- One pot synthesis of aryl nitriles from aromatic aldehydes in a water environment
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In this study, we found a green method to obtain aryl nitriles from aromatic aldehyde in water. This simple process was modified from a conventional method. Compared with those approaches, we used water as the solvent instead of harmful chemical reagents. In this one-pot conversion, we got twenty-five aryl nitriles conveniently with pollution to the environment being minimized. Furthermore, we confirmed the reaction mechanism by capturing the intermediates, aldoximes.
- Chen, Qingqing,Han, Hongwei,Lin, Hongyan,Ma, Xiaopeng,Qi, Jinliang,Wang, Xiaoming,Yang, Yonghua,Zhou, Ziling
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p. 24232 - 24237
(2021/07/29)
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- Development and Molecular Understanding of a Pd-Catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis
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A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand σ-donation, π-acidity and sterics are key drivers that govern yield. Categorization into three ligand groups – monophosphines, bisphosphines and miscellaneous – was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong σ-donating, weak π-accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts.
- De Jesus Silva, Jordan,Bartalucci, Niccolò,Jelier, Benson,Grosslight, Samantha,Gensch, Tobias,Schünemann, Claas,Müller, Bernd,Kamer, Paul C. J.,Copéret, Christophe,Sigman, Matthew S.,Togni, Antonio
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- Palladium-Catalyzed Late-Stage Direct Arene Cyanation
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Methods for direct benzonitrile synthesis are sparse, despite the versatility of cyano groups in organic synthesis and the importance of benzonitriles for the dye, agrochemical, and pharmaceutical industries. We report the first general late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method is applicable to direct cyanation of several marketed small-molecule drugs, common pharmacophores, and organic dyes. Benzonitriles are some of the most versatile building blocks for organic synthesis, in particular in the pharmaceutical industry, but general methods to make them by direct C–H functionalization are unknown. In this issue of Chem, Ritter and coworkers describe a late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance, enabled by a palladium-dual-ligand catalyst system. The reaction may serve for the late-stage modification of drug candidates. Aryl nitriles constitute an important class of organic compounds that are widely found in natural products, pharmaceuticals, agricultural chemicals, dyes, and materials. Moreover, nitriles are versatile building blocks to access numerous other important molecular structure groups. However, no general method for direct aromatic C–H cyanation is known. All approaches to date require either an appropriate directing group or reactive electron-rich substrates, such as indoles, which limit their synthetic applications. Here we describe an undirected, palladium-catalyzed late-stage aryl C–H cyanation reaction for the synthesis of complex aryl nitriles that would otherwise be more challenging to produce. The wide substrate scope and good functional-group tolerance of this reaction provide direct and quick access to structural diversity for pharmaceutical and agrochemical development.
- Zhao, Da,Xu, Peng,Ritter, Tobias
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supporting information
p. 97 - 107
(2019/01/21)
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- Perfluoroalkanosulfonyl fluoride: A useful reagent for dehydration of aldoximes to nitriles
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The reaction of a variety of aldoximes with perfluoroalkanosulfonyl fluoride in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane smoothly generated the corresponding nitriles in 70%-95% yields.
- Yan, Zhao-Hua,Tian, Huan,Zhao, Dong-Dong,Jin, Hong-Ai,Tian, Wei-Sheng
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- Synthesis of aryl dihydrothiazol acyl shikonin ester derivatives as anticancer agents through microtubule stabilization
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The high incidence of cancer and the side effects of traditional anticancer drugs motivate the search for new and more effective anticancer drugs. In this study, we synthesized 17 kinds of aryl dihydrothiazol acyl shikonin ester derivatives and evaluated their anticancer activity through MTT assay. Among them, C13 showed better antiproliferation activity with IC50 = 3.14 ± 0.21 μM against HeLa cells than shikonin (IC50 = 5.75 ± 0.47 μM). We then performed PI staining assay, cell cycle distribution, and cell apoptosis analysis for C13 and found that it can cause cell arrest in G2/M phase, which leads to cell apoptosis. This derivative can also reduce the adhesive ability of HeLa cells. Docking simulation and confocal microscopy assay results further indicated that C13 could bind well to the tubulin at paclitaxel binding site, leading to tubulin polymerization and mitotic disruption.
- Lin, Hong-Yan,Li, Zi-Kang,Bai, Li-Fei,Baloch, Shahla Karim,Wang, Fang,Qiu, Han-Yue,Wang, Xue,Qi, Jin-Liang,Yang, Raong-Wu,Wang, Xiao-Ming,Yang, Yong-Hua
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- Ammoxidation of 2,6-dichloro toluene - From first trials to pilot plant studies
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The scaling-up of the gas phase catalytic ammoxidation of 2,6-dichloro toluene (DCT) to 2,6-dichloro benzonitrile (DCBN) over a promoted vanadium phosphate (VPO) catalyst from first lab-scale experiments to pilot plant runs is reported. First experiments in a row of conversions of isomeric dichloro toluenes using simple, non-promoted VPO catalysts only show poor yield and selectivity. In particular, DCT ammoxidation is hindered due to bulky chlorine substituents probably preventing a sufficient interaction of the methyl group and lattice oxygen and/or N-containing surface species. Improved synthesis of VPO catalyst with the addition of promoters and γ-alumina or titania leads to significant increase in DCT conversion and DCBN yield. A Cr containing vanadyl pyrophosphate catalyst admixed with titania (anatase) showed conversion up to 97% with DCBN yields of ca. 80%. The same catalyst was also used for pilot plant runs, usually in the form of 5 mm × 3.5 mm shaped tablets that were prepared from a larger batch of solid synthesis. The scaling-up of the process using 100 ml of catalyst was investigated both by catalytic experiments and reactor simulations. The results showed that the temperature control will be crucial in scaling-up. Validation of simulation results with that of experimental results was also checked and a good agreement between measured and simulated results is observed.
- Martin,Kalevaru,Smejkal
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scheme or table
p. 275 - 279
(2011/01/04)
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- NMR Studies and electrophilic properties of triphenylphosphine-trifluoromethanesulfonic anhydride; a remarkable dehydrating reagent system for the conversion of aldoximes into nitriles
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NMR Studies on the reaction of triphenylphosphine with various amounts of triflic anhydride at 0 °C is described. The reagent structure resulting from mixing 1.3 equiv of Ph3P with Tf2O (1.0 mmol) has been established as an equilibrium mixture consisting mainly of triphenyl(trifluoromethylsulfonyloxy)phosphonium trifluoromethanesulfinate and the corresponding bis(triphenyl)oxodiphosphonium trifluoromethanesulfinate dimer. The electrophilic properties of the system have been exploited in the development of a mild method for converting aldoximes into nitriles. The dehydration occurs at 0 °C under very mild conditions by initial activation of the oxime oxygen, followed by treatment with a base and subsequent elimination of triphenylphosphine oxide. The substrate scope and functional group tolerance of this useful method are explored.
- Moussa, Ziad,Ahmed, Saleh A.,ElDouhaibi, Ahmad S.,Al-Raqa, Shaya Y.
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experimental part
p. 1826 - 1831
(2010/09/07)
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- Process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, commonly known as lamotrigine
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A process for the preparation of 6-(2,3-dichlorophenyl)-1,2,4-triazine-3-5-diamine (lamotrigine) of the formula I: 2,3-Dichloronitrobenzene in C1-C6aliphatic alkanol is hydrogenated at 55-90 psi gas pressure using metal catalyst at 27-35° C. 2,3-Dichloroaniline is diazotised and cyano-de-diazonised with metal cyanide at 65-80° C. 2,3-Dichlorobenzonitrile is hydrolysed and 2,3-dichlorobenzoic acid is chlorinated at 55-130° C. Cyano-de-halogenation of 2,3-dichlorobenzoyl chloride is carried out with a metal cyanide and alkali metal iodide by refluxing in an aprotic solvent under an inert atmosphere. 2,3-Dichlorobenzoyl cyanide is condensed with aminoguanidine bicarbonate in an organic solvent in acidic conditions using catalyst at 90-125° C. followed by insitu cyclisation of the Schiff's base by refluxing in an aliphatic alkanol with base. Crude lamotrigine is purified.
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Page/Page column 7
(2010/01/31)
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- Structure-activity studies for a novel series of tricyclic substituted hexahydrobenz[e]isoindole α(1A) adrenoceptor antagonists as potential agents for the symptomatic treatment of benign prostatic hyperplasia (BPH)
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In search of a uroselective agent that exhibits a high level of selectivity for the α(1A) receptor, a novel series of tricyclic hexahydrobenz[e]isoindoles was synthesized. A generic pharmacophoric model was developed requiring the presence of a basic amine core and a fused heterocyclic side chain separated by an alkyl chain. It was shown that the 6- OMe substitution with R, R stereochemistry of the ring junction of the benz[e]isoindole and a two-carbon spacer chain were optimal. In contrast to the highly specific requirements for the benz[e]isoindole portion and linker chain, a wide variety of tricyclic fused heterocyclic attachments were tolerated with retention of potency and selectivity. In vitro functional assays for the α1 adrenoceptor subtypes were used to further characterize these compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity.
- Meyer, Michael D.,Altenbach, Robert J.,Basha, Fatima Z.,Carroll, William A.,Condon, Stephen,Elmore, Steven W.,Kerwin Jr., James F.,Sippy, Kevin B.,Tietje, Karin,Wendt, Michael D.,Hancock, Arthur A.,Brune, Michael E.,Buckner, Steven A.,Drizin, Irene
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p. 1586 - 1603
(2007/10/03)
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- TRICYCLIC SUBSTITUTED HEXAHYDROBENZ [E]ISOINDOLE ALPHA-1 ADRENERGIC ANTAGONISTS
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The present invention relates to a compound of the formula STR1 and the pharmaceutically acceptable salts thereof wherein W is a tricyclic heterocyclic ring system; which is an α-1 adrenergic antagonist and is useful in the treatment of BPH; also disclosed are . alpha.-1 antagonist compositions and a method for antagonizing α-1 receptors and treating BPH.
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- Process for preparing aromatic nitriles
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Aromatic nitriles having the general formula (I): wherein: - Rrepresents the hydrogen atom., a fluorine, chlorine, bromine or iodine atom, a (C1-C5)-alkoxy group, a carboxy group, a (C1-C5)-carboxy-alkyl, or an aryl group selected from among phenyl, halo-phenyl, phenyl-ether or nitrile; - R' and R"either equal to, or different from, each other, represent the hydrogen atom or a fluorine, chlorine, bromine or iodine atom; are obtained by reacting an organic or inorganic ammonium salt (III):, , NH4(+) X(-) (III), , and an aromatic trichloromethyl derivative having formula (II): wherein R, R' and R" have the above set forth meaning, with the exception that when R in formula (I) represents the nitrile group, the corresponding R group in formula (II) represents the trichloromethyl group, operating in the presence of a catalyst consisting of a metal oxide or a metal salt. The process makes it possible high yields and high selectivities to the useful reaction product to be obtained.
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- Studies on some mono- and di-substitution reactions with cyclopentadienyliron complexes of o-, m- and p-dichlorobenzenes
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Reaction of the cyclopentadienyliron (CpFe) complex of o-, m- or p-dichlorobenzene (Ia, Ib or Ic, respectively) with an excess of n-butylamine gave only monosubstitution of one of the two chloro groups, while a similar reaction carried out in the presence of some added HOAc resulted in disubstitution of both chloro groups.On the other hand, in the reaction of Ia, Ib or Ic with one equivalent or with an excess of pyrrolidine, respectively, mono- or disubstitution took place.These observations support the previous suggestion that, under the basic conditions of the reaction, deprotonation of the monosubstitution product from a reaction with a primary amine would render the second chloro group incapable of undergoing another nucleophilic substitution, while for a reaction with a secondary amine, there could be no deprotonation with the monosubstitution product, thus allowing disubstitution to occur.When Ia, Ib or Ic are reported with an excess of NaCN in DMF for up to 4 days, only monosubstitution was observed, a pure product being obtained with Ia, while with Ib or Ic, the product was contaminated with a large amount of starting material.When the same reaction of Ia, Ib or Ic with NaCN was carried out for 30 min and then worked up without any added aqueous NH4PF6, cyclohexadienyl complexes from the nucleophilic addition of a cyanide ion were obtained.Under similar reaction conditions but with the reaction time extended for 2 days, Ia could also give rise to products derived from monosubstitution and cyanide addition.Mechanistic implications of these results are discussed.
- Lee, C. C.,Zhang, C. H.,Abd-El-Aziz, A. S.,Piorko, A.,Sutherland, R. G.
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p. 217 - 230
(2007/10/02)
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- 7-Substituted Benzothiophenes and 1,2-Benzisothiazoles. Part 2. Chloro and Nitro Derivatives
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The 7-chloro and 7-nitro derivatives of benzothiophene and 1,2-benzisothiazole have been prepared from readily available precursors, which for each substituent are common to both ring systems. 7-Chlorobenzothiophene has been obtained from 3-chloro-2-mercaptobenzoic acid via 7-chlorobenzothiophen-3(2H)-one, or from 2,3-dichlorobenzaldehyde, either via β-(2,3-dichlorophenyl)-α-mercaptoacrylic acid (16) or, preferably, via 7-chlorobenzothiophene-2-carboxylic acid.Hexamethylphosphoric triamide is a particularly useful solvent in which to effect the selective nucleophilic replacement of the 2-chloro substituent in 2,3-dichlorobenzaldehyde. 7-Chloro-1,2-benzisothiazole is available by treatment of 3-chloro-2-mercaptobenzaldehyde with chloramine (57percent), or by heating 2,3-dichlorobenzaldehyde with sulphur and aqueous ammonia (46percent). 7-Nitrobenzothiophene has been obtained by treatment of 2-bromo-3-nitrobenzaldehyde with mercaptoacetic acid under alkaline conditions, followed by decarboxylation of the resulting 2-carboxylic acid.Cyclisation of 2-(n- or t-butylthio)-3-nitrobenzaldoxime with polyphosphoric acid gives 7-nitro-1,2-benzisothiazole in high yield. 3-Nitro-2-t-bytylthiobenzaldehyde behaves unexpectedly with chloramine, to give what is believed to be 7-nitro-2-t-butyl-1,2-benzothiazolium chloride (24) (73percent).
- Rahman, Loay K. A.,Scrowston, Richard M.
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p. 385 - 390
(2007/10/02)
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