- Copper-catalyzed cascade radical cyclization of alkynoates: Construction of aryldifluoromethylated coumarins
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A mild and simple method is reported for the construction of 3-difluoroarylmethylated coumarins using α,α-difluoroarylacetic acids as an easily handled difluoromethyl source in reaction with ester 3-arylpropiolates under the promotion of copper. The reaction involves a proposed radical-triggered domino decarboxylative aryldifluoromethylation/5-exo cyclization/ester migration process that directly forms Csp2-CF2Ar and C-C bonds with good functional group tolerance. This journal is
- Chen, Zhiwei,Huang, Xiaoxiao,Tang, Wei,Zeng, Piaopiao
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supporting information
p. 10223 - 10227
(2021/12/10)
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- Silver-catalyzed decarboxylative radical allylation of α,α-difluoroarylacetic acids for the construction of CF2-allyl bonds
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An efficient silver-catalyzed method of decarboxylative radical allylation of α,α-difluoroarylacetic acids to build CF2-allyl bonds has been developed. Using allylsulfone as an allyl donor, α,α-difluorine substituted arylacetic acids bearing various functional groups are successfully allylated to access a series of 3-(α,α-difluorobenzyl)-1-propylene compounds in moderate to excellent yields in aqueous CH3CN solution under the mild conditions. Experimental studies disclosed that the α-fluorine substitution of arylacetic acid has a great influence on free radical activity and reactivity.
- Wang, Pingyang,Du, Pengcheng,Sun, Qianqian,Zhang, Jianhua,Deng, Hongmei,Jiang, Haizhen
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p. 2023 - 2029
(2021/03/16)
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- Generation of Axially Chiral Fluoroallenes through a Copper-Catalyzed Enantioselective β-Fluoride Elimination
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Herein we report the copper-catalyzed silylation of propargylic difluorides to generate axially chiral, tetrasubstituted monofluoroallenes in both good yields (27 examples >80%) and enantioselectivities (82-98% ee). Compared to previously reported synthetic routes to axially chiral allenes (ACAs) from prochiral substrates, a mechanistically distinct reaction has been developed: the enantiodiscrimination between enantiotopic fluorides to set an axial stereocenter. DFT calculations and vibrational circular dichroism (VCD) suggest that β-fluoride elimination from an alkenyl copper intermediate likely proceeds through a syn-β-fluoride elimination pathway rather than an anti-elimination pathway. The effects of the C1-symmetric Josiphos-derived ligand on reactivity and enantioselectivity were investigated. Not only does this report showcase that alkenyl copper species (like their alkyl counterparts) can undergo β-fluoride elimination, but this elimination can be achieved in an enantioselective fashion.
- Liu, Peng,Mai, Binh Khanh,Nafie, Jordan,O'Connor, Thomas J.,Toste, F. Dean
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p. 13759 - 13768
(2021/09/07)
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- Synthetic method of aromatic ring group or aromatic heterocyclic tetrazole
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The synthetic method comprises the following steps: (1) reacting 1.0 eq of ArI or HArI with 1.2 eq of ethyl 2, 2-difluoroacetate in the presence of DMSO as a solvent and 4.0 eq of Cu under the protection of nitrogen at 30 DEG C and 50 DEG C, and purifying to obtain a first intermediate compound; (2) dissolving 1.0 eq of the first intermediate compound in a mixed solvent of THF and water, adding 2.0 eq of LiOH, reacting at room temperature for 2 hours, spin-drying the solvent, adding HCl until the pH value is equal to 3, and filtering to obtain a second intermediate compound; and (3) reacting 1.0 eq of the second intermediate compound with 2.0 eq of diphenyl azide phosphate in the presence of 2.5 eq of triethylamine by taking tert-butyl alcohol as a solvent to generate aromatic ring group or aromatic heterocyclic tetrazole. The invention provides a novel synthetic method of aromatic ring group or aromatic heterocyclic tetrazole, wherein a target compound can be more conveniently obtained, and reagents participating in the reaction are low in toxicity, mild in reaction condition, simple and safe in aftertreatment, good in product quality and suitable for large-scale production.
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Paragraph 0055-0062; 0070
(2020/12/30)
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- Optimization and sustainability assessment of a continuous flow Ru-catalyzed ester hydrogenation for an important precursor of a β2-adrenergic receptor agonist
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The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of abediterol, a β2-adrenoceptor agonist that has undergone phase IIa clinical trials for the treatment of asthma and chronic obstructive pulmonary disorder. The reaction was investigated within a batch autoclave by using a design of experiments (DoE) approach to identify important parameter effects. The optimized flow process was successfully operated over 6 h with inline benchtop19F NMR spectroscopy for reaction monitoring. The protocol is shown to be high yielding (98% yield, 3.7 g h?1) with very low catalyst loading (0.065 mol%). The environmental impact of the Ru-catalyzed hydrogenation was assessed and compared to an existing stoichiometric lithium aluminum hydride (LAH) reduction and sodium borohydride (NaBH4) reduction. The process mass intensity (PMI) for the Ru-catalyzed hydrogenation (14) compared favorably to a LAH reduction (52) and NaBH4reduction (133).
- García-Lacuna, Jorge,Hone, Christopher A.,Kappe, C. Oliver,Leslie, Kevin,Munday, Rachel,O'Kearney-McMullan, Anne,Prieschl, Michael
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supporting information
p. 5762 - 5770
(2020/09/21)
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- Fe(III)-Catalyzed Decarboxylative C3-Difluoroarylmethylation of Coumarins with α,α-Difluoroarylacetic Acids
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A facile Fe(III)-catalyzed oxidative decarboxylative radical coupling reaction of α,α-difluoroarylacetic acids with coumarins has been developed. This transformation, which provides a series of C-3 difluoroarylmethylated coumarins containing various functional groups in moderate-to-good yields, features easily accessible starting materials and operational simplicity.
- Chen, Zhiwei,Bai, Xiang,Sun, Jie,Xu, Yicheng
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p. 7674 - 7682
(2020/07/15)
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- Easy Access to Difluoromethylene-Containing Arene Analogues through Palladium-Catalysed C–H Olefination
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An efficient palladium-catalysed ortho-C–H olefination of α,α-difluorophenylacetic acid derivatives using 8-aminoquinoline as a bidentate directing group has been developed. A range of olefinated arenes can thus be synthesized in a concise way. This reaction provides an easy and straightforward route to a panel of difluoromethylated arene analogues in moderate to good yields, with a satisfactory tolerance of common functional groups. Transformation of the products into a variety of other difluoromethylene-containing compounds demonstrates the utility of this method.
- Shao, Changdong,Shi, Guangfa,Zhang, Yanghui
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p. 5529 - 5538
(2016/11/25)
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- A new method for aromatic difluoromethylation: Copper-catalyzed cross-coupling and decarboxylation sequence from aryl iodides
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A new methodology for aromatic difluoromethylation is described. Aryl iodides reacted with α-silyldifluoroacetates upon treatment with copper catalyst in DMSO or DME to give the corresponding aryldifluoroacetates in moderate to good yields. The subsequent hydrolysis of aryldifluoroacetates and KF-promoted decarboxylation afforded a variety of difluoromethyl aromatics.
- Fujikawa, Kenichi,Fujioka, Yasutaka,Kobayashi, Akira,Amii, Hideki
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p. 5560 - 5563
(2011/12/05)
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- Tricomponent catalytic α,α-difluorination of acid chlorides
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The selective α,α-difluorination of carbonyl compounds remains a challenge in modern organic synthesis; current methods often incorporate stepwise processes and/or harsh conditions, providing unsatisfactory mixtures of mono- and difluorinated products. In this communication, a practical, mild, and one-pot method for the selective α,α-difluorination of readily available acid chlorides is reported in which three separate catalysts act synergistically to form products in outstanding selectivity and fair to excellent yields.
- Bloom, Steven,Scerba, Michael T.,Erb, Jeremy,Lectka, Thomas
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supporting information; experimental part
p. 5068 - 5071
(2011/11/29)
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- The effect of substituents and operating conditions on the electrochemical fluorination of alkyl phenylacetates in Et3N·4HF medium
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Selective electrochemical fluorination of alkyl phenylacetates (Ph-CH2-COOR, where R is methyl, ethyl, n-propyl, n-butyl, i-propyl and sec-butyl) under galvanostatic conditions were reported in Et3N·4HF medium. Preparative electrolysis experiments were carried out both in pre-electrolysed dry Et3N·4HF and the same electrolyte medium without pre-electrolysis. Very little hydrolysed fluorinated products were obtained in pre-electrolysed medium where as significant quantities of hydrolysed products leading to fluorinated phenylacetic acid were obtained from Et3N·4HF without pre-electrolysis. Under optimum experimental conditions up to 87% selectivity of monofluoro ester could be achieved. Difluoro alkyl phenylacetate, monofluoro and difluoro phenylacetic acids were the other predominant side products obtained. The hydrolysis appears to be initiated by tautomeric transformation of proton after the initial electro oxidative formation of the cation radical. 19F as well as 1H NMR spectroscopy have been employed to identify the minor constituents formed during the electro oxidative process.
- Ilayaraja,Manivel,Velayutham,Noel
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p. 185 - 192
(2008/09/17)
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- Electrochemical carboxylation of α,α-difluorotoluene derivatives and its application to the synthesis of α-fluorinated nonsteroidal anti-inflammatory drugs
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Electrochemical carboxylation of α,α-difluorotoluene derivatives resulted in an efficient fixation of carbon dioxide to give the corresponding α-fluorophenylacetic acids in good yields, and this reaction was successfully applied to the synthesis of α-fluorinated nonsteroidal anti-inflammatory drugs (NSAIDs). Georg Thieme Verlag Stuttgart.
- Yamauchi, Yusuke,Fukuhara, Tsuyoshi,Hara, Shoji,Senboku, Hisanori
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p. 428 - 442
(2008/09/16)
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- ARYLPOLYFLUOROLEFIN PEROXIDES. I. SYNTHESIS OF α,β,β-TRIFLUOROSTYRENE, β-CHLORO-α,β-DIFLUOROSTYRENE, AND (PERFLUOROPROPENYL)BENZENE EPOXIDES
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By the oxidation of α,β,β-trifluorostyrene, β-chloro-α,β-difluorostyrene, and (perfluoropropenyl)benzene with oxygen in presence of chlorine and UV radiation 1,2-epoxy-1,2,2-trifluoro-1-phenylethane, 2-chloro-1,2-epoxy-1,2-difluoro-1-phenylethane, and 1,2-epoxy-1,2,3,3,3-pentafluoro-1-phenylpropane were prepared. α,β,β-Trifluorostyrene and β-chloro-α,β-difluorostyrene epoxides under the action of triethylamine are rearranged into difluorophenylacetyl and chlorofluorophenylacetyl fluorides, by the hydrolysis of which the corresponding acids are obtained. β-Chloro-α,β-difluorostyrene epoxide reacts with fluoride ions with the formation of a mixture of chlorofluorophenylacetic acid and 2,2,2-trifluoro- and 2-chloro-2,2-difluoro-acetophenones.
- Kremlev, M. M.,Maznyi, I. S.,Yagupol'skii, L. M.
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p. 105 - 108
(2007/10/02)
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- &α,&α-Difluoroarylacetic Acids: Preparation from (Diethylamino)sulfur Trifluoride and &α-Oxoarylacetates
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Several α,α-difluoroarylacetic acids have been prepared by reaction of DAST ((diethylamino)sulfur trifluoride) with esters of α-oxoarylacetic acids and then hydrolysis of the resulting difluoro ester.Examples include the α,α-difluoro derivates of the synthetic plant auxin, α-naphthylacetic acid, and the antiinflammatory drug, ibufenac.
- Middleton, W. J.,Bingham, E. M.
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p. 2883 - 2887
(2007/10/02)
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