- Copper-Catalyzed Enantioselective Difluoromethylation of Amino Acids via Difluorocarbene
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Difluoromethyl amino acids (DFAA) exhibit intriguing biological properties, making them highly desirable motifs in agrochemical and pharmaceutical science. However, stereochemical control of direct difluoromethyl transformation via the difluorocarbene spe
- Peng, Lingzi,Wang, Hongyi,Guo, Chang
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- Difluoromethylation of Phenols and Thiophenols with the S-(Difluo-romethyl)sulfonium Salt: Reaction, Scope, and Mechanistic Study
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A facile and practical approach for the difluoromethylation of phenols and thiophenols was described. Making use of the recently developed bench-stable S-(difluoromethyl)sulfonium salt as the difluorocarbene precursor, a wide variety of diversely functionalized phenols and thiophenols were readily converted to their corresponding aryl difluoromethyl ethers in good to excellent yields in the presence of lithium hydroxide. Chemoselectivity of various O,S-nucleophiles toward difluorocarbene was systematically studied, suggesting the reactivity order ArS- > RS-, ArO- > ROH > RO-, ArSH, ArOH, RSH.
- Liu, Guo-Kai,Qin, Wen-Bing,Li, Xin,Lin, Li-Ting,Wong, Henry N. C.
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p. 15948 - 15957
(2019/11/16)
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- Triple Mode of Alkylation with Ethyl Bromodifluoroacetate: N, or O-Difluoromethylation, N-Ethylation and S-(ethoxycarbonyl)difluoromethylation
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In this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate. Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted difluoromethylation of tosyl-protected aniline and electron-deficient phenols respectively. Interestingly, switching the base from lithium hydroxide to 4-N,N-dimethylamino pyridine (DMAP) tosyl-protected anilines afforded the corresponding N-ethylation product. Whereas, highly nucleophilic thiophenols furnished the corresponding S-carboethoxydifluoromethylation product via a rapid SN2 attack to the bromine atom prior to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It was revealed that difluoromethylation reaction proceeds through a tandem in situ ester hydrolysis/decarboxylative-debrominative difluorocarbene formation and subsequent trapping by the soft nucleophile-NHTs or electron-deficient phenolic ?OH groups. In the presence of DMAP the hydrolysis of the ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N-ethylation product. Hence, besides the development of a practical base-promoted N-difluoromethylation of amines and electron-deficient phenols, divergent reactivity pattern of inexpensive and user-friendly ethyl bromodifluoroacetate has been explored. (Figure presented.).
- Polley, Arghya,Bairy, Gurupada,Das, Pritha,Jana, Ranjan
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supporting information
p. 4161 - 4167
(2018/09/21)
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- Difluoro methylation reagent, preparation method and application thereof (by machine translation)
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The present invention discloses a two-trifluoromethylation of the reagent, preparation method and application thereof. The invention [...] methylation reagent preparation process is simple, high yield; and the reagent can be a more moderate, high-efficiently the sulfonic acid, alcohol, carbonyl and on the α carbon atom of the difluoromethyl. (by machine translation)
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Paragraph 0514; 0515; 0516; 0518; 0519; 0520
(2017/10/23)
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- Visible-Light Photoredox Difluoromethylation of Phenols and Thiophenols with Commercially Available Difluorobromoacetic Acid
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A simple and efficient visible-light photoredox one-pot method for difluoromethylation of phenols and thiophenols has been developed. The protocol uses commercially available, inexpensive, and easy handling difluorobromoacetic acid as the difluoromethylating agent, and the diverse O- and S-difluoromethylated products were prepared in good yields with tolerance of many functional groups.
- Yang, Jinyan,Jiang, Min,Jin, Yunhe,Yang, Haijun,Fu, Hua
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supporting information
p. 2758 - 2761
(2017/05/24)
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- Model II fluorine asia [...] inner salt synthesis and its application
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The present invention provides synthesis and application of difluoro methylene phosphorus inner salt, wherein the compound has a structure shown in Formula A: (R1R2R3)P+CF2CO2 -. The definitions of substituent groups are described in the specification. Th
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Paragraph 0249-0252
(2018/01/11)
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- Difluoromethyl bioisostere: Examining the lipophilic hydrogen bond donor concept
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There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.
- Zafrani, Yossi,Yeffet, Dina,Sod-Moriah, Gali,Berliner, Anat,Amir, Dafna,Marciano, Daniele,Gershonov, Eytan,Saphier, Sigal
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p. 797 - 804
(2017/02/05)
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- Decarboxylative Trifluoromethylating Reagent [Cu(O2CCF3)(phen)] and Difluorocarbene Precursor [Cu(phen)2][O2CCF2Cl]
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This article describes the new economic decarboxylative trifluoromethylating reagent [Cu(phen)(O2CCF3)] (1; phen=1,10-phenanthroline) and the efficient difluorocarbene precursor [Cu(phen)2][O2CCF2Cl] (2). Treatment of copper tert-butoxide with phen and subsequent addition of trifluoroacetic acid or chlorodifluoroacetic acid afforded air-stable complexes 1 and 2, respectively, which were characterized by X-ray crystallography. The copper(I) ion in 1 is coordinated by a bidentate phen ligand, a monodentate trifluoroacetate group, and a molecule of CH3CN in a distorted tetrahedral coordination geometry. The molecular structure of 2 adopts an ionic form that consists of a [Cu(phen)2]+ cation and a chlorodifluoroacetate anion. Complex 1 reacted with a variety of aryl and heteroaryl halides to form trifluoromethyl (hetero)arenes in good yields. The corresponding Hammett plot exhibited a linear relationship and a reaction parameter (ρ)=+0.56±0.02, which indicated that the trifluoromethylation reaction proceeded via a nucleophilic reactive species. Complex 2 reacts with phenols to produce aryl difluoromethyl ethers in modest-to-excellent yields. Mechanistic investigations revealed that the difluoromethylation reaction proceeds by initial copper-mediated formation of difluorocarbene and subsequent concerted addition of difluorocarbene to the phenol to form a three-center transition state.
- Lin, Xiaoxi,Hou, Chuanqi,Li, Haohong,Weng, Zhiqiang
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supporting information
p. 2075 - 2084
(2016/02/12)
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- Use of fluoroform as a source of difluorocarbene in the synthesis of N-CF2H heterocycles and difluoromethoxypyridines
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Fluoroform is used as a source of difluorocarbene to convert various N-, O-, and C-nucleophiles to their difluoromethylated derivatives. Imidazole, benzimidazole, benztriazole, hydroxypyridines, and their derivatives underwent reaction at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/acetonitrile) process to provide moderate to good yields of the respective products. Nitrophenols required addition of a co-solvent (methanol) to obtain good yields of products.
- Thomoson, Charles S.,Wang, Linhua,Dolbier, William R.
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- Three step procedure for the preparation of aromatic and aliphatic difluoromethyl ethers from phenols and alcohols using a chlorine/fluorine exchange methodology
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Difluoromethyl ethers are prepared from phenols in three steps via their respective formate ester derivatives. The formates are first converted to dichloromethyl ethers by treatment with PCl5. These ethers are then induced to undergo chlorine/fluorine exchange to form the respective difluoromethyl ethers. The chlorine/fluorine exchange is carried out by either a room temperature, solvolytic process using THF-5HF or Et3N-3HF as exchange medium, where HF is the ultimate source of fluorine, or by a direct displacement process in sulfolane at 125 C, where KF is the source of fluorine. By one or another of these processes, virtually all phenols, electron-rich and electron-poor, can be converted to their respective difluoromethyl ethers in good yields. Aliphatic alcohols are also able to be converted to their difluoromethyl ether derivatives using the Et3N-3HF exchange medium.
- Dolbier Jr., William R.,Wang, Fei,Tang, Xiaojun,Thomoson, Charles S.,Wang, Linhua
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- SYNTHESIS OF DIFLUOROMETHYL ETHERS AND SULFIDES
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The synthesis of difluoromethyl ethers and sulfides with a simple, non-ozone- depleting reagent is described. The difluoromethylation of phenols with this reagent occurs at room temperature within minutes with exceptional functional group tolerance. The mild conditions makes possible tandem processes for the conversion of aryl boronic acids, aryl halides and arenes to difluoromethyl ethers. Mechanistic studies support a reaction pathway involving nucleophilic attack of the phenolate to difluorocarbene.
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Paragraph 0078-0082; 0099-00102
(2014/07/22)
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- Conversion between difluorocarbene and difluoromethylene ylide
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The interconversion between difluoromethylene ylide and difluorocarbene is described. The difluoromethylene ylide precursor, Ph3P +CF2CO2-, could be turned into an efficient difluorocarbene reagent, w
- Zheng, Jian,Lin, Jin-Hong,Cai, Ji,Xiao, Ji-Chang
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supporting information
p. 15261 - 15266
(2013/11/06)
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- Oxidation of primary aliphatic and aromatic aldehydes with difluoro(aryl)-λ3-bromane
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Oxidation of primary aliphatic aldehydes with p- trifluoromethylphenyl(difluoro)-λ3-bromane in dichloromethane at 0 °C afforded acid fluorides selectively in good yields, while that of aromatic aldehydes in chloroform at room temperature produced aryl difluoromethyl ethers. A larger migratory aptitude of aryl groups compared to primary alkyl groups during a 1,2-shift from carbon to an electron-deficient oxygen atom in bromane(III) Criegee-type intermediates will result in these differences in the reaction courses.
- Ochiai, Masahito,Yoshimura, Akira,Hoque, Md. Mahbubul,Okubo, Takuji,Saito, Motomichi,Miyamoto, Kazunori
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supporting information; experimental part
p. 5568 - 5571
(2011/12/03)
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- Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents: The substituent effect
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We have investigated the different chlorodifluoromethyl aryl ketones 1a-1g and sulfones 2a-2h as difluorocarbene reagents for O- and N- difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-difluoromethylations.
- Wang, Fei,Zhang, Laijun,Zheng, Ji,Hu, Jinbo
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experimental part
p. 521 - 528
(2011/08/22)
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- Diethyl bromodifluoromethylphosphonate: a highly efficient and environmentally benign difluorocarbene precursor
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A convenient method for the difluoromethylation of phenols and thiophenols, using diethyl bromodifluoromethylphosphonate (1) as a difluorocarbene precursor, is described. This commercially available phosphonate was found to undergo an extremely facile P-C
- Zafrani, Yossi,Sod-Moriah, Gali,Segall, Yoffi
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experimental part
p. 5278 - 5283
(2009/11/30)
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- Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (e.g., indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 64
(2010/11/26)
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- Chlorodifluoromethyl phenyl sulfone: A novel non-ozone-depleting substance-based difluorocarbene reagent for O- and N-difluoromethylations
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Chlorodifluoromethyl phenyl sulfone, a previously unknown compound that can be readily prepared from non-ODS-based precursors, was found to act as a robust difluorocarbene reagent for O- and N-difluoromethylations. The Royal Society of Chemistry.
- Zheng, Ji,Li, Ya,Zhang, Laijun,Hu, Jinbo,Meuzelaar, Gerrit Joost,Federsel, Hans-Juergen
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p. 5149 - 5151
(2008/09/18)
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- NICOTINIC ALPHA-7 RECEPTOR LIGANDS AND PREPARATION AND USES THEREOF
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 43
(2008/06/13)
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- INDOLES, 1H-INDAZOLES, 1,2-BENZISOXAZOLES, AND 1,2-BENZISOTHIAZOLES, AND PREPARATION AND USES THEREOF
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds for example, indoles, 1H-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 47
(2008/06/13)
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- 1H-INDAZOLES, BENZOTHIAZOLES, 1,2-BENZOISOXAZOLES, 1,2-BENZOISOTHIAZOLES, AND CHROMONES AND PREPARATION AND USES THEREOF
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nAChR), activation of nAChRs, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nAChR subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 72-75
(2008/06/13)
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- Indoles, 1h-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof
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The present invention relates generally to the field of ligands for nicotinic acetylcholine receptors (nACh receptors), activation of nACh receptors, and the treatment of disease conditions associated with defective or malfunctioning nicotinic acetylcholine receptors, especially of the brain. Further, this invention relates to novel compounds (indazoles and benzothiazoles), which act as ligands for the α7 nACh receptor subtype, methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 41
(2008/06/13)
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- Utility of silicon tetrafluoride as a catalyst of reactions with xenon difluoride: Fluorinations of phenyl alkenes and benzaldehydes
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Application of silicon tetrafluoride to fluorinations with xenon difluoride as a catalyst is investigated. It was found that vic-difluorination of phenyl alkenes and transformation of benzaldehydes to difluoromethoxybenzenes using xenon difluoride are enhanced by silicon tetrafluoride.
- Tamura, Masanori,Takagi, Toshiyuki,Quan, Heng-Dao,Sekiya, Akira
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p. 163 - 166
(2007/10/03)
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- Method for synthesis of aryl difluoromethyl ethers
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This invention relates to a method for preparing difluoromethyl ethers, thiols and amines without using chlorofluorocarbon gases. The intermediates prepared by this method can be used to make certain compounds which act as PDE IV inhibitors which are useful for treating asthma and other diseases implicated with the PDE IV isozyme.
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- Process for preparing difluoromethoxyarenes and difluoromethylthioarenes
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Difluoromethoxyarenes and difluoromethylthioarenes of the general formula (I), in which Ar represents optionally substituted aryl, and Q represents oxygen or sulphur, (which can be used as intermediates for preparing biologically active products) are obta
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- 2-imino-1,3-dithietanes, their use as pesticides
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There are described new 2-imino-1,3-dithietanes of general formula I STR1 in which R is the group STR2 in which A is CFHal, C(CH3)C1-4 -alkyl, C(CH3)CHal3, C(CH3)CF2 Cl, C(CH3)CFCl2, C2 H4, C2 H3 Hal, C2 H2 Hal2, C2 HHal3, C2 F2 Cl2, C2 F4 or C2 F3 Cl, in which Hal is F or Cl, Y is nitrogen or CH, R1 is fluoro-C1-12 -alkyl, fluoro-C2-12 -alkenyl, fluoro-C2-12 -alkynyl, fluorocyclopropyl or fluorocyclopropylmethyl; X is oxygen or sulphur, 2 is defined in the specification and n is 0, 1 or 2, as well as their acid addition salts, a process for their preparation and their use as pesticides. The new compounds are especially useful as nematicides.
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- A SIMPLE CONVENIENT METHOD FOR PREPARATION OF DIFLUOROMETHYL ETHERS USING FLUOROSULFONYLDIFLUOROACETIC ACID AS A DIFLUOROCARBENE PRECURSOR
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In the presence of catalytic amounts of sodium sulfate or cuprous iodide, a variety of alkyl and aryl difluoromethyl ethers were synthesized in moderate yields by the reaction of the corresponding alcohols and phenols with fluorosulfonyldifluoroacetic acid (1) in acetonitrile under mild conditions.Fluorosulfonyldifluoroacetate anion (5) is believed to readily eliminate SO2, CO2 and F(1-), thus liberating CF2:; insertion of difluorocarbene into O-H bonds and its capture by fluorode ion then result in the formation of ethers and by-product CF3H, respectively.
- Chen, Qing-Yun,Wu, Sheng-Wen
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p. 433 - 440
(2007/10/02)
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- Anilinopyrimidine fungicides
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There are described new pyrimidine derivatives of the general formula I STR1 in which n is 0, 1 or 2; R1 is (a) the group --CXR5, where X is oxygen or sulphur and R5 is hydrogen, a nitrogen or sulphur containing heterocyclic group, which can contain other hetero atoms, optionally substituted alkenyl, acyl, alkoxycarbonyl, alkyl substituted by aryloxy, or optionally substituted mono- or dialkylamino; or R5 is the group --NHR6, where R6 is substituted amino, substituted carbamoyl, optionally substituted alkylsulphonyl, acyl or arylsulphonyl, and when n is 0 or when X is sulphur, R5 can also be alkyl, haloalkyl, aryl, aralkyl, alkoxycarbonylalkyl or arylamino; (b) cyano or the group --CXYR7, where X and Y are the same or different and are oxygen, sulphur or optionally substituted imino and R7 is optionally substituted alkyl, aryl, acyl or a nitrogen or sulphur containing heterocyclic group, which can contain other hetero atoms; or (c) when n is 1 or 2 and at least one R4 group is haloalkoxy, R1 can be hydrogen; R2 and R3 are the same or different and are alkyl, and R4 is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, nitro or cyano. The compounds have fungicidal activity.
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- SYNTHESE DE COMPOSES AROMATIQUES COMPORTANT LES GROUPEMENTS OCF2Br ET SCF2Br-II; ACTION DE CF2Br2 ET DE CF2BrCl SUR DES THIOPHENATES ET PHENATES DE POTASSIUM DIVERSEMENT SUBSTITUES
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The reaction of dibromodifluoromethane and bromochlorodifluoromethane with substituted potassium thiophenoxides and phenoxides leads to the formation of new aromatic compounds bearing OCF2Br and SCF2Br groups.
- Rico, I,Wakselman, C.
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p. 4209 - 4214
(2007/10/02)
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