- Visible-Light-Driven Sulfonation of α-Trifluoromethylstyrenes: Access to Densely Functionalized CF3-Substituted Tertiary Alcohol
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Reported herein is a visible-light-induced sulfonation of α-trifluoromethylstyrenes with sodium sulfinates, which provides a series of α-trifluoromethyl-β-sulfonyl tertiary alcohols. This new synthetic protocol is enabled by a charge-transfer complex between oxygen and sulfinates, featuring broad substrate scope and scalability. Excellent functional group compatibility and chemoselectivity render this method suitable for sulfonation of pharmaceutically relevant molecules. In the presence of D2O, deuteriotrifluorinated products were also obtained, further demonstrating the flexibility and synthetic potentials of this strategy.
- Chen, Yi-Xuan,Wang, Zhu-Jun,Xiao, Jun-An,Chen, Kai,Xiang, Hao-Yue,Yang, Hua
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Read Online
- Visible-Light-Induced Deoxygenation/Defluorination Protocol for Synthesis of γ,γ-Difluoroallylic Ketones
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Herein, we describe an efficient, practical photocatalytic deoxygenation/defluorination protocol for the synthesis of γ,γ-difluoroallylic ketones from commercially available aromatic carboxylic acids, triphenylphosphine, and α-trifluoromethyl alkenes. The protocol has good functional group tolerance and a broad substrate scope. Using this method, we accomplished the late-stage functionalization of several bioactive molecules.
- Guo, Yuan-Qiang,Wang, Ruiguo,Song, Hongjian,Liu, Yuxiu,Wang, Qingmin
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- Photoredox/Hydrogen Atom Transfer Cocatalyzed C-H Difluoroallylation of Amides, Ethers, and Alkyl Aldehydes
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Herein, we report a method that combines hydrogen atom transfer and photoredox catalysis to achieve the dehydrogenative difluoroallylation of amides, ethers, and alkyl aldehydes. This operationally convenient method transforms a broad scope of substrates into the corresponding gem-difluoroalkenes via the construction of C(sp3)-C(sp3) or C(sp3)-C(sp2) bonds. Excellent functional group compatibility and high selectivity make this method have a wide range of substrate types and render it suitable for late-stage modification of pharmaceutical intermediates.
- Guo, Yuan-Qiang,Wu, Yifan,Wang, Ruiguo,Song, Hongjian,Liu, Yuxiu,Wang, Qingmin
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Read Online
- Electroreductive Cross-Coupling of Trifluoromethyl Alkenes and Redox Active Esters for the Synthesis of Gem-Difluoroalkenes
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An electroreductive access to gem-difluoroalkenes has been developed through the decarboxylative/defluorinative coupling of N-hydroxyphtalimides esters and α-trifluoromethyl alkenes. The electrolysis is performed under very simple reaction conditions in a
- Claraz, Aurélie,Allain, Clémence,Masson, Géraldine
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supporting information
(2021/11/17)
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- One-pot synthesis of α-trifluoromethylstyrenes from aryl ketones and the Ruppert–Prakash reagent
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A new synthesis of α-trifluoromethylstyrenes from aromatic ketones and (trifluoromethyl) trimethylsilane is described. The reaction involves nucleophilic trifluoromethylation and elimination of trimethylsilanol, which are performed within one reaction fla
- Dilman, Alexander D.,Levin, Vitalij V.
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p. 684 - 685
(2021/11/26)
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- Remote Regioselective Radical C-H Functionalization of Unactivated C-H Bonds in Amides: The Synthesis of gem-Difluoroalkenes
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The site-selective functionalization of unactivated aliphatic amines is an attractive and challenging synthetic approach. We herein report a general strategy for the remote site-selective functionalization of unactivated C(sp3)-H bonds in amides by photogenerated amidyl radicals to form gem-difluoroalkenes with trifluoromethyl-substituted alkenes. The site selectivity is controlled by a 1,5-hydrogen atom transfer (HAT) process of the amide. This photocatalyzed transformation shows both chemo- and site-selectivity, facilitating the formation of a secondary, tertiary, or quaternary carbon center.
- Hu, Qu-Ping,Cheng, Jing,Wang, Ying,Shi, Jie,Wang, Bi-Qin,Hu, Ping,Zhao, Ke-Qing,Pan, Fei
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supporting information
p. 4457 - 4462
(2021/05/26)
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- Photoredox relay-catalyzedgem-difluoroallylation of alkyl iodides
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Herein, a new example of relay catalysis, using a combination of Mn2(CO)10and an iridium-based photocatalyst, is reported. In our relay catalytic reaction, the Mn catalyst and iridium-based photocatalyst catalyze the reaction at different stages in the desired sequence under the same reaction conditions, and do not inhibit each other. This convenient method transforms a broad scope of alkyl iodides into the correspondinggem-difluoroalkenesviaC(sp3)-C(sp3) bond construction. The protocol has good functional group tolerance and is suitable for the late-stage modification of multifunctional complex molecules.
- Cao, Yunpeng,Guo, Yuanqiang,Liu, Yuxiu,Song, Hongjian,Wang, Qingmin
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supporting information
p. 9768 - 9771
(2021/09/30)
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- Electrochemical heterodifunctionalization of α-CF3alkenes to access α-trifluoromethyl-β-sulfonyl tertiary alcohols
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An unprecedented electrochemical heterodifunctionalization of α-CF3alkenes with benzenesulfonyl hydrazides was accomplished in this work, wherein a β-sulfonyl and a α-hydroxyl group were simultaneously incorporated across the olefinic double bond in a single operation. Consequently, a series of potentially medicinally valuable and densely functionalized α-trifluoromethyl-β-sulfonyl tertiary alcohols were assembled under mild conditions. Electrochemically-driven oxidative 1,2-difunctionlization of electron-deficient alkenes well obviates the need for oxidizing reagents, thus rendering this protocol more eco-friendly.
- Chen, Kai,Duan, Xin-Yu,Gao, Jie,Guan, Jian-Ping,Liu, Fang,Xiang, Hao-Yue,Xiao, Jun-An,Yang, Hua,Ye, Zhi-Peng
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supporting information
p. 8969 - 8972
(2021/09/10)
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- Photoredox-Catalyzed Difunctionalization of Unactivated Olefins for Synthesizing Lactam-Substituted gem-Difluoroalkenes
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Herein, the synthesis of lactam-substituted gem-difluoroalkenes has been developed through a photoredox-catalyzed radical cascade reaction. This developed photoredox-catalyzed, Br?nsted base-assisted intramolecular 5-exo-trig cyclization/intermolecular radical addition/β-fluoride elimination reaction offers a simple method for producing lactam, carbamate, or urea-substituted gem-difluoroalkenes with good functional group tolerance and high yields.
- Shi, Jie,Guo, Li-Yun,Hu, Qu-Ping,Liu, Yu-Tao,Li, Qing,Pan, Fei
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supporting information
p. 8822 - 8827
(2021/11/20)
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- A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis
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An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the iPr group is reported. The difluorination of readily accessible α-CF3-styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X-ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.
- Meyer, Stephanie,H?fliger, Joel,Sch?fer, Michael,Molloy, John J.,Daniliuc, Constantin G.,Gilmour, Ryan
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supporting information
p. 6430 - 6434
(2021/02/26)
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- Photoinduced Single-Electron Transfer as an Enabling Principle in the Radical Borylation of Alkenes with NHC–Borane
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A photoinduced SET process enables the direct B?H bond activation of NHC–boranes. In contrast to common hydrogen atom transfer (HAT) strategies, this photoinduced reaction simply takes advantage of the beneficial redox potentials of NHC–boranes, thus obviating the need for extra radical initiators. The resulting NHC–boryl radical was used for the borylation of a wide range of α-trifluoromethylalkenes and alkenes with diverse electronic and structural features, providing facile access to highly functionalized borylated molecules. Labeling and photoquenching experiments provide insight into the mechanism of this photoinduced SET pathway.
- Chen, Xiao-Qing,Hu, Yuan-Zhuo,Song, Dan,Xia, Peng-Ju,Xiang, Hao-Yue,Xiao, Jun-An,Yang, Hua,Ye, Zhi-Peng
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supporting information
p. 6706 - 6710
(2020/02/05)
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- Visible-Light-Induced Radical Defluoroborylation of Trifluoromethyl Alkenes: An Access to gem-Difluoroallylboranes
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A photoredox-catalyzed defluoroborylation of trifluoromethyl alkenes with N-heterocyclic carbene boranes is described for the synthesis of gem-difluoroallylboranes. This protocol exhibits a broad substrate scope and good functional group compatibility, which enables the late-stage functionalization of structurally complex compounds. Further transformations of the defluoroborylation products to valuable CF2-containing molecules are also demonstrated. (Figure presented.).
- Chen, Guojun,Wang, Liling,Liu, Xiaozu,Liu, Peijun
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supporting information
p. 2990 - 2996
(2020/06/10)
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- The coupling of alkylboronic acids with α-(trifluoromethyl)styrenes by Lewis base/photoredox dual catalysis
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Under Lewis base/photoredox dual catalysis, the defluorinative alkylation of alkylboronic acids with α-(trifluoromethyl)styrenes has been reported. In this system, both primary and secondary alkyl radicals produced by alkylboronic acids can react with α-(trifluoromethyl)styrenes to generate alkylated gem-difluoroalkenes. In general, the method has mild conditions, a wide substrate scope, and good functional group tolerance, which provides a new route for the synthesis of gem-difluoroalkenes.
- Chen, Yuefeng,Ni, Niannian,Cheng, Dongping,Xu, Xiaoliang
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supporting information
(2020/09/21)
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- Synthesis of ethyl 5-aryl-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-carboxylates, exhibiting plant growth-regulating properties
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A convenient method for the synthesis of high-boiling-point α-(trifluoromethyl)styrenes was proposed. The regioselective synthesis of a series of ethyl 5-aryl-5-(trifluoromethyl)-4,5- dihydroisoxazole-3-carboxylates was conducted by the reaction of ethyl
- Sigan,Golubev,Belyaeva,Gorfinkel,Kagramanov,Spiridonov, Yu. Ya.,Chkanikov
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- Photocatalytic, Phosphoranyl Radical-Mediated N-O Cleavage of Strained Cycloketone Oximes
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A photoinduced, phosphoranyl radical-mediated protocol for the direct N-O cleavage of strained cycloketone oximes via a polar/SET crossover process was developed for the first time. This visible-light-driven direct N-O activation mode for oxime offers beneficial features such as streamlined synthetic process and versatile photochemical reactivities. Consequently, the alkenes and α-trifluoromethyl alkenes with varied electronic and structural features acted as competent radical receptors in this protocol, enabling facile accesses to a range of elongated cyano and/or gem-difluoroalkene-bearing compounds.
- Xia, Peng-Ju,Ye, Zhi-Peng,Hu, Yuan-Zhuo,Song, Dan,Xiang, Hao-Yue,Chen, Xiao-Qing,Yang, Hua
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supporting information
p. 2658 - 2662
(2019/04/25)
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- Catalytic Geminal Difluorination of Styrenes for the Construction of Fluorine-rich Bioisosteres
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A geminal difluorination of alkenes based on I(I)/I(III) catalysis is disclosed, which is compatible with a range of electronically and substitutionally diverse styrenes (27 examples, up to 89% yield). Employing inexpensive p-TolI as the organocatalyst, turnover is enabled by Selectfluor-mediated oxidation to generate the ArIF2 species in situ. Extension to include α-substituted styrenes bearing fluorine-containing groups is disclosed and provides an expansive platform for the generation of fluorine-rich architectures.
- Scheidt, Felix,Neufeld, Jessica,Sch?fer, Michael,Thiehoff, Christian,Gilmour, Ryan
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p. 8073 - 8076
(2019/01/04)
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- Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover
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A benchtop stable, bifunctional reagent for the redox-neutral cyclopropanation of olefins has been developed. Triethylammonium bis(catecholato)iodomethylsilicate can be readily prepared on multigram scale. Using this reagent in combination with an organic photocatalyst and visible light, cyclopropanation of an array of olefins, including trifluoromethyl- and pinacolatoboryl-substituted alkenes, can be accomplished in a matter of hours. The reaction is highly tolerant of traditionally reactive functional groups (carboxylic acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds. Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3-exo-tet ring closure, a pathway consistent with experimental and computational data.
- Phelan, James P.,Lang, Simon B.,Compton, Jordan S.,Kelly, Christopher B.,Dykstra, Ryan,Gutierrez, Osvaldo,Molander, Gary A.
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supporting information
p. 8037 - 8047
(2018/07/03)
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- Photocatalytic alkene reduction by a B12-TiO2 hybrid catalyst coupled with C-F bond cleavage for: Gem -difluoroolefin synthesis
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Photocatalytic syntheses of gem-difluoroolefins were performed using the B12-TiO2 hybrid catalyst during the CC bond reduction of α-trifluoromethyl styrenes with C-F bond cleavage at room temperature under nitrogen. The gem-difluoroolefins were used as synthetic precursors for fluorinated cyclopropanes.
- Tian, Hui,Shimakoshi, Hisashi,Imamura, Kenji,Shiota, Yoshihito,Yoshizawa, Kazunari,Hisaeda, Yoshio
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supporting information
p. 9478 - 9481
(2017/09/01)
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- Synthesis of gem-Difluoroallylboronates via FeCl2-Catalyzed Boration/β-Fluorine Elimination of Trifluoromethyl Alkenes
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The first ferrous chloride catalyzed boration/β-fluorine elimination of trifluoromethyl alkenes is described. Thus, a full range of gem-difluoroallylboronates were obtained in high yield under mild conditions. As an important fluorinated building block, gem-difluoroallylboronate can be readily converted into diverse difluoro-substituted species.
- Liu, Yang,Zhou, Yuhan,Zhao, Yilong,Qu, Jingping
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supporting information
p. 946 - 949
(2017/02/26)
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- Palladium-Catalyzed Trimethylenemethane Cycloaddition of Olefins Activated by the δ-Electron-Withdrawing Trifluoromethyl Group
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α-Trifluoromethyl-styrenes, trifluoromethyl-enynes, and dienes undergo palladium-catalyzed trimethylenemethane cycloadditions under mild reaction conditions. The trifluoromethyl group serves as a unique δ-electron-withdrawing group for the activation of the olefin toward the cycloaddition. This method allows for the formation of exomethylene cyclopentanes bearing a quaternary center substituted by the trifluoromethyl group, compounds of interest for the pharmaceutical, agrochemical, and materials industries. In the diene series, the cycloaddition operates in a [3 + 4] and/or [3 + 2] manner to give rise to seven- and/or five-membered rings. This transformation greatly improves the scope of the TMM cycloaddition technology and provides invaluable insights into the reaction mechanism.
- Trost, Barry M.,Debien, Laurent
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p. 11606 - 11609
(2015/09/28)
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- SUBSTITUTED 1H-PYRROLOPYRIDINONE DERIVATIVES AS KINASE INHIBITORS
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The present invention provides novel substituted 1H-Pyrrolopyridinone derivatives of formula (1) as protein kinase inhibitors, in which R1, R2, R3, R4, R5, R6 and 'p' have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly BTK enzyme. The present invention also provides methods for synthesizing and administering the kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.
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- Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N′-arylpiperazine series
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We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP) these initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3- pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3, 3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).
- Nishimura, Nobuko,Norman, Mark H.,Liu, Longbin,Yang, Kevin C.,Ashton, Kate S.,Bartberger, Michael D.,Chmait, Samer,Chen, Jie,Cupples, Rod,Fotsch, Christopher,Helmering, Joan,Jordan, Steven R.,Kunz, Roxanne K.,Pennington, Lewis D.,Poon, Steve F.,Siegmund, Aaron,Sivits, Glenn,Lloyd, David J.,Hale, Clarence,St. Jean, David J.
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p. 3094 - 3116
(2014/05/06)
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- TRICYCLIC ALKYNES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN
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The present invention relates to tricyclic alkyne compounds of formula I that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where gluco
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Page/Page column 73-74
(2014/03/25)
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- N-(2-CYANO HETEROCYCLYL)PYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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Provided are compounds of Formula I, a JAK inhibitor, and use thereof for the treatment of JAK-mediated diseases by the application.
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Page/Page column 66
(2014/10/03)
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- GEMINALLY SUBSTITUTED CYANOETHYLPYRAZOLO PYRIDONES AS JANUS KINASE INHIBITORS
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The instant invention provides compounds of Formula (I) which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
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Page/Page column 127
(2014/10/03)
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- Metabolically stable tert-butyl replacement
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Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp3 C-Hs from a tert-butyl group: replacing some C-Hs with C-Fs and increasing the s-character of the remaining C-Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-containing analogues had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-containing counterparts.
- Barnes-Seeman, David,Jain, Monish,Bell, Leslie,Ferreira, Suzie,Cohen, Scott,Chen, Xiao-Hui,Amin, Jakal,Snodgrass, Brad,Hatsis, Panos
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supporting information
p. 514 - 516
(2013/07/26)
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- SULFONYL COMPOUNDS THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN
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The present invention relates to sulfonyl compounds that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
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Page/Page column 114
(2013/08/28)
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- Extremely efficient and reversible visible-light photochromism and accompanying switch of electronic communication in N-phenylcarbazole-appended diethynylethene
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Photoisomerization: N-phenylcarbazole-conjugated dimethyl 2,3-diethynylfumarate/maleate, E/Z-4, shows highly efficient and reversible visible-light E/Z photoisomerization (φtotal=0.40) upon excitation with an intramolecular charge-transfer band. This photochromism induces switching of electronic communication between the two N-phenylcarbazole moieties in the one-electron oxidized mixed-valent state (see scheme). Copyright
- Hayashi, Mikihiro,Sakamoto, Ryota,Nishihara, Hiroshi
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supporting information; experimental part
p. 8610 - 8613
(2012/08/27)
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- SULFONYLPIPERAZINE DERIVATIVES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES
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The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
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Page/Page column 216; 217
(2012/03/26)
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- Syntheses of mono-, di-, and trifluorinated styrenic monomers
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Concise syntheses of gram quantities of three fluorinated -methylstyrenic monomers suitable for polymerisation studies are disclosed, all based on the use of reasonably priced commercially available starting materials and reagents. Georg Thieme Verlag Stuttgart New York.
- Walkowiak, Justyna,Del Campo, Teresa Martinez,Ameduri, Bruno,Gouverneur, Veronique
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experimental part
p. 1883 - 1890
(2010/08/20)
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- Synthesis of gem-difluoroalkenes via β-fluoride elimination of organorhodium(I)
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Treatment of α-(trifluoromethyl)styrenes with arylboronic esters and MeMgCl in the presence of a rhodium(I) catalyst affords gem-difluoroalkenes. The reaction proceeds through the addition of arylrhodium(I) species across the electron-deficient carbon-carbon double bond and the subsequent β-fluoride elimination. Copyright
- Miura, Tomoya,Ito, Yoshiteru,Murakami, Masahiro
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supporting information; experimental part
p. 1006 - 1007
(2009/04/06)
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