- A Convenient Synthesis of Ethyl (Diethoxyphosphoryl)fluoroacetate from Ethyl Fluoroacetate
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A new synthesis of ethyl (diethoxyphosphoryl)fluoroacetate starting from ethyl fluoroacetate is described for a mole scale.This synthesis does not require the use of special equipment for fluorine chemistry since no hydrogen fluoride is evolved.
- Elkik, Elias,Imbeaux, Michele
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Read Online
- Application of fluorocarbethoxy-substituted phosphonate: A facile entry to substituted 2-fluoro-3-oxoesters
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Diethyl(fluorocarbethoxymethyl)phosphonate 1a or diisopropyl(fluorocarbethoxymethyl)phosphonate 1b, prepared from triethyl phosphite or triisopropyl phosphite with ethyl bromofluoroacetate, react with n-butyllithium in THF to give the corresponding phosphonate carbanions [(RO)2P(O)CFCO2Et]-Li+ 2a (R = Et) and 2b (R = i-Pr). Addition of trimethylsilyltrifluoroacetate CF3C(O)OSiMe3 to a THF solution of phosphonate carbanions formed the enolate of ethyl trifluoroacetylfluoroacetate [CF3C(O)CFCO2Et]-Li+ 3. Subsequent protonation, alkylation or allylation of the enolate afforded substituted 2,4,4,4-tetrafluoro-3-oxoesters CF3C(O)CFR1CO2Et 10.
- Tsai, Hou-Jen
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Read Online
- Synthesis of fluorinated phosphonoacetate derivatives of carbocyclic nucleoside monophosphonates and activity as inhibitors of HIV reverse transcriptase
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The syntheses of compounds 8-10 are described; the compounds showed some activity as inhibitors of HIV reverse transcriptase (IC50 ≥ 365 μM).
- Hamilton, Chris J.,Roberts, Stanley M.
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- New routes to diethyl 1-fluoromethylphosphonocarboxylates and diethyl 1-fluoromethylphosphonocarboxylic acid
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Diethyl 1-fluoromethylphosphonocarboxylic esters 4, bearing a variety of ester groups (alkyl, aryl), have been conveniently prepared in a one-pot process, by reaction of chloroformates with 1-lithio-1-fluoro-1-(trimethylsilyl)methylposphonate 2 derived from 1,1-dibromo-1-fluoromethylphosphonate 1. The overall yields generally range from 80 to 91%. Reaction of 2 with CO2 leads to a novel efficient synthesis of diethyl 1-fluoromethylphosphonocarboxylic acid 7 in 86% yield.
- Waschbuesch, Rachel,Carran, John,Savignac, Philippe
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Read Online
- Preparation of triethyl 2-fluoro-2-phosphonoacetate
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Triethyl 2-fluoro-2-phosphonoacetate was prepared in one step from dibromofluoromethyl phosphonate and ethyl chloroformate.
- Patois,Savignac
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Read Online
- Triethyl 2-fluoro-2-phosphonoacetate synthesis method
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The invention discloses a triethyl 2-fluoro-2-phosphonoacetate synthesis method. According to the present invention, ethyl bromofluoroacetate and triethyl phosphite are used as starting raw materials,and are subjected to a Michaelis-Arbuzov reaction to synthesize triethyl 2-fluoro-2-phosphonoacetate, wherein the steps are less, such that the obtained by-products are few, and the yield is increased.
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Paragraph 0017-0021
(2019/08/01)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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Compounds of formula (I') and methods of their use and preparation, as well as compositions comprising compounds of formula (I').
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Page/Page column 161; 165-166; 339
(2018/06/30)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
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The present disclosure is directed to compounds of formula I and methods of their use and preparation, as well as compositions comprising compounds of formula I.
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Page/Page column 162
(2017/09/02)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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Disclosed herein are compounds that inhibit Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
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Paragraph 00644
(2016/01/25)
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- HETEROARYL SUBSTITUTED AMINOPYRIDINE COMPOUNDS
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Disclosed are compounds of Formula (I) Formula(I) or salts thereof, wherein HET is a heteroaryl selected from oxazolyl, pyrazolyl, imidazo[l,2-b]pyridazin-3-yl, and pyrazolo[l,5-a]pyrimidin-3-yl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a carbon ring atom in the heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb; and R1, R3, and Rb are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases, or in the treatment of cancer.
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Page/Page column 178
(2017/01/09)
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- Unexpected reactivity of 2-fluorolinalyl diphosphate in the active site of crystalline 2-methylisoborneol synthase
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The crystal structure of 2-methylisoborneol synthase (MIBS) from Streptomyces coelicolor A3(2) has been determined in its unliganded state and in complex with two Mg2+ ions and 2-fluoroneryl diphosphate at 1.85 and 2.00 A resolution, respectively. Under normal circumstances, MIBS catalyzes the cyclization of the naturally occurring, noncanonical 11-carbon isoprenoid substrate, 2-methylgeranyl diphosphate, which first undergoes an ionization-isomerization-ionization sequence through the tertiary diphosphate intermediate 2-methyllinalyl diphosphate to enable subsequent cyclization chemistry. MIBS does not exhibit catalytic activity with 2-fluorogeranyl diphosphate, and we recently reported the crystal structure of MIBS complexed with this unreactive substrate analogue [ Koeksal, M., Chou, W. K. W., Cane, D. E., Christianson, D. W. (2012) Biochemistry 51, 3011-3020 ]. However, cocrystallization of MIBS with the fluorinated analogue of the tertiary allylic diphosphate intermediate, 2-fluorolinalyl diphosphate, reveals unexpected reactivity for the intermediate analogue and yields the crystal structure of the complex with the primary allylic diphosphate, 2-fluoroneryl diphosphate. Comparison with the structure of the unliganded enzyme reveals that the crystalline enzyme active site remains partially open, presumably due to the binding of only two Mg2+ ions. Assays in solution indicate that MIBS catalyzes the generation of (1R)-(+)-camphor from the substrate 2-fluorolinalyl diphosphate, suggesting that both 2-fluorolinalyl diphosphate and 2-methyllinalyl diphosphate follow the identical cyclization mechanism leading to 2-substituted isoborneol products; however, the initially generated 2-fluoroisoborneol cyclization product is unstable and undergoes elimination of hydrogen fluoride to yield (1R)-(+)-camphor.
- Koeksal, Mustafa,Chou, Wayne K. W.,Cane, David E.,Christianson, David W.
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p. 5247 - 5255
(2013/09/02)
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- Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
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Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).
- Jakobsche, Charles E.,Peris, Gorka,Miller, Scott J.
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supporting information; experimental part
p. 6707 - 6711
(2009/03/12)
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- Iridium-catalyzed asymmetric hydrogenation of fluorinated olefins using N,P-ligands: A struggle with hydrogenolysis and selectivity
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To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type. Copyright
- Engman, Mattias,Diesen, Jarle S.,Paptchikhine, Alexander,Andersson, Pher G.
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p. 4536 - 4537
(2007/10/03)
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- Synthesis of α-fluorinated phosphonoacetate derivatives using electrophilic fluorine reagents: Perchloryl fluoride versus 1-chloromethyl-4- fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor)
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Triethyl fluorophosphonoacetate and triethyl difluorophosphonoacetate are directly synthesized from triethyl phosphonoacetate by treatment with NaH and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor). Contrary to a recent report [C.J. Hamilton, S.M. Roberts, J. Chem. Soc., Perkin Trans. 1 (1999) 1051-1056], the reaction proceeded in THF without the need for DMF as a co-solvent. This method is more selective and provides greater convenience and safety than fluorination of the same substrate by treatment with t-BuOK and perchloryl fluoride (FClO3) in toluene while offering advantages over a number of previously described methods employing alternative electrophilic fluorinating reagents or other approaches. Either the monofluoro or the difluoro product can be obtained predominantly by adjusting the molar ratio of base and Selectfluor. Triethyl 2-fluoro-2-phosphonopropionate (ethyl 2-(diethoxyphosphinyl)-2-fluoropropanoate) is also more conveniently made from triethyl 2-phosphonopropanoate using NaH/Selectfluor in THF than with FClO3/t-BuOK in toluene. Detailed procedures are given for obtaining the corresponding triacids in quantitative yield from the fluorinated triesters by P,P-silyldealkylation with bromotrimethylsilane followed by one-pot double hydrolysis with H2O, and isolation as stable dicyclohexylammonium (DCHA) or pyridinium (Py) salts. Substitution of EtOH for H2O in the latter procedure provides the CO-ester phosphonic diacids, isolated as DCHA salts, in one step. 1H, 13C, 31P and 19F NMR data are given for the compounds prepared.
- Marma, Mong S.,Khawli, Leslie A.,Harutunian, Vahak,Kashemirov, Boris A.,McKenna, Charles E.
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p. 1467 - 1475
(2007/10/03)
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- Practical synthesis of DQ-113, a new quinolone antibacterial agent, by using the intramolecular Horner-Wadsworth-Emmons reaction
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A practical route was developed for synthesizing the C-7 substituent of DQ-113 (6, 5-amino-7-[(3S,4R)-4-(1-aminocycloprop-1-yl)-3-fluoropyrrolidin-1-yl] -6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-1, 4-dihydro-8-methyl-4-oxoquinolin-3-carboxylic acid),
- Inagaki, Hiroaki,Takeda, Toshiyaki,Miyauchi, Rie N.,Kawakami, Katsuhiro,Takahashi, Hisashi,Takemura, Makoto
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p. 699 - 706
(2007/10/03)
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- Preparation of intermediates for fluorinated lignans by conjugated and tandem additions on 3-fluorofuran-2(5H)-one
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Two syntheses of 3-fluorofuran-2(5H)-one (1) based on Wittig-Horner reaction of ethyl (diethoxyphosphoryl)fluoroacetate (15) with 2-oxoethyl acetate (16) or on transformation of D-erythronolactone (10) are given. 3-Fluorofuran-2(5H)-one (1) and ethyl 2-fluorobut-2-enoate (2) undergo conjugate addition with soft nucleophiles based on arenecarboxaldehyde dithioacetals 7 to form 2-fluorolactones 3 and 2-fluoroalkanoates 4. Intermediate enolates can be trapped in the sense of tandem addition with arenecarboxaldehydes 8 or (arylmethyl)bromides 9 to form intermediates 5 and 6 for fluorolignans. Although the conjugate addition proceeds with low stereoselectivity yielding mixture of both diastereoisomers, the electrophile in tandem addition attacks the intermediary fluoroenolate exclusively anti to its bulky β-substituent in good accord with non-fluorinated furan-2(5H)-ones.
- Kvicala, Jaroslav,Vlasakova, Ruzena,Plocar, Jakub,Paleta, Oldrich,Pelter, Andrew
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p. 772 - 788
(2007/10/03)
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- Microwave irradiation in organophosphorus chemistry 1: The Michaelis-Arbuzov reaction
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A diverse series of phosphonate esters have been prepared using a domestic microwave oven. The microwave enhanced Michaelis-Arbuzov reaction shows remarkable rate acceleration under microwave irradiation and allows the facile synthesis, and in certain cases easy workup, of alkyl, α-substituted and aryl phosphonates.
- Kiddle, James J.,Gurley, Alison F.
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p. 195 - 205
(2007/10/03)
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- The preparation of (EtO)2P(O)CFHZnBr and (EtO)2P(O)CFHCu and their utility in the preparation of functionalized α-fluorophosphonates
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The organometallic reagent, (EtO)2P(O)CFHZnBr, was generated in situ in excellent yields via the reaction of (Eto)2P(O)CFHBr with zinc metal. Metathesis with Cu(I)Br gave (EtO)2P(O)CFHCu. The reagents exhibit excellent reactivity with substrates, such as allyl halides, alkynyl halides, vinyl halides, aryl halides and acyl or phosphoryl halides, and provide a useful one flask route to functionalized α-fluorophosphonates.
- Zhang, Xin,Weiming, Qiu,Burton, Donald J.
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p. 2681 - 2684
(2007/10/03)
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- Elemental fluorine. Part 9 : Catalysis of the direct fluorination of 2-substituted carbonyl compounds
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Catalysis of the reaction between fluorine and a range of 2-substituted carbonyl compounds has been investigated. Most notably, the preparation of diethyl-2-fluoromalonate has been achieved in high yield by fluorination of diethylmalonate in the presence of hydrated copper nitrate. Reactions between fluorine and carbanions derived from 2-substituted carbonyl compounds, including phosphonates, sulphones and nitriles, are also discussed.
- Chambers, Richard D.,Hutchinson, John
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- Synthesis of phenyl and ester substituted vinyl fluorides via reduction and olefination of esters
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A reduction-olefination sequence has been used to convert ethyl pentafluoropropanoate 6 to 1-fluoro-1-phenyl-2-pentafluoroethyl ethene 7 and ethyl 2,4,4,5,5,5-hexafluoro-2-pentenoate 8. Addition of lithium diethyl α-fluorobenzylphosphonate [(EtO)2P(O)CFPh]- Li+ 4 or lithium fluorocarboethoxymethylene dialkylphosphonate [(RO)2P(O)CFCO2Et]- Li+ 5 (R = Et, i-Pr) to a THF solution of fluorinated aldehydes prepared in situ from 6 and diisobutylaluminum hydride (DIBAL) affords the vinyl fluorides C2F5CH=CFPh 7 and C2F5CH=CFCO2Et 8 in good yields. However, yields of the final products 7 and 8 are low when in situ reduction of 6 to aldehyde was performed in the presence of lithium salts of 4 or 5.
- Tsai, Hou-Jen,Burton, Donald J.
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p. 135 - 145
(2007/10/03)
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- Synthesis of 2-fluoroabscisic acid: A potential photo-stable abscisic acid
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Novel fluorinated abscisic acid (ABA) analogs were synthesized by introducing fluorine through the Wittig reaction of α-ionone derivatives with triethyl phosphono-2-fluoroacetate. Molecular orbital calculations showed that the introduction of fluorine at the 2 position stabilized the configuration of the side chain.
- Kim, Bum Tae,Min, Yong Ki,Asami, Tadao,Park, No Kyun,Kwon, Oh Young,Cho, Kwang Yun,Yoshida, Shigeo
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p. 1797 - 1800
(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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- A ONE-POT SYNTHESIS OF UNSYMMETRICAL AND SYMMETRICAL TETRASUBSTITUTED α-FLUORO-α,β-UNSATURATED ESTERS
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Acylation of -Li+ 1 with acid chlorides RC(O)Cl or phosgene ClC(O)Cl and subsequent reaction of the acylated phosphonate with organometallic reagents (R'M) provide unsymmetrical and symmetrical tetrasubstituted α-f
- Tsai, Hou-Jen,Thenappan, Alagappan,Burton, Donald J.
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p. 205 - 212
(2007/10/02)
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- α-phosphonocarboxylate squalene synthetase inhibitors
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α- Phosphonocarboxylate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula STR1 wherein R1 is a lipophilic group which contains at least 7 carbons and is substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted aryl; Z is H, halogen, hydroxy, hydroxyalkyl or lower alkyl; R2 and R3 are independently H, metal ion or other pharmaceutically acceptable cation, or a prodrug ester; R4 is H, metal ion or other pharmaceutically acceptable cation, lower alkyl, lower alkenyl, arylalkyl, aryl or a prodrug ester.
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- A Novel Intramolecular Horner-Wadsworth-Emmons Reaction: A Simple and General Route to α-Fluoro-α,β-unsaturated Diesters
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Diethyl (fluorocarbethoxymethyl)phosphonate (1), prepared from triethyl phosphite and ethyl bromofluoroacetete, reacts with n-butyllithium in THF to give the phosphonate carbanion 2.Addition of the pregenerated carbanion 2 to a THF solution of methyl or ethyl oxalyl chloride at -78 deg C forms the acylated phosphonate (EtO)2P(O)CF(COCO2R)CO2Et (3).In situ reaction of 3 with Grignard reagents affords α-fluoro-α,β-unsaturated diesters R'(CO2R)C=CFCO2Et in moderate to good yields with high E-stereoselectivity.The reaction is applicable to primary, secondary, and tertiary alkyl, alkenyl, alkynyl, aryl, cyclohexyl, and perfluorinated Grignard reagents.The assignment of E and Z configuration is based on NOE experiment.The E/Z ratio of unsaturated diesters formed in the reaction varies with the metal ion and cosolvent.However, solvents and bases have little influence on the stereoselectivity.
- Tsai, Hou-Jen,Thenappan, Alagappan,Burton, Donald J.
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p. 7085 - 7091
(2007/10/02)
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- Phenyl or bicyclo-alkenylfluoro amide pesticides
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Compound of the formula (I): or a salt thereof, wherein Q1 is a phenyl ring or a fused bicyclic ring system containing 9 or 10 ring carbon atoms at least one ring being aromatic, or Q1 is a dihalovinyl group; Q is an alkyl chain containing 1 to 12 carbon atoms and optionally containing one or two oxygen atoms and/or an unsaturated group --CR7 =CR8 --, or --C=C--, wherein R7 and R8 are selected from hydrogen or halo; a is 0 or 1; b is 0 or 1; the sum of a and b is 0 or 1; R2, R3, R4, R5 and R6 are the same or different, and are independently selected from hydrogen, halo and C1-4 alkyl; R1 is selected from hydrogen and C1-6 hydrocarbyl optionally substituted by dioxalanyl, halo, cyano, trifluoromethyl, trifluoromethylthio or C1-6 alkoxy are disclosed which have pesticidal activity. Pesticidal formulations containing the compounds of the formula (I), their use in the control of pests and methods for their preparation are also disclosed.
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- Pesticidal cyclopropyl-2,4-dieneamides
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The present Application discloses pesticidally active compounds of the formula (I): or a salt thereof, wherein Q is an monocyclic aromatic ring. or fused bicyclic ring system of which at least one ring is aromatic containing 9 or 10 atoms of which one may be nitrogen and the rest carbon each optionally substituted, or Q is a dihalovinyl group or a group R6 --C C-- where R6 is C1-4 alkyl, tri C1-4 alkylsilyl, halogen or hydrogen; Q1 is a 1,2-cyclopropyl ring optionally substituted by one or more groups selected from C1-3 alkyl. halo, C1-3 haloalkyl, alkynyl, or cyano; R2,R3, R4 and R5 are the same or different with at least one being hydrogen and the others being independently selected from hydrogen, halo. C1-4 alkyl or C1-4 haloalkyl; X is oxygen or sulphur; and R1 is selected from hydrogen and C1-8 hydrocarbyl optionally substituted by dioxalanyl, halo, cyano, trifluoromethyl, trifluoromethylthio or C1-6 alkoxy. their preparation, pesticidal compositions containing them and their use against pests.
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- Pesticidal compounds
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The present invention provides a class of novel substituted bicyclooctanes which have pesticidal activity, particularly against arthropod pests. Pesticidal formulations containing the compounds of the formula (I), their use in the control of pests and methods for their preparation are also disclosed.
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- Pesticides
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Compound of the formula (I) are disclosed or a salt thereof, wherein Ar is an optionally substituted polycyclic ring system containing n rings, where n is the integer 2 or 3, at least n-1 rings being aromatic and containing one to three ring nitrogen atoms and optionally containing one or more additional heteroatoms; Q is an alkyl chain containing 1 to 12 carbon atoms and optionally containing a sulphur or one or two oxygen atoms; Q1 is a group (C(R2)=C(R3))a --(C(R4)=C(R5)) wherein a is 0 or 1, R2, R3, R4 and R5 are the same or different, at least two being hydrogen and the other two being independently selected from hydrogen, halo, C1-4 haloalkyl; X is oxygen or sulphur; and R1 is selected from hydrogen and C1-8 hydrocarbyl optionally substituted by dioxalanyl, halo, cyano, trifluoromethyl, trifluoromethylthio or C1-6 alkoxy are described which have activity particularly against arthropod pests. Pesticidal formulations containing the compounds of the formula (1), their use in the control of pests and method for their preparation are also disclosed.
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- Acylation of Fluorocarbethoxy-Substituted Ylids: A Simple and General Route to α-Fluoro β-Keto Esters
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(Fluorocarbethoxymethylene)tri-n-butylphosphorane (3) reacts with acid chlorides and anhydrides to form the corresponding carbon acylated phosphonium salt 4, and hydrolysis of 4 under mild basic conditions provides RCOCFHCOOEt (8) in moderate yields.The reaction is applicable to primary, secondary, tertiary, cyclic, aromatic, and ester-substituted acid chlorides.Acylation with ethyl chloroformate and ethyl chlorothioformate leads to the diesters CFH(COOEt)2 and EtSCOCFHCOOEt.Extension of this reaction sequence to perfluorinated and partially fluorinated acid chlorides did not proceed cleanly to give the expected phosphonium salts.However, the anion derived from (EtO)2P(O)CFHC(O)OEt reacts with RFCOCl to form the corresponding C-acylated phosphonates 10, and hydrolysis of 10 gives RFCOCFHCOOEt.
- Thenappan, Alagappan,Burton, Donald J.
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p. 273 - 277
(2007/10/02)
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- Reduction-Olefination of Esters: A New and Efficient Synthesis of α-Fluoro α,β-Unsaturated Esters
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A reduction-olefination sequence has been used to convert esters to α-fluoro α,β-unsaturated esters.In the presence of diisobutylaluminum hydride, esters are reduced to aldehydes that react in situ with -Li+ to form the title compounds in good yield with high stereoselectivity.The reaction is applicable to aliphatic, aromatic, cyclic, unsaturated, perfluorinated, and partially fluorinated esters.The E/Z ratio of unsaturated esters formed in the reaction varies with the cations present in the reaction mixture.Solvents have very little influence on stereochemistry.The sequential transformation of PhC(O)OBun to (E)-PhCH=CFC(O)OEt and then to (E,E)-PhCH=CFCH=CFC(O)OEt illustrates the scope of this methodology, which introduces a fluorine atom adjacent to an ester functionality with concomitant elongation of the chain by two carbon atoms.
- Thenappan, Alagappan,Burton, Donald J.
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p. 4639 - 4642
(2007/10/02)
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- Alkylation of (Fluorocarbethoxymethylene)-tri-n-butylphosphorane: A Facile Entry to α-Fluoroalkanoates
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(Fluorocarbethoxymethyl)trialkylphosphonium bromides 6, prepared from ethyl bromofluoroacetate and tertiary phosphines, react with n-butyllithium in THF to give the corresponding phosphoranes 7.Reaction of the pregenerated (fluorocarbethoxymethylene)tri-n-butylphosphorane 7a with primary alkyl iodides and activated alkyl bromides followed by in situ hydrolysis of the alkylated salts provides the fluoroalkanoates 9 in a one-pot reaction.In the case of secondary alkyl halides, no substitution was observed, the main reaction being decomposition of the phosphorane.However, the anion obtained from diisopropyl (fluorocarbethoxymethyl)phosphonate 10 b reacts with CH3CH(Ph)Br and (CH3)2CHI to afford the corresponding alkylated phosphonates in good yields.Displacement of the phosphonate moiety either by base-induced hydrolysis or by reduction was unsuccessful.
- Thenappan, Alagappan,Burton, Donald J.
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p. 2311 - 2317
(2007/10/02)
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