- Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium
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Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF2H), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF2H) from ClCF2H into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCF2H with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal-difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal-difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal- difluorocarbene complex catalysed reactions.
- Feng, Zhang,Min, Qiao-Qiao,Fu, Xia-Ping,An, Lun,Zhang, Xingang
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- Electrochemical-Promoted Nickel-Catalyzed Oxidative Fluoroalkylation of Aryl Iodides
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This work describes a general strategy for metal-catalyzed cross-coupling of fluoroalkyl radicals with aryl halides under electrochemical conditions. The contradiction between anodic oxidation of fluoroalkyl sulfinates and cathodic reduction of low-valent nickel catalysts can be well addressed by paired electrolysis, allowing for direct introduction of fluorinated functionalities into aromatic systems.
- Zou, Zhenlei,Li, Heyin,Huang, Mengjun,Zhang, Weigang,Zhi, Sanjun,Wang, Yi,Pan, Yi
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supporting information
p. 8252 - 8256
(2021/11/01)
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- Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes
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Difluorocarbene has important applications in pharmaceuticals, agrochemicals and materials, but all these applications proceed using just a few types of reaction by taking advantage of its intrinsic electrophilicity. Here, we report a palladium-catalysed strategy that confers the formed palladium difluorocarbene (Pd=CF2) species with both nucleophilicity and electrophilicity by switching the valence state of the palladium centre (Pd(0) and Pd(ii), respectively). Controllable catalytic difluorocarbene transfer occurs between readily available arylboronic acids and the difluorocarbene precursor diethyl bromodifluoromethylphosphonate (BrCF2PO(OEt)2). From just this simple fluorine source, difluorocarbene transfer enables access to four types of product: difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones. The transfer can also be applied to the modification of pharmaceuticals and agrochemicals as well as the one-pot diversified synthesis of fluorinated compounds. Mechanistic and computational studies consistently reveal that competition between nucleophilic and electrophilic palladium difluorocarbene ([Pd]=CF2) is the key factor controlling the catalytic difluorocarbene transfer.
- Fu, Xia-Ping,Xue, Xiao-Song,Zhang, Xue-Ying,Xiao, Yu-Lan,Zhang, Shu,Guo, Yin-Long,Leng, Xuebing,Houk, Kendall N.,Zhang, Xingang
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p. 948 - 956
(2019/11/05)
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- A fluorine-containing methyl compounds and its preparation method (by machine translation)
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The invention discloses a fluorine-containing methyl compounds and its preparation method. The invention provides a fluorine-containing shown as formula C methyl compounds, wherein R is aryl group containing, or, containing a hetero aryl group, and the aryl group or the heteroaryl on the aromatic carbon atom and CFm Hn Connected, m is 1 or 2, m + n=3. The compounds according to the prior art is difficult to make, the preparation method of the raw material and the catalyst are the ordinary industrial raw materials, cheap and easy to obtain, high reaction efficiency, high yield, after treatment is simple, low toxicity, environmental protection, functional group compatibility is good, broad-spectrum is strong, the production cost is low, it has very good market application prospect. (by machine translation)
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Paragraph 0182; 0183; 0189; 0190; 0191; 0192; 0210-0214
(2019/05/11)
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- Difluoromethyl-substituted compound (by machine translation)
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[Problem] to provide a, simple and inexpensive manufacturing method is difluoromethyl substituted compounds using a reagent. [Solution] a method for producing a compound using a catalyst [...] difluoromethyl-substituted,(I) the catalyst, a nickel compound and nitrogen in the bidentate ligand, raw Ar a-Z " in the formula, the Ar, substituted or unsubstituted aryl group or a substituted or unsubstituted 5 - 10 membered heteroaryl group C6 a-14, Z is, (OR) B2 Or a group represented by a is represented MgX. " Compound represented, difluoromethyl-substituted compounds, Ar e CF2 A method for producing a compound represented by H, or(II) catalyst, a palladium compound and a diphosphine ligand, raw material is Q-a B (OR1 )2 " In the formula, Q is, substituted or unsubstituted aryl C6 a-10, 5 - 10 membered heteroaryl or substituted or unsubstituted, or Ar1 A group represented by - CH=CH - shown. R1 Is, a hydrogen atom or an alkyl group C1 a-6. " Compounds, a compound represented by Q-a Zn-to-Q or, difluoromethyl-substituted compounds, Q-to-CF2 A method for producing a compound represented by H. [Drawing] no (by machine translation)
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Paragraph 0060; 0061
(2019/10/17)
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- Ligand-Less Iron-Catalyzed Aromatic Cross-Coupling Difluoromethylation of Grignard Reagents with Difluoroiodomethane
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Iron-catalyzed cross-coupling difluoromethylations of the Grignard reagents with difluoroiodomethane provide various aromatic difluoromethyl products in good yields, not employing sterically demanding ligands. Difluoromethylations proceed within 30 min at -20 °C with 2.0 equiv of the Grignard reagents and FeCl3 or Fe(acac)3 (2.5 mol %). Mechanistic investigations clarify difluoromethyl radical intervention; Fe(0) ate is initially generated. Single-electron transfer from Fe(0) ate to difluoroiodomethane takes place. Recombination with aryl groups gives Ar-CF2Hs. The catalyst can be regenerated by the Grignard reagents.
- Motohashi, Hirotaka,Kato, Miki,Mikami, Koichi
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p. 6483 - 6490
(2019/05/16)
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- Method for preparing alpha-aryl/heteroaryl/alkenyl-alpha,alpha-difluoromethyl compounds
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The invention discloses a method for preparing alpha-aryl/heteroaryl/alkenyl-alpha,alpha-difluoromethyl compounds. The preparation method for the alpha-aryl/heteroaryl/alkenyl-alpha,alpha-difluoromethyl compounds as shown in a formula C which is described
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Paragraph 0141; 0142; 0143; 0150; 0151; 0152; 0189; 0190
(2018/09/08)
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- Metallaphotoredox Difluoromethylation of Aryl Bromides
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Herein, we report a convenient and broadly applicable strategy for the difluoromethylation of aryl bromides by metallaphotoredox catalysis. Bromodifluoromethane, a simple and commercially available alkyl halide, is harnessed as an effective source of difluoromethyl radical by silyl-radical-mediated halogen abstraction. The merger of this fluoroalkyl electrophile activation pathway with a dual nickel/photoredox catalytic platform enables the difluoromethylation of a diverse array of aryl and heteroaryl bromides under mild conditions. The utility of this procedure is showcased in the late-stage functionalization of several drug analogues.
- Bacauanu, Vlad,Cardinal, Sébastien,Yamauchi, Motoshi,Kondo, Masaru,Fernández, David F.,Remy, Richard,MacMillan, David W. C.
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supporting information
p. 12543 - 12548
(2018/09/18)
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- Nickel-Catalyzed Aromatic Cross-Coupling Difluoromethylation of Grignard Reagents with Difluoroiodomethane
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The nickel-catalyzed cross-coupling difluoromethylation of the Grignard reagents with difluoroiodomethane is shown to provide the corresponding aromatic difluoromethyl products in excellent to moderate yields. The difluoromethylation proceeds smoothly within 1 h at room temperature with 1.5 equiv of the Grignard reagents in the presence of Ni(cod)2/TMEDA (2.5-0.5 mol %). Mechanistic studies clarify that the oxidative addition of the Ni(0) catalyst to difluoroiodomethane provides the TMEDA-Ni(II)(CF2H)I complex. This intermediate is transformed to TMEDA-Ni(II)(CF2H)Ph via transmetalation with PhMgBr. The reductive elimination takes place to give the aromatic cross-coupling difluoromethylation product along with regeneration of the TMEDA-Ni(0) catalyst. Electron paramagnetic resonance (EPR) and radical clock analyses of the nickel-catalyzed reaction provide no EPR active Ni(I) and Ni(III) species at around g = 2 and only a trace amount of the cyclization product.
- Motohashi, Hirotaka,Mikami, Koichi
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supporting information
p. 5340 - 5343
(2018/09/12)
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- Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate
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An unprecedented example of Pd-catalyzed difluoromethylation of aryl boronic acids with bromodifluoroacetate is described. The reaction proceeds under mild reaction conditions with hydroquinone and Fe(acac)3 as additives. Preliminary mechanistic studies reveal that a difluorocarbene pathway is involved in the reaction, which is unusual compared to the most traditional approaches. This reaction has advantages of high efficiency and excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug discovery and development.
- Feng, Zhang,Min, Qiao-Qiao,Zhang, Xingang
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supporting information
p. 44 - 47
(2016/01/15)
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