- The 3F Library: Fluorinated Fsp3-Rich Fragments for Expeditious 19F NMR Based Screening
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Fragment-based drug discovery (FBDD) is a popular method in academia and the pharmaceutical industry for the discovery of early lead candidates. Despite its wide-spread use, the approach still suffers from laborious screening workflows and a limited diversity in the fragments applied. Presented here is the design, synthesis, and biological evaluation of the first fragment library specifically tailored to tackle both these challenges. The 3F library of 115 fluorinated, Fsp3-rich fragments is shape diverse and natural-product-like with desirable physicochemical properties. The library is perfectly suited for rapid and efficient screening by NMR spectroscopy in a two-stage workflow of 19F NMR and subsequent 1H NMR methods. Hits against four diverse protein targets are widely distributed among the fragment scaffolds in the 3F library and a 67 % validation rate was achieved using secondary assays. This collection is the first synthetic fragment library tailor-made for 19F NMR screening and the results demonstrate that the approach should find broad application in the FBDD community.
- Troelsen, Nikolaj S.,Shanina, Elena,Gonzalez-Romero, Diego,Danková, Daniela,Jensen, Ida S. A.,?niady, Katarzyna J.,Nami, Faranak,Zhang, Hengxi,Rademacher, Christoph,Cuenda, Ana,Gotfredsen, Charlotte H.,Clausen, Mads H.
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Read Online
- Inter- and intramolecular diels-alder reaction of ethenetricarboxylate derivatives
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Inter- and intramolecular [4+2] cycloaddition reactions of highly electron-deficient ethenetricarboxylates have been studied. Intermolecular Diels-Alder reaction of ethenetricarboxylate esters and cyclopentadiene proceeded at room temperature or -20 °C to give cycloadducts with 1:1.5-1.9 endo:exo ratio. Lewis acids such as EtAlCl2, Zn(OTf)2 and Cu(OTf)2 catalyzed reaction at room temperature or -40 °C gave cycloadducts with 3.1-5.4:1 endo:exo ratio. Reaction of N-benzyl- or N-allyl-2-furylmethylamine and 1,1-diethyl 2-hydrogen ethenetricarboxylate in the presence of EDCI/HOBt/Et3N at room temperature led directly to an intramolecular Diels-Alder adduct stereoselectively. The observed stereoselectivities were explained by the use of DFT calculations.
- Yamazaki, Shoko,Sugiura, Hirotaka,Niina, Mamiko,Mikata, Yuji,Ogawa, Akiya
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Read Online
- Switching Selectivity in Copper-Catalyzed Transfer Hydrogenation of Nitriles to Primary Amine-Boranes and Secondary Amines under Mild Conditions
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A simple and efficient copper-catalyzed selective transfer hydrogenation of nitriles to primary amine-boranes and secondary amines with an oxazaborolidine-BH3 complex is reported. The selectivity control was achieved under mild conditions by switching the solvent and the copper catalysts. More than 30 primary amine-boranes and 40 secondary amines were synthesized via this strategy in high selectivity and yields of up to 95%. The strategy was applied to the synthesis of 15N labeled in 89% yield.
- Song, Hao,Xiao, Yao,Zhang, Zhuohua,Xiong, Wanjin,Wang, Ren,Guo, Liangcheng,Zhou, Taigang
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p. 790 - 800
(2022/01/11)
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- Sulfated polyborate: A dual catalyst for the reductive amination of aldehydes and ketones by NaBH4
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An efficient, quick, and environment-friendly one-pot reductive amination of aldehydes or ketones was developed. In ethanol at 70 °C, a imination catalyzed by sulfated polyborate and further reduced by sodium borohydride yields various amines. The present method has many significant benefits, including a shorter reaction time, excellent yields, and a hassle-free, straightforward experimental process. The reaction has a wide range of applications due to its flexibility, including secondary amine for reductive amination.
- Ganwir, Prerna,Chaturbhuj, Ganesh
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supporting information
(2021/05/19)
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- Selective butyryl cholinesterase inhibitor or pharmaceutically acceptable salt thereof as well as preparation method and application thereof
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The invention discloses a selective butyryl cholinesterase inhibitor or a pharmaceutically acceptable salt thereof, and a preparation method and application thereof, wherein the inhibitor has the selective butyrylcholinesterase inhibitor of the general formula (I) or the formula (II) or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention has good in-vitro target activity and extremely high selectivity, and can be used as a leader substance for further developing an anti-'s disease through selective inhibition of butyrylcholine esterase.
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Paragraph 0027; 0030-0031
(2021/08/25)
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- Nickel Complexes Bearing N,N,O-Tridentate Salicylaldiminato Ligand: Efficient Catalysts for Imines Formation via Dehydrogenative Coupling of Primary Alcohols with Amines
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Treatment of salicylaldiminato ligand L1H-L2H (L1H = 2,4-di-tert-butyl-6-((quinolin-8-ylimino)methyl)phenol; L2H = 2,4-di-tert-butyl-6-(((2-(diethylamino)ethyl)imino)methyl)phenol) with Ni(OAc)2·4H2O in refluxing ethanol afforded nickel complexes [(L1)Ni(OAc)] (1) and [(L2)Ni(OAc)] (2), respectively. Reaction of L3H (L3H = (2,4-di-tert-butyl-6-(((2-(pyridin-2-yl)ethyl)imino)methyl)phenol)) with Ni(OAc)2·4H2O in the presence of excess triethylanmine gave the dual ligands coordinated nickel complex [(L2)2Ni] (3). Complexes 1-3 were well characterized by high-resolution mass spectrometry, infrared spectroscopy, elemental analysis, and X-ray diffraction analysis. All the three Ni(II) complexes exhibited efficient activity and good selectivity in the acceptorless dehydrogenative coupling of alcohols and amines to produce imines and diimines. The present protocol provides an atom-economical and sustainable route for the synthesis of various imine derivatives by employing an earth-abundant nickel salt and easily prepared salicylaldiminato ligands.
- Han, Zhangang,Hao, Zhiqiang,Lin, Jin,Lu, Guo-Liang,Zhang, Junhua,Zhang, Xiaoying
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p. 3843 - 3853
(2021/11/18)
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- Aluminum Metal-Organic Framework-Ligated Single-Site Nickel(II)-Hydride for Heterogeneous Chemoselective Catalysis
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The development of chemoselective and heterogeneous earth-abundant metal catalysts is essential for environmentally friendly chemical synthesis. We report a highly efficient, chemoselective, and reusable single-site nickel(II) hydride catalyst based on robust and porous aluminum metal-organic frameworks (MOFs) (DUT-5) for hydrogenation of nitro and nitrile compounds to the corresponding amines and hydrogenolysis of aryl ethers under mild conditions. The nickel-hydride catalyst was prepared by the metalation of aluminum hydroxide secondary building units (SBUs) of DUT-5 having the formula of Al(μ2-OH)(bpdc) (bpdc = 4,4′-biphenyldicarboxylate) with NiBr2 followed by a reaction with NaEt3BH. DUT-5-NiH has a broad substrate scope with excellent functional group tolerance in the hydrogenation of aromatic and aliphatic nitro and nitrile compounds under 1 bar H2 and could be recycled and reused at least 10 times. By changing the reaction conditions of the hydrogenation of nitriles, symmetric or unsymmetric secondary amines were also afforded selectively. The experimental and computational studies suggested reversible nitrile coordination to nickel followed by 1,2-insertion of coordinated nitrile into the nickel-hydride bond occurring in the turnover-limiting step. In addition, DUT-5-NiH is also an active catalyst for chemoselective hydrogenolysis of carbon-oxygen bonds in aryl ethers to afford hydrocarbons under atmospheric hydrogen in the absence of any base, which is important for the generation of fuels from biomass. This work highlights the potential of MOF-based single-site earth-abundant metal catalysts for practical and eco-friendly production of chemical feedstocks and biofuels.
- Antil, Neha,Kumar, Ajay,Akhtar, Naved,Newar, Rajashree,Begum, Wahida,Dwivedi, Ashutosh,Manna, Kuntal
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p. 3943 - 3957
(2021/04/12)
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- Polyoxometalate-Driven Ease Conversion of Valuable Furfural to trans- N, N-4,5-Diaminocyclopenten-2-ones
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We investigated the catalytic efficacy of silicotungstic acid (H4SiW12O40) polyoxometalate (POM) toward the reaction between furfural and amines that selectively yields trans-N,N-4,5-substituted-diaminocyclopenten-2-ones (trans-DACPs). H4SiW12O40 facilita
- Fountoulaki, Stella,Lykakis, Ioannis N.,Tzani, Marina A.
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- Preparation and synthesis method of aromatic amine compound with function of specifically inhibiting HIF-2alpha
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The invention relates to a preparation method of an HIF-2alpha small-molecule inhibitor (2-((benzyl(furan-2-yl methyl) amino) methyl)-8-methyl-4H-pyrido[1, 2-a]pyrimidine-4-ketone). The compound is characterized in that 4-methylpyridine-2-amine is used as an initial raw material, and 2-chloro-8-methyl-4H-pyrido [1, 2-a] pyrimidine-4-ketone is obtained through condensation cyclization of 4-methylpyridine-2-amine and the compound, furfural is taken as an initial raw material, an addition reaction is carried out on the furfural and benzylamine to obtain N-furan benzylamine, and a N-alkylation reaction is carried out on the obtained 2-chloro-8-methyl-4H-pyrido[1, 2-a]pyrimidine-4-ketone and N-furan benzylamine to obtain the HIF-2alpha small-molecule inhibitor. The invention discloses the preparation method of the HIF-2alpha small-molecule inhibitor for the first time, the method has the advantages of few steps, simple operation, rapid reaction and no need of high pressure, the yield and purity of the prepared compound are high, and the raw materials are easy to obtain.
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Paragraph 0024; 0027-0028; 0031; 0034-0035; 0038; 0041-0042
(2021/05/05)
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- Preparation of HIF-2alpha small-molecule inhibitor and application thereof
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The invention belongs to the technical field of medicines, and relates to an HIF-2 alpha small-molecule inhibitor as well as a preparation method and an application thereof. The HIF-2alpha small-molecule inhibitor is a compound as shown in a structural general formula I and a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof. According to the invention, molecular simulation drug design software MOE is used for screening and molecular docking of pharmacophores, according to a final docking dominant structure and an isosteric principle, a series of compounds are designed and synthesized, and an in-vitro anti-tumor activity screening test shows that the compounds have anti-tumor activity. The HIF-2 alpha small-molecule inhibitor provided by the invention has a relatively good application prospect in the aspect of preventing or treating cancers, particularly glioma.
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Paragraph 0099; 0105
(2021/06/22)
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- Efficient One-Pot Reductive Aminations of Carbonyl Compounds with Aquivion-Fe as a Recyclable Catalyst and Sodium Borohydride
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A one-pot reductive amination of aldehydes and ketones with NaBH4 was developed with a view to providing efficient, economical and greener synthetic conditions. A recyclable iron-based Lewis catalyst, Aquivion-Fe, was used to promote imine formation in cyclopentyl methyl ether, followed by the addition of a small amount of methanol to the reaction mixture to enable C=N reduction by NaBH4. The protocol, applied to a wide number of amines and carbonyl compounds, resulted in ever complete conversion of these latter with excellent chemoselectivity towards the expected amination products in the most cases. Isolated yields, determined for a selection of the screened substrates, were found consistent with the previously obtained conversion and selectivity data. Cinacalcet, an important active pharmaceutical ingredient, was efficiently prepared by the title procedure.
- Airoldi, Veronica,Piccolo, Oreste,Roda, Gabriella,Appiani, Rebecca,Bavo, Francesco,Tassini, Riccardo,Paganelli, Stefano,Arnoldi, Sebastiano,Pallavicini, Marco,Bolchi, Cristiano
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supporting information
p. 162 - 168
(2019/12/11)
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- Secondary amine derivative synthesized through rare earth catalysis, and preparation method thereof
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The invention discloses a secondary amine derivative synthesized through rare earth catalysis, and a preparation method thereof. According to the preparation method, the secondary amine derivative isprepared by carrying out a reaction on reactants of secondary amide and pinacol borane; a rare earth catalyst bis(trimethylsilyl) amino yttrium is added; the reaction temperature is 100-140 DEG C, andthe reaction time is 20-25 h; the whole reaction is carried out under a normal pressure, and the reaction conditions are mild, easy to achieve and safe; the method is simple and convenient to operateand high in reaction selectivity, can directly synthesize the target product without intermediate product separation, can obtain the target product only through a reaction under a normal pressure, issimple in reaction process, has the yield of 90% at most, substantially simplifies the process engineering, reduces the energy consumption, and has high yield; the reaction raw materials are stable and easy to store; a series of secondary amine derivatives can be prepared; and the method has high substrate universality so as to provide the good guarantee for development of related substances related to secondary amine derivatives, and is suitable for large-scale application and popularization.
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Paragraph 0043; 0044; 0045; 0046; 0047; 0048; 0049
(2020/03/12)
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- Homoleptic Bis(trimethylsilyl)amides of Yttrium Complexes Catalyzed Hydroboration Reduction of Amides to Amines
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Homoleptic lanthanide complex Y[N(TMS)2]3 is an efficient homogeneous catalyst for the hydroboration reduction of secondary amides and tertiary amides to corresponding amines. A series of amides containing different functional groups such as cyano, nitro, and vinyl groups were found to be well-tolerated. This transformation has also been nicely applied to the synthesis of indoles and piribedil. Detailed isotopic labeling experiments, control experiments, and kinetic studies provided cumulative evidence to elucidate the reaction mechanism.
- Ye, Pengqing,Shao, Yinlin,Ye, Xuanzeng,Zhang, Fangjun,Li, Renhao,Sun, Jiani,Xu, Beihang,Chen, Jiuxi
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p. 1306 - 1310
(2020/02/22)
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- Phthalimide compound used as PDE2/4 dual inhibitor and preparation method thereof
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The invention discloses a phthalimide compound used as a PDE2/4 dual inhibitor and a preparation method thereof. The general formula of the phthalimide compound is shown in the specification, and thephthalimide compound has good PDE2/4 dual inhibitory activity, can show more excellent pharmacodynamic properties and has small side effects compared with the traditional single PDEs inhibitor. The compound can be used for preparing medicines for treating senile dementia, depression, arthritis, asthma, chronic obstructive pulmonary diseases and the like.
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Paragraph 0024-0027
(2020/06/17)
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- Integrated Synthetic, Biophysical, and Computational Investigations of Covalent Inhibitors of Prolyl Oligopeptidase and Fibroblast Activation Protein α
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Over the past decade, there has been increasing interest in covalent inhibition as a drug design strategy. Our own interest in the development of prolyl oligopeptidase (POP) and fibroblast activation protein α (FAP) covalent inhibitors has led us to question whether these two serine proteases were equal in terms of their reactivity toward electrophilic warheads. To streamline such investigations, we exploited both computational and experimental methods to investigate the influence of different reactive groups on both potency and binding kinetics using both our own series of POP inhibitors and others' discovered hits. A direct correlation between inhibitor reactivity and residence time was demonstrated through quantum mechanics methods and further supported by experimental studies. This computational method was also successfully applied to FAP, as an overview of known FAP inhibitors confirmed our computational predictions that more reactive warheads (e.g., boronic acids) must be employed to inhibit FAP than for POP.
- Plescia, Jessica,De Cesco, Stéphane,Patrascu, Mihai Burai,Kurian, Jerry,Di Trani, Justin,Dufresne, Caroline,Wahba, Alexander S.,Janmamode, Na?la,Mittermaier, Anthony K.,Moitessier, Nicolas
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supporting information
p. 7874 - 7884
(2019/10/11)
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- Rapid Ring-Opening Metathesis Polymerization of Monomers Obtained from Biomass-Derived Furfuryl Amines and Maleic Anhydride
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Well-controlled and extremely rapid ring-opening metathesis polymerization of unusual oxanorbornene lactam esters by Grubbs third-generation catalyst is used to prepare a range of bio-based homo- and copolymers. Bio-derived oxanorbornene lactam monomers were prepared at room temperature from maleic anhydride and secondary furfuryl amines by using a 100 % atom economical, tandem Diels–Alder lactamization reaction, followed by esterification. Several of the resulting homo- and copolymers show good control over polymer molecular weight and have narrow molecular weight distributions.
- Blanpain, Anna,Clark, James H.,Farmer, Thomas J.,Guo, Yuanlong,Ingram, Ian D. V.,Kendrick, John E.,Lawrenson, Stefan B.,North, Michael,Rodgers, George,Whitwood, Adrian C.
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p. 2393 - 2401
(2019/05/28)
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- Synthesis and Cytotoxicity of Octahydroepoxyisoindole-7-carboxylic Acids and Norcantharidin–Amide Hybrids as Norcantharidin Analogues
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Octahydroepoxyisoindole analogues of norcantharidin were accessed through a Diels–Alder reaction of an amine-substituted furan with maleic anhydride and subsequent reduction of the bicyclo[2.2.1]heptene olefin. Despite retention of the carboxylate and the ether bridgehead known to impart cytotoxic activity to norcantharidin, none of these analogues displayed notable cytotoxicity against the 11 cell lines examined: HT29 (colon), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma), SJ-G2 and U87 (glioblastoma), MIA (pancreatic), and SMA (spontaneous murine astrocytoma). The incorporation of an amino-substituted system post-synthesis of norcantharidin afforded facile access to 14 acid/amide-substituted norcantharidin analogues. Of these, only four displayed sufficient activity at the initial 25 μm compound screening dose to warrant full evaluation of growth inhibition. Common to these analogues was the presence of a 4-biphenyl moiety, and in particular 3-(2-(furan-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (13 c) and 3-(2-(pyrrole-2-ylmethyl)-3-(4-biphenylamino)-3-oxopropylcarbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (24) displayed high levels of cytotoxicity, returning GI50 values of 15 nm (HT29) to 2.9 μm (U87) and 17 nm (SMA) to 2.8 μm (U87), respectively. These are the most cytotoxic norcantharidin analogues reported to date.
- Hizartzidis, Lacey,Gilbert, Jayne,Gordon, Christopher P.,Sakoff, Jennette A.,McCluskey, Adam
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supporting information
p. 1152 - 1161
(2019/05/24)
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- N–Alkylation of Amines Catalyzed by a Ruthenium–Pincer Complex in the Presence of in situ Generated Sodium Alkoxide
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We report the use of ruthenium–NNN-pincer complexes of the type (R2NNN)RuCl2(PPh3) (R = tBu, iPr, Cy and Ph) for the catalytic N-alkylation of primary amines under solvent-free conditions. For the first time, the base that is required to promote these reactions is generated in situ from the alcohol by the use of sodium. The resulting sodium alkoxide regenerates the alcohol substrate while acting as the water scavenger thus mitigating the need of an additional base. Among the catalysts screened, (tBu2NNN)RuCl2(PPh3) (0.02 mol-%) gives very high turnovers and good yields at 140 °C. The (tBu2NNN)RuCl2(PPh3) catalyzed N-alkylation tolerates a variety of amine and alcohol substrates. While excellent turnover (29000) was obtained for the (tBu2NNN)RuCl2(PPh3) (0.002 mol-%) catalyzed alkylation of aniline with cyclohexyl methanol, the turnovers obtained in the corresponding catalytic methylation of p-anisidine was also very high (12000). The (tBu2NNN)RuCl2(PPh3) catalyzed reactions have also been accomplished under open-vessel conditions resulting in a net dehydrogenative coupling reaction. This protocol has been used to transform benzene-1,2-diamines to benzimidazoles with high productivity (12000 turnovers). DFT studies indicate that while β-hydride elimination is rate-determining (RDTS: 24.31 kcal/mol) for the alcohol dehydrogenation segment which is endothermic, insertion of the imine is rate-determining (RDTS: 11.26 kcal/mol) for its hydrogenation that is exothermic.
- Das, Kanu,Nandi, Pran Gobinda,Islam, Khadimul,Srivastava, Hemant Kumar,Kumar, Akshai
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p. 6855 - 6866
(2019/11/03)
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- Improving C=N bond reductions with (Cyclopentadienone)iron complexes: Scope and limitations
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Herein, we broaden the application scope of (cyclo-pentadienone)iron complexes 1 in C=N bond reduction. The catalytic scope of pre-catalyst 1b, which is more active than the “Kn?lker complex” (1a) and other members of its family, has been expanded to the catalytic transfer hydrogenation (CTH) of a wider range of aldimines and ketimines, either pre-isolated or generated in situ. The kinetics of 1b-promoted CTH of ketimine S1 were assessed, showing a pseudo-first order profile, with TOF = 6.07 h–1 at 50 % conversion. Moreover, the chiral complex 1c and its analog 1d were employed in the enantioselective reduction of ketimines and reductive amination of ketones, giving fair to good yields and moderate enantioselectivity.
- Cettolin, Mattia,Bai, Xishan,Lübken, Dennis,Gatti, Marco,Facchini, Sofia Vailati,Piarulli, Umberto,Pignataro, Luca,Gennari, Cesare
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p. 647 - 654
(2018/10/24)
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- Efficient and Selective Hydrosilylation of Secondary and Tertiary Amides Catalyzed by an Iridium(III) Metallacycle: Development and Mechanistic Investigation
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Readily accessible cationic IrIII metallacycles catalyze efficiently the chemoselective hydrosilylation of tertiary and secondary amides to amines. The catalyst described herein operates at low loadings using inexpensive 1,1,3,3-tetramethyldisiloxane and allows fast reactions with high yields, selectivities, and turnover numbers. A transient iminium intermediate has been observed for the first time by using mass spectrometry, and the activation of the catalyst and the silane reagent have been studied by using DFT calculations. These fundamental insights support the present and future improvements of IrIII metallacycles through proper ligand modifications and enable further broad applications of catalysts based on metallacycles.
- Corre, Yann,Trivelli, Xavier,Capet, Frédéric,Djukic, Jean-Pierre,Agbossou-Niedercorn, Francine,Michon, Christophe
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p. 2009 - 2017
(2017/06/13)
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- Nickel-Catalyzed Reduction of Secondary and Tertiary Amides
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The nickel-catalyzed reduction of secondary and tertiary amides to give amine products is reported. The transformation is tolerant of extensive variation with respect to the amide substrate, proceeds in the presence of esters and epimerizable stereocenters, and can be used to achieve the reduction of lactams. Moreover, this methodology provides a simple tactic for accessing medicinally relevant α-deuterated amines.
- Simmons, Bryan J.,Hoffmann, Marie,Hwang, Jaeyeon,Jackl, Moritz K.,Garg, Neil K.
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supporting information
p. 1910 - 1913
(2017/04/11)
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- Synthesis, characterization, cytotoxicity and antimicrobial studies on Bi(III) dithiocarbamate complexes containing furfuryl group and their use for the preparation of Bi2O3nanoparticles
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Bismuth(III) dithiocarbamate complexes, tris(N-furfuryl-N-propyldithiocarbamato-S,S')bismuth(III) (1), tris(N-furfuryl-N-butyldithiocarbamato-S,S')bismuth(III) (2) and tris(N-furfuryl-N-benzyldithiocarbamato-S,S')bismuth(III) (3), have been prepared and characterized by microanalysis, and spectroscopy (IR and NMR). Structure of 3 has been obtained by single crystal X-ray diffraction. This complex contains distorted pentagonal pyramidal Bi(III) centres which attain an overall distorted pentagonal bipyramidal coordination via long range intermolecular Bi?S interactions. DFT quantum mechanical studies of 3 were carried out, supporting the partial double bond character of C–N (thioureide) and C–S bonds in dithiocarbamate ligands. All the compounds have been screened against a panel of microbes viz. Vibrio cholerae, Bacillus subtilis, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Aspergillus niger and Candida albicans. Complexes 1 and 3 were found to have better activity against K. pneumoniae, V. cholerae, A. niger and C. albicans than the complex 2. Complexes 1–3 have been evaluated for their in vitro cytotoxic activity against KB cells. Complexes 1 and 3 showed higher activity than 2. Bi2O3obtained from thermal decomposition of 3 has been characterized by PXRD, HRTEM, EDAX, UV–Vis and Fluorescence spectroscopy. PXRD study showed that the sample is composed of monoclinic phase of α-Bi2O3. Photocatalytic activity of as-prepared α-Bi2O3was determined by decolourization of rhodamine-B in aqueous solution under ultra violet irradiation.
- Tamilvanan, Sundaramoorthy,Gurumoorthy, Govindasamy,Thirumaran, Subbiah,Ciattini, Samuele
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- Highly Efficient Rh(I) Homo- and Heterogeneous Catalysts for C-N Couplings via Hydrogen Borrowing
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Rhodium(I) complexes were explored as catalysts for the hydrogen borrowing reactions of amines and alcohols. Bidentate carbene-triazole ligands were readily synthesized via "click" reactions which allowed a diversity of ligand backbones to be accessed. The catalytic transformations are highly efficient, able to reach completion in under 6 h, and promote C-N bond formation across a range of primary alcohol and amine substrates. Moreover, site-selective catalysis can be achieved using substrates with more than one reactive site. A rhodium(I) complex covalently attached to a carbon black surface was also deployed in the hydrogen borrowing coupling reaction of aniline with benzyl alcohol. This represents the first report of a heterogeneous rhodium catalyst used for hydrogen borrowing.
- Wong, Chin M.,Peterson, Matthew B.,Pernik, Indrek,McBurney, Roy T.,Messerle, Barbara A.
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supporting information
p. 14682 - 14687
(2017/12/15)
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- Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls
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The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.
- Dorkó, éva,Szabó, Márk,Kótai, Bianka,Pápai, Imre,Domján, Attila,Soós, Tibor
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supporting information
p. 9512 - 9516
(2017/08/01)
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- Anagostic, mono- and hexahapta interactions in Tl(I) dithiocarbamates: A new precursor for the preparation of Tl2S nanoparticles
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Two new homoleptic complexes, [Tl(bzfdtc)]2 (1) and [Tl(bu2-OHbzdtc)]2 (2) (where bzfdtc = N-benzyl-N-furfuryldithiocarbamate and bu2-OHbzdtc = (N-butyl-N-(2-hydroxybenzyl)dithiocarbamate), have been prepared an
- Gomathi, Govindaraju,Thirumaran, Subbiah,Ciattini, Samuele
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p. 424 - 433
(2015/11/11)
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- Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy
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The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
- Papeo, Gianluca,Posteri, Helena,Borghi, Daniela,Busel, Alina A.,Caprera, Francesco,Casale, Elena,Ciomei, Marina,Cirla, Alessandra,Corti, Emiliana,D'Anello, Matteo,Fasolini, Marina,Forte, Barbara,Galvani, Arturo,Isacchi, Antonella,Khvat, Alexander,Krasavin, Mikhail Y.,Lupi, Rosita,Orsini, Paolo,Perego, Rita,Pesenti, Enrico,Pezzetta, Daniele,Rainoldi, Sonia,Riccardi-Sirtori, Federico,Scolaro, Alessandra,Sola, Francesco,Zuccotto, Fabio,Felder, Eduard R.,Donati, Daniele,Montagnoli, Alessia
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p. 6875 - 6898
(2015/09/22)
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- Reductive amination of aldehydes and amines with an efficient Pd/NiO catalyst
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By applying a simple Pd/NiO catalyst, the reductive amination of amines and aldehydes can progress efficiently under mild reaction conditions, and 24 substituted amines with different structures were synthesized with up to 98% isolated yields.
- Yang, Huimin,Cui, Xinjiang,Deng, Youquan,Shi, Feng
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supporting information
p. 1314 - 1322
(2014/04/17)
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- Palladium meditated CPhenyl-H bond activation of 2-furylimines versus tert-2-furylbenzylamines
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The reactions of 2-furylimines 2a-f and Na2PdCl4 in the presence of NaOAc at 8-10°C result in nitrogen-palladium coordinated complexes 3a-f. Reduction of 2d-f with NaBH4 followed by N-methylation leads to the corresponding tert-2-furylbenzylamines 5a-c. Treatment of 5a-c with Na2PdCl4 at the same reaction condition as mentioned above affords palladacycles 6a-c where the Pd atoms connect to the phenyl ring rather than the furyl ring. The fact that 5a-c are more active than 2d-f in CPhenyl-H bond activation implies that the electron density of C10 or C8 atom in former is higher than those in latter. Compounds 3a-f, 5a-c, 6a-c were identified by elemental analysis, IR and NMR. In addition, the structures of 3b, 3f and 6c were also confirmed by their single crystal X-ray diffractions.
- Hu, Zhao-Xia,Ma, Nan,Zhang, Jin-Hua,Hu, Wen-Ping,Wang, Hong-Xing
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- PROCESS FOR THE PRODUCTION OF FURANIC COMPOUNDS COMPRISING AT LEAST ONE AMINE FUNCTION
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Disclosed is a process for the production of furanic compound comprising at least one amine function, comprising reacting a furanic compound having at least one hydroxyl function or at least one aldehyde function with a second reactant having an amine function, in the presence of an iridium catalyst.
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Page/Page column 11
(2015/01/09)
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- Chemoselective flow hydrogenation approaches to isoindole-7-carboxylic acids and 7-oxa-bicyclio[2.2.1]heptanes
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Two libraries of highly decorated norcantharidin analogues were accessed via a series of sequential chemoselective flow hydrogenations and solvent-free transformations. Utilising a 10% Pd/C catalyst, modifications to reaction parameters (H2 pressure, temperature and flow rate conditions) allowed facile access to effect selective direct reductive aminations and olefin reductions in the presence of furan, benzyl and nitrile moieties were established. The use of 20% Pd(OH)2/C; Pd tetrakis; 5% Pt/C (sulfided) gave mixtures of furan and olefin (both reduced) and olefin reduced products. RuO2; 0.5% Re/C and Re2O7 resulted in no reduction. Concurrent olefin and nitrile reduction was achieved in the presence of furan moieties by employing a RANEY nickel catalyst. In total, 31 reaction conditions were examined using less than 200 mg of reagents allowing optimised conditions to be efficiently determined. These optimised hydrogenation conditions afforded desired analogues in near quantitative yields thus removing the requirements of reaction workup and chromatography.
- Hizartzidis,Tarleton,Gordon,McCluskey
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p. 9709 - 9722
(2014/03/21)
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- Cooperative catalysis with aldehydes and copper: Development and application in aerobic oxidative C-H amination at room temperature
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A conceptually new cooperative catalytic system via a synergistic combination of aldehyde and copper catalysis has been established based on systemic mechanistic studies. This new cooperative catalysis has been successfully applied in the direct aerobic oxidative C-H amination of azoles at room temperature, which was previously realized under harsh conditions. Mechanistic studies including isotopic labeling experiments and kinetic isotope effect (KIE) experiments support a reaction pathway that involves formation of an aminal, hydrolysis of the aminal to generate the copper-amide species, subsequent C-H amination and re-oxidation of copper(I) to copper(II) by oxygen. It not only provides an efficient method to realize the oxidative C-H amination of benzoxazoles with free amines at room temperature, but also paves the way for establishing new C-N bond formation reactions by using this efficient cooperative catalysis. Copyright
- Xie, Yinjun,Qian, Bo,Xie, Pan,Huang, Hanmin
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supporting information
p. 1315 - 1322
(2013/06/27)
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- Synthesis of trisubstituted ureas by a multistep sequence utilizing recyclable magnetic reagents and scavengers
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Unprecedented magnetic borohydride exchange (mBER), magnetic Wang aldehyde (mWang) and magnetic amine resins were prepared from highly magnetic polymer-coated cobalt or iron nanoparticles. Microwave irradiation was used to obtain excellent degrees of functionalization (>95 %) and loadings (up to 3.0 mmol g-1) in short reaction times of 15 min or less. A small library of ureas and thioureas was synthesized by the exclusive application of these magnetic resins. As a first step, a reductive amination of aromatic and aliphatic aldehydes was carried out with mBER. The excess of primary amine needed to complete the reaction was subsequently scavenged selectively by mWang. Simple magnetic decantation from the resins resulted in secondary amines in good to excellent yields and purities. The used magnetic resins were efficiently regenerated and reused for the next run. In a second step, the secondary amines were converted to trisubstituted (thio)ureas in excellent yields and purities by stirring with an excess of iso(thio)cyanate, which was scavenged by addition of the magnetic amine resin after completion of the reaction. The whole reaction sequence is carried out without any purification apart from magnetic decantation; moreover, conventional magnetic stirring can be used as opposed to the vortexing required for polystyrene resins. Do it magnetically! A small library of trisubstituted ureas and thioureas was synthesized in high yields and purities by a multistep sequence exclusively applying magnetic reagents and scavengers. No purification steps were necessary apart from magnetic decantation, and the resins were recycled if possible. The novel resins were conveniently and efficiently prepared starting from polymer-coated magnetic Co/C or Fe/C nanobeads by microwave protocols. Copyright
- Kainz, Quirin M.,Zeltner, Martin,Rossier, Michael,Stark, Wendelin J.,Reiser, Oliver
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p. 10038 - 10045
(2013/08/23)
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- Pt/C catalysed direct reductive amination of nitriles with primary amines in a continuous flow multichannel microreactor
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Aliphatic and aromatic secondary amines were synthesised selectively by one pot reductive amination of nitriles with primary amines using Pt/C (3% by weight) catalyst in a continuous flow multichannel microreactor. Molecular hydrogen was used as a clean reducing agent at moderate reaction conditions. The Royal Society of Chemistry 2013.
- Sharma, Sumeet K.,Lynch, James,Sobolewska, Anna M.,Plucinski, Pawel,Watson, Robert J.,Williams, Jonathan M. J.
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- Iridium-catalyzed reduction of secondary amides to secondary amines and imines by diethylsilane
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Catalytic reduction of secondary amides to imines and secondary amines has been achieved using readily available iridium catalysts such as [Ir(COE) 2Cl]2 with diethylsilane as reductant. The stepwise reduction to secondary amine proceeds through an imine intermediate that can be isolated when only 2 equiv of silane is used. This system requires low catalyst loading and shows high efficiency (up to 1000 turnovers at room temperature with 99% conversion have been attained) and an appreciable level of functional group tolerance.
- Cheng, Chen,Brookhart, Maurice
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supporting information; experimental part
p. 11304 - 11307
(2012/09/05)
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- A general and selective copper-catalyzed reduction of secondary amides
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In situ-generated cationic copper/pybox catalyst systems allow for the selective reduction of secondary amides into the corresponding amines under mild conditions. This novel protocol has a wide substrate scope and shows good functional group tolerance. The Royal Society of Chemistry 2012.
- Das, Shoubhik,Join, Benoit,Junge, Kathrin,Beller, Matthias
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supporting information; experimental part
p. 2683 - 2685
(2012/04/04)
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- Synthesis and spectral studies on Pb(II) dithiocarbamate complexes containing benzyl and furfuryl groups and their use as precursors for PbS nanoparticles
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Nine lead bis(dithiocarbamate) complexes based on benzyl and furfuryl groups have been prepared. The complexes were characterized using IR and NMR spectroscopy. All the complexes showed the expected signals in 1H and 13C NMR spectra associated with the dithiocarbamate ligands. IR and 13C NMR spectral studies indicate that the S2CN double bond character increases with increase in length of alkyl chain bonded to nitrogen atom. Bis(N-benzyl-N-(2-phenylethyl)dithiocarbamato-S,S′)lead(II) (3) and bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S′)lead(II) (4) have been used as single source precursors for the synthesis of ethylenediamine capped PbS nanoparticles. Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), FTIR, UV-vis and fluorescence spectroscopy have been used to characterize the as-prepared lead sulfide nanoparticles. The PXRD measurements suggest that PbS nanoparticles are single phase with face-centered-cubic structure.
- Sathiyaraj, Ethiraj,Thirumaran, Subbiah
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p. 575 - 581,7
(2012/12/11)
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- Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells
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Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
- De Cesco, Stéphane,Deslandes, Sébastien,Therrien, Eric,Levan, David,Cueto, Micka?l,Schmidt, Ralf,Cantin, Louis-David,Mittermaier, Anthony,Juillerat-Jeanneret, Lucienne,Moitessier, Nicolas
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experimental part
p. 6306 - 6315
(2012/09/22)
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- Cycloaddition of furfurylamines to maleic anhydride and its substituted derivatives
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The regio- and stereoselectivity of the [4+2] cycloaddition of maleic, citraconic, dichloromaleic, and dibromomaleic anhydrides to difurfuryl amines and secondary furfurylamines were studied. N-Furfuryl-, N-phenyl-, and N-benzylhexahydrooxoepoxyisoindole-7-carboxylic acids were synthesized. An approach was developed for obtaining hexahydroepoxyoxoisoindole-7-carboxylic acid unsubstituted at the nitrogen atom. Aromatization of the oxabicycloheptene fragment of the dihaloepoxyiso-indolonecarboxylic acids gave a series of 7-carboxy-2-R-isoindol-1-ones.
- Zaytsev,Mikhailova,Airiyan,Galkina,Golubev,Nikitina,Zubkov,Varlamov
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p. 505 - 513
(2012/10/29)
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- Synthesis of α-amino acids through samarium(II) iodide promoted reductive coupling of nitrones with CO2
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Several N-benzylnitrones reacted with carbon dioxide in the presence of samarium(II) iodide leading to α-amino acids as the products of reductive C-C coupling. The best selectivities were observed at a carbon dioxide pressure of 50 bar at ambient temperature. The influences of different functional groups in the nitrone backbone and of the coordinating additives to samarium(II) iodide on the product distribution were investigated. The racemic α-amino acids were obtained in up to 70% yield based on HPLC data. A novel approach to the synthesis ofα-amino acids is disclosed, involvingC-carboxylation of nitrones by gaseous CO2 under reductive coupling reaction conditions (SmI2, 0.1 M in THF) at ambient temperature and 50 bar of CO 2 pressure. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- Prikhod'Ko, Alexander,Walter, Olaf,Zevaco, Thomas A.,Garcia-Rodriguez, Jaime,Mouhtady, Omar,Py, Sandrine
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supporting information; experimental part
p. 3742 - 3746
(2012/09/25)
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- Aryne cycloaddition with 3-oxidopyridinium species
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The [3 + 2] cycloaddition of arynes with 3-oxidopyridinium species is examined using the Kobayashi benzyne precursor. The reaction affords a bicyclo[3.2.1] skeleton under mild conditions. A [7 + 2] cycloaddition mode with a subsequent pyridine ring-opening event has also been observed.
- Ren, Hailong,Wu, Chunrui,Ding, Xiuxiu,Chen, Xiaoge,Shi, Feng
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supporting information
p. 8975 - 8984,10
(2012/12/12)
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- Zinc-catalyzed chemoselective reduction of tertiary and secondary amides to amines
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General and convenient procedures for the catalytic hydrosilylation of secondary and tertiary amides under mild conditions have been developed. In the presence of inexpensive zinc catalysts, tertiary amides are easily reduced by applying monosilanes. Key to success for the reduction of the secondary amides is the use of zinc triflate and disilanes with dual Si-H moieties. The presented hydrosilylations proceed with excellent chemoselectivity in the presence of sensitive ester, nitro, azo, nitrile, olefins, and other functional groups, thus making the method attractive for organic synthesis.
- Das, Shoubhik,Addis, Daniele,Junge, Kathrin,Beller, Matthias
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experimental part
p. 12186 - 12192
(2011/11/07)
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- Reductive amination with zinc powder in aqueous media
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Zinc powder in aqueous alkaline media was employed to perform reductive amination of aldehydes with primary amines. The corresponding secondary amines were obtained in good yields along with minor amounts of hydrodimerization byproducts. The protocol is a green alternative to the use of complex hydrides in chlorinated or highly flammable solvents.
- Giovenzana, Giovanni B.,Imperio, Daniela,Penoni, Andrea,Palmisano, Giovanni
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experimental part
p. 1095 - 1099
(2011/10/05)
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- Palladium-catalysed direct 5-arylation of furfurylamine or 2-(aminoalkyl)-thiophene derivatives
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The palladium-catalysed direct 5-arylation of furan or thiophene derivatives bearing CH2NHR substituents (with. R = COMe or CO 2tBu) generally proceeds in good yields by using a catalysts loading of only 0.1-2 mol-%. A wide range of functions such as acetyl, propionyl, formyl, ester, nitrile, trifluoromethyl or fluoro on the aryl bromide is tolerated. Higher yields were generally obtained in the presence of electron-deficient aryl bromides than with, electron-rich aryl bromides.
- Roger, Julien,Doucet, Henri
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experimental part
p. 4412 - 4425
(2010/10/19)
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- A facile, protic ionic liquid route to N-substituted 5-hydroxy-4-methyl-3- oxoisoindoline-1-carboxamides and N-substituted 3-oxoisoindoline-4-carboxylic acids
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Treatment of highly decorated bicyclo[2.2.1]heptadienes with the protic ionic liquid, TfOH:TEA effected quantitative conversion to the corresponding N-substituted 5-hydroxy-4-methyl-3-oxoisoindoline-1-carboxamides. This approach provides rapid access important chemical space for the rapid development of highly functionalised oxoisoindoline and is highly substrate tolerant.
- Gordon, Christopher P,Byrne, Nolene,McCluskey, Adam
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experimental part
p. 1000 - 1006
(2010/10/18)
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- Doubly dearomatising intramolecular coupling of a nucleophilic and an electrophilic heterocycle
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Isonicotinamides carrying N-furanylmethyl, N-pyrrolylalkyl or N-thiophenylmethyl substituents at nitrogen undergo cyclisation induced by an electrophile, giving spirocyclic compounds or doubly spirocyclic compounds in which both the nucleophilic and elect
- Brice, Heloise,Clayden, Jonathan
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supporting information; experimental part
p. 1964 - 1966
(2009/09/05)
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- Secondary amine formation from reductive amination of carbonyl compounds promoted by lewis acid using the InCl3ZEt3SiH system
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A robust and reliable method has been developed for reductive amination of primary amines with various aldehydes and ketones using Zn(ClO4) 2.6H20 as a catalyst. [In-H] generated in situ via a combination of InCl3 and Et3SiH is employed as an effective reducing system. A variety of secondary amines can be synthesized in a one-pot procedure in excellent yields.
- Lee, On-Yi,Law, Ka-Lun,Yang, Dan
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supporting information; experimental part
p. 3302 - 3305
(2009/11/30)
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- Synthesis and domino metathesis of functionalized 7-oxanorbornene analogs?toward cis-fused heterocycles
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Here, we report our strategy to synthesize structurally diverse cis-fused heterocycles via 7-oxanorbornene analogs. By the intramolecular Diels-Alder reaction of 3-iodoacrylamide, followed by the domino metathesis reaction, the cis-fused heterobicyclic sk
- Ikoma, Minoru,Oikawa, Masato,Sasaki, Makoto
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p. 2740 - 2749
(2008/09/19)
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- Synthesis of advanced intermediates of lennoxamine analogues
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A simple and convenient method for synthesis of advanced isoindolone intermediates of lennoxamine and analogues is described in this paper. The intramolecular Diels-Alder reaction of furan is used as a key step in this synthesis. Georg Thieme Verlag Stuttgart.
- Sarang, Prajakta S.,Yadav, Arun A.,Patil, Prashant S.,Krishna, Urlam Murali,Trivedi, Girish K.,Salunkhe, Manikrao M.
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p. 1091 - 1095
(2008/02/02)
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- General and environmentally friendly synthesis of heterocyclic multidentate molecules based on microwave-assisted heating protocol
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An efficient microwave heating methodology for the synthesis of heterocyclic multidentate molecules is reported. Each compound was obtained with high yield and purity in a few minutes from easily available starting materials such as amines, heteroaldehydes and N-hydroxymethyl pyrazoles or triazoles. In addition, this approach allows synthesis without any solvent or organic and inorganic by-products.
- Regnier, Thomas,Lavastre, Olivier
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p. 155 - 159
(2007/10/03)
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