- Improved preparation method of indole-2-formic acid as starting material of perindopril
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The invention discloses an improved preparation method of indole-2-formic acid by using perindopril as a starting raw material, which comprises the following steps: S1, taking 2-bromobenzaldehyde and ethyl acetate as raw materials, under the action of sodium ethoxide, carrying out Claisen-Schmidt condensation reaction to synthesize ethyl 2-bromocinnamate; s2, carrying out cyclization reaction on the ethyl 2-bromocinnamate in an amide solvent by using cuprous halide as a coupling catalyst and sodium azide as a nitrogen source to synthesize the indole-2-formic acid in one pot. According to the invention, 2-bromobenzaldehyde is used as a raw material for preparation, ethyl 2-bromocinnamate is firstly prepared, then cuprous halide is used as a coupling catalyst, sodium azide is used as a nitrogen source, cyclization reaction is carried out in an amide solvent, indole-2-formic acid is synthesized in one pot, and the HPLC content is 99% or above.
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- Preparation method of indole-2-formic acid derivative
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The invention discloses a preparation method of an indole-2-formic acid derivative, wherein the preparation method comprises the steps: by using an oxazolone compound as a raw material, carrying out areaction in an organic solvent at the temperature of 70-150 DEG C under the action of alcohol, alkali and a catalyst, tracking by TLC until the raw material is completely reacted, and separating andpurifying the obtained reaction solution to obtain the indole-2-formic acid derivative. The technology is adopted, the target product indole-2-formic acid derivative is prepared by taking an oxazolonecompound as a raw material through one-pot reaction under the action of alcohol, alkali and a catalyst, so that direct conversion from an oxazolone ring to an indole ring is realized, reaction stepsand an intermediate process are reduced, and the method has the characteristics of cheap raw materials, environmental friendliness and the like, and is suitable for industrial production.
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Paragraph 0030-0041
(2020/07/14)
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- MnOx/catechol/H2O: A cooperative catalytic system for aerobic oxidative dehydrogenation of N-heterocycles at room temperature
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Amorphous manganese oxide doped by Na+ ion (Na-AMO) was successfully prepared and found to be an efficient heterogeneous catalyst in aerobic oxidative dehydrogenation of N-heterocycles, cooperate with catechol. Na-AMO was fully characterized by XRD, XPS BET H2-TPR, CO2-TPD FT-IR, TEM, SEM and had rich amounts of surface absorbed active oxygen species which are responsible for superior catalytic performance. The synergistic interaction between Na-AMO and catechol makes catalytic system efficient and tolerant, which offers various N-heterocycles in good to excellent yields under mild conditions.
- Tang, Tao,Bi, Xiuru,Meng, Xu,Chen, Gexin,Gou, Mingxia,Liu, Xiang,Zhao, Peiqing
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- Visible-Light-Promoted Efficient Aerobic Dehydrogenation of N-Heterocycles by a Tiny Organic Semiconductor Under Ambient Conditions
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An efficient reusable catalytic system has been developed based on perylene diimide (PDI) organic semiconductor for the aerobic dehydrogenation of N-heterocycles with visible light. This practical catalytic system without any additives proceeds under ambient conditions. The minute aggregates of PDI molecules on the surface of SiO2 nanospheres form tiny organic semiconductors, resulting in high-efficiency photo-oxidative activity. Notably, the robustness of this method is demonstrated by the synthesis of a wide range of N-heteroarenes, gram-scale experiments as well as reusability tests.
- Su, Chenliang,Yu, Kunyi,Zhang, Hanjie,Zhu, Yongfa
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supporting information
p. 1956 - 1960
(2020/04/10)
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- Aerobic oxidative dehydrogenation of N-heterocycles over OMS-2-based nanocomposite catalysts: Preparation, characterization and kinetic study
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OMS-2-based nanocomposites doped with tungsten were prepared for the first time and their remarkably enhanced catalytic activity and recyclability in aerobic oxidative dehydrogenation of N-heterocycles were examined in detail. Many tetrahydroquinoline derivatives and a broad range of other N-heterocycles could be tolerated by the catalytic system using a biomass-derived solvent as a reaction medium. Newly generated mixed crystal phases, noticeably enhanced surface areas and labile lattice oxygen of the OMS-2-based nanocomposite catalysts might contribute to their excellent catalytic performance. Moreover, a kinetic study was extensively performed which concluded that the dehydrogenation of 1,2,3,4-tetrahydroquinoline is a first-order reaction, and the apparent activation energy is 29.66 kJ mol-1
- Bi, Xiuru,Tang, Tao,Meng, Xu,Gou, Mingxia,Liu, Xiang,Zhao, Peiqing
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p. 360 - 371
(2020/02/04)
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- Design and synthesis of thiadiazolo-carboxamide bridged β-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity
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The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged β-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a–k, with an IC50 50 value of 2.82 ± 0.10 μM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 μM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 μM) with a selectivity index range of 14.9–25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.
- Tokala, Ramya,Sana, Sravani,Lakshmi, Uppu Jaya,Sankarana, Prasanthi,Sigalapalli, Dilep Kumar,Gadewal, Nikhil,Kode, Jyoti,Shankaraiah, Nagula
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- Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: A novel and potent cell cycle arrest and apoptosis inducer through the p53-MDM2 pathway
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A series of novel oridonin derivatives bearing various substituents on the 14-OH position were designed and synthesised. Their antitumour activity was evaluated in vitro against three human cancer cell lines (HCT116, BEL7402, and MCF7). Most tested derivatives showed improved anti-proliferative activity compared to the lead compound oridonin and the positive control drug 5-fluorouracil (5-Fu). Among them, compound C7 (IC50 = 0.16 μM) exhibited the most potent anti-proliferative activity against HCT116 cells; it was about 43- and 155-fold more efficacious than that of oridonin (IC50 = 6.84 μM) and 5-Fu (IC50 = 24.80 μM) in HCT116 cancer cells. Interestingly, the IC50 value of compound C7 in L02 normal cells was 23.6-fold higher than that in HCT116 cells; it exhibited better selective anti-proliferative activity and specificity than oridonin and 5-Fu. Furthermore, compound C7 possibly induced cell cycle arrest and apoptosis by regulating the p53-MDM2 signalling pathway. Notably, C7 displayed more significant suppression of tumour growth than oridonin in colon tumour xenograft models where the tumour growth inhibition rate was 85.82%. Therefore, compound C7 could be a potential lead compound for the development of a novel antitumour agent.
- Shen, Qing-Kun,Deng, Hao,Wang, Shi-Ben,Tian, Yu-Shun,Quan, Zhen-Shan
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- RhCl3·3H2O-Catalyzed Regioselective C(sp2)-H Alkoxycarbonylation: Efficient Synthesis of Indole- and Pyrrole-2-carboxylic Acid Esters
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The C2-selective C-H alkoxycarbonylation of indoles with alcohols and CO catalyzed by RhCl3·3H2O is disclosed that offers convenient access to diverse indole-2-carboxylic esters. The rhodium-based catalysts outperformed all other precious-metal catalysts investigated. In addition, this protocal was found applicable to the synthesis of pyrrole-2-carboxylic esters, and allowed the C-H alkoxycarbonylation in an intramolecular fashion. Preliminary mechanistic studies indicate that C-H cleavage is not likely involved in the rate-determining step, and a five-membered rhodacycle might be an intermediate involved in the reaction.
- Zhao, Kang,Du, Rongrong,Wang, Bingyang,Liu, Jianhua,Xia, Chungu,Yang, Lei
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p. 5545 - 5551
(2019/06/18)
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- A Reusable Cobalt Catalyst for Reversible Acceptorless Dehydrogenation and Hydrogenation of N-Heterocycles
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The development of robust catalytic systems based on base-metals for reversible acceptorless dehydrogenation (ADH) and hydrogenation of feedstock chemicals is very important in the context of ‘hydrogen storage’. Herein, we report a highly efficient reusable cobalt-based heterogeneous catalyst for reversible dehydrogenation and hydrogenation of N-heterocycles. Both the ADH and the hydrogenation processes operate under mild, benign conditions.
- Jaiswal, Garima,Subaramanian, Murugan,Sahoo, Manoj K.,Balaraman, Ekambaram
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p. 2449 - 2457
(2019/05/10)
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- 1H-indole-2-carboxamide derivative and preparation method and applications thereof
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The invention belongs to the technical field of medicine, and discloses a 1H-indole-2-carboxamide derivative of a formula (I) and a preparation method thereof. The preparation method includes the following steps: a compound of a formula (II) and sodium hydroxide are subjected to a hydrolysis reaction to synthetize a compound of a formula (III); the compound of the formula (III) and H2NR2 are subjected to an amidation reaction to synthetize a compound of a formula (IV); the compound of the formula (IV) and halogenated R1 are subjected to a nucleophilic substitution reaction to synthetize a compound of a formula (V); the compound of the formula (V) and a selectfluor are subjected to an electrophilic substitution reaction to synthetize a compound of a compound (VI), and the compound of the formula (VI) and the halogenated R1 are subjected to the nucleophilic substitution reaction to synthetize the compound of the formula (I). The 1H-indole-2-carboxamide derivative of the formula (I) is aagonist with high affinity, selectivity and activity for CB2 receptors, and can be potentially used for treating a plurality of diseases such as multiple sclerosis, autoimmune diseases, osteoporosis,arthralgia, inflammatory pain, and neurodegenerative diseases.
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Paragraph 0125; 0126
(2018/12/05)
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- Mild and versatile potassium fluoride/tetrabutylammonium fluoride protocol for ester hydrolysis
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A mild and versatile protocol of potassium fluoride/tetrabutylammonium fluoride (KF/TBAF) in aqueous tetrahydrofuran for ester hydrolysis has been developed. The method is applied on variety of aliphatic and aromatic ester moieties bearing acid or base sensitive functional groups. The conditions have been also applied on acetates to yield alcohols. The chirality of optically pure esters remained intact with the conditions of the reaction.
- Vijayalakshmi,Balakrishna,Mustafa, Shaik
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p. 309 - 311
(2018/01/11)
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- Method for preparing perindopril despinner and intermediate thereof
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The invention discloses a method for preparing perindopril despinner and an intermediate thereof. The method comprises the following steps: halogenating N-propionyl indole-2-carboxylic acid under theaction of a halogenation reagent so as to obtain a halogenation product, and further carrying out amine substitution and catalytic hydrogenation reduction on the obtained halogenation product, therebyobtaining the perindopril despinner. Compared with the prior art, the method is cheap and easy in reaction raw material, has a total yield as high as 64%, is high in product purity and is applicableto industrial production.
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Paragraph 0038; 0045-0047
(2018/11/22)
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- A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction
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The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na2S2O4 in dioxane/water at reflux.
- Mamedov, Vakhid A.,Mamedova, Vera L.,Syakaev, Victor V.,Khikmatova, Gul'naz Z.,Korshin, Dmitry E.,Kushatov, Temur A.,Latypov, Shamil K.
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supporting information
p. 3923 - 3925
(2018/10/02)
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- CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies
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CO2-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO2 radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.
- Riemer, Daniel,Schilling, Waldemar,Goetz, Anne,Zhang, Yu,Gehrke, Sascha,Tkach, Igor,Hollóczki, Oldamur,Das, Shoubhik
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p. 11679 - 11687
(2018/11/23)
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- Tandem Wittig – Reductive annulation decarboxylation approach for the synthesis of indole and 2-substituted indoles
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A simple tandem Wittig reaction-reductive decarboxylation route is established for the synthesis of indoles from commercially available o-nitrobenzaldehydes and a stable phosphorane. The method allows access to indoles in a very fast manner without involving any metal or expensive reagents or inert atmosphere. Also 2-substituted indoles are obtained which forms an important core of many biological active compounds.
- Volvoikar, Prajesh S.,Tilve
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p. 1851 - 1854
(2018/04/14)
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- Substituted indole - 2 - formic acid (by machine translation)
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This invention relates to a substituted indole - 2 - carboxylic acid synthesis method, is to replace the phenyl hydrazine hydrochloride or arylhydrazines as raw materials, through with pyruvic acid ethyl ester cheng zong, Fischer indole synthesis by reaction of substituted indole - 2 - carboxylic acid ethyl ester, hydrolysis to obtain the substituted - 2 - carboxylic acid. Product purity is greater than 97%, the reaction yield is 64%. Synthesis method of the invention with non-harsh conditions, the operation is simple, and environmental friendliness, it has certain economic benefits. It is a kind of raw materials are easy, simple operation, three wastes, high yield of indole - 2 - carboxylic acid synthesis method. (by machine translation)
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Paragraph 0035; 0038; 0058
(2017/10/28)
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- Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents
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Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the “Malaria Box”. After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.
- Pieroni, Marco,Azzali, Elisa,Basilico, Nicoletta,Parapini, Silvia,Zolkiewski, Michal,Beato, Claudia,Annunziato, Giannamaria,Bruno, Agostino,Vacondio, Federica,Costantino, Gabriele
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p. 1959 - 1970
(2017/03/17)
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- Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity
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Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.
- Franz, Nicholas D.,Belardinelli, Juan Manuel,Kaminski, Michael A.,Dunn, Louis C.,Calado Nogueira de Moura, Vinicius,Blaha, Michael A.,Truong, Dan D.,Li, Wei,Jackson, Mary,North, E. Jeffrey
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p. 3746 - 3755
(2017/06/13)
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- Amidoalkylindoles as Potent and Selective Cannabinoid Type 2 Receptor Agonists with in Vivo Efficacy in a Mouse Model of Multiple Sclerosis
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Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16-28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114-142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.
- Shi, Ying,Duan, Yan-Hui,Ji, Yue-Yang,Wang, Zhi-Long,Wu, Yan-Ran,Gunosewoyo, Hendra,Xie, Xiao-Yu,Chen, Jian-Zhong,Yang, Fan,Li, Jing,Tang, Jie,Xie, Xin,Yu, Li-Fang
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p. 7067 - 7083
(2017/09/07)
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- A Pd/C reduction method adopting water as a solvent for preparing indole-2-carboxylic acid
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The invention relates to a Pd/C reduction method adopting water as a solvent for preparing indole-2-carboxylic acid. Ethyl 2-nitrophenyl pyruvate is subjected to hydrogenation reduction cyclization in a high-pressure reaction kettle by adopting water as the solvent and adopting Pd/C as a catalyst, the Pd/C is recovered by filtering, and a filtrate is subjected to distillation, acidity adjustment and crystallization to obtain the indole-2-carboxylic acid. The catalyst is easily available and low in cost and can be repeatedly used. According to the method, the raw material can be easily recovered, post-treatment operation is simple, environment pollution is low, reaction operation safety is high, a reaction yield is high, and product quality is good, thus facilitating industrialization.
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Paragraph 0010; 0012; 0014; 0016
(2017/04/26)
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- Halogen–metal exchange on bromoheterocyclics with substituents containing an acidic proton via formation of a magnesium intermediate
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A selective and practical bromine–metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.
- Tian, Qingqiang,Shang, Suqin,Wang, Huajun,Shi, Guoqiang,Li, Zhiyao,Yuan, Jianyong
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supporting information
(2017/12/05)
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- Synthesis of 3,3-Dihalo-2-oxindoles from 2-Substituted Indoles via Halogenation–Decarboxylation/Desulfonamidation–Oxidation Process
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A novel one-pot reaction which combines halogenation, decarboxylation/desulfonamidation with oxidation has been developed. Diverse valuable 3,3-dihalo-2-oxindole compounds can be produced rapidly and safely with isolated yields of up to 98% under mild conditions. (Figure presented.).
- Jiang, Xiaojian,Zhang, Feng,Yang, Junjie,Yu, Pei,Yi, Peng,Sun, Yewei,Wang, Yuqiang
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supporting information
p. 3938 - 3942
(2016/12/30)
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- Synthesis of new functionalized indoles based on ethyl indol-2-carboxylate
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Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis.
- Boraei, Ahmed T. A.,El Ashry, El Sayed H.,Barakat, Assem,Ghabbour, Hazem A.
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- MAGNETICALLY SEPARABLE IRON-BASED HETEROGENEOUS CATALYSTS FOR DEHYDROGENATION OF ALCOHOLS AND AMINES
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The present invention discloses an iron-based nitrogen doped graphene catalyst, process for preparation thereof and use of said catalyst in oxidant-free catalytic dehydrogenation of alcohols and amines to the corresponding carbonyl compounds, amines and N-heterocylic compounds with extraction of molecular hydrogen as the only by-product.
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Page/Page column 19; 20; 21
(2016/12/22)
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- Synthetic method of indole-2-formic acid
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The invention discloses a synthetic method of indole-2-formic acid. According to the synthetic method, o-nitrotoluene and diethyl oxalate are used as raw materials; after an o-nitrotoluene pyruvic acid ethyl acetate solution is prepared, a silver chloride-manganese dioxide-titanium dioxide-calcium carbonate mixed catalyst is added under an alkaline condition, and is used for catalyzing to synthesize the indole-2-formic acid. The invention further discloses components of a mixed catalyst and a preparation method: calcium carbonate is used as a carrier, and silver chloride and manganese dioxide are used as active components, wherein the silver chloride accounts for 12 percent to 17 percent of the total mass of the catalyst, the manganese dioxide accounts for 5 percent to 9 percent of the total mass of the catalyst, titanium dioxide accounts for 1 percent to 2.5 percent of the total mass of the catalyst, and the balance is the calcium carbonate; the synthetic method belongs to the field of organic synthetic chemistry. The indole-2-formic acid is synthesized by adopting a mixed catalyst catalytic hydrogenation reaction; the raw materials of the catalyst are easy to obtain and the preparation method is simple and convenient; meanwhile, the catalytic efficiency is high and the yield of the indole-2-formic acid is high; the synthetic method is efficient and environmentally friendly and has extremely high economic benefits, and industrialized popularization is facilitated.
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Paragraph 0029; 0030
(2016/10/17)
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- Development of Novel Bis(indolyl)-hydrazide-Hydrazone Derivatives as Potent Microtubule-Targeting Cytotoxic Agents against A549 Lung Cancer Cells
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The biological significance of microtubules makes them a validated target of cancer therapy. In this study, we have utilized indole, an important pharmacological scaffold, to synthesize novel bis(indolyl)-hydrazide-hydrazone derivatives (NMK-BH compounds) and recognized NMK-BH3 as the most effective one in inhibiting A549 cell proliferation and assembly of tissue-purified tubulin. Cell viability experiments showed that NMK-BH3 inhibited proliferation of human lung adenocarcinoma (A549) cells, normal human lung fibroblasts (WI38) and peripheral blood mononuclear cells (PBMC) with IC50 values of -2, 48.5, and 62 μM, respectively. Thus, the relatively high cytotoxicity of NMK-BH3 toward lung carcinoma (A549) cells over normal lung fibroblasts (WI38) and PBMC confers a therapeutic advantage of reduced host toxicity. Flow cytometry, Western blot, and immunofluorescence studies in the A549 cell line revealed that NMK-BH3 induced G2/M arrest, mitochondrial depolarization, and apoptosis by depolymerizing the cellular interphase and spindle microtubules. Consistent with these observations, study in cell free system revealed that NMK-BH3 inhibited the microtubule assembly with an IC50 value of -7.5 μM. The tubulin-ligand interaction study using fluorescence spectroscopy indicated that NMK-BH3 exhibited strong and specific tubulin binding with a dissociation constant of -1.4 μM at a single site, very close to colchicine site, on β-tubulin. Collectively, these findings explore the cytotoxic potential of NMK-BH3 by targeting the microtubules and inspire its development as a potential candidate for lung cancer chemotherapy.
- Das Mukherjee, Dipanwita,Kumar, N. Maruthi,Tantak, Mukund P.,Das, Amlan,Ganguli, Arnab,Datta, Satabdi,Kumar, Dalip,Chakrabarti, Gopal
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p. 3020 - 3035
(2016/06/14)
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- Rhodium catalyzed C2-selective cyanation of indoles and pyrroles
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An efficient and general rhodium(III) catalyzed C2-selective cyanation of indoles and pyrroles was accomplished employing easily accessible and environmentally friendly cyanating reagent, NCTS. This methodology tolerates various functional groups, uses re
- Chaitanya, Manthena,Anbarasan, Pazhamalai
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supporting information
p. 3695 - 3700
(2015/04/14)
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- Optimization of novel indole-2-carboxamide inhibitors of neurotropic alphavirus replication
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Neurotropic alphaviruses, which include western equine encephalitis virus (WEEV) and Fort Morgan virus, are mosquito-borne pathogens that infect the central nervous system causing acute and potentially fatal encephalitis. We previously reported a novel series of indole-2-carboxamides as alphavirus replication inhibitors, one of which conferred protection against neuroadapted Sindbis virus infection in mice. We describe here further development of this series, resulting in 10-fold improvement in potency in a WEEV replicon assay and up to 40-fold increases in half-lives in mouse liver microsomes. Using a rhodamine123 uptake assay in MDR1-MDCKII cells, we were able to identify structural modifications that markedly reduce recognition by P-glycoprotein, the key efflux transporter at the blood-brain barrier. In a preliminary mouse PK study, we were able to demonstrate that two new analogues could achieve higher and/or longer plasma drug exposures than our previous lead and that one compound achieved measurable drug levels in the brain.
- Sindac, Janice A.,Barraza, Scott J.,Dobry, Craig J.,Xiang, Jianming,Blakely, Pennelope K.,Irani, David N.,Keep, Richard F.,Miller, David J.,Larsen, Scott D.
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p. 9222 - 9241
(2014/01/06)
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- Rh-IndOlefOx catalyzed conjugate addition/Heck-type coupling of organoboronics to a lactam or a lactone
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Four indole-olefin-oxazoline (IndOlefOx) ligands were synthesized and evaluated in Rh-catalyzed reactions between organoboronics and a lactam or a lactone. In addition to the expected conjugate addition products, the formation of significant amounts of Heck-type products was observed. The scope and limitations of these reactions were investigated.
- Kuuloja, Noora,Vaismaa, Matti,Franzén, Robert
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supporting information; scheme or table
p. 2313 - 2318
(2012/04/04)
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- ARBOVIRUS INHIBITORS AND USES THEREOF
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The present invention relates to chemical compounds, methods for their discovery, and their therapeutic use. In particular, the present invention provides compounds as inhibitors of arboviruses.
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Page/Page column 57-58
(2012/10/08)
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- Palladium-catalyzed intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides
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Give me a ring? An efficient approach has been developed for the intramolecular decarboxylative coupling of arene carboxylic acids/esters with aryl bromides catalyzed by palladium (see scheme). From a synthetic viewpoint, this method is highly attractive because the catalyst loading is low, the optimized reaction conditions are mild, and the substrate scope is broad. Copyright
- Shen, Zengming,Ni, Zhenjie,Mo, Song,Wang, Jing,Zhu, Yamin
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supporting information; experimental part
p. 4859 - 4865
(2012/06/04)
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- Well-defined NHC-Pd complex-mediated intermolecular direct annulations for synthesis of functionalized indoles (NHC = N-hetero-cyclic carbene)
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As alternatives to the common tertiary phosphine/Pd systems, well-defined N-heterocyclic carbene-Pd complexes have been proven to be highly efficient precatalysts for intermolecular direct annalution of o-haloanilines and ketones at lower catalyst loadings. A highly efficient and practical protocol for synthesis of functionalized indoles was developed using (IPr)Pd(acac)Cl as catalyst. Both o-bromoanilines and o-chloroanilines gave rise to efficient coupling under the reaction conditions. Related to acyclic ones, cyclic ketones coupled more effectively with o-haloanilines. With [Pd(IPr)2] as catalyst, the base-sensitive groups including OH and CO2H groups could be tolerated. Copyright
- Jin, Zhong,Guo, Su-Xian,Qiu, Ling-Ling,Wu, Gui-Ping,Fang, Jian-Xin
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scheme or table
p. 502 - 507
(2012/05/04)
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- Desulfonylation of indoles and 7-azaindoles using sodium tert-butoxide
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A mild method for the desulfonylation of N-indoles and N-azaindoles is described. Deprotection is carried out under basic conditions, using sodium tert-butoxide in dioxane. Several functionalized indoles and 7-azaindoles were efficiently deprotected by this method, which is mild enough to be used to deprotect compounds including functions that are known to be sensitive to acidic or basic conditions.
- Chaulet, Charlotte,Croix, Cécile,Basset, Joan,Pujol, Maria-Dolores,Viaud-Massuard, Marie-Claude
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experimental part
p. 1481 - 1484
(2010/08/22)
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- Synthesis and receptor binding studies of halogenated N,N-dialkylel-(2-phenyl-1H-indol-3-yl)glyoxylamides to visualize peripheral benzodiazepine receptors with SPECT or PET
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A library of halogenated 2-arylindolyl-3-oxocarboxamides was prepared to develop radioligands to visualize cerebral PBR by SPECT and PET imaging. In vitro evaluation showed that most of the synthesized compounds were selective,high-affinity PBR ligands with adequate lipophilicity (log D7.4 in the range of 1.6-2.4). The iodinated derivative 11 (Ki = 2.6 nM) and the fluorinated analog 26 (Ki = 6.2 nM) displayed higher affinity than reference compounds.
- Bennacef, Idriss,Haile, Colin N.,Schmidt, Anne,Koren, Andrei O.,Seibyl, John P.,Staley, Julie K.,Bois, Frederic,Baldwin, Ronald M.,Tamagnan, Gilles
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p. 7582 - 7591
(2008/02/08)
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- Synthesis of indoles: Tetrahydropyrazino[1,2-a]indole-1,4-dione and pyrazino[1,2-a]indole-6,13-diones from piperazine-2,5-diones
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The readily available piperazine-2,5-dione has been used to prepare both 1:1 (1-3), with stereotopic methylene protons; and 2:1 (4-6) arylmethylenepiperazine-2,5-diones in above average yields. The halo-derivatives, 1, 4 and 5 were cyclized to pyrazino[1,2-a]indoles, 7-9, using copper bronze. Indole compounds 7 and 9 were further treated, separately, with lithium aluminium hydride, sodium borohydride, lithium hydroxide monohydrate and butyl lithium to yield 2-substituted indoles 10-13.
- Akeng'a,Read
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- Factor Xa inhibitors based on a 2-carboxyindole scaffold: SAR of neutral P1 substituents
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A series of novel, highly potent 2-carboxyindole-based factor Xa inhibitors is described. Structural requirements for neutral ligands, which bind in the S1 pocket of factor Xa were investigated with the 2-carboxyindole scaffold. This privileged fragment assembly approach yielded a set of equipotent, selective inhibitors with structurally diverse neutral P1 substituents.
- Nazare, Marc,Essrich, Melanie,Will, David W.,Matter, Hans,Ritter, Kurt,Urmann, Matthias,Bauer, Armin,Schreuder, Herman,Dudda, Angela,Czech, Joerg,Lorenz, Martin,Laux, Volker,Wehner, Volkmar
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p. 4191 - 4195
(2007/10/03)
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- 4-indole derivatives as serotonin agonists and antagonists
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The present invention relates to compounds of the formula
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- Generation and reactivity of 1,2-dilithioindole
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The generation of a 1,2-dianion (1) from 2-iodoindole is described. This dianion reacts at the carbanionic center with a range of electrophiles to give 2-substituted indoles in good yields.
- Herbert, John M.,Maggiani, Maria
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p. 947 - 951
(2007/10/03)
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- Reactions of ethyl indole-2-carboxylate in aqueous media at high temperature
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Direct, preparative methods utilizing high-temperature aqueous media were developed for indole and indole-2-carboxylic acid from ethyl indole-2-carboxylate. Yields were excellent for these reactions, which were carried out in 1 h or less, at temperatures up to 270°C, in a microwave batch reactor of the authors' design. Avoidance of undesirable copper salts, high-boiling organic bases and heat-transfer oils made the methods environmentally benign.
- Strauss, Christopher R.,Trainor, Robert W.
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p. 703 - 705
(2007/10/03)
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- BICYCLIC HETEROCYCLIC DERIVATIVES HAVING ALPHA1 ADRENERGIC AND 5HT1A ACTIVITIES
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This invention provides bicyclic heterocyclic derivatives and their pharmaceutically acceptable salts useful for the treatment of hypertension, urethral and lower urinary tract contractions, and other disorders. The compounds are also useful for binding α 1-adrenergic and 5HT. sub.1A serotonergic receptors, in vitro or in vivo.
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- Indoles and pyridazinoindoles as nonnucleoside analog inhibitors of HIV-1 reverse transcriptase
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The synthesis and the study of the activity of new indol-2-carboxamides and pyridazinoindoles as inhibitors of HIV-1 reverse transcriptase (RT) are presented.The activity of the compounds synthesized as inhibitors of different types of HIV-1 RT (wild type enzyme and mutant forms P236L, Y181C and P236L/Y181C) was evaluated.The activity of the most active compounds was investigated in the syncytia reduction in vitro assay, in HIV-1IIIB-infected HT4lacZ-1 cells.Their potential cytotoxicity was determined in parallel.Two lead compounds,N-piperazin>-5,6-methylenedioxy indol-2-carboxamide 7q and N-piperazin>-5,6-methylenedioxyindol-2-carboxamide 7s have been identified. - Keywords: indole; nonnucleoside RT inhibitor; syncytia assay; HIV-1IIIBHT4lacZ-1 cells
- Font, M.,Monge, A.,Cuartero, A.,Ellorriaga, A.,Martinez-Irujo, J.J.,et al.
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p. 963 - 972
(2007/10/03)
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- Aspects of the Palladium-Catalyzed Coupling between Aryl Halides and 2-Amidoacrylates
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The effect of using different salts, bases, catalysts and solvents as well as protecting froups in 2-amidoacrylate derivatives (olefin component) in the Heck coupling with iodobenzene has been studied.Salt effects, resulting in increased yields, were observed in combination with either NaHCO3 or triethylamine as the base.Pd(OAc)2, PdCl2, Pd/C and hydrogen-activated Pd black could all be used as catalyst with similar results.The best solvents were DMF or acetonitrile.Olefins 1a and 1c, both carrying orthogonal protecting groups, show the most potential for further app lications in peptide synthesis. 1,2-Diodobenzene and 1,8-diiodonaphthalene did not given any coupling products and 1-bromo-2-iodobenzene gave only mono-coupling in modest yield.In fact, small amounts of either 1,2-diiodobenzene or 1,8-diiodinaphthalene inhibited the coupling in other, normally reactive, cases.In experiments stoichiometric in Pd(OAc)2 it was found that an indolecarboxylic acid derivative was formed from iodobenzene, 2-bromoiodobenzene and 1,2-diiodobenzene, suggesting that ortho-palladation of a phenyl didehydroalanine derivative is involved.
- Carlstroem, Anne-Sofie,Frejd, Torbjoern
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p. 163 - 171
(2007/10/02)
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- Cobalt (II) catalyzed oxidation of aldehydes to carboxylic acid with molecular oxygen
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A variety of aromatic and some aliphatic aldehydes are efficiently transformed to the corresponding carboxylic acid in presence of catalytic amount of Cobalt (II) chloride, molecular oxygen and acetic anhydride at room temperature. Phenolic aldehydes undergo acylative oxidation to give the corresponding acylated carboxylic acid.
- Bhatia, Beena,Iqbal, Javed
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p. 7961 - 7964
(2007/10/02)
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- The N-tert-butylcarbamoyl directed metalation group for the regiospecific synthesis of 2-substituted pyrroles and indoles
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The N-tert-butylcarbamoyl serves as a useful, readily removable (LiOH/MeOH/THF) new directed metalation group for the synthesis of 2-substituted pyrroles and indoles.
- Gharpure,Stoller,Bellamy,Firnau,Snieckus
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p. 1079 - 1082
(2007/10/02)
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- 1,3-Dipolar Cycloaddition Reactions. Regioselective Synthesis of Heterocycles and Theoretical Studies
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We report a 1,3-dipolar cycloaddition reaction between a oxazolium 5-oxide derivative with chloroacrylonitrile or ethyl propiolate as dipolarophiles, in order to obtain substituted pyrrolizidines.Experimentally we found that the reaction is regiospecific with chloroacrylonitrile and regioselective with ethyl propiolate.The secondary attractive orbital interactions from the Frontier Molecular Orbital Theory, the differences in stability of the possible biradical intermediaries postulated for the reaction and some hindrance effects, explain the regioselectivity observed experimentally.
- Pierini, Adriana B.,Cardozo, Mario G.,Montiel, Aida A.,Albonico, Sem M.,Pizzorno, Maria T.
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p. 1003 - 1008
(2007/10/02)
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- CARBON DIOXIDE: A REAGENT FOR THE PROTECTION OF NUCLEOPHILIC CENTRES AND THE SIMULTANEOUS ACTIVATION OF ALTERNATIVE LOCATIONS TO ELECTROPHILIC ATTACK. PART I. A NEW SYNTHETIC METHOD FOR THE 2-SUBSTITUTION OF 1-UNSUBSTITUTED INDOLES.
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Indole was converted into several 2-substituted derivatives by using carbon dioxide both for N-protection and to give an intermediate carbanion stabilizing group. t-Butyllithium was used as a lithiating agent at the alpha-carbon atom of the indole enamino group.The resulting 2-substituted indole-1-carboxylic acids underwent smooth thermal decarboxylation under mild conditions.Alternatively, with longer reaction times the protecting group is lost during the reaction.
- Katritzky, By Alan R.,Akutagawa, Kunihiko
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p. 5935 - 5938
(2007/10/02)
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- Direct Observation of 1-Azafulven-6-one and Annelated Derivatives
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1-Azafulven-6-one, 2-carbonyl-2H-indole, 5-carbonyl-5H-furopyrrole, and thieno- and pyrrolo-analogues are isolated at low temperatures following thermal elimination of water or methanol from the corresponding carboxylic acids or esters; the azafulvenones dimerise at -100 to -40 deg C to diketopiperazine derivatives.
- Gross, Gerhard,Wentrup, Curt
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p. 360 - 361
(2007/10/02)
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