- Assembly of α-(Hetero)aryl Nitriles via Copper-Catalyzed Coupling Reactions with (Hetero)aryl Chlorides and Bromides
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α-(Hetero)aryl nitriles are important structural motifs for pharmaceutical design. The known methods for direct synthesis of these compounds via coupling with (hetero)aryl halides suffer from narrow reaction scope. Herein, we report that the combination of copper salts and oxalic diamides enables the coupling of a variety of (hetero)aryl halides (Cl, Br) and ethyl cyanoacetate under mild conditions, affording α-(hetero)arylacetonitriles via one-pot decarboxylation. Additionally, the CuBr/oxalic diamide catalyzed coupling of (hetero)aryl bromides with α-alkyl-substituted ethyl cyanoacetates proceeds smoothly at 60 °C, leading to the formation of α-alkyl (hetero)arylacetonitriles after decarboxylation. The method features a general substrate scope and is compatible with various functionalities and heteroaryls.
- Chen, Ying,Xu, Lanting,Jiang, Yongwen,Ma, Dawei
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supporting information
p. 7082 - 7086
(2021/02/26)
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- Robust and Scalable Approach to 1,3-Disubstituted Pyridylcyclobutanes
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An approach to all isomeric 3-pyridylcyclobutane-derived building blocks, i.e. ketones, alcohols and amines, is described. Synthesis of the title compounds relied on the five-step reaction sequence including alkylation of isomeric pyridyl acetonitriles with 1,3-dibromo-2,2-dimethoxypropane. Hydrolysis, decarboxylation and removal of the ketal moiety led to the key 3-pyridylcyclobutanones (obtained on up to 120 g scale in a single run), which were transformed into the corresponding alcohols and amines with high diastereoselectivity. The title cyclobutanone derivatives were used to synthesize three isomeric nicotine analogues, as well as for parallel synthesis of a small lead-like compound library via reductive amination.
- Demchuk, Oleksandr P.,Hryshchuk, Oleksandr V.,Vashchenko, Bohdan V.,Radchenko, Dmytro S.,Kovtunenko, Volodymyr O.,Komarov, Igor V.,Grygorenko, Oleksandr O.
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p. 5937 - 5949
(2019/08/30)
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- Corresponding amine nitrile and method of manufacturing thereof
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The invention relates to a manufacturing method of nitrile. Compared with the prior art, the manufacturing method has the characteristics of significantly reduced using amount of an ammonia source, low environmental pressure, low energy consumption, low production cost, high purity and yield of a nitrile product and the like, and nitrile with a more complex structure can be obtained. The invention also relates to a method for manufacturing corresponding amine from nitrile.
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- Tetrazolylhydrazides as selective fragment-like inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
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The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr=142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases. Anchor fragment: To develop non-promiscuous metalloenzyme inhibitors, a metal-complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.
- Rüger, Nicole,Roatsch, Martin,Emmrich, Thomas,Franz, Henriette,Schüle, Roland,Jung, Manfred,Link, Andreas
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supporting information
p. 1875 - 1883
(2015/11/10)
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- Two-step cyanomethylation protocol: Convenient access to functionalized aryl- and heteroarylacetonitriles
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A two-step protocol has been developed for the introduction of cyanomethylene groups to metalated aromatics through the intermediacy of substituted isoxazoles. A palladium-mediated cross-coupling reaction was used to introduce the isoxazole unit, followed by release of the cyanomethylene function under thermal or microwave-assisted conditions. The intermediate isoxazoles were shown to be amenable to further functionalization prior to deprotection of the sensitive cyanomethylene motif, allowing access to a wide range of aryl- and heteroaryl-substituted acetonitrile building blocks.
- Lindsay-Scott, Peter J.,Clarke, Aimee,Richardson, Jeffery
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supporting information
p. 476 - 479
(2015/03/05)
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- A heterogeneous palladium catalyst hybridised with a titanium dioxide photocatalyst for direct C-C bond formation between an aromatic ring and acetonitrile
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A palladium catalyst hybridised with a titanium dioxide photocatalyst can promote cyanomethylation of an aromatic ring by using acetonitrile, where the photocatalyst activates acetonitrile to form a cyanomethyl radical before the C-C bond formation using the palladium catalyst.
- Yoshida, Hisao,Fujimura, Yuki,Yuzawa, Hayato,Kumagai, Jun,Yoshida, Tomoko
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supporting information
p. 3793 - 3795
(2013/05/22)
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- A practical and cost-efficient, one-pot conversion of aldehydes into nitriles mediated by 'activated DMSO'
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Participation of activated DMSO in the one-pot transformation of aldehydes to nitriles has been described by reacting aldehydes with NHHHCl in DMSO in the absence of any added base or catalyst. The method is applicable to access a wide range of aromatic, heterocyclic, and aliphatic nitriles, in which only water is a byproduct. A straightforward and practical procedure is demonstrated on a multigram scale. Georg Thieme Verlag Stuttgart - New York.
- Augustine, John Kallikat,Bombrun, Agnes,Atta, Rajendra Nath
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scheme or table
p. 2223 - 2227
(2011/10/31)
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- Kinetics and mechanism of the formation of N-vinyl pyridinium cations in elimination reactions in aqueous base
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The rates of the elimination reactions of N-(2-bromoethyl) pyridinium cations (1) and N,N'-ethylene bispyridinium dications (3) to give the corresponding N-vinyl pyridinium cations (2) have been measured spectrophotometrically in basic aqueous solutions (ionic strength 0.1, 25 deg C) for a variety of substituents in the pyridine rings of each of these classes of pyridinium cation.The reaction kinetics are first order in 1 or 3 and first order in hydroxide ion.Bronsted-type plots of the second-order rate constants (kOH) as a function of the basicity (as pKBH) of the corresponding substituted pyridine are nonlinear for each of 1 and 3 and can be interpreted in terms of E1cb reaction mechanism.For 1, the Bronsted-type plot displays two distinct ''concave down'' linear regions; rate-determining deprotonation for pKBH > 5.16 (slope = -0.30), and a change in rate-determining step to bromide ion departure for pKBH > 5.16 (slope -0.58).For 3, the Bronsted-type plot appears to be smoothly curved for symmetrically disubstituted bispyridinium dications, as a consequence of the multiple substituent effects upon each step of the E1cb reactions of these dications.However, log kOH for 3 is a smooth linear function of the previously reported log kOH for the E1cb reactions of N-(2-cyanoethyl) pyridinium cations over a range in which a change in rate-determining step has been directly demonstrated for these latter cations.Thus a change in rate-determining step as a function of pyridine basicity is also required within the E1cb mechanism for 3.The E1cb reactions of 1 are approximately 104-fold faster than the corresponding hydroxide ion catalyzed E2 eliminations from 2-phenylethyl bromides that are isoelectronic with 1.
- Bunting, John W.,Toth, Andrea,Kanter, James P.
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p. 1195 - 1203
(2007/10/02)
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- A Change in the Rate-Determining Step in the E1cB Reactions of N-(2-(4-Nitrophenyl)ethyl)pyridinium Cations
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Second-order rate constants have been measured (aqueous solution, I = 1.0, 25 deg C) for the hydroxide ion catalyzed elimination reactions of 12 N-(2-(4-nitrophenyl)ethyl)pyridinium cations (3) bearing a variety of substituents in the pyridine ring.Broensted plots as a function of the basicity of the pyridine leaving group are concave-down, which is consistent with a change in rate-determining step within an E1cB mechanism.These plots are characterized by βlg = -0.17 for the rate-determining deprotonation for pKBH lg = -0.39 for the rate-determining expulsion of the pyridine nucleofuge from the carbanionic intermediate for pKBH > 6.5.Elimination reactions in basic D2O occur without any significant incorporation of deuterium into the 4-nitrostyrene product, and require the presence of a hydrogen-bonded carbanionic intermediate in which nucleofuge expulsion occurs faster than exchange of hydrogen-bonding water molecules.Rate-determining deprotonation in these elimination reactions occurs 50-fold more slowly than for the corresponding reactions of the N-quinuclidinium cations that have also been reported to have βlg = -0.17, but which do not show an analogous change in the rate-determining step upon variation of the nucleofuge basicity.The analogous elimination of the 1-methyl-3-imidazolium cation occurs a further 30-fold more slowly than that predicted for 3 having a pyridine leaving group of the same basicity as 1-methylimidazole.The E1cB reactions of 3 are similar to the analogous reactions of N-(2-cyanoethyl)pyridinium cations (1) in displaying a change in the rate-determining step with nucleofuge basicity; however, theβlg values for 1 and 3 are quite different for both k1 and k2/k-1.
- Bunting, John W.,Kanter, James P.
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p. 6950 - 6954
(2007/10/02)
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- Equilibration of N-(2-cyanoethyl)pyridinium cations with substituted pyridines and acrylonitrile. A change in rate-determining step in an E1cb reaction
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The rates of equilibration of N-(2-cyanoethyl)pyridinium cations (1) with the corresponding pyridines and acrylonitrile have been measured in aqueous solutions of ionic strength 0.1 at 25 °C. Second-order rate constants (kOH) have been obtained for the hydroxide ion catalyzed elimination reactions of 16 ring-substituted 1 having pyridine leaving groups of pKBH in the range 1.5-9.7. Bronsted plots of log kOH vs pKBH are "concave down" with two distinct linear regions having β1g = -0.30 (for pKBH 1g = -0.93 (for pKBH > 5.8). This observation is consistent with a change in rate-determining step within an E1cb reaction mechanism from rate-determining deprotonation of 1 (i.e., (E1cb)irrev) for pKBH rev) for pKBH > 5.8. This interpretation is supported by 1H NMR spectral observations in basic D2O, which show no incorporation of deuterium into the acrylonitrile product for pKBH BH > 5.8. Rates of nucleophilic attack of pyridines and pyridinone anions (pKBH > 6) upon acrylonitrile have also been measured. These display a linear Br?nsted plot of βnuc = 0.20. Combination of β1g and βnuc gives βeq = 0.13 for the Michael-type addition of pyridinium cations to acrylonitrile to produce 1. Although the rates of the addition of pyridines of pKBH nuc = 0.20 for pyridines of pKBH > 5.8 to rate-determining protonation of the carbanionic intermediate with βnuc = 0.83 for pyridine nucleophiles of pKBH irrev region but is extremely weak under the current experimental conditions.
- Bunting, John W.,Toth, Andrea,Heo, Christina K. M.,Moors, Rodney G.
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p. 8878 - 8885
(2007/10/02)
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- NEW APPLICATION OF COMPLEX BASES: NUCLEOPHILIC CONDENSATIONS OF PYRIDINE
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3,4-Dehydropyridine can be easily generated from 3-bromopyridine by complex bases.Nucleophilic condensations of amines, ketones and nitrile enolates are thus performed for the first time in good to very good yields.
- Jamart-Gregoire, Brigitte,Leger, Christian,Caubere, Paul
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p. 7599 - 7602
(2007/10/02)
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- Imidazole urea and amido compounds
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The invention relates to urea and amido compounds of the formula STR1 which have a powerful action on tumors, and to processes for their preparation and pharmaceutical preparations containing such compounds.
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- σ-bonded organotransition-metal ions. Part IV. Kinetics and mechanism of the acid-catalysed decomposition of the 4- pyridiomethylpentacyanocobaltate(III) ion
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Potassium 4-pyridylmethylpentacyanocobaltate(III) monohydrate, prepared by the reaction of cobaltous cyanide with 4-bromomethylpyridinium bromide, is stable to air in aqueous solution. In solutions of pH 9·2 and below the pyridine ring is protonated to form the 4-pyridiomethylpentacyanocobaltate(III) ion and in perchloric acid of ca. 4M a second proton is added, presumably to one of the cyanide ligands. The kinetics of decomposition of these species have been investigated. In > 1M-perchloric acid the rate of decomposition increases linearly with increasing acid concentration to a maximum in ≥ 7·5M-acid, owing to the unimolecular decomposition of the protonated 4-pyridiomethylpentacyanocobalate(III) ion to the 4-cyanomethylpyridinium ion. At lower acidities (pH 1-5) the kinetics are complicated by the slowly established equilibrium between the 4-pyridiomethylpentacyanocobaltate(III) ion and the 4-pyridiomethylaquotetracyanocobaltate(III) ion and by the further decomposition of the latter ion at a rate comparable with the initial rate of approach to equilibrium. The kinetics in this pH region can however be simplified by the addition of small quantities of HCN sufficient to suppress the formation of the aquotetracyano-complex so that only the acid-catalysed decomposition of the pentacyano-complex is observed.
- Johnson,Tobe,Wong, Lai-Yoong
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p. 491 - 497
(2008/10/08)
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