- Eleven amino acid glucagon-like peptide-1 receptor agonists with antidiabetic activity
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Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acidGLP-1 receptor agonists. These peptides consist of a structurally optimized 9- mer, which is closely related to the N-terminal 9 amino acids ofGLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.
- Mapelli, Claudio,Natarajan, Sesha I.,Meyer, Jean-Philippe,Bastos, Margarita M.,Bernatowicz, Michael S.,Lee, Ving G.,Pluscec, Jelka,Riexinger, Douglas J.,Sieber-McMaster, Ellen S.,Constantine, Keith L.,Smith-Monroy, Constance A.,Golla, Rajasree,Ma, Zhengping,Longhi, Daniel A.,Shi, Dan,Xin, Li,Taylor, Joseph R.,Koplowitz, Barry,Chi, Cecilia L.,Khanna, Ashish,Robinson, Gordon W.,Seethala, Ramakrishna,Antal-Zimanyi, Ildiko A.,Stoffel, Robert H.,Han, Songping,Whaley, Jean M.,Huang, Christine S.,Krupinski, John,Ewing, William R.
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- Metal-Organic Framework-Confined Single-Site Base-Metal Catalyst for Chemoselective Hydrodeoxygenation of Carbonyls and Alcohols
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Chemoselective deoxygenation of carbonyls and alcohols using hydrogen by heterogeneous base-metal catalysts is crucial for the sustainable production of fine chemicals and biofuels. We report an aluminum metal-organic framework (DUT-5) node support cobalt(II) hydride, which is a highly chemoselective and recyclable heterogeneous catalyst for deoxygenation of a range of aromatic and aliphatic ketones, aldehydes, and primary and secondary alcohols, including biomass-derived substrates under 1 bar H2. The single-site cobalt catalyst (DUT-5-CoH) was easily prepared by postsynthetic metalation of the secondary building units (SBUs) of DUT-5 with CoCl2 followed by the reaction of NaEt3BH. X-ray photoelectron spectroscopy and X-ray absorption near-edge spectroscopy (XANES) indicated the presence of CoII and AlIII centers in DUT-5-CoH and DUT-5-Co after catalysis. The coordination environment of the cobalt center of DUT-5-Co before and after catalysis was established by extended X-ray fine structure spectroscopy (EXAFS) and density functional theory. The kinetic and computational data suggest reversible carbonyl coordination to cobalt preceding the turnover-limiting step, which involves 1,2-insertion of the coordinated carbonyl into the cobalt-hydride bond. The unique coordination environment of the cobalt ion ligated by oxo-nodes within the porous framework and the rate independency on the pressure of H2 allow the deoxygenation reactions chemoselectively under ambient hydrogen pressure.
- Antil, Neha,Kumar, Ajay,Akhtar, Naved,Newar, Rajashree,Begum, Wahida,Manna, Kuntal
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supporting information
p. 9029 - 9039
(2021/06/28)
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- Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands
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The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.
- Hu, Zhiyong,Wei, Xiao-Jing,Handelmann, Jens,Seitz, Ann-Katrin,Rodstein, Ilja,Gessner, Viktoria H.,Goo?en, Lukas J.
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supporting information
p. 6778 - 6783
(2021/02/01)
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- Combined Photoredox/Enzymatic C?H Benzylic Hydroxylations
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Chemical transformations that install heteroatoms into C?H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C?H oxyfunctionalization, or the one step conversion of a C?H bond to a C?O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products,. Here we report a single-flask photoredox/enzymatic process for direct C?H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.
- Betori, Rick C.,May, Catherine M.,Scheidt, Karl A.
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supporting information
p. 16490 - 16494
(2019/11/03)
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- Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives
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Iron-catalyzed hydromagnesiation of styrene derivatives offers a rapid and efficient method to generate benzylic Grignard reagents, which can be applied in a range of transformations to provide products of formal hydrofunctionalization. While iron-catalyzed methodologies exist for the hydromagnesiation of terminal alkenes, internal alkynes, and styrene derivatives, the underlying mechanisms of catalysis remain largely undefined. To address this issue and determine the divergent reactivity from established cross-coupling and hydrofunctionalization reactions, a detailed study of the bis(imino)pyridine iron-catalyzed hydromagnesiation of styrene derivatives is reported. Using a combination of kinetic analysis, deuterium labeling, and reactivity studies as well as in situ 57Fe M?ssbauer spectroscopy, key mechanistic features and species were established. A formally iron(0) ate complex [iPrBIPFe(Et)(CH2a?CH2)]- was identified as the principle resting state of the catalyst. Dissociation of ethene forms the catalytically active species which can reversibly coordinate the styrene derivative and mediate a direct and reversible β-hydride transfer, negating the necessity of a discrete iron hydride intermediate. Finally, displacement of the tridentate bis(imino)pyridine ligand over the course of the reaction results in the formation of a tris-styrene-coordinated iron(0) complex, which is also a competent catalyst for hydromagnesiation.
- Neate, Peter G. N.,Greenhalgh, Mark D.,Brennessel, William W.,Thomas, Stephen P.,Neidig, Michael L.
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supporting information
p. 10099 - 10108
(2019/07/04)
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- Homogeneous Palladium-Catalyzed Transfer Hydrogenolysis of Benzylic Alcohols Using Formic Acid as Reductant
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We report the first homogeneous palladium-based transfer hydrogenolysis of benzylic alcohols using an in situ formed palladium-phosphine complex and formic acid as reducing agent. The reaction requires a catalyst loading as low as only 1 mol % of palladium and just a slight excess of reductant to obtain the deoxygenated alkylarenes in good to excellent yields. Besides demonstrating the broad applicability for primary, secondary and tertiary benzylic alcohols, a reaction intermediate could be identified. Additionally, it could be shown that partial oxidation of the applied phosphine ligand was beneficial for the course of the reaction, presumably by stabilizing the active catalyst. Reaction profiles and catalyst poisoning experiments were used to characterize the catalyst, the results of which indicate a homogeneous metal complex as the active species.
- Ciszek, Benjamin,Fleischer, Ivana
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p. 12259 - 12263
(2018/08/28)
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- ortho-Difunctionalization of arynes by LiZnEt2(TMP)-mediated deprotonative zincation/elimination of aryl triflates
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Generation of arynes from aryl triflates has been achieved using lithium diethyl(tetramethylpiperidyl)-zincate base LiZnEt2(TMP), via a directed ortho-deprotonative zincation and subsequent elimination of the triflate group. The aryne formation
- Cho, Seoyoung,Wang, Qiu
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supporting information
p. 3325 - 3328
(2018/04/02)
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- BICYCLIC COMPOUND AND USE THEREOF FOR INHIBITING SUV39H2
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The present invention directs to a compound represented by formula (I).
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Page/Page column 220
(2017/08/01)
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- Alkylation of pyridines at their 4-positions with styrenes plus yttrium reagent or benzyl grignard reagents
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A new regioselective alkylation of pyridines at their 4-position was achieved with styrenes in the presence of yttrium trichloride, BuLi, and diisobutylaluminium hydride (DIBAL-H) in THF. Alternatively, similar products were more simply prepared from pyridines and benzyl Grignard reagents. These reactions are not only a useful preparation of 4-substituted pyridines but are also complementary to other relevant reactions usually giving 2-substituted pyridines.
- Mizumori, Tomoya,Hata, Takeshi,Urabe, Hirokazu
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supporting information
p. 422 - 426
(2015/02/19)
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- Efficient palladium-catalyzed C-O hydrogenolysis of benzylic alcohols and aromatic ketones with polymethylhydrosiloxane
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A simple method has been developed for the reductive deoxygenation of aromatic ketones and benzylic alcohols in the presence of polymethylhydrosiloxane (PMHS). The reductive deoxygenation of aromatic ketones and benzylic alcohols, including secondary alcohols, to the corresponding methylene hydrocarbons has been achieved in good to excellent yields using palladium chloride (PdCl2) as catalyst and PMHS as hydride source. Such deoxygenations were successfully with aryl alkyl ketones and diaryl ketones, as exemplified by the reductive deoxygenation of acetophenone and benzopheneone, respectively. The corresponding benzylic alcohols and secondary alcohol analogues could also be converted into their respective methylene hydrocarbons by the PdCl2/PMHS system.
- Wang, Hu,Li, Li,Bai, Xing-Feng,Shang, Jun-Yan,Yang, Ke-Fang,Xu, Li-Wen
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supporting information
p. 341 - 347
(2013/05/08)
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- One-by-one hydrogenation, cross-coupling reaction, and Knoevenagel condensations catalyzed by PdCl2 and the downstream palladium residue
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A novel catalyst-economic strategy with a recovered palladium catalyst was successfully applied for multi-task and maximum reuse in different types of one-by-one downstream reactions, from catalytic hydrogenation to Suzuki and Sonogashira-type cross-coupling reactions, Knoevenagel condensations, and trans-Knoevenagel-like condensations.
- Wang, Hu,Li, Li,Bai, Xing-Feng,Deng, Wen-Hui,Zheng, Zhan-Jiang,Yang, Ke-Fang,Xu, Li-Wen
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supporting information
p. 2349 - 2355
(2013/09/12)
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- A mild and efficient rhenium-catalyzed transfer hydrogenation of terminal olefins using alcoholysis of amine-borane adducts as a reducing system
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[ReBr2(NO)(CH3CN)(PTA)2] (PTA = 1, 3, 5-triaza-7-phosphaadamantane) catalyzes the alcoholysis of ammonia-borane and amine-boranes and the catalytic transfer hydrogenations of various terminal olefins. Excellent yields were achieved at 70 °C in isopropanol using tBuOK as a co-catalyst affording TOF values up to 396 h-1.
- Dong, Hailin,Berke, Heinz
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experimental part
p. 1803 - 1808
(2011/06/19)
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- A palladium wall coated microcapillary reactor for use in continuous flow transfer hydrogenation
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Herein we describe the preparation of a novel continuous flow multi-channel microreactor in which the internal surface has been functionalised with a palladium coating, enabling its use in catalytic heterogeneous liquid-phase reactions. Simple chemical deposition techniques were used to immobilise palladium(O) on the channel wall surface of a polymeric multi-capillary extrudate made from ethylenevinyl alcohol copolymer. The Pd coating of the mi- crocapillaries has been characterised by mass spectrometry and light and electron microscopy. The functional activity of the catalytic Pd layer was tested in a series of transfer hydrogenation reactions using triethylsilane as the hydrogen source.
- Hornung, ChristianH,Hallmark, Bart,Mackley, Malcolm R.,Baxendale, Ian R.,Ley, Steven V.
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experimental part
p. 1736 - 1745
(2010/09/09)
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- Synthesis of novel structurally simplified estrogen analogues with electron-donating groups in ring A
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A library of 25 novel estrogen analogues were prepared in five to eight steps from mostly commercially available substituted anisoles via bromination, formylation, Corey-Fuchs reaction, elimination, and Sonogashira reaction. Georg Thieme Verlag Stuttgart.
- Tietze, Lutz F.,Vock, Carsten A.,Krimmelbein, Ilga K.,Nacke, Linda
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experimental part
p. 2040 - 2060
(2009/12/27)
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- Hydrogen-transfer reduction of carbonyl compounds catalysed by nickel nanoparticles
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We report for the first time the hydrogen-transfer reduction of carbonyl compounds catalysed by well-defined nickel(0) nanoparticles. The nickel nanoparticles could be reutilised several times in a very simple reaction medium composed of the nickel nanoparticles, isopropanol and the substrate, without any added base.
- Alonso, Francisco,Riente, Paola,Yus, Miguel
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p. 1939 - 1942
(2008/09/19)
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- Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
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The present invention provides process useful for the preparation of intermediates which are useful in the preparation of amino acids useful in preparing peptide receptor modulators, for example agonists or partial agonists of such peptide receptors. Such
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Page/Page column 1; 3; 5
(2010/02/15)
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- Photochemistry of substituted benzyl acetates and benzyl pivalates: A reinvestigation of substituent effects
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The photosolvolysis reactions, in methanol, of six substituted benzyl acetates (7a-f) and benzyl pivalates (8a-f) were studied. Five major benzylic products were formed from two critical intermediates. The ethers (9) were formed from the ion pair, 15, and all of the other products (10-14) were formed from the radical pair, 16. Quenching studies showed that only excited singlet state reactivity was important. The product yields were found to be highly substituent dependent. For instance, for the acetate esters, the yield of ether (9) varied from 2% for X = 4-OCH3 to 32% for X = 3-OCH3. Most of the differences in the yields could be attributed to ground state processes that occur after bond cleavage. The important competition is between electron transfer, converting the radical pair to the ion pair, and decarboxylation of RCO2*. The rates of electron transfer are shown to fit Marcus theory in both the normal and inverted regions. Direct heterolytic cleavage to form the ion pair is of minimal importance.
- Hilborn,MacKnight,Pincock,Wedge
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p. 3337 - 3346
(2007/10/02)
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- Catalyst composition and method for selective dehydrogenation
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A method for selective dehydrogenation of a compound, comprising contacting a compound of the formula STR1 wherein each R1, R2, R3 and R4 is independently selected from the group consisting of H, (C1 -C20) alkyl, (C3 -C20) cycloalkyl, (C6 -C20) aryl, (C7 -C20) alkylaryl, (C7 -C20) aralkyl groups, as well as substituted (C1 -C20) alkyl, (C3 -C20) cycloalkyl, (C6 -C20) aryl, (C7 -C20) aralkyl and (C7 -C20) arylalkyl moieties, optionally further substituted with --OR, wherein R is R1, R2, R3 or R4 ; and wherein R1 and R2 or R3 and R4 may be joined as part of a ring structure, at a dehydrogenation temperature in the presence of a catalyst comprising about 0.01 wt %-19.9 wt % Pd and about 0.01 wt %-19.9 wt % Cu on a carbon support, wherein the total amount of (Pd+Cu) on the support is about 0.02 wt % to 20 wt %, the weight ratio of Pd:Cu is about 1:1 to 10:1, and the carbon support has a surface area of at least about 100 m2 /g and is essentially free of reactive sulfur. A selective dehydrogenation catalyst having the composition described supra is disclosed as is a method of preparing the same. This catalyst is highly selective for dehydrogenating a variety of substrates while minimizing the formation of unwanted hydrogenolysis by-products.
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- Preparation and Reactions of Dianions from the Cresols
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With n-BuLi/KO-t-Bu, protons are removed from the hydroxyl and methyl groups of cresols 5 to give dianions 6 in yields of 85percent (ortho), 95percent (meta), and 42percent (para).These dianions react with alkyl halides, Me3SiCl, Bu3SnCl, CO2, and oxidizing agents at carbon only and with dialkyl sulfates at both carbon and oxygen.Thus phenol derivatives bearing primary alkyl groups can be prepared from the corresponding methylphenols via dianions 6.
- Bates, Robert B.,Siahaan, Teruna J.
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p. 1432 - 1434
(2007/10/02)
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- FRIEDEL-CRAFTS ALKYLATION OF ANISOLE AND ITS COMPARISON WITH TOLUENE. PREDOMINANT ORTHO-PARA SUBSTITUTION UNDER KINETIC CONDITIONS AND THE EFFECT OF THERMODYNAMIC ISOMERIZATIONS
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The AlCl3 and BF3, as well as 65percent HPF6, catalyzed Friedel-Crafts alkylation of anisole with alkyl halides and alkohols was investigated.The alkylation of anisole with lower catalyst concentrations under mild conditions shows predominant ortho/para directing effect generally with a ratio of c.a. 2:1, with the amount of meta isomer uniformly less than 3percent.With "swamping" catalyst conditions the amount of meta substitution in methylation and ethylation can substantially increase.The isomer distribution in tert-butylation changes with time due to rapid ortho-para interconversion.Consequently, the AlCl3-catalyzed isomerization of isomeric alkylanisoles was also studied.In case of tert-butylanisoles, the ortho isomer shows relatively rapid conversion into para followed by much slower isomerization to meta.The para and meta isomers show isomerization to meta-para mixtures.Isomerization of ethyl-, isopropyl-, and benzylanisoles is generally slow whereas methylanisoles do not isomerize.Comparing results of the alkylation of anisole with toluene leads to the conclusion that the latter are readily affected by concurrent (and in some cases consecutive) isomerization.As the barrier for isomerization in the benzenium ion intermediates of the alkylations is higher in the case of CH3O- than CH3-substituted systems, anisole tends to give the kinetically controlled ortho-para alkylation products and the amount of meta isomer is low.Study of alkylation of 3,5-di- and 2,4,6-trideuterated toluene and anisole and comparing retained deuterium contents with isomer distributions shows that alkylated product formation in case of toluene, but not of anisole, is proceeded by intramolecular, 1,2-alkyl, and hydrogen-deuterium shifting resulting also in increased meta substitution.This effect is most predominant in methylation and ethylation where the alkyl shifts are intramolecular but not in tert-butylation and benzylation, where alkyl transfer is intermolecular.Isopropylation is intermediate in nature.No simple selectivity-reactivity relationship is indicated in the studied alkylation reactions.As shown in benzylations with increasingly electron-donating and -withdrawing substituted benzyl chlorides overall rate (i.e., substrate selectivity) and isomer distributions (i.e., regioselectivity) are not determined in the same step as significantly decreased substrate selectivity is not accompanied by loss of positional selectivity.Previously reported alkylations showing high degree of meta substitution therefore, must have been affected by thermodynamically controlled rearrangement processes, including intramolecular alkyl and hydrogen shifts in the arenium ion intermediates of the alkylation reactions.These are to be differentiated from possible subsequent product isomerizations.Under predominantly kinetic conditions anisole as well as toluene are substantially ortho-para directing in alkylations, as in other electrophilic aromatic substitutions.
- Olah, George A.,Olah, Judith A.,Ohyama, Toshiyuki
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p. 5284 - 5290
(2007/10/02)
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