- A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals
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Reported herein is a visible-light-mediated radical approach to the α-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon SN2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α-alkylation of ketones.
- Goti, Giulio,Melchiorre, Paolo,O?eka, Maksim,Schweitzer-Chaput, Bertrand,Spinnato, Davide
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supporting information
p. 9485 - 9490
(2020/04/09)
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- Method for preparing nitrile by reacting acetone cyanohydrin with haloalkane
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The invention provides a method for preparing nitrile by reacting acetone cyanohydrin with haloalkane. According to the invention, by using acetone cyanohydrin as a cyaniding reagent, the problems, such as long reaction time, low yield, strict reaction conditions and the like enchanted in an existing preparation method in which highly toxic sodium cyanide or potassium cyanide or expensive trimethylsilyl cyanide is used as a cyanogen source, are solved. The method comprises the following steps: dissolving acetone cyanohydrin in a mixed solvent of a high boiling point dipolar aprotic solvent anda low boiling point aprotic solvent, adding a catalyst lithium hydroxide, stirring at 25-50 DEG C for one hour and then adding a haloalkane for continuous reaction for 2-3 hours; next, adding saturated saline water for washing twice, separating out an organic layer, and boiling off the solvent after drying, thereby obtaining a nitrile compound. The method for preparing a nitrile compound disclosed in the invention is characterized by low reaction toxicity, simple process, easy of operation, low production cost, and a yield of more than 95%.
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Paragraph 0043-0049; 0051-0057; 0060
(2019/08/20)
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- Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2
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It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.
- Mostyn, Shannon N.,Carland, Jane E.,Shimmon, Susan,Ryan, Renae M.,Rawling, Tristan,Vandenberg, Robert J.
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p. 1949 - 1959
(2017/09/26)
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- "Nanorust"-catalyzed benign oxidation of amines for selective synthesis of nitriles
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Organic nitriles constitute key precursors and central intermediates in organic synthesis. In addition, nitriles represent a versatile motif found in numerous medicinally and biologically important compounds. Generally, these nitriles are synthesized by traditional cyanation procedures using toxic cyanides. Herein, we report the selective and environmentally benign oxidative conversion of primary amines for the synthesis of structurally diverse aromatic, aliphatic and heterocyclic nitriles using a reusable "nanorust" (nanoscale Fe2O3)-based catalysts applying molecular oxygen.
- Jagadeesh, Rajenahally V.,Junge, Henrik,Beller, Matthias
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- Tetrazolylhydrazides as selective fragment-like inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
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The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr=142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases. Anchor fragment: To develop non-promiscuous metalloenzyme inhibitors, a metal-complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.
- Rüger, Nicole,Roatsch, Martin,Emmrich, Thomas,Franz, Henriette,Schüle, Roland,Jung, Manfred,Link, Andreas
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p. 1875 - 1883
(2015/11/10)
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- Synthesis of the neurotransmitter 4-aminobutanoic acid (GABA) from diethyl cyanomalonate
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GABA was synthesized by deethoxycarbonylation, ester hydrolysis and nitrile reduction of a highly functionalized intermediate obtained by alkylation of diethyl cyanomalonate with ethyl bromoacetate. By judicious employment of D 2O or NaBD4 in one of the three functional group transformation steps, deuterium was selectively introduced into each of the three possible sites in GABA.
- Cook, Matthew C.,Witherell, Ross D.,White, Robert L.
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experimental part
p. 9 - 13
(2011/01/03)
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- Studies on the titanium-catalyzed cyclopropanation of nitriles
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The Ti-mediated reaction of Grignard reagents with nitriles was investigated with sub-stoichiometric amounts of titanium isopropoxide. Cyanoesters were converted to spirocyclopropanelactams in good yields using as low as 0.05 eq of Ti(OiPr)sub
- Laroche, Christophe,Harakat, Dominique,Bertus, Philippe,Szymoniak, Jan
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p. 3482 - 3487
(2007/10/03)
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- Phase-transfer catalysed (PTC) reactions of 1,1-dichloro-2-cyanocyclopropane with nucleophiles. Identification of intermediates
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An addition-elimination mechanism for PTC reactions of phenols with 1,1-dichloro-2-cyanocyclopropane (1) is supported by trapping of intermediate cyclopropenes 3 and 5. PTC reactions of 1 with a series of phenols 2a-d, thiophenol (2e), alcohols 2f,g and dithioles 11a,b led to formation of disubstituted cyanocyclopropanes 6a-d, 6e, 6f,g or spiroproducts 12a,b, respectively. Under acidic conditions or thermally, dialkoxycyclopropanes 6f,g or spirane 12a were transformed into alkyl 3-cyanopropionates 10f,g and ketene dithioacetal 13a.
- Jonczyk, Andrzej,Kocmierowski, Tomasz,Zdrojewski, Tadeusz
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p. 295 - 299
(2007/10/03)
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- Preparation of [1,2,3,4,5-13C 5]-5-Amino-4-oxopentanoic Acid (ALA) - Design of a Synthetic Scheme to Prepare Any 13C- and 15N-Isotopomer with High Isotopic Enrichment
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5-Amino-4-oxopentanoic acid (5-aminolevulinic acid) is a precursor in the biosynthesis of the biologically active porphyrins such as chlorophyll, bacteriochlorophyll, heme, etc. These systems are central in photosynthesis, oxygen transport, electron transport, etc. In this paper we describe a simple scheme to prepare any isotopomer of 5-aminolevulinic acid in a few steps in high yield. Using a similar scheme, levulinic acid can now also be prepared in any isotopomeric form. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Shrestha-Dawadi, Prativa Bade,Lugtenburg, Johan
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p. 4654 - 4663
(2007/10/03)
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- SYNTHESIS OF POLYFUNCTIONAL ALIPHATIC CARBONYL COMPOUNDS UNDER PHASE-TRANSFER CONDITIONS
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We have studied mono- and dialkylation of malonic, acetoacetic, and cyanoacetic esters with esters of haloacetic and β-halopropionic acids and addition of the CH acids mentioned and their analogues to methyl and ethyl acrylate under phase-transfer catalysis conditions, and also deethoxycarbonylation of the obtained products.We have demonstrated for the first time the possibility of Dieckmann cyclization under phase-transfer catalysis conditions and have developed a simple method for the synthesis of 2,3-di(ethoxycarbonyl)cyclopentanone, a key intermediate in the synthesis of deoxyprostaglandins, by cyclization of triethyl 1,2,4-butanetricarboxylate.
- Sizov, A. Yu.,Dombrovskii, V. A.,Yanovskaya, L. A.
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p. 955 - 961
(2007/10/02)
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- Cobalt Carbonyl Mediated Michael Addition: Direct Synthesis of Esters Containing Other Functional Groups from Activated Olefins
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Hydrocarbalkoxylation of acrylonitrile with stoichiometric amounts of alcohols in the presence of catalytic amounts of Co2(CO)8 and pyridine bases leads to 2,4-dicyano-2-methylbutanoic acid esters.The yield of these Michael adducts shows a maximum as a function of the pyridine/cobalt ratio.Analogues reactions using equimolar amounts of alcohol, acrylonitrile, and an other activated olefin result in products with at least three different functional groups.Acrylonitrile with pyH gives (1-cyanoethyl)cobalt tetracarbonyl, which is proposed to be the key intermediate of the hydrocarbalkoxylation.This complex may be deprotonated to a "Michael donor" anion, i.e. the Michael adducts are most probably formed in a cobalt-mediated way.The above catalytic system promoted also the Michael addition of some C-H acids to activated olefins under atmospheric conditions.
- Sisak, Attila,Ungvary, Ferenc,Marko, Laszlo
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p. 2508 - 2513
(2007/10/02)
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- NON-AQUEOUS CYANATION OF HALIDES USING LITHIUM CYANIDE
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Efficient conversion of various halides into the corresponding nitriles with lithium cyanide in tetrahydrofuran is described.
- Harusawa, Shinya,Yoneda, Ryuji,Omori, Yukie,Kurihara, Takushi
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p. 4189 - 4190
(2007/10/02)
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- NUCLEOPHILIC SUBSTITUTION OF HALOGEN ATOMS IN gem-DICHLOROCYCLOPROPANES ACTIVATED BY ELECTRON-WITHDRAWING SUBSTITUENTS
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The reactions of the methyl ester, N,N-dimethylamide, and nitrile of gem-dichlorocyclopropanecarboxylic acid with sodium methoxide and ethoxide take place with opening of the three-membered ring and lead to the correponding derivatives of succinic acid.Methyl and ethyl 3-formyl-2-methylpropionate were obtained from 2,2-dichloro-1-formyl-3-methylcyclopropane under analogous conditions.The reaction of sodium thiophenolate with the functionally substituted gem-dichlorocyclopropanes takes place with retention of the three-membered ring and the formation of the corresponding substituted diphenyl thioacetals of cyclopropanone.
- Kulinkovich, O. G.,Tishchenko, I. G.,Romashin, Yu. N.
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p. 213 - 216
(2007/10/02)
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