- Study on the mild, rapid and selective difluorocarbene-mediated triclassification of iododifluoroacetophenone with secondary amines and tree model for product classification
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Difluorocarbene is a very active and widely used intermediate in organic synthesis. In this work, a room temperature difluorocarbene-mediated triclassification reaction of iododifluoroacetophenone (2) and secondary amines with mild condition, short reaction time (only 10 min) and high selectivity had been studied, which produced one of the following three substances: N-CF2H derivatives (up to 87% yield), formamides (82–89% yield) or the recycled starting secondary amines. This phenomenon was related to the structural stability of the corresponding products. If unstable, it would be hydrolyzed to formamides first, and then further hydrolyzed to starting amines. Based on the geometric structure of the raw materials, the corresponding prediction tree model was established, which provided guidance for the further application of difluoromethylation of Vemurafenib (1ee) and AZD9291 (1ff).
- Chen, Xiu-Ping,Han, Jie,Hu, Yin-Jie,Li, Yun-Fang,Wang, Xiang-Cong,Ran, Jian-Xiong,Wang, Zhong-Hua,Wu, Fan-Hong
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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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supporting information
p. 15948 - 15957
(2019/11/16)
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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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- 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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- 18F-Labeling of Aryl-SCF3, -OCF3 and -OCHF2 with [18F]Fluoride
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We report that halogenophilic silver(I) triflate permits halogen exchange (halex) nucleophilic 18F-fluorination of aryl-OCHFCl, -OCF2Br and -SCF2Br precursors under mild conditions. This AgI-mediated process allows for the first time access to a range of 18F-labeled aryl-OCHF2, -OCF3 and -SCF3 derivatives, inclusive of [18F]riluzole. The 18F-labeling of these medicinally important motifs expands the radiochemical space available for PET applications. A halogen exchange (halex) 18F-fluorination process offers access for the first time to 18F-labeled arylOCF3, arylOCHF2 and arylSCF3, three motifs of established medicinal importance in PET radiotracers. The use of silver(I) triflate is critical to permit 18F-labeling under mild conditions.
- Khotavivattana, Tanatorn,Verhoog, Stefan,Tredwell, Matthew,Pfeifer, Lukas,Calderwood, Samuel,Wheelhouse, Katherine,Leecollier, Thomas,Gouverneur, Vronique
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supporting information
p. 9991 - 9995
(2015/08/19)
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- Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine
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Background: 1,1-Difluoroalkenes cannot only be used as valuable precursors for organic synthesis, but also act as bioisosteres for enzyme inhibitors. Among various methods for their preparation, the carbonyl olefination with difluoromethylene phosphonium ylide represents one of the most straightforward methods. Results: The combination of (chlorodifluoromethyl)trimethylsilane (TMSCF2Cl) and triphenylphosphine (PPh3) can be used for the synthesis of gem-difluoroolefins from carbonyl compounds. Comparative experiments demonstrate that TMSCF2Cl is superior to (bromodifluoromethyl)trimethylsilane (TMSCF2Br) and (trifluoromethyl)trimethylsilane (TMSCF3) in this reaction. Conclusion: Similar to many other Wittig-type gem-difluoroolefination reactions in the presence of PPh3, the reaction of TMSCF2Cl with aldehydes and activated ketones is effective.
- Wang, Fei,Li, Lingchun,Ni, Chuanfa,Hu, Jinbo
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supporting information
p. 344 - 351
(2014/03/21)
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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 gem-difluorocyclopropa(e)nes and O-, S-, N-, and P-difluoromethylated compounds with TMSCF2Br
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Two-in-one: Me3SiCF2Br is an efficient difluorocarbene source and is compatible with both neutral and aqueous basic conditions. Bromide-ion-initiated [2+1] cycloaddition with alkenes/alkynes and hydroxide ion promoted α-addition with (thio)phenols, (thio)alcohols, sulfinates, heterocyclic amines, and H-phosphine oxides give the corresponding gem-difluorinated compounds with broad functional-group tolerance. Copyright
- Li, Lingchun,Wang, Fei,Ni, Chuanfa,Hu, Jinbo
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supporting information
p. 12390 - 12394
(2013/12/04)
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- Use of fluoroform as a source of difluorocarbene in the synthesis of difluoromethoxy- and difluorothiomethoxyarenes
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Fluoroform, CHF3, a non-ozone-depleting, nontoxic, and inexpensive gas can be used as a difluorocarbene source in a process for the conversion of phenols and thiophenols to their difluoromethoxy and difluorothiomethoxy derivatives. The reactions are carried out at moderate temperatures and atmospheric pressure, using potassium hydroxide as base in a two-phase (water/dioxane or water/acetonitrile) process to provide moderate to good yields of the respective products.
- Thomoson, Charles S.,Dolbier, William R.
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p. 8904 - 8908
(2013/09/24)
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- NHC-catalyzed generation of difluorocarbene and its application to difluoromethylation of oxygen nucleophiles
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Controlled generation of difluorocarbene was effected by an NHC catalyst under mild conditions starting from trimethylsilyl 2,2-difluoro-2- fluorosulfonylacetate (TFDA). Cyclohexenones and tetralones were treated with TFDA in the presence of catalytic amo
- Fuchibe, Kohei,Koseki, Yuta,Aono, Tatsuya,Sasagawa, Hisashi,Ichikawa, Junji
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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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- N-heterocyclic carbene-catalyzed difluorocarbene generation and its application to aryl difluoromethyl ether synthesis
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NHC-catalyzed generation of difluorocarbene from trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (TFD(A) enables the synthesis of enol difluoromethyl ethers starting from cyclohexenones and tetralones. The resultant enol difluoromethyl ethers were successively dehydrogenated with DDQ to furnish aryl difluoromethyl ethers in good to high yield.
- Fuchibe, Kohei,Koseki, Yuta,Sasagawa, Hisashi,Ichikawa, Junji
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p. 1189 - 1191
(2012/08/28)
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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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- 2-Chloro-2,2-difluoroacetophenone: A non-ODS-based difluorocarbene precursor and its use in the difluoromethylation of phenol derivatives
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A novel and non-ODS-based (ODS = ozone-depleting substance) preparation of 2-chloro-2,2-difluoroacetophenone (1) was achieved in high yield by using 2,2,2-trifluoroacetophenone as the starting material. Compound 1 was found to act as a good difluorocarbene reagent, which readily reacts with a variety of structurally diverse phenol derivatives 4 in the presence of potassium hydroxide or potassium carbonate to produce aryl difluoromethyl ethers 5 in good yields. This new and easy-to-handle synthetic methodology offers an environmentally friendly alternative to other Freon- or Halon-based difluoromethylating approaches.
- Zhang, Laijun,Zheng, Ji,Hu, Jinbo
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p. 9845 - 9848
(2007/10/03)
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