- Optically Active 1-Deuterio-1-phenylethane – Preparation and Proof of Enantiopurity
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Enantiopure (S)-(1-2H)ethylbenzene was prepared in two steps from optically active (S)-1-phenylethanol via (R)-(1-chloroethyl)benzene (two inversions of configuration). Since the value for the specific rotation [α] is very low for the enantiomers of (1-2H)ethylbenzene, the enantiopurity of the synthetic product could not be determined with certainty by polarimetry. Therefore, bis-sulfonamides were prepared by twofold chlorosulfonation (para and ortho) of (S)-(1-2H)ethylbenzene and subsequent amidation with (R)- and (S)-α-phenethylamine. For both diastereoisomers, the (R,R,S)- and the (S,S,S)-sulfonamides, 92 % de was determined by 1H NMR spectroscopy. Therefore, it could be concluded, that (S)-(1-2H)ethylbenzene had been obtained with 92 % ee.
- Küppers, Julian,Rabus, Ralf,Wilkes, Heinz,Christoffers, Jens
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Read Online
- Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity
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Herein, detailed mechanistic investigations into formamide-catalyzed nucleophilic substitution (SN) of alcohols are reported. Alkoxyiminium chlorides and hexafluorophosphates were synthesized and characterized as a key intermediate of the catalytic cycle. The determination of reaction orders and control experiments indicated that the nucleophilic attack of the formamide catalyst onto the reagent BzCl is the rate-determining step. Linear free energy relationship revealed a correlation between the quantified Lewis basicity strength of formamides by means of 11B NMR spectroscopy and their catalytic activity in SN-transformations. The observed difference in catalytic ability was attributed to the natural bond order charge, dipole moment, and Sterimol parameter B5. Importantly, this rationalization enables the prediction of the capacity of formamides to promote SN-type transformations in general.
- Hilt, Gerhard,Huy, Peter H.,Kohlmeyer, Corinna,Sch?fer, André
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p. 11567 - 11577
(2020/11/17)
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- A PROCESS FOR THE STEREOSELECTIVE PREPARATION OF CHIRAL 2-[(HETERO)ARYLALKYLSULFANYL]PYRIMIDINES AND PRODUCTS OBTAINABLE THEREFROM
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There is provided a process for the preparation of a compound of formula I, wherein R1 and R2 each have the meanings provided in the description. There is also provided a process for the preparation of pharmaceutically-active compoun
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Page/Page column 31; 32
(2019/12/04)
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- A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions
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A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method.
- Huy, Peter H.,Filbrich, Isabel
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supporting information
p. 7410 - 7416
(2018/04/30)
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- Nucleophilic Substitutions of Alcohols in High Levels of Catalytic Efficiency
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A practical method for the nucleophilic substitution (SN) of alcohols furnishing alkyl chlorides, bromides, and iodides under stereochemical inversion in high catalytic efficacy is introduced. The fusion of diethylcyclopropenone as a simple Lewis base organocatalyst and benzoyl chloride as a reagent allows notable turnover numbers up to 100. Moreover, the use of plain acetyl chloride as a stoichiometric promotor in an invertive SN-type transformation is demonstrated for the first time. The operationally straightforward protocol exhibits high levels of stereoselectivity and scalability and tolerates a variety of functional groups.
- Stach, Tanja,Dr?ger, Julia,Huy, Peter H.
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supporting information
p. 2980 - 2983
(2018/05/28)
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- Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic Substitutions of Alcohols
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Herein, a method for the nucleophilic substitution (SN) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol-%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2-methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side-reaction also provided the explanation, why sulfoxide catalyzed SN-reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.
- Motsch, Sebastian,Schütz, Christian,Huy, Peter H.
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supporting information
p. 4541 - 4547
(2018/09/13)
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- Formamides as Lewis Base Catalysts in SNReactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers
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A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
- Huy, Peter H.,Motsch, Sebastian,Kappler, Sarah M.
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supporting information
p. 10145 - 10149
(2016/08/16)
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- METHOD OF CONVERTING ALCOHOL TO HALIDE
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The present invention relates to a method of converting an alcohol into a corresponding halide. This method comprises reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. The present invention also relates to a method of converting an alcohol into a corresponding substitution product. The second method comprises: (a) performing the method of the invention of converting an alcohol into the corresponding halide; and (b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.
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Page/Page column 50; 63; 79; 80; 81; 83; 86; 88; 118; 119; 182
(2017/01/02)
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- Nucleophilic substitution catalyzed by a supramolecular cavity proceeds with retention of absolute stereochemistry
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While the reactive pocket of many enzymes has been shown to modify reactions of substrates by changing their chemical properties, examples of reactions whose stereochemical course is completely reversed are exceedingly rare. We report herein a class of wa
- Zhao, Chen,Toste, F. Dean,Raymond, Kenneth N.,Bergman, Robert G.
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supporting information
p. 14409 - 14412
(2015/02/02)
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- DMSO-catalyzed chlorination of alcohols using N-phenylbenzimidoyl chloride
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N-phenylbenzimidoyl chloride has been demonstrated as an efficient chlorination reagent catalyzed by dimethyl sulfoxide (DMSO) in conversion of alcohols to corresponding chlorides. The reaction conditions were mild, and most of the substrates gave satisfactory yields. The configuration inversion of the chlorination was proved using optically active phenyl alcohols. The amount of DMSO can be as low as 0.001 eq without reducing the efficiency of the chlorination. A plausible mechanism for the reaction was proposed and proved by experiments. The reaction is stereoselective and potentially chemoselective among primary benzyl alcohols, secondary benzyl alcohols, and unactivated aliphatic alcohols.
- Wang, Qiang,Xu, Jian,Xu, Zhou-Qing,Yan, Ji-Dan
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p. 2071 - 2076
(2013/06/05)
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- Supercritical carbon dioxide: A promoter of carbon-halogen bond heterolysis
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Amazing reaction medium: Supercritical carbon dioxide, with zero dipole moment, lower dielectric constant than pentane, and non-hydrogen-bonding behavior, ionizes carbon-halogen bonds, dissociates the resulting ion pairs, and escapes from capture by the carbocation intermediates at temperatures above 40 °C. These properties allow the observation of carbocation chemistry in the absence of acids.
- Delgado-Abad, Thais,Martinez-Ferrer, Jaime,Caballero, Ana,Olmos, Andrea,Mello, Rossella,Gonzalez-Nunez, Maria Elena,Perez, Pedro J.,Asensio, Gregorio
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supporting information
p. 13298 - 13301
(2014/01/06)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0531; 0532
(2013/10/08)
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- Kinetics and mechanism of benzyl chloride reaction with zinc in dimethylacetamide
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Oxidative dissolution of zinc in the system of benzyl chloride- dimethylacetamide was investigated. The reaction stereochemistry as well as intermediates and reaction products formed were studied. The kinetic and thermodynamic parameters of the process were measured. The process was shown to follow the Langmuir-Hinshelwood mechanism with the formation of benzyl radicals and mono-solvated organozinc compound on the zinc surface. The components of mixture are adsorbed at various sites of the zinc surface, while recombination and the isomerization of the benzyl radicals occurs in solution. Pleiades Publishing, Ltd., 2012.
- Egorov,Matyukhova,Dashkova
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p. 1686 - 1699
(2013/02/23)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including CNS or neurodegeneration disorder.
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Page/Page column 88
(2012/04/10)
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- Catalytic phosphorus(V)-mediated nucleophilic substitution reactions: Development of a catalytic appel reaction
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Catalytic phosphorus(V)-mediated chlorination and bromination reactions of alcohols have been developed. The new reactions constitute a catalytic version of the classical Appel halogenation reaction. In these new reactions oxalyl chloride is used as a consumable stoichiometric reagent to generate the halophosphonium salts responsible for halogenation from catalytic phosphine oxides. Thus, phosphine oxides have been transformed from stoichiometric waste products into catalysts and a new concept for catalytic phosphorus-based activation and nucleophilic substitution of alcohols has been validated. The present study has focused on a full exploration of the scope and limitations of phosphine oxide catalyzed chlorination reactions as well as the development of the analogous bromination reactions. Further mechanistic studies, including density functional theory calculations on proposed intermediates of the catalytic cycle, are consistent with a catalytic cycle involving halo- and alkoxyphosphonium salts as intermediates.
- Denton, Ross M.,An, Jie,Adeniran, Beatrice,Blake, Alexander J.,Lewis, William,Poulton, Andrew M.
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experimental part
p. 6749 - 6767
(2011/10/02)
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- Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis
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The addition of an aryllithium reagent to a secondary boronic ester leads to an intermediate boron-ate complex that behaves as a chiral nucleophile, reacting with a broad range of electrophiles with inversion of stereochemistry. Depending on the electrophile, the C-B bond can be converted into C-I, C-Br, C-Cl, C-N, C-O, and C-C, all with very high levels of stereocontrol. This discovery now adds a new, readily available, configurationally stable, chiral organometallic-type reagent to the arsenal of methods for use in asymmetric organic synthesis.
- Larouche-Gauthier, Robin,Elford, Tim G.,Aggarwal, Varinder K.
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supporting information; experimental part
p. 16794 - 16797
(2011/12/04)
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- Aromatic cation activation of alcohols: Conversion to alkyl chlorides using dichlorodiphenylcyclopropene
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(Chemical Equation Presented) A novel paradigm for the activation of alcohols toward nucleophilic displacement via formation of cyclopropenium ethers is described. The conversion of a range of alcohol substrates to the corresponding alkyl chlorides occurs rapidly upon treatment with 3,3-dichloro-1,2-diphenylcyclopropene. 1H NMR data support the intermediacy of a cyclopropenium intermediate, and the reaction is demonstrated to proceed primarily via the SN2 mechanism for 1-phenylethanol. A total of 12 examples of substrate scope are provided.
- Kelly, Brendan D.,Lambert, Tristan H.
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supporting information; experimental part
p. 13930 - 13931
(2009/12/25)
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- The mechanism of 1,4 alkyl group migration in hypervalent halonium ylides: The stereochemical course
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Rhodium(II)-acetate-catalyzed decomposition of either 1,3-cyclohexanedione phenyliodonium ylide or 5,5-dimethyl-1,3-cyclohexanedione phenyliodonium ylide in the presence of alkyl halides yields the corresponding 3-alkoxy-2-halocyclohex-2-enones via a 1,4 alkyl group migration shown to be concerted and intramolecular. In the case of (S)-α-phenethyl chloride, the rearrangement proceeds with essentially 88.6% retention of configuration. Theoretical calculations at the B3LYP/6-31G level reveal an activation energy of 5.4 kcal/mol for the process. A Claisen-like rearrangement occurs in the case where allylic halides, such as dimethylallyl or methallyl chorides, are used. The mechanistic pathway proposed for these processes involves addition of the halogen atom of the alkyl or allyl halide to the rhodium carbenoid from the iodonium ylide to yield a halonium intermediate that undergoes halogen to oxygen group migration. Aryl halides, such as chloro-, bromo-, iodo-, and fluorobenzene, behave differently under the same reaction conditions, yielding the product of electrophilic aromatic substitution, namely, the 2-(4-halophenyl) 1,3-cyclohexanedione. Copyright
- Moriarty, Robert M.,Tyagi, Sachin,Ivanov, Daniela,Constantinescu, Mircea
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p. 7564 - 7565
(2008/12/22)
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- Transformation of tertiary amines into alkylating reagents by treatment with 2-chloro-4,6-dimethoxy-1,3,5-triazine. A synthetic application of side-reaction accompanying coupling by means of 4-(4,6-dimethoxy-[1,3,5] triazin-2-yl)-4-methyl-morpholin-4-ium chloride (DMTMM)
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Mild reaction conditions are described for the preparation of a number of alkyl chlorides and 2-dialkyl(aryl)amino-4,6-dirnethoxy-1,3,5-triazines by dealkylation of quaternary triazinylammonium chlorides formed as reactive intermediates in reaction of tertiary amines with 2-chloro-4,6-dimethoxy-1,3,5- triazine. The high selectivity of substitution was observed within the reactivity order of the alkyl groups: benzyl ~ allyl > methyl > n-alkyl. Studies on dealkylation of S-(-)-J-dimethyl-(1-phenylethyl)amine to R-(+)-1-chloro-1-phenylethane revealed that reaction proceeded with an inversion of configuration on the carbon atom as may be expected for SN2 type substitution. The scope of reaction was extended by exchange of anion in quaternary triazinylammonium chlorides with 1-, SCN-, C6H5O-, CH3COO- followed by N-dealkylation step.
- Kolesinska,Kaminski
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experimental part
p. 2115 - 2123
(2009/04/07)
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- Kinetics and mechanism of the reaction of benzyl halides with zinc in dimethylformamide
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The reaction of metal zinc with various benzyl halides in dimethylformamide has been studied. The low-temperature ESR-spectroscopy is used to show that reaction of zinc with benzyl bromide and benzyl iodide occurs to form benzyl radicals. Benzyl chloride reacts with zinc at 77 K to form benzyl radicals and ion-radical pairs RX- - Zn+. Nevertheless these pairs disappear at temperatures higher than 110 K. The investigation of the reaction stereochemistry and the use of a radical trap provide evidence in favor of a radical mechanism. The optical activity has been proved in the course of the formation of organozinc halide from (+)-R-1-halogen-1-phenylethane at low temperature. The kinetic features of the reaction have been studied. Benzyl iodide reacts with zinc at transport-controlled rate. The reaction of zinc with benzyl chloride and benzyl bromide in DMF occurs according to Langmuir-Hinshelwood scheme, the adsorption of reagents taking place on similar active centers of metal. The kinetic and thermodynamic parameters of the reaction have been clarified. The comparison of kinetic parameters with those reported in literature evidences that the limiting step of reaction is halogen atom transfer (inner sphere electron transfer). Copyright
- Egorov, Anatoly M.
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p. 664 - 675
(2008/02/08)
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- NOVEL 5,7-DISUBSTITUTED [1,3]THIAZOLO[4,5-D]PYRIMIDIN-2(3H)-ONE DERIVATIVES
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There are disclosed novel 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one derivatives of formula (I) [Chemical formula should be inserted here. Please see paper copy] wherein R1, R2, R3, R4 and R5 are as defined in the specification, and pharmaceutically acceptable salts thereof, together with processes for their preparation, pharmaceutical compositions comprising them and their use in therapy. The compounds of formula (I) are CX3CR1 receptor antagonists and are thereby particularly useful in the treatment or prophylaxis of neurodegenerative disorders, demyelinating disease, cardio- and cerebrovascular atherosclerotic disorders, peripheral artery disease, rheumatoid arthritis, pulmonary diseases such as COPD, asthma or pain.
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Page/Page column 33
(2008/06/13)
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- NOVEL 5-SUBSTITUTED 7-AMINO-[1,3]THIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES
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There are disclosed novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives of formula (I) wherein R1, R2, R3, R4 and R5 are as defined in the specification, and pharmaceutically accept
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Page/Page column 27
(2010/11/24)
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- Rhodium-catalyzed reaction of thiols with polychloroalkanes in the presence of triethylamine
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(Chemical Equation Presented) RhCl(PPh3)3 catalyzes a reaction of thiols with polychloroalkanes in the presence of triethylamine. This reaction serves as a convenient new method to produce formaldehyde dithioacetals, ethylenedithioethers, thioformates, and dithiocarbonic esters under mild conditions.
- Tanaka, Ken,Ajiki, Kaori
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p. 1537 - 1539
(2007/10/03)
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- Kinetics and mechanism of the reaction of substituted benzyl chlorides with copper in dimethylformamide
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The reaction of copper metal with various substituted benzyl chlorides in dimethylformamide was studied. The kinetic and thermodynamic parameters of the reaction was clarified. Hammett plots of log(k/k0) vs the substituent constant a gave a good correlation (ρ = .43, Sρ = 0.05, r = 0.960). The structure of the organic group has little effect on the rate of reaction of substituted benzyl chlorides with copper. In the absence of atmospheric oxygen, the oxidative dissolution of copper proceeded via a single-electron transfer mechanism with formation of 1,2-diphenylethanes and copper(I) complexes. The stereochemistry and intermediate compound were also studied. The reaction mechanism is discussed. Copyright
- Egorov, Anatoly M.,Matyukhova, Svetlana A.,Anisimov, Alexander V.
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p. 1023 - 1031
(2007/10/03)
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- Optical activity retention in the reaction of magnesium with (+)-R-1-chloro-1-phenylethane
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Optical activity retention has been proved in the course of the formation of Grignard reagent from optically active (+)-R-1-chloro-1-phenylethane.Key words: Magnesium; Optical activity
- Egorov, Anatoly M.,Anisimov, Alexander V.
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p. 197 - 198
(2007/10/02)
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- Side Chain Hydroxylation of Aromatic Hydrocarbons by Fungi. Part 2. Isotope Effects and Mechanism
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The benzylic hydroxylation of ethylbenzene, p-diethylbenzene, tetralin, indane, and toluene by the fungi Mortierella isabellina, Cunninghamella echinulata, and Helminthosporium species has been investigated by the use of deuterium-labelled substrates.An i
- Holland, Herbert L.,Brown, Frances M.,Munoz, Benito,Ninnis, Ronald W.
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p. 1557 - 1564
(2007/10/02)
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- EFFECT OF THE NATURE OF THE ACYLATING AGENT ON THE ASYMMETRIC ACYLATION OF ALCOHOLS
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During the acylation of racemic 1-phenylethanol by the action of carboxylic acid anhydrides in the presence of S-(-)-N,N-dimethyl-α-phenylethylamine the unreacted alcohol is enriched in the S isomer.Its optical purity increases with increase in the steric demands of the anhydride from 2percent for acetic anhydride to 9percent for benzoic anhydride.When carboxylic acid chlorides are used, optically active 1-phenyl-1-chloroethane and bis-1-phenylethyl ether are isolated in addition to S-(-)-1-phenylethanol.
- Potapov, V. M.,Dem'yanovich, V. M.,Klebnikov, V. A.,Korovina, T. G.
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p. 1095 - 1097
(2007/10/02)
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- Stereochemical Aspects of Conjugation Reactions Catalyzed by Rat Liver Glutathione S-Transferase Isozymes
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Substrate enantioselectivity in the conjugation of phenethyl halides catalyzed by the glutathione S-transferases was studied with partially purified isozymes from rat liver.All of the isozymes tested possessed measurable activity with phenethyl chloride.Transferase A was the most active isozyme tested.Each of the isozymes demonstrated a high degree of substrate enantioselectivity, with transferase A being the most enantioselective isozyme.The enantioselectivity was determined by high-pressure liquid chromatographic analysis of the enzymatically formed diastereomeric products.The effect of limiting glutathione concentrations on the stereochemical outcome of the transferase A catalyzed conjugation of the chiral substrate, (S)-phenethyl chloride (4mM), was investigated.The stereochemical course of the enzymatic reaction was not significantly altered at glutathione concentrations as low as 25 μM.The major product of conjugation had the opposite stereochemistry at the benzylic carbon, indicating that the reaction proceeded primarily with inversion of configuration.The glutathione conjugates, S-glutathione, S-glutathione, S-benzylglutathione, and S-methylglutathione were studied as inhibitors of the transferase A catalysed conjugation of 1-chloro-2,4-dinitrobenzene.The order of the inhibitory potency was S-glutathione = S-benzylglutathione > S-glutathione > S-methylglutathione.This represented the first demonstration of the stereoselective product inhibition of the glutathione S-transferases.
- Mangold, James B.,Abdel-Monem, Mahmoud M.
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