- Enolization rates control mono-: Versus di-fluorination of 1,3-dicarbonyl derivatives
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Fluorine-containing 1,3-dicarbonyl derivatives are essential building blocks for drug discovery and manufacture. To understand the factors that determine selectivity between mono- and di-fluorination of 1,3-dicarbonyl systems, we have performed kinetic studies of keto-enol tautomerism and fluorination processes. Photoketonization of 1,3-diaryl-1,3-dicarbonyl derivatives and their 2-fluoro analogues is coupled with relaxation kinetics to determine enolization rates. Reaction additives such as water accelerate enolization processes, especially of 2-fluoro-1,3-dicarbonyl systems. Kinetic studies of enol fluorination with Selectfluor and NFSI reveal the quantitative effects of 2-fluorination upon enol nucleophilicity towards reagents of markedly different electrophilicity. Our findings have important implications for the synthesis of α,α-difluoroketonic compounds, providing valuable quantitative information to aid in the design of fluorination and difluorination reactions.
- Rozatian, Neshat,Beeby, Andrew,Ashworth, Ian W.,Sandford, Graham,Hodgson, David R.W.
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p. 10318 - 10330
(2019/11/20)
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- Chemoselective Mono- And Difluorination of 1,3-Dicarbonyl Compounds
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By altering the amount of Selectfluor, the highly selective mono- and difluorination of 1,3-dicarbonyl compounds has been achieved, affording a variety of 2-fluoro- and 2,2-difluoro-1,3-dicarbonyl compounds in good to excellent yields. The reaction can be readily performed in aqueous media without any catalyst and base, which features practical and convenient fluorination. Importantly, a gram-scale reaction, transformation of 2-fluoro-1,3-diphenylpropane-1,3-dione to 4-fluoro-1,3,5-triphenyl-1H-pyrazole, and chlorination and bromination of 1,3-dicarbonyl compounds are realized to further exhibit its synthetic utility.
- Cui, Ying,Jiao, Jingchao,Ma, Xiantao,Rao, Weihao,Tang, Lin,Yang, Zhen,Zhou, Qiuju,Zhou, Yuqiang,Zou, Guodong
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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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- 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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supporting information
p. 16104 - 16108
(2018/11/23)
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- SelectfluorTMon a PolyHIPE Material as Regenerative and Reusable Polymer-Supported Electrophilic Fluorinating Agent
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The first recyclable polymer-supported electrophilic fluorinating agent was prepared by reaction of molecular fluorine with the triethylenediamine motif that is grafted onto a poly(4-vinylbenzyl chloride-co-divinylbenzene) polyHIPE material. The resulting
- Kawada, Kosuke,Okano, Koji,Iskra, Jernej,Krajnc, Peter,Cahard, Dominique
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supporting information
p. 584 - 589
(2017/02/23)
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- Controlling reactivity through liquid assisted grinding: The curious case of mechanochemical fluorination
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We have identified an example of a mechanochemically milled organic reaction where liquid-assisted grinding controls the selectivity, such a phenomenon has not been reported/observed before. It was found that upon milling dibenzoylmethane with Selectfluor in the absence of any solvent, a 3:1 ratio of monofluorinated:difluorinated product was observed. Whereas, addition of 0.125 mL of acetonitrile (~10% of the total volume of materials present) to the ground reaction mixture afforded 50:1 selectivity. Furthermore, this phenomenon is applicable to a small range of diketone substrates thus far explored. Additionally, we have demonstrated that difluorination can be achieved by simply switching from adding acetonitrile to addition of sodium carbonate. Most notable, in the latter case, is the reduced reaction time compared to a conventional solvent approach, 2 hours in the mill and 24 hours in the flask.
- Howard, Joseph L.,Sagatov, Yerbol,Repusseau, Laura,Schotten, Christiane,Browne, Duncan L.
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supporting information
p. 2798 - 2802
(2017/07/24)
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- A Route to α-Fluoroalkyl Sulfides from α-Fluorodiaroylmethanes
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α,α-Difluorodiaroylmethane can be used as a nucleophilic difluoromethylation reagent for generating α-thioaryl-α,α-difluoroacetophenones (Ar1COCF2SAr) and difluoromethylthiolated arenes (ArSCF2H) under transition-metal-free conditions. The reaction selectivity is mainly dependent on temperature. The method has also been extended to the synthesis of α-thioaryl-α-monofluoroacetophenones using α-monofluorodibenzoylmethane. Moreover, the benzoyl cation derived from α,α-difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a one-pot process.
- Lin, Ya-Mei,Yi, Wen-Bin,Shen, Wan-Zhao,Lu, Guo-Ping
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supporting information
p. 592 - 595
(2016/02/18)
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- 2,2-Difluoro-1,3-diketones as gem-Difluoroenolate Precusors for Asymmetric Aldol Addition with N-Benzylisatins
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2,2-Difluoro-1,3-diketones are introduced as gem-difluoroenolate precursors for the first example of an organocatalytic asymmetric aldol addition with N-benzylisatins to form 3-difluoroalkyl-3-hydroxyoxindoles. (Figure presented.).
- Qian, Jinlong,Yi, Wenbin,Huang, Xin,Jasinski, Jerry P.,Zhang, Wei
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p. 2811 - 2816
(2016/09/13)
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- Apparent electrophilic fluorination of 1,3-dicarbonyl compounds using nucleophilic fluoride mediated by PhI(OAc)2
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The apparent electrophilic fluorination of 1,3-dicarbonyl compounds using Et3N·3HF as a nucleophilic fluoride source is reported. This reaction requires PhI(OAc)2 as oxidant and can be conducted safely in standard laboratory glassware. Alternative selectivity compared to Selectfluor was observed in some cases. This approach may reduce our reliance on difficult-to-handle fluorine gas and expensive electrophilic fluorinating agents derived from elemental fluorine. Mechanistic analysis related to the active fluorinating species and fluoride/acetate exchange is presented. The apparent electrophilic fluorination of 1,3-dicarbonyl compounds using Et3N·3HF mediated by the in-situ formation of PhIF2 from PhI(OAc)2 is reported. This can be performed safely in standard laboratory glassware, and this approach may reduce our reliance on difficult-to-handle fluorine gas and expensive electrophilic fluorinating agents derived from elemental fluorine.
- Nash, Toby J.,Pattison, Graham
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supporting information
p. 3779 - 3786
(2015/06/16)
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- Preparation of iodonium ylides: Probing the fluorination of 1,3-dicarbonyl compounds with a fluoroiodane
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The isolation of iodonium ylide 8, from the reaction of fluoroiodane 1 with ethyl 3-oxo-3-phenylpropanoate 5 in the presence of potassium fluoride, provides strong evidence that 1,3-dicarbonyl compounds undergo an addition reaction with fluoroiodane 1 to form an iodonium intermediate which can be deprotonated to generate an iodonium ylide. In the presence of TREAT-HF, however, the iodonium intermediate reacts to form the 2-fluoro-1,3-dicarbonyl product and we propose that fluoroiodane 1 simulates electrophilic fluorination via an addition/substitution mechanism. Further evidence to support this mechanism was obtained by successfully reacting the isolated iodonium ylide 8 with TREAT-HF, hydrochloric acid, acetic acid and p-toluenesulfonic acid to form the 2-fluoro-, 2-chloro-, 2-acetyl- and 2-tosyl-1,3-ketoesters respectively. This journal is
- Geary, Gemma C.,Hope, Eric G.,Singh, Kuldip,Stuart, Alison M.
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p. 16501 - 16506
(2015/03/04)
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- Electrophilic fluorination using a hypervalent iodine reagent derived from fluoride
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The air and moisture stable fluoroiodane 8, readily prepared on a 6 g scale by nucleophilic fluorination of the hydroxyiodane 7 with TREAT-HF, has been used as an electrophilic fluorinating reagent for the first time to monofluorinate 1,3-ketoesters and d
- Geary, Gemma C.,Hope, Eric G.,Singh, Kuldip,Stuart, Alison M.
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p. 9263 - 9265
(2013/10/01)
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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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supporting information; experimental part
p. 2838 - 2846
(2011/02/21)
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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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- Microwave-assisted rapid electrophilic fluorination of 1,3-dicarbonyl derivatives with Selectfluor
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A microwave-assisted fluorination method for 1,3-dicarbonyl compounds using Selectfluor has been developed. 2-Monofluorinated products can be obtained in high yield in neutral reaction conditions with addition of 1 eq. of Selectfluor. Treatment of 1,3-dicarbonyls with 3 eq. of Selectfluor in the presence of tetrabutylammonium hydroxide (TBAH) as the base results in the formation of 2,2-difluorinated derivatives only.
- Xiao, Ji-Chang,Shreeve, Jean'ne M.
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p. 475 - 478
(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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- 1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate): An electrophilic fluorinating agent
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1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), NFTh, is a electrophilic fluorinating that can be used to fluorinate aromatic rings, olefins, dienol acetates and enol ethers. When NFTh is reacted with an active methylene compound in the presence of ZnCl2, the corresponding mono- or di-fluoro derivative can be isolated.
- Poss, Andrew J.,Shia, George A.
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p. 2673 - 2676
(2007/10/03)
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- Electrochemical fluorination of β-dicarbonyl compounds using p-iodotoluene difluoride as a mediator
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The selective and direct introduction of the fluorine atom into the α-position of β-dicarbonyl compounds was electrochemically achieved using iodotoluene difluoride as the mediator. The resulting α-fluoro-β-dicarbonyl compounds are important building blocks for biologically active compounds.
- Hara, Shoji,Hatakeyama, Tsuyoshi,Chen, Sheng-Qi,Ishi-I, Kenji,Yoshida, Masanori,Sawaguchi, Masanori,Fukuhara, Tsuyoshi,Yoneda, Norihiko
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p. 189 - 192
(2007/10/03)
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- Synthesis, Properties, and Reactivity of N,N'-Difluorobipyridinium and Related Salts and Their Applications as Reactive and Easy-To-Handle Electrophilic Fluorinating Agents with High Effective Fluorine Content
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N,N′-Difluoro-2,2′-, -2,4′-, -3,3′-, -4,4′-bipyridinium and substituted N,N′-difluoro-2,2′-bipyridinmm bis(triflates), bis(tetrafluoroborates), bis(hexafluorophosphates), and bis(hexafluoroantimonates) 1-9 were synthesized in high yields by the direct fluorination of a mixture of a bipyridyl and a Lewis acid, a Br?nsted acid, or the alkali metal salt of an acid. The higher homologues, trimer 10 and polymer 11, were also synthesized. Unsubstituted or electron-donating group-substituted N,N′- difluorobipyridinium salts are stable nonhygroscopic crystals, while the electron-withdrawing group- substituted N,N′-diflurobipyridinium salts 3, 5, and 6 are moisture-sensitive crystals. Hydrolysis of 1b in boiling water gave 3,3′-dihydroxy-2,2′-bipyridyl. The reactivity determination indicated that the fluorinating capability decreased in the order 2,2′- ? 2,4' > 3,3′- ≈ 4,4′-isomer ? N-fluoropyridinium salt and that the two N-F moieties in a molecule were effective for fluorination. This fluorination occurred in a step-by-step manner, and the reactivity difference between the first and second fluorinations was very small. N,N′-Difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (1b) is thus shown to be a highly reactive and easy-to-handle electrophilic fluorinating agent with the high effective fluorine content (103.3 g/kg) for preparing many fluoro organic compounds.
- Umemoto, Teruo,Nagayoshi, Masayuki,Adachi, Kenji,Tomizawa, Ginjiro
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p. 3379 - 3385
(2007/10/03)
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- Selective, Electrophilic Fluorinations Using N-Fluoro-o-benzenedisulfonimide
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The synthesis of N-fluoro-o-benzenedisulfonimide (NFOBS, 2) and its use as an "electrophilic" fluorinating reagent with nucleophilic substrates is described and compared with that of N-fluorobenzenesulfonimide (NFSi, 3).NFOBS (2) is prepared in three steps in 81percent overall yield from commercially available o-benzenedisulfonic acid (4) and involves treatment of o-benzenedisulfonimide (6) with dilute fluorine (10percent F2/N2).Reaction of 2 with metal enolates, silyl enol ethers, and 1,3-dicarbonyl compounds affords the corresponding α-fluoro compounds in yields up to 95percent, with good control of mono- and difluorination.Fluorination of ortho-metalated aromatic compounds was achieved in modest to good yields (10-80percent).While the reactivities of 2 and 3 are similar, better yields were observed with the former reagent in the fluorination of metal enolates, Grignard and lithium reagents, while 3 gave better results with the ortho-lithiated aromatic substrates.The available evidence suggests an SN2-type mechanism for the fluorination of nucleophilic substrates by these reagents.
- Davis, Franklin A.,Han, Wei,Murphy, Christopher K.
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p. 4730 - 4737
(2007/10/02)
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- Highly Selective Fluorinating Agents: A Counteranion-Bound N-Fluoropyridinium Salt System
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A series of alkyl- or (trifluoromethyl)-substituted N-fluoropyridinium-2-sulfonates 2a-h, differing in fluotinating power, were synthesized, and assessment was made of the effectiveness of each selective fluorinating agent.N-Fluoropyridinium-3- and -4-sulfonates 3 and 4 were also synthesized.Power-variables 2a-h were found to be highly selective fluorinating agents for a wide range of nucleophilic substrates such as activated aromatics, enol trialkylsilyl and alkyl ethers, active methylene compounds, activated olefins, and sulfides.Thus, phenol, naphthol, phenylurethane, and the trimethylsilyl ether of phenol were exclusively or highly selectively fluorinated at the o-position with 2f-h.Conjugated enol trialkylsilyl ethers of a steroid were regioselectively fluorinated at the 6-position with moderately powerful 2b-e.This regioselectivity increased with the bulkiness of the silyl part, and with the most bulky triisopropylsilyl group exclusive 6-fluorination was achieved.Preferential β-stereoselective fluorination at the 6-position was observed.N-Fluoropyridinium-2-sulfonates were activated with an acid.This acid-catalyzed fluorination led to the preferential p-fluorination of anisole.The present results can be explained based on the capacity of the 2-sulfonate anion to interact with the hydroxy group of phenol or naphthol, NH group of phenylurethane, silicon atoms of silyl ethers, or protons of acids.
- Umemoto, Teruo,Tomizawa, Ginjiro
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p. 6563 - 6570
(2007/10/03)
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- Efficient Electrophilic Fluorination of β-Dicarbonyl Compounds with the Selectfluor Reagent F-TEDA-BF4 octane bis(tetrafluoroborate)>
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1,3-Dicarbonyl compounds (acyclic and cyclic 1,3-diketones, β-ketoesters, β-ketoamides) are converted efficiently to 2-monofluoro derivatives, and thence to 2,2-difluoro derivatives, with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclooctane bis(tetrafluoroborate).
- Banks, R. Eric,Lawrence, Nicholas J.,Popplewell, Allan L.
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p. 343 - 344
(2007/10/02)
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- Power and structure-variable fluorinating agents. The N-fluoropyridinium salt system
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The usefulness of the N-fluoropyridinium salt system as a source of fluorinating agents was examined by using substituted or unsubstituted N-fluoropyridinium triflates 1-11, N-fluoropyridinium salts possessing other counteranions 1a-d and 3a, and the counteranion-bound salts, N-fluoropyridinium-2-sulfonates 12 and 13. Electrophilic fluorinating power was found to vary remarkably according to the electronic nature of the ring substituents. This power increased as the electron density of positive nitrogen sites decreased, and this was correlated to the pKa values of the corresponding pyridines. By virtue of this variation, it was possible to fluorinate a wide range of nucleophilic substrates differing in reactivity. It is thus possible to fluorinate aromatics, carbanions, active methylene compounds, enol alkyl or silyl ethers, vinyl acetates, ketene silyl acetals, and olefins through the proper use of salts pentachloro 6 through 2,4,6-trimethyl 2, their power decreasing in this order. All the reactions could be explained on the basis of a one-electron-transfer mechanism. N-Fluoropyridinium salts showed high chemoselectivity in fluorination, the extent depending on the reactive moiety. In consideration of these Findings, selective 9α-fluorination of steroids was carried out by reacting 1 with tris(trimethylsilyl ether) 73 of a triketo steroid. Regio- or stereoselectivity in fluorination was determined by a N-fluoropyridinium salt structure. Steric bulkiness of the N-F surroundings hindered the ortho fluorination of phenols and aniline derivatives, while the capacity for hydrogen bonding on the part of the counteranions prompted this process, and the counteranion-bound salts 12 and 13 underwent this fluorination exclusively or almost so. Both bulky N-fluoropyridinium triflates 2 and 7 preferentially attacked the 6-position of the conjugated vinyl ester of a steroid from the unhindered β-direction to give a thermally unstable 6β-fluoro isomer. On the basis of these results, N-fluoropyridinium salts may be concluded to constitute a system that can serve as a source of the most ideal fluorinating agents for conducting desired selective fluorination through fluorinating capacity or structural alteration.
- Umemoto, Teruo,Fukami, Shinji,Tomizawa, Ginjiro,Harasawa, Kikuko,Kawada, Kosuke,Tomita, Kyoichi
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p. 8563 - 8575
(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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