- Ketoprofen-induced formation of amino acid photoadducts: Possible explanation for photocontact allergy to ketoprofen
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Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-l-Trp ethyl ester and l-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp-Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
- Karlsson, Isabella,Persson, Elin,Ekebergh, Andreas,M?rtensson, Jerker,B?rje, Anna
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- Cyclization of N-Alkenyl-o-chloroanilides with Organonickel(0) Complexes: Conformational Analysis of 3-Substituted Oxindoles
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3-substituted oxindoles (1)-(6) have been obtained as the main products of the cyclization reaction of N-alkenyl-o-chloroanilides with the zerovalent complex tetrakis(triphenylphosphine)nickel(0). 1H N.m.r. spectra of the oxindoles (2)-(6) show an AMX pro
- Rodriguez, J. Gonzalo,Canoira, Laureano,Temprano, Fernando
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- Reduction of 3-acyl derivatives of oxindoles, benzo[b]furan-2-ones, and benzo[b]thiophen-2-ones to the corresponding alkyl derivatives by sodium borohydride-acetic acid
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It was found that 3-acyl derivatives of oxindoles, benzo[b]furan-2-ones, and benzo[b]thiophen-2-ones could be efficiently and conveniently reduced to the corresponding alkyl derivatives by pelletized sodium borohydride in acetic acid. A typical procedure
- Smith, Francis X.,Williams, Brian D.,Gelsleichter, Eric,Podcasy, Judy A.,Sisko, John T.,Hrubowchak, David M.
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- Ionic liquids as solvents of choice for electrophilic fluorination: Fluorination of indoles by F-TEDA-BF4
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Selectfluor was shown to be soluble in ionic liquid, thus allowing the 'green' electrophilic fluorination of indole compounds in high chemoselectivity and yields.
- Baudoux, Jér?me,Salit, Anne-Frédérique,Cahard, Dominique,Plaquevent, Jean-Christophe
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- Intramolecular Reactions Using Amide Links: Aryl Radical Cyclisation of Silylated Acryloylanilides
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Aryl radical cyclisations of in situ silylated o-bromoacryloylanilides are presented and shown to lead to N-unsubstituted oxindoles and dihydroquinolones in very different ratios than those previously observed for the N-alkyl o-bromoacryloylanilides.
- Jones, Keith,Wilkinson, James,Ewin, Richard
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- A novel and efficient synthesis of 3-fluorooxindoles from indoles mediated by selectfluor
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(equation presented) Treatment of several 3-substituted indoles, including derivatives of tryptophan and serotonin, with commercially available Selectfluor in acetonitrile/ water furnished 3-substiuted 3-fluorooxindoles in good to high yields. Since 3-fluorooxindoles obtained are sterically similar to both oxindoles and 3-hydroxyoxindoles, they should be useful as probes for investigating the enzymatic mechanism of indole biosynthesis and metabolism.
- Takeuchi, Yoshio,Tarui, Takanao,Shibata, Norio
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- Friedel-crafts alkylation of N-(2-chloropropionyl)aniline and the generation mechanism of byproducts
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The cyclization of N-(2-chloropropionyl)aniline to 3-methylindolin-2-one through Friedel-Crafts alkylation was studied. It was found that N-phenylacrylamide (12.6%) and 3,4-dihydro-2(1H)-quinolinone (1.5%) as main byproducts were obtained. On the basis of the mechanism of Friedel-Crafts alkylation, the generation mechanisms of these two compounds were proposed.
- Tian, Jun,Li, Lei,Yan, Xilong,Chen, Ligong
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- Evaluation of 3-ethyl-3-(phenylpiperazinylbutyl)oxindoles as PET ligands for the serotonin 5-HT7 receptor: Synthesis, pharmacology, radiolabeling, and in vivo brain imaging in pigs
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We have investigated several oxindole derivatives in the pursuit of a 5-HT7 receptor PET ligand. Herein the synthesis, chiral separation, and pharmacological profiling of two possible PET candidates toward a wide selection of CNS-targets are de
- Herth, Matthias M.,Andersen, Valdemar L.,Hansen, Hanne D.,Stroth, Nikolas,Volk, Balázs,Lehel, Szabolcs,Dyssegaard, Agnete,Ettrup, Anders,Svenningsson, Per,Knudsen, Gitte M.,Kristensen, Jesper L.
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Read Online
- Iron-Catalyzed Oxidative Cross-Coupling of Phenols and Tyrosine Derivatives with 3-Alkyloxindoles
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In this study, a novel iron-catalyzed oxidative cross-coupling reaction between phenols and 3-alkyloxindole derivatives is reported. The efficient method, which is based on the FeCl3 catalyst and the t-BuOOt-Bu oxidant in 1,2-dichloroethane at 70 °C, affords 3-alkyl-3-(hydroxyaryl)oxindole compounds with a high degree of selectivity. The generality of the conditions was proven by reacting various substituted phenols, naphthols, and tyrosine derivatives with 3-alkyloxindoles. To apply the chemistry for the conjugation of tyrosine-containing short peptides with oxindolylalanine (Oia) derivatives, the reaction conditions were modified [Fe(O2CCF3)3 catalyst, t-BuOOt-Bu, HFIP, 70 °C], and amino acids with acid-stable N-protecting groups were used.
- Mintz, Tomer,More, Nagnath Yadav,Gaster, Eden,Pappo, Doron
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supporting information
p. 18164 - 18178
(2021/12/17)
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- Rapid Oxidation Indoles into 2-Oxindoles Mediated by PIFA in Combination with n-Bu4NCl ? H2O
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We report the development of a rapid approach for directly converting indoles into 2-oxindoles promoted by HOCl formed in situ from the combination of (bis(trifluoroacetoxy) iodo)benzene (PIFA) and n-Bu4NCl ? H2O. The procedure is widely functional group tolerant and provides 2-oxindoles in up to 95% yield within 5 min. The potential applications of the developed methodology are demonstrated by the gram-scale preparation of 3-methyl-2-oxindole (11 a), the one-pot two-step syntheses of spiro-oxindoles 26 a and 26 b, and the formal synthesis of (-)-folicanthine (2). (Figure presented.).
- Liang, Peng,Zhao, Hang,Zhou, Tingting,Zeng, Kaiyun,Jiao, Wei,Pan, Yang,Liu, Yazhou,Fang, Dongmei,Ma, Xiaofeng,Shao, Huawu
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supporting information
p. 3532 - 3538
(2021/06/09)
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- Fenton chemistry enables the catalytic oxidative rearrangement of indoles using hydrogen peroxide
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Oxidative rearrangement of indoles is an important transformation to yield 2-oxindoles and spirooxindoles, which are present in many pharmaceutical agents and bioactive natural products. Previous oxidation methods show either broad applicability or greenness but rarely achieve both. Reported is the discovery of Fenton chemistry-enabled green catalytic oxidative rearrangement of indoles, which has wide substrate scope (42 examples) and greenness (water as the only stoichiometric byproduct) at the same time. Detailed mechanistic studies revealed that the Fenton chemistry generated hydroxyl radicals that further oxidize bromide to reactive brominating species (RBS: bromine or hypobromous acid). Thisin situgenerated RBS is the real catalyst for the oxidative rearrangement. Importantly, the RBS is generated under neutral conditions, which addresses a long-lasting problem of many haloperoxidase mimics that require a strong acid for the oxidation of bromide with hydrogen peroxide. It is expected that this new catalytic Fenton-halide system will find wide applications in organic synthesis.
- Zhao, Guodong,Liang, Lixin,Wang, Eryu,Lou, Shaoyan,Qi, Rui,Tong, Rongbiao
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supporting information
p. 2300 - 2307
(2021/04/12)
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- Green method for preparing oxindole derivative
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The invention relates to the technical field of green organic synthesis, and provides a green method for preparing oxindole derivatives, which comprises the following steps: taking indole compounds with different functional groups as raw materials, under the conditions of room temperature, opening and neutral, adopting MBrx (M is Fe,Fe,Ce and the like) as a catalyst with X equal to 2 or 3, and adopting hydrogen peroxide as a sole oxidant to generate active bromine (RBS) in situ, and catalytically synthesizing the oxindole derivative. According to the method disclosed by the invention, MBrx (such as FeBr2, CeBr3 and the like) is used as the catalyst, so that an expensive or complex catalyst is avoided, and the method is green, environment-friendly, safe, simple, efficient, mild in reaction condition and wide in substrate application range, has a relatively good application prospect and is expected to be widely applied to organic synthesis, fine chemical engineering and pharmaceutical industry.
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Paragraph 0042-0044
(2021/06/26)
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- The benzyl can be selectively removed by visible light or near visible light. Method for protecting allyl and propargyl group
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The invention provides a method for selectively removing benzyl, allyl and propargyl protecting groups by visible light or near visible light, namely a substrate containing benzyl, allyl or propargyl protecting groups. The method has the advantages of simple operation, safe and clean visible light or near visible light as excitation conditions, cheap and easily available reagents, high reaction yield, high reaction chemistry and regional selectivity, and is suitable for selective removal of benzyl, allyl and propargyl protecting groups in various substrates.
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Paragraph 0011
(2021/10/16)
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- B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles
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The direct C3 alkylation of indoles and oxindoles is a challenging transformation, and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C-H bonds in amines, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine-based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade.
- Basak, Shyam,Alvarez-Montoya, Ana,Winfrey, Laura,Melen, Rebecca L.,Morrill, Louis C.,Pulis, Alexander P.
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p. 4835 - 4840
(2020/04/22)
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- Design, synthesis and biological evaluation of novel human monoamine oxidase B inhibitors based on a fragment in an X-ray crystal structure
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Herein we report our efforts of developing reversible selective hMAO-B inhibitors based on isatin, a fragment in an X-ray crystal structure. Five different scaffolds were designed and many compounds were synthesized. Among them, compound A3 demonstrated very high potency and isoform selectivity against hMAO-B, 11 and 13 times more potent (IC50 = 3 nM) and 23.64 and 6.8 times more selective than the marked drugs, selegiline and safinamide. However, the endeavors to modify the polar 3-one group of isatin, that is in a hydrophobic environment in the binding site of hMAO-B, to small nonpolar hydrophobic groups did not bring about improved hMAO-B inhibitors, which may challenge our understanding of molecular interactions and molecular recognition in biological systems.
- Cheng, Kai,Li, Shiyu,Lv, Xiao,Tian, Yongbin,Kong, Haiyan,Huang, Xufeng,Duan, Yajun,Han, Jihong,Xie, Zhouling,Liao, Chenzhong
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supporting information
p. 1012 - 1018
(2019/02/24)
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- Catalytic C1 Alkylation with Methanol and Isotope-Labeled Methanol
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A metal-catalyzed methylation process has been developed. By employing an air- and moisture-stable manganese catalyst together with isotopically labeled methanol, a series of D-, CD3-, and 13C-labeled products were obtained in good yields under mild reaction conditions with water as the only byproduct.
- Sklyaruk, Jan,Borghs, Jannik C.,El-Sepelgy, Osama,Rueping, Magnus
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supporting information
p. 775 - 779
(2019/01/04)
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- Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles with Alcohols
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A general and efficient iron-catalyzed C-alkylation of oxindoles has been developed. This borrowing hydrogen approach employing a (cyclopentadienone)iron carbonyl complex (2 mol %) exhibited a broad reaction scope, allowing benzylic and simple primary and secondary aliphatic alcohols to be employed as alkylating agents. A variety of oxindoles underwent selective mono-C3-alkylation in good-to-excellent isolated yields (28 examples, 50–92 % yield, 79 % average yield).
- Dambatta, Mubarak B.,Polidano, Kurt,Northey, Alexander D.,Williams, Jonathan M. J.,Morrill, Louis C.
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p. 2345 - 2349
(2019/05/16)
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- Manganese catalyzed α-methylation of ketones with methanol as a C1 source
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The direct α-methylation of ketones with methanol under hydrogen borrowing conditions using a well-defined manganese PN3P complex as a pre-catalyst was, for the first time, achieved. The reactions typically proceed at 120 °C for 20 h with 3 mol% pre-catalyst loading and in the presence of NaOtBu (50 mol%) as base. The scope of the reaction was extended to the α-methylation of esters.
- Bruneau-Voisine, Antoine,Pallova, Lenka,Bastin, Stéphanie,César, Vincent,Sortais, Jean-Baptiste
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supporting information
p. 314 - 317
(2019/01/09)
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- Enabling CO Insertion into o-Nitrostyrenes beyond Reduction for Selective Access to Indolin-2-one and Dihydroquinolin-2-one Derivatives
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The transition metal-catalyzed reductive cyclization of o-nitrostyrene in the presence of carbon monoxide (CO) has been developed to be a general synthetic route to an indole skeleton, wherein CO was used as a reductant to deoxidize nitroarene into nitrosoarene and/or nitrene with CO2 release, but the selective insertion of CO into the heterocyclic product with higher atom economy has not yet been realized. Herein, the Pd-catalyzed reduction of o-nitrostyrene by CO and its regioselective insertion were efficiently achieved to produce synthetically useful five- and six-membered benzo-fused lactams. Detailed investigations revealed that the chemoselectivity to indole or lactam was sensitive to the nature of the counteranions of Pd2+ precursors, whereas ligands significantly decided the carbonylative regioselectivity by different reaction pathways. Using PdCl2/PPh3/B(OH)3 (condition A), an olefin hydrocarboxylation was primarily initiated followed by partial reduction of the NO2 moiety and cyclization reaction to give N-hydroxyl indolin-2-one, which was further catalytically reduced by CO to afford the indolin-2-one as the final product with up to 95% yield. When the reaction was conducted under the Pd(TFA)2/BINAP/TsOH·H2O system (condition B), complete deoxygenation and carbonylation of the NO2 group occurred initially to yield the corresponding isocyanate followed by internal hydrocyclization to generate 3,4-dihydroquinolin-2-one with up to 98% yield. Importantly, the methodology could be efficiently applied in the synthesis of marketed drug Aripiprazole.
- Yang, Li,Shi, Lijun,Xing, Qi,Huang, Kuo-Wei,Xia, Chungu,Li, Fuwei
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p. 10340 - 10348
(2018/10/20)
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- Enantioseletive Fluorination of 3-Functionalized Oxindoles Using Electron-rich Amino Urea Catalyst
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An enantioselective fluorination of 3-functionalized oxindoles using electron-rich amino urea catalyst is described. Various 3-functionalized 3-fluoro-2-oxindoles were obtained in good yields and enantio-selectivity. The resulting enantioenriched 3-methylene nitrile 3-fluoro-2-oxindole product was found to inhibit indoleamine 2,3-dioxygenase considerably. (Figure presented.).
- Jiang, Xiaojian,Wang, Haitao,He, Haoquan,Wang, Wei,Wang, Yuqiang,Ke, Zhihai,Yeung, Ying-Yeung
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supporting information
p. 4710 - 4714
(2018/11/10)
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- Preparation method of 3-substituted oxidized indole and derivative
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The invention belongs to the technical field of organic chemistry and pharmaceutical chemistry and particularly relates to a method of preparing 3-substituted oxidized indole and a derivative. In themethod, with a 3-substituted indole derivative as a raw material and one or more of a tetrabutyl ammonium halide compound/sodium chloride/sodium iodide/potassium iodide as additives, and one or more of dichloromethane/1,2-dichloroethane/tetrahydrofurane/methylbenzene/1,4-dioxane/ethyl acetate/methanol are added as solvents; then one or more of [bis(trifluoroacetoxyl)iodine]benzene/iodosobenzene diacetate are added as oxidants in order to carry out a reaction with reaction temperature being controlled, thus producing the 3-substituted oxidized indole derivative. The method has gentle reaction conditions, simple operations, short reaction time and high yield, and is free of a metal catalyst and is environment-friendly.
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Paragraph 0073; 0074; 0076; 0077; 0078
(2018/06/26)
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- Synthesis of 2-Oxindoles from Substituted Indoles by Hypervalent-Iodine Oxidation
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A practical conversion of indoles into the corresponding 2-oxindoles is achieved efficiently using a hypervalent iodine reagent. This oxidation is amenable to different substituted indoles, and allows the synthesis of a wide range of synthetically valuable substituted 2-oxindoles in up to 90 % yield. Furthermore, Ropinirole, a drug used to alleviate the symptoms of Parkinson's disease, was synthesized in three steps in an overall yield of 44 % using this method.
- Jiang, Xinpeng,Zheng, Cong,Lei, Lijun,Lin, Kai,Yu, Chuanming
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p. 1437 - 1442
(2018/04/06)
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- Iron-Catalyzed Methylation Using the Borrowing Hydrogen Approach
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A general iron-catalyzed methylation has been developed using methanol as a C1 building block. This borrowing hydrogen approach employs a Kn?lker-type (cyclopentadienone)iron carbonyl complex as catalyst (2 mol %) and exhibits a broad reaction scope. A variety of ketones, indoles, oxindoles, amines, and sulfonamides undergo mono- or dimethylation in excellent isolated yields (>60 examples, 79% average yield).
- Polidano, Kurt,Allen, Benjamin D. W.,Williams, Jonathan M. J.,Morrill, Louis C.
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p. 6440 - 6445
(2018/07/25)
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- Chiral N,N′-Dioxide/Scandium(III)-Catalyzed Asymmetric Alkylation of N-Unprotected 3-Substituted Oxindoles
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An efficient enantioselective alkylation of N-unprotected 3-substituted oxindoles was realized by using a chiral N,N′-dioxide/scandium(III) complex as the catalyst. A wide range of 3,3-dialkyl substituted oxindoles with quaternary stereocenters were obtained in high yields and ee values (up to 98% yield and 99% ee). (Figure presented.).
- He, Changqiang,Cao, Weidi,Zhang, Jianlin,Ge, Shulin,Feng, Xiaoming
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supporting information
p. 4301 - 4305
(2018/10/02)
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- Metal- and Oxidant-Free Modular Approach to Access N-Alkoxy Oxindoles via Aryne Annulation
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An unprecedented metal- and oxidant-free (intermolecular) approach to access N-alkoxy oxindoles via [3 + 2] cycloadition of in situ generated electrophilic species viz. aryne and (putative) aza-oxyallyl cation is reported. This approach is amenable to both C3-unsubstituted as well as C3-substituted oxindoles. A one-pot manipulation further makes this reaction highly practical. The versatility of this approach was demonstrated through valuable synthetic transformations.
- Singh, Ritesh,Nagesh, Kommu,Yugandhar, Doddapaneni,Prasanthi
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p. 4848 - 4853
(2018/08/24)
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- Regioselective synthesis of 2,3′-biindoles mediated by an NBS-induced homo-coupling of indoles
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Mild conditions have been developed to achieve NBS-induced homodimerization of indole derivatives with excellent regioselectivity at 15 °C in high efficiency. This method provides a simple route to a 2,3′-linked biindolyl scaffold from the electron-rich to moderately electron-poor indoles. In addition, [3,2-a]carbazole derivatives can also be prepared through this method.
- Huang, Panpan,Peng, Xiangjun,Hu, Dan,Liao, Huiwu,Tang, Shaobin,Liu, Liangxian
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supporting information
p. 9622 - 9629
(2017/11/30)
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- Oxidative Fragmentations and Skeletal Rearrangements of Oxindole Derivatives
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An oxidative sequence for the conversion of oxindoles to structurally distinct heterocyclic scaffolds and aniline derivatives is disclosed by the combination of a copper-catalyzed C-H peroxidation and subsequent base-mediated fragmentation reaction. In contrast to classic enzymatic (i.e., kynurenine pathway) and biomimetic methods (i.e., Witkop-Winterfeldt oxidation) for oxidative indole cleavage, this protocol allows for the incorporation of external nucleophiles. The new transformation displays broad functional group tolerance and is applicable to tryptophan derivatives, opening potential new avenues for postsynthetic modification of polypeptides, bioconjugation, and unnatural amino acid synthesis.
- Klare, Hendrik F. T.,Goldberg, Alexander F. G.,Duquette, Douglas C.,Stoltz, Brian M.
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supporting information
p. 988 - 991
(2017/03/14)
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- Characterization of 2-Oxindole Forming Heme Enzyme MarE, Expanding the Functional Diversity of the Tryptophan Dioxygenase Superfamily
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3-Substituted 2-oxindoles are important structural motifs found in many biologically active natural products and pharmaceutical lead compounds. Here, we report an enzymatic formation of the 3-substituted 2-oxindoles catalyzed by MarE in the maremycin biosynthetic pathway in Streptomyces sp. B9173. MarE is a homologue of FeII/heme-dependent tryptophan 2,3-dioxygenases (TDOs). Typical TDOs usually catalyze the insertion of two oxygen atoms from O2 into an indole ring to generate N-formylkynurenine (NFK)-like products. In contrast, MarE catalyzes the insertion of a single oxygen atom from O2 into an indole ring, to probably generate an epoxyindole intermediate that undergoes an unprecedented 2,3-hydride migration to form 2-oxindole structure. MarE shows substrate robustness to catalyze the conversion of a series of 3-substituted indoles into their corresponding 3-substituted 2-oxindoles. Although containing most key amino acid residues conserved in well-known TDO homologues, MarE falls into a separate new subgroup in the phylogenetic tree. The characterization of MarE and its homologue enriches the functional diversities of TDO superfamily and provides a new strategy for discovering novel natural products containing 3-substituted 2-oxindole pharmacophores by genome mining.
- Zhang, Yuyang,Zou, Yi,Brock, Nelson L.,Huang, Tingting,Lan, Yingxia,Wang, Xiaozheng,Deng, Zixin,Tang, Yi,Lin, Shuangjun
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supporting information
p. 11887 - 11894
(2017/09/07)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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The instant invention provides compounds of formula (I) which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.
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Page/Page column 61-62
(2017/11/01)
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- Biocatalysed olefin reduction of 3-alkylidene oxindoles by baker's yeast
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3-Substituted oxindoles are very interesting molecules both for their potential biological activity and for their role as starting materials toward more complex oxindole-based structures. These molecules can be prepared by the reduction of a 3-ylidene oxi
- Rossetti, Arianna,Sacchetti, Alessandro,Bonfanti, Marta,Roda, Gabriella,Rainoldi, Giulia,Silvani, Alessandra
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p. 4584 - 4590
(2017/07/11)
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- Magnesium-Catalyzed Electrophilic Trifluoromethylation: Facile Access to All-Carbon Quaternary Centers in Oxindoles
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The first example of a magnesium-catalyzed direct trifluoromethylation of 3-substituted oxindoles using an electrophilic hypervalent iodine reagent is reported. The reaction proceeds under unprecedented mild conditions leading to the formation of an all-carbon quaternary center in oxindoles in high chemical yield and demonstrates excellent functional group tolerance. In addition to trifluoromethyl, other perfluoroalkyl groups can be introduced with similar level of efficacy. Mechanistic investigations are consistent with the involvement of a radical pathway. The chemical versatility of the obtained products is further illustrated through their conversion in situ into valuable organofluorine building blocks, making the protocol more widely applicable.
- Katayev, Dmitry,Kajita, Harutake,Togni, Antonio
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supporting information
p. 8353 - 8357
(2017/06/28)
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- Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach
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Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from 1H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.
- Wilson, Jonathan E.,Kurukulasuriya, Ravi,Reibarkh, Mikhail,Reiter, Maud,Zwicker, Aaron,Zhao, Kake,Zhang, Fengqi,Anand, Rajan,Colandrea, Vincent J.,Cumiskey, Anne-Marie,Crespo, Alejandro,Duffy, Ruth A.,Murphy, Beth Ann,Mitra, Kaushik,Johns, Douglas G.,Duffy, Joseph L.,Vachal, Petr
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supporting information
p. 261 - 265
(2016/03/22)
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- Molybdenum hexacarbonyl mediated synthesis of indolin-2-one & azaindolin-2-one under catalyst free conditions
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Syntheses of indolin-2-ones and azaindolin-2-ones have been realized. The strategy involves the formation of tosylhydrazone from tosylhydrazine and 2-amino aryl or pyridyl aldehydes/ketones which then undergo intramolecular aminocarbonylation to afford indolin-2-ones and azaindolin-2-ones. The generality of the method was demonstrated by synthesizing C3 substituted and unsubstituted indolin-2-one and azaindolin-2-one derivatives.
- Patil, Vikas S.,Pal, Shyam S.,Pathare, Ramdas S.,Reddy,Pathak, Arunendra
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supporting information
p. 6370 - 6372
(2015/11/16)
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- Imidazole derivatives as accelerators for ruthenium-catalyzed hydroesterification and hydrocarbamoylation of alkenes: Extensive ligand screening and mechanistic study
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Imidazole derivatives are effective ligands for promoting the [Ru3(CO)12]-catalyzed hydroesterification of alkenes using formates. Extensive ligand screening was performed to identify 2-hydroxymethylated imidazole as the optimal ligand. Neither carbon monoxide gas nor a directing group was required, and the reaction also showed a wide substrate generality. The Ru-imidazole catalyst system also promoted intramolecular hydrocarbamoylation to afford lactams. A Ru-imidazole complex was unambiguously analyzed by X-ray crystallography, and it had a trinuclear structure derived from one [Ru3(CO)12] and two ligands. This complex was also successfully used for hydroesterification. The mechanism was examined in detail by using D- and 13C-labeled formates, indicating that the hydroesterification reaction proceeds by a decarbonylation-recarbonylation pathway. Effective imidazole assistant: [Ru3(CO)12]-catalyzed hydroesterification of alkenes by using formates is drastically accelerated by imidazole derivatives and exhibits a broad substrate scope for both alkenes and formates. The Ru-imidazole complex also catalyzes the intramolecular hydrocarbamoylation of alkenes.
- Konishi, Hideyuki,Muto, Takashi,Ueda, Tsuyoshi,Yamada, Yayoi,Yamaguchi, Miyuki,Manabe, Kei
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p. 836 - 845
(2015/03/14)
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- An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: Generality, applications and mechanistic investigations
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The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.
- Richmond, Edward,Ling, Kenneth B.,Duguet, Nicolas,Manton, Lois B.,elebi-?lcüm, Nihan,Lam, Yu-Hong,Alsancak, Sezen,Slawin, Alexandra M. Z.,Houk,Smith, Andrew D.
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p. 1807 - 1817
(2015/02/19)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN
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The invention relates to the compounds of formula I and formula II or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I or formula II, and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.
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Paragraph 0121; 0122; 0123
(2015/05/26)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for the treatment of inflammation may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease, Ulcerative colitis, Crohn's disease, Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0112; 0113; 0114
(2015/06/03)
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- NIS-mediated regioselective amidation of indole with quinazolinone and pyrimidone
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A mild, metal-free condition was developed for the direct regioselective C2 amidation of indoles and pyrroles with quinazolinone and pyrimidone derivatives in intermolecular fashion, which led to novel indolyl/pyrrolyl quinazolinone and pyrimidone derivatives in moderate to good yields. This journal is the Partner Organisations 2014.
- Ghosh, Suman Kr,Nagarajan, Rajagopal
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p. 20136 - 20144
(2014/06/09)
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- Regiodivergent access to five- and six-membered benzo-fused lactams: Ru-catalyzed olefin hydrocarbamoylation
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We report herein a new strategy of the Ru-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of five- and six-membered benzo-fused lactams starting from N-(2-alkenylphenyl)formamides. Using a combined catalyst of Ru3
- Li, Bin,Park, Yoonsu,Chang, Sukbok
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supporting information
p. 1125 - 1131
(2014/02/14)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF INFLAMMATION
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The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of inflammation may he formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of Type II diabetes, Type I diabetes, insulin resistance, cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, macular adema, arthritis, osteoarthritis, rheumatoid arthritis, inflammatory bowel syndrome, neudegeneration, Alzheimer's disease, Huntington's disease. Ulcerative colitis, Crohn's disease. Multiple Sclerosis, muscular dystropthy, metabolic syndrome, fatty liver, bone diseases, inflammatory diseases.
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Paragraph 0094; 0095; 0096
(2013/12/03)
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- COMPOSITIONS AND METHODS FOR THE TREATMENT OF MODERATE TO SEVERE PAIN
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The invention relates to the compounds of formula (I) and formula (II) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I) or formula (II), and methods for treating or preventing or modulating moderate to severe pain in a disease may be formulated for oral buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of pain, severe pain, chronic pain, chemotherapy induced pain, epilepsy, glaucoma, arthritis, tooth aches, inflammation, musculoskeletal pain, sciatica, radiculopathy pain, migraine, neuropathic pain, post herpetic neuralgia, neuralgia pain, multiple sclerosis, multiple sclerosis, restless legs syndrome (RLS), cluster headache, depression, fibromyalgia, amyotrophic lateral sclerosis (ALS), convulsions, partial seizures, mood-stabilizing agent and bipolar disorder.
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Paragraph 0097-0099
(2013/12/03)
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- Direct N-carbamoylation of 3-monosubstituted oxindoles with alkyl imidazole carboxylates
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(Chemical Equation Presented) Regioselective N-carbamoylation of oxindoles was achieved through the use of imidazole carboxylate reagents. This reaction provides ready access to N-carbamoyl-3-monosubstituted oxindoles.
- Trost, Barry M.,Zhang, Yong,Zhang, Ting
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supporting information; experimental part
p. 5115 - 5117
(2009/10/24)
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- Osmium (VII)-catalyzed oxidation of indoles by potassium hexacyanoferrate (III) in alkaline media: A kinetic and mechanistic study
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THE REACTION of indoles with Os(VIIl) catalyzed hexacyanoferrate (III) in alkaline media to produce the corresponding oxindole has been studied at constant temperature and ionic strength. The reaction followed first order kinetics with respect to [indole], [OH] and [Os(VIII)], fractional order in [Fe(CN)63-]. The effects of added electrolytes, potassium hexacyanoferrate(II), relative permitivity and temperature have also been studied. A mechanism consistent with the kinetic data is proposed. Furthermore, the structural influence of the indoles on the reactivity has been discussed.
- Taha,Abu-Zuhri,EI Hadi,Amer
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experimental part
p. 1 - 13
(2010/02/28)
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- Kinetics and mechanism of the oxidation of indoles by alkaline potassium hexacyanoferrate (III)
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THE REACTION of indoles with hexacyanoferrate(III) in alkaline media to produce the corresponding oxindoie has been studied at constant temperature and ionic strength. The reaction followed first order kinetics with respect to [indole] and [OH-], whereas fractional order with respect to [Fe(CN)63-] was found. The effects of added electrolytes, potassium hexacyanoferrate(Π), relative permitivity and temperature have also been studied. On the basis of experimental observations, a probable reaction mechanism has been proposed.
- Taha,Abu-Zuhrf,El Hadi,Amer
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experimental part
p. 15 - 27
(2010/03/25)
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- Oxidative cleavage reaction of substituted indoles catalyzed by plant cell cultures
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We have developed a novel method for the oxidative cleavage of indole carbon double bonds in the presence of H2O2 using plant cell cultures as peroxidase. The oxidative method has some advantage, as features such as mild reactions, good yields, easy work-up and safety.
- Takemoto, Masumi,Iwakiri, Yasutaka,Tanaka, Kiyoshi
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p. 373 - 383
(2008/03/12)
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- Enantioselective TADMAP-catalyzed carboxyl migration reactions for the synthesis of stereogenic quaternary carbon
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The chiral, nucleophilic catalyst TADMAP [1, 3-(2,2,2-triphenyl-1- acetoxyethyl)-4-(dimethylamino)-pyridine] has been prepared from 3-lithio-4-(dimethylamino)pyridine (5) and triphenylacetaldehyde (3), followed by acylation and resolution. TADMAP catalyzes the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselection. The oxazole reactions are especially efficient and are used to prepare chiral lactams (23) and lactones (30) containing a quaternary asymmetric carbon. TADMAP-catalyzed carboxyl migrations in the indole series are relatively slow and proceed with inconsistent enantioselectivity. Modeling studies (B3LYP/6-31G*) have been used in qualitative correlations of catalyst conformation, reactivity, and enantioselectivity.
- Shaw, Scott A.,Aleman, Pedro,Christy, Justin,Kampf, Jeff W.,Va, Porino,Vedejs, Edwin
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p. 925 - 934
(2007/10/03)
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- Recyclable selective palladium-catalyzed synthesis of five-, six- or seven-membered ring lactones and lactams by cyclocarbonylation in ionic liquids
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The ionic liquids, BMIM PF6 or BMIM NTf2, are used successfully for the palladium-catalyzed cyclocarbonylation of 2-allylphenols and anilines, 2-vinylphenols, and 2-aminostyrenes. The reaction proceeds cleanly and efficiently to afford high yields of lactones or lactams with good or excellent selectivity for one isomer. The ionic liquid containing the palladium catalyst, and ligand, is recyclable in all cases.
- Ye, Fangguo,Alper, Howard
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p. 1855 - 1861
(2007/10/03)
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- Horseradish peroxidase-mediated aerobic and anaerobic oxidations of 3-alkylindoles
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Little is known about the HRP-mediated oxidations of 3-alkylindoles. Whereas 3-methylindole and 3-ethylindole were found to be turned over smoothly by HRP, reactions of tryptophol and N-acetyltryptamine were inefficient. Oxidations of the former two indoles by HRP under aerobic conditions led to the corresponding ring-opened o-acylformanilides and oxindoles, whereas anaerobic oxidations resulted in oxidative dimerization. The major products of anaerobic oxidation of 3-methylindole were shown to be two hydrated dimers, while anhydrodimers were obtained in the 3-ethyl case. The proposed mechanism involves HRP-mediated one-electron oxidation to give an indole radical that either dimerizes (anaerobic conditions) or reacts with O2 (aerobic conditions). Measured kinetics of indole oxidation by HRP compounds I and II mirrored their relative reactivities under turnover conditions. The observed comparable binding affinities for all four indole substrates investigated suggest that the low reactivity of tryptophol and N-acetyltryptamine reflect binding to HRP in an orientation that is disadvantageous to electron transfer oxidation of the indole ring.
- Ling, Ke-Qing,Sayre, Lawrence M.
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p. 3543 - 3551
(2007/10/03)
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- A mild procedure for the oxidative cleavage of substituted indoles catalyzed by plant cell cultures
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We have developed a mild procedure for the oxidative cleavage of indole carbon double bonds using plant cell cultures as a catalytic system in the presence of H2O2. We have developed a novel procedure for the oxidative cleavage of indole carbon double bonds in the presence of H 2O2 using plant cell cultures as a catalytic system. The oxidative procedure has some advantages, such as mild reactions, good yields, easy work-up and safety.
- Takemoto, Masumi,Iwakiri, Yasutaka,Suzuki, Yuki,Tanaka, Kiyoshi
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p. 8061 - 8064
(2007/10/03)
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- Synthesis of five-, six-, and seven-membered ring lactams by Cp*Rh complex-catalyzed oxidative N-heterocyclization of amino alcohols
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A new effective catalytic system consisting of [Cp*RhCl 2]2/K2CO3 (Cp* = pentamethylcyclopentadienyl) for the lactamization of amino alcohols has been developed. As an example, the reaction of 3-(2-aminophenyl)-1-propanol in the presence of [Cp*RhCl2]2 (5.0% Rh) and K 2CO3 (10%) in acetone gives 3,4-dihydro-2(1H)-quinolinone in an isolated yield of 80%. A variety of five-, six-, and seven-membered benzo-fused lactams are synthesized by this catalytic system.
- Fujita, Ken-Ichi,Takahashi, Yoshinori,Owaki, Maki,Yamamoto, Kazunari,Yamaguchi, Ryohei
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p. 2785 - 2788
(2007/10/03)
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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- New One-Pot Synthesis of 3-Alkyl- and 3-(ω-Hydroxyalkyl)oxindoles from Isatins
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A new and efficient one-pot procedure has been developed for the synthesis of 3-alkyl- and 3-(ω-hydroxyalkyl)oxindoles from isatins by treatment with alcohols and diols in the presence of Raney nickel, under hydrogen atmosphere. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Volk, Balazs,Simig, Gyula
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p. 3991 - 3996
(2007/10/03)
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- "Untypical aging off-flavor" in wine: Synthesis of potential degradation compounds of indole-3-acetic acid and kynurenine and their evaluation as precursors of 2-aminoacetophenone
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Kynurenine (1) and indole-3-acetic acid (2) are considered as potential precursors of 2-aminoacetophenone (3), which is regarded to be the aroma impact compound causing an "untypical aging off-flavor" (UTA) in Vitis vinifera wines. The mechanism of the formation of 3 was studied using model fermentation and model sulfuration media spiked with 1 or 2 as potential precursors. Possible degradation products such as kynurenamine (4) and kynurenic acid (5), or skatole (6), 2-oxoskatole (7), 2-formamidoacetophenone (8), 2-oxindole-3-acetic acid (9), and 3-(2-formylaminophenyl)-3-oxopropionic acid (10) were evaluated by HPLC-UV of the fermentation and sulfuration media and comparison with synthesized 7, 8, 9, and 10. The synthesis of the possible precursor 4-(2-aminophenyl)-2,4-dioxobutanoic acid (11), a proposed metabolite of 1 failed because a spontaneous cyclization yields 5 and N-oxo-kynurenic acid (12), but not 11. It could be shown that the formation of 3 is triggered by an oxidative degradation of 2 after sulfuration with potassium bisulfite via the intermediates 10 and 8. However, no formation of 3 occurred during sulfuration of a model wine spiked with 1 or during fermentation of a model must spiked with 1 or 2.
- Hoenicke, Katrin,Borchert, Ole,Gruening, Kai,Simat, Thomas J.
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p. 4303 - 4309
(2007/10/03)
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