- Copper-promoted cross-coupling reactions for the synthesis of aryl(difluoromethyl)phosphonates using trimethylsilyl(difluoromethyl)phosphonate
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A convenient and effective route for the synthesis of aryl(difluoromethyl)phosphonates has been developed based on cross-coupling reactions. Upon treatment with a stoichiometric amount (or a catalytic amount in some cases) of CuI and CsF, aryl iodides reacted smoothly with (silyldifluoromethyl)phosphonates to give the corresponding aryl(difluoromethyl)phosphonates in good yields.
- Komoda, Kazuki,Iwamoto, Rei,Kasumi, Masakazu,Amii, Hideki
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- Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and Limitations
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Herein, a general procedure to access CF2PO(OEt)2-containing molecules is reported. The reagent CuCF2PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalised. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated molecules at room temperature. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalised, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2PO(OEt)2-containing molecules.
- Ivanova, Maria V.,Bayle, Alexandre,Besset, Tatiana,Pannecoucke, Xavier,Poisson, Thomas
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p. 17318 - 17338
(2017/11/20)
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- X-ray Characterization and Structure-Based Optimization of Striatal-Enriched Protein Tyrosine Phosphatase Inhibitors
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Excessive activity of striatal-enriched protein tyrosine phosphatase (STEP) in the brain has been detected in numerous neuropsychiatric disorders including Alzheimer's disease. Notably, knockdown of STEP in an Alzheimer mouse model effected an increase in the phosphorylation levels of downstream STEP substrates and a significant reversal in the observed cognitive and memory deficits. These data point to the promising potential of STEP as a target for drug discovery in Alzheimer's treatment. We previously reported a substrate-based approach to the development of low molecular weight STEP inhibitors with Ki values as low as 7.8 μM. Herein, we disclose the first X-ray crystal structures of inhibitors bound to STEP and the surprising finding that they occupy noncoincident binding sites. Moreover, we utilize this structural information to optimize the inhibitor structure to achieve a Ki of 110 nM, with 15-60-fold selectivity across a series of phosphatases.
- Witten, Michael R.,Wissler, Lisa,Snow, Melanie,Geschwindner, Stefan,Read, Jon A.,Brandon, Nicholas J.,Nairn, Angus C.,Lombroso, Paul J.,K?ck, Helena,Ellman, Jonathan A.
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p. 9299 - 9319
(2017/11/30)
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- Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics
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A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodology using TMSCF2PO(OEt)2, iodonium salts and a copper salt provided a straightforward manifold to re
- Ivanova, Maria V.,Bayle, Alexandre,Besset, Tatiana,Poisson, Thomas,Pannecoucke, Xavier
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supporting information
p. 13406 - 13410
(2015/11/09)
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- Copper-mediated oxidative difluoromethylenation of aryl boronic acids with α-silyldifluoromethylphosphonates: A new method for aryldifluorophosphonates
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An unprecedented copper-mediated oxidative difluoromethylenation of aryl boronic acids with α-silyldifluoromethylphosphonates has been developed, allowing rapid access to a wide range of aryldifluorophosphonates containing various functional groups. This method provides a complementary and alternative method to Cu-mediated cross-couplings of aryl iodides with metalated difluoromethylphosphonates.
- Jiang, Xueliang,Chu, Lingling,Qing, Feng-Ling
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p. 1736 - 1741
(2013/06/27)
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- Cuprous chloride promoted coupling reaction of diethoxyphosphinyldifluoromethylcadmium reagent with aryl iodides: A practical and convenient preparation of α,α-difluoro benzylic phosphonates
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The cross coupling reaction of diethoxyphosphinyldifluoromethylcadmium reagent with aryl iodides was promoted by CuCl under mild conditions to give α,α-difluoro benzylic phosphonates in good yields. A variety of functional groups, including halides, phosphonate, nitro, ketone, carboxylic acid and ester in aryl iodides, could be tolerated. This methodology has been successfully applied to prepare α,α-difluoro Fostedil 9.
- Qiu, Weiming,Burton, Donald J.
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- Synthesis and biological evaluation of α,α-difluorobenzylphosphonic acid derivatives as small molecular inhibitors of protein-tyrosine phosphatase 1B
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A series of α,α-difluorobenzylphosphonic acids having a hydrophobic functional group were prepared via the Stille coupling reaction from halogenated α,α-difluorobenzylphosphonates. Evaluation of inhibitory activity toward protein tyrosine phosphatase (PTP 1B) revealed that the ethynyl, phenylethynyl and (E)-styryl groups on the benzene nuclei increased the inhibitory activity of α,α-difluorobenzylphosphonic acid. Inhibitory activities significantly increased upon introducing both (E)-styryl and bis- methylsulfonamide functional groups onto the benzene nuclei of α,α- difluorobenzylphosphonic acid.
- Yokomatsu, Tsutomu,Murano, Tetsuo,Umesue, Ikuko,Soeda, Shinji,Shimeno, Hiroshi,Shibuya, Shiroshi
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p. 529 - 532
(2007/10/03)
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- Synthesis of aryl(difluoromethylenephosphonates) via electrophilic fluorination of α-carbanions of benzylic phosphonates with N- fluorobenzenesulfonimide.
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The electrophilic fluorination of a wide variety of benzylic phosphonates with N-fluorobenzenesulfonimide has been examined. The fluorination reaction proceeds well in the presence of an array of functional groups such as nitro, bromo, ketone, ester, phenyl and ether groups. Phenyl and biphenyl derivatives containing two α,α-difluoromethylenephosphonate groups can also be prepared. This procedure is compatible with methyl or ethyl phosphonate esters but not with t-butyl esters or with benzylic phosphonates containing an additional benzylic moiety at the para-position.
- Taylor, Scott D.,Kotoris, Christopher C.,Dinaut, A. Nicole,Chen, Mei-Jin
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p. 1691 - 1714
(2007/10/03)
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- A facile and general preparation of α,α-difluoro benzylic phosphonates by the CuCl promoted coupling reaction of the (diethylphosphonyl)difluoromethylcadmium reagent with aryl iodides
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A series of α,α-difluoro benzylic phosphonates have been prepared in good yield (65-88%) by the CuCl promoted coupling reaction of the (diethylphosphonyl)difluoromethylcadmium reagent with aryl iodides.
- Qiu, Weiming,Burton, Donald J.
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p. 2745 - 2748
(2007/10/03)
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