- 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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- Radical Difluororomethylation of Thiols with Difluoromethylphosphonium Triflate under Photoredox Catalysis
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A convenient, visible light-induced radical difluoromethylation of aryl-, heteroaryl-, and alkylthiols with difluoromethyltriphenylphosphonium triflate was developed to afford various difluoromethyl thioethers in moderate to excellent yields. The key reaction features include the use of a readily available CF2H radical source, mild reaction conditions, and excellent chemoselective thiol-difluoromethylation.
- Ran, Yang,Lin, Qing-Yu,Xu, Xiu-Hua,Qing, Feng-Ling
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p. 7373 - 7378
(2017/07/26)
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- Silver-catalyzed fluoroalkylation of thiols using fluoroalkanesulfinates
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A practical sliver-catalyzed fluoroalkylation of aryl-, heteroaryl- and alkylthiols has been developed. The reaction has a good functional-group tolerance and excellent selectivity. A variety of stable and solid fluoroalkanesulfinates including di- and perfluoroalkanesulfinates can be employed. This methodology provides a straightforward and streamlined access to perfluoroalkylthiolated organic molecules. [Figure presented]
- Ma, Jing-jing,Liu, Qi-ran,Lu, Guo-ping,Yi, Wen-bin
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supporting information
p. 113 - 117
(2017/01/03)
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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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- 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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- PhSO2SCF2H: A Shelf-Stable, Easily Scalable Reagent for Radical Difluoromethylthiolation
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A new shelf-stable and easily scalable difluoromethylthiolating reagent S-(difluoromethyl) benzenesulfonothioate (PhSO2SCF2H) was developed. PhSO2SCF2H is a powerful reagent for radical difluoromethylthiolation of aryl and alkyl boronic acids, decarboxylative difluoromethylthiolation of aliphatic acids, and a phenylsulfonyl-difluoromethylthio difunctionalization of alkenes under mild reaction conditions.
- Zhu, Dianhu,Shao, Xinxin,Hong, Xin,Lu, Long,Shen, Qilong
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supporting information
p. 15807 - 15811
(2016/12/16)
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- Preparation of difluoromethylthioethers through difluoromethylation of disulfides using TMS-CF2H
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We report an operationally simple, metal-free approach for the late-stage introduction of the important lipophilic hydrogen-bond donor motif, SCF2H. This reaction converts diaryl- and dialkyl-disulfides into the corresponding aryl/alkyl-SCF2H through the nucleophilic transfer of a difluoromethyl group with good functional group tolerance. This method is notable for its use of commercially available TMSCF2H, and does not rely on the need for handling of sensitive metal complexes.
- Howard, Joseph L.,Schotten, Christiane,Alston, Stephen T.,Browne, Duncan L.
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supporting information
p. 8448 - 8451
(2016/07/07)
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- Palladium-catalyzed difluoromethylthiolation of heteroaryl bromides, iodides, triflates and aryl iodides
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A palladium-catalyzed difluoromethylthiolation of heteroaryl halides and triflates under mild conditions was described. A vast range of heteroaryl halides such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl and pyazolyl halides could be difluoromethylthiolated efficiently, thus providing medicinal chemists with new tools for their search of new lead compounds for drug discovery. Likewise, aryl iodides were difluoromethylthiolated in high yields under a modified reaction condition.
- Wu, Jiang,Liu, Yafei,Lu, Changhui,Shen, Qilong
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p. 3757 - 3762
(2016/06/09)
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- A Route to α-Fluoroalkyl Sulfides from α-Fluorodiaroylmethanes
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α,α-Difluorodiaroylmethane can be used as a nucleophilic difluoromethylation reagent for generating α-thioaryl-α,α-difluoroacetophenones (Ar1COCF2SAr) and difluoromethylthiolated arenes (ArSCF2H) under transition-metal-free conditions. The reaction selectivity is mainly dependent on temperature. The method has also been extended to the synthesis of α-thioaryl-α-monofluoroacetophenones using α-monofluorodibenzoylmethane. Moreover, the benzoyl cation derived from α,α-difluorodibenzoylmethane can react with nucleophiles to afford the desired products in a one-pot process.
- Lin, Ya-Mei,Yi, Wen-Bin,Shen, Wan-Zhao,Lu, Guo-Ping
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supporting information
p. 592 - 595
(2016/02/18)
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- Direct S-difluoromethylation of thiols using the Ruppert-Prakash reagent Dedicated to Prof. Veronique Gouverneur on the occasion of receiving the ACS Award for Creative Work in Fluorine Chemistry.
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Direct S-difluoromethylation of aryl and aliphatic thiols using the Ruppert-Prakash reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfides, which upon cleavage with fluoride produces the difluoromethyl sulfides. The key reaction features are the use of relatively inexpensive and commercially available starting materials, shorter reaction times, ambient temperatures, easy reaction procedure, and selective S-difluoromethylation in the presence of -OH, -NH2 and -CO2H functional groups. Furthermore, one-pot arylthiodifluoromethyl transfer to PhCHO is also demonstrated.
- Prakash, G.K. Surya,Krishnamoorthy, Sankarganesh,Kar, Sayan,Olah, George A.
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p. 186 - 191
(2015/10/28)
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- N-Difluoromethylthiophthalimide: A Shelf-Stable, Electrophilic Reagent for Difluoromethylthiolation
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A new, electrophilic difluoromethylthiolating reagent N-difluoromethylthiophthalimide 3 was developed. Reagent 3 can be readily synthesized in four steps from easily available starting materials phthalimide and TMSCF2H. N-difluoromethylthiophthalimide 3 is a powerful electrophilic difluoromethylthiolating reagent that allows the difluoromethylthiolation of a wide range of nucleophiles including aryl/vinyl boronic acids, alkynes, amines, thiols, β-ketoesters, and oxindoles and electron-rich heteroarenes such as indole, pyrrole, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyridine, aminothiazole, isoxazole, and pyrazole under mild conditions.
- Zhu, Dianhu,Gu, Yang,Lu, Long,Shen, Qilong
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supporting information
p. 10547 - 10553
(2015/09/28)
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- Copper-promoted sandmeyer difluoromethylthiolation of aryl and heteroaryl diazonium salts
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An efficient copper-promoted difluoromethylthiolation of aryl and heteroaryl diazonium salts is described. The reaction is conducted under mild reaction conditions and various functional groups were compatible. In addition, reactions of heteroaryl diazonium salts such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl, and pyrazolyl diazonium salts occurred smoothly to afford the medicinally important difluoromethylthiolated heteroarenes. Furthermore, a more practical one-pot direct diazotization and difluoromethylthiolation protocol was developed, and it converts the aniline derivatives into difluoromethylthiolated arenes. The utility of the method is demonstrated by difluoromethylthiolation of a number of natural products and drug molecules. A dose of salt: The title reaction is conducted under mild reaction conditions and various functional groups are compatible. (Hetero)aryl diazonium salts reacted smoothly to afford the medicinally important difluoromethylthiolated (hetero)arenes. A practical one-pot direct diazotization and difluoromethylthiolation protocol was developed for aniline derivatives to generate difluoromethylthiolated arenes.
- Wu, Jiang,Gu, Yang,Leng, Xuebing,Shen, Qilong
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supporting information
p. 7648 - 7652
(2015/06/25)
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- Synthesis of difluoromethyl thioethers from difluoromethyl trimethylsilane and organothiocyanates generated in situ
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A copper-CF2H complex generated in situ from copper thiocyanate and TMS-CF2H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts. This strategy enables the introduction of difluoromethylthio groups - a largely unexplored substituent with highly promising properties - into drug-like molecules. A copper-CF2H complex generated in situ from copper thiocyanate and TMS-CF2H smoothly converts organothiocyanates into valuable difluoromethyl thioethers. This reaction step can be combined with several thiocyanation methods to one-pot protocols, allowing late-stage difluoromethylthiolations of widely available alkyl halides and arenediazonium salts.
- Bayarmagnai, Bilguun,Matheis, Christian,Jouvin, Kvin,Goossen, Lukas J.
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supporting information
p. 5753 - 5756
(2015/06/10)
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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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- 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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- SUBSTITUTED 5-AMINOTHIENO[2,3-C]PYRIDAZINE-6-CARBOXAMIDE ANALOGS AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4
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In one aspect, the invention relates to substituted 5-aminothieno[2,3-c]pyridazine-6- carboxamide analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M4 (mAChR M4); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
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Paragraph 001112; 001113
(2013/09/12)
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- N,N-Dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoroborate: A versatile electrophilic difluoromethylating reagent
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Over the past decade, sulfur-based fluoromethyl containing compounds have been exhaustively investigated as versatile fluoroalkylating reagents by our research laboratory as well as many others. Lately, we have designed a novel electrophilic difluoromethylating protocol employing in situ prepared N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt. The present reagent provides excellent reactivity toward a broad spectrum of nucleophilic species (N-, P-, S-, and O-nucleophiles) to yield the corresponding difluoromethylated products with high efficacy under mild conditions. Additional studies have been performed to elucidate the mechanistic fundamentals of the reactions.
- Prakash, G.K. Surya,Zhang, Zhe,Wang, Fang,Ni, Chuanfa,Olah, George A.
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experimental part
p. 792 - 798
(2011/10/09)
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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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- 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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