- Preparation and synthetic application of diethyl 2-oxo-1,1-difluorophosphonates
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Reaction of diethyl(bromodifluoromethyl)phosphonate (EtO)2P(O)CF2Br 1 with activated zinc gave [(diethoxyphosphonyl)difluoromethyl]zinc bromide (EtO)2P(O)CF2ZnBr 2, which was acylated with various acylating agents to afford diethyl 2-oxo-1,1-difluorophosphonates (EtO)2P(O)CF2C(O)R 4 in good yields. Treatment of phosphonates 4 such as diethyl 2-oxo-1,1-difluoropropylphosphonate (EtO)2P(O)CF2C(O)CH3 4a, ethyl difluoro(diethoxyphosphonyl)pyruvate (EtO)2P(O)CF2C(O)CO2Et 4e and N,N-diethyldifluoro(diethoxyphosphonyl)acetamide (EtO)2P(O)CF2C(O)NEt2 4h with Grignard reagents R'MgX provided 1,1-difluoroolefins R′(CH3)C=CF2, R′(CO2Et)C=CF2 and R′(NEt2) C=CF2, respectively.
- Tsai, Hou-Jen
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- Automated lineshape analysis of complex NMR spectra for a novel synthetic tetrafluorobisphosphonate, a potential ligand for phosphoglycerate kinase
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Tetraalkyl 1,1,3,3-tetrafluoro-2,2-dihydroxypropane-1,3-bisphosphonates were prepared. The complex 31P{1H}- and 19F-NMR spectra were analyzed as [[A]2X]2 and related systems. Modern methods of automated spectral analysis using DAISY under WIN-NMR were applied.
- Blackburn,H?gele,Hottgenroth,Ivory,Jakeman,Spiske
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- Nucleophilic fluoroalkylation of (bromomethyl)pinacolborane using silicon reagents
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A method for the synthesis of pinacol boronic esters bearing a fluorinated group at the a-carbon atom (RfCH2Bpin) from corresponding bromomethyl borane (BrCH2Bpin) and fluorinated silanes (RfSiMe3) is described. The fluoroalkylation reaction involves formation of borate anions followed by intramolecular nucleophilic substitution of bromine.
- Levin, Vitalij V.,Elkin, Pavel K.,Struchkova, Marina I.,Dilman, Alexander D.
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- Syntheses of ω-hydroxy-α,α-difluoromethylphosphonates by oxacycle ring-opening reactions
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(Chemical Equation Presented) Oxacycle ring-opening reactions from a non-HCFC-based source of phosphonodifluoromethyl carbanion 1 are reported. This straightforward strategy opens access to a variety of primary and secondary ω-hydroxy-α,α-difluoromethylphosphonates via one step. The syntheses of a glycerol monophosphate analogue and precursors to nucleoside phosphorylase inhibitors are described using this method.
- Ozouf, Paul,Binot, Gregory,Pommelet, Jean-Claude,Lequeux, Thierry P.
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- 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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- Synthesis of Novel Fluorinated Bisphosphonates and Bisphosphonic Acids
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The synthesis of novel fluorinated bisphosphonates with two, three, four, and six difluoromethylene groups (1a, 1b, 8, 12, and 15) (44-78percent) by different approaches is described.The bisphosphonates were converted to the corresponding trimethylsilyl esters which on treatment with deionized water afforded the respective bisphosphonic acids (6, 10, and 14) in good yields.
- Nair, Haridasan K.,Guneratne, Ranil D.,Modak, Anil S.,Burton, Donald J.
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- Direct and straightforward transfer of C1 functionalized synthons to phosphorous electrophiles for accessinggem-P-containing methanes
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The direct transfer of different α-substituted methyllithium reagents to chlorinated phosphorous electrophiles of diverse oxidation state (phosphates, phosphine oxides and phosphines) is proposed as an effective strategy to synthesize geminal P-containing
- Touqeer, Saad,Ielo, Laura,Miele, Margherita,Urban, Ernst,Holzer, Wolfgang,Pace, Vittorio
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supporting information
p. 2425 - 2429
(2021/04/02)
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- Siladifluoromethylation and Deoxo-trifluoromethylation of PV-H Compounds with TMSCF3: Route to PV-CF2- Transfer Reagents and P-CF3 Compounds
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A method for siladifluoromethylation of dialkyl phosphonates and secondary phosphine oxides with TMSCF3 to produce nucleophilic PV-CF2- transfer reagents is disclosed, with multigram scale reactions included. Condition-dependent divergent reactivity under the established conditions is demonstrated by the formation of trifluoromethylphosphines. Both one-pot transformations are operationally simple and employ inexpensive materials. Mechanistic investigations suggest the divergent reactivity originates from a common intermediate, with Li+ concentration directing the chemoselectivity.
- Krishnamurti, Vinayak,Barrett, Colby,Prakash, G. K. Surya
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p. 1526 - 1529
(2019/03/07)
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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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- Synthetic and mechanistic aspects of halo-F-methylphosphonates
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The synthesis of a variety of new halo-F-methylphosphonates has been achieved by a Michaelis-Arbuzov type reaction between a halo-F-methane and a trialkyl phosphite. This synthesis has proved to be of wide scope and utility for the high yield preparation of a number of heretofore unknown compounds. The 1H, 19F, 13C and 31P NMR spectroscopic properties are reported in detail. The mechanism for the formation of bromodifluoromethylphosphonates has been shown to proceed through the intermediacy of difluorocarbene:CF2. The phosphonate products have been shown to react with a wide variety of reagents. Fluoride and alkoxide ions react by attack at phosphorus with cleavage of the carbon-phosphorus bond and formation of [:CF2] from the bromodifluoromethylphosphonates and the CFBr2- anion from the dibromofluoromethylphosphonates. Iodide ion and tertiary phosphines react by attack at the ester carbon to give stable phosphonate salts. Hydrolysis of the phosphonate esters with 50% aqueous HCl gives the expected phosphonic acids. Trimethylsilyl bromide attacks phosphoryl oxygen to afford the bis(trimethylsilyl) esters.
- Flynn, Richard M.,Burton, Donald J.
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experimental part
p. 815 - 828
(2011/10/08)
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- Virtual screening, selection and development of a benzindolone structural scaffold for inhibition of lumazine synthase
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Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a Ki of 70 μM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π-π stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87.
- Talukdar, Arindam,Morgunova, Ekaterina,Duan, Jianxin,Meining, Winfried,Foloppe, Nicolas,Nilsson, Lennart,Bacher, Adelbert,Illarionov, Boris,Fischer, Markus,Ladenstein, Rudolf,Cushman, Mark
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scheme or table
p. 3518 - 3534
(2010/08/05)
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- Nucleophilic difluoromethylenation of aldehydes and ketones using diethyl difluoro(trimethylsilyl)methylphosphonate
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A new nucleophilic difluoromethylenation of aldehydes and ketones using diethyl difluoro(trimethylsilyl)methylphosphonate (1) has been achieved. The reactive carbanion species were generated under mild reaction conditions with a catalytic amount of initiator. This methodology was compatible with non-enolizable and in some cases with enolizable aldehydes and ketones and provided a straightforward access to phosphates of syn and anti 2,2-difluoro-1,3-diols.
- Alexandrova, Anastasia V.,Beier, Petr
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scheme or table
p. 493 - 500
(2009/12/06)
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- Synthetic and mechanistic aspects of the reactions between bromodifluoromethyltriphenylphosphonium bromide and dibromofluoromethyltriphenylphosphonium bromide and trialkylphosphites
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Bromofluoromethyltriphenylphosphonium bromides react with trialkylphosphites in two distinct ways. Bromodifluoromethyltriphenylphosphonium bromide undergoes a rapid exchange reaction with trialkylphosphites to give the corresponding bromodifluoromethylphosphonates in good to excellent yields. A similar exchange reaction also occurred with an analogous diethoxyphenylphosphonite to give the corresponding ethoxyphenylphosphinate. Mechanistically, the exchange process involves the formation of difluorocarbene via dissociation of the intermediate difluoromethylene ylide, capture of the difluorocarbene by the trialkylphosphite to give [ (RO)3 over(P, +) C over(F2, -) ], which captures bromine followed by dealkylation to the product, bromodifluoromethylphosphonate. The equilibria involved in the multi-step mechanism are all shifted to the phosphonate product by the final dealkylation step. In contrast, the dibromofluoromethyltriphenylphosphonium bromide does not under exchange reactions with trialkylphosphite. The phosphite serves as a halophilic reagent to abstract Br from the dibromofluoromethylphosphonium salt to generate the bromofluoromethylene ylide, which can easily be trapped in situ with aldehydes or ketones to give good yields of the E/Z-bromofluoroalkenes. No dissociation of the bromofluoromethylene ylide was observed.
- Flynn, Richard M.,Burton, Donald J.,Wiemers, Denise M.
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p. 583 - 589
(2008/12/22)
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- Phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals. Generation and addition onto alkenes and alkynes
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Selanylated difluoromethylphosphonates and difluoromethylphosphonothioates are good precursors to phosphonodifluoromethyl and phosphonothiodifluoromethyl radicals, respectively. When generated in the presence of alkenes and a hydrogen donor, the corresponding α,α-difluorinated alkylphosphonates or alkylphosphonothioates are produced in fair to good yields. The use of alkynes results in the formation of α,α-difluorinated allyl derivatives in useful yields. The presence of the sulfur atom in phosphonothiodifluoromethyl radicals usually translates into higher isolated yields.
- Pignard, Sebastien,Lopin, Chrystel,Gouhier, Geraldine,Piettre, Serge R.
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- A useful magnesium reagent for the preparation of 1,1-difluoro-2-hydroxyphosphonates from diethyl bromodifluoromethylphosphonate via a metal-halogen exchange reaction
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When (EtO)2P(O)CF2Br (1) is treated with isopropylmagnesium chloride in THF at low temperature it gives a magnesium species (2) which undergoes reactions with strong electrophiles (HCl, TMSCl, halogens, aldehydes and ketones). The formation of products depends strongly on the reaction conditions. With 1.5 equivalents of 2 between - 78 and 0°C, a conversion of more than 90% of aldehydes and ketones into 2-hydroxyphosphonates (7 and 8) can be achieved. These compounds (7 and 8) in the presence of base (NaH, LDA) are rearranged into 2,2-difluoroethylphosphates without concomitant formation of 1,1-difluoroolefines.
- Waschbuesch, Rachel,Samadi, Mohammad,Savignac, Philippe
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p. 267 - 278
(2007/10/03)
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- A New Synthetic Route to Perfluoroalkylidene-α,ο-Biisphosphonates
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The UV irradiation of a mixture of (EtO)2POP(OEt)2 and I(CF2)nI (n = 3,4,6) or I(CF2)nP(O)(OEt)2 (n = 1,2) results in the corresponding bisphosphonites or mixed phosphonitephosphonates, respectively, which on oxidation by Me3COOH afforded the perfluoroalkylidene-α,ο-bisphosphonates in 64-77 percent isolated yields.
- Nair, Haridasan K.,Burton, Donald J.
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p. 347 - 350
(2007/10/02)
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- Addition of Diethyl Bromodifluoromethylphosphonate to Various Alkenes Initiated by Co(III)/Zn Bimetal Redox System
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The addition of diethyl bromodifluoromethylphosphonate 1 to various alkenes 2 initiated by cobaloxime(III)/Zn bimetal redox system gives 1:1 Michael-type adducts 3 in moderate to good yields.A radical mechanism is proposed.
- Hu, Chang-Ming,Chen, Jian
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p. 327 - 330
(2007/10/02)
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- Synthesis and NMDA receptor binding of 2-amino-7,7-difluoro-7-phosphonoheptanoic acid
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In an NMDA specific receptor binding assay, 1 had lower affinity than its parent, APH. This result suggests that for competitive antagonists, diionization of the phosphonic acid moiety may be detrimental to receptor affinity.
- Bigge,Drummond,Johnson
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p. 7013 - 7016
(2007/10/02)
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- FLUORINE IN ENZYME CHEMISTRY: PART 1. SYNTHESIS OF DIFLUOROMETHYLENEPHOSPHONATE DERIVATIVES AS PHOSPHATE MIMICS
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Diethyl difluoromethylphosphonylcadmium bromide reacts with allyl and benzyl halides in THF to give the corresponding difluoromethylenephosphonate derivatives.The reaction with allyl bromide affords a versatile synthetic intermediate which undergoes a variety of synthetic transformations and therefore becomes a key compound in the preparation of elaborated difluoromethylenephosphonates of biological significance.
- Chambers, R. D.,Jaouhari, R.,O'Hagan, D.
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p. 275 - 284
(2007/10/02)
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- Allylations of zinc Bromide as a Convenient Route to 1,1-Difluoro-3-alkenephosphonates
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The reaction of zinc bromide, (EtO)2P(O)CF2ZnBr, with allylic halides was found to be catalyzed by CuBr and represents a synthetically viable and convenient route to the title phosphonates.However, the reaction could no
- Burton, Donald J.,Sprague, Lee G.
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p. 613 - 617
(2007/10/02)
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- Novel fluorophosphonate nucleotide derivatives
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This invention relates to fluoromethylphosphonate derivatives of certain nucleosides, to methods for their preparation and to their use as antiviral and antitumoral agents.
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- Preparation of Difluorophosphonoacetic Acid and Its Derivatives
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The preparation of ethyl difluoro(diethoxyphosphinyl)acetate (1) has been effected by the acylation of zinc bromide with ethyl chloroformate in the presence of a catalytic amount of cuprous bromide.Similarly prepared were ethyl difluoro(diethoxyphosphinyl)pyruvate (2) and N,N-diethyldifluoro(diethoxyphosphinyl)acetamide (3).Bromotrimethylsilane selectively reacted with 1 to yield ethyl difluoroacetate (9).The remaining ethyl carboxylic ester of 9 reacted with iodotrimethylsilane to produce trimethylsilyl difluoroacetate (10), which was subsequently hydrolyzed to yield difluorophosphonoacetic acid (8).The phosphonate 9 was gently chlorinated to yield ethyl difluoro(dichlorophosphinyl)acetate (11).
- Burton, Donald J.,Sprague, Lee G.
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p. 1523 - 1527
(2007/10/02)
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- (DIETHYLPHOSPHINYL)DIFLUOROMETHYLLITHIUM. -PREPARATION AND SYNTHETIC APPLICATION-
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The action of lithium diisopropylamide on diethyl difluoromethylphosphonate gives the title reagent which reacts with various electrophiles to introduce difluoromethylene or difluoromethyl unit.
- Obayashi, Michio,Ito, Eiji,Matsui, Kiyohide,Kondo, Kiyosi
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p. 2323 - 2326
(2007/10/02)
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- PREPARATION, STABILITY AND ACIDITY OF DIFLUOROMETHYLENE BIS PHOSPHONIC ACID
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Hydrolysis of difluoromethylene phosphonate esters quantitatively yields difluoromethylene bis phosphonic acid as a dihydrate.In vacuo drying leads to either the monohydrate or the anhydrous acid.Titration of either the free acid or its disodium salt and computer fit of the data gives all four pKa s.The disodium salt and the free acid are thermally stable, and the disodium salt is extremely stable even to strong base.
- Burton, D. J.,Pietrzyk, D. J.,Ishihara, T.,Fonong, T.,Flynn, R. M.
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p. 617 - 626
(2007/10/02)
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- Preparation, Stability, Reactivity and Synthetic Utility of a Cadmium Stabilized Complex of Difluoromethylene Phosphonic Acid Ester
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Diethyl bromodifluoromethylphosphonate reacts readily with cadmium metal to form a stable cadmium complex.Depending on solvent, this functionalized organocadmium reagent exhibits stability for days to months.It reacts with a variety of electrophiles and serves as a synthetically useful source for the introduction of the difluoromethylene phosphonate group into organic compounds.
- Burton, Donald J.,Takei, Ryutaro,Shin-Ya, Seiji
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p. 197 - 202
(2007/10/02)
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