- Increased antibacterial properties of indoline-derived phenolic Mannich bases
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The search for antibacterial agents for the combat of nosocomial infections is a timely problem, as antibiotic-resistant bacteria continue to thrive. The effect of indoline substituents on the antibacterial properties of aminoalkylphenols was studied, leading to the development of a library of compounds with minimum inhibitory concentrations (MICs) as low as 1.18 μM. Two novel aminoalkylphenols were identified as particularly promising, after MIC and minimum bactericidal concentrations (MBC) determination against a panel of reference strain Gram-positive bacteria, and further confirmed against 40 clinical isolates (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes). The same two aminoalkylphenols displayed low toxicity against two in vivo models (Artemia salina brine shrimp and Saccharomyces cerevisiae). The in vitro cytotoxicity evaluation (on human keratinocytes and human embryonic lung fibroblast cell lines) of the same compounds was also carried out. They demonstrated a particularly toxic effect on the fibroblast cell lines, with IC50 in the 1.7–5.1 μM range, thus narrowing their clinical use. The desired increase in the antibacterial properties of the aminoalkylphenols, particularly indoline-derived phenolic Mannich bases, was reached by introducing an additional nitro group in the indolinyl substituent or by the replacement of a methyl by a bioisosteric trifluoromethyl substituent in the benzyl group introduced through use of boronic acids in the Petasis borono-Mannich reaction. Notably, the introduction of an additional nitro moiety did not confer added toxicity to the aminoalkylphenols.
- Rimpil?inen, Tatu,Nunes, Alexandra,Calado, Rita,Fernandes, Ana S.,Andrade, Joana,Ntungwe, Epole,Spengler, Gabriella,Szemerédi, Nikoletta,Rodrigues, Jo?o,Gomes, Jo?o Paulo,Rijo, Patricia,Candeias, Nuno R.
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- Dual-Active-Sites Design of Co@C Catalysts for Ultrahigh Selective Hydrogenation of N-Heteroarenes
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The dual-active-sites Co@C catalyst provides a general powerful strategy to break the limitation of scaling relation on traditional metal surfaces and thus affords unprecedentedly selective hydrogenation of various N-heteroarenes as well as high activity and stability. A porous carbon shell not only allows H2 diffusion to Co sites for activation but also blocks accessibility of N-heteroarenes, and the hydrogenation of N-heteroarenes is achieved on carbon by the spilled hydrogen from Co sites. In addition, the presence of surface/subsurface carbon at the Co sites shows high anti-sulfur poisoning and anti-oxidant capability. Ideal heterogeneous metal hydrogenation catalysts are featured by simultaneously high activity, selectivity, and stability. Herein, we report a general yet powerful strategy to design and fabricate dual-active-sites Co@C core-shell nanoparticle for boosting selective hydrogenation of various N-heteroarenes. It can break the limitation of scaling relation on traditional metal surfaces, and thus afford unprecedentedly high selectivity, activity, and stability. Combining kinetics analysis and DFT calculations with multiple techniques directly unveil that the critical porous carbon shell with a pore size of 0.53 nm not only allows H2 diffusion to Co sites for activation and blocks accessibility of N-heteroarenes but also catalyzes hydrogenation of N-heteroarenes via hydrogen spillover from Co sites. In addition, the presence of surface/subsurface carbon at the Co sites shows high anti-sulfur poisoning and anti-oxidant capability. This work is valuable for guiding the design and manipulation of cost-effective and robust hydrogenation catalysts. Our research can provide an environmentally friendly approach to afford unprecedentedly selective N-heteroarenes hydrogenation, which will greatly reduce the resource and energy consumption and decrease the amount of waste discharge and water pollution. Therefore, these results could help in achieving the “Clean water and sanitation” goal in the 10 UN Sustainable Development Goals. Meanwhile, the products of N-heteroarenes hydrogenation are the core structural motifs in both fine and bulk chemicals, which will make our life more beautiful. Thus, our research also benefits the “Good health and well-being” goal.
- Zhang, Sai,Gan, Jie,Xia, Zhaoming,Chen, Xiao,Zou, Yong,Duan, Xuezhi,Qu, Yongquan
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supporting information
p. 2994 - 3006
(2020/09/04)
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- Re-Catalyzed Annulations of Weakly Coordinating N-Carbamoyl Indoles/Indolines with Alkynes via C?H/C?N Bond Cleavage
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Described herein are rhenium-catalyzed [3+2] annulations of N-carbamoyl indoles with alkynes via C?H/C?N bond cleavage, which provide rapid access to fused-ring pyrroloindolone derivatives. For the first time, the weakly coordinating O-directing group was successfully employed in rhenium-catalyzed C?H activation reactions, enabled by the unique catalytic trio of Re2(CO)10, Me2Zn and ZnCl2. Mechanistic studies revealed that aminozinc species plays an important role in the reaction. Based on the mechanistic understanding, a more powerful catalytic trio of Re2(CO)10, [MeZnNPh2]2 and Zn(OTf)2 was devised and applied successfully in the [4+2] annulations of indolines and alkynes affording pyrroloquinolinone derivatives.
- Yang, Yunhui,Wang, Congyang
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supporting information
p. 8245 - 8248
(2019/05/28)
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- Design, synthesis and biological evaluation of novel 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole triazole derivatives as potent TRPV1 antagonists
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Reported herein is the design, synthesis, and pharmacologic evaluation of a class of TRPV1 antagonists constructed on 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as A-region and triazole as B-region. The SAR analysis indicated that 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed better potency compared to the corresponding dihydroindole analogues. Optimization of this design led to the eventual identification of 2-((1-(2-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (6g), a potent TRPV1 antagonist. In vitro, using cells expressing recombinant human TRPV1 channels, 6g displayed potent antagonism activated by capsaicin (IC50 = 0.075 μM) and only partially blocked acid activation of TRPV1. In vivo, 6g exhibited good efficacy in capsaicin-induced and heat-induced pain models and had almost no hyperthermia side-effect. Furthermore, pharmacokinetic studies revealed that compound 6g had a superior oral exposure after oral administration in rats. To understand its binding interactions with the receptor, the docking study of 6g was performed in rTRPV1 model and showed an excellent fit to the binding site. On the basis of its superior profiles, 6g could be considered as the lead candidate for the further development of antinociceptive drugs.
- Li, Jinyu,Nie, Cunbin,Qiao, Yue,Hu, Jing,Li, Qifei,Wang, Qiang,Pu, Xiaohui,Yan, Lin,Qian, Hai
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p. 433 - 445
(2019/06/18)
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- Hydrophobic Metal Halide Perovskites for Visible-Light Photoredox C?C Bond Cleavage and Dehydrogenation Catalysis
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Two-dimensional lead and tin halide perovskites were prepared by intercalating the long alkyl group 1-hexadecylammonium (HDA) between the inorganic layers. We observed visible-light absorption, narrow-band photoluminescence, and nanosecond photoexcited lifetimes in these perovskites. Owing to their hydrophobicity and stability even in humid air, we applied these perovskites in the decarboxylation and dehydrogenation of indoline-2-carboxylic acids. (HDA)2PbI4 or (HDA)2SnI4 were investigated as photoredox catalysts for these reactions, and quantitative conversion and high yields were observed with the former.
- Hong, Zonghan,Chong, Wee Kiang,Ng, Andrew Yun Ru,Li, Mingjie,Ganguly, Rakesh,Sum, Tze Chien,Soo, Han Sen
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p. 3456 - 3460
(2019/02/13)
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- Sustainable Radical Cascades to Synthesize Difluoroalkylated Pyrrolo[1,2-a]indoles
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We disclose herein a photocatalytic difluoroalkylation and cyclization cascade reaction of N-(but-2-enoyl)indoles with broad substrate scopes in up to 90% isolated yield. This method provides sustainable and efficient access to synthesize difluoroalkylated pyrrolo[1,2-a]indoles with a quaternary carbon center under mild conditions.
- Huang, Honggui,Yu, Menglin,Su, Xiaolong,Guo, Peng,Zhao, Jia,Zhou, Jiabing,Li, Yi
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p. 2425 - 2437
(2018/02/23)
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- ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ALLOSTERIC MODULATORS, THEIR DERIVATIVES AND USES THEREOF
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The present application is related to compounds represented by Formula I, which are novel positive allosteric modulators of α7 nAChRs. The application also discloses the treatment of disorders that are responsive to enhancement of acetylcholine action on α7 nAChRs in a mammal by administering an effective amount of a compound of Formula I.
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Paragraph 00126; 00127; 00128
(2016/09/26)
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- Rh(III)-Catalyzed C7-Thiolation and Selenation of Indolines
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The rhodium(III)-catalyzed intermolecular C7-thiolation and selenation of indolines with disulfides and diselenides were developed. This protocol relies on the use of a removable pyrimidyl directing group to access valuable C-7 functionalized indoline scaffolds with ample substrate scope and broad functional group tolerance.
- Xie, Wucheng,Li, Bin,Wang, Baiquan
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p. 396 - 403
(2016/01/25)
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- Indoline derivative and application of indoline derivative in medicine
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The invention discloses an indoline derivative, or stereisomer, tautomer, nitric oxide, solvate, metabolite, pharmacy-acceptable salt or other prodrugs of the indoline derivative. The indoline derivative is used for resisting 5-HT6 receptors. The invention further relates to a method for preparing the compound and application of the compound in treating or preventing diseases related to 5-HT6 receptors.
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Paragraph 0194; 0195; 0196; 0197; 0277; 0278; 0279; 0280
(2016/10/08)
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- Palladium-catalyzed C-7 alkenylation of indolines using molecular oxygen as the sole oxidant
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A general and efficient method for the intermolecular direct C-7-selective C-H alkenylation of indolines using palladium(ii) as the catalyst and molecular oxygen as the sole oxidant has been developed. The reaction showed complete regio- and stereoselectivity. All products were E-isomers at the C-7 position, and no Z-isomers or other position substituted products could be detected. The approach also presented an efficient route for the synthesis of C-7 alkenylated indoles.
- Yang, Dong,Mao, Shuai,Gao, Ya-Ru,Guo, Dong-Dong,Guo, Shi-Huan,Li, Bin,Wang, Yong-Qiang
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p. 23727 - 23736
(2015/04/14)
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- Versatile (Pentamethylcyclopentadienyl)rhodium-2,2′-Bipyridine (Cp?Rh-bpy) Catalyst for Transfer Hydrogenation of N-Heterocycles in Water
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An investigation employing the catalytic system consisting of (pentamethylcyclopentadienyl)rhodium dichloride dimer [Cp?RhCl2]2 and 2,2′-bipyridine (bpy) for transfer hydrogenation of a variety of quinoxalines, quinoxalinones, quinolines and indoles under aqueous conditions with formate as the hydrogen source is reported. This approach provides various tetrahydroquinoxalines, dihydroquinoxalinones, tetrahydroquinolines and indolines in good to excellent yields. The activity of the catalyst towards quinoxalines and quinoxalinones is excellent, with a substrate to catalyst ratio (S/C) of 10000 being feasible. The choice of ligand is critical to the catalysis, and the aqueous phase reduction is shown to be highly pH-dependent, with acidic pH values needed for optimal reduction. The catalyst is easy to access, and the reaction is operationally simple without requiring an inert atmosphere.
- Zhang, Lingjuan,Qiu, Ruiying,Xue, Xiao,Pan, Yixiao,Xu, Conghui,Li, Huanrong,Xu, Lijin
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p. 3529 - 3537
(2016/01/25)
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- ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR ALLOSTERIC MODULATORS, THEIR DERIVATIVES AND USES THEREOF
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The present application is related to compounds represented by Formula I, which are novel positive allosteric modulators of al nAChRs. The application also discloses the treatment of disorders that are responsive to enhancement of acetylcholine action on al nAChRs in a mammal by administering an effective amount of a compound of Formula I.
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Paragraph 00108
(2013/12/03)
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- Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists
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A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.
- Wu, Lingyun,Lu, Kai,Packiarajan, Mathivanan,Jubian, Vrej,Chandrasena, Gamini,Wolinsky, Toni C.,Walker, Mary W.
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scheme or table
p. 2167 - 2171
(2012/04/18)
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- Heterogeneous catalytic hydrogenation of unprotected indoles in water: A green solution to a long-standing challenge
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An environmentally benign procedure for the hydrogenation of unprotected indoles is described. The hydrogenation reaction is catalyzed by Pt/C and activated by p-toluenesulfonic acid in water as a solvent. The efficacy of the method is illustrated by the hydrogenation of a variety of substituted indoles to their corresponding indolines which were obtained in excellent yields.
- Kulkarni, Aditya,Zhou, Weihong,Toeroek, Bela
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supporting information; experimental part
p. 5124 - 5127
(2011/12/05)
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- Discovery of novel N -β- d -Xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes
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A novel series of N-linked β-d-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl) -1-(β-d-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC50 value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
- Yao, Chun-Hsu,Song, Jen-Shin,Chen, Chiung-Tong,Yeh, Teng-Kuang,Hung, Ming-Shiu,Chang, Chih-Chun,Liu, Yu-Wei,Yuan, Mao-Chia,Hsieh, Chieh-Jui,Huang, Chung-Yu,Wang, Min-Hsien,Chiu, Ching-Hui,Hsieh, Tsung-Chih,Wu, Szu-Huei,Hsiao, Wen-Chi,Chu, Kuang-Feng,Tsai, Chi-Hui,Chao, Yu-Sheng,Lee, Jinq-Chyi
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experimental part
p. 166 - 178
(2011/02/28)
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- Fascaplysin-inspired diindolyls as selective inhibitors of CDK4/cyclin D1
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We present the design, synthesis and biological activity of a new series of substituted 3-(2-(1H-indol-1-yl)ethyl)-1H-indoles and 1,2-di(1H-indol-1-yl)alkanes as selective inhibitors of CDK4/cyclin D1. The compounds were designed to explore the relationship between the connection mode of the indolyl moieties and their CDK inhibitory activities. We found all the above-mentioned designed compounds to be selective inhibitors of CDK4/cyclin D1 compared to the closely related CDK2/cyclin A, with IC50 for the best compounds 10m and 13a being 39 and 37 μm, respectively.
- Aubry, Carine,Wilson, A. James,Emmerson, Daniel,Murphy, Emma,Chan, Yu Yam,Dickens, Michael P.,Garcia, Marcos D.,Jenkins, Paul R.,Mahale, Sachin,Chaudhuri, Bhabatosh
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experimental part
p. 6073 - 6084
(2009/12/24)
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- 1H-Indole-Pyridinecarboxamide and 1H-Indole-Piperidinecarboxamide Compounds
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Compounds of formula (I): wherein: A represents a divalent radical: wherein: Z represents an oxygen atom or a sulphur atom,R6 represents a hydrogen atom, an alkyl, alkenyl, arylalkyl or polyhaloalkyl group or a substituted, linear or branched alkyl chain, represents a single bond or a double bond,R1, R2, R3 and R4 represent a hydrogen or halogen atom,an alkyl, alkoxy, hydroxy, cyano, nitro, polyhaloalkyl or optionally substituted amino group, or a linear or branched alkyl chain substituted by one or more groups,R5 represents a hydrogen atom or an alkyl, aminoalkyl or hydroxyalkyl group,X and Y represent a hydrogen atom or an alkyl group,Ra, Rb, Rc and Rd represent a hydrogen or halogen atom, an alkyl, hydroxy, alkoxy, cyano, nitro, polyhaloalkyl, optionally substituted amino group, or a substituted, linear or branched alkyl chain,Re represents a hydrogen atom or an alkyl, arylalkyl or alkenyl group or a substituted, linear or branched alkyl chain, their enantiomers, diastereoisomers, and N-oxides, and also addition salts thereof with a pharmaceutically acceptable acid or base.
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Page/Page column 10
(2009/10/21)
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- The design and synthesis of novel 3-[2-indol-1-yl-ethyl]-1H-indole derivatives as selective inhibitors of CDK4
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We present the design, synthesis and biological activity of novel 3-[2-indol-1-yl-ethyl]-1H-indole selective inhibitors of CDK4.
- Aubry, Carine,Patel, Asma,Mahale, Sachin,Chaudhuri, Bhabatosh,Maréchal, Jean-Didier,Sutcliffe, Michael J.,Jenkins, Paul R.
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p. 1423 - 1425
(2007/10/03)
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- KINASE INHIBITORS
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The present invention provides kinase inhibitors of Formula (I)
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Page/Page column 41
(2010/02/07)
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- Novel and selective 5-HT(2C/2B) receptor antagonists as potential anxiolytic agents: Synthesis, quantitative structure - Activity relationships, and molecular modeling of substituted 1-(3- pyridylcarbamoyl)indolines
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The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB- 206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT(2C/2B) receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor, we have identified a number of compounds which are the most potent and selective 5-HT(2C/2B) receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT(2C) receptor model and our proposed binding mode for this class of ligands within that model.
- Bromidge, Steven M.,Dabbs, Steven,Davies, David T.,Duckworth, D. Malcolm,Forbes, Ian T.,Ham, Peter,Jones, Graham E.,King, Frank D.,Saunders, Damian V.,Starr, Susannah,Thewlis, Kevin M.,Wyman, Paul A.,Blaney, Frank E.,Naylor, Christopher B.,Bailey, Fiona,Blackburn, Thomas P.,Holland, Vicky,Kennett, Guy A.,Riley, Graham J.,Wood, Martyn D.
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p. 1598 - 1612
(2007/10/03)
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- DIRECTED LITHIATION OF 1-(tert-BUTOXYCARBONYL)INDOLINES. A CONVENIENT ROUTE TO 7-SUBSTITUTED INDOLINES
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1-(tert-Butoxycarbonyl)indolines were regioselectively lithiated at 7-position with s-BuLi-TMEDA in ether or THF at -78 deg C.The lithiated species were reacted with a range of electrophiles to give 7-substituted indoline derivatives.
- Iwao, Masatomo,Kuraishi, Tsukasa
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p. 1031 - 1038
(2007/10/02)
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- 5-Chloro-indole preparation
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An improved process for the preparation of 5-chloro-indole comprising reacting indoline in a chlorine-inert organic solvent with an acylating agent of an organic carboxylic acid to obtain the corresponding 1-acyl-indoline, reacting the latter in the presence of water and a basic agent with chlorine to form 5-chloro-1-acyl-indoline, subjecting the latter to saponification to obtain 5-chloro-indoline and reacting the latter in a water-immiscible organic solvent by heating with an aromatic nitrocompound in the presence of a finely powdered ruthenium catalyst to form 5-chloro-indole in excellent yields.
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