- Trifluoromethyl reagent as well as synthesis method and application thereof
-
The invention discloses a trifluoromethyl reagent as well as a synthesis method and application thereof, wherein the structural formula of the trifluoromethyl reagent is as shown in formula I in the specification. According to the invention, diphenyl trifluoromethylphosphine and iodomethane are used as raw materials, and are heated in an organic solvent to carry out an addition reaction to prepare the trifluoromethylation reagent. The method is simple and convenient in process, high in yield and capable of realizing 10-gram-level large-scale preparation; more importantly, the trifluoromethylation reagent can be used as a free radical and a nucleophilic reagent to be applied to free radical addition reaction and simple nucleophilic addition reaction to prepare different types of trifluoromethylation products, so that the method has important application value.
- -
-
Paragraph 0105-0109
(2022/01/08)
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- Photochemical C-H Activation Enables Nickel-Catalyzed Olefin Dicarbofunctionalization
-
Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.
- Campbell, Mark W.,Yuan, Mingbin,Polites, Viktor C.,Gutierrez, Osvaldo,Molander, Gary A.
-
supporting information
p. 3901 - 3910
(2021/04/06)
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- Highly enantioselective construction of CF3-bearing all-carbon quaternary stereocenters: Hiral spiro-fused bisoxazoline ligands with 1,1′-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction
-
A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared. The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields (up to 99%) and good to excellent enantioselectivies (up to > 99.9% ee). Moreover, a proposed model of chiral pocket revealed that the attack of indole from the Re-face of β-CF3-β-disubstituted nitroalkene was favorable.
- Bao, Robert Li-Yuan,Fu, Kang,Shi, Lei
-
supporting information
(2021/11/27)
-
- C1-Symmetric PNP Ligands for Manganese-Catalyzed Enantioselective Hydrogenation of Ketones: Reaction Scope and Enantioinduction Model
-
A family of ferrocene-based chiral PNP ligands is reported. These tridentate ligands were successfully applied in Mn-catalyzed asymmetric hydrogenation of ketones, giving high enantioselectivities (92%~99% ee for aryl alkyl ketones) as well as high efficiencies (TON up to 2000). In addition, dialkyl ketones could also be hydrogenated smoothly. Manganese intermediates that might be involved in the catalytic cycle were analyzed. DFT calculation was carried out to help understand the chiral induction model. The Mn/PNP catalyst could discriminate two groups with different steric properties by deformation of the phosphine moiety in the flexible 5-membered ring.
- Zeng, Liyao,Yang, Huaxin,Zhao, Menglong,Wen, Jialin,Tucker, James H. R.,Zhang, Xumu
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p. 13794 - 13799
(2020/11/30)
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- Process Development of Tryptophan Hydroxylase Inhibitor LX1031, a Drug Candidate for the Treatment of Irritable Bowel Syndrome
-
Two process routes for LX1031, a tryptophan hydroxylase inhibitor for the treatment of irritable bowel syndrome, were developed. They shared the same left-hand and right-hand starting materials as well as the penultimate intermediate. The chiral center in
- Bednarz, Mark S.,Iimura, Shinya,Kanamarlapudi, Ramanaiah C.,Lim, Ngiap-Kie,Wu, Wenxue,Yan, Jie,Zhang, Haiming,Zhao, Matthew M.
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p. 261 - 273
(2020/03/10)
-
- One-Pot Successive Turbo Grignard Reactions for the Facile Synthesis of α-Aryl-α-Trifluoromethyl Alcohols
-
A novel straightforward one-pot methodology for two successive turbo Grignard reagent (iPrMgCl·LiCl) reactions, was developed for a facile synthesis of α-aryl-α-trifluoromethyl alcohols, motifs of value in pharmaceutical chemistry. The method displayed broad functional group tolerance, including reducible groups. Dual roles of iPrMgCl·LiCl were exploited in the tandem reaction with commercially available iodoarenes or iodoheteroarenes and 2,2,2-trifluoroethyl trifluoroacetate. The process encompasses three successive reactions in a one-pot process: the iPrMgCl·LiCl-mediated iodine/magnesium-exchange reaction of iodoarenes or iodoheteroarenes; nucleophilic addition of various generated aryl or heteroarylmagnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate; and the reduction of in-situ generated aryl trifluoromethyl ketones with iPrMgCl·LiCl, to produce the corresponding α-aryl or α-heteroaryl-α-trifluoromethyl alcohols bearing various substituents, including reducible functional groups in good to excellent yields.
- Kani, Ryunosuke,Inuzuka, Toshiyasu,Kubota, Yasuhiro,Funabiki, Kazumasa
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supporting information
p. 4487 - 4493
(2020/06/01)
-
- A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis
-
Described is a physical organic study of the reduction of three sets of carbonyl compounds by the NADPH-dependent enzyme Clostridium acetobutylicum alcohol dehydrogenase (CaADH). Previous studies in our group have shown this enzyme to display broad substrate promiscuity, yet remarkable stereochemical fidelity, in the reduction of carbonyl compounds, including α-, β- and γ-keto esters (d -stereochemistry), as well as α,α-difluorinated-β-keto phosphonate esters (l -stereochemistry). To better mechanistically characterize this promising dehydrogenase enzyme, we report here the results of a Hammett linear free-energy relationship (LFER) study across three distinct classes of carbonyl substrates; namely aryl aldehydes, aryl β-keto esters and aryl trifluoromethyl ketones. Rates are measured by monitoring the decrease in NADPH fluorescence at 460 nm with time across a range of substrate concentrations for each member of each carbonyl compound class. The resulting v 0 versus [S] data are subjected to least-squares hyperbolic fitting to the Michaelis-Menton equation. Hammett plots of log(V max) versus σ X yield the following Hammett parameters: (i) for p -substituted aldehydes, ρ = 0.99 ± 0.10, ρ = 0.40 ± 0.09; two domains observed, (ii) for p -substituted β-keto esters ρ = 1.02 ± 0.31, and (iii) for p -substituted aryl trifluoromethyl ketones ρ = -0.97 ± 0.12. The positive sign of ρ indicated for the first two compound classes suggests that the hydride transfer from the nicotinamide cofactor is at least partially rate-limiting, whereas the negative sign of ρ for the aryl trifluoromethyl ketone class suggests that dehydration of the ketone hydrate may be rate-limiting for this compound class. Consistent with this notion, examination of the 13 C NMR spectra for the set of p -substituted aryl trifluo romethyl ketones in 2percent aqueous DMSO reveals significant formation of the hydrate (gem -diol) for this compound family, with compounds bearing the more electron-withdrawing groups showing greater degrees of hydration. This work also presents the first examples of the CaADH-mediated reduction of aryl trifluoromethyl ketones, and chiral HPLC analysis indicates that the parent compound α,α,α-trifluoroacetophenone is enzymatically reduced in 99percent ee and 95percent yield, providing the (S)-stereoisomer, suggesting yet another compound class for which this enzyme displays high enantioselectivity.
- Berkowitz, David B.,Kudalkar, Gaurav P.,Lee, Joshua D.,Tiwari, Virendra K.
-
supporting information
p. 237 - 247
(2020/02/18)
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- Chemoenzymatic Synthesis of an Odanacatib Precursor through a Suzuki-Miyaura Cross-Coupling and Bioreduction Sequence
-
A series of 1-aryl-2,2,2-trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)-alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)-enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo-1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium-catalyzed cross coupling between 1-(4-bromophenyl)-2,2,2-trifluoroethanone and 4-(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanone has been extensively studied. Finally, the desired (R)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L?1 d?1 productivity following a sequential approach.
- González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 5800 - 5807
(2019/11/05)
-
- Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands
-
The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.
- Brüning, Fabian,Nagae, Haruki,K?ch, Daniel,Mashima, Kazushi,Togni, Antonio
-
supporting information
p. 10818 - 10822
(2019/07/31)
-
- One-Pot and Reducible-Functional-Group-Tolerant Synthesis of α-Aryl- and α-Heteroaryl-α-Trifluoromethyl Alcohols via Tandem Trifluoroacetylation and MPV Type Reduction
-
We have developed a new one-pot synthesis of α-aryl- and α-heteroaryl-α-trifluoromethyl alcohols carrying not only arenes with electron-withdrawing groups but also electron-deficient nitrogen-containing heteroarenes, which are of increasing interest becau
- Funabiki, Kazumasa,Hayakawa, Ayaka,Kani, Ryunosuke,Inuzuka, Toshiyasu,Kubota, Yashuhiro
-
p. 5978 - 5984
(2019/08/30)
-
- Gas/Liquid-Phase Micro-Flow Trifluoromethylation using Fluoroform: Trifluoromethylation of Aldehydes, Ketones, Chalcones, and N-Sulfinylimines
-
A micro-flow nucleophilic trifluoromethylation of carbonyl compounds using gaseous fluoroform was developed. This method also allows the first micro-flow transformation of N-sulfinylimines into trifluoromethyl amines with excellent diastereoselectivity. To demonstrate the synthetic utility of this micro-flow synthesis, the formal micro-flow synthesis of Efavirenz is described.
- Hirano, Kazuki,Gondo, Satoshi,Punna, Nagender,Tokunaga, Etsuko,Shibata, Norio
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p. 406 - 410
(2019/02/13)
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- Nucleophilic fluorination facilitated by a CsF-CaF2 packed bed reactor in continuous flow
-
A simple to prepare, dry and handle packed bed reactor carrying CsF on CaF2, towards nucleophilic fluorinations in continuous flow, is reported. The reactor also proved adaptable for silyl-ether deprotection and trifluoromethylations with Ruppert's reagent. The study includes reactor stability and scale-up investigations.
- Johansen,Lindhardt
-
supporting information
p. 825 - 828
(2018/02/06)
-
- Visible light-promoted umpolung coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines
-
Tertiary alcohols bearing a trifluoromethyl group are of considerable medicinal interest. Using an umpolung strategy, we herein report the first intermolecular reductive cross-coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines with the aid of a Br?nsted acid catalyst upon visible-light irradiation. This metal-free reaction is operationally simple and performed at ambient temperature, allowing access to desired tertiary alcohols with tri-/difluoromethyl groups in moderate to excellent yields. The commercially available and easily handled Hantzsch ester effectively serves as an electron donor, as well as a hydrogen atom source.
- Xu, Xiao,Min, Qing-Qiang,Li, Na,Liu, Feng
-
supporting information
p. 11017 - 11020
(2018/10/08)
-
- METHOD FOR PRODUCING TRIFLUOROMETHYL GROUP-CONTAINING ALCOHOLS
-
PROBLEM TO BE SOLVED: To provide a method for producing trifluoromethyl group-containing alcohols useful as synthetic intermediates for medicines and agrochemicals. SOLUTION: This invention relates to a method for producing trifluoromethyl group-containing alcohols expressed by a formula (2), comprising: making carbonyl compounds expressed by a formula (1) react with trifluoromethane in an organic solvent in the presence of polyvalent ethers and potassium tert-butoxide, or kalium hexamethyldisilazide. (R1 and R2 are each independently a phenyl group etc.; R2 may combine with R1, to form a ring, and both R1 and R2 are not hydrogen atoms). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0081; 0082; 0093
(2018/04/10)
-
- JAK kinase inhibitor and application
-
The present invention discloses a compound having the following general formula (I). The present invention also discloses a JAK kinase inhibitor comprising the compound and application of the compoundin preparation of a medicament for treating JAK-associated diseases. The JAK kinase inhibitor can inhibit the biological activities of JAK1, JAK2, JAK3 and TYK2 kinases involved in various kinds of signal transduction, can effectively treat various inflammatory diseases and various JAK-mediated signal transduction-driven diseases, and has a very broad application prospect.
- -
-
Paragraph 0059-0060; 0062-0064
(2018/09/08)
-
- Hydrogenation of Carbonyl Derivatives with a Well-Defined Rhenium Precatalyst
-
The first efficient and general rhenium-catalyzed hydrogenation of carbonyl derivatives was developed. The key to the success of the reaction was the use of a well-defined rhenium complex bearing a tridentate diphosphinoamino ligand as the catalyst (0.5 mol %) at 70 °C in the presence of H2 (30 bar). The mechanism of the reaction was investigated by DFT(PBE0-D3) calculations.
- Wei, Duo,Roisnel, Thierry,Darcel, Christophe,Clot, Eric,Sortais, Jean-Baptiste
-
-
- Hydrogenation of ketones with a manganese PN3P pincer pre-catalyst
-
A catalytic hydrogenation of carbonyl derivatives with a manganese pre-catalyst has been developed. The key feature is the use of an air stable cationic manganese pre-catalyst bearing a tridendate ligand with a 2,6-(diaminopyridinyl)diphosphine scaffold. Under 50?bar of H2, at 130?°C, various ketones were reduced to the corresponding alcohols with moderate to good yield.
- Bruneau-Voisine, Antoine,Wang, Ding,Roisnel, Thierry,Darcel, Christophe,Sortais, Jean-Baptiste
-
-
- ETHYL N-BOC PIPERIDINYL PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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Provided are compounds of Formula I as JAK inhibitors, which are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 41
(2016/05/24)
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- Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via CuI-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with β-CF3-β,β-Disubstituted Nitroalkenes
-
A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF3 group at the C-3 position of the pyrrolidine ring. The synthesis system, CuI/Si-FOXAP-catalyzed exo-selective 1,3-dipolar cycloaddition of azomethine ylides with β-CF3-β,β-disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.
- Tang, Li-Wei,Zhao, Bao-Jing,Dai, Li,Zhang, Man,Zhou, Zhi-Ming
-
supporting information
p. 2470 - 2477
(2016/09/13)
-
- A method of manufacturing a trifluoromethyl group-containing compound
-
PROBLEM TO BE SOLVED: To provide a method for producing a trifluoromethyl group-containing compound useful as a synthetic intermediate for a pharmaceutical or an agricultural chemical product.SOLUTION: There is provided a method for producing a trifluoromethyl group-containing compound represented by the following general formula (2) which is obtained by reacting a carbonyl compound having a specific structure with trifluoromethane and an organic base in an organic solvent (wherein, Rrepresents a methyl group, an ethyl group, a linear, branched or cyclic alkyl group having 3 to 10 carbon atoms, a phenyl group, a substituted phenyl group, a naphthyl group, a substituted naphthyl group, an ethenyl group, a 2-phenylethenyl group, a 9-anthryl group or a hetero ring; Rrepresents a hydrogen atom, a methyl group or a phenyl group.)
- -
-
Paragraph 0046; 0050; 0051
(2018/02/10)
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- Chemo- and Enantioselective Addition and β-Hydrogen Transfer Reduction of Carbonyl Compounds with Diethylzinc Reagent in One Pot Catalyzed by a Single Chiral Organometallic Catalyst
-
Using a single chiral phosphoramide-Zn(II) complex as the catalyst, the asymmetric β-H transfer reduction of aromatic α-trifluoromethyl ketones and enantioselective addition of aromatic aldehydes with Et2Zn in one pot were successfully realized, affording the corresponding additive products of secondary alcohols in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee) and the reduction products of α-trifluoromethyl alcohols in good to excellent yields with up to 77% ee.
- Huang, Huayin,Zong, Hua,Bian, Guangling,Song, Ling
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p. 12614 - 12619
(2016/01/09)
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- Synthesis of Perfluoroalkyl-Substituted Vinylcyclopropanes by Way of Enhanced Neighboring Group Participation
-
A simple, high yielding, two-step, one-pot protocol for the preparation of trifluoromethyl-substituted vinylcyclopropanes from α-CF3 homoallyl alcohols is disclosed. Destabilization of the cationic intermediate by the electron-withdrawing CF3 group greatly enhances neighboring group participation of the alkene, allowing ring closure to predominate. The reaction can be extended to the difluoromethyl and pentafluoroethyl group, enabling the preparation of a diverse array of fluoroalkyl-substituted vinylcyclopropanes. A diverse array of fluoroalkyl-substituted vinylcyclopropanes are prepared in a simple, high-yielding, two-step, one-pot protocol by means of cationic ring-closure.
- Kelly, Christopher B.,Mercadante, Michael A.,Carnaghan, Emma R.,Doherty, Matthew J.,Fager, Diana C.,Hauck, John J.,Macinnis, Allyson E.,Tilley, Leon J.,Leadbeater, Nicholas E.
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supporting information
p. 4071 - 4076
(2015/06/30)
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- Photoinduced additive-free trifluoromethylation of aromatic aldehydes with TMSCF3
-
We report herein a new and effective method for additive-free trifluoromethylation of aromatic aldehydes with TMSCF3. Normal acidic hydrolysis for desilylation in the workup process is not required in this transformation. This reaction presents
- Sun, Jing,Peng, Xinhua,Guo, Hao
-
supporting information
p. 797 - 800
(2015/01/30)
-
- Continuous flow whole cell bioreduction of fluorinated acetophenone
-
Several microorganism strains were used to reduce 2,2,2- trifluoroacetophenone (1) and 4′-Br-2,2,2-trifluoroacetophenone (3). Immobilized cells of Geotrichum candidum in calcium alginate led to conversion and enantiomeric excess higher than 99%. By using immobilized G. candidum cells under continuous flow conditions, the same conversion and enantiomeric excess were achieved in 90 min of residence time.
- De Oliveira Lopes, Raquel,Ribeiro, Joyce Benzaquem,Silva De Miranda, Amanda,Vieira Da Silva, Gabriela Veloso,Miranda, Leandro S.M.,Ramos Leal, Ivana Corrêa,Mendon?a Alves De Souza, Rodrigo Octavio
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p. 3239 - 3242
(2014/05/06)
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- CYCLOALKYL NITRILE PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
-
The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 62
(2014/10/03)
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- CYCLOALKYL NITRILE PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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Compounds of formula I are provided, which are JAK inhibitors and are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 73
(2014/10/03)
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- Polyfluoroalkylation of carbonyl compounds by polyfluoroalkyl anions generated from polyfluorocarboxamides
-
Polyfluoroalkyl anions, generated by reduction of (polyfluoroalkanoyl)piperidines with Et3BHK, were used for the polyfluoroalkylation of carbonyl compounds. Trifluoromethylation of aromatic aldehydes proceeded in good yields, and that of aliphatic aldehydes afforded a moderate yield. In contrast, the yield was low when the reaction involved benzophenone. Pentafluoroethylation and octafluorobutylation of aldehydes were also carried out by using the corresponding (polyfluoroalkanoyl)piperidines, which were prepared from commercially available polyfluorocompounds. The (polyfluoroalkanoyl)piperidines were also prepared through polyfluorination, and were used in the polyfluoroalkylation of aldehydes.
- Wakita, Natshumi,Hara, Shoji
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p. 1201 - 1212
(2016/11/07)
-
- Diversity-oriented approach to CF3CHF-, CF3CFBr-, CF3CF2-, (CF3)2CH-, and CF3(SCF3)CH-substituted arenes from 1-(Diazo-2,2,2-trifluoroethyl)arenes
-
Arenes substituted with perfluoroalkyl groups are attractive targets for drug and agrochemical development. Exploiting the carbenic character of donor/acceptor diazo compounds, a diversity-oriented synthesis of perfluoroalkylated arenes, for late stage fluorofunctionalization, is described. The reaction of 1-(diazo-2,2,2-trifluoroethyl)arenes with HF, F/Br, F2, CF3H, and CF3SH sources give direct access to a variety of perfluoroalkyl-substituted arenes presenting with incremental fluorine content. The value of this approach is also demonstrated for radiochemistry and positron emission tomography with the [18F]-labeling of CF3CHF-, CF3CBrF-, and CF3CF2-arenes from [18F]fluoride.
- Emer, Enrico,Twilton, Jack,Tredwell, Matthew,Calderwood, Samuel,Collier, Thomas Lee,Ligault, Benot,Taillefer, Marc,Gouverneur, Vronique
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supporting information
p. 6004 - 6007
(2015/01/09)
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- Combined batch and continuous flow procedure to the chemo-enzymatic synthesis of biaryl moiety of Odanacatib
-
The development of chemo-enzymatic reaction under continuous flow conditions is an emerging area where biotechnology and organic chemistry can joint efforts in order to develop better process. Here in we report our effort on the development of a continuou
- De Oliveira Lopes, Raquel,De Miranda, Amanda S.,Reichart, Benedikt,Glasnov, Toma,Kappe, C. Oliver,Simon, Robert C.,Kroutil, Wolfgang,Miranda, Leandro S.M.,Leal, Ivana C.R.,De Souza, Rodrigo O.M.A.
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p. 101 - 107
(2014/05/06)
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- N-(2-CYANO HETEROCYCLYL)PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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Provided are compounds of Formula I, a JAK inhibitor, and use thereof for the treatment of JAK-mediated diseases by the application.
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Page/Page column 56-57
(2014/10/03)
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- ACYCLIC CYANOETHYLPYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
- -
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Page/Page column 62
(2014/10/03)
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- GEMINALLY SUBSTITUTED CYANOETHYLPYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
-
The instant invention provides compounds of Formula (I) which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
- -
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Page/Page column 89; 109
(2014/10/03)
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- The enantioselective trifluoromethylation of aromatic aldehydes by quaternary ammonium bromide and (IPr)CuF at low catalyst loading
-
A general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF and quinidine-derived quaternary ammonium salt as catalysts has been developed. A wide range of aromatic aldehydes are converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading.
- Wu, Shaoxiang,Guo, Jiyi,Sohail, Muhammad,Cao, Chengyao,Chen, Fu-Xue
-
-
- CYCLOALKYLNITRILE PYRAZOLE CARBOXAMIDES AS JANUS KINASE INHIBITORS
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Cycloalkylnitrile pyrazole carboxamides as JAK inhibitors useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer are provided.
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Page/Page column 104
(2013/04/10)
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- Direct monofluoromethylation of O-, S-, N-, and P-nucleophiles with PhSO(NTs)CH2F: The accelerating effect of α-fluorine substitution
-
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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- Trifluoromethylation of ketones and aldehydes with Bu3SnCF 3
-
The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH 4Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.
- Sanhueza, Italo A.,Bonney, Karl J.,Nielsen, Mads C.,Schoenebeck, Franziska
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p. 7749 - 7753
(2013/09/02)
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- Highly efficient synthesis of aryl and heteroaryl trifluoromethyl ketones via o-iodobenzoic acid (IBX)
-
A two-step process for the synthesis of aryl and heteroaryl trifluoromethyl ketones from the corresponding aldehydes is described. Trifluoromethyl alcohols were prepared from aryl and heteroaryl aldehydes in excellent yields using catalytic amount of K2CO3. The trifluoromethyl alcohols were then oxidized conveniently and efficiently by o-iodoxybenzoic acid (IBX) under mild conditions to get the desired functionalized aryl and heteroaryl trifluoromethyl ketones.
- Cheng, Huicheng,Pei, Yu,Leng, Faqiang,Li, Jingya,Liang, Apeng,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
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p. 4483 - 4486
(2013/07/26)
-
- METALLOENZYME INHIBITOR COMPOUNDS
-
The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 71
(2013/07/05)
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- Nucleophilic trifluoromethylation of carbonyl compounds: Trifluoroacetaldehyde hydrate as a trifluoromethyl source
-
A feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atom-economical trifluoromethyl source. The reaction was found to be applicable to the nucleophilic trifluoromethylation of a broad spectrum of carbonyl compounds with satisfactory yields in general. DFT calculations have been performed to provide mechanistic insight into the present and related reactions employing 2,2,2-trifluoro-1- methoxyethanol and hexafluoroacetone hydrate.
- Surya Prakash,Zhang, Zhe,Wang, Fang,Munoz, Socrates,Olah, George A.
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p. 3300 - 3305
(2013/06/27)
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- A sterically demanding organo-superbase avoids decomposition of a naked trifluoromethyl carbanion directly generated from fluoroform
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A simple strategy avoiding the decomposition of a naked trifluoromethyl anion to difluorocarbene by a sterically very demanding organo-superbase without the help of a trifluoromethyl anion reservoir such as DMF is reported. The direct non-metallic trifluoromethylation of carbonyl compounds using fluoroform in the presence of t-Bu-P4 base afforded trifluoromethyl alcohols in high yields.
- Kawai, Hiroyuki,Yuan, Zhe,Tokunaga, Etsuko,Shibata, Norio
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supporting information
p. 1446 - 1450
(2013/05/09)
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- Potent BRAF kinase inhibitors based on 2,4,5-trisubstituted imidazole with naphthyl and benzothiophene 4-substituents
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The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC50 = 190 nM and with cellular GI50 = 2100 nM, and 6-{2-[4-(2- dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC50 = 9 nM and GI50 = 220 nM.
- Niculescu-Duvaz, Dan,Niculescu-Duvaz, Ion,Suijkerbuijk, Bart M.J.M.,Ménard, Delphine,Zambon, Alfonso,Davies, Lawrence,Pons, Jean-Francois,Whittaker, Steven,Marais, Richard,Springer, Caroline J.
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p. 1284 - 1304
(2013/03/14)
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- Enzymatic resolution by CALB of organofluorine compounds under conventional condition and microwave irradiation
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Enzymatic kinetic resolution of organofluorine rac-alcohols by CALB yielded ( )-(R)-2,2,2-trifluoro-1- phenylethanol (2a), ()-(R)-1-(3-bromophenyl)-2,2,2- trifluoroethanol (2b), ()-(R)-1-(4-bromophenyl)- 2,2,2-trifluoroethanol (2c), ()-(S)-1-(2,4,5-trifluorophenyl)ethanol (2d), (+)-(S)-2,2,2-trifluoro-1- phenylethyl acetate (3a), (+)-(S)-1-(3-bromophenyl)-2,2,2-trifluoroethyl acetate (3b), (+)-(S)-1-(4- bromophenyl)-2,2,2-trifluoroethyl acetate (3c) and (+)-(R)-1-(2,4,5-trifluorophenyl)ethyl acetate (3d) in high enantiomeric excess (up to >99% ee). The reactions were conducted under conventional conditions (orbital shaking) and microwave irradiation in toluene and vinyl acetate as acylating agent. The CALB showed excellent selectivities and good yields in the transesterification of fluorinated aromatic compounds.
- Ribeiro, Sandra S.,Raminelli, Cristiano,Porto, André L.M.
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- Asymmetric trifluoromethylation of aromatic aldehydes by cooperative catalysis with (IPr)CuF and quinidine-derived quaternary ammonium salt
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A general enantioselective trifluoromethylation of aldehydes has been developed using (IPr)CuF and quinidine-derived quaternary ammonium salt as the cooperative catalyst. Thus, a wide range of aromatic aldehydes have been converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading. The greatly enhanced activity and enantioselectivity result from the initiative generation of active [(IPr)CuCF3] as well as additional coordination activation of other copper species.
- Wu, Shaoxiang,Zeng, Wei,Wang, Qi,Chen, Fu-Xue
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supporting information
p. 9334 - 9337
(2013/01/15)
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- Investigation into the enantioselection mechanism of ruthenium-arene- diamine transfer hydrogenation catalysts using fluorinated substrates
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The effects of both steric and electronic properties of ketones on the selectivity in asymmetric transfer hydrogenation have been studied with aryl alkyl/fluoroalkyl ketones using four ruthenium based catalysts and two different media. The 1-arylethanones, 1-aryl-2-fluoroethanones and 2,2- difluoroacetophenones could be reduced with medium to high ee (86-99%), while the 1-aryl-2,2,2-trifluoroethanones were reduced with low selectivity in most systems. The change in enantioselectivity upon structural variation has been rationalised aided by regression analysis with substituent constants and the partial charge of the carbonyl carbon as predictors. The steric bulk of the alkyl/fluoroalkyl chain was found to be the major factor in determining selectivity in formic acid/triethylamine, while for reduction of a series of substituted 1-arylethanones and 1-aryl-2-fluoroethanones, the selectivity was found to depend on the electronic properties of the aromatic ring, supporting previous evidence that π-π interaction between the substrate and catalyst is important in determining the selectivity. For reductions in water using sodium formate as the hydrogen donor, altered and more complex selectivity mechanisms were observed. Experiments and regression focused on the variation of the alkyl/fluoroalkyl group of phenyl and 1-naphthyl ketones, showed that the selectivity correlated with the size of the substituent, but also the partial charge of the carbonyl carbon.
- Slungrd, Sigrid Volden,Krakeli, Tor-Arne,Thvedt, Thor Hkon Krane,Fuglseth, Erik,Sundby, Eirik,Hoff, Brd Helge
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experimental part
p. 5642 - 5650
(2011/08/22)
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- Enantioselectivity, swelling and stability of 4-hydroxyprolinol containing acrylic polymer beads in the asymmetric reduction of ketones
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A new 4-hydroxy-α,α-diphenyl-l-prolinol containing polymethacrylate, prepared without chromatography by a large scale adaptable synthesis, has been evaluated as a catalyst in the asymmetric reduction of 1-arylethanones. Using 1-(4-bromophenyl)ethanone as the model substance, the reduction was tested with various borane sources and solvents. The best swellings of the polymer and reactivity were observed in THF using N,N-diethylaniline borane complex as the hydride source. The selectivity in the reduction of 1-(4-bromophenyl)ethanone was found to depend on the substrate concentration and catalyst loading. Using the best conditions identified, a series of 1-arylethanones was reduced to their corresponding enantioenriched secondary alcohols. High rates and ee-values were obtained in the reduction of acetophenones containing electron withdrawing groups in the aromatic ring, whereas a moderate selectivity was the result for products containing electron donating aromatic substituents. Upon recovery of the polymer beads, it was found that vacuum drying led to extensive rupturing, while the bead structure was intact if washed with methanol and air dried at atmospheric pressure. Repeated use of the polymer catalyst gave the product alcohol with a lower 90% ee. Elemental analysis showed this to be due to the loss of the chiral prolinol unit.
- Krane Thvedt, Thor H.,Kristensen, Tor Erik,Sundby, Eirik,Hansen, Tore,Hoff, Brd Helge
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scheme or table
p. 2172 - 2178
(2012/03/27)
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- Iron dihydride complex as the pre-catalyst for efficient hydrosilylation of aldehydes and ketones under visible light activation
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A general and efficient hydrosilylation of aldehydes and ketones into the corresponding alcohols using the well-defined bis(diphenylphosphinoethane)iron dihydride complex as the pre-catalyst is reported using polymethylhydrosiloxane (PMHS) as the reducing silylating agent and sodium tetraethoxyborate [NaB(OEt)4] as a co-catalyst under visible light irradiation. The low catalyst loadings (0.1-1 mol%), the amount of economical hydride source, PMHS and the unconventional way of activation of the pre-catalyst make this new approach attractive.
- Castro, Luis C. Misal,Bezier, David,Sortais, Jean-Baptiste,Darcel, Christophe
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supporting information; experimental part
p. 1279 - 1284
(2011/06/26)
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- Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones
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Synthesis of novel C2-symmetric chiral crown ethers and their application to enantioselective trifluoromethylation of aldehydes and ketones are discussed. The use of a series of C2-symmetric chiral crown ethers 2 or 3 derived from commercially available (R)-1,1′-bi-2-naphthol for the enantioselective trifluoromethylation of 2-naphthyl aldehyde 1a with (trifluoromethyl)trimethylsilane in the presence of a base was attempted. Iodo-substituted crown ether 2b was found to be the most effective in the model reaction. Moderate enantioselectivities were observed for the trifluoromethylation of both aryl or alkyl aldehydes and alkyl aryl ketones in 21-44% ees. Although the ees are still improvable, this is the first example of a chiral crown ether-catalyzed enantioselective trifluoromethylation reaction.
- Kawai, Hiroyuki,Kusuda, Akihiro,Mizuta, Satoshi,Nakamura, Shuichi,Funahashi, Yasuhiro,Masuda, Hideki,Shibata, Norio
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scheme or table
p. 762 - 765
(2009/12/26)
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- SOLID FORMS OF (S)-2-AMINO-3-(4-(2-AMINO-6-((R)-2,2,2-TRIFLUORO-1-(3'-METHOXYBIPHENYL- 4-YL)ETHOXY)PYRIMIDIN-4-YL)PHENYL) PROPANOIC ACID AND METHODS OF THEIR USE
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Solid forms of (S)-2-amino-3-(4-(2-amino-6-((R)-2,2,2-trifluoro-1-(3'-methoxybiphenyl-4-yl)ethoxy)pyrimidin-4-yl)phenyl)propanoic acid and salts thereof are disclosed
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Page/Page column 4
(2009/04/24)
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- METHODS OF TREATING SEROTONIN-MEDIATED DISEASES AND DISORDERS
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Methods are disclosed for treating serotonin-mediated diseases and disorders, which comprise inhibiting tryptophan hydroxylase (TPH) in patients in need thereof.
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- METHODS OF USING AND COMPOSITIONS COMPRISING TRYPTOPHAN HYDROXYLASE INHIBITORS
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Methods and compositions comprising tryptophan hydroxylase inhibitors are disclosed. Particular methods are directed at reducing or avoiding serotonin-mediated adverse effects associated with some drugs.
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