- Tandem reorganisation of 1,3-dipolar cycloadducts of C-(4-oxo- 4H[1]benzopyran-3-yl)-N-phenylnitrone and allenic esters, leading to novel functionalized benzo[b]indolizines
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C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenylnitrone (1) adds regiospecifically to the C2-C3 π-bond of allenic esters (2a-c) and the 1,3-dipolar cycloadducts formed undergo a series of intramolecular reorganisations including an intramolecular (4+2) cycloaddition, in situ, to yield novel functionalized benzo[b]indolizines (3a-c) in good yields.
- Ishar,Kumar, Kamal
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- Exploring of indole derivatives for ESIPT emission: A new ESIPT-based fluorescence skeleton and TD-DFT calculations
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Appropriate synthesis methods gave six different indole derivatives substituted at the C-2 or C-3 position. ESIPT emission capacities of these derivatives were investigated. It was concluded that the indole derivative containing the 1,2-dicarbonyl group at the C-2 position has ESIPT emission. Although adding water to the DMSO solution of the ESIPT-based molecule (9:1) resulted in ESIPT quenching, steady-state measurements in MeOH did not occur ESIPT quenching. TD-DFT calculation for uncovering the ESIPT mechanism emerged that the ESIPT mechanism occurred as a barrierless process. The X-ray analysis and DFT conformational analysis revealed that NH and CO groups involving proton transfer mechanisms are in the cis position. A mono-exponential decay was observed in DMSO and MeOH solutions, in which lifetimes were measured as 6.1 and 5.5 ns, respectively. pH studies revealed that acidic and basic solutions of molecule 7 did not influence ESIPT emission.
- Ayd?n, Hatice Gülten,Ekmekci, Zeynep,Kaya, Serdal,Keskin, Selbi,Menges, Nurettin
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- Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16
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The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2α2β2 and its monomeric subunits CK2α and CK2β. A series of analogues of W16 ((3aR,4S,10S,10aS)-4-{[(S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydrofuro[3,4-b]carbazole-1,3(3aH)-dione ((+)-3 a)) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide (9) and N-methylimide (10) substructure. The enantiomer (?)-3 a (Ki=4.9 μM) of the lead compound (+)-3 a (Ki=31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (?)-3 a did not show an increased enzyme inhibition of the CK2α2β2 holoenzyme, the CK2α subunit or the mutated CK2α′ C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (?)-9 a (Ki=3.6 μM) and the N-methylimide (+)-10 a (Ki=2.8 μM) represent the most promising inhibitors of the CK2α/CK2β interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (±)-12, with a carboxy moiety in the 4-position, displays the highest CK2α/CK2β interaction inhibition (Ki=1.8 μM) of this series of compounds.
- Borgert, Sebastian,Daniliuc, Constantin G.,Ensan, Deeba,Jose, Joachim,Kr?ger, Lukas,Lauwers, Miriam,Nienberg, Christian,Pietsch, Markus,Steinkrüger, Michaela,Wünsch, Bernhard
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supporting information
p. 871 - 881
(2020/05/06)
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- Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio- and Stereocontrolled Cooperative Catalysis
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We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (?)-akuammicine and (?)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.
- Fyfe, James W. B.,Hutchings-Goetz, Luke S.,Snaddon, Thomas N.,Yang, Chao
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supporting information
p. 17556 - 17564
(2020/08/14)
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- Photocatalytic Alkylation of Pyrroles and Indoles with α-Diazo Esters
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This article describes the photoalkylation of electron-rich aromatic compounds with diazo esters. C-2-alkylated indoles and pyrroles are obtained with good yields even though the photocatalyst loading is as low as 0.075 mol %. For EWG-substituted substrates, the addition of a catalytic amount of N,N-dimethyl-4-methoxyaniline is required. Both EWG-EWG- and EWG-EDG-substituted diazo esters are suitable as alkylating agents. The reaction selectivity and mechanistic experiments suggest that carbenes/carbenoid intermediates are not involved in the reaction pathway.
- Ciszewski, Lukasz W.,Durka, Jakub,Gryko, Dorota
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supporting information
p. 7028 - 7032
(2019/09/12)
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- Involving Single-Atom Silver(0) in Selective Dehalogenation by AgF under Visible-Light Irradiation
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The dehalogenation-arylation and the hydrodehalogenation of various types of organic halides are selectively realized using AgF and visible light without any organic additives under mild conditions. Single-atom silver(0) (denoted as SAAg) serves as the catalytically active center, and the TOF of SAAg reaches 6000 h-1. This elusive activity of Ag is beyond that expected from its ionic, nano, or bulk forms.
- Wu, Wenli,Cui, Enxin,Zhang, Yun,Zhang, Chen,Zhu, Feng,Tung, Chen-Ho,Wang, Yifeng
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p. 6335 - 6341
(2019/07/04)
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- Visible light/Ir(III) photocatalytic initiation of xanthate-based radical-chain reactions: Xanthate group transfer and oxidative addition to aromatic systems
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A photocatalyzed redox generation of radicals from O-ethyl xanthates to generate electrophilic radicals under photoredox catalysis, using Ir(ppy)3 and blue LEDs irradiation is described. The protocol can be used in classical xanthate-based inter- and intra-molecular group transfer reactions and oxidative radical addition to several heteroaromatic systems. The process does not require high temperature and reactions are cleaner compared with the traditional peroxide initiation. In the oxidative addition to aromatic systems, the oxidation process is part of the catalytic cycle and does not require a stoichiometric oxidant such as DLP which is particularly difficult to separate from the product.
- López-Mendoza, Pedro,Díaz, John E.,Loaiza, Alix E.,Miranda, Luis D.
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supporting information
p. 5494 - 5502
(2018/05/16)
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- Versatile synthesis of functionalized β- And γ-carbolines: Via Pd-catalyzed C-H addition to nitriles/cyclization sequences
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The first example of versatile synthesis of functionalized β-carbolines and γ-carbolines via redox-free Pd-catalyzed C-H addition of indole to nitrile/cyclization sequences is reported. A wide range of functionalized β-carbolines and γ-carbolines can be prepared from readily accessible indoles and nitriles in good to excellent yields under the optimal conditions.
- Wang, Ting-Ting,Zhang, Di,Liao, Wei-Wei
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supporting information
p. 2048 - 2051
(2018/03/01)
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- Environmentally Friendly Synthesis of Indoline Derivatives using Flow-Chemistry Techniques
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Flow chemistry proved to be a valuable technique to improve the synthesis route to melanin-concentrating hormone receptor 1 (MCHr1) antagonists with the 1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole scaffold. A one-step route for the heterogeneous catalytic hydrogenation of ethyl 4-(2-nitrophenyl)-3-oxobutanoate for the synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl)acetate was developed, and the use of common reducing chemicals was avoided. N-Alkylation of the indoline nitrogen atom was also optimized by using a purpose-built flow reactor and by design of experiment (DoE). Applying an optimal set of parameters allowed us to decrease the amount of carcinogenic 1,2-dibromoethane used by a factor of 10. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 d); therefore, the productivity (space-time yield) of the flow-reactor system was proven to be ca. 200 times higher than that of the batch process.
- ?rkényi, Róbert,Beke, Gyula,Riethmüller, Eszter,Szakács, Zoltán,Kóti, János,Faigl, Ferenc,éles, János,Greiner, István
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supporting information
p. 6525 - 6532
(2017/12/02)
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- Palladium-Catalyzed Dearomatizing Difunctionalization of Indoles and Benzofurans
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A palladium-catalyzed dearomatizing difunctionalization of N-Boc-indoles and benzofurans to give tricyclic indolines and 2,3-dihydrobenzofurans with a fully substituted carbon center is described. Product formation occurs under mild conditions at room temperature with commercially available aryl boronic acids and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a mild oxidant in good yields. 2-Carboxyalkyl-substituted indoles and benzofurans react under Pd-catalysis with aryl boronic acids and TEMPO through dearomatizing arylation/cyclization to the corresponding indolines and dihydrobenzofurans containing a lactone moiety bearing a fully substituted carbon center.
- Ramella, Vincenzo,He, Zhiheng,Daniliuc, Constantin G.,Studer, Armido
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supporting information
p. 2268 - 2273
(2016/05/19)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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Paragraph 1723
(2015/09/22)
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- Facile synthesis of indolines by a tandem nitro-reduction Aza Michael addition reaction
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A diverse array of substrates are conveniently prepared by coupling diazonium salts to ethyl vinyl ether and subjecting the resultant aldehyde intermediate to a Wittig reaction to provide α,β-unsaturated esters with only one purification step. The cyclisation of 4-aryl-but-2-enoates is carried out in the presence of stoichiometric amounts of SnCl 22H2O and thus this one-pot strategy also permitted the expeditious synthesis of indolines in good yield. The Japan Institute of Heterocyclic Chemistry.
- Ventura, Wellington Martins,Souza De Assis, Luiz Guilherme,Taylor, Jason Guy
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p. 2023 - 2029
(2013/10/22)
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- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- An unusual route to a quinoline 1-oxide via intramolecular addition of an enolate to an aromatic nitro group
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A mixture of ethyl 4-(2-nitrophenyl)butenoates undergoes an unusual intramolecular cyclisation in the presence of a catalytic amount of potassium tert-butoxide. 2011 · Copyright by Walter de Gruyter.
- Moreira, Nayara Da Rocha F.,De Oliveira, Tania T.,Nagem, Tanus J.,Taylor, Jason G.
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p. 203 - 205
(2012/03/12)
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- Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway
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Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addit
- Kapur, Ashish,Kumar, Kamal,Singh, Lakhwinder,Singh, Parminder,Elango, Munusamy,Subramanian, Venkatesan,Gupta, Vivek,Kanwal, Priyanka,Ishar, Mohan Paul S.
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experimental part
p. 4593 - 4603
(2009/10/23)
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- Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines
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A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.
- Maruyama, Jun,Yamashita, Hiromichi,Watanabe, Takeshi,Arai, Shigeru,Nishida, Atsushi
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experimental part
p. 1327 - 1335
(2009/04/10)
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- Diastereodivergence and appendage diversity in the multicomponent synthesis of aryl-pyrrolo-tetrahydrocarbazoles
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A one-pot approach using a subsequent Cu(II)/Cu(I) catalysis and a highly diastereodivergent three-component reaction allow an easy access to various aryl-pyrrolo-tetrahydrocarbazoles with the control of up to four variable fragments and two different diastereoselectivities.
- Royer, Daniel,Wong, Yung-Sing,Plé, Sophie,Chiaroni, Angèle,Diker, Khalid,Lévy, Jean
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p. 9607 - 9618
(2008/12/22)
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- Modulators of ATP-binding cassette transporters
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Compounds of the present invention and pharmaceutically acceptable compositions thereof, are useful as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”). The present invention also relates to methods of treating ABC transporter mediated diseases using compounds of the present invention.
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Page/Page column 133
(2008/06/13)
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- Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a′]diindole analogues as melatonin receptor ligands
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A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate 2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5- b]diindole 3a, was revised based on the 13C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4- a′]diindole 4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12-16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT1 and MT2 receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT2 selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT1 (Ki = 49 nM) than for MT2 (Ki = 246 nM) receptor. This journal is The Royal Society of Chemistry.
- Attia, Mohamed I.,Gueclue, Deniz,Hertlein, Barbara,Julius, Justin,Witt-Enderby, Paula A.,Zlotos, Darius P.
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p. 2129 - 2137
(2008/03/14)
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- Et3B-Mediated radical alkylation of pyrroles and indoles
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An efficient Et3B-mediated oxidative radical substitution of substituted pyrroles and indoles using xanthate based radical chemistry in the presence of iron(II) sulfate is described. Unsubstituted indole gave only low yield or failed in the process. 2-Cyanofuran and 2-benzoylthiophene did not afford the corresponding alkylated products under these conditions.
- Guerrero, Miguel A.,Miranda, Luis D.
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p. 2517 - 2520
(2007/10/03)
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- PYRAZOLO[3,4-c]QUINOLINES, PYRAZOLO[3,4-c]NAPHTHYRIDINES, ANALOGS THEREOF, AND METHODS
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Pyrazolo[3,4-c]quinolines, pyrazolo[4,5-c]naphthyridines, and analogs thereof, eg., 6,7,8,9-tetrahydro pyrazolo[3,4-c]quinolines, and, pharmaceutical compositions containing the compounds, intermediates, methods of making these compounds, and methods of use of these compounds as immunomodulators, for inhibiting cytokine biosynthesis in animals and in the therapeutic or prophylactic treatment of diseases by inhibiting cytokine biosynthesis are disclosed.
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Page/Page column 65
(2008/06/13)
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- Efficient, intermolecular, oxidative radical alkylation of heteroaromatic systems under "tin-free" conditions
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Novel and efficient radical alkylation of several heterocyclic systems including pyrroles, indoles, furan and thiophenes is described using xanthate based radical chemistry. The present methodology could be used to provide rapid access to various nonstero
- Osornio, Yazmin M.,Cruz-Almanza, Raymundo,Jimenez-Montano, Vicente,Miranda, Luis D.
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p. 2316 - 2317
(2007/10/03)
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- Novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole compounds
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Certain 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indoles are 5-HT ligands and are useful for treating diseases wherein modulation of 5-HT activity is desired.
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- Radical aromatic substitution via atom-transfer addition
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New methodology for radical aromatic substitution has been developed involving the addition of electron-deficient radicals to unprotected pyrroles and indole. This non-oxidative process is presumed to be occurring via atom- transfer addition of suitable organoiodides and bromides with subsequent non- radical elimination of HI or HBr, respectively. The process also occurs under stannane-free conditions.
- Byers, Jeffrey H.,Campbell, John E.,Knapp, Faith H.,Thissell, Jameson G.
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p. 2677 - 2680
(2007/10/03)
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- Benzocarbapenems from indoles
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The 8,8a-dihydroazeto[1,2-a]indol-2(1H)-ones (benzocarbapenems) 1a, 16, 17, 22, 27, 35 and 36 have been prepared by cyclodehydration of the corresponding β-amino acids, these amino acids being obtained by reduction of the analogous 2-substituted or 2,7-disubstituted indoles. The hydroxy group of compound 36 is designed to mimic the carboxylic acid function of the carbapenems on the basis of molecular modelling. The azetidinones 1a and 27, which are unsubstituted at the methylene group of the four-membered ring, are unstable and highly susceptible to ring opening by nucleophiles but the compounds 22,35 and 36 with two methyl substituents at this position are much more stable. The carbonyl stretching frequency in the IR is close to 1770 cm-1 for all the azetidinones except the phenol 36 for which the absorption is at 1735 cm-1. An X-ray crystal structure of compound 36 is reported.
- Coulton, Steven,Gilchrist, Thomas L.,Graham, Keith
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p. 1193 - 1202
(2007/10/03)
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- SELECTIVITY IN THE REACTIONS OF ELECTRON-RICH PENTATOMIC HETEROAROMATIC COMPOUNDS WITH CARBON-CENTRED FREE RADICALS
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The relative reactives of pyrrole, N-methylpyrrole, furan and thiophene with electrophilic carbon-centred free radicals .CH2CN, .CH2CO2Et and .CH(CO2Et)2 have been determined.The results have indicated a relatively low intermolecular selectivity, with a reactivity order N-methylpyrrole > pyrrole ca. furan > thiophene.The intramolecular selectivities (relative reactivity of the α and β positions) of these reactions, as well as that of indole with .CH2CN and .CH2CO2Et have also been determined.The α/β ratio is very high (> 50) with N-methylpyrrole, pyrrole, furan and thiophene, but becomes lower (between 6 and 12) with indole.These results can be rationalized by suggesting that in the homolytic substitutions of electrophilic carbon radicals with electron-rich pentatomic heteroaromatics, the SOMO of the radical probably interacts with both the HOMO and the LUMO of the substrate, and not only with the HOMO as expected.
- Baciocchi, Enrico,Manna, Livia,Muraglia, Ester
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p. 249 - 252
(2007/10/02)
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- Diels-Alder Reactivity of Pyranoindol-3-ones, Indole 2,3-Quinodimethane Analogues
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The pyranoindol-3-ones (7) are stable indole-2,3-quinodimethane type dienes, which undergo Diels-Alder reaction with alkynes to give, after loss of carbon dioxide, carbazoles.The reactivity of the diene is increased by the presence of the electron-withdrawing t-butoxycarbonyl group on the indole nitrogen.The pyranoindolones (7) are less reactive, and exhibit the opposite regiochemistry in their Diels-Alder reactions than the isomeric pyranoindol-3-ones (1).Factors which affect the regiochemistry of the Diels-Alder reaction are discussed.
- Moody, Christopher J.,Rahimtoola, Kulsum F.
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p. 673 - 679
(2007/10/02)
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- Mixed Copper, Zinc 2-Amino Benzylic Organometallics as Efficient Reagents for the Synthesis of Heterocycles
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The mixed copper, zinc benzylic organometallics 1a-1c react efficiently with various electrophiles.By the reaction with acylchlorides, highly functionalized 2-substituted indoles are produced.The treatment of 1a with allylic bromides, 3-iodo-cyclohexenone and ethyl propiolate furnishes polyfunctionalized anilines.Several of them could be converted into five or seven-membered heterocycles.
- Chen, Gu Huai,Hoechstetter, Craig,Knochel, Paul
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p. 4795 - 4798
(2007/10/02)
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- HETERO-COPE REARRANGEMENTS - VI; SHORT AND STEREOSELECTIVE SYNTHESIS OF 2-VINYLINDOLES BY A TANDEM-PROCESS
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The initially formed N-phenylnitrone-intermediates are converted by a tandem-reaction (cycloaddition, Cope rearrangement, retro-Michael addition, and indolization) to 2-vinylindoles 7.Thus these indoles can be synthesized simply and stereoselectively in a one-pot reaction from N-phenylhydroxylamine 4, aldehydes 5, and electrondeficient allenes 6.
- Wilkens, Jochen,Kuehling, Andrea,Blechert, Siegfried
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p. 3237 - 3246
(2007/10/02)
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- New Syntheses of 2-Acylbenzofurans, 2-Acylindoles, 2-Indolylcarboxylates, and 2-Quinolones by Intramolecular Wittig Reaction
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The title compounds are obtained by intramolecular Wittiig reaction of 2-(α-ketoacyloxy)-, 2-(α-ketoacylamino)-, or 2-benzyltriphenylphosphonium salts, respectively.
- Capuano, Lilly,Ahlhelm, Alfred,Hartmann, Herbert
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p. 2069 - 2074
(2007/10/02)
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