- Direct Synthesis of Tri-/Difluoromethyl Ketones from Carboxylic Acids by Cross-Coupling with Acyloxyphosphonium Ions
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A simple and straightforward approach to the synthesis of trifluoromethyl and difluoromethyl ketones from widely available carboxylic acids is disclosed. The transformation utilizes an acyloxyphosphonium ion as the active electrophile, conveniently generated in situ from the carboxylic acid substrate by using commodity chemicals. The utility of the reaction system is exemplified by its chemoselectivity, with tolerance to a variety of important functional groups. The late-stage functionalization of carboxylic acid active pharmaceutical ingredients and pharmaceutically relevant compounds is also discussed.
- Ispizua-Rodriguez, Xanath,Munoz, Socrates B.,Krishnamurti, Vinayak,Mathew, Thomas,Prakash
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supporting information
p. 15908 - 15913
(2021/10/07)
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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
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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
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supporting information
(2021/11/27)
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- Trifluoromethylation of Benzoic Acids: An Access to Aryl Trifluoromethyl Ketones
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The trifluoromethylation of benzoic acids with TMSCF3 was achieved through nucleophilic substitution with the use of anhydrides as an in situ activating reagent. Under the reaction conditions, a wide range of carboxylic acids including the bioactive ones worked well, thus providing a facile and efficient method for preparing aryl trifluoromethyl ketones from the readily available starting materials.
- Liu, Xue,Liu, Long,Huang, Tianzeng,Zhang, Jingjing,Tang, Zhi,Li, Chunya,Chen, Tieqiao
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supporting information
p. 4930 - 4934
(2021/06/30)
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- Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system
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A straightforward method that enables the formation of biologically attractive trifluoromethyl ketones from readily available methyl esters using the potent greenhouse gas fluoroform (HCF3, HFC-23) was developed. The combination of fluoroform and KHMDS in triglyme at ?40 °C was effective for this transformation, with good yields as high as 92%. Substrate scope of the trifluoromethylation procedure was explored for aromatic, aliphatic, and conjugated methyl esters. This study presents a straightforward trifluoromethylation process of various methyl esters that convert well to the corresponding trifluoromethyl ketones. The tolerance of various pharmacophores under the reaction conditions was also explored.
- Fujihira, Yamato,Liang, Yumeng,Ono, Makoto,Hirano, Kazuki,Kagawa, Takumi,Shibata, Norio
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supporting information
p. 431 - 438
(2021/03/20)
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- Synthesis of Enantioenriched α,α-Difluoro-β-arylbutanoic Esters by Pd-Catalyzed Asymmetric Hydrogenation
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Synthesis of optically active gem-difluorinated organic molecules attracts a great deal of interest due to their unique properties in pharmaceutical and agrochemical areas. Herein, a series of enantioenriched α,α-difluoro-β-arylbutanoic esters were prepar
- Dong, Kaiwu,Feng, Sitian,Shen, Chaoren,Tang, Yitian,Yang, Chenjue
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p. 7508 - 7512
(2020/10/09)
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- Palladium-catalyzed fluoroacylation of (Hetero)arylboronic acid with fluorothioacetates at ambient temperature
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A palladium-catalyzed fluoroacylation of (hetero)aryl boronic acid with the fluorothioacetates is described at ambient temperature. A variety of aryl, and heteroaryl boronic acids are compatible in the reaction, affording the corresponding fluoroalkyl ketones in moderate to good yields. Further late-stage di-, and trifluoroacylation of drug molecule clofibrate and estrone demonstrated the synthetic practicability of this protocol.2009 Elsevier Ltd. All rights reserved.
- Ban, Shu-Rong,Cao, Ya-Fang,Dai, Hui-Xiong,Wang, Xing,Xu, Hui,Yi, Xing
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supporting information
(2020/03/23)
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- Fluoroform: an Efficient Precursor for the Trifluoromethylation of Aromatic Esters by Sodium Diisopropylamide with Trialkylamines
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The trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. It is believed to be incompatible with Na+ cation due to the strong Na–F bond. However, herein we demonstrate that it could be prepared for the first time. Trialkylamines can be used as cation chelating agents to stabilize the isolated –CF3 ion to realize trifluoromethylation reaction. With this strategy, trifluoromethyl aromatic ketones could be effectively synthesized from fluoroform and aromatic esters with diisopropyl aminosodium (NaDA) and trialkylamines.
- Han, Zhaomeng,Chen, Sihan,Tu, Yongjun,Lian, Xiongdong,Li, Gongyong
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supporting information
p. 4658 - 4661
(2019/08/07)
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- Enantioselective Synthesis of Trifluoromethyl α,β-Unsaturated δ-Lactones via Vinylogous Aldol-Lactonization Cascade
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The novel vinylogous aldol-lactonization cascade of alkylidene oxindole with trifluoromethyl ketones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of alkylidene oxindoles for the preparation of enantioenriched trifluoromethylated α,β-unsaturated δ-lactones.
- Crotti, Simone,Di Iorio, Nicola,Mazzanti, Andrea,Righi, Paolo,Bencivenni, Giorgio
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p. 12440 - 12448
(2018/10/09)
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- Enantioselective Palladium-Catalyzed [3+2] Cycloaddition of Trimethylenemethane and Fluorinated Ketones
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A nitrile-substituted trimethylenemethane (TMM) donor undergoes palladium-catalyzed [3+2] cycloadditions with fluorinated ketones to generate tetrasubstituted trifluoromethylated centers in high enantioselectivity under mild conditions. The generation of the palladium–TMM complex was achieved by a self-deprotonation strategy, which shows remarkable improvements in regiocontrol, efficiency, and atom economy of asymmetric [3+2] cycloadditions. Moreover, the versatility of the nitrile group provides direct access to a variety of synthetically useful intermediates, including amides, aldehydes, and esters. The developed reaction conditions allow for the synthesis of a wide variety of aromatic, heteroaromatic, and aliphatic fluorinated dihydrofurans in excellent regio- and enantioselectivities.
- Trost, Barry M.,Mata, Guillaume
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supporting information
p. 12333 - 12337
(2018/09/10)
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- Visible light-promoted umpolung coupling of aryl tri-/difluoroethanones with 2-alkenylpyridines
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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
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p. 11017 - 11020
(2018/10/08)
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- Copper-Mediated Trifluoroacetylation of Arenediazonium Salts with Ethyl Trifluoropyruvate
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A copper-mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines.
- Wu, Wei,Tian, Qinli,Chen, Taotao,Weng, Zhiqiang
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supporting information
p. 16455 - 16458
(2016/11/11)
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- High-Pressure-Mediated Asymmetric Organocatalytic Hydroxyalkylation of Indoles with Trifluoromethyl Ketones
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An enantioselective hydroxyalkylation of indoles and 7-azaindole with trifluoromethyl ketones was found to be effectively promoted under high-pressure conditions with a low loading of Cinchona alkaloids (e.g., 1–3 mol% of cinchonidine). Chiral tertiary alcohols containing a trifluoromethyl group were obtained at 9 kbar with good yield and enantioselectivity up to 89%, whereas usually merely traces of products were detected at atmospheric pressure. (Figure presented.).
- Kasztelan, Adrian,Biedrzycki, Micha?,Kwiatkowski, Piotr
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supporting information
p. 2962 - 2969
(2016/09/16)
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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
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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
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p. 2470 - 2477
(2016/09/13)
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- Catalytic highly enantioselective transfer hydrogenation of β-trifluoromethyl nitroalkenes. An easy and general entry to optically active β-trifluoromethyl amines
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In the presence of a thiourea catalyst, β-CF3 nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of β-CF3 amine precursors with a tertiary stereocentre at the β-position. This reaction
- Martinelli, Emilie,Vicini, Anna Chiara,Mancinelli, Michele,Mazzanti, Andrea,Zani, Paolo,Bernardi, Luca,Fochi, Mariafrancesca
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p. 658 - 660
(2015/01/09)
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- Catalytic asymmetric hydrogenation of α-CF3- or β-CF3-Substituted acrylic acids using Rhodium(I) complexes with a combination of chiral and achiral ligands
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Only the mixture works! Acrylic acid derivatives with CF3 substituents in α or β position were efficiently hydrogenated in the presence of a RhI complex with a chiral secondary phosphine oxide (SPO; see scheme) and an achiral Ph3P as ligands. The corresponding propanoic acid derivatives were obtained with generally high conversion (>99 %) and high enantioselectivity (92->99 %). Copyright
- Dong, Kaiwu,Li, Yang,Wang, Zheng,Ding, Kuiling
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supporting information
p. 14191 - 14195
(2014/01/06)
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- Design, synthesis and evaluation of novel hydroxyamides as orally available anticonvulsants
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Themisone, also known as Atrolactamide, was found, in the 1950s, to be a very potent anticonvulsant. It was hypothesized that the -CF3 substitution would maintain the anticonvulsant activity. Anticonvulsant testing of our novel compounds by the
- Schenck, Hilary A.,Lenkowski, Paul W.,Choudhury-Mukherjee, Indrani,Ko, Seong-Hoon,Stables, James P.,Patel, Manoj K.,Brown, Milton L.
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p. 979 - 993
(2007/10/03)
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- Catalytic aerobic oxidative decarboxylation of α-trifluoromethyl-α-hydroxy acids to trifluoromethyl ketones
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The oxidative decarboxylation of α-trifluoromethyl-α-hydroxy acids to trifluoromethyl ketones is carried out under mild catalytic aerobic conditions using a cobalt(III) complex in the presence of pivalaldehyde.
- Blay, Gonzalo,Fernández, Isabel,Marco-Aleixandre, Alicia,Monje, Belén,Pedro, José R,Ruiz, Rafael
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p. 8565 - 8571
(2007/10/03)
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- Synthesis of trifluoromethyl ketones by palladium-catalyzed cross-coupling reaction of phenyl trifluoroacetate with organoboron compounds
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Cross-coupling reaction of aryl trifluoroacetates with organoboron compounds catalyzed by palladium complexes gives trifluoromethyl ketones in moderate to excellent yields under mild conditions. The catalytic process has been designed on the basis of fundamental studies dealing with oxidative addition of phenyl trifluoroacetate to a Pd(0) complex to give a (phenoxo)(trifluoroacetyl)palladium(II) complex and its subsequent reaction with phenylboronic acid to liberate phenyl trifluoromethyl ketone. The catalytic cycle is proposed to be composed of (a) oxidative addition of the ester to give acyl(aryloxo)palladium intermediate, (b) the subsequent transmetallation with arylboron compounds, and (c) reductive elimination. Palladium(0) complexes, as well as catalysts prepared in situ from palladium acetate and 3 molar amounts of tributylphosphine or phosphite at room temperature, serve as convenient and effective catalysts. The process is applicable to a wide range of phenyl- and naphthylboronic acids to give various aryl trifluoromethyl ketones under mild conditions. Aryl perfluoroalkyl ketone derivatives can be similarly prepared in high yields from various phenyl perfluoroalkanecarboxylates and arylboronic acids.
- Kakino,Shimizu,Yamamoto
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p. 371 - 376
(2007/10/03)
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- Lipase-catalysed Enantioselective Synthesis of Naphthyl Trifluoromethyl Carbinols and Their Corresponding Non-Fluorinated Counterparts
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Enantioselective synthesis of both enantiomers of β- and α-naphthyl trifluoromethyl carbinols (R)-1a, (S)-1a, (R)-2a, (S)-2a has been achieved through acylation of the corresponding racemic alcohols (RS)-1a and (RS)-2a with vinyl acetate in the presence of lipase PS.The effect of fluorine atoms on the extent and enantioselectivity of the process has been tested by carrying out the same biocatalytic transformation on their non-fluorinated counterparts (RS)-1b and (RS)-2b.The order of reactivity follows the trend (RS)-1b > (RS)-2b ca. (RS)-1a > (RS)-2a.Effect of thehydrophobicity of the solvent in the resolution of (RS)-1a is also presented.
- Gaspar, Jordi,Guerrero, Angel
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p. 231 - 238
(2007/10/02)
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- Chiral Synthesis Via Organoboranes. 38 Selective Reductions. 48. Asymmetric Reduction of Trifluoromethyl Ketones by B-Chlorodiisopinocampheylborane in High Enantiomeric Purity
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(-)-B-Chlorodiisopinocampheylborane TM,1>, introduced by us several years ago, has been shown to reduce prochiral aryl and alkyl perfluorinated ketones to the corresponding optically active alcohols in very high ee.For example, 2,2,2-trifluoroacetophenone, trifluoroacetyl-1-naphthalene, and trifluoroacetyl-2-naphthalene are all reduced with 1 within 1-3 d at rt in 90percent ee, 78percent ee and 91percent ee, respectively.The optical purity of 1-phenyl-2,2,2-trifluoroethanol is upgraded to = 99percent ee by crystallizing the initially formed products from pentane. 1,1,2,2,2- pentafluoropropiophenone and 1,1,2,2,3,3,3-heptafluorobutyrophenone are reduced in 3 d with 1 to the corresponding alcohols in 92percent ee and 87 percent ee, respectively.The reagent reduces alkyl trifluoromethyl ketones at a rate faster than that of the aryl derivatives, while still providing the product alcohols in very high ee.Thus, 1,1,1-trifluoroacetone, 1,1,1-trifluorononan-2-one, and 1,1,1-trifluorodecan-2-one are all reduced within 4 - 8 h in 89percent ee, 92percent ee, and 91percent ee, respectively.Even α-sec-alkyl trifluoromethyl ketones are handled by 1 very efficiently.Thus cyclohexyl trifluoromethyl ketone is reduced by 1 at rt in 12 h to the product alcohol in 87percent ee.In all of these cases the trifluoromethyl group acts as the enantiocontrolling larger group as compared to the aryl or alkyl group.This produces alcohol products with stereochemistry opposite to those obtained for the corresponding hydrogen analogs.The steric and electronic influence of the trifluoromethyl group in achieving enantiocontrol in assymmetric reductions is discussed.Keywords: asymmetric reduction; trifluoromethyl ketones; DIP-Chloride; high enantiomeric purity
- Ramachandran, P. Veeraraghavan,Teodorovic, Aleksandar V.,Brown, Herbert C.
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p. 1725 - 1738
(2007/10/02)
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- A Convenient Trifluoroacetylation of Arenes with 2-(Trifluoroacetoxy)pyridine
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2-(Trifluoroacetoxy)pyridine (TFAP) is useful for trifluoroacetylating arenes under Friedel-Crafts conditions.Benzene, alkylbenzenes, naphthalene, and dibenzofuran have reacted with TFAP in the presence of aluminum chloride in dichloromethane to give the corresponding trifluoromethyl aryl ketones in good isolated yields.
- Keumi, Takashi,Shimada, Masakazu,Takahashi, Masahiro,Kitajima, Hidehiko
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p. 783 - 786
(2007/10/02)
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