- Evidence of crystal packing effects in stabilizing high or low spin states of iron(ii) complexes with functionalized 2,6-bis(pyrazol-1-yl)pyridine ligands
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The molecular structures and magnetic properties of homoleptic iron(ii) compounds [Fe(bpp-COOMe)2](ClO4)2 (1) and [Fe(bpp-triolH3)2](ClO4)2 (2) have been investigated to ascertain their spin crossover (SCO) behaviour. In these hexacoordinated complexes, the bpp (2,6-bis(pyrazol-1-yl)pyridine) ligands adopt a mer-mer coordination mode and carry COOMe or C(O)NHC(CH2OH)3para substituents, respectively, on the central pyridyl ring. In spite of the almost equal donor power of the ligands to the iron(ii) centre, the two compounds feature different spin state configurations at room temperature. Compound 1 displays a highly-distorted octahedral environment around the iron(ii) centre, which adopts a high spin (HS) state at all temperatures, even under an external applied pressure up to 1.0 GPa. By contrast, 2 is characterized by a more regular octahedral coordination around the metal ion and exhibits a low spin (LS) configuration at or below room temperature. However, it shows a thermally-induced SCO behaviour at T > 400 K, along with Light-Induced Excited Spin State Trapping (LIESST) at low temperature, with TLIESST = 38 K. Since DFT (U)M06/6-311+G(d) geometry optimizations in vacuo indicate that both complexes should adopt a HS state and a highly-distorted coordination geometry, the stabilization of a LS configuration in 2 is ultimately ascribed to the effect of intermolecular hydrogen bonds, which align the [Fe(bpp-triolH3)2]2+ cations in 1D chains and impart profound differences in the geometric arrangement of the ligands.
- Bridonneau, Nathalie,Rigamonti, Luca,Poneti, Giordano,Pinkowicz, Dawid,Forni, Alessandra,Cornia, Andrea
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Read Online
- Preparation method of 4-amino-2,6-dichloropyridine
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The invention relates to a preparation method of a halogen-substituted pyridylamine compound, particularly to a preparation method of 4-amino-2,6-dichloropyridine, wherein 2,6-dihydroxy isonicotinic acid is used as a raw material and is subjected to chlorination reaction, Curtius rearrangement or further amine protection group removal to obtain the product. The method has the advantages of accessible raw materials, high yield and low impurity content, avoids the use of explosive reagent sodium azide, and can be further applied to industrial production.
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Paragraph 0111-0113
(2021/03/21)
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- FUSED HETEROCYCLIC COMPOUNDS AS CAM KINASE INHIBITORS
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The present disclosure relates to compounds that are CaM Kinase inhibitors and to their use in the treatment of various disease states, including atrial fibrillation and myocardial infarction. In particular embodiments, the general structure of the compounds is given by Formula I: wherein R1, R2, R3, R4, R5, R6, R9 and R10 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.
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Paragraph 1335; 1336
(2018/06/09)
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- TRICYCLIC COMPOUNDS FOR USE IN TREATMENT OF PROLIFERATIVE DISORDERS
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The present invention relates to compounds of Formula (I) as defined herein, and salts, hydrates and solvates thereof. The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to the use of compounds of Formula (I) in the treatment or prevention of PRMT5-mediated disorders, such as cancer.
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Paragraph 00137; 00138
(2018/10/19)
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- Practical Synthesis of a S1P Receptor 1 Agonist via a Guareschi-Thorpe Reaction
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A practical synthesis of S1P receptor 1 agonist ACT-334441 (1) through late-stage convergent coupling of two key intermediates is described. The first intermediate is 2-cyclopentyl-6-methoxyisonicotinic acid whose skeleton was built from 1-cyclopentylethanone, ethyl oxalate, and cyanoacetate in a Guareschi-Thorpe reaction in 42% yield over five steps. The second, chiral intermediate, is a phenol ether derived from enantiomerically pure (R)-isopropylidene glycerol ((R)-solketal) and 3-ethyl-4-hydroxy-5-methylbenzonitrile in 71% yield in a one-pot reaction. The overall sequence entails 18 chemical steps with 10 isolated intermediates. All raw materials are cheap and readily available in bulk quantities, the reaction conditions match with standard pilot plant equipment, and the route reproducibly afforded 3-20 kg of 1 in excellent purity and yield for clinical studies.
- Schmidt, Gunther,Bolli, Martin H.,Lescop, Cyrille,Abele, Stefan
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p. 1637 - 1646
(2016/09/23)
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- Selective photosensitization through an and logic response: Optimization of the pH and glutathione response of activatable photosensitizers
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A series of pH and GSH responsive photosensitizers were designed and synthesized. pKa values were optimized by adjusting the inductive contribution of substituents to reach a pH range (6.0-7.4) relevant to the tumour microenvironment. pH-Activatable behaviour and redox mediated release of the quencher from the PS by GSH allow the construction of an AND logic operator for selective photodynamic action in aqueous solutions.
- Erbas-Cakmak, Sundus,Cakmak, Fatma Pir,Topel, Seda Demirel,Uyar, Taha Bilal,Akkaya, Engin U.
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supporting information
p. 12258 - 12261
(2015/07/27)
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- Design and structural analysis of aromatic inhibitors of type II dehydroquinase from mycobacterium tuberculosis
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3-Dehydroquinase, the third enzyme in the shikimate pathway, is a potential target for drugs against tuberculosis. Whilst a number of potent inhibitors of the Mycobacterium tuberculosis enzyme based on a 3-dehydroquinate core have been identified, they generally show little or no in vivo activity, and were synthetically complex to prepare. This report describes studies to develop tractable and drug-like aromatic analogues of the most potent inhibitors. A range of carbon-carbon linked biaryl analogues were prepared to investigate the effect of hydrogen bond acceptor and donor patterns on inhibition. These exhibited inhibitory activity in the high-micromolar range. The addition of flexible linkers in the compounds led to the identification of more potent 3-nitrobenzylgallate- and 5-aminoiso-phthalate-based analogues.
- Howard, Nigel I.,Dias, Marcio V.B.,Peyrot, Fabienne,Chen, Liuhong,Schmidt, Marco F.,Blundell, Tom L.,Abell, Chris
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p. 116 - 133
(2015/04/14)
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- Self-assembly formation of a healable lanthanide luminescent supramolecular metallogel from 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) ligands
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The synthesis of five new 2,6-bis(1,2,3-triazol-4-yl)pyridine (btp) ligands is described: the self-assembly behaviour of the tri-methyl ester, 1, with Eu(iii) showed the formation of a luminescent 1 : 3 Eu : btp complex, Eu13, which was studied in solution and in the solid state; while the tri-carboxylic acid, 2, formed a hydrogel and its corresponding complex Eu23, gave rise to a strongly red luminescent healable metallogel.
- McCarney, Eoin P.,Byrne, Joseph P.,Twamley, Brendan,Martínez-Calvo, Miguel,Ryan, Gavin,M?bius, Matthias E.,Gunnlaugsson, Thorfinnur
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p. 14123 - 14126
(2015/09/15)
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- Optimization of Triazine Nitriles as Rhodesain Inhibitors: Structure-Activity Relationships, Bioisosteric Imidazopyridine Nitriles, and X-ray Crystal Structure Analysis with Human CathepsinL
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The cysteine protease rhodesain of Trypanosoma brucei parasites causing African sleeping sickness has emerged as a target for the development of new drug candidates. Based on a triazine nitrile moiety as electrophilic headgroup, optimization studies on the substituents for the S1, S2, and S3 pockets of the enzyme were performed using structure-based design and resulted in inhibitors with inhibition constants in the single-digit nanomolar range. Comprehensive structure-activity relationships clarified the binding preferences of the individual pockets of the active site. The S1 pocket tolerates various substituents with a preference for flexible and basic side chains. Variation of the S2 substituent led to high-affinity ligands with inhibition constants down to 2nM for compounds bearing cyclohexyl substituents. Systematic investigations on the S3 pocket revealed its potential to achieve high activities with aromatic vectors that undergo stacking interactions with the planar peptide backbone forming part of the pocket. X-ray crystal structure analysis with the structurally related enzyme human cathepsinL confirmed the binding mode of the triazine ligand series as proposed by molecular modeling. Sub-micromolar inhibition of the proliferation of cultured parasites was achieved for ligands decorated with the best substituents identified through the optimization cycles. In cell-based assays, the introduction of a basic side chain on the inhibitors resulted in a 35-fold increase in antitrypanosomal activity. Finally, bioisosteric imidazopyridine nitriles were studied in order to prevent off-target effects with unselective nucleophiles by decreasing the inherent electrophilicity of the triazine nitrile headgroup. Using this ligand, the stabilization by intramolecular hydrogen bonding of the thioimidate intermediate, formed upon attack of the catalytic cysteine residue, compensates for the lower reactivity of the headgroup. The imidazopyridine nitrile ligand showed excellent stability toward the thiol nucleophile glutathione in a quantitative invitro assay and fourfold lower cytotoxicity than the parent triazine nitrile.
- Ehmke, Veronika,Winkler, Edwin,Banner, David W.,Haap, Wolfgang,Schweizer, W. Bernd,Rottmann, Matthias,Kaiser, Marcel,Freymond, Celine,Schirmeister, Tanja,Diederich, Francois
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supporting information
p. 967 - 975
(2013/07/27)
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- PYRIDINE AND ISOQUINOLINE DERIVATIVES AS SYK- AND JAK-KINASE INHIBITORS
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The present invention relates to a compound of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Syk kinase and/or Janus kinases.
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Page/Page column 187-188
(2012/04/17)
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- Pyridine- and isoquinoline-derivatives as Syk and JAK kinase inhibitors
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The present invention relates to a compound of formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by inhibition of Syk kinase and/or Janus kinases.
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Paragraph 0332
(2013/03/26)
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- Designing Structural Motifs for Clickamers: Exploiting the 1,2,3-Triazole Moiety to Generate Conformationally Restricted Molecular Architectures
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Noncovalent interactions, especially hydrogen-bonding interactions as well as electrostatic forces, confined within one macromolecule are the key to designing foldamers that adopt well-defined conformations in solution. In the context of significant recent activities in the area of triazole-connected foldamers, so-called clickamers, we present a fundamental study that compares various model compounds that bear adjacent N-, O-, or F-heteroatom substituents. The interplay of attractive and repulsive interactions leads to rotational constraints around the single bonds attached to both the 1- and 4-positions of the 1,2,3-triazole moiety and should therefore be able to induce well-defined conformational preferences in higher oligomers and polymers, that is, foldamers. Various compounds were synthesized and characterized with regard to their preferred conformations in all three aggregation statesa-that is, in the gas phase, in solution as well as in the solid statea-by employing DFT calculations, NMR spectroscopic experiments, and X-ray crystallography, respectively. On the basis of the thus-obtained general understanding of the conformational behavior of the individual connection motifs, heterostructures were prepared from different motifs without affecting their distinct folding characteristics. Therefore, this work provides a kind of foldamer construction kit, which should enable the design of various clickamers with specific shape and incorporated functionality. A foldamer construction kit: Various heterostructures "clicked" together by structure-directing triazole moieties were investigated with regard to their conformational behavior. Different heteroatoms (X; see graphic) can be used to bias the conformation around the N(1)- and C(4)-connecting single bonds of the triazoles based on tunable noncovalent interactions.
- Zornik, Denise,Meudtner, Robert M.,Ela Malah, Tamer,Thiele, Christina M.,Hecht, Stefan
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supporting information; experimental part
p. 1473 - 1484
(2011/04/15)
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- Titanocene(III)-catalyzed conversion of N-(epoxyalkyl)anilines into indolines
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Densely substituted indolines and azaindolines can be obtained by the titanocene(III) chloride catalyzed reductive opening of N-(oxiran-2-ylmethyl) anilines. The reaction optimization, substrate scope, and limitations are discussed, and a mechanistic pathway for the epoxideopening rearrangement is proposed. ARKAT-USA, Inc.
- MacIejewski, John P.,Wipf, Peter
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experimental part
p. 92 - 119
(2011/06/20)
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- Complexes of click-derived bistriazolylpyridines: Remarkable electronic influence of remote substituents on thermodynamic stability as well as electronic and magnetic properties
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2,6-Bis(1,2,3-triazol-4-yl)pyridine (btp) ligands with substitution patterns ranging from strongly electrondonating to strongly electron-accepting groups, readily prepared by means of Cu-catalyzed 1,3-dipolar cycloaddition (the "click" reaction), were investigated with regard to their complexation behavior, and the properties of the resulting transition-metal compounds were compared. Metal-btp complexes of 1:1 stoichiometry, that is, [Ru-(btp)Cl2(dmso)] and [Zn(btp)Br2], could be isolated and were crystallographically characterized: they display octahedral and trigonal-bipyramidal coordination geometries, respectively, and exhibit high aggregation tendencies due to efficient π-π stacking leading to low solubilities. Metal-btp complexes of 1:2 stoichiometry, that is, [Fe-(btp) 2]2+ and [Ru(btp)2]2+, could also be synthesized and their metal centers show the expected octahedral coordination spheres. The iron compounds exhibit quite a complex magnetic behavior in the solid state including spin crossover near room temperature, and hysteresis and locking into high-spin states on tempering at 400 K, depending on the substituents on the btp ligands. Cyclic voltammetry studies of [Ru(btp) 2]2+ reveal strong modulation of the oxidation potentials by more than 0.6 V and a clear linear correlation to the Hammett constant (σpara) of the substituent at the pyridine core. Isothermal titration calorimetry was used to measure the thermodynamics of the Fe II-btp complexation process and enabled accurate determination of the complexation enthalpies, which display a linear relationship with the σpara values for the terminal phenyl substituents. Detailed NMR spectroscopic studies finally revealed that in the case of FeII complexation, dynamics are rapid for all investigated btp derivatives in acetonitrile, while replacing FeII by RuII or changing the solvent to dichloromethane effectively slows down ligand exchange. The results nicely demonstrate the utility of substituent parameters, originally developed for linear free-energy relationships to explain reactivity in organic reactions, in coordination chemistry, and to illustrate the potential to customdesign btp ligands and complexes thereof with predictable properties. The fast equilibration of the [Fe-(btp)2]2+ complexes together with their tunable stability and interesting magnetic properties should enable the design of dynamic metallosupramolecular materials with advantageous properties.
- Ostermeier, Marc,Berlin, Marie-Anne,Meudtner, Robert M.,Demeshko, Serhiy,Meyer, Franc,Limberg, Christian,Hecht, Stefan
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supporting information; experimental part
p. 10202 - 10213
(2010/11/18)
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- Buchwald-Hartwig Mono-N-arylation with 2,6-dihaloisonicotinic acid derivatives: A convenient desymmetrization method
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A method for the Buchwald-Hartwig mono-N-arylation of aniline with methyl 2,6-dichloroisonicotinate using Pd(OAc)2, XPhos, and t-BuONa is reported. Use of m-anisidine under the same conditions resulted in the amidation of the methyl ester. Mono-N-arylation of m-anisidine with 2,6-dichloro-N,N- diisopropylisonicotinamide and 2,6-dibromo-N,N-diisopropylisonicotinamide, however, was successfully achieved using Pd(OAc)2/XPhos/t-BuONa or Pd(OAc)2/(±)-BINAP/K2CO3, respectively. The present study demonstrates the sensitivity of this cross-coupling method to both the steric and electronic nature of the coupling partners. Georg Thieme Verlag Stuttgart.
- Lorimer, Anna V.,O'Connor, Patrick D.,Brimble, Margaret A.
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experimental part
p. 2764 - 2770
(2009/04/07)
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- Titanocene(III)-catalyzed formation of indolines and azaindolines
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(Chemical Equation Presented) Reductive cyclization of epoxides tethered to substituted anilines and aminopyridines in the presence of 3 mol % of titanocene dichloride and stoichiometric manganese metal promotes a radical annulation to form 3,3-disubstituted indolines and azaindolines.
- Wipf, Peter,Maciejewski, John P.
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supporting information; experimental part
p. 4383 - 4386
(2009/05/30)
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- Synthesis of 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine, and its conversion to other 2,6-di(pyrazol-1-yl)pyridines substituted at the pyridine ring
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Two routes to 2,6-di(pyrazol-1-yl)-4-hydroxymethylpyridine (1) from 2,6-dihydroxy-isonicotinic acid, in four and six steps, are reported. Reaction of 1 with 48% HBr yields 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine (2), which is a powerful precursor to a range of new tridentate ligands for transition metals functionalised at the pyridine ring. As a proof of principle, we describe the further elaboration of 2 to give two 2,6-di(pyrazol-1-yl)pyridines bearing nucleobase substituents, and the back-to-back ligand 1,2-bis[2,6-di(pyrazol-1-yl)pyrid-4-yl]ethane. Crystal structures of two of these new derivatives are presented.
- Elha?k, Jér?me,Pask, Christopher M.,Kilner, Colin A.,Halcrow, Malcolm A.
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p. 291 - 298
(2007/10/03)
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- Reversing the discovery paradigm: A new approach to the combinatorial discovery of fluorescent chemosensors
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We report here a new approach to the discovery of fluorescent chemosensors in which a new signaling mechanism allows a core fluorophore to be used in a combinatorial search for new binding events, thus reversing the reigning discovery paradigm. Copyright
- Mello, Jesse V.,Finney, Nathaniel S.
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p. 10124 - 10125
(2007/10/03)
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- ARYLPYRIDINE COMPOUNDS
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The present invention relates to arylpyridine compounds and methods of using them.
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- Exploiting the versatile assembly of arylpyridine fluorophores for wavelength tuning and SAR
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(Matrix presented) The facile modular assembly of polyarylpyridine fluorophores provides two important advantages in the development of fluorescent chemosensors: it allows rapid dissection of the structural requirements for fluorescent chemosensing and it allows dramatic tuning of emission wavelength by changes in a substituent remote from the binding site.
- Fang, Albert G.,Mello, Jesse V.,Finney, Nathaniel S.
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p. 967 - 970
(2007/10/03)
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- Functionalized 2,2′-bipyridines and 2,2′:6′,2″-terpyridines via stille-type cross-coupling procedures
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Stille-type cross-coupling procedures are utilized in order to prepare a variety of functionalized 2,2′-bipyridines and 2,2′:6′,2″-terpyridines. Such N-heterocyclic compounds are of great interest as chelating ligands for transitionmetal ions in the field of supramolecular chemistry. Various mono- and disubstitued 2,2′-bipyridines were synthesized in high yields and multigram scales using a modular design principle. The terpyridines may be functionalized in one step with different substituents at the outer pyridine rings and at the 4′-position of the centered ring, leading to multifunctionalized compounds. The initially obtained methyl ester and ethyl ester groups can be simply converted into bromomethyl and hydroxymethyl groups which allow further functionalization reactions.
- Heller, Marcel,Schubert, Ulrich S.
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p. 8269 - 8272
(2007/10/03)
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- Convenient synthesis and transformation of 2,6-dichloro-4-iodopyridine
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(Matrix Presented) We describe a convenient scalable synthesis of 2,6-dichloro-4-iodopyridine and demonstrate its utility by stepwise elaboration to a number of 2,4,6-trisubstituted pyridines.
- Mello, Jesse V.,Finney, Nathaniel S.
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p. 4263 - 4265
(2007/10/03)
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- CONTRASTING REACTIONS OF 2,6-DICHLORO-4-TRICHLOROMETHYLPYRIDINE, 2,6-DICHLORO-3-TRICHLOROMETHYLPYRIDINE AND THEIR N-OXIDES WITH NUCLEOPHILES
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Various nucleophiles react with 2,6-dichloro-4-trichloromethylpyridine and 2-chloro-6-trichloromethylpyridine as expected, by displacement of ring chlorine atoms.But in the reactions of nucleophiles with 2,6-dichloro-3-trichloromethylpyridine and 2,6-difluoro-3-trifluoromethylpyridine, displacement of ring halogen atoms is accompained or followed by multiple attack at the trihalogenomethyl group.The reactivity of the trihalogenomethyl groups is modified by N-oxidation.A mechanism for the peculiar reactivity of the trihalogenomethyl groups is proposed, involving loss of halide ion from the CX3 group assisted by Ione pairs on substituents or negative charge in Meisenheimer intermediates.Both geometrical isomers of 1,2-dichloro-1,2-bis(2,6-dichloro-3-pyridyl)ethene are described.
- Dainter, Ronald S.,Suschitzky, Hans,Wakefield, Basil J.
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p. 227 - 234
(2007/10/02)
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- Substituted pyridyl compounds, herbicidal compositions and method of use
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Substituted pyridyl compounds, e.g. 2,6-dichloro-4(2-(2,2,2-trichloroethyl)oxiranyl) pyridine; herbicidal compositions containing such compounds and method for the control of undesired vegetation using these compositions.
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