- Structure-activity relationships of valine, tert -leucine, and phenylalanine amino acid-derived synthetic cannabinoid receptor agonists related to ADB-BUTINACA, APP-BUTINACA, and ADB-P7AICA
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Synthetic cannabinoid receptor agonists (SCRAs) remain one the most prevalent classes of new psychoactive substances (NPS) worldwide, and examples are generally poorly characterised at the time of first detection. We have synthesised a systematic library of amino acid-derived indole-, indazole-, and 7-azaindole-3-carboxamides related to recently detected drugs ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA, and characterised these ligands for in vitro binding and agonist activity at cannabinoid receptor subtypes 1 and 2 (CB1 and CB2), and in vivo cannabimimetic activity. All compounds showed high affinity for CB1 (Ki 0.299-538 nM) and most at CB2 (Ki = 0.912-2190 nM), and most functioned as high efficacy agonists of CB1 and CB2 in a fluorescence-based membrane potential assay and a βarr2 recruitment assay (NanoBiT), with some compounds being partial agonists in the NanoBiT assay. Key structure-activity relationships (SARs) were identified for CB1/CB2 binding and CB1/CB2 functional activities; (1) for a given core, affinities and potencies for tert-leucinamides (ADB-) > valinamides (AB-) ? phenylalaninamides (APP-); (2) for a given amino acid side-chain, affinities and potencies for indazoles > indoles ? 7-azaindoles. Radiobiotelemetric evaluation of ADB-BUTINACA, APP-BUTINACA and ADB-P7AICA in mice demonstrated that ADB-BUTINACA and ADB-P7AICA were cannabimimetic at 0.1 mg kg-1 and 10 mg kg-1 doses, respectively, as measured by pronounced decreases in core body temperature. APP-BUTINACA failed to elicit any hypothermic response up to the maximally tested 10 mg kg-1 dose, yielding an in vivo potency ranking of ADB-BUTINACA > ADB-P7AICA > APP-BUTINACA.
- Auw?rter, Volker,Banister, Samuel D.,Boyd, Rochelle,Cairns, Elizabeth A.,Chen, Shuli,Deventer, Marie H.,Ellison, Ross,Gerona, Roy R.,Glass, Michelle,Grafinger, Katharina Elisabeth,Hibbs, David E.,Kevin, Richard C.,Lai, Felcia,Martin, Lewis J.,McGregor, Iain S.,Sparkes, Eric,Stove, Christophe
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p. 156 - 174
(2022/03/30)
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- Regioselective 2-alkylation of indoles with α-bromo esters catalyzed by Pd/P,P=O system
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A palladium-catalyzed 2-alkylation of indoles with α-bromo esters is developed by employing a P,P=O ligand. The method features excellent regioselectivities, mild reaction conditions, and good functional group compatibility. The employment of the P,P=O ligand as well as 4? molecular sieves were crucial for the success of the transformation. Mechanistic studies indicate the reaction proceed through a radical pathway.
- Tian, Wei,Li, Bowen,Tian, Duanshuai,Tang, Wenjun
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supporting information
p. 197 - 200
(2021/08/13)
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- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
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The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
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p. 14895 - 14911
(2021/10/12)
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- Ir-Catalyzed Reversible Acceptorless Dehydrogenation/Hydrogenation of N-Substituted and Unsubstituted Heterocycles Enabled by a Polymer-Cross-Linking Bisphosphine
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The polystyrene-cross-linking bisphosphine ligand PS-DPPBz was effective for the Ir-catalyzed reversible acceptorless dehydrogenation/hydrogenation of N-heterocycles. Notably, this protocol is applicable to the dehydrogenation of N-substituted indoline derivatives with various N-substituents with different electronic and steric natures. A reaction pathway involving oxidative addition of an N-adjacent C(sp3)-H bond to a bisphosphine-coordinated Ir(I) center is proposed for the dehydrogenation of N-substituted substrates.
- Zhang, Deliang,Iwai, Tomohiro,Sawamura, Masaya
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supporting information
p. 5240 - 5245
(2020/07/03)
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- The palladium-catalyzed direct C3-cyanation of indoles using acetonitrile as the cyanide source
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The ligand-free palladium-catalyzed C3-cyanation of indoles via direct C-H functionalization was achieved. This protocol, utilizing CH3CN as a green and readily available cyanide source, produced the desired products in moderate to good yields through transition-metal-catalyzed C-CN bond cleavage. This journal is
- Feng, Kejun,Li, Qiang,Li, Yuanhua,Liu, Bifu,Liu, Min,Zhou, Yongbo
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supporting information
p. 6108 - 6114
(2020/10/21)
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- Manganese-Catalyzed Regioselective Dehydrogenative C-versus N-Alkylation Enabled by a Solvent Switch: Experiment and Computation
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The first base metal-catalyzed regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagent is reported. A single air-and moisture-stable manganese catalyst provides access to either C3-or N-alkylated indoles depending on the solvent used. Mechanistic studies indicate that the reaction takes place through a combined acceptorless dehydrogenation and hydrogen autotransfer strategy.
- Borghs, Jannik C.,Zubar, Viktoriia,Zubar, Viktoriia,Azofra, Luis Miguel,Sklyaruk, Jan,Rueping, Magnus,Rueping, Magnus
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supporting information
p. 4222 - 4227
(2020/06/04)
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- Cobalt-Catalyzed Cycloamination: Synthesis and Photophysical Properties of Polycyclic N-Heterocycles
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The first earth-abundant cobalt-catalyzed cycloamination of indolylquinones and various (hetero)aromatic amine under ligand-free conditions for the synthesis of polycyclic N-heterocycles has been developed. The process allows facile access to polycyclic N-heterocycles with tolerance of chloride, bromide, amino, thio, etc. groups in moderate to high yields (up to 89percent). In addition, The photophysical properties of the synthesized products were evaluated. These products exhibit interesting fluorescence properties, which is promising for fluorescent probes.
- Dong, Yu,He, Shuai,Shi, Zhi-Chuan,Wang, Ji-Yu,Yang, Jian,Zhan, Xiao-Yu,Zhang, Hua,Zhang, Xiao-Mei
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supporting information
(2020/07/15)
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- Catalyst-free assembly of giant tris(heteroaryl)methanes: Synthesis of novel pharmacophoric triads and model sterically crowded tris(heteroaryl/aryl)methyl cation salts
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A series of giant tris(heteroaryl)methanes are easily assembled by one-pot three-component synthesis by simple reflux in ethanol without catalyst or additives. Diversely substituted indoles (Ar1) react with quinoline aldehydes, quinolone aldehydes, chromone aldehydes, and fluorene aldehydes (Ar2CHO) and coumarins (Ar3) in 1:1:1 ratio to form the corresponding tris(heteroaryl)methanes (Ar1Ar2Ar3)CH along with (Ar1Ar1Ar2)CH triads. A series of new 2:1 triads were also synthesized by coupling substituted indoles with Ar2CHO. The coupling reactions could also be carried out in water (at circa 80 °C) but with chemoselectivity favoring (Ar1Ar1Ar2)CH(Ar1Ar2Ar3)CH. The molecular structure of a representative (Ar1Ar2Ar3)CH triad was confirmed by X-ray analysis. Model tris(heteroaryl/aryl)methylium salts were generated by reaction with DDQ/HPF6 and studied by NMR and by DFT and GIAO-DFT.
- Abonia, Rodrigo,Gutiérrez, Luisa F.,Insuasty, Braulio,Quiroga, Jairo,Laali, Kenneth K.,Zhao, Chunqing,Borosky, Gabriela L.,Horwitz, Samantha M.,Bunge, Scott D.
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p. 642 - 654
(2019/04/17)
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- Electrochemical Regioselective Bromination of Electron-Rich Aromatic Rings Using n Bu 4 NBr
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Electrochemical regioselective bromination of electron-rich aromatic rings using stoichiometric tetrabutylammonium bromide (n Bu 4 NBr) has been accomplished under mild conditions. This protocol provides an environmentally friendly and simple way for the construction of C-Br bond in moderate to high yields with wide functional group tolerance.
- Bai, Ya,Che, Xin,Liu, Nian,Ning, Shulin,Shi, Lingling,Wang, Shutao,Wang, Siyu,Xiang, Jinbao,Xie, Wenxia
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supporting information
p. 1313 - 1316
(2019/06/20)
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- Synthesis of 3-Formylindoles via Electrochemical Decarboxylation of Glyoxylic Acid with an Amine as a Dual Function Organocatalyst
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A new method for 3-formalytion of indoles has been developed through electrochemical decarboxylation of glyoxylic acid with the amine as a dual function organocatalyst. The amine facilitated both the electrochemical decarboxylation and the nucleophilic reaction efficiently, whose loading can be as low as 1 mol %. This protocol has a broad range of functional group tolerance under ambient conditions. The gram-scale experiment has shown great potential in the synthetic application of this strategy.
- Lin, Dian-Zhao,Huang, Jing-Mei
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supporting information
p. 5862 - 5866
(2019/08/26)
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- Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria
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The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.
- Barker, William T.,Chandler, Courtney E.,Melander, Roberta J.,Ernst, Robert K.,Melander, Christian
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p. 1776 - 1788
(2019/03/21)
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- Design, synthesis and biological evaluation of novel 2-sulfonylindoles as potential anti-inflammatory therapeutic agents for treatment of acute lung injury
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Acute lung injury (ALI) is primarily driven by inflammation that severely impacts lung function. Novel 2-sulfonylindoles were recently shown to exhibit anti-inflammatory activity through the inhibition of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Here, we synthesized 31 compounds which contained 2-sulfonylindole structure. The compounds 8a, 9g, 9h and 9k exhibited dose-dependent anti-inflammatory activity in vitro. Structural-activity relationship analysis revealed that the introduction of sulfonyl group in indole nucleus may be successful to obtain new anti-inflammatory structures and leads. The compounds 9h and 9k also decreased liposaccharide (LPS)-induced IL-6, IL-1β and vascular cell adhesion molecule-1 (VCAM-1) mRNA expression, both in vitro and in an in vivo model of ALI. Furthermore, the compounds 9h and 9k at a high dose (20 mg/kg) significantly protected against LPS-induced ALI in mice. These results show that compounds 9h and 9k could be a promising lead structure for the treatment of ALI.
- Xia, Qinqin,Bao, Xiaodong,Sun, Chuchu,Wu, Di,Rong, Xiaona,Liu, Zhiguo,Gu, Yugui,Zhou, Jianmin,Liang, Guang
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p. 120 - 132
(2018/10/21)
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- Novel indolo-sophoridinic scaffold as Topo I inhibitors: Design, synthesis and biological evaluation as anticancer agents
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Based on the mechanism of action, novel scaffolds as Topo I inhibitors bearing indole and sophoridinine were designed. Preliminary docking study revealed that some molecules among the designed series possessed promising Topo I inhibitor properties. Subsequently, thirty new compounds were synthesized and characterized by 1H NMR, 13C NMR, and Mass spectral analyses. The compounds were then screened for their antiproliferative and enzymatic inhibitory activities. The results affirmed the consistency between docking and activities and the rationality of the design strategy. Furthermore, compound 10b was chosen as a representative compound to test its anticancer effects in vitro and in vivo. The results showed that 10b caused prominent S phase cell cycle arrest and significantly suppressed tumor growth in HepG2 cell derived mouse model. These findings present a promising series of lead molecules which can serve as potential Topo I inhibitors for the treatment of cancer and a theoretical basis for structural modifications.
- Xu, Yiming,Wu, Lichuan,Rashid, Haroon Ur,Jing, Dewang,Liang, Xiaole,Wang, Haodong,Liu, Xu,Jiang, Jun,Wang, Lisheng,Xie, Peng
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p. 479 - 492
(2018/07/25)
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- Design and synthesis of multipotent 3-aminomethylindoles and 7-azaindoles with enhanced protein phosphatase 2A-activating profile and neuroprotection
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We report the synthesis and pharmacological evaluation of new 3-aminomethylindoles derivatives with neuroprotective properties designed to present multi-target activity centered on reducing the neuronal Ca2+ overload and preventing phosphatase
- Lajarín-Cuesta, Rocío,Arribas, Raquel L.,Nanclares, Carmen,García-Frutos, Eva M.,Gandía, Luis,de los Ríos, Cristóbal
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p. 294 - 309
(2018/08/17)
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- Visible-Light-Driven Palladium-Catalyzed Radical Alkylation of C?H Bonds with Unactivated Alkyl Bromides
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Reported herein is a novel visible-light photoredox system with Pd(PPh3)4 as the sole catalyst for the realization of the first direct cross-coupling of C(sp3)?H bonds in N-aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra- and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp3)?C(sp3) and C(sp2)?C(sp3) bonds in moderate to excellent yields. These redox-neutral reactions feature broad substrate scope (>60 examples), good functional-group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible-light photocatalyst and radicals are involved in the process.
- Zhou, Wen-Jun,Cao, Guang-Mei,Shen, Guo,Zhu, Xing-Yong,Gui, Yong-Yuan,Ye, Jian-Heng,Sun, Liang,Liao, Li-Li,Li, Jing,Yu, Da-Gang
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supporting information
p. 15683 - 15687
(2017/11/16)
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- Divergent dehydrogenative coupling of indolines with alcohols
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The dehydrogenative coupling of indolines with alcohols catalyzed by an iridium complex has been achieved to afford both N- and C3-alkylated indoles selectively, by simply changing the addition time of a base additive. The iridacycle catalyst plays multiple roles in these reactions, which dehydrogenates both amines and alcohols and catalyzes the coupling reactions. Mechanistic studies reveal that a borrowing hydrogen-dehydrogenation process and a dehydrogenationborrowing hydrogen process are involved in N-alkylation and C3-alkylation reactions, respectively. The C3-alkylation reaction involves the direct coupling of two sp3 carbon centers.
- Jiang, Xue,Tang, Weijun,Xue, Dong,Xiao, Jianliang,Wang, Chao
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p. 1831 - 1835
(2017/08/01)
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- Isocyanide-Induced Activation of Copper Sulfate: Direct Access to Functionalized Heteroarene Sulfonic Esters
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A novel and direct approach to alkyl/aryl heteroarene sulfonic esters using copper sulfate as the environmentally benign inorganic sulfonation reagent was first realized with the aid of isocyanide. A variety of heterocycles reacted to afford the corresponding sulfonic esters through C?H functionalization. In this transformation, the otherwise inert copper sulfate was unusually activated by an isocyanide and employed as the source of the sulfonic substituents in an unprecedented fashion. The findings suggest that an appropriate activator may liberate the chemical activities of some relatively inert inorganic salts for organic synthesis.
- Hong, Xiaohu,Tan, Qitao,Liu, Bingxin,Xu, Bin
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supporting information
p. 3961 - 3965
(2017/03/27)
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- Gold-catalyzed oxidative couplings of two indoles with one aryldiazo cyanide under oxidant-free conditions
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Gold-catalyzed oxidative couplings of two indoles and one α-cyano gold carbene to form bis(indolyl)methane derivatives are described. Two different indoles are compatible with these reactions to provide reasonable yields. A plausible mechanism is postulated to rationalize the experimental data including product distributions, D2O labeling, and the significant effects of gold catalysts and cyano groups.
- Singh, Rahulkumar Rajmani,Liu, Rai-Shung
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supporting information
p. 4593 - 4596
(2017/04/28)
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- An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer
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A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of redu
- Colley, Helen E.,Muthana, Munitta,Danson, Sarah J.,Jackson, Lucinda V.,Brett, Matthew L.,Harrison, Joanne,Coole, Sean F.,Mason, Daniel P.,Jennings, Luke R.,Wong, Melanie,Tulasi, Vamshi,Norman, Dennis,Lockey, Peter M.,Williams, Lynne,Dossetter, Alexander G.,Griffen, Edward J.,Thompson, Mark J.
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p. 9309 - 9333
(2015/12/23)
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- Indole functionalization via photoredox gold catalysis
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The use of photoredox catalyst [Au2(dppm)2]Cl2 to initiate free-radical cyclizations onto indoles is reported. Excitation of the dimeric Au(I) photocatalyst for the reduction of unactivated bromoalkanes and bromoarenes is used for the generation of carbon-centered radicals. Previous to this work, reduction processes leading to indole functionalization utilizing photoredox catalysts were limited to activated benzylic or α-carbonyl-positioned bromoalkanes. This method offers a mild and safe alternative to organostannanes and pyrophoric initiators for access to high energy radicals that were previously inaccessible through catalytic or stoichiometric means.
- Kaldas, Sherif J.,Cannillo, Alexandre,McCallum, Terry,Barriault, Louis
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supporting information
p. 2864 - 2866
(2015/06/16)
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- An efficient ultrasound-assisted synthesis of n-alkyl derivatives of carbazole, indole, and phenothiazine
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Heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen such as carbazole, indole, and phenothiazine can be efficiently alkylated in DMSO or N,N-DMF under ultrasonic irradiation in the presence of potassium hydroxide as a base. In almost all cases, a dramatic reduction of the reaction time results and a clear yield increase accompanied by an improved quality of the products occurs.
- Zhao, Sanhu,Kang, Jin,Du, Yuting,Kang, Jingyan,Zhao, Xiaoni,Xu, Yinfeng,Chen, Ruixi,Wang, Qianqian,Shi, Xitao
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supporting information
p. 683 - 689
(2014/06/10)
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- Copper-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids
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A novel and efficient Cu-promoted decarboxylative direct C3-acylation of N-substituted indoles with α-oxocarboxylic acids for the synthesis of 3-acylindoles was developed. The Royal Society of Chemistry.
- Yu, Lin,Li, Pinhua,Wang, Lei
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supporting information
p. 2368 - 2370
(2013/06/27)
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- Pd-catalyzed direct coupling of indoles with carbon monoxide and alkynes: Selective synthesis of linear α,β-unsaturated ketones
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A new strategy is described for the direct coupling of indoles with CO and alkynes to generate α,β-unsaturated ketones. This procedure, employing Xantphos and Pd(CH3CN)4(BF4) 2, is attractive from both environmental and operational points of view and adds value to the method for the carbonylation of alkynes by using carbon nucleophiles and affording linear regioselectivity.
- Zeng, Fanlong,Alper, Howard
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supporting information
p. 2034 - 2037
(2013/06/04)
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- Palladium-assisted regioselective C-H cyanation of heteroarenes using isonitrile as cyanide source
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A palladium-catalyzed regioselective C-H cyanation of heteroarenes was achieved using tert-butyl isocyanide as "CN" source, which provides a new and unique strategy for the preparation of (hetero)aryl nitriles. Indoles, pyrroles, and aromatic rings could be efficiently cyanated through C-H bond activation with high regioselectivity.
- Xu, Shuguang,Huang, Xiaomei,Hong, Xiaohu,Xu, Bin
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supporting information
p. 4614 - 4617
(2012/11/06)
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- Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C-H activation: Mechanism and applications
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A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles was developed based on a norbornene-mediated regioselective cascade C-H activation. The detailed reaction mechanism was investigated by NMR spectroscopic analyses, characterization of the key intermediate, deuterium labeling experiments, and kinetic studies. The results indicate that a catalytic cycle operates, in which an N-norbornene type palladacycle is formed as the key intermediate. Oxidative addition of alkyl bromide to the Pd(II) center in this intermediate is the rate-determining step of the reaction. The synthetic utility of this indole 2-alkylation method was demonstrated by its application in natural product total synthesis. A new and general strategy to synthesize Aspidosperma alkaloids was established employing the indole 2-alkylation reaction as the key step, and two structurally different Aspidosperma alkaloids, aspidospermidine and goniomitine, were synthesized in concise routes.
- Jiao, Lei,Herdtweck, Eberhardt,Bach, Thorsten
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supporting information
p. 14563 - 14572
(2012/10/29)
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- Copper-catalysed direct C-H bond oxidative acetoxylation and iodination of indoles
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A novel Cu(OAc)2-catalysed direct C-H bond oxidative acetoxylation and iodination of indoles using PhI(OAc)2 as a terminal oxidant is reported. Adopting this method, a series of 3-iodoindoles and indol-3-yl acetates were obtained in nearly 1:1 ratio yield.
- Ge, Shao-Peng,Zhang, Xiao-Hong,Han, Jiang-Sheng,Zhong, Ping
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experimental part
p. 356 - 359
(2012/10/08)
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- Palladium-catalyzed direct 2-alkylation of indoles by norbornene-mediated regioselective cascade C-H activation
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A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles has been developed. This reaction relies on a norbornene-mediated cascade C-H activation process at the indole ring, which features high regioselectivity and excellent functional group tolerance. The reaction represents the first example for a generally applicable, direct C-H alkylation of indole at the 2-position.
- Jiao, Lei,Bach, Thorsten
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supporting information; experimental part
p. 12990 - 12993
(2011/10/03)
-
- Directed synthesis and immunoactive properties of (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanyl(sulfonyl)alkanecarboxylic acids
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A general method for the synthesis of 1-alkyl(allyl)(benzyl)-substituted (indol-3-yl)-sulfanylalkanecarboxylic acids and hexane-1,6-diyl(1,4- phenylenemethylene)bisindol-3-ylsulfanylalkanecarboxylic acids from the corresponding N-substituted indoles and bisindoles, thiourea, iodine, and halogencarboxylic acids was developed. The oxidation of substituted (indol-3-yl)sulfanylalkanecarboxylic acids for the first time afforded their analogs containing the sulfonyl group. New (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanyl(sulfonyl)-alkanecarboxylic acids, which are structural analogs of highly active immunomodulators of indacetamin and VILIM, were synthesized. Among the studied (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanylacetic and -sulfonylalkanecarboxylic acids, the compounds exhibiting high dose-dependent antiproliferative activity by the ability to affect the spontaneous and mitogen-stimulated splenocyte proliferation of mice in vitro were found.
- Mirskova,Levkovskaya,Kolesnikova,Perminova,Rudyakova,Adamovich
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experimental part
p. 2236 - 2246
(2011/08/05)
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- Alkylation of the ambident indole ion in ionic liquids
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Alkylation of the ambident indole anion in ionic liquids has been investigated. The reaction rate is greater in ionic liquids than in organic solvents. The polarity of certain ionic liquids has been determined to be located between methanol and acetonitrile. 2008 Springer Science+Business Media, Inc.
- Vavilina,Zicmanis,Drozdova,Mekss,Klavins
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p. 530 - 541
(2013/07/27)
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- Organic Reactions in Ionic liquids: N-Alkylation of Phthalimide and Several Nitrogen Heterocycles
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N-Alkylation of heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen with alkyl halides is accomplished in ionic liquids ([bmim]BF4= 1-butyl-3-methylimidazolium te trafluoroborate, [bmim]PF6 = 1-butyl-3-methylimidazolium hexafluorophosphate, [buPy]BF4 = butylpyridiniurri tetrafluoroborate) in the presence of potassium hydroxide as a base. In this manner, phthalimide, indole, benzimidazole, succinimide can be successfully alkylated. The procedure is convenient, efficient, and generally affords the N-alkylated product exclusively.
- Le, Zhang-Gao,Chen, Zhen-Chu,Hu, Yi,Zheng, Qin-Guo
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p. 208 - 212
(2007/10/03)
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- Efficient nickel-mediated intramolecular amination of aryl chlorides
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(Matrix presented) The use of an in situ generated Ni(0) catalyst associated with 2,2′-bipyridine or N,N′ -bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr) as a ligand and NaO-t-Bu as the base for the intramolecular coupling of aryl chlorides with amines is described. The procedure has been applied to the formation of five-, six-, and seven-membered rings.
- Omar-Amrani, Rafik,Thomas, Antoine,Brenner, Eric,Schneider, Raphael,Fort, Yves
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p. 2311 - 2314
(2007/10/03)
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- Synthesis of 2,3-dihydroindoles, indoles, and anilines by transition metal-free amination of aryl chlorides
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Aliphatic and aromatic amines react with 2- and 3-chlorostyrene in the presence of potassium tert-butoxide to give N-substituted 2,3-dihydroindoles in good yields. The combination of this domino-amination protocol with a suitable dehydrogenation reaction gives access to pharmacologically interesting indoles in a one-pot procedure. Overall product yields of N-substituted indoles > 50% are obtained by this method starting from commercially available substrates. In addition to the intramolecular base-promoted amination of aromatic C-Cl, bonds, metal-free intermolecular aminations of aryl chlorides with primary and secondary amines are described. The use of potassium tert-butoxide as base allows the synthesis of various anilines in good to excellent yields. Due to the formation of aryne intermediates, either N-substituted anilines or meta-substituted anilines are produced with excellent selectivities.
- Beller,Breindl,Riermeier,Tillack
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p. 1403 - 1412
(2007/10/03)
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- Ortho-Vinylation reaction of anilines
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N-Alkylanilines and anilines are vinylated at the ortho-position with ethyne in the presence of SnCl4-Bu3N.
- Yamaguchi, Masahiko,Arisawa, Mieko,Hirama, Masahiro
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p. 1399 - 1400
(2007/10/03)
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- Regioselective alkylation in ionic liquids
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The room temperature ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6], is used as a 'green' recyclable alternative to dipolar aprotic solvents for the regioselective alkylation at the heteroatom of indole and 2-naphthol.
- Earle, Martyn J.,McCormac, Paul B.,Seddon, Kenneth R.
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p. 2245 - 2246
(2007/10/03)
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- 29. Synthesis of Indole Derivatives by [2 + 2] Photocycloaddition of Indoline-2-thiones with Alkenes and Photodesulfurization of Indoline-2-thiones
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The photochemical synthesis of indole derivatives starting from the indoline-2-thiones 1 is described. Irradiation of indoline-2-thiones 1 in the presence of alkenes 3 gave 2-alkyl-3H-indoles 4-7 or 2-alkylindoles 8-22 through the ring cleavage of the intermediates, spirocyclic amino-thietanes, initially derived by [2 + 2] cycloaddition of the C=S bond of 1 and the C=C bond of 3. Irradiation of 1 in the presence of trialkylamines 26 gave desulfurization products 27-32 and unexpected 3-alkylindoles 33-40. N-Acylindoline-2-thiones 1l-p yielded the deacylated products, indoline-2-thiones 1a-b, and ethyl esters 43 through γ-H abstraction by the excited thioamide S-atom when irradiated in CDCl3/EtOH or benzene/EtOH. Oxygen analogues 2a-d also underwent intramolecular H abstraction to give the indolin-2-ones 2e-f and ethyl esters 43 in a similar way.
- Nishio, Takehiko,Oka, Mitsuru
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p. 388 - 397
(2007/10/03)
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- Radical cycloaddition by nickel(II) complex-catalyzed electroreduction. A method for preparation of pyrrolopyridine and pyrrolopyrrole derivatives
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Cycloalkano[a]pyrroles were obtained by reductive radical cycloaddition of 1-(2-iodoethyl)pyrrole and activated olefins or by cyclization of 1-(ω- iodoalkyl)pyrroles, through electroreduction of the iodides using nickel(II) complex as an electron-transfer catalyst.
- Ozaki, Shigeko,Mitoh, Shizue,Ohmori, Hidenobu
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p. 2020 - 2024
(2007/10/03)
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- Synthesis of indoles from N-substituted anilines and triethanolamine by a homogeneous ruthenium catalyst
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N-substituted anilines react with triethanolamine in the presence of a catalytic amount of a homogeneous ruthenium catalyst to give the corresponding 1-substituted indoles in good yields.
- Shim,Youn,Lee,Kim,Cho,Uemura,Watanabe
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p. 1349 - 1353
(2007/10/03)
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- Reduction of N-Acylsatins with Complex
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N-acylsatins can be directly converted in high yields to N-alkylindoles by reduction, at room temperature, with freshly prepared BH3*THF complex.This reduction represents an alternative method for the preparation of N-alkylindoles with long-chain alkyl groups, especially those with halogens within the carbon chain.
- Pinto, Angelo C.,Silva, Filipe Soares Q. da,Silva, Rosangela B. da
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p. 8923 - 8926
(2007/10/02)
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- Regioselectivity Control in Alkylation Reactions of Indolyl Ambident Anion
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The regioselectivity of N- and C-3(β)-alkylations of indolylmetal salts was studied under various conditions.The effect of counter metal ion is crucial in determining the regioselectivity.In tetrahydrofuran, exclusive N-alkylation occurred with the potassium salt, but the extent of C-3-alkylation increased with the sodium and lithium salts and became predominant with the magnesium bromide salt.However, N-alkylation was favoured generally in more polar solvents and for alkyl toluene-p-sulphonates it was favoured even with magnesium bromide salts.The reactivity and regioselectivity of the alkylations were correlated with the calculated electron density of the indolyl anion and with 13C n.m.r. chemical shifts of the metal salts.
- Nunomoto, Sadaaki,Kawakami, Yuhsuke,Yamashita, Yuya,Takeuchi, Hisato,Eguchi, Shoji
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p. 111 - 114
(2007/10/02)
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- Ruthenium Complex Catalyzed N-Heterocyclization. Syntheses of Quinolines and Indole Derivatives from Aminoarenes and 1,3-Propanediol of Glycols
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Aniline reacts with 1,3-propanediol under reflux in diglyme with spontaneous hydrogen evolution in the presence of a catalytic amount of ruth enium trichloride hydrate ( RuCl3*nH2O)-tributylphosphine (PBu3) to give quinoline in good yield.The yield of quinoline was markedly affected by the molar ratios of aniline to 1,3-propanediol and PBu3 to RuCl3*nH2O.The best yield (76percent) was achieved at the molar ratios of 2.5 of aniline / 1,3-propanediol and 2.0 of PBu3 / RuCl3*nH2O.Also, N-substituted anilines react with ethylene glycol in the presence of a catalytic amount of dichlor otris(triphenylphosphine)ruthenium (RuCl2(PPh3)3) to give N-substituted indole derivatives.The reactions were carried out at 180 deg C in dioxane with spontaneus hydrogen evolution.Aminoarenes also react with 2,3-butanediol and 1,2-cyclohexanediol ( mixture of cis and trans ) in the presence of RuCl2(PPh3)3 to give the corresponding 2,3-dimethylindoles and 1,2,3,4-tetrahydrocarbazoles in good to excellent yields.As the key intermediates of the reactions, N,N'-diarylpropylenediamine (5a) and N,N'-diarylethylenediamine (5b) and their dehydrogenated imine derivatives are postulated.
- Tsuji, Yasushi,Huh, Keun-Tae,Watanabe, Yoshihisa
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p. 1673 - 1680
(2007/10/02)
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- ELECTROREDUCTIVE N-ALKYLATION OF AMIDES, CARBAMATES, AND N-HETEROCYCLES
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The N-alkylation of amides, lactams, carbamates, and N-heterocycles was easily attained in good yields by the electroreduction of the substrates in the presence of alkyl halides.
- Shono, Tatsuya,Kashimura, Shigenori,Nogusa, Hideo
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p. 425 - 428
(2007/10/02)
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- INDOLE SYNTHESES UTILIZING o-METHYLPHENYL ISOCYANIDES.
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New indole synthesis starting with o-methylphenyl isocyanides such as o-tolyl, 2,4-xylyl, and 2,6-xylyl isocyanide is described. Treatment of o-tolyl isocyanide with LDA in diglyme at minus 78 degree C generated selectively o-(lithiomethyl)phenyl isocyanide in an almost quantitative yield, which on warming up to room temperature was cyclized to indole after aqueous workup. Similarly, 2,4-xylyl and 2,6-xylyl and 2,6-xylyl isocyanides were cyclized to 5-methylindole and 7-methylindole quantitatively. The o-(lithiomethyl)phenyl isocyanides reacted with electrophiles such as alkyl halides and alkylene oxides to give o-alkylphenyl isocyanides, which were cyclized via the lithiation at the orthobenzylic carbon to afford 3-substituted indoles.
- Ito,Kobayashi,Seko,Saegusa
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- N-Alkylation of Pyrrole, Indole, and Several Other Nitrogen Heterocycles Using Potassium Hydroxide as a Base in the Presence of Polyethylene Glycols or Their Dialkyl Ethers
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The alkylation of pyrrole and indole in aqueous potassium hydroxide-organic two-phase systems in the presence of polyethylene glycols (PEG) or their dialkyl ethers (PEG-ether) as phase transfer catalysts (PTC) gave substantial quantities of the C-alkylated and C,N-polyalkylated products as well as the N-alkylated products.This fact is similar to that obtained in the presence of quaternary ammonium salts as PTC.In powdered potassium hydroxide-organic two-phase system, the yields of the N-alkylated products were generally high.Especially, when PEG-ether were employed as solvents, the N-alkylated products were obtained in excellent yields under mild conditions.Imidazole, benzimidazole, carbazole, 2-methylindole, and benzotriazole were similarly N-alkylated in high yields by this method.
- Sukata, Kazuaki
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p. 280 - 284
(2007/10/02)
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- INDOLE DERIVATIVES. 121. CONVENIENT METHOD FOR THE PREPARATION OF N-ALKYLINDOLES
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A new method was developed for the synthesis of N-alkylindoles from phenylhydrazones of aldehydes and ketones that makes it possible to obtain diverse N-alkylindoles under mild conditions.
- Suvorov, N. N.,Plutitskii, D. N.,Smushkevich, Yu. I.
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p. 268 - 270
(2007/10/02)
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- A NEW MODIFICATION OF THE FISCHER REACTION. SYNTHESIS OF N-ALKYLINDOLES UNDER THE CONDITIONS OF EXTRACTIVE BASE CATALYSIS
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A new modification of the Fischer reaction, which makes it possible to obtain 1-alkyl-, 1-alkyl-2-aryl, 1,3-dialkyl-, and 1,2,3-trialkylindoles under the conditions of interphase base catalysis, was developed.
- Suvorov, N. N.,Plutitskii, D. N.,Smushkevich, Yu. I.
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p. 766 - 769
(2007/10/02)
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- Phase-Transfer Alkylation of Heterocycles in the Presence of 18-Crown-6 and Potassium tert-Butoxide
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It has been found that the N-alkylation of heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen can be accomplished in diethyl ether via a phase-transfer process in which 18-crown-6 is employed as the catalyst and potassium tert-butoxide is employed as the base.In this manner, pyrrole (1), indole (2), pyrazole (3), imidazole (4), benzimidazole (5), benzotriazole (6), carbazole (7), and methyl indole-3-acetate (8) can be successfully alkylated.The procedure is convenient and mild and generally gives rise to exclusive N-alkylation.
- Guida, Wayne C.,Mathre, David J.
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p. 3172 - 3176
(2007/10/02)
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