- Redox-Neutral TEMPO Catalysis: Direct Radical (Hetero)Aryl C?H Di- and Trifluoromethoxylation
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Applications of TEMPO. catalysis for the development of redox-neutral transformations are rare. Reported here is the first TEMPO.-catalyzed, redox-neutral C?H di- and trifluoromethoxylation of (hetero)arenes. The reaction exhibits a broad substrate scope, has high functional-group tolerance, and can be employed for the late-stage functionalization of complex druglike molecules. Kinetic measurements, isolation and resubjection of catalytic intermediates, UV/Vis studies, and DFT calculations support the proposed oxidative TEMPO./TEMPO+ redox catalytic cycle. Mechanistic studies also suggest that Li2CO3 plays an important role in preventing catalyst deactivation. These findings will provide new insights into the design and development of novel reactions through redox-neutral TEMPO. catalysis.
- Lee, Johnny W.,Lim, Sanghyun,Maienshein, Daniel N.,Liu, Peng,Ngai, Ming-Yu
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supporting information
p. 21475 - 21480
(2020/10/02)
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- Catalytic radical difluoromethoxylation of arenes and heteroarenes
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Intermolecular C-H difluoromethoxylation of (hetero)arenes remains a long-standing and unsolved problem in organic synthesis. Herein, we report the first catalytic protocol employing a redox-active difluoromethoxylating reagent 1a and photoredox catalysts for the direct C-H difluoromethoxylation of (hetero)arenes. Our approach is operationally simple, proceeds at room temperature, and uses bench-stable reagents. Its synthetic utility is highlighted by mild reaction conditions that tolerate a wide variety of functional groups and biorelevant molecules. Experimental and computational studies suggest single electron transfer (SET) from excited photoredox catalysts to 1a forming a neutral radical intermediate that liberates the OCF2H radical exclusively. Addition of this radical to (hetero)arenes gives difluoromethoxylated cyclohexadienyl radicals that are oxidized and deprotonated to afford the products of difluoromethoxylation.
- Lee, Johnny W.,Zheng, Weijia,Morales-Rivera, Cristian A.,Liu, Peng,Ngai, Ming-Yu
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p. 3217 - 3222
(2019/03/21)
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- DIFLUOROMETHOXYLATION AND TRIFLUOROMETHOXYLATION COMPOSITIONS AND METHODS FOR SYNTHESIZING SAME
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The present invention provides a compound having the structure (I), a processing of making the compound; and a process of using the compound as a reagent for the difluoromethoxylation and trifluoromethoxylation of arenes or heteroarenes.
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Page/Page column 75; 79; 89; 94
(2019/09/18)
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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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- 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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- 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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- 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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- 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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- 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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- IMPROVEMENT OF THE SYNTHESIS OF ARYL DIFLUOROMETHYL ETHERS AND THIOEHTERS BY USING A SOLID-LIQUID PHASE-TRANSFER TECHNIQUE
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A new solid-liquid phase-transfer technique has been used to synthesize aryl difluoromethyl ehters and thioethers.Phenols (or thiophenols) and chlorodifuoromethane, dissolved in a cheap aprotic solvent of low polarity, are contacted with solid sodium hydroxide in the presence of a catalytic amount of tris-(3,6-dioxaheptyl)amine.The work-up of the reaction mixtures is very simple.Although yields are similar in both homogeneous and heterogeneous procedures using phenols, improved yields are obtained for thiophenols when using phase-transfer conditions.
- Langlois, Bernard R.
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p. 247 - 262
(2007/10/02)
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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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