- KI-Mediated One-Pot Transition-Metal-Rree Synthesis of 4-Phenylpyrrolo[1,2-a]quinoxalines
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An efficient and eco-friendly method for the synthesis of pyrrolo[1,2-a]quinoxalines is presented. Compared to previous methods, this protocol is transition-metal-free and only potassium iodide is required. A series of substituted 4-phenylpyrrolo[1,2-a]quinoxalines are obtained in moderate to good yields.
- Li, Shichen,Xie, Caixia,Chu, Xianglong,Dai, Zhen,Feng, Lei,Ma, Chen
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supporting information
p. 4950 - 4956
(2020/08/10)
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- Synthesis of indolo- And pyrrolo[1,2-: a] quinoxalinones through a palladium-catalyzed oxidative carbonylation of the C 2 position of indole
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A methodology that involves the Pd-catalyzed direct C(sp2)-H bond carbonylation of the C2 position of indole has been introduced for the synthesis of indolo[1,2-a]quinoxalin-6(5H)-ones. The methodology developed herein was used for the synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones. The reaction of N-substituted 2-(1H-indol-1-yl)anilines or 2-(1H-pyrrol-1-yl)anilines and carbon monoxide in the presence of Pd(OCOCF3)2 as a catalyst and Cu(OAc)2 as an oxidant in toluene at 80 °C forms the corresponding quinoxalinones as exclusive products in good yields. The catalytically active C-H activated intermediate Pd complex was isolated and characterized for the first time which on exposure to CO gas in toluene at 80 °C gave the corresponding quinoxalinone derivative. On the basis of isolation of the intermediate, a possible mechanism has been proposed for the C-H activated direct carbonylative annulation of 2-(5-methoxy-1H-indol-1-yl)-N,4-dimethylaniline.
- Chandrasekhar, Attoor,Sankararaman, Sethuraman
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p. 1612 - 1622
(2020/03/06)
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- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
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The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
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- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
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The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
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p. 3924 - 3939
(2019/05/06)
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- Optimization of Drug Candidates That Inhibit the D-Loop Activity of RAD51
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RAD51 is the central protein in homologous recombination (HR) repair, where it first binds ssDNA and then catalyzes strand invasion via a D-loop intermediate. Additionally, RAD51 plays a role in faithful DNA replication by protecting stalled replication forks; this requires RAD51 to bind DNA but may not require the strand invasion activity of RAD51. We previously described a small-molecule inhibitor of RAD51 named RI(dl)-2 (RAD51 inhibitor of D-loop formation #2, hereafter called 2 h), which inhibits D-loop activity while sparing ssDNA binding. However, 2 h is limited in its ability to inhibit HR in vivo, preventing only about 50 % of total HR events in cells. We sought to improve upon this by performing a structure–activity relationship (SAR) campaign for more potent analogues of 2 h. Most compounds were prepared from 1-(2-aminophenyl)pyrroles by forming the quinoxaline moiety either by condensation with aldehydes, then dehydrogenation of the resulting 4,5-dihydro intermediates, or by condensation with N,N′-carbonyldiimidazole, chlorination, and installation of the 4-substituent through Suzuki–Miyaura coupling. Many analogues exhibited enhanced activity against human RAD51, but in several of these compounds the increased inhibition was due to the introduction of dsDNA intercalation activity. We developed a sensitive assay to measure dsDNA intercalation, and identified two analogues of 2 h that promote complete HR inhibition in cells while exerting minimal intercalation activity.
- Budke, Brian,Tueckmantel, Werner,Miles, Kelsey,Kozikowski, Alan P.,Connell, Philip P.
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p. 1031 - 1040
(2019/04/30)
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- Dimethyl Sulfoxide Involved One-Pot Synthesis of Quinoxaline Derivatives
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An efficient, green, and novel method for the synthesis of N-heterocycle-fused quinoxalines is reported herein. Dimethyl sulfoxide was used as both a reactant and a solvent in this reaction. A wide range of products in moderate to excellent yields were obtained, including pyrrolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxalines, 1H-pyrrolo[3,2-c]quinolines, and benzo[4,5]imidazo[1,2-c]quinazolines.
- Xie, Caixia,Zhang, Zeyuan,Li, Danyang,Gong, Jian,Han, Xushuang,Liu, Xuan,Ma, Chen
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p. 3491 - 3499
(2017/04/11)
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- A catalytic intramolecular nitrene insertion into a copper(i)-N-heterocyclic carbene bond yielding fused nitrogen heterocycles
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N-(2-Azidophenyl)azolium salts were easily prepared and reacted with copper(i) under conditions allowing the formation of NHC complexes. Under these conditions, the formation of benzimidazo-fused heterocycles occurred under catalytic, efficient and very mild conditions. This reaction is proposed to proceed via dinitrogen elimination and imido/nitrene-NHC cyclization.
- Fauché, Kévin,Nauton, Lionel,Jouffret, Laurent,Cisnetti, Federico,Gautier, Arnaud
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p. 2402 - 2405
(2017/02/23)
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- 3-(Diphenylphosphino)propanoic acid: An efficient ligand for the Cu-catalyzed N-arylation of imidazoles and 1H-pyrazole with aryl halides
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3-(Diphenylphosphino)propanoic acid (L2) has proved to be an efficient ligand for the copper-catalyzed CN coupling reactions. N-arylation of imidazoles with aryl iodides catalyzed by CuCl/L2 was smoothly carried out in DMSO at 100 °C with a yield up to 98%. N-arylation of 1H-pyrazole with aryl iodides and bromides catalyzed by Cu(OAc)2/L2 in 1,4-dioxane also gave the corresponding products with yields of 40%-98%.
- Liu, Ya-Shuai,Liu, Yan,Ma, Xiao-Wei,Liu, Ping,Xie, Jian-Wei,Dai, Bin
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p. 775 - 778
(2014/06/09)
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- A facile one-step approach for the synthesis of uniform spherical Cu/Cu2O nano- and microparticles with high catalytic activity in the Buchwald-Hartwig amination reaction
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In the present work, we have developed a rapid, one step, calcination-free protocol for the synthesis of uniform spherical Cu/Cu2O nano/microparticles (NMPs). The synthesis of Cu/Cu2O NMPs was achieved by microwave irradiation of copper acetate as a precursor and 1,4-butanediol as a solvent in a few minutes. The prepared Cu/Cu2O NMPs gave 100% yield of uniform spherical morphology. 1,4-Butanediol plays a crucial role in reactions such as a solvent, reactant, stabilizer and capping agent which control the crystal morphology. The resultant product was characterized with the help of different techniques such as XRD, FEG-SEM, EDS, TEM, FT-IR, TPR, DSC-TGA, XPS and BET surface area analysis. The results confirm that the Cu/Cu2O NMPs had good crystallinity and were essentially pure. This is a simple, faster, inexpensive and additive-free protocol for synthesis of nanocrystalline Cu/Cu2O compared to the conventional method. These Cu/Cu2O NMPs showed excellent catalytic activity in the Buchwald-Hartwig amination coupling reaction. Notably the reaction does not require any ligand source, and requires low catalyst loading, and low temperature with catalyst recyclability. the Partner Organisations 2014.
- Bhosale, Manohar A.,Bhanage, Bhalchandra M.
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p. 15122 - 15130
(2014/04/17)
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- Synthesis of highly functionalized polycyclic quinoxaline derivatives using visible-light photoredox catalysis
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A mild and facile method for preparing highly functionalized pyrrolo[1,2-a]quinoxalines and other nitrogenrich heterocycles, each containing a quinoxaline core or an analogue thereof, has been developed. The novel method features a visible-light-induced decarboxylative radical coupling of ortho-substituted arylisocyanides and radicals generated from phenyliodine(III) dicarboxylate reagents and exhibits excellent functional group compatibility. A wide range of quinoxaline heterocycles have been prepared. Finally, a telescoped preparation of these polycyclic compounds by integration of the in-line isocyanide formation and photochemical cyclization has been established in a three-step continuousflow system.
- He, Zhi,Bae, Minwoo,Wu, Jie,Jamison, Timothy F.
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supporting information
p. 14451 - 14455
(2015/02/19)
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- Sequential decarboxylative azide-alkyne cycloaddition and dehydrogenative coupling reactions: One-pot synthesis of polycyclic fused triazoles
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Herein, we describe a one-pot protocol for the synthesis of a novel series of polycyclic triazole derivatives. Transition metalcatalyzed decarboxylative CuAAC and dehydrogenative cross coupling reactions are combined in a single flask and achieved good yi
- Bharathimohan, Kuppusamy,Ponpandian, Thanasekaran,Ahamed, A. Jafar,Bhuvanesh, Nattamai
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p. 3031 - 3037
(2015/02/19)
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- Tetrazole-1-acetic acid as a ligand for copper-catalyzed N-arylation of imidazoles with aryl iodides under mild conditions
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Tetrazole-1-acetic acid was found to serve as a superior ligand for CuI-catalyzed N-arylation of imidazoles with aryl iodides under a low catalyst loading (5 mol% of CuI). A variety of aryl iodides could be aminated to provide the N-arylated products in good to excellent yields without the need of an inert atmosphere.
- Wu, Feng-Tian,Liu, Ping,Ma, Xiao-Wei,Xie, Jian-Wei,Dai, Bin
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p. 893 - 896
(2013/09/24)
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- Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet-Spengler reaction
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An efficient tandem approach for the selective synthesis of 4,5-dihydroimidazo[1,5-a]quinoxalines 6a-g and imidazo[1,5-a]quinoxalines 7a-h by the reaction of 2-imidazolyl anilines 4a-c with aryl aldehydes 5a-k under mild reaction conditions is described.
- Verma, Akhilesh Kumar,Jha, Rajeev Ranjan,Kasi Sankar,Singh, Raj Pal
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p. 5984 - 5990
(2013/10/22)
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- Ligand effects on the hydrogenation of biomass-inspired substrates with bifunctional Ru, Ir, and Rh complexes
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We herein report on the application and structural investigation of a new set of complexes that contain bidentate N-heterocyclic carbenes (NHCs) and primary amine moieties of the type [M(arene)Cl(L)] [M=Ru, Ir, or Rh; arene=p-cymene or pentamethylcyclopentadienyl; L=1-(2-aminophenyl)-3-(n-alkyl) imidazol-2-ylidine]. These complexes were tested and compared in the hydrogenation of acetophenone with hydrogen. Structural variations in the chelate ring size of the heteroditopic ligand revealed that smaller chelate ring sizes in combination with ring conjugation in the ligand are beneficial for the activity of this type of catalyst, favoring an inner-sphere coordination pathway. Additionally, increasing the steric bulk of the alkyl substituent on the NHC aided the reaction, showing almost no induction period and formation of a more active catalyst for the n-butyl complex relative to complexes with smaller Me and Et substituents. As is common in hydrogenation reactions, the activity of the complexes decreases in the order Ru>Ir>Rh. The application of [Ru(p-cym)Cl(L)]PF6, which outperforms its reported analogues, has been successfully extended to the hydrogenation of more challenging biomass-inspired substrates. Adding value to biomass: The influence of structural variations of N-heterocyclic carbene-amine motif in half-sandwich Ru, Ir, and Rh complexes on the hydrogenation of biomass-inspired substrates is reported. Through this study insight is gained for the future rational design of hydrogenation catalysts for the conversion of biomass into useful/added-value compounds. Copyright
- Jansen, Eveline,Jongbloed, Linda S.,Tromp, Dorette S.,Lutz, Martin,De Bruin, Bas,Elsevier, Cornelis J.
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p. 1737 - 1744
(2013/10/21)
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- Copper-catalyzed aerobic oxidative intramolecular C-H amination leading to imidazobenzimidazole derivatives
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A highly efficient copper-catalyzed aerobic oxidative intramolecular C-H amination has been developed using substituted 2-(1H-imidazol-1-yl)-N- alkylbenzenamines as the starting materials, and the corresponding imidazobenzimidazole derivatives were obtain
- Wang, Xiaoqiang,Jin, Yunhe,Zhao, Yufen,Zhu, Lin,Fu, Hua
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p. 452 - 455
(2012/02/16)
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- Variable coordination of amine functionalised N-heterocyclic carbene ligands to Ru, Rh and Ir: C-H and N-H activation and catalytic transfer hydrogenation
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Chelating amine and amido complexes of late transition metals are highly valuable bifunctional catalysts in organic synthesis, but complexes of bidentate amine-NHC and amido-NHC ligands are scarce. Hence, we report the reactions of a secondary-amine funct
- Cross, Warren B.,Daly, Christopher G.,Boutadla, Youcef,Singh, Kuldip
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experimental part
p. 9722 - 9730
(2011/12/13)
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- Lewis acid-catalyzed selective synthesis of diversely substituted indolo-and pyrrolo[1,2-a]quinoxalines and quinoxalinones by modified pictet-spengler reaction
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An efficient tandem process for the selective synthesis of 1,2-annulated α-fused quinoxalines using benzotriazole methodology by a modified Pictet-Spengler reaction is described. The approach involves the reaction of arylamines 4 with aromatic aldehydes 5 to furnish 6-endo-dig-cyclized products. Dihydroquinoxalines 6 were selectively obtained by using AlCl3 in tetrahydrofuran (THF) at room temperature for two hours. However, after ten hours, quinoxalines 7 were obtained exclusively in excellent yields. A series of biologically important fluoro-and piperazenyl-substituted quinoxalines were also synthesized. This developed methodology also provides access to a novel tandem synthesis of quinoxalinones 9.
- Verma, Akhilesh K.,Jha, Rajeev R.,Sankar, V. Kasi,Aggarwal, Trapti,Singh, Rajendra P.,Chandra, Ramesh
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p. 6998 - 7010
(2012/01/06)
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- EFFICIENT LIGAND-MEDIATED ULLMANN COUPLING OF ANILINES AND AZOLES
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The present invention provides of method of preparing phenyl-substituted azoles. This method uses an efficient ligand-accelerated Ullmann coupling reaction of anilines with azoles. The coupling products are useful for preparing factor Xa inhibitors.
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- Efficient ligand-mediated ullmann coupling of anilnies and azoles
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The present invention provides of method of preparing phenyl-substituted azoles. This method uses an efficient ligand-accelerated Ullmann coupling reaction of anilines with azoles. The coupling products are useful for preparing factor Xa inhibitors.
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- Imidazoquinoxaline protein tyrosine kinase inhibitors
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Novel imidazoquinoxalines and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic disorders.
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- Gas-phase pyrolysis of 1-(2-azidophenyl)imidazole
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Flash vacuum pyrolysis (FVP) of the azide 4 leads to imidazo[1,2-a]benzimidazole 8 exclusively, via highly regioselective insertion of the triplet nitrene intermediate 5 into the 2-CH bond of the imidazole ring. The X-ray crystal structure and NMR spectro
- Blake, Alexander J.,Clark, Bernard A. J.,McNab, Hamish,Sommerville, Craig C.
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p. 1605 - 1608
(2007/10/03)
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- Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity. Synthesis and cardiovascular effects of a series of imidazo[1,2-a]quinoxalinones and imidazo[1,5-a]quinoxalinones and their aza analogues
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A series of novel imidazoquinoxalinones and their aza analogues were prepared by the cyclization of o-amino(1H-imidazol-1-yl)aryls and heteroaryls with carbonyldiimidazole. The compounds were screened for inhibition of Type I and Type IV phosphodiesterase
- Davey,Erhardt,Cantor,Greenberg,Ingebretsen,Wiggins
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p. 2671 - 2677
(2007/10/02)
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