- Reactions of triflate esters and triflamides with an organic neutral super-electron-donor
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The bis-pyridinylidene 13 converts aliphatic and aryl triflate esters to the corresponding alcohols and phenols respectively, using DMF as solvent, generally in excellent yields. While the deprotection of aryl triflates has been seen with other reagents and by more than one mechanism, the deprotection of alkyl triflates is a new reaction. Studies with 18O labelled DMF indicate that the C-O bond stays intact and hence it is the S-O bond that cleaves, underlining that the cleavage results from the extraordinary electron donor capability of 13. Trifluoromethanesulfonamides are converted to the parent amines in like manner, representing the first cleavage of such substrates by a ground-state organic reducing reagent.
- Jolly, Phillip I.,Fleary-Roberts, Nadia,O'Sullivan, Steven,Doni, Eswararao,Zhou, Shengze,Murphy, John A.
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Read Online
- Rhodium-catalyzed cascade reactions: A methylenation-hydroboration homologative process
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A very efficient rhodium-catalyzed cascade process allowing the transformation of aldehydes and ketones into their corresponding one or two-carbon homologated alcohol products through a methylenation-hydroboration sequence is reported. Wilkinson's complex is used to catalyze both reactions in a one-pot procedure that does not require the isolation of the alkene intermediate.
- Lebel, Hélène,Ladjel, Chehla
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Read Online
- Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations
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Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50 = 143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.
- Vasilakaki, Sofia,Barbayianni, Efrosini,Leonis, Georgios,Papadopoulos, Manthos G.,Mavromoustakos, Thomas,Gelb, Michael H.,Kokotos, George
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Read Online
- Generation of a low-valent titanium species from titanatrane and its catalytic reactions: Radical ring opening of oxetanes
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Treatment of a titanatrane complex with trimethylsilyl chloride and magnesium powder in tetrahydrofuran generated a low-valent titanium species. This species catalyzed the radical ring opening of epoxides and oxetanes to produce the corresponding less substituted alcohols. The reagent also catalyzed the deallylation and depropargylation of allylic and propargylic ethers, respectively, to provide the parent alcohols.
- Takekoshi, Naoto,Miyashita, Kenji,Shoji, Noriaki,Okamoto, Sentaro
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Read Online
- Epoxide Electroreduction
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Selective hydrogenation of epoxides would be a direct and powerful approach for alcohol synthesis, but it has proven to be elusive. Here, electrochemically epoxide hydrogenation using electrons and protons as reductants is reported. A wide range of primary, secondary, and tertiary alcohols can be achieved through selective Markovnikov or anti-Markovnikov ring opening in the absence of transition metals. Mechanistic investigations revealed that the regioselectivity is controlled by the thermodynamic stabilities of the in situ generated benzyl radicals for aryl-substituted epoxides and the kinetic tendency for Markovnikov selective ring opening for alkyl-substituted epoxides.
- Huang, Cheng,Lu, Qingquan,Ma, Wan,Qi, Xiaotian,Xu, Minghao,Zheng, Xuelian
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supporting information
p. 1389 - 1395
(2022/01/19)
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- Access to Trisubstituted Fluoroalkenes by Ruthenium-Catalyzed Cross-Metathesis
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Although the olefin metathesis reaction is a well-known and powerful strategy to get alkenes, this reaction remained highly challenging with fluororalkenes, especially the Cross-Metathesis (CM) process. Our thought was to find an easy accessible, convenient, reactive and post-functionalizable source of fluoroalkene, that we found as the methyl 2-fluoroacrylate. We reported herein the efficient ruthenium-catalyzed CM reaction of various terminal and internal alkenes with methyl 2-fluoroacrylate giving access, for the first time, to trisubstituted fluoroalkenes stereoselectively. Unprecedent TON for CM involving fluoroalkene, up to 175, have been obtained and the reaction proved to be tolerant and effective with a large range of olefin partners giving fair to high yields in metathesis products. (Figure presented.).
- Nouaille, Augustin,Pannecoucke, Xavier,Poisson, Thomas,Couve-Bonnaire, Samuel
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supporting information
p. 2140 - 2147
(2021/03/06)
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- Selective hydroboration of equilibrating allylic azides
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The iridium(i)-catalyzed hydroboration of equilibrating allylic azides is reported to provide only the anti-Markovnikov product of alk-1-ene isomers in good yields and with good functional group tolerance.
- Liu, Ruzhang,Xu, Jun,Zhang, Yuanyuan
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supporting information
p. 8913 - 8916
(2021/09/13)
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- Selective Production of Linear Aldehydes and Alcohols from Alkenes using Formic Acid as Syngas Surrogate
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Performing carbonylation without the use of carbon monoxide for high-value-added products is an attractive yet challenging topic in sustainable chemistry. Herein, effective methods for producing linear aldehydes or alcohols selectively with formic acid as both carbon monoxide and hydrogen source have been described. Linear-selective hydroformylation of alkenes proceeds smoothly with up to 88 % yield and >30 regioselectivity in the presence of single Rh catalyst. Strikingly, introducing Ru into the system, the dual Rh/Ru catalysts accomplish efficient and regioselective hydroxymethylation in one pot. The present processes utilizing formic acid as syngas surrogate operate simply under mild condition, which opens a sustainable way for production of linear aldehydes and alcohols without the need for gas cylinders and autoclaves. As formic acid can be readily produced via CO2 hydrogenation, the protocols represent indirect approaches for chemical valorization of CO2.
- Chen, Junjun,Hua, Kaimin,Liu, Xiaofang,Deng, Yuchao,Wei, Baiyin,Wang, Hui,Sun, Yuhan
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p. 9919 - 9924
(2021/05/31)
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- Matteson Reaction under Flow Conditions: Iterative Homologations of Terpenes
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The Matteson reaction is ideally suited for flow chemistry since it allows iterative homologation of boronate esters. The present study provides accurate data on reaction times of the individual steps of the Matteson reaction, which occurs in less than 10 s in total. The protocol allows terpenes to be (per-)homologated in a controlled manner to yield homo-, bishomo-, and trishomo-terpenols after oxidative workup. The new terpene alcohols are validated with respect to their olfactoric properties.
- Kuhwald, Conrad,Kirschning, Andreas
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supporting information
p. 4300 - 4304
(2021/05/26)
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- A General Method for Photocatalytic Decarboxylative Hydroxylation of Carboxylic Acids
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A general and practical method for decarboxylative hydroxylation of carboxylic acids was developed through visible light-induced photocatalysis using molecular oxygen as the green oxidant. The addition of NaBH4 to in situ reduce the unstable peroxyl radical intermediate much broadened the substrate scope. Different sp3 carbon-bearing carboxylic acids were successfully employed as substrates, including phenylacetic acid-type substrates, as well as aliphatic carboxylic acids. This transformation worked smoothly on primary, secondary, and tertiary carboxylic acids.
- Khan, Shah Nawaz,Zaman, Muhammad Kashif,Li, Ruining,Sun, Zhankui
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p. 5019 - 5026
(2020/05/01)
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- Controlled Reduction of Carboxamides to Alcohols or Amines by Zinc Hydrides
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New protocols for controlled reduction of carboxamides to either alcohols or amines were established using a combination of sodium hydride (NaH) and zinc halides (ZnX2). Use of a different halide on ZnX2 dictates the selectivity, wherein the NaH-ZnI2 system delivers alcohols and NaH-ZnCl2 gives amines. Extensive mechanistic studies by experimental and theoretical approaches imply that polymeric zinc hydride (ZnH2)∞ is responsible for alcohol formation, whereas dimeric zinc chloride hydride (H?Zn?Cl)2 is the key species for the production of amines.
- Ong, Derek Yiren,Yen, Zhihao,Yoshii, Asami,Revillo Imbernon, Julia,Takita, Ryo,Chiba, Shunsuke
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supporting information
p. 4992 - 4997
(2019/03/13)
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- Hydrofunctionalization of Olefins to Higher Aliphatic Alcohols via Visible-Light Photocatalytic Coupling
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Abstract: An atomically economical green protocol for the hydrofunctionalization of olefins to higher aliphatic alcohols with 100% anti-Markovnikov regioselectivity was developed via visible-light photocatalytic coupling. This method employs cheap, readily available and abundant methanol as both the C1 feedstock and the hydrogen source under visible light irradiation over CdS photocatalyst. A wide scope of olefin substrates could be hydrofunctionalized successfully to the corresponding higher alcohols with high selectivity. Besides alcohol, acetone and acetonitrile can also couple with olefins to generate the corresponding hydrofunctionalization products, suggesting promising potential industrial application. Graphical Abstract: [Figure not available: see fulltext.] Hydrofunctionalization of olefins to value-added chemicals with high selectivity was achieved via visible-light photocatalytic cross-coupling.
- Bao, Jingxian,Fan, Yonghui,Zhang, Shuyi,Zhong, Liangshu,Wu, Minghong,Sun, Yuhan
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- N-Heterocyclic Carbene Iron(III) Porphyrin-Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides
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Metal-catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands which catalyzes the intramolecular C(sp3)–H amination of a wide variety of alkyl azides under microwave-assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re-bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis-octahydroindole, and leelamine derivatives.
- Shing, Ka-Pan,Liu, Yungen,Cao, Bei,Chang, Xiao-Yong,You, Tingjie,Che, Chi-Ming
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supporting information
p. 11947 - 11951
(2018/09/11)
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- Hydrofunctionalization of olefins to value-added chemicals: Via photocatalytic coupling
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A green strategy was developed for the synthesis of various value-added chemicals using methanol, acetonitrile, acetic acid, acetone and ethyl acetate as the hydrogen source by coupling them with olefins over heterogeneous photocatalysts. A radical coupling mechanism was proposed for the hydrofunctionalization of olefins with methanol to higher aliphatic alcohols over the Pt/TiO2 catalyst as the model reaction. C-H bond cleavage and C-C bond formation between photogenerated radicals and terminal olefins were accomplished in a single reaction at high efficiency. Our approach is atomically economical with high anti-Markovnikov regioselectivity and promising application potential under mild reaction conditions.
- Fan, Yonghui,Li, Shenggang,Bao, Jingxian,Shi, Lei,Yang, Yanzhang,Yu, Fei,Gao, Peng,Wang, Hui,Zhong, Liangshu,Sun, Yuhan
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supporting information
p. 3450 - 3456
(2018/08/06)
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- Synthesis, in vitro and in silico evaluation of diaryl heptanones as potential 5LOX enzyme inhibitors
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A new series of diaryl heptanones (12a-q) were synthesized and their structures were confirmed by its 1H, 13C NMR and Mass spectral data. These analogs were evaluated for their anti-oxidant activity and potential to inhibit 5-lipoxygenase. Compounds 12k and 12o showed potent in vitro 5-lipoxygenase enzyme inhibitory activity with IC50 values of 22.2, 21.5 μM, which are comparable to curcumin (24.4 μM). Further they also have shown significant antioxidant activity. Molecular docking studies clearly showed correlation between binding energy and potency of these compounds.
- Meka, Bharani,Ravada, Suryachandra Rao,Muthyala, Murali Krishna Kumar,Kurre, Purna Nagasree,Golakoti, Trimurtulu
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p. 408 - 421
(2018/07/13)
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- Practical Intermolecular Hydroarylation of Diverse Alkenes via Reductive Heck Coupling
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The hydroarylation of alkenes is an attractive approach to construct carbon-carbon (C-C) bonds from abundant and structurally diverse starting materials. Herein we report a palladium-catalyzed reductive Heck hydroarylation of aliphatic and heteroatom-substituted terminal alkenes and select internal alkenes with an array of (hetero)aryl iodides. The reaction is anti-Markovnikov selective with terminal alkenes and tolerates a wide variety of functional groups on both the alkene and (hetero)aryl coupling partners. Additionally, applications of this method to complex molecule diversifications are demonstrated. Mechanistic experiments are consistent with a mechanism in which the key alkylpalladium(II) intermediate is intercepted with formate and undergoes a decarboxylation/C-H reductive elimination cascade to afford the saturated product and turn over the cycle.
- Gurak, John A.,Engle, Keary M.
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p. 8987 - 8992
(2018/09/11)
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- Disubstituted beta-lactones as inhibitors of N-acylethanolamine acid amidase (NAAA)
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The present invention provides compounds and pharmaceutical compositions for inhibiting N-acylethanolamine acid amidase (NAAA). Inhibition of NAAA is contemplated as a method to sustain the levels of palmitoylethanolamide (PEA) and oleylethanolamide (OEA), two substrates of NAAA, in conditions characterized by reduced concentrations of PEA and OEA. The invention also provides methods for treating inflammatory diseases and pain, and other disorders in which decreased levels of PEA and OEA are associated with the disorder.
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Page/Page column 98
(2016/06/28)
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- Visible-light-promoted conversion of alkyl benzyl ether to alkyl ester or alcohol via O-α-sp3 C-H cleavage
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A mild and high-yielding visible-light-promoted conversion of alkyl benzyl ethers to the alkyl esters or alkyl alcohols was developed. Mechanistic studies provided evidence for a radical chain reaction involving the homolytic cleavage of O-α-sp3 C-H bonds in the substrate as one of the propagation steps. We propose that α-bromoethers are key intermediates in the transformation.
- Lu, Ping,Hou, Tianyuan,Gu, Xiangyong,Li, Pixu
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supporting information
p. 1954 - 1957
(2015/04/27)
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- Oxidative cleavage of allyl ethers by an oxoammonium salt
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A method to oxidatively cleave allyl ethers to their corresponding aldehydes mediated by an oxoammonium salt is described. Using a biphasic solvent system and mild heating, cleavage proceeds readily, furnishing a variety of α,β-unsaturated aldehydes and ketones.
- Kelly, Christopher B.,Ovian, John M.,Cywar, Robin M.,Gosselin, Taylor R.,Wiles, Rebecca J.,Leadbeater, Nicholas E.
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supporting information
p. 4255 - 4259
(2015/04/14)
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- Access to nitriles from aldehydes mediated by an oxoammonium salt
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A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl-imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.
- Kelly, Christopher B.,Lambert, Kyle M.,Mercadante, Michael A.,Ovian, John M.,Bailey, William F.,Leadbeater, Nicholas E.
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supporting information
p. 4241 - 4245
(2015/04/14)
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- Solvent-free reduction of carboxylic acids to alcohols with NaBH4 promoted by 2,4,6-trichloro-1,3,5-triazine and PPh3 in the presence of K2CO3
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A simple, rapid, and eco-friendly method for NaBH4 reduction of carboxylic acids to alcohols under solvent-free conditions was developed using a combination of 2,4,6-trichloro-1,3,5-triazine (TCT) with a catalytic amount of triphenylphosphine as an acid activator. With the 1 : 0.2 : 1.5 : 2 mole ratio of TCT : PPh3 : K2CO3 : NaBH4, carboxylic acids including aromatic acids, aliphatic acids, and N-protected α-amino acids (Fmoc, Z) could readily undergo reduction to give the corresponding alcohols in good to excellent yields within 10 min.
- Jaita, Subin,Kaewkum, Pantitra,Duangkamol, Chuthamat,Phakhodee, Wong,Pattarawarapan, Mookda
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p. 46947 - 46950
(2014/12/10)
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- Ring-opening of cyclic ethers with carbon-carbon bond formation by Grignard reagents
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The ring-opening of cyclic ethers with concomitant C-C bond formation was studied with a number of Grignard reagents. The transformation was performed in a sealed vial by heating to ~160 °C in an aluminum block or at 180 °C in a microwave oven. Good yields of the product alcohols were obtained with allyl- and benzylmagnesium halides when the ether was tetrahydrofuran or 3,3-dimethyloxetane. Lower yields were obtained with substituted tetrahydrofurans while no ring-opening was observed with tetrahydropyran. Only highly reactive allyl and benzyl Grignard reagents participated in the transformation while no reaction occurred with other alkylmagnesium halides.
- Christensen, Stig Holden,Holm, Torkil,Madsen, Robert
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p. 4942 - 4946
(2014/07/07)
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- Comparative performance evaluation and systematic screening of solvents in a range of Grignard reactions
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The solvent effect on the Grignard reaction of benzyl, aryl and heteroaromatic substrates has been systematically evaluated based on reaction efficiency, ease of subsequent work-up, safety and greenness. 2-Methyltetrahydrofuran (2-MeTHF), which can be derived from renewable resources, had at least an equal if not a superior overall process most notably in suppressing the Wurtz coupling by-product from the benzyl Grignard reactions. It is therefore a recommended alternative solvent to Et2O and THF for the preparation of most Grignard reagents and their subsequent reactions.
- Kadam, Asha,Nguyen, Mylinh,Kopach, Michael,Richardson, Paul,Gallou, Fabrice,Wan, Zhao-Kui,Zhang, Wei
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p. 1880 - 1888
(2013/09/24)
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- DISUBSTITUTED BETA-LACTONES AS INHIBITORS OF N-ACYLETHANOLAMINE ACID AMIDASE (NAAA)
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The present invention provides compounds and pharmaceutical compositions for inhibiting N-acylethanolamine acid amidase (NAAA). Inhibition of NAAA is contemplated as a method to sustain the levels of palmitoylethanolamide (PEA) and oleylethanolamide (OEA), two substrates of NAAA, in conditions characterized by reduced concentrations of PEA and OEA. The invention also provides methods for treating inflammatory diseases and pain, and other disorders in which decreased levels of PEA and OEA are associated with the disorder.
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Paragraph 0276
(2013/06/06)
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- Ni-catalyzed cascade cyclization-kumada alkyl-alkyl cross-coupling
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Suggesting novel disconnections: A powerful Ni-catalyzed cascade reaction involving cyclization followed by cross-coupling allows the formation of up to three alkyl-alkyl bonds in a single operation by using alkene-containing alkyl iodides and Grignard reagents (see scheme; acac=acetylacetonate; TMEDA=N,N′,N′-tetramethyl ethylenediamine). Mechanistic experimental and computational studies suggest a NiI-NiII-Ni III catalytic cycle and the intermediacy of radicals. Copyright
- Guisan-Ceinos, Manuel,Soler-Yanes, Rita,Collado-Sanz, Daniel,Phapale, Vilas B.,Bunuel, Elena,Cardenas, Diego J.
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supporting information
p. 8405 - 8410
(2013/07/25)
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- A general electron transfer reduction of lactones using SmI 2-H2O
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Herein we describe a strategy for the selective, electron transfer reduction of lactones of all ring sizes and topologies using SmI 2-H2O and a Lewis base to tune the redox properties of the complex. The current protocol permits instantaneous reduction of lactones to the corresponding diols in excellent yields, under mild reaction conditions and with useful chemoselectivity. We demonstrate the broad utility of this transformation through the reduction of complex lactones and sensitive drug-like molecules. Sequential electron transfer reactions and syntheses of deuterated diols are also described.
- Szostak, Michal,Collins, Karl D.,Fazakerley, Neal J.,Spain, Malcolm,Procter, David J.
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supporting information; experimental part
p. 5820 - 5824
(2012/08/28)
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- Ion-pair complexation with a cavitand receptor
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The capability of resorcinarenes to bind anions within the alkyl feet at the lower rim has been exploited as the starting point for developing a new cavitand able to engulf contact ion pairs of primary ammonium salts in chlorinated solvents with association constants (Kass) in the range of 103104M-1. Methylene bridges were introduced into the upper rim to freeze the resorcinarene in the cone conformation with the four Hdown protons converging in the lower pocket, thereby maximizing the CH-anion interactions responsible for the anion binding. Four additional phosphate moieties were introduced into the lower rim in close prox-imity to the anionic site to provide hydrogen-bonding-acceptor P=O groups and promote cation complexation at the bottom of the cavitand. The binding ability of the synthesized ligands was analyzed by 1H NMR spectroscopy and, when possible, by isothermal titration calorimetry (ITC); the data were in agreement when complementary techniques were used.
- Tancini, Francesca,Gottschalk, Thomas,Bernd Schweizer,Diederich, Francois,Dalcanale, Enrico
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experimental part
p. 7813 - 7819
(2010/09/05)
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- Organic thin film transistor comprising phosphate-based self-assembled monolayer and method of manufacturing the same
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Disclosed is an organic thin film transistor including a phosphate-based self-assembled monolayer and a method of manufacturing the same. Example embodiments relate to an organic thin film transistor, which may include a single bond type phosphate-based self-assembled monolayer without intermolecular cross-linking, between source/drain electrodes and an organic semiconductor layer, thus exhibiting improved electrical properties, e.g., increased charge mobility, and to a method of manufacturing the organic thin film transistor.
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- A new method for the synthesis of α-thio aldehydes and alcohols from aldehydes with one-carbon elongation
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A two-step and high-yield method for the synthesis of α-thio aldehydes from aldehydes with one-carbon elongation is realized by using chloromethyl phenyl sulfoxide as a one-carbon homologating agent. The α-thio aldehydes are easily converted to desulfurized alcohols with Bu3SnH and AIBN in refluxing benzene in good yield. (C) 2000 Elsevier Science Ltd.
- Satoh, Tsuyoshi,Kubota, Ko-Ichi
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p. 2121 - 2124
(2007/10/03)
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- Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles.
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The influence of lipophilic moieties attached to a 4-1H-imidazole ring on the histamine H3 receptor activity was systematically investigated. Series of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles were prepared, with an alkyl chain varying from 2-9 methylene groups and from 1-9 methylene groups, respectively. The compounds were tested for their activity on the H3 receptor under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is proportional to chain length, ranging from a pA2 value of 6.3 +/- 0.2 for 4-(n-propyl)-1H-imidazole to a pA2 value of 7.2 +/- 0.1 for 4-(n-decyl)-1H-imidazole. For the series 4-(omega-phenylalkyl)-4H-imidazoles an optimum in H3 activity was found for the pentylene spacer: 4-(omega-phenylpentyl)-1H-imidazole has a pA2 value of 7.8 +/- 0.1.
- De Esch,Gaffar,Menge,Timmerman
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p. 3003 - 3009
(2007/10/03)
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- Facile generation of alkoxy radicals from N-alkoxyphthalimides
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N-Alkoxyphthalimides, stable and readily accessible from alcohols and alkyl halides, are found to be very efficient alkoxy radical precursors.
- Kim, Sunggak,Lee, Tai Au,Song, Yukwan
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p. 471 - 472
(2007/10/03)
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- ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme
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ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible K(i)'s in the 1-3 μM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP- citrate lyase.
- Gribble, Andrew D.,Dolle, Roland E.,Shaw, Antony,McNair, David,Novelli, Riccardo,Novelli, Christine E.,Slingsby, Brian P.,Shah, Virendra P.,Tew, David,Saxty, Barbara A.,Allen, Mark,Groot, Pieter H.,Pearce, Nigel,Yates, John
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p. 3569 - 3584
(2007/10/03)
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- Compounds having one or more aminosulfaonyloxy radicals useful as pharmaceuticals
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Methods of treating chronic arthritis and osteoporosis which utilize both known and novel compounds which would fall under the general formula:(HO)p--A--[--OS(O) 2 NR 1 R 2 ] zwherein A encompasses a wide range of values including but not limited to aryl, loweralkyl, cycloalkyl, and carbohydrates including sucrose and fructose; p is equal to the number of unreacted hydroxy groups contained on the molecule and may be zero; z is the number of --OS(O) 2 NR 1 R 2 groups and is always at least one; R 1 and R 2 are selected from hydrogen, loweralkyl, carboxy and the like; a novel process for preparing the compounds is provided wherein an appropriate sulfamic acid aryl ester is reacted with a hydroxy substituted A radical which may or may not contain thereon protected carboxyl, amino or hydroxy substituents, in an aprotic solvent containing a tertiary amine base. Pharmaceutical compositions for the treatment of chronic arthritis and osteoporosis are also provided.
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- Thiol esters in organic synthesis XVII. S,S'-diethyl dithiomalonate as masked ethanol carbanion and 1,3-diol equivalent in the Knoevenagel condensation
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S,S'-Diethyl dithiomalonate (1) has been shown to be a useful reagent in the Knoevenagel condensation with aldehydes, using DABCO as the base. The resultant products can be reduced either to 1,3-diols by use of sodium borohydride or to ethanol derivatives using Raney Nickel.
- Rose,Liu
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p. 2089 - 2095
(2007/10/02)
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- β-Halogeno Ether Synthesis of Olefinic Alcohols: Stereochemistry of the Ring-scission of 2-Substituted 3-Halogenotetrahydro-pyrans and -furans
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The stereochemical outcome of the sodium ring-scission of 2-substituted 3-halogenotetrahydro-pyrans and -furans, with 2-substitution represented by alkyl, alkenyl or aryl, is presented.Although the cis- and the trans-tetrahydropyran scissions are hyghly stereoselective for (E)-5-substituted pent-4-enol, this stereoselectivity breaks down when the 2-substituent is conformationally undiscriminating (deuterium) or has substantial anomeric effects (methoxy).Consideration of this, along with conformational data from the preceding paper, provides an explanation of the stereoselectivity of the tetrahydropyran scission.Evidence against a radical, and for a carbanion intermediate is presented and a common, very rapidly inverting, 3-carbanion is considered to be formed from either cis- or trans-stereoisomers.Ring scission is also rapid (the carbanion cannot be trapped), but less rapid than carbanion inversion, and takes place before the slower conformational inversion can occur so that the (E)/(Z)-nature of the unsaturated alcohol produced is controlled by the initial tetrahydropyran conformation.The unstereospecific nature of the ring scission of both cis- and trans-2-alkyl-3-chlorotetrahydrofurans is explained as a consequence of their existence in conformational equilibria. The high stereoselectivity of the ring scission of cis- and trans-3-chloro-2,3-dimethyltetrahydropyrans, and the poor stereoselectivity of the scission of 2-alkyl-3-chloro-2-methyltetrahydrpyrans, is explained; the reaction of sodium with 2-butyl-3,3-dichlorotetrahydropyran is considered.Using the ring-scission of 3-chlor-2-ethyltetrahydropyran, short syntheses of (+/-)-endo-brevicomin are described to illustrate the utility of β-halogen ether synthesis.
- Crombie, Leslie,Wyvill, Robert D.
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p. 1983 - 1996
(2007/10/02)
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- EFFETS POLAIRES DANS LES REACTIONS DE TRANSFERT HOMOLYTIQUE INTRAMOLECULAIRE D'HYDROGENE
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In this paper we analyse the influence of a phenyl substituent on the relative rates of the 1-5 and 1-6 intramolecular hydrogen transfers.Compared to the abstraction of an aliphatic H atom, the activation energy for the abstraction of a benzylic H atom is smaller.The effect is nevertheless more important with a primary alkyl radical (1,3 kcal/mole) than with an alkoxy radical (0,9 kcal/mole).This can be analysed in terms of a polar effect.In addition, the size of the effect is too small to make a short distance transfer of a H atom feasible; this is in keeping with the statement that H atom migration requires a linear transition state.
- Lefort, D.,Nedelec, J. Y.
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p. 2681 - 2686
(2007/10/02)
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- Cob(I)alamin als Katalysator. 6. Mitteilung . Bildung und Fragmentierung von Alkylcobalaminen, ein Gleichgewichtsprozess zwischen nukleophiler Addition und reduktiver Fragmentierung
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Isolated olefines can be saturated using catalytic amounts of cob(I)alamin in aqueous acetic acid; as electron source an excess of zinc dust is added to the solution containing the homogeneous catalyst.During this overall hydrogenation of isolated double bonds intermediate alkylcobalamins are formed (compare e.g.Schemes 2, 4, 5, 7 and 12).Clear evidence is presented that the nucleophilic attack on the isolated double bond is carried out by cob(I)alamin and not by cob(II)alamin also present in the system (see Scheme 3b and 3c).As this catalytic saturation of olefins depends on the pH of the solution, characterized by a slow reaction at pH=7.0 compared to the same reduction in aqueous acetic acid (see Scheme 2, 2 -> 4, and Scheme 3a), it is reasonable to accept the participation of an electrophilic attack by a proton during the generation of alkylcobalamins. - We use the term nucleophilic addition to describe the formation of alkylcobalamins from a proton, an olefin and cob(I)alamin (compare Schemes 4-7 and 12).A special sequence of experiments showed the nucleophilic addition to beregioselective.Preferentially the higher substituted alkylcobalamin revealed to be produced.Therefore, the nucleophilic addition of cob(I)alamin follows the Markownikoff rule (compare chap. 4: formation and fragmentation of β-hydroxyalkylcobalamins).Under the reaction conditions applied the intermediate alkylcobalamins can be present in base-on and base-off forms.They are known to exist as octahedral complexes and might also be stable to some extent as tetragonal-pyramidal species.In addition the base-off forms can partially be protonated at the dimethylbenzimidazole moiety in aqueous acetic acid (compare Scheme 12).From this equilibrium of intermediate alkylcobalamins three modes of decay disclosed to be possible: (i) The reductive fragmentation leading to an olefin, a proton, and cob(I)alamin is the formal retro-reaction of the nucleophilic addition (see Schemes 2, 4 and 6-12).This equilibrium of an associated alkylcobalamin and the corresponding dissociation products revealed to be a fast process compared to the reductive cleavage of the Co, C-bond cited below (s. (iii)). (ii) As the second reaction pattern an oxidative fragmentation producing an olefin, a hydroxy anion (or water, respectively) and cob(III)alamin has been observed (see Schemes 7, 8, 10 and 12). (iii) The slow reductive cleavage of the Co, C-bond, initiated by addition of electrons (see ), was the third reaction path observed (see Schemes 2, 4-8 and 10-12. - The stereochemistry of the three transformations originating from the intermediate alkylcobalamins is unknown up to now.The antiperiplanar pattern of the fragmentation reactions presented in the Schemes has been chosen arbitrarily (see e.g.Scheme 12).
- Fischli, Albert,Mueller, Peter Michael
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p. 529 - 554
(2007/10/02)
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