- Metal-free electrochemical fluorodecarboxylation of aryloxyacetic acids to fluoromethyl aryl ethers
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Electrochemical decarboxylation of aryloxyacetic acids followed by fluorination provides easy access to fluoromethyl aryl ethers. This electrochemical fluorodecarboxylation offers a sustainable approach with electric current as traceless oxidant. Using Et3N·5HF as fluoride source and as supporting electrolyte, this simple electrosynthesis affords various fluoromethoxyarenes in yields up to 85%.
- Berger, Michael,De Kruijff, Goswinus H. M.,Herszman, John D.,Kurimoto, Yuji,Ruf, Sven,Schüll, Aaron,Waldvogel, Siegfried R.
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p. 6053 - 6057
(2020/07/10)
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- Continuous Heterogeneous Photocatalysis in Serial Micro-Batch Reactors
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Solid reagents, leaching catalysts, and heterogeneous photocatalysts are commonly employed in batch processes but are ill-suited for continuous-flow chemistry. Heterogeneous catalysts for thermal reactions are typically used in packed-bed reactors, which cannot be penetrated by light and thus are not suitable for photocatalytic reactions involving solids. We demonstrate that serial micro-batch reactors (SMBRs) allow for the continuous utilization of solid materials together with liquids and gases in flow. This technology was utilized to develop selective and efficient fluorination reactions using a modified graphitic carbon nitride heterogeneous catalyst instead of costly homogeneous metal polypyridyl complexes. The merger of this inexpensive, recyclable catalyst and the SMBR approach enables sustainable and scalable photocatalysis.
- Pieber, Bartholom?us,Shalom, Menny,Antonietti, Markus,Seeberger, Peter H.,Gilmore, Kerry
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supporting information
p. 9976 - 9979
(2018/03/21)
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- Fluorine in drug design: A case study with fluoroanisoles
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Anisole and fluoroanisoles display distinct conformational preferences, as evident from a survey of their crystal structures. In addition to altering the free ligand conformation, various degrees of fluorination have a strong impact on physicochemical and pharmacokinetic properties. Analysis of anisole and fluoroanisole matched molecular pairs in the Pfizer corporate database reveals interesting trends: 1) PhOCF3 increases log D by ~1 log unit over PhOCH3 compounds; 2) PhOCF3 shows lower passive permeability despite its higher lipophilicity; and 3) PhOCF3 does not appreciably improve metabolic stability over PhOCH3. Emerging from the investigation, difluoroanisole (PhOCF2H) strikes a better balance of properties with noticeable advantages of log D and transcellular permeability over PhOCF3. Synthetic assessment illustrates that the routes to access difluoroanisoles are often more straightforward than those for trifluoroanisoles. Whereas replacing PhOCH3 with PhOCF3 is a common tactic to optimize ADME properties, our analysis suggests PhOCF2H may be a more attractive alternative, and greater exploitation of this motif is recommended.
- Xing, Li,Blakemore, David C.,Narayanan, Arjun,Unwalla, Ray,Lovering, Frank,Denny, R. Aldrin,Zhou, Huanyu,Bunnage, Mark E.
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p. 715 - 726
(2015/04/14)
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- Radical decarboxylative fluorination of aryloxyacetic acids using N-fluorobenzenesulfonimide and a photosensitizer
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Fluorinated methoxy arenes are emerging as important motifs in both agrochemicals and pharmaceuticals. A novel technique for the synthesis of monofluoromethoxy arenes through the direct fluorodecarboxylation of carboxylic acids was developed that uses photosensitizers and N-fluorobenzenesulfonimide (NFSI). Utilization of the oxidatively mild fluorine transfer agent NFSI enabled the synthesis of fluoromethyl ethers that were previously inaccessible with decarboxylative fluorinations performed with Selectfluor. Mechanistic studies are consistent with the photosensitizer effecting oxidation of the aryloxyacetic acid.
- Leung, Joe C. T.,Sammis, Glenn M.
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supporting information
p. 2197 - 2204
(2015/04/14)
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- Direct C-F bond formation using photoredox catalysis
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We have developed the first example of a photoredox catalytic method for the formation of carbon-fluorine (C-F) bonds. The mechanism has been studied using transient absorption spectroscopy and involves a key single-electron transfer from the 3MLCT (triplet metal-to-ligand charge transfer) state of Ru(bpy)32+ to Selectfluor. Not only does this represent a new reaction for photoredox catalysis, but the mild reaction conditions and use of visible light also make it a practical improvement over previously developed UV-mediated decarboxylative fluorinations.
- Rueda-Becerril, Montserrat,Mahe, Olivier,Drouin, Myriam,Majewski, Marek B.,West, Julian G.,Wolf, Michael O.,Sammis, Glenn M.,Paquin, Jean-Francois
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supporting information
p. 2637 - 2641
(2014/03/21)
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- Direct monofluoromethylation of O-, S-, N-, and P-nucleophiles with PhSO(NTs)CH2F: The accelerating effect of α-fluorine substitution
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An efficient and direct monofluoromethylation of O-, S-, N-, and P-nucleophiles with PhSO(NTs)CH2F 1 has been developed. In contrast to the previously known detrimental effect of α-fluorine substitution on SN2 reactions, the current monofluoromethylation is accelerated by the α-fluorine substitution. Based on a mechanistic study, a new reactivity of sulfoximine (as a radical monofluoromethylation reagent) is disclosed.
- Shen, Xiao,Zhou, Min,Ni, Chuanfa,Zhang, Wei,Hu, Jinbo
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p. 117 - 122
(2014/01/06)
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- Fluorine transfer to alkyl radicals
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The development of new synthetic technologies for the selective fluorination of organic compounds has increased with the escalating importance of fluorine-containing pharmaceuticals. Traditional methods potentially applicable to drug synthesis rely on the use of ionic forms of fluorine (F - or F+). Radical methods, while potentially attractive as a complementary approach, are hindered by a paucity of safe sources of atomic fluorine (F?). A new approach to alkyl fluorination has been developed that utilizes the reagent N-fluorobenzenesulfonimide as a fluorine transfer agent to alkyl radicals. This approach is successful for a broad range of alkyl radicals, including primary, secondary, tertiary, benzylic, and heteroatom-stabilized radicals. Furthermore, calculations reveal that fluorine-containing ionic reagents are likely candidates for further expansion of this approach to polar reaction media. The use of these reagents in alkyl radical fluorination has the potential to enable powerful new transformations that otherwise would take multiple synthetic steps.
- Rueda-Becerril, Montserrat,Chatalova Sazepin, Claire,Leung, Joe C. T.,Okbinoglu, Tulin,Kennepohl, Pierre,Paquin, Jean-Francois,Sammis, Glenn M.
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supporting information; experimental part
p. 4026 - 4029
(2012/04/10)
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- Photo-fluorodecarboxylation of 2-aryloxy and 2-aryl carboxylic acids
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Coming to light: The title reaction simply requires an aqueous alkaline solution of Selectfluor and light. The method is inexpensive and effective for a wide range of neutral and electron-poor 2-aryloxy and 2-aryl acetic acids to provide fluoromethyl ethers (see scheme) and benzyl fluorides, respectively. The mechanism most likely proceeds through an initial aryl excitation with a subsequent single-electron transfer. Copyright
- Leung, Joe C. T.,Chatalova-Sazepin, Claire,West, Julian G.,Rueda-Becerril, Montserrat,Paquin, Jean-Fran?ois,Sammis, Glenn M.
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supporting information
p. 10804 - 10807
(2013/01/15)
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- Oxidation of benzyl alcohols with difluoro(aryl)-λ3-bromane: formation of benzyl fluoromethyl ethers via oxidative rearrangement
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Oxidative rearrangement of benzyl alcohols with difluoro(p-trifluoromethylphenyl)-λ3-bromane (5 × 10-2 M) in chloroform at room temperature afforded aryl fluoromethyl ethers selectively in good yields, probably via 1,2-shift of aryl groups from benzylic carbon to oxygen atoms.
- Ochiai, Masahito,Yoshimura, Akira,Miyamoto, Kazunori
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supporting information; experimental part
p. 4792 - 4795
(2011/03/18)
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- Electrophilic monofluoromethylation of O-, S-, and N-nucleophiles with chlorofluoromethane
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CH2ClF has been found to be a useful electrophilic monofluoromethylating agent for a variety of O-, S-, and N-nucleophiles. The reaction is not sensitive to the radical scavenger such as nitrobenzene, which strongly supports an SN2 m
- Zhang, Wei,Zhu, Lingui,Hu, Jinbo
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p. 10569 - 10575
(2008/02/12)
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- [18F]Fluoromethyl iodide ([18F]FCH2I): Preparation and reactions with phenol, thiophenol, amide and amine functional groups
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In this study, we report the synthesis and reactivity of [ 18F]fluoromethyl iodide ([18F]FCH2I) with various nucleophilic substrates and the stabilities of [18F] fluoromethylated compounds. [18F]FCHs
- Zhang, Ming-Rong,Ogawa, Masanao,Furutsuka, Kenji,Yoshida, Yuichiro,Suzuki, Kazutoshi
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p. 1879 - 1886
(2007/10/03)
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- Process for the preparation of halogenated derivatives and Lewis acid base catalysts thereof
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A process for the preparation of halide compounds, preferably aryl halides, by contacting a gaseous mixture of hydrohalic acid and a compound selected from an aryl halogen formate, an aryl carbonate and equivalents thereof with a Lewis acid catalyst.
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- Synthesis and nucleophilic substitution reactions of mono α-fluoro ethers
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Mono α-fluoro ethers have been prepared by cleavage of α-alkoxy sulfoxides with diethylaminosulfur trifluoride (DAST) and by an exchange reaction of the corresponding α-chloro ether with tetrabutylammonium fluoride (TBAF). The reactivity of different α-fluoro ethers in some nucleophilic substitution reactions has been investigated. Copyright Acta Chemica Scandinavica 1999.
- Ringom, Rune,Benneche, Tore
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- Room temperature reactions of XeF2 with phenyl substituted alcohols
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Benzyl alkohol and its analogues with a non-activated benzene ring are transformed to fluoromethoxy derivatives by reaction with XeF2. The same reaction with diphenyl methanol gives di diphenylmethylether, while 2-phenyl-2-propanol transforms to 2,4-diphenyl-4-methyl-1-pentene.
- Stavber, Stojan,Zupan, Marko
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p. 4355 - 4356
(2007/10/02)
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- Facile Transformation of β-D-Ribofuranosyl Purines and Pyrimidines into Their Respective 3'-Deoxy-threo-pentofuranosyl Nucleosides
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Practical syntheses of 3'-deoxy-β-D-threo-pentofuranosyl-uracil, -cytosine, -adenine, and -guanine (3U, C, A, G) from the corresponding ribonucleosides by two one-pot reactions with readily accessible reagents are described.The key reactions are the selective 3'-O-methanesulphonylations of the ribonucleosides, the deoxygenative -hydride shift of the methanesulphonates, and the reduction of in situ generated 3'-deoxy-2'-keto nucleosides therefrom.
- Kawana, Masajiro,Nishikawa, Masahiro,Yamasaki, Noritsugu,Kuzuhara,Hiroyoshi
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p. 1593 - 1596
(2007/10/02)
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- Replecement of the carboxylic acid function with fluorine
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Replacement of a carbonyl function by fluorine, fluorodecarboxylation, is a new process that can be accomplished by the reaction of alkanoic acids with xenon difluoride.Primary, tertiary, and benzylic acids perform best in the reaction, which is conducted at room temperature in methylene chloride or chloroform solution.A reaction mechanism is proposed in which the acid is initially converted to a fluoroxenon ester, RCO2XeF.The esters of the primary and secondary acids react by nucleophilic displacement by fluoride, as evidenced by incorporation of 18F- and no reactions common to free radicals or carbocations.The esters of the tertiary and benzylic acids react by converting to free radicals that can be further oxidized to carbocations.Thus incorporation of 18F- and racemization are observed with α-methoxy-α-trifluoromethylphenylacetic acid.Hydroxyl and amino functions inhibit the reaction.Aromatic and vinylic acids do not react.
- Patrick, Timothy B.,Johri, Kamalesh K.,White, David H.,Bertrand, William S.,Mokhtar, Rodziah,et al.
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p. 138 - 141
(2007/10/02)
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- Fluorodecarboxylation with Xenon Difluoride
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The reaction between xenon difluoride and aliphatic carboxylic acids causes decarboxylation with replacement of the carboxyl group by fluorine.
- Patrick, Timothy B.,Johri, Kamalesh K.,White, David H.
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p. 4158 - 4159
(2007/10/02)
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