- Decarbonylative Fluoroalkylation at Palladium(II): From Fundamental Organometallic Studies to Catalysis
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This Article describes the development of a decarbonylative Pd-catalyzed aryl-fluoroalkyl bond-forming reaction that couples fluoroalkylcarboxylic acid-derived electrophiles [RFC(O)X] with aryl organometallics (Ar-M′). This reaction was optimized by interrogating the individual steps of the catalytic cycle (oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination) to identify a compatible pair of coupling partners and an appropriate Pd catalyst. These stoichiometric organometallic studies revealed several critical elements for reaction design. First, uncatalyzed background reactions between RFC(O)X and Ar-M′ can be avoided by using M′ = boronate ester. Second, carbonyl de-insertion and Ar-RF reductive elimination are the two slowest steps of the catalytic cycle when RF = CF3. Both steps are dramatically accelerated upon changing to RF = CHF2. Computational studies reveal that a favorable F2C-H - -X interaction contributes to accelerating carbonyl de-insertion in this system. Finally, transmetalation is slow with X = difluoroacetate but fast with X = F. Ultimately, these studies enabled the development of an (SPhos)Pd-catalyzed decarbonylative difluoromethylation of aryl neopentylglycol boronate esters with difluoroacetyl fluoride.
- Lalloo, Naish,Malapit, Christian A.,Taimoory, S. Maryamdokht,Brigham, Conor E.,Sanford, Melanie S.
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p. 18617 - 18625
(2021/11/16)
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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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- Synthesis of L-Au(I)-CF2H Complexes and Their Application as Transmetalation Shuttles to the Difluoromethylation of Aryl Iodides
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We describe herein two alternative protocols to efficiently prepare difluoromethylgold(I) complexes bearing ancillary ligands with different electronic and steric properties. LAu-OX (X = H andt-Bu) species, formed in the presence of base, have been identified as intermediate complexes involved in these transformations. The application of these compounds as “CF2H transmetalation shuttles” from gold to palladium has been demonstrated in a Pd-catalyzed difluoromethylation reaction of aryl iodides, in which the Au-to-Pd transfer of “CF2H” is feasible under stoichiometric conditions. These findings will pave the way for catalytic manifolds in gold chemistry.
- García-Domínguez, Patricia
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supporting information
p. 2923 - 2928
(2021/09/07)
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- Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery
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Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.
- Sap, Jeroen B.I.,Straathof, Natan J.W.,Knauber, Thomas,Meyer, Claudio F.,Meyer, Claudio F.,Médebielle, Maurice,Buglioni, Laura,Genicot, Christophe,Trabanco, Andrés A.,No?l, Timothy,Am Ende, Christopher W.,Gouverneur, Véronique
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supporting information
p. 9181 - 9187
(2020/07/10)
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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 0464; 0465; 0466; 0467
(2019/05/11)
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- Accessing Difluoromethylated and Trifluoromethylated cis-Cycloalkanes and Saturated Heterocycles: Preferential Hydrogen Addition to the Substitution Sites for Dearomatization
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Reported here is a straightforward process in which a cyclic (alkyl)(amino)carbene/Rh catalyst system facilitates the preferential addition of hydrogen to the substitution sites of difluoromethylated and trifluoromethylated arenes and heteroarenes, leading to dearomative reduction. This strategy enables the diastereoselective synthesis of cis-difluoromethylated and cis-trifluoromethylated cycloalkanes and saturated heterocycles, and even allows formation of all-cis multi-trifluoromethylated cyclic products with a defined equatorial orientation of the di- and trifluoromethyl groups. Deuterium-labeling studies indicate that hydrogen preferentially attacks the substitution sites of planar arenes, resulting in dearomatization, possibly with heterogeneous Rh as the reactive species, followed by either reversible or irreversible hydrogen addition to the nonsubstitution sites.
- Zhang, Xue,Ling, Liang,Luo, Meiming,Zeng, Xiaoming
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supporting information
p. 16785 - 16789
(2019/11/11)
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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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- 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 0070
(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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- Precatalyst Effects on Pd-Catalyzed Cross-Coupling Difluoromethylation of Aryl Boronic Acids
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The Pd-catalyzed difluoromethylation of aryl boronic acids with difluoroiodomethane is shown to provide the difluoromethyl compounds in high to moderate yields by Pd(PPh3)2/DPEphos catalyst in H2O/toluene. Mechanistic studies show that the oxidative addition by Pd(PPh3)4 rather than Pd2(dba)3 precatalyst to difluoroiodomethane provides a square-planar trans-(PPh3)2Pd(II)(CF2H)I complex defined by X-ray crystallographic analysis. The trans-(PPh3)2Pd(CF2H)I complex is transformed to cis-(PPh3)2Pd(CF2H)Ph detected by low temperature NMR analysis, via transmetalation with phenylboronic acids. The reductive elimination occurs via ligand exchange to DPEphosPd(CF2H)Ph to give Ph-CF2H (t1/2 = 144.7 min at 20 °C) with formation of the Pd(0)(PPh3)2/DPEphos catalyst.
- Hori, Kaishi,Motohashi, Hirotaka,Saito, Daichi,Mikami, Koichi
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p. 417 - 421
(2019/01/11)
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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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- SUBSTITUTED 6-(1H-PYRAZOL-1-YL)PYRIMIDIN-4-AMINE DERIVATIVES AND USES THEREOF
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The present invention covers substituted 6-(1H-pyrazol-1-yl)pyrimidin-4-amine compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular and renal diseases, as a sole agent or in combination with other active ingredients.
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Page/Page column 253
(2018/04/27)
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- Nickel-Catalyzed Difluoromethylation of Arylboronic Acids with Bromodifluoromethane
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Although bromodifluoromethane (BrCF2H) is a simple and readily available fluorine source, direct formation of difluoromethylated arenes with BrCF2H has not been reported. Herein, we describe an efficient method to access difluoromethylated arenes through a nickel-catalyzed difluoromethylation of arylboronic acids with BrCF2H. The reaction exhibits high efficiency, good functional group tolerance and broad substrate scope, thus providing an efficient route for applications in drug discovery and development. Preliminary mechanistic studies reveal that a difluoromethyl radical is involved in the reaction.
- Fu, Xia-Ping,Xiao, Yu-Lan,Zhang, Xingang
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supporting information
p. 143 - 146
(2018/01/05)
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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; 0186; 0187
(2018/09/08)
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- 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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p. 918 - 923
(2017/09/01)
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- Copper-Catalyzed Difluoromethylation of Aryl Iodides with (Difluoromethyl)zinc Reagent
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The combination of difluoroiodomethane and zinc dust or diethylzinc can readily lead to (difluoromethyl)zinc reagents. Therefore, the first copper-catalyzed difluoromethylation of aryl iodides with the zinc reagents is accomplished to afford the difluorom
- Serizawa, Hiroki,Ishii, Koki,Aikawa, Kohsuke,Mikami, Koichi
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supporting information
p. 3686 - 3689
(2016/08/16)
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- Palladium-Catalyzed Negishi Cross-Coupling Reaction of Aryl Halides with (Difluoromethyl)zinc Reagent
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The palladium-catalyzed Negishi cross-coupling reaction of aryl iodides and bromides with (difluoromethyl)zinc reagent bearing a diamine such as TMEDA is achieved to provide the difluoromethylated aromatic compounds in good to excellent yields. The advantages of (difluoromethyl)zinc reagent are that (1) the derivatives, which possess different stability and reactivity, can be readily prepared via ligand screening and (2) transmetalation of a difluoromethyl group from the zinc reagent to palladium catalyst efficiently proceeds without an activator.
- Aikawa, Kohsuke,Serizawa, Hiroki,Ishii, Koki,Mikami, Koichi
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supporting information
p. 3690 - 3693
(2016/08/16)
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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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- Method of manufacturing arom. defluoromethyl compd.
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PROBLEM TO BE SOLVED: To provide a method for easily producing an aromatic compound having a difluoromethyl group in high yield while using a reagent having low toxicity. SOLUTION: The method for producing the aromatic difluoromethyl compound includes reacting an aromatic difluoroacetic acid in the presence of a metal halide (especially potassium fluoride). COPYRIGHT: (C)2011,JPOandINPIT
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Paragraph 0066; 0072; 0073
(2018/11/22)
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- Pd-catalyzed α-arylation of α,α-difluoroketones with aryl bromides and chlorides. A route to difluoromethylarenes
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We report the Pd-catalyzed α-arylation of α,α- difluoroketones with aryl and heteroaryl bromides and chlorides catalyzed by an air- and moisture-stable palladacyclic complex containing P(t-Bu)Cy2 as ligand. The combination of this Pd-catalyzed arylation and base-induced cleavage of the acyl-aryl C-C bond within the α-aryl-α,α- difluoroketone constitutes a one-pot, two-step procedure to synthesize difluoromethylarenes from aryl halides. A broad range of electronically varied aryl and heteroaryl bromides and chlorides underwent these two transformations, providing α-aryl-α,α-difluoroketones, difluoromethylarenes, and difluoromethylheteroarenes in high yields.
- Ge, Shaozhong,Cha?adaj, Wojciech,Hartwig, John F.
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supporting information
p. 4149 - 4152
(2014/04/03)
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- METAL-CATALYZED COUPLING OF ARYL AND VINYL HALIDES WITH ALPHA, ALPHA-DIFLUOROCARBONYL COMPOUNDS
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The coupling of aryl, heteroaryl, and vinyl halides with α,α-difluoroketones or silyl ethers or siylenol ethers of α,α-difluoroketones and α,α-difluoroamides and esters are described. Further derivatization of the coupling products (such as ketone cleavage and Baeyer-Villiger oxidation) is also described.
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Paragraph 0009; 00154-00155
(2014/10/18)
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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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supporting information; experimental part
p. 5560 - 5563
(2011/12/05)
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