Kálmán J.
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p. 8311 - 8319
(2020/07/16)
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- Connecting remote C–H bond functionalization and decarboxylative coupling using simple amines
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Transition metal-catalysed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements ‘C–H activation’ strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general para-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of the reaction conditions. [Figure not available: see fulltext.].
- de Azambuja, Francisco,Yang, Ming-Hsiu,Feoktistova, Taisiia,Selvaraju, Manikandan,Brueckner, Alexander C.,Grove, Markas A.,Koley, Suvajit,Cheong, Paul Ha-Yeon,Altman, Ryan A.
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p. 489 - 496
(2020/03/23)
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- Switching Chemoselectivity: Using Mechanochemistry to Alter Reaction Kinetics
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A reaction manifold has been discovered in which the chemoselectivity can be altered by switching between neat milling and liquid assisted grinding (LAG) with polar additives. After investigation of the reaction mechanism, it has been established that this switching in reaction pathway is due to the neat mechanochemical conditions exhibiting different kinetics for a key step in the transformation. This proof of concept study demonstrates that mechanochemistry can be used to trap the kinetic product of a reaction. It is envisaged that, if this concept can be successfully applied to other transformations, novel synthetic processes could be discovered and known reaction pathways perturbed or diverted.
- Howard, Joseph L.,Brand, Michael C.,Browne, Duncan L.
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p. 16104 - 16108
(2018/11/23)
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- Divergent Reactivity of gem-Difluoro-enolates toward Nitrogen Electrophiles: Unorthodox Nitroso Aldol Reaction for Rapid Synthesis of α-Ketoamides
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An amination reaction of in situ generated gem-difluoro-enolates has been explored with electrophilic nitrogen sources. While their exposure to azodicarboxylates smoothly produced fluorinated α-amino ketones, reaction with nitrosoarenes (nitroso aldol rea
- Reddy, Mallu Kesava,Ramakrishna, Isai,Baidya, Mahiuddin
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p. 4610 - 4613
(2018/08/07)
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- Palladium-Catalyzed Benzodifluoroalkylation of Alkynes: A Route to Fluorine-Containing 1,1-Diarylethylenes
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A palladium(0)-catalyzed three-component reaction of 2-iodo-2,2-difluoroacetophenones, alkynes and arylboronic acids is introduced for the synthesis of 1-benzoyldifluoromethyl-2,2-diphenylethylenes in good yields and with excellent stereoselectivity. The
- Liang, Junqing,Huang, Guozhi,Peng, Peng,Zhang, Tianyu,Wu, Jingjing,Wu, Fanhong
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p. 2221 - 2227
(2018/04/17)
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- Translating solid state organic synthesis from a mixer mill to a continuous twin screw extruder
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A study on the translation of a solid-state synthetic reaction from a mechanochemical mixer-mill to a continuous twin-screw extruder is discussed herein. The study highlights some considerations to be made and parameters to be tested in the context of a model fluorination reaction, which is the first organic fluorination to be attempted using extrusion. Upon optimization, which features the first use of grinding auxiliary solids to enable effective synthetic extrusion, the difluorination reaction was successfully translated to the extruder, leading to a 100-fold improvement in Space Time Yield (STY); 29 kg m-3 day-1 in a mixer mill to 3395 kg m-3 day-1 in a twin screw extruder.
- Cao, Qun,Howard, Joseph L.,Crawford, Deborah E.,James, Stuart L.,Browne, Duncan L.
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supporting information
p. 4443 - 4447
(2018/10/17)
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- Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes
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The first catalytic asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes is described. The method, based on a rhodium-catalyzed cyclopropanation of difluoromethylated olefins, gives access to a broad range of cyclopropanes bearing ester, ketone, or nitro functional groups. By using Rh2((S)-BTPCP)4 as a catalyst, the corresponding products were obtained in high yields and high diastereo- and enantioselectivities (up 20:1 d.r. and 99 % ee). This methodology allowed preparation of enantioenriched difluoromethylcyclopropanes for the first time.
- Bos, Maxence,Huang, Wei-Sheng,Poisson, Thomas,Pannecoucke, Xavier,Charette, André B.,Jubault, Philippe
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supporting information
p. 13319 - 13323
(2017/10/17)
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- Lithium triethylborohydride-promoted generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones: An unprecedented utilization of lithium triethylborohydride
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Lithium triethylborohydride was found to promote the generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones, and applied to the synthesis of polyfluorinated β-hydroxy ketones via self-condensation or aldol reaction. The reaction indicate
- Peng, Peng,Wu, Jing-Jing,Liang, Jun-Qing,Zhang, Tian-Yu,Huang, Jin-Wen,Wu, Fan-Hong
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p. 56034 - 56037
(2017/12/26)
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- Synthesis of Difluoromethyl Ketones from Weinreb Amides, and Tandem Addition/Cyclization of o-Alkynylaryl Weinreb Amides
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[Difluoro(phenylsulfanyl)methyl]trimethylsilane (PhSCF2SiMe3) underwent a fluoride-induced nucleophilic addition to the carbonyl group of Weinreb amides to provide the corresponding difluoro(phenylsulfanyl)methyl ketones. These were
- Phetcharawetch, Jongkonporn,Betterley, Nolan M.,Soorukram, Darunee,Pohmakotr, Manat,Reutrakul, Vichai,Kuhakarn, Chutima
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p. 6840 - 6850
(2017/12/26)
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- Copper-catalysed difluoroalkylation of aromatic aldehydes via a decarboxylation/aldol reaction
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A copper-catalysed tandem decarboxylation/aldol reaction of simple aromatic aldehydes with 2,2-difluoro-3-oxo-3-arylpropanoic acid has been developed under mild conditions. This method provides a new route for the direct one-pot synthesis of difluorinated aldols in moderate to good yields from simple substrates.
- Yuan, Jin-Wei,Liu, Shuai-Nan,Mai, Wen-Peng
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p. 7654 - 7659
(2017/09/27)
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- Practical Access to Difluoromethyl Ketones via Straightforward Decarboxylative Difluorination of β-Ketoacids
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A facile synthetic approach to a series of difluoromethyl ketones from β-ketoacids has been described. This transformation is achieved through the straightforward decarboxylative difluorination of β-ketoacids in the absence of any catalyst. Furthermore, the resulted difluoromethyl ketones can be easily converted into corresponding difluoromethylated building blocks for pharmaceuticals and materials. (Figure presented.).
- Li, Yin-Long,Li, Jian,Deng, Jun
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p. 1407 - 1412
(2017/04/18)
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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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- Photoreductive transformation of fluorinated acetophenone derivatives on titanium dioxide: Defluorination vs. reduction of carbonyl group
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Photoreductive transformation of mono- and di-fluoromethyl acetophenone (AP) derivatives on the P25 titanium dioxide (TiO2) has been studied in deaerated ethanol solution under UV irradiation. 2-Monofluoromethyl AP (MFAP) was stable in the dark and existed as keto form in ethanol, whereas 64% of 2,2-difluoromethyl AP (DFAP) transformed into hemiketal form (photocatalytically inactive form) under the same condition. Under the UV irradiation with the TiO2 particles, the reduction of MFAP afforded only the defluorinated ketone, while the reduction of DFAP provided not only defluorinated ketones but also a hydrogenated alcohol. The reduction of carbonyl group and defluorination of DFAP concurrently occurred on TiO2, in which the formation of MFAP was observed as an intermediate of the sequential defluorinations. These two parallel reactions were initiated by electron transfer from the surface defect sites (Tisd) to DFAP adsorbed on the TiO2 surface. A possible reaction mechanism for DFAP is proposed and discussed on the basis of thermodynamic data upon the C-F bond cleavage of anion radical species generated during the photocatalysis.
- Kohtani, Shigeru,Kurokawa, Takuya,Yoshioka, Eito,Miyabe, Hideto
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- One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process
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Difluoromethyl ketones are an under-studied class of ketones which have great potential as useful building blocks for materials and drug design. Here we report a simple and convenient synthesis of this class of compounds via a one-pot difluorination/fragm
- Leng, Daniel J.,Black, Conor M.,Pattison, Graham
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supporting information
p. 1531 - 1535
(2016/02/10)
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- Synthesis of difluoroalkyl-γ-butyrolactones from iododifluoromethyl ketones and 4-pentenoic acids
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A convenient and efficient approach for difluoroalkyl-containing γ-butyrolactones via the radical addition reaction of iododifluoromethyl ketones with 4-pentenoic acids initiated by AIBN in CH3CN at 60 °C was reported. Various difluoroalkyl-containing δ-valerolactones were also synthesized under this reaction conditions.
- Wang, Jie-Xiong,Wu, Jing-Jing,Chen, Heng,Zhang, Shao-Wu,Wu, Fan-Hong
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p. 1381 - 1384
(2015/10/28)
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- Highly efficient "on water" catalyst-free nucleophilic addition reactions using difluoroenoxysilanes: Dramatic fluorine effects
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A remarkable fluorine effect on "on water" reactions is reported. The C-FaH-O interactions between suitably fluorinated nucleophiles and the hydrogen-bond network at the phase boundary of oil droplets enable the formation of a unique microstructure to facilitate on water catalyst-free reactions, which are difficult to realize using nonfluorinated substrates. Accordingly, a highly efficient on water, catalyst-free reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to the highly efficient synthesis of a variety of α,α- difluoro-β-hydroxy ketones and quaternary oxindoles. It's on! The C-FaH-O interactions between suitably fluorinated nucleophiles and a hydrogen-bond network at the phase boundary of an oil droplet facilitate "on water" catalyst-free reactions. Accordingly, the title reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to α,α-difluoro-β-hydroxy ketones and quaternary oxindoles.
- Yu, Jin-Sheng,Liu, Yun-Lin,Tang, Jing,Wang, Xin,Zhou, Jian
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supporting information
p. 9512 - 9516
(2014/10/15)
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- Formation of chiral fluoroalkyl products through copper-free enantioselective allylic alkylation catalyzed by an NHC ligand
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A valuable Cu-free protocol is reported where an NHC ligand has been employed to form quaternary carbon centers bearing fluoroalkyl units. The results obtained, from this allylic substitution, are better in terms of enantioselectivity and regioselectivity compared to the copper catalyzed system.
- Grassi, David,Li, Hailing,Alexakis, Alexandre
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p. 11404 - 11406
(2013/01/15)
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- A new entry for the oxidation of fluoroalkyl-substituted methanol derivatives: Scope and limitation of the organoiodine(V) reagent-catalyzed oxidation
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Oxidation of various fluoroalkyl-substituted methanol derivatives under the influence of a catalytic amount of sodium 2-iodobenzenesulfonate and Oxone in CH3CN or CH3NO2 was investigated in detail. The efficiency of the newly developed oxidation was also evaluated by comparison to other oxidations, such as Dess-Martin, PDC, and Swern oxidation.
- Tanaka, Yusuke,Ishihara, Takashi,Konno, Tsutomu
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experimental part
p. 99 - 104
(2012/05/07)
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- Fluoro-substituted ketones from nitriles using acidic and basic reaction conditions
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Fluoro-substituted aliphatic nitriles are shown to undergo the Houben-Hoesch reactions with arenes in CF3SO3H to give fluoro-substituted ketones in good yields. The fluorine substituents appear to enhance the reactivities of the nitriles (and the nitrilium ion intermediates) compared to similar aliphatic nitriles. Fluoro-substituted ketones are also shown to be accessible through the reactions of organometallic reagents and fluoro-substituted nitriles.
- Raja, Erum K.,Klumpp, Douglas A.
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supporting information; experimental part
p. 5170 - 5172
(2011/10/13)
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- Microwave assisted fluorination: an improved method for side chain fluorination of substituted 1-arylethanones
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A two-step, one-pot microwave (MW) assisted fluorination of 1-arylethanones to their corresponding 1-aryl-2-fluoroethanones has been developed. The first step utilises Selectfluor as a fluorinating agent in methanol forming 1-aryl-2-fluoroethanones and their corresponding dimethyl acetals. In the second step, water is added and Selectfluor acts as a Lewis acid in the hydrolytic cleavage of the dimethyl acetals. Compared to the thermal synthesis, the MW assisted method leads to a reduction in reaction time both in the fluorination and for the dimethyl acetal cleavage. Moreover, the one-pot procedure reduces reagent and solvent consumption. The method is best suited for the preparation of 1-aryl-2-fluoroethanones containing substituents that deactivates electrophilic aromatic substitution, however highly electron deficient ketones such as 1-(3,5-dinitrophenyl)ethanone reacts more slowly. Reactions using electron rich aromatic ketones had a low regioselectivity, and also produced fluoroaromatic products.
- Krane Thvedt, Thor H?kon,Fuglseth, Erik,Sundby, Eirik,Hoff, B?rd Helge
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experimental part
p. 9550 - 9556
(2010/02/27)
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- Pd-catalyzed arylation of silyl enol ethers of substituted α-fluoroketones
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α-Fluoro-α-aryl-ketones were synthesized by the Pd-catalyzed cross-coupling of aryl bromides with either α-fluoroketones or their corresponding silyl enol ethers. The direct arylation with an α-fluoroketone requires a strong base, such as potassium tert-b
- Guo, Yong,Twamley, Brendan,Shreeve, Jean'Ne M.
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experimental part
p. 1716 - 1722
(2009/06/28)
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- Trifluoromethylation of non-activated aldimines with trimethyl(trifluoromethyl)silane in the presence of tetramethylammonium fluoride: A closer look into the reaction route
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The reactions of non-activated aldimines with trimethyl(trifluoromethyl)silane and 1 equiv. of tetramethylammonium fluoride proceed via the formation of tetramethylammonium amides which were identified by low-temperature 19F NMR experiments. Consecutive reactions of the salts formed in situ with electrophiles yielded trifluoromethylated amines. Fluoride elimination is observed in the absence of electrophilic substrates leading to the formation of difluoromethylated ketimines.
- Kirij, Nataliya V.,Babadzhanova, Lesya A.,Movchun, Valeria N.,Yagupolskii, Yurii L.,Tyrra, Wieland,Naumann, Dieter,Fischer, Hendrik T.M.,Scherer, Harald
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- An efficient preparation of new sulfonyl fluorides and lithium sulfonates
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(Formula Presented) An efficient preparation of several polyfluoroalkanesulfonyl fluorides is reported. This method, based on the synthesis of polyfluoroalkyl trimethyl silanes (precursors of polyfluoroalkylsulfinates) as intermediates, allows the successive transformations to be carried out in one pot. Moreover, these sulfonyl fluorides can be obtained from the corresponding sulfinates by electrophilic fluorination. This original approach avoids isolation and purification of some thermally or hydrolytically unstable intermediates. A series of new sulfonyl fluorides have been thus prepared from halogenodifluoromethylated precursors RCF2X (X = F, Br; R = ArC(O), ArS(O)n(CF2) m; n = 0, 1, 2; m = 1, 2) and have been transformed into the corresponding lithium sulfonates, which have potential applications as electrolytes for lithium batteries.
- Toulgoat, Fabien,Langlois, Bernard R.,Medebielle, Maurice,Sanchez, Jean-Yves
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p. 9046 - 9052
(2008/03/27)
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- One-pot synthesis of α,α-difluoroimines from alkynes through tandem catalytic diboration/fluorination/imination reaction
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Tandem catalytic diboration/fluorination/imination of arylacetylenes leads to the formation of α,α-difluoroimines, where the adjacent C{double bond, long}N and C-F2 bonds are formed simultaneously. The convenient one-pot protocol involves a Pt(0)-catalyzed diboration of terminal or internal arylalkynes followed by electrophilic fluorination with Selectfluor in the presence of primary amines and a dehydrating agent. A plausible mechanism for the three consecutive steps (diboration/fluorination/imination) is suggested in accordance with the electronic properties of the substrates. Alkynes/catalytic diboration/alkenyl diboronate esters/Selectfluor/electrophilic fluorination/α,α-difluoroimines.
- Ramírez, Jesús,Fernández, Elena
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p. 3841 - 3845
(2008/02/07)
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- Efficient synthesis of α,α-difluoro ketones using selectfluor F-TEDA-BF4
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Selective and efficient synthesis of α,α-difluoro ketones was achieved following a protocol which includes the transformation of α-methylene ketones to the corresponding n-butylimine derivatives and their further treatment with Selectfluor F-TEDA-BF4
- Pravst, Igor,Zupan, Marko,Stavber, Stojan
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p. 3140 - 3146
(2007/10/03)
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- Reactions of enamines with selectfluor: A straightforward route to difluorinated carbonyl compounds
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Reactions of enamines, preformed from β-dicarbonyl and monocarbonyl compounds, with Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoroborate) under mild conditions (triethylamine (TEA) or molecular sieves) easily led to the corresponding difluorinated carbonyl compounds in high yields.
- Peng, Weimin,Shreeve, Jean'ne M.
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p. 5760 - 5763
(2007/10/03)
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- Convenient synthesis of α,α-difluorinated carbonyl compounds from alkynes through a fluoro-deboronation process
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Catalytic diboration of alkynes towards alkenyl diboronates provides suitable intermediates that can be converted into α-fluorinated and α,α-difluorinated carbonyl compounds via electrophilic fluorination with Selectfluor. Georg Thieme Verlag Stuttgart.
- Ramirez, Jesus,Fernandez, Elena
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p. 1698 - 1700
(2007/10/03)
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- Facile preparation of di- and monofluoromethyl ketones from trifluoromethyl ketones via fluorinated enol silyl ethers
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Di- and monofluoromethyl ketones were prepared from the readily available trifluoromethyl ketones in high yields. Magnesium metal mediated reductive defluorination readily generates fluorinated enol silyl ethers, which upon fluoride or acid assisted hydrolysis give the respective ketones in good to excellent yields.
- Surya Prakash,Hu,Olah
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p. 357 - 362
(2007/10/03)
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- The reduction of α-silyloxy ketones using phenyldimethylsilyllithium
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Phenyldimethylsilyllithium reacts with acyloin silyl ethers RCH(OSiMe3)COR 8 to give regiodefined silyl enol ethers RCH=C(OSiMe2Ph)R 9, and hence by hydrolysis ketones RCH2COR 10. The yields can be high but are usually moderate. The mechanism of this reduction is established to involve a Brook rearrangement (Scheme 6) rather than a Peterson elimination (Scheme 1). Although the mechanism appears to be the same in each case, the stereochemistries of the silyl enol ethers 9 are opposite in sense in the aromatic series (R = Ph, Scheme 7) and the aliphatic series (R = cyclohexyl, Scheme 8), with the major aromatic silyl enol ether being the thermodynamically less stable isomer E-PhCH=C(OSiMe2Ph)Ph E-9aa, and the major aliphatic silyl enol ether being the thermodynamically more stable isomer Z-c-C6H11CH= C(OSiMe2Ph)-c-C6H11 Z-9ba. This is a consequence of anomalous anti-Felkin attack in the aromatic series. The reaction with the silyl ether ButCH(OSiMe3)COPh 13b is normal in giving Z-ButCH= C(OSiMe2Ph)Ph Z-38 (Scheme 11), but reduction of the silyl ether 8a with lithium aluminium hydride is also anti-Felkin giving with high selectivity the meso diol PhCH(OH)CH(OH)Ph 39. The reaction between Phenyldimethylsilyllithium and the acyloin silyl ether 8d (R = But) does not give the ketone ButCH2COBut, but gives instead the anti-Felkin meso diol ButCHOHCHOHBut 40 also with high selectivity (Scheme 12). Silyllithium and some related reagents react with trifluoromethyl ketones 46 and 48 to give α,α-difluoro silyl enol ethers 47 and 49 (Scheme 14).
- Fleming, Ian,Roberts, Richard S.,Smith, Stephen C.
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p. 1215 - 1228
(2007/10/03)
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- Preparation of 2,2-difluoroenol silyl ethers by electroreductive defluorination of trifluoromethyl ketones
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2,2-Difluoroenol silyl ethers (5) were prepared by electroreductive defluorination of trifluoromethyl ketones (4) in the presence of chlorotrialsilanes (TMSCl, TESCl, TBDMSCl).
- Uneyama, Kenji,Maeda, Kazushige,Kato, Tsuyoshi,Katagiri, Toshimasa
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p. 3741 - 3744
(2007/10/03)
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- Study on the effect of di- and trifluoromethyl groups on the Baeyer-Villiger reaction
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Case studies of the Baeyer-Villiger reaction applied to di-and trifluoromethylketone derivatives and the effect of the fluoromethyl groups on the Baeyer-Villiger reaction, are described.
- Kitazume, Tomoya,Kataoka, Junichi
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p. 157 - 158
(2007/10/03)
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- N-Fluoro-bis[(trifluoromethyl)sulfonyl]imide: Electrophilic fluorination of imines and some methyl-substituted pyridines
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Direct fluorination of imines with N-fluoro-bis[(trifluoromethyl)sulfonyl]imide 1 afforded mono and/or difluoroketones without the need of a strong base to first generate the imine anions. Structurally related 2- and 4-methyl-substituted pyridines gave the respective fluoromethyl pyridines with 1. Our results suggest that an enamine intermediate plays a key role in these reactions.
- Ying,DesMarteau,Gotoh
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- Synthesis of α,α-Difluoro-Functionalized Ketones
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In the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium , iododifluoromethyl alkyl and phenyl ketones 1 react with alkenes to give the corresponding α,α-difluoro-γ-iodo ketones in high yields at room temperature either neat or in hexane at 60 deg C.A variety of functional groups, such as alkyl, trimethylsilyl, hydroxy, epoxy, ketone, and ester, are tolerated under the reaction conditions.The reaction can be completely suppressed by a radical inhibitor, di-tert-butyl nitroxide or hydroquinone.A ring closure reaction occurs when 1 reacts with diethyl diallylmalonate in the presence of a catalytic amount of Pd(PPh3)4.Under UV irradiation, the reaction of 1 with diallyl ether gives a tetrahydrofuran derivative.All these results are consistent with a radical chain mechanism initiated by single electron transfer from Pd(PPh3)4 to 1.In the presence of a catalytic amount of nickel dichloride hexahydrate, the iodine in the 1:1 addition adducts is readily reduced by zinc in moist THF under mild conditions to give the corresponding α,α-difluoro ketones in high yields.A one-pot addition-reduction reaction has been developed for the synthesis of α,α-difluoroketones without the isolation of the 1:1 addition adducts, which provides a new, efficient, and practical method for the preparation of a variety of α,α-difluorofunctionalized ketones.
- Qiu, Zai-Ming,Burton, Donald J.
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p. 5570 - 5578
(2007/10/03)
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- Synthesis of γ-(Electron-withdrawing group)-Substituted α,α-Difluoro Ketones by UV-Initiated Addition of Iododifluoromethyl Ketones with Electron-Deficient Alkenes
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Under UV irradiation (254 nm), iododifluoromethyl phenyl, alkyl, and chlorodifluoromethyl ketones were reacted with a series of alkyl acrylates (CH2=CHCO2R', R': Et, n-Bu, t-Bu, and Me), N,N-dimethylacrylamide, acrylonitrile, and vinyl methyl ketone in the absence of solvent at ambient temperature.High yields of the corresponding 1:1 addition products were obtained when 1 reacted with ethyl acrylates (50-79percent).The reaction of 1a with n-butyl acrylate gave a similar 1:1 adduct (51percent).However, an addition-reduction product, PhC(O)CF2CH2CH2CO2H, was isolated in 44percent yield when tert-butyl acrylate was reacted wit 1a.More interestingly, both 1:1 and 1:2 adducts were formed in a 1.3:1 ratio when 1a was reacted with methyl acrylate under similar conditions, which indicated that the ester group exhibited an important effect on reaction selectivity.In the reaction with 1a, ethyl and methyl acrylates also displayed significantly higher reactivity than that of n- or tert-butyl acrylates. 1 also reacted with N,N-dimethylacrylamide to afford high yields of the 1:1 adducts.However, telomeric products were obtained in the reaction of 1a with acrylonitrile, and the 1:1 and pure 1:2 addition products were isolated in low yield.The reaction of acrylonitrile with alkyl-substituted iododifluoromethyl ketone, 1b, gave only the reduced product, n-C4H9C(O)CF2H, under similar conditions.With vinyl methyl ketone, the reaction of 1a produced an addition-reduction product, PhC(O)CF2CH2CH2C(O)Me, in 50percent yield.The reactivity of RC(O)CF2I (1) varied with the substituted R groups in the reaction with ethyl acrylate and N,N-dimethylacrylamide: R, ClCF2 > Ph > n-C4H9 > n-C6H13.Correspondingly, the reaction of 1a with ethyl acrylate generated a polymer in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium.Treatment of the adducts with zinc in the presence of a catalytic amount of NiCl2*6H2O in moist THF afforded the corresponding γ-(electron-withdrawing group)-substituted α,α-difluoro ketones in high yields.
- Qiu, Zai-Ming,Burton, Donald J.
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p. 6798 - 6805
(2007/10/03)
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- UV Initiated Addition of Iododifluoromethyl Ketones to Electron-Deficient Olefins
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Under UV irradiation, iododifluoromethyl ketones reacted with electron-deficient olefins in the absence of solvent to give high yields of the 1:1 adducts, providing a useful method for the synthesis of α,α-difluoro-γ-(electron-withdrawing-group) substitut
- Qiu, Zai-Ming,Burton, Donald J.
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p. 1813 - 1816
(2007/10/02)
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- Selective Reductions. 53. Asymmetric Reduction of α-Fluoromethyl Ketones with B-Chlorodiisopinocampheylborane or B-Isopinocampheyl-9-borabicyclononane. Combined Electronic and Steric Contributions to the Enantiocontrol Process
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A systematic study of the asymmetric reduction of aryl and alkyl α-fluoroalkyl ketones with (-)-diisopinocampheylchloroborane ((-)-DIP-Chloride, 1) and (-)-B-isopinocampheyl-9-borabicyclononane (R-Alpine-Borane, 2) has been made.In the case of reagent 1, the direction of asymmetric induction in the chiral reduction of aryl trifluoromethyl ketones differs from that of the corresponding mono- and difluoromethyl ketones.For example, while 2-fluoro, and 2,2-difluoroacetophenones are reduced with 1 to the R-alcohols in 95percent and 85percent ee, respectively, 2,2,2-trifluoroacetophenone is reduced, under neat conditions at room temperature, to the S-alcohol in 90percent ee.Though DIP-Chloride reduces unhindered prochiral dialkyl ketones in poor ee, alkyl α-fluoroalkyl ketones are reduced in improved ee depending on the number of α-fluorine atoms present in the ketone.While monofluoromethyl ketones provide moderate ee in the R-isomer, the di- and trifluoromethyl ketones are reduced in moderate to excellent ee in the opposite isomer.For example, 1-fluoro-2-octanone is reduced in 40percent ee (R), whereas 1,1-difluoro- and 1,1,1-trifluoro-2-octanone are reduced in 32percent (S), and 91percent ee (S), respectively.In the case of the asymmetric reduction of the above series of ketones with 2, the results are different.There is no change in the direction of chiral induction in the reduction of α-fluoroacetophenones with 2. 2-Fluoroacetophenone and 2,2-difluoroacetophenone are reduced with 2 to the R-alcohol in 89percent and 97percent ee, respectively.The reaction of 2,2,2-trifluoroacetophenone is very slow, only 90percent complete in 45 d, and provides the R-alcohol in 32percent ee.In contrast, while 1-fluoro- and 1,1-difluoro-2-octanone are reduced by 2 in 65percent (R) and 50percent ee (R), respectively, 1,1,1-trifluoro-2-octanone is reduced in 60percent ee (S), raising the question of which factors other than the steric size of the trifluoromethyl group, control the enantioselectivity of these reductions.The effect of steric versus electronic influence in such chiral reductions is discussed.
- Ramachandran, P. Veeraraghavan,Teodorovic, Aleksandar V.,Gong, Baoqing,Brown, Herbert C.
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p. 1075 - 1086
(2007/10/02)
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- A microbially-based approach for the synthesis of chiral secondary alcohols bearing the difluoromethyl or chlorodifluoromethyl group
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A synthetic approach to both enantiomers of the secondary alcohols , involving the stereoselective hydrolysis of ester derivatives, is described.The absolute configurations of these difluoromethylated or chlorodifluoromethylated molecules were determined.
- Kitazume, Tomoya,Asai, Masatomo,Tsukamoto, Takashi,Yamazaki, Takashi
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p. 271 - 284
(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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- MECHANISMS OF FREE-RADICAL REACTIONS. XX. REACTIVITY IN THE FREE-RADICAL HALOGENATION REACTIONS OF ARYLFLUOROALKANES
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The free-radical chlorination and bromination of meta- and para-substituted benzyl fluorides and 1,1-difluoro-2-phenylethane and also the chlorination of 1-fluoro-2-arylethanes by phenylchloroiodonium chloride and the bromination of meta- and para-substituted benzyl bromides were studied by the method of competing reactions.In all cases a good correlation is observed between log krel and the Brown ?+ constants.In cases where change in the reactivity in the transition from one reaction series to another is due mainly to the polar effect of the substituent whilethe selectivity is measured in relation to the polar effect direct relationships are observed between the reactivity and the selectivity.
- Dneprovskii, A. S.,Eliseenkov, E. V.
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p. 711 - 719
(2007/10/02)
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- Photoreactivity of α-Fluorinated Phenyl Alkyl Ketones
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The photoreactivities of the mono-, di-, and tri-α-fluorinated acetophenones have been compared to that of acetophenone itself.All four ketones have similar triplet excitation energies; the three fluorinated ketones have reduction potentials 0.5-0.7 eV lower than that of acetophenone.Triplet reactivity toward alkylbenzenes keeps increasing with fluorine substitution, Since the rate-determining step becomes charge-transfer complexation as the ketone reduction potential decreases.The primary/tertiary C-H selectivity toward p-cymene increases with the number of fluorines.Triplet reactivity toward cyclopentane also is increased by fluorination but peaks at two fluorines, since the lowest triplet switches from n,?* to ?,?* with two or three fluorines and ?,?*triplets are unreactive in simple hydrogen atom abstraction.In contrast, α-fluorination of valerophenone does not significantly increase the rate of triplet γ-hydrogen abstraction.The inductive effect on reactivity apparently is offset by a conformational effect.Th α-fluorinated phenones give predominantly cyclobuthanols instead of Norrish type II elimination. α-fluoroacetophenone forms predominantly acetophenone and HF when irradiated with 2-propanol, in what appears a short chain process involving electron transfer to ketone followed by fluoride ion loss.Finally, the radical coupling products in these reactions are formed in varying yields, depending on solvent and additives.It is suggested that radical solvation can affect radical coupling rates sufficiently to prevent statistical ratios of cross-coupling and homo-coupling.
- Wagner, Peter J.,Thomas, Michael J.,Puchalski, Allen E.
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p. 7739 - 7744
(2007/10/02)
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