- Enantioselective addition of organolithium reagents on isoquinoline
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1-Methyl-1,2-dihydroisoquinoline and 1-butyl-1,2-dihydroisoquinoline were obtained by enantioselective addition of organolithium reagents on the isoquinoline. (-)-Sparteine was used as an external catalytic chiral ligand and an enantiomeric excess of 57%
- Alexakis, Alexandre,Amiot, Franck
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- Chemoenzymatic dynamic kinetic resolution of secondary amines
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The kinetic resolution of amines using a novel iridium based catalyst coupled with an enzyme catalysed step is achieved on a large scale with high yields and ee.
- Stirling, Matthew,Blacker, John,Page, Michael I.
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- Isoquinoline thiosemicarbazone displays potent anticancer activity with: In vivo efficacy against aggressive leukemias
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A potent class of isoquinoline-based Α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice.
- Sun, Daniel L.,Poddar, Soumya,Sun, Daniel L.,Pan, Roy D.,Poddar, Soumya,Rosser, Ethan W.,Pan, Roy D.,Abt, Evan R.,Rosser, Ethan W.,Van Valkenburgh, Juno,Abt, Evan R.,Le, Thuc M.,Van Valkenburgh, Juno,Lok, Vincent,Le, Thuc M.,Song, Janet,Li, Joanna,Hernandez, Selena P.,Mona, Christine E.,Stuparu, Andreea D.,Czernin, Johannes,Turlik, Aneta,Donahue, Timothy R.,Chen, Xiaohong,Radu, Caius G.,Cheng, Chi-An,Hernandez, Selena P.,Chen, Wei,Mona, Christine E.,Stuparu, Andreea D.,Vergnes, Laurent,Reue, Karen,Damoiseaux, Robert,Zink, Jeffrey I.,Czernin, Johannes,Donahue, Timothy R.,Houk, Kendall N.,Jung, Michael E.,Radu, Caius G.
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- Selective functionalization of methane, ethane, and higher alkanes by cerium photocatalysis
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With the recent soaring production of natural gas, the use of methane and other light hydrocarbon feedstocks as starting materials in synthetic transformations is becoming increasingly economically attractive, although it remains chemically challenging. W
- Hu, Anhua,Guo, Jing-Jing,Pan, Hui,Zuo, Zhiwei
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- Synthesis of novel functionalized 5-nitroisoquinolines and evaluation of in vitro antimalarial activity
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Novel aldimine and hydrazone isoquinoline derivatives were obtained after subjecting 1-formyl-5-nitroisoquinoline to classical reactions. Some of these compounds were found to have activity against a chloroquine-resistant Plasmodium falciparum strain (ACC Niger).
- Rathelot,Vanelle,Gasquet,Delmas,Crozet,Timon-David,Maldonado
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- Radical trideuteromethylation with deuterated dimethyl sulfoxide in the synthesis of heterocycles and labelled building blocks
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The potential of deuterated pharmaceuticals is being widely demonstrated. Here we describe the first trideuteromethylation under radical reaction conditions using deuterated dimethyl sulfoxide as a reagent for the synthesis of labelled heterocycles and trideuteromethylated compounds. A broad scope of the developed method for the synthesis of various scaffolds was demonstrated.
- Caporaso, Roberta,Manna, Srimanta,Zinken, Sarah,Kochnev, Alexander R.,Lukyanenko, Evgeny R.,Kurkin, Alexander V.,Antonchick, Andrey P.
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- 1,4-Dehydrochlorination of 1-(1-haloalkyl)-3,4-dihydroisoquinolines as a convenient route to functionalized isoquinolines
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1-Chloroalkyl-, 1-(2,2-dichloroalkyl)-, and 1-(trichloromethyl)-3,4-dihydroisoquinolines are synthesized by chlorination of 1-alkyl-3,4-dihydroisoquinolines with N-chlorosuccinimide. These novel chlorinated 3,4-dihydroisoquinolines are suitable precursors for functionalized isoquinolines by aromatization involving sequential 1,4-dehydrochlorination, tautomerization, and nucleophilic substitution.
- Jacobs, Jan,Van, Tuyen Nguyen,Stevens, Christian V.,Markusse, Peter,De Cooman, Paul,Maat, Leendert,De Kimpe, Norbert
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- Efficient acceptorless dehydrogenation of hydrogen-rich N-heterocycles photocatalyzed by Ni(OH)2@CdSe/CdS quantum dots
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Hydrogen storage using liquid organic hydrogen carriers (LOHCs) is a promising hydrogen storage technology; however, the hydrogen release process typically requires a high temperature. Developing dehydrogenation technology under mild conditions is highly desirable. Herein, a new approach for photocatalytic acceptorless dehydrogenation of hydrogen-rich LOHCs using Ni(OH)2@CdSe/CdS QDs as the photocatalyst was demonstrated. 1,2,3,4-Tetrahydroquinoline (THQ), iso-THQ, indoline, and their derivatives were selected as hydrogen-rich substrates, which exhibit excellent dehydrogenation efficiency with the release of hydrogen photocatalyzed by Ni(OH)2@CdSe/CdS QDs. Up to 100% yields of hydrogen and over 90% yields of complete dehydrogenation products were obtained at ambient temperature. Isotope tracer studies indicate a stepwise pathway, beginning with the photocatalytic oxidation of the substrate to release a proton and followed by proton exchange with heavy water. This work provides a promising alternative strategy to develop highly efficient, low cost and earth-abundant photocatalysts for acceptorless dehydrogenation of hydrogen-rich LOHCs.
- Liu, Yanpeng,Yu, Tianjun,Zeng, Yi,Chen, Jinping,Yang, Guoqiang,Li, Yi
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p. 3810 - 3817
(2021/06/18)
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- ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism
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The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.
- Jo, Woohyun,Baek, Seung-Yeol,Hwang, Chiwon,Heo, Joon,Baik, Mu-Hyun,Cho, Seung Hwan
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supporting information
p. 13235 - 13245
(2020/09/01)
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- Preparation method of formaldehyde-substituted aza-condensed ring compound
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The invention provides a preparation method of a formaldehyde-substituted aza-condensed ring compound, comprising the following steps: by using an aza-condensed ring lactam compound as a starting material, carrying out halogenation reaction, methylation reaction and methyl oxidation reaction to obtain the formaldehyde-substituted aza-condensed ring compound. According to the preparation method ofthe formaldehyde-substituted aza-condensed ring compound, the whole synthesis route is good in step repeatability, mild in operation condition and high in safety, and large-scale production and industrial popularization are facilitated; post-treatment energy consumption is low, a large amount of toxic wastewater is not generated, no pollution is caused to the environment, the production safety level and the production cost are reduced, application of green and environment-friendly industrial production is facilitated, and wide application prospects are achieved.
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Paragraph 0141-0142; 0144
(2020/06/02)
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- Rh/TiO2-Photocatalyzed Acceptorless Dehydrogenation of N-Heterocycles upon Visible-Light Illumination
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TiO2 is an effective and extensively employed photocatalyst, but its practical use in visible-light-mediated organic synthesis is mainly hindered by its wide band gap energy. Herein, we have discovered that Rh-photodeposited TiO2 nanoparticles selectively dehydrogenate N-heterocyclic amines with the concomitant generation of molecular hydrogen gas in an inert atmosphere under visible light (λmax = 453 nm) illumination at room temperature. Initially, a visible-light-sensitive surface complex is formed between the N-heterocycle and TiO2. The acceptorless dehydrogenation of N-heterocycles is initiated by direct electron transfer from the HOMO energy level of the amine via the conduction band of TiO2 to the Rh nanoparticle. The reaction condition was optimized by examining different photodeposited noble metals on the surface of TiO2 and solvents, finding that Rh0 is the most efficient cocatalyst, and 2-propanol is the optimal solvent. Structurally diverse N-heterocycles such as tetrahydroquinolines, tetrahydroisoquinolines, indolines, and others bearing electron-deficient as well as electron-rich substituents underwent the dehydrogenation in good to excellent yields. The amount of released hydrogen gas evinces that only the N-heterocyclic amines are oxidized rather than the dispersant. This developed method demonstrates how UV-active TiO2 can be employed in visible-light-induced synthetic dehydrogenation of amines and simultaneous hydrogen storage applications.
- Bahnemann, Detlef W.,Balayeva, Narmina O.,Dillert, Ralf,Mamiyev, Zamin,Zheng, Nan
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p. 5542 - 5553
(2020/08/25)
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- A Visible-Light Promoted Amine Oxidation Catalyzed by a Cp*Ir Complex
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Through a rapid screening of Cp*Ir complexes based on a turn-on type fluorescence readout, a [Cp*Ir(dipyrido[3,2-a : 2’,3’-c]phenazine)Cl]+ complex was found to catalyze the blue-light promoted dehydrogenation of N-heterocycles under physiological conditions. In the dehydrogenation of tetrahydroisoquinolines, the catalyst preferentially yielded the monodehydrogenated product, accompanying H2O2 generation. We surmise that this mechanism may be reminiscent of flavin-dependent oxidases.
- Davis, Holly Jane,H?ussinger, Daniel,Ward, Thomas R.,Okamoto, Yasunori
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p. 4512 - 4516
(2020/07/27)
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- Nickel-Catalyzed Dehydrogenation of N-Heterocycles Using Molecular Oxygen
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Herein, an efficient and selective nickel-catalyzed dehydrogenation of five- and six-membered N-heterocycles is presented. The transformation occurs in the presence of alkyl, alkoxy, chloro, free hydroxyl and primary amine, internal and terminal olefin, trifluoromethyl, and ester functional groups. Synthesis of an important ligand and the antimalarial drug quinine is demonstrated. Mechanistic studies revealed that the cyclic imine serves as the key intermediate for this stepwise transformation.
- Banerjee, Debasis,Bera, Atanu,Bera, Sourajit
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supporting information
(2020/09/02)
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- Ir-Catalyzed Reversible Acceptorless Dehydrogenation/Hydrogenation of N-Substituted and Unsubstituted Heterocycles Enabled by a Polymer-Cross-Linking Bisphosphine
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The polystyrene-cross-linking bisphosphine ligand PS-DPPBz was effective for the Ir-catalyzed reversible acceptorless dehydrogenation/hydrogenation of N-heterocycles. Notably, this protocol is applicable to the dehydrogenation of N-substituted indoline derivatives with various N-substituents with different electronic and steric natures. A reaction pathway involving oxidative addition of an N-adjacent C(sp3)-H bond to a bisphosphine-coordinated Ir(I) center is proposed for the dehydrogenation of N-substituted substrates.
- Zhang, Deliang,Iwai, Tomohiro,Sawamura, Masaya
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supporting information
p. 5240 - 5245
(2020/07/03)
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- Iodine-catalyzed convergent aerobic dehydro-aromatization toward benzazoles and benzazines
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An iodine-catalyzed aerobic dehydro-aromatization has been developed, providing straightforward and efficient access to various benzoazoles and benzoazines. The present transition-metal-free protocol enables the dehydro-aromatization of tetrahydrobenzazoles and tetrahydroquinolines with molecular oxygen as the green oxidant, along with some other N-heterocycles. Hence, a broad range of heteroaromatic compounds are generated in moderate to good yields under facile reaction conditions.
- Chen, Shanping,Deng, Guo-Jun,Jiang, Pingyu,Ni, Penghui,Tuo, Xiaolong,Wang, Xiaodong
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p. 8348 - 8351
(2020/03/11)
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- Catalytically Active Co?Nx Species Stabilized on Nitrogen-doped Porous Carbon for Efficient Hydrogenation and Dehydrogenation of N-heteroarenes
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The development of bifunctional, highly active and stable non-noble-metal catalysts is important for synthetic chemistry. In this study, a highly dispersed Co catalyst stabilized on the mesoporous N-doped carbon layers was prepared by adsorption and pyrolysis of cobalt complex on dendritic fibrous silica nanospheres (KCC-1@Co?N?C?T). The characterizations of HAADF-STEM, XRD and XPS together with the KSCN poisoning tests determine the absence of Co0 or CoOx nanoparticles and suggest that the Co?Nx species are the active sites. The formation of Co?Nx species results from the properties of N-rich cobalt-phenanthroline complex and dendritic fibrous silica supports, increasing the original spatial distance between Co atoms and thus preventing them from aggregation. The KCC-1@Co?N?C-800 catalyst showed excellent activity and selectivity for the oxidative dehydrogenation (ODH) of saturated N-heterocycles and base-free catalytic transfer hydrogenation (CTH) of unsaturated N-heterocycles.
- Xu, Dan,Zhao, Hong,Dong, Zhengping,Ma, Jiantai
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p. 4406 - 4415
(2020/07/06)
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- A ortho position alkylation method of organic compound containg pyridine
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A process for introducing alkyl at ortho positions of organic compounds containing pyridine. The method is not affected by the kind of substituent bonded to the pyridine and can be alkylated with high positional selectivity and high yield at N-based ortho-position of pyridine without being affected by the kind of substituent introduced to pyridine ortho position (pyridine N-based) can be advantageously used for the preparation of a compound containing an alkyl-introduced pyridine structure.
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Paragraph 0108-0116
(2020/12/05)
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- Variability of Rhodium(III)-Catalyzed Reactions of Aromatic Oximes with Alkenes
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Acetophenone oxime reacts with various alkenes in the presence of the rhodium catalyst [Cp*RhCl 2 ] 2 (2.5 molpercent; Cp? = pentamethylcyclopentadienyl) and 1,1,1,3,3,3-hexafluoropropan-2-ol as an important cosolvent. Styrene, aliphatic terminal alkenes, and strained cyclic alkenes gave the corresponding substituted dihydroisoquinolines in yields of 50-99percent. On the other hand, alkenes containing functional groups close to the double bond gave a variety of different products. The reactions of acetophenone oxime with styrene or dec-1-ene in the presence of the chiral catalyst [(C 5 H 2 t Bu 2 CH 2 t Bu)RhI 2 ] 2 provided the corresponding dihydroisoquinolines with improved regioselectivity but a low enantiomeric ratio (61:39 in both cases).
- Chusov, Denis,Komarova, Alina A.,Perekalin, Dmitry S.,Trifonova, Evgeniya A.
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supporting information
p. 1117 - 1120
(2020/07/04)
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- Transition-Metal-Free Desulfinative Cross-Coupling of Heteroaryl Sulfinates with Grignard Reagents
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A mild cross-coupling reaction of heteroaryl sulfinates with Grignard reagents has been developed under transition-metal-free conditions. This study provides an example of the SO22- as a leaving group in an aromatic system and an effective methodology for the construction of C-C bond.
- Wei, Jun,Liang, Huamin,Ni, Chuanfa,Sheng, Rong,Hu, Jinbo
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- Visible-Light-Mediated Photocatalytic Aerobic Dehydrogenation of N-heterocycles by Surface-Grafted TiO2 and 4-amino-TEMPO
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Herein, the visible-light-induced dehydrogenation of N-heterocycles such as tetrahydroquinolines, tetrahydroisoquinolines, and indolines in O2-containing suspensions of a commercially available titanium dioxide photocatalyst yielding the corresponding heteroarenes is presented. 4-Amino-2,2,6,6-tetramethylpipiridinyloxyl (4-amino-TEMPO) was found to exhibit a beneficial role, as it increased the yield and improved the selectivity of the dehydrogenation reaction. Both the selectivity and the yield are further enhanced by grafting 0.1 wt % of Ni(II) ions onto the TiO2 surface. It is proposed that the basic reactant adsorbs at Lewis acid sites present at the TiO2 surface. The dehydrogenation reaction is initiated by visible-light excitation of the resulting surface complex and a subsequent single-electron transfer from the excited N-heterocycle via the conduction band of TiO2 to O2. Ni(II) ions possibly serve as an electron transfer bridge between the conduction band of TiO2 and O2, while the TEMPO derivative is assumed to act as a selective redox mediator involved in reactions of the generated reactive oxygen species.
- Balayeva, Narmina O.,Zheng, Nan,Dillert, Ralf,Bahnemann, Detlef W.
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p. 10694 - 10704
(2019/11/14)
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- Potassium tert-Butoxide-Promoted Acceptorless Dehydrogenation of N-Heterocycles
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Potassium tert-butoxide-promoted acceptorless dehydrogenation of N-heterocycles was efficiently realized for the generation of N-heteroarenes and hydrogen gas under transition-metal-free conditions. In the presence of KOtBu base, a variety of six- and five-membered N-heterocyclic compounds efficiently underwent acceptorless dehydrogenation to afford the corresponding N-heteroarenes and H2 gas in o-xylene at 140 °C. The present protocol provides a convenient route to aromatic nitrogen-containing compounds and H2 gas. (Figure presented.).
- Liu, Tingting,Wu, Kaikai,Wang, Liandi,Yu, Zhengkun
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supporting information
p. 3958 - 3964
(2019/08/01)
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- Cobalt Nanoparticles Apically Encapsulated by Nitrogen-doped Carbon Nanotubes for Oxidative Dehydrogenation and Transfer Hydrogenation of N-Heterocycles
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It is important to develop a highly active and stable transition-metal catalyst with dual-functional properties in the reversible transformations between various saturated and unsaturated N-heterocycles. Herein, we prepared the cobalt nanoparticles (Co NPs) apically encapsulated by the N-doped carbon nanotubes catalyst (Co@NCNTs) via a multiple pyrolysis of low-cost dicyandiamide and cobalt (II) acetylacetonate. The catalyst shows excellent activity and recyclability towards the oxidative dehydrogenation (ODH) and the catalytic transfer hydrogenation (CTH) for various N-heterocycles. The structure of outer N-doped carbon nanotubes (NCNTs) can protect Co NPs from aggregation and leaching. Moreover, the encapsulated Co NPs and the NCNTs may generate a synergistic effect. Both of them facilitate the high performance. The poisoning tests with KSCN were to clarify the different active sites for ODH and CTH reactions: the Co NPs could modify the NCNTs through electrons redistribution, therefore the NCNTs could directly activate O2 in ODH. The encapsulated Co NPs is enhanced by the doped N atoms which is good for the H2 activation in CTH. What's more, the mechanisms of ODH and CTH reactions were also proposed. This work provides a facile and low-cost method to design catalysts, which are dual-functional, highly active and stable, for industrial applications.
- Xu, Dan,Zhao, Hong,Dong, Zhengping,Ma, Jiantai
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p. 5475 - 5486
(2019/11/05)
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- Isoquinoline synthesis by C-H activation/annulation using vinyl acetate as an acetylene equivalent
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Vinyl acetate is used as an acetylene equivalent in rhodium(III)-catalysed C-H activation/annulation with aryl ketoxime esters. Extension to an aldoxime ester allows for a concise formal synthesis of decumbenine B.
- Webb, Nicola J.,Raw, Steven A.,Marsden, Stephen P.
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p. 5200 - 5205
(2018/06/19)
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- Reductive C2-Alkylation of Pyridine and Quinoline N-Oxides Using Wittig Reagents
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The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N-oxides using Wittig reagents. A wide range of pyridine and quinoline N-oxides were converted into C2-alkylated pyridines and quinolines with excellent site selectivity and functional-group compatibility. Sequential C?H functionalization reactions of pyridine and quinoline N-oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.
- Han, Sangil,Chakrasali, Prashant,Park, Jihye,Oh, Hyunjung,Kim, Saegun,Kim, Kyuneun,Pandey, Ashok Kumar,Han, Sang Hoon,Han, Soo Bong,Kim, In Su
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supporting information
p. 12737 - 12740
(2018/09/20)
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- DMSO as a Switchable Alkylating Agent in Heteroarene C?H Functionalization
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Herein, we report a novel strategy for the activation of DMSO to act as a versatile alkylating agent in heteroarene C?H functionalization. This direct, simple, and mild switch between methylation/trideuteromethylation and methylthiomethylation of heteroarenes was achieved under reagent-controlled photoredox catalysis conditions. The proposed mechanism is supported by both experimental and computational studies.
- Garza-Sanchez, R. Aleyda,Patra, Tuhin,Tlahuext-Aca, Adrian,Strieth-Kalthoff, Felix,Glorius, Frank
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supporting information
p. 10064 - 10068
(2018/07/29)
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- Dehydrogenation of Nitrogen Heterocycles Using Graphene Oxide as a Versatile Metal-Free Catalyst under Air
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Graphene oxide (GO) has been developed as an inexpensive, environmental friendly, metal-free carbocatalyst for the dehydrogenation of nitrogen heterocycles. Valuable compounds, such as quinoline, 3,4-dihydroisoquinoline, quinazoline, and indole derivatives, have been successfully used as substrates. The investigation of various oxygen-containing molecules with different conjugated systems indicated that both the oxygen-containing groups and large π-conjugated system in GO sheets are essential for this reaction. (Figure presented.).
- Zhang, Jingyu,Chen, Shiya,Chen, Fangfang,Xu, Wensheng,Deng, Guo-Jun,Gong, Hang
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supporting information
p. 2358 - 2363
(2017/07/22)
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- Simple and Clean Photo-induced Methylation of Heteroarenes with MeOH
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Heteroarene methylation utilizing a cheap and safe methylation source without involving transition metals represents an important yet challenging objective. Here, a simple and clean catalyst-free protocol for the methylation of various heteroarenes (including six- and five-membered types) is described under light irradiation. This protocol employs cheap, readily available, and abundant MeOH as both the solvent and the methylation source. It was found that adding dichloromethane (DCM) as a co-solvent could significantly increase the yield of the methylation products. Heteroarenes bearing various functional groups could be methylated and tri-deuteromethylated successfully. Deuterium labeling studies suggested that the newly generated methyl group in the products consisted of two hydrogens from the methyl group and one hydrogen from the OH group in MeOH.
- Liu, Wenbo,Yang, Xiaobo,Zhou, Zhong-Zhen,Li, Chao-Jun
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supporting information
p. 688 - 702
(2017/05/15)
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- Hybrid Catalysis Enabling Room-Temperature Hydrogen Gas Release from N-Heterocycles and Tetrahydronaphthalenes
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Hybrid catalyst systems to achieve acceptorless dehydrogenation of N-heterocycles and tetrahydronaphthalenes-model substrates for liquid organic hydrogen carriers-were developed. A binary hybrid catalysis comprising an acridinium photoredox catalyst and a Pd metal catalyst was effective for the dehydrogenation of N-heterocycles, whereas a ternary hybrid catalysis comprising an acridinium photoredox catalyst, a Pd metal catalyst, and a thiophosphoric imide organocatalyst achieved dehydrogenation of tetrahydronaphthalenes. These hybrid catalyst systems allowed for 2 molar equiv of H2 gas release from six-membered N-heterocycles and tetrahydronaphthalenes under mild conditions, i.e., visible light irradiation at rt. The combined use of two or three different catalyst types was essential for the catalytic activity.
- Kato, Shota,Saga, Yutaka,Kojima, Masahiro,Fuse, Hiromu,Matsunaga, Shigeki,Fukatsu, Arisa,Kondo, Mio,Masaoka, Shigeyuki,Kanai, Motomu
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supporting information
p. 2204 - 2207
(2017/02/23)
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- A new approach to 1-substituted β-carbolines and isoquinolines utilizing tributyl[(Z)-2-ethoxyvinyl]stannane as a C-3,C-4 building block
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Starting from readily available indole-2-carboxylic acids, 1-substituted β-carbolines (among them the alkaloids harmane and isoharmine) are readily obtained via the corresponding 2-acylindoles, bromination at C-3, followed by a one-pot Stille cross-coupling with tributyl[(Z)-2-ethoxyvinyl]stannane, and ring closure with ammonium acetate. 1-Substituted isoquinolines are available in an analogous manner starting from 2-bromobenzoic acid.
- Kamlah, Alexandra,Lirk, Florian,Bracher, Franz
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p. 837 - 845
(2016/01/20)
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- Transition-Metal-Free Regioselective Alkylation of Pyridine N-Oxides Using 1,1-Diborylalkanes as Alkylating Reagents
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Reported herein is an unprecedented base-promoted deborylative alkylation of pyridine N-oxides using 1,1-diborylalkanes as alkyl sources. The reaction proceeds efficiently for a wide range of pyridine N-oxides and 1,1-diborylalkanes with excellent regioselectivity. The utility of the developed method is demonstrated by the sequential C?H arylation and methylation of pyridine N-oxides. The reaction also can be applied for the direct introduction of a methyl group to 9-O-methylquinine N-oxide, thus it can serve as a powerful method for late-stage functionalization.
- Jo, Woohyun,Kim, Junghoon,Choi, Seoyoung,Cho, Seung Hwan
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supporting information
p. 9690 - 9694
(2016/08/10)
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- Alcohols as alkylating agents in heteroarene C-H functionalization
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Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.
- Jin, Jian,MacMillan, David W. C.
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- Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates to access isoquinolines
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The concise synthesis of 3-substituted or non-C3-substituted isoquinolines through Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates was developed with good functional group tolerance. The protocol was successfully applied to the total synthesis of the natural product papaverine.
- Chu, Haoke,Sun, Song,Yu, Jin-Tao,Cheng, Jiang
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supporting information
p. 13327 - 13329
(2015/08/24)
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- Acceptorless dehydrogenation of nitrogen heterocycles with a versatile iridium catalyst
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Gas up: A cyclometalated iridium complex is found to catalyze the dehydrogenation of various benzofused N-heterocycles, thus releasing H 2. Driven by as low as 0.1 mol % catalyst, the reaction affords quinolines, indoles, quinoxalines, isoquinolines, and β-carbolines in high yields. Copyright
- Wu, Jianjun,Talwar, Dinesh,Johnston, Steven,Yan, Ming,Xiao, Jianliang
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supporting information
p. 6983 - 6987
(2013/07/26)
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- Regioselective photochemical C-OMe bond formation initiated by one-electron transfer and N-OMe bond fragmentation in electron donor-acceptor systems
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Compounds that integrate electron donor-acceptor subunits with N-methoxyisoquinolinium as acceptors and substituted (methoxy)benzenes as donors were synthesized and their luminescent and photochemical properties studied. Photolysis yielded the corresponding photomethoxylation products in a two-step process that involves N-OMe bond scission followed by C-OMe bond formation. Homolysis of the N-OMe bond restores the aromatic isoquinoline nucleus and produces a methoxy radical that can couple to the required ring carbon atom in the benzene cation radical to give the products in a regioselective process controlled by the spin density of the cation radical. This photoprocess involves two different pathways: methoxylation of the acceptor (intracomponent methoxylation) or the donor (intercomponent metoxylation). Both methoxy-transfer pathways are controlled by the donoating ability (redox potential) of the donor subunit, consistent with the emission observed upon excitation of the charge-transfer state in systems that undergo intermethoxylation.
- Collado, Daniel,Perez-Inestrosa, Ezequiel
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experimental part
p. 1800 - 1808
(2012/05/04)
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- Nickel-catalyzed cyclization of ortho-iodoketoximes and ortho-iodoketimines with alkynes: Synthesis of highly substituted isoquinolines and isoquinolinium salts
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A convenient method for the synthesis of highly substituted isoquinolines and isoquinolinium salts by the nickel-catalyzed cyclization of ortho-haloketoximes and -ketimines, respectively, with alkynes is described. The reaction of ortho-haloketoximes and various alkynes in the presence of [Ni(PPh3)2Br2] and zinc powder in a mixture of acetonitrile and tetrahydrofuran at 80 °C for 15 hours gave 1,3,4-trisubstituted isoquinoline products in moderate to excellent yields and high regioselectivity. The corresponding isoquinoline N-oxide was found to be the intermediate in the cyclization reaction pathway. In contrast, the reaction of ortho-haloketimines and alkynes under similar catalytic conditions in tetrahydrofuran at 70 °C for two hours gave 1,2,3,4-tetrasubstituted isoquinolinium salts in good to excellent yields. In the nickel of time: ortho-Haloketoximes and -ketimines undergo [4+2] cyclization reactions with alkynes, catalyzed by nickel complexes to give highly substituted isoquinolines and isoquinolinium salts, respectively, in good to excellent yields (see scheme).
- Shih, Wei-Chun,Teng, Chu-Chun,Parthasarathy, Kanniyappan,Cheng, Chien-Hong
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supporting information; experimental part
p. 306 - 313
(2012/05/05)
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- Direct 1,4-difunctionalization of isoquinoline
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The synthesis of 1,4-disubstituted isoquinoline derivatives was achieved in one step starting from isoquinoline. The process involved a nucleophilic addition in 1-position followed by an electrophilic trapping in 4-position. Interesting features were noted when C2Cl6 was used as the electrophile since different compounds could be isolated selectively only by adjusting the reaction parameters.
- Lou?rat, Frédéric,Fort, Yves,Mamane, Victor
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supporting information; experimental part
p. 5716 - 5718
(2009/12/09)
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- Effect of π-electron delocalization on tautomeric equilibria - Benzoannulated 2-phenacylpyridines
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Most benzoannulated 2-methylpyridines react with phenyllithium and substituted alkyl benzoates to give the corresponding 2-phenacylpyridines. 3-Methylisoquinoline is transformed into 2-benzoyl-3-methyl-1-phenyl-1,2- dihydroisoquinoline under these conditions, but replacement of phenyllithium with lithium isopropylcyclohexylamide is effective for production of 3-phenacylisoquinolines. Except in the cases of some substituted 6-phenacylphenanthridines, tautomeric mixtures of benzoannulated 2-phenacylpyridines in chloroform solution always contain the ketimine forms. (Z)-2-(2-Hydroxy-2-phenylvinyl)pyridine (enolimine) forms also contribute if the pyridine ring is not benzoannulated or if such annulation is at positions 4,5. On the other hand, (Z)-2-benzoylmethylene-1,2-dihydropyridine (enaminone) forms exist in equilibrium with the ketimine tautomers if the pyridine ring is benzoannulated at positions 3,4 or 5,6, or at both of these locations. As well as the effectiveness of π-electron delocalization, other effects, such as the strength of the intramolecular hydrogen bonding, should also be considered in order to infer the tautomeric preferences. Strongly electron-donating substituents were found to stabilize the ketimine forms in each series. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.
- Gawinecki, Ryszard,Kolehmainen, Erkki,Loghmani-Khouzani, Hossein,O?mia?owski, Borys,Lovász, Tamás,Rosa, Pavel
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p. 2817 - 2824
(2007/10/03)
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- New light-induced iminyl radical cyclization reactions of acyloximes to isoquinolines
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An efficient photochemical approach for the unusual generation of six-membered heterocyclic rings is reported. Iminyl radicals, generated by the irradiation of acyloximes, participate in intramolecular cyclization processes and in intermolecular addition-intramolecular cyclization sequences.
- Alonso, Rafael,Campos, Pedro J.,Garcia, Barbara,Rodriguez, Miguel A.
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p. 3521 - 3523
(2007/10/03)
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- Indium metal as a reducing agent in organic synthesis
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The low first ionisation potential (5.8 eV) of indium coupled with its stability towards air and water, suggest that this metallic element should be a useful reducing agent for organic substrates. The use of indium metal for the reduction of C=N bonds in imines, the heterocyclic ring in benzo-fused nitrogen heterocycles, of oximes, nitro compounds and conjugated alkenes and the removal of 4-nitrobenzyl protecting groups is described. Thus the heterocyclic ring in quinolines, isoquinolines and quinoxalines is selectively reduced using indium metal in aqueous ethanolic ammonium chloride. Treatment of a range of aromatic nitro compounds under similar conditions results in selective reduction of the nitro groups; ester, nitrile, amide and halide substituents are unaffected. Likewise indium in aqueous ethanolic ammonium chloride is an effective method for the deprotection of 4-nitrobenzyl ethers and esters. Indium is also an effective reducing agent under non-aqueous conditions and α-oximino carbonyl compounds can be selectively reduced to the corresponding N-protected amine with indium powder, acetic acid in THF in the presence of acetic anhydride or di-tert-butyl dicarbonate. Conjugated alkenes are also reduced by indium in THF-acetic acid.
- Pitts,Harrison,Moody
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p. 955 - 977
(2007/10/03)
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- Isoxazolinoisoquinoline Heterocycles via Solid-Phase Reinsert and Suzuki Reactions
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A traceless solid-phase synthesis strategy has been developed that delivers novel isoxazolinoisoquinoline heterocycles. The process consists of solid-phase Reissert formation (isoquinoline → I), Suzuki coupling lithiation, and subsequent C1-alkylation (I → II), and exo-olefin selective 1,3-dipolar nitrile oxide cycloaddition followed by Reissert hydrolysis (II → III) to liberate the targeted heterocycle.
- Lorsbach, Beth A.,Bagdanoff, Jeffrey T.,Bryan Miller,Kurth, Mark J.
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p. 2244 - 2250
(2007/10/03)
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- Reductive trans-1,3-dialkylation of isoquinoline on treatment with RLi and triallylborane
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The preparative synthesis of trans-1-alkyl(aryl)-3-allyl-1,2,3,4-tetrahydroisoquinolines based on the 1,2-addition of RLi to isoquinoline and trans-allylboration is described.
- Bubnov,Klimkina,Ignatenko
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p. 1175 - 1178
(2007/10/03)
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- Synthesis and Antitumor Activity of 4- and 5-Substituted Derivatives of Isoquinoline-1-carboxaldehyde Thiosemicarbazone
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Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones (12 compounds) have been synthesized and evaluated for antineoplastic activity in mice bearing the L1210 leukemia.Condensation of 4-bromo-1-methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamine, and N-acetylethylenediamine gave the corresponding 4-amino, 4-methylamino, 4-ethylamino, and 4-N-(acetylethyl)amino derivatives, which were then converted to amides and subsequently oxidized to aldehydes followed by condensation with thiosemicarbazide to yield thiosemicarbazones 8a-c, 9a-c, and 16.Nitration of 4, followed by oxidation with selenium dioxide, produced aldehyde 18, which was then converted to the cyclic ethylene acetal 19.Condensation of 19 with morpholine followed by catalytic reduction of the nitro group and treatment with thiosemicarbazide afforded 5-amino-4-morpholinoisoquinoline-1-carboxaldehyde thiosemicarbazone (22).N-Oxidation of 1,5-dimethylisoquinoline, followed by rearrangement with acetic anhydride, gave, after acid hydrolysis, 1,5-dimethyl-4-hydroxyisoquinoline, which was converted to its acetate and then oxidized to yield 4-acetoxy-5-methylisoquinoline-1-carboxaldehyde (32).Sulfonation of 1,4-dimethylisoquinoline, followed by reaction with potassium hydroxide, acetylation, and oxidation, gave 5-acetoxy-4-methylisoquinoline-1-carboxaldehyde (40).Condensation of compounds 32 and 39 with thiosemicarbazide afforded the respective 4- and 5-acetoxy(5- and 4-methyl)thiosemicarbazones 33 and 40, which were then converted to their respective 4- and 5-hydroxy derivatives 34 and 41 by acid hydrolysis.The most active compounds synthesized were 4-aminoisoquinoline-1-carboxaldehyde thiosemicarbazone (9a) and 4- (methylamino)isoquinoline-1-carboxaldehyde thiosemicarbazone (9b), which both produced optimum percent T/C values of 177 against the L1210 leukemia in mice when used at daily dosage of 40 mg/kg for 6 consecutive days.Furthermore, when 9a was given twice daily at a dosage of 40 mg/kg for 6 consecutive days, a T/C value of 165 was obtained and 60percent of the mice were 60-day long-term survivors.
- Liu, Mao-Chin,Lin, Tai-Shun,Penketh, Philip,Sartorelli, Alan C.
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p. 4234 - 4243
(2007/10/03)
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- ELECTROCHEMICAL REDUCTION OF PRISTINAMYCIN IA AND RELATED STREPTOGRAMINS IN AQUEOUS ACIDIC MEDIUM
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The electrochemical reduction of the picolinoyl residue of pristinamycinIA and related streptogramins was performed at a mercury cathode, in aqueous medium.The presence of a peptidic lactone residue at the amide nitrogen atom markedly modified the expected cathodic behaviour of pyridyl carboxamides: in particular, we observed the reduction of the pyridyl ring into tetrahydropyridine derivatives.Thanks to a series of model heterocyclic carboxamides, increasing steric hindrance at the amide nitrogen position was shown to lead to enhanced reduction of the heterocyclic ring.
- Largeron, M.,Vuilhorgne, M.,Potier, I. Le,Auzeil, N.,Bacque, E.,and al.
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p. 6307 - 6332
(2007/10/02)
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- Vilsmeier-Haack reaction of 1-methyl-3,4-dihydroisoquinolines - Formation of (3,4-dihydroisoquinolin-1-yl)acetaldehydes and pyrroloisoquinolines and an attempted synthesis of aaptamine
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Treatment of dihydroisoquinolines (1a-d) with DMF-POCl3 yields, depending upon the molar concentrations of reagents, temperature and duration, isoquinolinylacetaldehydes (2), propanedials (3) or pyrroloisoquinolines (4).N-Acetylhomoveratryl amine (6) also affords under similar conditions the dialdehyde 3b and pyrroloisoquinoline 4b.Vilsmeier-Haack (VH) reaction of the 1-methyl-8-nitroisoquinoline 1e under mild conditions gives the N-formyl derivative 8 and under vigorous conditions, pyrroloisoquinoline 4e. 1-Methylisoquinoline (9) and its 5,6,7,8-tetrahydro derivative (10) remain unchanged under these conditions, whereas 1-ethyl-3,4-dihydroisoquinoline (11) forms only the N-formyl derivative (12). 2-Methylquinoline, 2-methylbenzimidazole and 2-methylbenzoxazole even under forcing VH conditions yield only the dialdehydes and not the fused pyrroles.
- Nagarajan, K.,Rodrigues, P. J.
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p. 1115 - 1118
(2007/10/02)
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- A Novel Method for the Synthesis of 4-Isoquinolinols
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1-Substituted 1,2-dihydroisoquinolines, derived from isoquinoline and organolithium reagents, readily undergo autoxidation to lead to 4-isoquinolinols in moderate yields.
- Uno, Hidemitsu,Okada, Shin-ichiro,Suzuki, Hitomi
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p. 341 - 346
(2007/10/02)
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- Substituted 2-[monoannelated (3,4-,4,5-, and 5,6-) pyridylalkylenesulfinyl]benzimidazoles
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The present invention provides novel substituted 2-[monoannelated(3,4- 4,5-, and 5,6-)pyridylalkylenesulfinyl]-benzimidazoles with gastric acid inhibiting effects.
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- Reissert Compound Studies. LXI. Preparation and Reactions of Quinazoline Di-Reissert Compounds
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Various di-Reissert compounds and analogs were prepared from quinazoline by use of trimethylsilyl cyanide together with a catalytic amount of anhydrous aluminum chloride.Reactions of these quinazoline di-Reissert compounds are reported.
- Hahn, Jung-Tai,Popp, Frank D.
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p. 1357 - 1372
(2007/10/02)
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