- Lewis Acid Catalyzed Enantioselective Desymmetrization of Donor–Acceptor meso-Diaminocyclopropanes
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The first Lewis acid catalyzed enantioselective ring-opening desymmetrization of a donor–acceptor meso-diaminocyclopropane is reported. The copper(II)-catalyzed Friedel–Crafts alkylation of indoles and one pyrrole with an unprecedented meso-diaminocyclopropane delivered enantioenriched, diastereomerically pure urea products, which are structurally related to natural and synthetic bioactive compounds. The development of a new ligand through the investigation of an underexplored subclass of bis(oxazoline) ligands was essential for achieving high enantioselectivities.
- Perrotta, Daniele,Wang, Ming-Ming,Waser, Jér?me
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- Immobilized Pd on a NHC functionalized metal–organic framework MIL-101(Cr): an efficient heterogeneous catalyst in Suzuki?Miyaura coupling reaction in water
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A novel Pd?NHC functionalized metal–organic framework (MOF) based on MIL-101(Cr) was synthesized and used as an efficient heterogeneous catalyst in the C-C bond formation reactions. Using this heterogeneous Pd catalyst system, the Suzuki?Miyaura coupling reaction was accomplished well in water, and coupling products were obtained in good to excellent yields in short reaction time. The Pd?NHC?MIL-101(Cr) was characterized using some different techniques, including Fourier transform-infrared, X-ray diffraction, scanning electron microscopy, energy-dispersive X-ray spectroscopy, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy, inductively coupled plasma and elemental analysis. The microscopic techniques showed the discrete octahedron structure of MIL-101(Cr), which is also stable after chemical modification process to prepare the catalyst system. The TEM images of the catalyst showed the existence of palladium nanoparticles immobilized in the structure of the catalyst, while no reducing agent was used. It seems that the NHC groups and imidazolium moieties in the structure of the MOF can reduce Pd (II) to Pd (0) species. This modified MOF substrate can also prevent aggregation of Pd nanoparticles, resulting in high stability of them in organic transformation. The Pd?NHC?MIL-101(Cr) catalyst system could be simply extracted from the reaction mixture, providing an efficient synthetic method for the synthesis of biaryls derivatives using the aforementioned coupling reaction. The Pd?NHC?MIL-101(Cr) catalyst could be recycled in this organic reaction with almost consistent catalytic efficiency.
- Khalafi-Nezhad, Ali,Niknam, Esmaeil,Panahi, Farhad
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- A one-pot "back-to-front" approach for the synthesis of benzene ring substituted indoles using allylboronic acids
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Synthesis of only benzene ring functionalized indoles and poly-substituted carbazoles is reported via a one-pot triple cascade benzannulation protocol. Usage of differently substituted and readily accessible allylboronic acids as a 3-carbon annulating partner enables diverse aliphatic and aromatic substitution patterns, which is still a daunting task. This scalable synthetic protocol tolerates broad scope, thus enabling further downstream modifications. As an application, carbazole based natural products glycozoline and glycozolinol were synthesized. This journal is
- Karan, Ganesh,Sahu, Samrat,Maji, Modhu Sudan
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p. 5274 - 5277
(2021/06/06)
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- Ligand-free Suzuki coupling reaction with highly recyclable ionic palladium catalyst, Ti1-xPdxO2-x (x?=?0.03)
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We synthesized a recyclable palladium ionic catalyst, Ti0.97Pd0.03O1.97, using a solution combustion method (SCM), and characterized by XRD and Rietveld refinement. The synthesized Pd ionic catalyst is stable, insensitive to moisture and air, and easy to handle. The new catalyst has exhibited a phenomenal result for the Suzuki-Miyaura cross-coupling reaction with a broad substrate scope, and the reaction proceeds in an aqueous medium. The new catalyst proved beneficial and produced excellent yields irrespective of aryl halide used in the reaction (electron-rich or electron-poor or heterocyclic compounds) and shown a turnover frequency (TOF) of 14–25 h?1 for different reactions. The catalyst was coated on a cordierite monolith (Mg2Al4Si5O18), which enhanced the applicability of the catalyst, and made the handling and recycling of the catalyst very easy. Suzuki Miyaura reaction was carried out using both Pd-powder catalysts as well as the Pd-coated honeycomb, which gave almost similar results. We have demonstrated the recyclability of Pd coated cordierite monolith and shown the superiority of the catalyst over the other Pd catalysts for the Suzuki-Miyaura reaction.
- Bhat K, Shrikanth,Lanke, Veeranjaneyulu,Prasad, Jagadeesh Dasappa,Prabhu, Kandikere Ramaiah
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- Synthesis of Enaminone-Pd(II) Complexes and Their Application in Catalysing Aqueous Suzuki-Miyaura Cross Coupling Reaction
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A series of Pd(II)-enaminone complexes, termed Pd(eao)2, have been synthesized and characterized. The investigation on the catalytic activities of these new Pd(II)-reagents has proved that the Pd(eao)2-1 possesses excellent catalytic activity for the Suzuki- Miyaura cross coupling reactions of aryl bromides/chlorides with aryl/vinyl boronic acids in the environmentally benign media of aqueous PEG400 at low loading (5 mol‰). The superiority of this Pd(II)-reagent to those commercial Pd(II) and Pd(0) catalysts in catalyzing the reactions has been confirmed by parallel experiments. What's more, Pd(eao)2-2 has been found as a practical catalyst for the homo-coupling reactions of aryl boronic acids.
- Fu, Leiqing,Cao, Xiaoji,Wan, Jie-Ping,Liu, Yunyun
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p. 254 - 258
(2020/01/25)
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- Iron catalysis for the synthesis of ligands: Exploring the products of hydrophosphination as ligands in cross-coupling
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Catalytic hydrophosphination is a useful technique for the synthesis of phosphines, however, the phosphine products have been little exploited as ligands in catalysis. We have selected three phosphines prepared by iron catalyzed hydrophosphination and used them as ligands in a series of cross-coupling reactions: Heck, Suzuki-Miyaura and Buchwald-Hartwig. Rather than limit the chemistry to simple cross-coupling partners which are almost guaranteed to perform well in these transformations, industrially relevant substrates which are challenging from and electronic and/or steric perspective, along with substrates which contain several heteroatoms, were explored in order to gauge the true potential of these phosphine ligands.
- Espinal-Viguri, Maialen,Mahon, Mary F.,Tyler, Simon N.G.,Webster, Ruth L.
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- Identification of an Indazole-Based Pharmacophore for the Inhibition of FGFR Kinases Using Fragment-Led de Novo Design
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Structure-based drug design (SBDD) has become a powerful tool utilized by medicinal chemists to rationally guide the drug discovery process. Herein, we describe the use of SPROUT, a de novo-based program, to identify an indazole-based pharmacophore for the inhibition of fibroblast growth factor receptor (FGFR) kinases, which are validated targets for cancer therapy. Hit identification using SPROUT yielded 6-phenylindole as a small fragment predicted to bind to FGFR1. With the aid of docking models, several modifications to the indole were made to optimize the fragment to an indazole-containing pharmacophore, leading to a library of compounds containing 23 derivatives. Biological evaluation revealed that these indazole-containing fragments inhibited FGFR1-3 in the range of 0.8-90 μM with excellent ligand efficiencies of 0.30-0.48. Some compounds exhibited moderate selectivity toward individual FGFRs, indicating that further optimization using SBDD may lead to potent and selective inhibitors of the FGFR family.
- Turner, Lewis D.,Summers, Abbey J.,Johnson, Laura O.,Knowles, Margaret A.,Fishwick, Colin W. G.
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supporting information
p. 1264 - 1268
(2017/12/26)
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- Highly functionalized biaryls via Suzuki-Miyaura cross-coupling catalyzed by Pd@MOF under batch and continuous flow regimes
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A diverse set of more than 40 highly functionalized biaryls was synthesized successfully through the Suzuki-Miyaura cross-coupling reaction catalyzed by Pd nanoparticles supported in a functionalized mesoporous MOF (8 wt% Pd@MIL-101(Cr)-NH2). This could be achieved under some of the mildest conditions reported to date and a strong control over the leaching of metallic species could be maintained, despite the presence of diverse functional groups and/or several heteroatoms. Some of the targeted molecules are important intermediates in the synthesis of pharmaceuticals and we clearly exemplify the versatility of this catalytic system, which affords better yields than currently existing commercial procedures. Most importantly, Pd@MIL-101-NH2 was packed in a micro-flow reactor, which represents the first report of metallic nanoparticles supported on MOFs employed in flow chemistry for catalytic applications. A small library of 11 isolated compounds was created in a continuous experiment without replacing the catalyst, demonstrating the potential of the catalyst for large-scale applications.
- Pascanu, Vlad,Hansen, Peter R.,Bermejo G?3mez, Antonio,Ayats, Carles,Platero-Prats, Ana E.,Johansson, Magnus J.,Peric??s, Miquel ??.,Mart??n-Matute, Bel??n
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p. 123 - 130
(2015/02/19)
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- Suzuki-miyaura cross-coupling of unprotected, nitrogen-rich heterocycles: Substrate scope and mechanistic investigation
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The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.
- Duefert, M. Alexander,Billingsley, Kelvin L.,Buchwald, Stephen L.
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supporting information
p. 12877 - 12885
(2013/09/23)
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- A mild robust generic protocol for the Suzuki reaction using an air stable catalyst
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A mild but robust procedure has been developed as a first pass generic protocol for the Suzuki-Miyaura reaction. The protocol employs an air stable palladium pre-catalyst at low loading (1 mol %) in aqueous solvent mixtures at moderate temperature using potassium carbonate as base. Under these mild conditions, most aryl bromides will react with sterically and electronically demanding aryl boronic acids to give complete conversion to the product biphenyls in less than 1 h. Aryl chlorides are also fully converted in most cases either under identical conditions in 8-24 h, or in 2 h at elevated temperature. A further advantage of these mild conditions of moderate temperature, weak base and benign solvent is that sensitive functional groups and structural motifs are well tolerated. In addition, the lipophilic biphenyl products are readily isolated after a simple work-up procedure. These generic conditions are ideal for proof of transformation, and as the starting point for development and optimization of a specific process. The discovery and fine-tuning of this generic protocol will be presented, supported extensively by examples to illustrate its scope and utility.
- Moseley, Jonathan D.,Murray, Paul M.,Turp, Edward R.,Tyler, Simon N.G.,Burn, Ross T.
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scheme or table
p. 6010 - 6017
(2012/09/21)
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- Phenylaminopropanol derivatives and methods of their use
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The present invention is directed to phenylaminopropanol derivatives of formulae I, II, and III: [image] or a pharmaceutically acceptable salt thereof, compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected from the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, schizophrenia, and combinations thereof.
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Page/Page column 48
(2010/11/26)
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- Discovery of 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat) and congeners as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
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Recent efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective 3-[(benzothiazol-2-yl)methyl]indole-N-alkanoic acid aldose reductase inhibitors. The lead candidate, 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]indole-N-acetic acid (lidorestat, 9) inhibits aldose reductase with an IC50 of 5 nM, while being 5400 times less active against aldehyde reductase, a related enzyme involved in the detoxification of reactive aldehydes. It lowers nerve and lens sorbitol levels with ED50's of 1.9 and 4.5 mg/kg/d po, respectively, in the 5-day STZ-induced diabetic rat model. In a 3-month diabetic intervention model (1 month of diabetes followed by 2 months of drug treatment at 5 mg/kg/d po), it normalizes polyols and reduces the motor nerve conduction velocity deficit by 59% relative to diabetic controls. It has a favorable pharmacokinetic profile (F, 82%; t1/2, 5.6 h; Vd, 0.694 L/kg) with good drug penetration in target tissues (Cmax in sciatic nerve and eye are 2.36 and 1.45 μg equiv/g, respectively, when dosed with [14C] lidorestat at 10 mg/kg po).
- Van Zandt, Michael C.,Jones, Michael L.,Gunn, David E.,Geraci, Leo S.,Jones, J. Howard,Sawicki, Diane R.,Sredy, Janet,Jacot, Jorge L.,DiCioccio, A. Thomas,Petrova, Tatiana,Mitschler, Andre,Podjarny, Alberto D.
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p. 3141 - 3152
(2007/10/03)
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- Methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substituted indolealkanoic acids
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Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds use
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- Methods for reducing uric acid levels
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Disclosed are methods of reducing serum uric acid levels, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds useful in the treatment of gout and related diseas
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- Substituted indolealkanoic acids
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Disclosed are substituted indolealkanoic acids useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as we
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- Compositions containing a substituted indolealkanoic acid and an angiotensin converting enzyme inhibitor
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Disclosed are methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis, the methods comprising administration of substituted indolealkanoic acids to patients in need of such treatment. Also disclosed are such compounds use
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- Indole derivatives and their use as fungicides, insecticides and pesticides
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Compounds of the formula: STR1 and stereoisomers thereof, wherein R1 and R2, which are the same or different, are hydrogen, cyano or halogen (fluorine, chlorine, bromine or iodine) or optionally substituted alkyl; V is either oxygen or sulphur; W, X, Y and Z, which may be the same or different, are hydrogen, halogen, nitro, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted alkoxy, optionally substituted arylalkoxy, optionally substituted alkenyl S(O)n R3 (wherein n is 0, 1 or 2), or optionally substituted heteroaryl, or W, X or X, Y or Y, Z together form methylenedioxy; and R3 is optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaryl. The compounds are useful as fungicides and also as plant growth regulators, insecticides and miticides.
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- 6-SUBSTITUTED INDOLES FROM o-HALONITROBENZENES
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o-Chloro- and o-bromonitrobenzenes are efficiently converted to 6-substituted indoles in a four step synthesis, proceeding through o-trimethylsilylethynylnitrobenzenes, o-nitrophenylacetaldehyde dimethylacetals and o-aminophenylacetaldehyde dimethylacetal
- Tischler, Allan N.,Lanza, Thomas J.
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p. 1653 - 1656
(2007/10/02)
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