- Axially Chiral Dibenzazepinones by a Palladium(0)-Catalyzed Atropo-enantioselective C?H Arylation
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Atropo-enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo-enantioselective palladium(0)-catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio-determining CMD to yield configurationally stable eight-membered palladacycles.
- Newton, Christopher G.,Braconi, Elena,Kuziola, Jennifer,Wodrich, Matthew D.,Cramer, Nicolai
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- A unique class of duocarmycin and CC-1065 analogues subject to reductive activation
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N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.
- Jin, Wei,Trzupek, John D.,Rayl, Thomas J.,Broward, Melinda A.,Vielhauer, George A.,Weir, Scott J.,Hwang, Inkyu,Boger, Dale L.
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- KRAS G12D INHIBITORS
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The present invention relates to compounds that inhibit KRas G12D. In particular, the present invention relates to compounds that inhibit the activity of KRas G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
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Paragraph 01245
(2021/03/05)
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- Compound for organic photoelectric device Composition for organic photoelectric device, organic photoelectric device, and display device
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A compound for an organic optoelectronic device, a composition for an organic optoelectronic device including the same, an organic optoelectronic device, and a display device, the compound being represented by a combination of Chemical Formula 1 and Chemical Formula 2:
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Paragraph 0201-0205
(2021/10/13)
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- Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C-H Olefination
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The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.
- Jin, Liang,Zhang, Peng,Li, Ya,Yu, Xin,Shi, Bing-Feng
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supporting information
p. 12335 - 12344
(2021/08/24)
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- Synthesis, kinetics, and mechanism of bromophenols by N-bromophthalimide in aqueous acetic acid
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The kinetics and mechanism of bromination of phenol and its substituents, viz. 4-chlorophenol, 4-bromophenol, 4-methylphenol, and 4-methoxyphenol by N-bromophthalimide (NBP) in the presence of mercuric acetate in the temperature range of 303–318?K in aqueous acetic acid medium have been investigated. The reaction follows first-order dependence on [NBP] and fractional order dependence of rate on [Phenol]. The activation parameters have been evaluated, and based on the observed kinetic results the probable mechanism has been proposed. Observed kinetic features and Hammett's reaction constant (ρ) suggests that bromination occurs through electrophilic substitution of bromonium ion (Br+) into the aromatic ring in the transition state. Large negative entropy of activation values probably suggests the rigid nature of transition state.
- Anjaiah, Birla,Prameela, Kethavath,Srinivas, Pabba,Rajanna, Kamatala Chinna
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p. 804 - 812
(2018/09/11)
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- Selenium-catalyzed oxidative c(sp2)-h amination of alkenes exemplified in the expedient synthesis of (Aza-)indoles
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A new selenium-catalyzed protocol for the direct, intramolecular amination of C(sp2)-H bonds using N-fluorobenzenesulfonimide as the terminal oxidant is reported. This method enables the facile formation of a broad range of diversely functionalized indoles and azaindoles derived from easily accessible ortho-vinyl anilines and vinylated aminopyridines, respectively. The procedure exploits the pronounced carbophilicity of selenium electrophiles for the catalytic activation of alkenes and leads to the formation of C(sp2)-N bonds in high yields and with excellent functional group tolerance.
- Ortgies, Stefan,Breder, Alexander
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supporting information
p. 2748 - 2751
(2015/06/16)
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- A Planar-Chiral Phosphino(alkenyl)ferrocene for Suzuki-Miyaura C-C Coupling Reactions
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Planar-chiral phosphinoferrocene [Fe(η5-C5H3-1-PPh2-2-(E)-CH=CHPh)(η5-C5H5)] (4) was applied in the presence of palladium in Suzuki-Miyaura couplings for the synthesis of sterically congested biaryls. The catalytic activity arises from homogeneous palladium phosphine complexes, of which the potential pre-catalyst [Pd(4)2Cl2] was characterized structurally. The catalytic system is excellently suited for the synthesis of tri-ortho-substituted biaryls under mild conditions (0.1 mol-%, 50-100 C), whereas its application towards the synthesis of tetra-ortho-substituted biaryls is quite limited. Comparing the performance of the reaction with 4 as catalyst and a range of substrates with differing ortho substituents suggests that transmetalation is rate determining. Complex (Sp)-4 was used in atropselective couplings, wherein enantioenrichments of up to 36 % were achieved. The stereoselectivity depends to some extent on the steric properties of the boronic acids; however, slight changes at the aryl halides influence the enantioselectivity.
- Schaarschmidt, Dieter,Grumbt, Martin,Hildebrandt, Alexander,Lang, Heinrich
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supporting information
p. 6676 - 6685
(2016/02/19)
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- Asymmetric formation of bridged benzoxazocines through an organocatalytic multicomponent dienamine-mediated one-pot cascade
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An organocatalytic one-pot cascade leading to the stereoselective formation of novel bridged benzoxazocines is presented. The developed methodology is based on the first example of a γ-selective-Mannich-initiated cascade reaction and allows for direct annulation of the bridged benzoxazocines by incorporation of various α,β-unsaturated aldehydes, electron-rich anilines, and electron-deficient salicylaldehydes. The synthetic applicability of the products is demonstrated by relevant transformations.
- Ransborg, Lars Krogager,Overgaard, Mette,Hejmanowska, Joanna,Barfüsser, Sebastian,J?rgensen, Karl Anker,Albrecht, ?ukasz
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supporting information
p. 4182 - 4185
(2014/10/15)
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- A High-Throughput Assay for Arylamine Halogenation Based on a Peroxidase-Mediated Quinone-Amine Coupling with Applications in the Screening of Enzymatic Halogenations
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Arylhalides are important building blocks in many fine chemicals, pharmaceuticals and agrochemicals, and there has been increasing interest in the development of more "green" halogenation methods based on enzyme catalysis. However, the screening and development of new enzymes for biohalogenation has been hampered by a lack of high-throughput screening methods. Described herein is the development of a colorimetric assay for detecting both chemical and enzymatic arylamine halogenation reactions in an aqueous environment. The assay is based on the unique UV/Vis spectrum created by the formation of an ortho-benzoquinone-amine adduct, which is produced by the peroxidase-catalysed benzoquinone generation, followed by Michael addition of either a halogenated or non-halogenated arylamine. This assay is sensitive, rapid and amenable to high-throughput screening platforms. We have also shown this assay to be easily coupled to a flavin-dependent halogenase, which currently lacks any convenient colorimetric assay, in a "one-pot" workflow.
- Hosford, Joseph,Shepherd, Sarah A.,Micklefield, Jason,Wong, Lu Shin
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supporting information
p. 16759 - 16763
(2016/02/12)
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- Synthesis of polycyclic aminocyclobutane systems by the rearrangement of N-(ortho-Vinylphenyl) 2-Azabicyclo[3.1.0]hexane derivatives
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The acid-catalysed thermal rearrangements of a family of N-aryl 2-azabicyclo[3.1.0]hexanes is described. These substrates, designed in such a way that the aromatic system is conjugated with an alkene group located at the ortho position relative to the nitrogen atom, have been prepared by using an intramolecular Kulinkovich-de Meijere reaction. The rearrangements can then be conducted either under standard thermal conditions or with microwave activation. Depending on the conditions applied and the substitution pattern, dihydroquinoline or polycyclic aminocyclobutane derivatives can be obtained. A mechanistic discussion is provided, with the proposition of the initial protonation of the aminocyclopropane moiety to give an iminium intermediate. By analogy with related intermolecular reactions, the involvement of electrocyclic reactions among the series of elementary steps that follow is put forward. Small rings: The acid-catalysed rearrangement of bicyclic N-aryl aminocyclopropanes with an alkene group located at the ortho position, either under standard thermal conditions or with microwave activation, is described (see scheme). The method provides access to dihydroquinoline and polycyclic aminocyclobutane derivatives. By analogy with related intermolecular reactions, the involvement of an electrocyclic reaction is proposed. Copyright
- Wasilewska, Agnieszka,Wozniak, Bartosz A.,Doridot, Gabriel,Piotrowska, Kamila,Witkowska, Natalia,Retailleau, Pascal,Six, Yvan
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supporting information
p. 11759 - 11767
(2013/09/12)
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- A facile, regioselective and controllable bromination of aromatic amines using a CuBr2/Oxone system
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A combination of cupric bromide and Oxone serves as a facile, mild and effective reagent for the bromination of aromatic amines. Primary, secondary and tertiary aromatic amines are all suitable substrates. The reaction possesses high regioselectivity and functional group tolerance, and mono- and multi-brominated products can be obtained controllably in moderate to excellent yields. The Royal Society of Chemistry 2013.
- Li, Xin-Le,Wu, Wei,Fan, Xin-Heng,Yang, Lian-Ming
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p. 12091 - 12095
(2013/09/02)
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- Simple catalyst-free regio- and chemoselective monobromination of aromatics using NBS in polyethylene glycol
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NBS in polyethylene glycol has been efficiently utilized for regio- and chemoselective bromination of activated aromatics at room temperature to form the corresponding bromo products in excellent yields. Copyright Taylor & Francis Group, LLC.
- Venkateswarlu, Katta,Suneel, Kanaparthy,Das, Biswanath,Reddy, Kuravallapalli Nagabhushana,Reddy, Thummala Sreenivasulu
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experimental part
p. 215 - 219
(2009/04/07)
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- Regioselective bromination of aromatic amines and phenols using N-benzyl-DABCO tribromide
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N-Benzyl-DABCO tribromide, a stable, solid organic ammonium tribromide, has been used as a bromine source for the regioselective and high-yielding bromination of aromatic amines and phenols. Mono-bromination proceeds well in the presence of a stoichiometric amount of bromine source at room temperature.
- Moghaddam, Firouz Matloubi,Zargarani, Dordaneh
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experimental part
p. 4212 - 4220
(2010/01/08)
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- Configurationally rigid pentaorganosilicates
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The intramolecular substituent interchange in recently reported pentaorganosilicates is investigated by B3LYP calculations, which show excellentagreement with the experimental thermochemical data. Two types of ligan d permutation are discerned (A and B), which both lead to racemization of the helical, spirocyclic anions. IRC calculations show that stereomutation A bifurcates into two enantiomeric reaction paths, which are inhibited by ortho substitution of the bidentate ligands. The other pathway (B) proceeds through a trigonal bipyramidal transition state with one bisequatorial bidentate ligand and is disfavored by increasing the ?-electron density of the ligand. A more electronegative fifth, monodentate substituent increases the barrier of pathway A and lowers that of pathway B, as in bis(biphenyl-2,2'-diyl)fluorosilicate, which is the first tetraorganofluorosilicate to be isolated and fully characterized. These concepts enabled us to design and synthesize methyl- and ethylbis([2]naphthylpyrrol-2,1'-diyl)silicate as Si-chiral pentaorganosilicates that are configurationally rigid at room temperature.
- Couzijn, Erik P. A.,Engel, Daniel W. F. van der,Slootweg, J. Chris,Kanter, Frans J. J. de,Ehlers, Andreas W.,et al.
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experimental part
p. 3741 - 3751
(2009/09/24)
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- CBI DERIVATIVES SUBJECT TO REDUCTIVE ACTIVATION
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A unique class of N-acyl O-amino phenol prodrugs of CBI-TMI and CBI-indole2 were synthesized and shown to be prodrugs, subject to reductive activation by nucleophilic cleavage of a weak N-O bond, effectively releasing the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Most impressively, assessment of the in vivo antitumor activity of a representative O- (acylamino) prodrug, 8, indicate that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that the inactive prodrugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.
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Page/Page column 36
(2009/06/27)
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- Synthesis of monofluorinated 1-(naphthalen-1-yl)piperazines
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A series of regioisomerically monofluorinated 1-(naphthalen-1-yl)piperazines is described.
- Repine, Joseph T.,Johnson, Douglas S.,White, Andrew D.,Favor, David A.,Stier, Michael A.,Yip, Judy,Rankin, Trent,Ding, Qizhu,Maiti, Samarendra N.
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p. 5539 - 5541
(2008/02/13)
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- An efficient, rapid and regioselective nuclear bromination of aromatics and heteroaromatics with NBS using sulfonic-acid-functionalized silica as a heterogeneous recyclable catalyst
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A simple, efficient and rapid method has been developed for high-yielding regioselective nuclear monobromination of aromatic and heteroaromatic compounds using NBS in the presence of sulfonic-acid-functionalized silica at room temperature. The catalyst works under heterogeneous conditions and can be recycled.
- Das, Biswanath,Venkateswarlu, Katta,Krishnaiah, Maddeboina,Holla, Harish
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p. 8693 - 8697
(2007/10/03)
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- A new method for the oxybromination of aromatic compounds with copper(II)bromide and potassium dichromate
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A new and mild method for oxybromination of aromatic compounds with CuBr2 and K2Cr2O7 in HOAC is reported. Copyright Taylor & Francis Inc.
- Badri, Rashid,Shushizadeh, Mohammad Reza
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p. 533 - 536
(2007/10/03)
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- The metalation of 1- and 2-(trifluoromethyl)naphthalenes: Noteworthy site selectivities
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This article provides insight into the various factors by which electronegative substituents affect the kinetic acidity of arenes and, more specifically, naphthalenes. Both 1- and 2-(trifluoromethyl)naphthalenes were consecutively treated with an organometallic or lithium dialkylamide-type base and carbon dioxide. Due to single electron-transfer triggered side reactions, the yields of (trifluoromethyl)naphthoic acids were moderate to poor. 1-(Trifluoromethyl)naphthalene was exclusively attacked at the 2-position as expected. The 2-isomer reacted with tert-butyllithium in the presence of potassium tert-butoxide solely at the 1-position, but with sec-butyllithium in the presence of N,N,N′,N′-tetramethylethylene-diamine concomitantly at the 3- and 4-positions. Authentic samples of the key acids 1, 4, 5 and 6 were prepared based on independent, unambiguous methods.
- Cottet, Fabrice,Castagnetti, Eva,Schlosser, Manfred
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p. 798 - 803
(2007/10/03)
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- [bmim]Br3 as a new reagent for regioselective monobromination of arylamines under solvent-free conditions
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Reaction of arylamines with 1-butyl-3-methylimidazolium tribromide ([bmim]Br3) under solvent-free conditions, gave selectively the corresponding monobromination products with excellent, yields.
- Le, Zhang-Gao,Chen, Zhen-Chu,Hu, Yi,Zheng, Qin-Guo
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p. 2809 - 2812
(2007/10/03)
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- Regioselective one-pot bromination of aromatic amines
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(Matrix Presented) Treatment of aniline with n-butyllithium and then trimethyltin chloride gave the tin amide (PhNH-SnMe3) in situ. Without isolation of the tin amide reaction with bromine and workup with aqueous fluoride ion gave p-bromoaniline in 76% yield, with no dibromoaniline or o-bromoaniline. Application of this sequence to 11 different aromatic amines gave selective bromination in 36-91% yields, without formation of dibromides. This constitutes a good general method for the regioselective bromination of aromatic amines.
- Smith, Michael B.,Guo, Lisa,Okeyo, Sherrad,Stenzel, Jason,Yanella, James,LaChapelle, Eric
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p. 2321 - 2323
(2007/10/03)
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- Ultrasound promoted bromination of activated arenes with N-bromosuccinimide
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Ultrasound irradiation has resulted in the selective monobromination of activated aromatics with N-Bromosuccinimide (NBS) in carbon tetrachloride at ambient conditions in the absence of any added catalyst.
- Paul,Sudalai,Daniel,Srinivasan
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p. 2401 - 2405
(2007/10/02)
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- Aromatic nucleophilic polysubstitution by sequential SRN1 reactions
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Substitution of aromatics (benzene, naphthalene and pyridine) by two or three distinct nucleophiles derived from phosphonates and/or thiolates can be performed by sequential photosimulated SRN1 reactions whose radical chain mechanism is compatible with the successively introduced substituents. aromatic polysubstitution / SRN1 mechanism / disubstituted aromatic / trisubstituted aromatic / distinct substituent
- Beugelmans, Rene,Chbani, Mohamed
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p. 290 - 305
(2007/10/02)
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- Reactions of Organic Anions. Part 180. Orientation of the Carbanion Attack of Chloromethyl p-Tolyl Sulphone on 1-Cyanonaphthalene Derivatives
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The carbanion of chloromethyl p-tolyl sulphone reacts with cyanonaphthalene derivatives to give bis-annulated products and/or SNAr products and/or products of nucleophilic substitution of hydrogen depending on the structure of the substrates and on reaction conditions.The orientation of the initial carbanion attack is discussed.
- Makosza, Mieczyslaw,Ostrowski, Stanislaw
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p. 1093 - 1097
(2007/10/02)
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