- Synthesis of acyl fluorides via photocatalytic fluorination of aldehydic C-H bonds
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Acyl fluorides are versatile acylating agents owing to their unique stability. Their synthesis, however, can present challenges and is typically accomplished through deoxyfluorination of carboxylic acids. Here, we demonstrate that acyl fluorides can be prepared directly from aldehydes via a C(sp2)-H fluorination reaction involving the inexpensive photocatalyst sodium decatungstate and electrophilic fluorinating agent N-fluorobenzenesulfonimide. This convenient fluorination strategy enables direct conversion of aliphatic and aromatic aldehydes into acylating agents.
- Meanwell, Michael,Lehmann, Johannes,Eichenberger, Marc,Martin, Rainer E.,Britton, Robert
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p. 9985 - 9988
(2018/09/11)
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- Nickel-Catalyzed Reductive Cross-Coupling of Aryl Halides with Monofluoroalkyl Halides for Late-Stage Monofluoroalkylation
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A combinatorial nickel-catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross-coupling has been developed. This method demonstrated high efficiency, mild conditions, and excellent functional-group tolerance, thus enabling the late-stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine-type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel-catalyzed reductive cross-coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.
- Sheng, Jie,Ni, Hui-Qi,Zhang, Hao-Ran,Zhang, Kai-Fan,Wang, Yi-Ning,Wang, Xi-Sheng
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supporting information
p. 7634 - 7639
(2018/06/26)
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- Combinatorial Nickel-Catalyzed Monofluoroalkylation of Aryl Boronic Acids with Unactivated Fluoroalkyl Iodides
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A combinatorial nickel-catalyzed cross-coupling between arylboronic acids and unactived 1-fluoro-1-iodoalkanes has been developed, which demonstrated high efficiency, mild conditions, and excellent functional-group compatibility. Readily available nitrogen and phosphine ligands were combined with a nitrogen source, which in situ generated a variety of easily tunable catalysts to promote the fluoroalkylation for broad scopes of both coupling partners. This new strategy on combinatorial catalysis offers new solutions for nickel-catalyzed cross-coupling reactions.
- Sheng, Jie,Ni, Hui-Qi,Liu, Ge,Li, Yan,Wang, Xi-Sheng
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supporting information
p. 4480 - 4483
(2017/09/11)
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- METHODS AND COMPOSITIONS FOR DIRECT RADIOACTIVE LABELING OF BIO-ACTIVE MOLECULES AND BUILDING BLOCKS
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Methods of direct radioactive labeling a carbon containing compound having an sp3 C-H bond are provided. Methods of carrier-free 18F fluorination of a carbon containing compound mediated by manganese salen complexes or manganese porphyrin complexes comprising weakly coordinated anions as axial ligands are provided. Methods of "dry-down" free radioactive labeling of a carbon containing compound having an sp3 C-H bond are provided. The radioactively labeled products of the methods are provided.
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Paragraph 00119; 00120; 00123
(2015/11/02)
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- Silver-catalyzed Meerwein arylation: Intermolecular and intramolecular fluoroarylation of styrenes
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The first example of silver-catalyzed intermolecular and intramolecular Meerwein fluoroarylation of styrenes with aryl diazonium salts has been developed. This reaction is operationally simple, scalable and proceeds under mild conditions. Furthermore, fluorinated dihydrobenzofurans and indolines were easily accessed using this method. This journal is
- Guo, Rui,Yang, Haodong,Tang, Pingping
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supporting information
p. 8829 - 8832
(2015/05/20)
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- Targeted fluorination with the fluoride ion by manganese-catalyzed decarboxylation
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We describe the first catalytic decarboxylative fluorination reaction based on the nucleophilic fluoride ion. The reported method allows the facile replacement of various aliphatic carboxylic acid groups with fluorine. Moreover, the potential of this method for PET imaging has been demonstrated by the successful 18F labeling of a variety of carboxylic acids with radiochemical conversions up to 50-%, representing a targeted decarboxylative 18F labeling method with no-carrier-added [18F]fluoride. Mechanistic probes suggest that the reaction proceeds through the interaction of the manganese catalyst with iodine(III) carboxylates formed in situ from iodosylbenzene and the carboxylic acid substrates. Nucleophile first: An efficient manganese porphyrin catalyzed decarboxylative fluorination reaction based on a nucleophilic fluorine source is described. The potential of the described method for use in PET imaging has been demonstrated by the successful 18F labeling of various aliphatic carboxylic acids, representing the first decarboxylative 18F labeling method with no-carrier-added [18F]fluoride.
- Huang, Xiongyi,Liu, Wei,Hooker, Jacob M.,Groves, John T.
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supporting information
p. 5241 - 5245
(2015/04/27)
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- Direct photocatalytic fluorination of benzylic C-H bonds with N-fluorobenzenesulfonimide
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The late-stage fluorination of common synthetic building blocks and drug leads is an appealing reaction for medicinal chemistry. In particular, fluorination of benzylic C-H bonds provides a means to attenuate drug metabolism at this metabolically labile position. Here we report two complimentary strategies for the direct fluorination of benzylic C-H bonds using N-fluorobenzenesulfonimide and either a decatungstate photocatalyst or AIBN-initiation.
- Nodwell, Matthew B.,Bagai, Abhimanyu,Halperin, Shira D.,Martin, Rainer E.,Knust, Henner,Britton, Robert
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supporting information
p. 11783 - 11786
(2015/07/15)
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- Cis-specific hydrofluorination of alkenylarenes under palladium catalysis through an ionic pathway
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This paper describes the hydrofluorination of alkenes through sequential H- and F+ addition under palladium catalysis. The reaction is cis specific, thus providing access to benzylic fluorides. The mechanism of this reaction involves an ionic pathway and is distinct from known hydrofluorinations involving radical intermediates. The first catalytic enantioselective hydrofluorination is also disclosed. See attached PdF: A series of benzylic fluorides was prepared by hydrofluorination which proceeds through a PdII/IV catalytic manifold. The method is mechanistically distinct from previously reported radical hydrofluorination, and is characterized by its clean regioselectivity and unique cis stereospecificity. The first example of enantioselective net HF addition onto 2-vinylnaphthalene is also disclosed.
- Emer, Enrico,Pfeifer, Lukas,Brown, John M.,Gouverneur, Veronique
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supporting information
p. 4181 - 4185
(2014/05/06)
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- Late stage benzylic C-H fluorination with [18F]fluoride for PET imaging
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We describe the first late-stage 18F labeling chemistry for aliphatic C-H bonds with no-carrier-added [18F]fluoride. The method uses Mn(salen)OTs as an F-transfer catalyst and enables the facile labeling of a variety of bioactive molecules and building blocks with radiochemical yields (RCY) ranging from 20% to 72% within 10 min without the need for preactivation of the labeling precursor. Notably, the catalyst itself can directly elute [18F]fluoride from an ion exchange cartridge with over 90% efficiency. Using this feature, the conventional and laborious dry-down step prior to reaction is circumvented, greatly simplifying the mechanics of this protocol and shortening the time for automated synthesis. Eight drug molecules, including COX, ACE, MAO, and PDE inhibitors, have been successfully [ 18F]-labeled in this way.
- Huang, Xiongyi,Liu, Wei,Ren, Hong,Neelamegam, Ramesh,Hooker, Jacob M.,Groves, John T.
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supporting information
p. 6842 - 6845
(2014/06/09)
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- Discovery of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride as a deoxofluorinating agent with high thermal stability as well as unusual resistance to aqueous hydrolysis, and its diverse fluorination capabilities including deoxofluoro-arylsulfinylation with high stereoselectivity
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Versatile, safe, shelf-stable, and easy-to-handle fluorinating agents are strongly desired in both academic and industrial arenas, since fluorinated compounds have attracted considerable interest in many areas, such as drug discovery, due to the unique effects of fluorine atoms when incorporated into molecules. This article describes the synthesis, properties, and reactivity of many substituted and thermally stable phenylsulfur trifluorides, in particular, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead, 1k), as a crystalline solid having surprisingly high stability on contact with water and superior utility as a deoxofluorinating agent compared to current reagents, such as DAST and its analogues. The roles of substiuents on 1k in thermal and hydrolytic stability, fluorination reactivity, and the high-yield fluorination mechanism it undergoes have been clarified. In addition to fluorinations of alcohols, aldehydes, and enolizable ketones, 1k smoothly converts non-enolizable carbonyls to CF2 groups, and carboxylic groups to CF3 groups, in high yields. 1k also converts C(=S) and CH3SC(=S)O groups to CF2 and CF3O groups, respectively, in high yields. In addition, 1k effects highly stereoselective deoxofluoro-arylsulfinylation of diols and amino alcohols to give fluoroalkyl arylsulfinates and arylsulfinamides, with complete inversion of configuration at fluorine and the simultaneous, selective formation of one conformational isomer at the sulfoxide sulfur atom. Considering the unique and diverse properties, relative safety, and ease of handling of 1k in addition to its convenient synthesis, it is expected to find considerable use as a novel fluorinating agent in both academic and industrial arenas.
- Umemoto, Teruo,Singh, Rajendra P.,Xu, Yong,Saito, Norimichi
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supporting information; scheme or table
p. 18199 - 18205
(2011/03/18)
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- Photolysis of bromo- and chloro-substituted benzyl derivatives. Competition between ionic and radical pathways
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Photolysis of 1-fluoro-2-halo-1,2-diphenylethanes was studied in solutions of tetrahydrofuran, acetonitrile, and cyclohexane. The effect of free radical inhibitor and metal hydrides on products formation as well as their ratio was analyzed to elucidate the reaction pathway. In the first step homolytic C-X bond cleavage occurs from a single excited state, resulting in a biradical pair. Further reaction path depends on the type of the halogen bonded and on the solvent polarity. Electron transfer within the radical pair cage is apparently more rapid for bromides than for chlorides and is opposite as expected on the basis of the relative electronegativities of chlorine and bromine. As radicals approach each other, they fall into ionic or radical product channels. This is influenced by solvent polarity, resulting in the larger yield of ionic products in the case of acetonitrile as in the case of less polar cyclohexane.
- Kosmrlj,Sket
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p. 6890 - 6896
(2007/10/03)
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- A method for generation of α-halo carbanions (carbenoids) from aryl α-haloalkyl sulfoxides with alkylmetals
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Ligand exchange reaction of simple aryl α-haloalkyl sulfoxides with alkyllithium and ethylmagnesium halide at low temperature was investigated. On treatment of aryl α-haloalkyl sulfoxide with n-BuLi, t-BuLi, or EtMgX exclusively sulfur-alkyl bond-cleavage took place to afford α-halo carbanion (carbenoid). When this reaction was carried out without a proton source, the intermediate α-halo carbanion decomposed to give olefines in good yield. The ligand exchange reaction of sulfoxide was found to be very fast and the reaction could be carried out with a proton or a deuterium source (internal quench) to afford alkyl halide. This procedure offers a new method for preparing α-deuterated) halides (the halogen is F, Cl, or Br).
- Satoh, Tsuyoshi,Takano, Koji
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p. 2349 - 2358
(2007/10/03)
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- The role of LiAlH4 in the photolysis of benzyl fluoride derivatives
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Benzyl fluoride derivatives show little reactivity under photochemical conditions, while an enhancement of conversion was observed when photoirradiation was performed in the presence of LiAlH4.
- Kosmirlj, Berta,Kralj, Bogdan,Sket, Boris
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p. 7921 - 7924
(2007/10/02)
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