- Palladium-catalyzed C-H ethoxycarbonyldifluoromethylation of electron-rich heteroarenes
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The first Pd-catalyzed C-H ethoxycarbonyldifluoromethylation with BrCF2CO2Et has been developed. The use of a bidentate phosphine ligand (Xantphos) is critical for the reaction to occur. A variety of electron-rich heteroarenes, including indoles, furans, thiophenes, and pyrroles, can be ethoxycarbonyldifluoromethylated in moderate to excellent yields. The reactions take place at the C-H bonds adjacent to the heteroatoms with high regioselectivity. This method provides a new protocol for the introduction of difuoroalkyl groups into electron-rich heteroarenes.
- Shao, Changdong,Shi, Guangfa,Zhang, Yanghui,Pan, Shulei,Guan, Xiaohong
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- Direct oxidative coupling of N-acetyl indoles and phenols for the synthesis of benzofuroindolines related to phalarine
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Inspired by the biogenetic synthesis of benzofuro-indoline-containing natural products, we designed an oxidative coupling between phenol and N-acetyl indoles. This straightforward and direct radical process, mediated by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and FeCl 3 allowed the regioselective synthesis of benzofuro[3,2-b]indolines, whose structure is found in the natural product phalarine.
- Tomakinian, Terry,Guillot, Rgis,Kouklovsky, Cyrille,Vincent, Guillaume
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- Synthesis of Pyrido[2,3-b]indole Derivatives via Rhodium-Catalyzed Cyclization of Indoles and 1-Sulfonyl-1,2,3-triazoles
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Acyloxy-substituted α,β-unsaturated imines generated in situ from triazoles can act as aza-[4 C] synthons and be trapped by indoles in a stepwise [4 + 2] cycloaddition reaction, thus providing rapid access to valuable pyrido[2,3-b]indoles in high yields. Attractive features of this reaction system include operational simplicity, readily available substrates, construction of sterically demanding quaternary centers, and convenient derivatization using triflate. (Figure presented.).
- An, Yuehui,Chen, Yidian,Duan, Shengguo,Li, Chuan-Ying,Xu, Ze-Feng,Xue, Bing,Zhang, Wan
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- Asymmetric Synthesis of Furo[3,4-b]indoles by Catalytic [3+2] Cycloaddition of Indoles with Epoxides
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A highly efficient N,N′-dioxide-NiII catalyst system for the catalytic [3+2] cycloaddition of indoles with epoxides through C-C cleavage of oxiranes was accomplished under mild conditions. It provided a promising approach for chiral furo[3,4-b]indoles in up to 98 % yield with up to 91 % enantiomeric excess (ee) and >95:5 diastereomeric ratio (d.r.). A promising approach: Catalytic de-aromatic [3+2] cycloaddition of indoles with epoxides by C-C cleavage of oxiranes is accomplished by using a highly efficient N,N′-dioxide-NiII catalyst system. A range of chiral furo[3,4-b]indoles is obtained with high enantiomeric excesses and diastereomeric ratios.
- Chen, Weiliang,Xia, Yong,Lin, Lili,Yuan, Xiao,Guo, Songsong,Liu, Xiaohua,Feng, Xiaoming
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- Organocatalytic Formal (3 + 2) Cycloaddition toward Chiral Pyrrolo[1,2- a]indoles via Dynamic Kinetic Resolution of Allene Intermediates
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We report the chiral phosphoric acid catalyzed formal (3 + 2) cycloaddition of 3-substituted 1H-indoles and propargylic alcohols containing a functional directing group (p-NHAc or p-OH). This work represents a straightforward method to synthesize chiral pyrrolo[1,2-a]indole bearing a tetrasubstituted carbon stereocenter. The reaction proceeds smoothly with a wide array of substrate tolerance to deliver various chiral pyrrolo[1,2-a]indoles in up to 93percent yield and 98percent ee. The utility of this method is highlighted by the diverse transformations of the products into various indole derivatives.
- Bai, Jian-Fei,Zhao, Lulu,Wang, Fang,Yan, Fachao,Kano, Taichi,Maruoka, Keiji,Li, Yuehui
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- Enantioselective 2-alkylation of 3-substituted indoles with dual chiral lewis acid/hydrogen-bond-mediated catalyst
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A chiral-at-metal bis-cyclometalated iridium complex combines electrophile activation via metal coordination with nucleophile activation through hydrogen bond formation. This new bifunctional chiral Lewis acid/hydrogenbond-mediated catalyst permits the challenging enantioselective 2-alkylation of 3-substituted indoles with α, β-unsaturated 2-acyl imidazoles in up to 99% yield and with up to 98% enantiomeric excess at a catalyst loading of 2 mol %. As an application, the straightforward synthesis of a chiral pyrrolo- [1, 2-a]indole is demonstrated.
- Zhou, Zijun,Li, Yanjun,Gong, Lei,Meggers, Eric
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Read Online
- Rhenium(I)-Catalyzed C-Methylation of Ketones, Indoles, and Arylacetonitriles Using Methanol
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A ReCl(CO)5/MeC(CH2PPh2)3 (L2) system was developed for the C-methylation reactions utilizing methanol and base, following the borrowing hydrogen strategy. Diverse ketones, indoles, and arylacetonitriles underwent mono-and dimethylation selectively up to 99% yield. Remarkably, tandem multiple methylations were also achieved by employing this catalytic system.
- Shee, Sujan,Kundu, Sabuj
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p. 6943 - 6951
(2021/05/29)
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- Constructing Saturated Guanidinum Heterocycles by Cycloaddition of N-Amidinyliminium Ions with Indoles
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We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.
- Allred, Tyler K.,Shaghafi, Michael B.,Chen, Pan-Pan,Tran, Quan,Houk,Overman, Larry E.
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supporting information
p. 7618 - 7623
(2021/10/12)
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- Selective Oxidative Cleavage of 3-Methylindoles with Primary Amines Affording Quinazolinones
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A selective functionalization of C-C-C bonds toward N-C-O bonds is realized by an n-Bu4NI-catalyzed reaction of 3-methylindoles with primary amines using TBHP as the unique oxidant. The systematic process involves oxygenation, nitrogenation, ring-opening, and recyclization, affording a broad range of quinazolinones in good to excellent yields.
- He, Junhui,Dong, Jianyu,Su, Lebin,Wu, Shaofeng,Liu, Lixin,Yin, Shuang-Feng,Zhou, Yongbo
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supporting information
p. 2522 - 2526
(2020/04/09)
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- Ruthenium Pincer Complex Catalyzed Selective Synthesis of C-3 Alkylated Indoles and Bisindolylmethanes Directly from Indoles and Alcohols
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Herein, we presented Ru-SNS complex that serves as a useful catalyst for C-3 alkylation of 1H-indoles with various aliphatic primary and secondary alcohols including cyclic alcohols as well as benzylic alcohols. The selective synthesis of bisindolylmethane derivatives is also achieved from the same set of indole and alcohol just by altering the reaction parameters. Furthermore, the sustainable synthesis of C-3 alkylated indoles directly from 2-(2-nitrophenyl)ethan-1-ol and alcohols catalysed by a Ru-complex via “borrowing hydrogen” strategy is reported. This protocol provides an atom-economical sustainable route to access structurally important compounds like arundine, vibrindole A and tryptamine based derivatives. (Figure presented.).
- Biswas, Nandita,Sharma, Rahul,Srimani, Dipankar
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supporting information
p. 2902 - 2910
(2020/06/03)
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- Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9)
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The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.
- Mussari, Christopher P.,Dodd, Dharmpal S.,Sreekantha, Ratna Kumar,Pasunoori, Laxman,Wan, Honghe,Posy, Shana L.,Critton, David,Ruepp, Stefan,Subramanian, Murali,Watson, Andrew,Davies, Paul,Schieven, Gary L.,Salter-Cid, Luisa M.,Srivastava, Ratika,Tagore, Debarati Mazumder,Dudhgaonkar, Shailesh,Poss, Michael A.,Carter, Percy H.,Dyckman, Alaric J.
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supporting information
p. 1751 - 1758
(2020/10/19)
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- SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF THE EGFR TYROSINE KINASE
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The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell pr
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Page/Page column 154
(2019/01/21)
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- SUBSTITUTED INDOLE COMPOUNDS
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Disclosed are compounds of Formula (I) or salts thereof, wherein Ring Het, R1, R2, R3, R4, R5, m, n, and p are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.
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Page/Page column 91; 92
(2019/06/09)
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- N-Alkylation-Initiated Redox-Neutral [5 + 2] Annulation of 3-Alkylindoles with o-Aminobenzaldehydes: Access to Indole-1,2-Fused 1,4-Benzodiazepines
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Described herein is an unprecedented N-Alkylation-initiated redox-neutral [5 + 2] annulation of 3-Alkylindoles with o-Aminobenzaldehydes via a cascade N-Alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. A series of indole-1,2-fused 1,4-benzodiazepines are facilely constructed in moderate to good yields in one step. This protocol features excellent regioselectivity, metal-free conditions, high step economy, and wide substrate scope.
- Wang, Shuai,Shen, Yao-Bin,Li, Long-Fei,Qiu, Bin,Yu, Liping,Liu, Qing,Xiao, Jian
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supporting information
p. 8904 - 8908
(2019/11/19)
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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 0037; 0039; 0204
(2018/06/26)
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- DIMETHOXYPHENYL SUBSTITUTED INDOLE COMPOUNDS AS TLR7, TLR8 OR TLR9 INHIBITORS
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Disclosed are compounds of Formula (I) or a salt thereof, wherein R1, R3, R4, R5, m, and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.
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Page/Page column 77; 78
(2018/03/28)
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- Methylation of C(sp3)-H/C(sp2)-H bonds with methanol catalyzed by cobalt system
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A highly efficient Co-based catalytic system, composed of a commercially available Co salt, a tetradentate phosphine ligand P-(CH2CH2PPh2)3(PP3), and a base (denoted as [Co]/PP3/base), is developed for the methylation of C(sp3)-H and C(sp2)-H bonds using methanol as a methylating reagent. The Co(BF4)2.6H2O/PP3/K2CO3 catalytic system showed high catalytic activity for the methylation of C-H bonds in aryl alkyl ketones, aryl acetonitriles, and indoles, with wide substrate scope and good functional group tolerance, and methylsubstituted products were obtained in good to excellent yields at 100 °C. This cheap, readily available, and highly efficient Co-based catalytic system may have promising applications in methylation reaction using methanol.
- Liu, Zhenghui,Yang, Zhenzhen,Yu, Xiaoxiao,Zhang, Hongye,Yu, Bo,Zhao, Yanfei,Liu, Zhimin
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supporting information
p. 5228 - 5231
(2017/11/06)
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- Active and Recyclable Catalytic Synthesis of Indoles by Reductive Cyclization of 2-(2-Nitroaryl)acetonitriles in the Presence of Co-Rh Heterobimetallic Nanoparticles with Atmospheric Hydrogen under Mild Conditions
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A cobalt-rhodium heterobimetallic nanoparticle-catalyzed reductive cyclization of 2-(2-nitroaryl)acetonitriles to indoles has been achieved. The tandem reaction proceeds without any additives under the mild conditions (1 atm H2 and 25 °C). This procedure could be scaled up to the gram scale. The catalytic system is significantly stable under these reaction conditions and could be reused more than ten times without loss of catalytic activity.
- Choi, Isaac,Chung, Hyunho,Park, Jang Won,Chung, Young Keun
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p. 5508 - 5511
(2016/11/17)
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- Iridium-catalyzed methylation of indoles and pyrroles using methanol as feedstock
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Iridium-catalyzed methylation of indoles and pyrroles using methanol as the methylating agent was achieved. This transformation takes place via a borrowing hydrogen methodology under an air atmosphere, which constitutes a direct route to 3-methyl-indoles and methyl-pyrroles.
- Chen, Shu-Jie,Lu, Guo-Ping,Cai, Chun
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p. 70329 - 70332
(2015/09/07)
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- AROMATIC HETEROCYCLIC COMPOUNDS AND THEIR APPLICATION IN PHARMACEUTICALS
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Provided herein are novel aromatic heterocyclic compounds or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, and their uses for treating Alzheimer's disease. Also provided herein are pharmaceutical compositions containing such compounds, and methods for using such compounds or pharmaceutical compositions thereof to treat Alzheimer's disease.
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Paragraph 00362; 00372
(2015/07/07)
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- Regioselective hydroarylation reactions of C3 electrophilic N-acetylindoles activated by FeCl3: An entry to 3-(Hetero)arylindolines
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A method for the direct and rare umpolung of the 3 position of indoles is reported. The activation of N-acetylindole with iron(III) chloride allows the C-H addition of aromatic and heteroaromatic substrates to the C2-C3 double bond of the indole nucleus to generate a quaternary center at C3 and leads regioselectively to 3-arylindolines. Optimization, scope (50 examples), practicability (gram scale, air atmosphere, room temperature), and mechanistic insights of this process are presented. Synthetic transformations of the indoline products into drug-like compounds are also described.
- Beaud, Rodolphe,Guillot, Regis,Kouklovsky, Cyrille,Vincent, Guillaume
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p. 7492 - 7500
(2014/06/23)
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- Visible light-mediated C-H difluoromethylation of electron-rich heteroarenes
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A novel method for visible-light photoredox-catalyzed difluoromethylation of electron-rich N-, O-, and S-containingheteroarenes under mild reaction conditions is developed. Mechanistic investigation indicates that the net C-H difluoromethylation proceeds through an electrophilic radical-type pathway.
- Su, Yi-Ming,Hou, Yu,Yin, Feng,Xu, Yue-Ming,Li, Yan,Zheng, Xiaoqi,Wang, Xi-Sheng
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p. 2958 - 2961
(2014/06/23)
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- Highly enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles
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A new ring for your indole: An unprecedented copper-catalyzed enantioselective Friedel-Crafts alkylation/N-hemiacetalization cascade reaction with indoles and β,γ-unsaturated α-ketoesters is reported. This mild strategy provides new access to various synthetically and biologically important 2,3-dihydro-1H-pyrrolo[1,2-a]indoles in a highly enantioselective manner.
- Cheng, Hong-Gang,Lu, Liang-Qiu,Wang, Tao,Yang, Qing-Qing,Liu, Xiao-Peng,Li, Yang,Deng, Qiao-Hui,Chen, Jia-Rong,Xiao, Wen-Jing
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supporting information
p. 3250 - 3254
(2013/04/10)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 184
(2012/09/21)
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- Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity
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Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20c and 21a. Compound 20c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21a, less potent as a dual PPARα/γ activator than 20c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.
- LeNaour, Morgan,Leclerc, Veronique,Farce, Amaury,Caignard, Daniel-Henri,Hennuyer, Nathalie,Staels, Bart,Audinot-Bouchez, Valérie,Boutin, Jean-Albert,Lonchampt, Michel,Dacquet, Catherine,Ktorza, Alain,Berthelot, Pascal,Lebegue, Nicolas
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p. 2179 - 2193
(2013/03/28)
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- Analogs of indole-3-carbinol metabolites as chemotherapeutic and chemopreventive agents
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Novel compounds useful as chemotherapeutic and chemopreventive agents are provided. The compounds are analogs of indole-3-carbinol metabolites wherein the structures and substituents of the compounds are selected to enhance the compounds' overall efficacy, particularly with respect to therapeutic activity, oral bioavailability, long-term safety, patient tolerability, and therapeutic window. The compounds are useful not only in treatment of cancer but also in prevention of cancer. One preferred class of the novel compounds have the structure of formula (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined herein. Pharmaceutical compositions are provided as well, as are methods of synthesis and use.
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Page/Page column 21-22
(2008/06/13)
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- New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(α-azolylbenzyl)-1H-indoles
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Six azolyl substituted indoles were synthesized and tested for their activity to inhibit two P450 enzymes: P450 arom and P450 17α. It was observed that the introduction of α-imidazolylbenzyl chain at carbon 3 or 5 on indole nucleus led to very active molecules. Compounds 22, 23 and especially 33 demonstrate very high potential against P450 arom. Under our assay conditions of high substrate concentration the IC50 are 0.057, 0.0785 and 0.041 μM, respectively. These compounds are moderate inhibitors against P450 17α.
- Le Borgne, Marc,Marchand, Pascal,Delevoye-Seiller, Benedicte,Robert, Jean-Michel,Le Baut, Guillaume,Hartmann, Rolf W.,Palzer, Martina
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p. 333 - 336
(2007/10/03)
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- O-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
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O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl-macrolides of the general structural Formula I: STR1 have been prepared from suitable precursors by alkylation and/or arylation at C-3"" and/or C-4"" of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.
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- D-heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides having immunosuppressive activity
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O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroarylmacrolides of the general structural Formula I: STR1 have been prepared from suitable precursors by alkylation and/or arylation at C-3" and/or C-4" of the cyclohexyl ring. These macrolide immunosuppressants are useful in a mammalian host for the treatment of autoimmune diseases, infectious diseases, the prevention of rejection of foreign organ transplants and/or related afflictions, diseases and illnesses.
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- A new synthesis of 5-bromo-DL-tryptophan
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A new synthesis of 5-bromotryptophan, a potential antisickling agent, from 5-bromo-3-methylindole is described.
- Nagarathnam,Johnson
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p. 2011 - 2017
(2007/10/02)
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