- Mechanistic Studies of 2-(1-Hydroxyethyl)-2,4,5-trimethyl-3-oxazoline Formation under Low Temperature in 3-Hydroxy-2-butanone/Ammonium Acetate Model Systems
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Volatile compounds formed from the reaction of 3-hydroxy-2-butanone/ammonium acetate at 25, 55 and 85 °C were investigated. Six compounds were characterized by gas chromatography - mass spectrometry (EI and CI). Among the volatile compounds identified, an interesting intermediate compound, 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline, was found. 15N-Labeled ammonium acetate was used to confirm the structure of 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline. The formation pathway of these volatile compounds was proposed. In these model systems, 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline was formed at the reaction temperature below 25 °C. On the other hand, tetramethylpyrazine was the major component when the reaction temperature was higher than 85 °C. The amounts of 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline and tetramethylpyrazine increased linearly with the increasing heating time at 55 °C. Protic solvents did not promote 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline formation but did favor the formation of tetramethylpyrazine. A kinetic study of 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline formation was also performed, and the activation energy was found to be 16.5 kcal/mol.
- Fu, Hui-Yin,Ho, Chi-Tang
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- Combined effects of a buffer and solvent on tetramethylpyrazine formation in a 3-hydroxy-2-butanone/ammonium hydroxide system
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A phosphate buffer was found to significantly promote tetramethylpyrazine (TMP) formation in an acetoin (3-hydroxy-2-butanone)/ammonium hydroxide system. The effect of the phosphate ion on TMP formation was additive in the range of 0.05-0.2 M. The change in pH value of the system reveals that a proton-coupled redox type of reaction occurred during TMP formation. Phosphate serves both as proton donor and acceptor to facilitate proton transfer during the Schiff base formation between ammonia and 3-hydroxy-2-butanone. Protic solvents, methanol, and ethanol, were found to attract the water released from the system. The combination of a phosphate buffer and protic solvent led to the completion of TMP formation. The TMP formation mechanism in a phosphate buffer (pH 7.2) is proposed.
- Huang
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- Formation of 2-(1-Hydroxyalkyl)-3-oxazolines from the Reaction of Acyloins and Ammonia Precursors under Mild Conditions
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Studies on the reaction between acetoin and an ammonia precursor under mild conditions revealed that two major products were formed, one of which was tetramethylpyrazine (TMP) and the other an unknown compound.By spectral elucidation (MS, IR, NMR), this unknown compound has been identified as 2,4,5-trimethyl-2-(1-hydroxyethyl)-3-oxazoline (OXZ).Two homologs of OXZ were also prepared.A 3-week storage study demonstrated that OXZ was readily formed, after which its formation declined.In contrast, TMP formation gradually increased before it leveled out in 15-20 days.At the end of this experiment, only TMP remained as the product, while OXZ was not found.Mechanistically, it is proposed that condensation of acetoin and ammonia generates α-hydroxyimine or α-amino ketone by tautomerism, which may lead to product formation via two pathways.One of the pathways is to form TMP via self-condensation of the α-amino ketone, dehydration, and dehydrogenation, which is well-known.The other pathway may be that the α-hydroxyimine condenses with a second molecule of acetoin and then is cyclized by Schiff base formation to OXZ.These storage results also indicate that the second pathway may be reversible, so that OXZ initially formed is able to be converted back to α-hydroxyimine, which, in turn, was tautomerized to α-amino ketone, so that the first pathway to form TMP could be followed. - Keywords: Acyloins; ammonia precursor; 2-(1-hydroxyalkyl)-3-oxazolines; 2,4,5-trimethyl-2-(1-hydroxyethyl)-3-oxazoline; 2,4-dimethyl-2-(hydroxymethyl)-3-oxazoline; 2,4,5-triethyl-2-(1-hydroxypropyl)-3-oxazoline; acetoin; acetol; 4-hydroxy-3-hexanone; diammonium hydrogen phosphate
- Shu, Chi-Kuen,Lawrence, Brian M.
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- Mechanistic Studies of Tetramethylpyrazine Formation under Weak Acidic Conditions and High Hydrostatic Pressure
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A significant enhancement of the tetramethylpyrazine (TMP) formation at high pressure was observed in the 3-hydroxy-2-butanone/ammonium acetate model system. In a water system, the activation volume of TMP formation under high pressure was found to be -6.82 mL/mol. A mechanism was proposed to elucidate the formation of TMP under a weak acidic condition and high hydrostatic pressure. Solvents such as propylene glycol (PG), glycerol, methanol, ethanol, propanol, and butanol were found to enhance TMP formation. Kinetic analyses indicated that TMP formation in aqueous, 80% PG, and ethanol systems followed pseudo-zero-order reaction kinetics. The activation energies were found to be 18.84 ± 1.3, 14.19 ± 7.1, and 13.09 ± 4.7 kcal/mol, respectively. The intermediate of TMP formation was characterized as tetramethyldihdyropyrazine using gas chromatography-mass spectrometry. A 15N-labeled ammonium acetate/3-hydroxy-2-butanone model system was used to confirm the incorporation of a nitrogen atom in the molecule of tetramethyldihydropyrazine. Hydrogen acceptors such as nicotinamide adenine dinucleotide and flavin adenine dinucleotide were found to increase TMP formation, and the formation of TMP from tetramethyldihydropyrazine through dehydrogenation was shown.
- Huang, Tzou-Chi,Fu, Hui-Yin,Ho, Chi-Tang
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- Chemo-Enzymatic Synthesis of Pyrazines and Pyrroles
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Herein we report the biocatalytic synthesis of substituted pyrazines and pyrroles using a transaminase (ATA) to mediate the key amination step of the ketone precursors. Treatment of α-diketones with ATA-113 in the presence of a suitable amine donor yielded the corresponding α-amino ketones which underwent oxidative dimerization to the pyrazines. Selective amination of α-diketones in the presence of β-keto esters afforded substituted pyrroles in a biocatalytic equivalent of the classical Knorr pyrrole synthesis. Finally we have shown that pyrroles can be prepared by internal amine transfer catalyzed by a transaminase in which no external amine donor is required.
- Xu, Jin,Green, Anthony P.,Turner, Nicholas J.
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- Characterization of volatile compounds from the reaction of 3-hydroxy- 2-butanone and ammonium sulfide model system
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The reactions between 3-hydroxy-2-butanone and ammoniun sulfide at 25, 50, 75, 100, 125, and 150 °C were studied. Four well-known flavor compounds, 2,4,5-trimethyloxazole, 2,4,5-trimethyl-3-oxazoline, 2,4,5-trimethylthiazole, and 2,4,5-trimethyl-3-thiazoline, were identified. Another four interesting intermediate compounds, 2-(1-hydroxyethyl)-2,4,5-trimethyl-3-oxazoline, 2- (1-mercaptoethyl)-2,4,5-trimethyl-3-oxazoline, 2-(1-hydroxyethyl)-2,4,5- trimethyl-3-thiazoline, and 2-(1-mercaptoethyl)-2,4,5-trimethyl-3-thiazoline, were also identified by GC-EIMS and GC-CIMS. All these intermediate compounds were formed at 25 °C. On the other hand, tetramethylpyrazine was the major product with a reaction temperature higher than 100 °C.
- Xi, Junwu,Huang, Tzou-Chi,Ho, Chi-Tang
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- Novel Ligustrazine-Based Analogs of Piperlongumine Potently Suppress Proliferation and Metastasis of Colorectal Cancer Cells in Vitro and in Vivo
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Piperlongumine 1 increases reactive oxygen species (ROS) levels and preferably induces cancer cell apoptosis by triggering different pathways. However, the poor solubility of 1 limits its intensive investigation and clinical application. Ligustrazine possesses a water-soluble pyrazine skeleton and can inhibit proliferation and metastasis of cancer cells. We synthesized compound 3 by replacement of the trimethoxyphenyl of 1 with ligustrazine moiety and further introduced 2-Cl, -Br, and -I to 3 for synthesis of 4-6, respectively. Compound 4 possessed 14-fold greater aqueous solubility than 1 and increased ROS levels in colorectal cancer HCT-116 cells. Additionally, 4 preferably inhibited proliferation, migration, invasion, and heteroadhesion of HCT-116 cells. Treatment with 4 suppressed tumor growth and lung metastasis in vivo and prolonged the survival of tumor-bearing mice. Furthermore, 4 mitigated TGF-β1-induced epithelial-mesenchymal transition and Wnt/β-catenin activation by inhibiting the Akt and GSK-3β phosphorylation in HCT-116 cells. Collectively, 4 displayed significant antiproliferation and antimetastasis activities, superior to 1.
- Zou, Yu,Zhao, Di,Yan, Chang,Ji, Yanpeng,Liu, Jin,Xu, Jinyi,Lai, Yisheng,Tian, Jide,Zhang, Yihua,Huang, Zhangjian
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- Acceptorless Dehydrogenative Coupling Using Ammonia: Direct Synthesis of N-Heteroaromatics from Diols Catalyzed by Ruthenium
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The synthesis of N-heteroaromatic compounds via an acceptorless dehydrogenative coupling process involving direct use of ammonia as the nitrogen source was explored. We report the synthesis of pyrazine derivatives from 1,2-diols and the synthesis of N-substituted pyrroles by a multicomponent dehydrogenative coupling of 1,4-diols and primary alcohols with ammonia. The acridine-based Ru-pincer complex 1 is an effective catalyst for these transformations, in which the acridine backbone is converted to an anionic dearomatized PNP-pincer ligand framework.
- Daw, Prosenjit,Ben-David, Yehoshoa,Milstein, David
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supporting information
p. 11931 - 11934
(2018/09/27)
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- A preparation method of Rhizoma Chuanxiong hydrochlorothizide
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The invention discloses a preparation method of ligustrazine, wherein the preparation method comprises the following steps: adding 3-hydroxy-2-butanone and ammonium acetate as main materials into a reaction vessel, then adding anhydrous ethanol, introducing nitrogen, carrying out water bath heating on the reaction vessel, stirring, stropping introduction of the nitrogen, and waiting the temperature to be dropped to room temperature; adding an aromatization catalyst, then stirring, and filtering to obtain a filtrate A; concentrating the filtrate A to obtain a solution B; adding water and an extraction agent into the B solution, extracting, and taking an upper-layer solution to obtain a solution C; carrying out reduced pressure distillation on the solution C to obtain a solution D; adding water into the solution D, and carrying out cooling crystallization to obtain a mixed material E; and filtering the mixed material E to obtain ligustrazine crystals. The reaction time is greatly shortened, the purification processing is more convenient, the method has the advantages of energy conservation and environmental protection, the prepared ligustrazine is in a needle-shaped crystal form, and the yield can reach 87%.
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Paragraph 0044-0049; 0053-0058; 0062-0067; 0071-0076
(2017/07/04)
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- A four-methyl pyrazine preparation method (by machine translation)
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The invention relates to a medicine intermediate four methyl pyrazine synthesis method, the method comprising: in order to diacetyl monoxime as raw materials, the addition of water as the solvent, palladium carbon as a catalyst, in backflow state by adding ammonium formate, after adding continue to stir at reflux 4 hours, filtering to remove the catalyst, the temperature and then the methylene chloride extraction, pressure reducing and concentrated to obtain four a [...]. The invention production four-methyl pyrazine mild reaction conditions, easy post treatment, the conversion is 95% or more, the yield is 80% or more, and the cost is low, and is favorable for industrial production. (by machine translation)
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Paragraph 0021; 0027; 0028; 0029; 0030; 0031; 0032
(2017/07/01)
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- 1H-pyrrole-2,4-dicarbonyl-derivatives and their use as flavoring agents
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The present invention primarily relates to 1H-pyrrole-2,4-dicarbonyl-derivatives of Formula (I) wherein R1, R2, R3, Z. Z' and J are as defined in the description, to mixtures thereof and to the use thereof as flavoring agents. The compounds in accordance with the present invention are suitable for producing, imparting, or intensifying an umami flavor. The invention further relates to flavoring mixtures, compositions for oral consumption as well as ready-to-eat, ready-to-use and semifinished products, comprising an effective amount of the compound of Formula (I) or of a mixture of compounds of Formula (I) and to specific methods for producing, imparting, modifying and/or intensifying specific flavor impressions.
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- Imidazo[1,2-a]pyridine-ylmethyl-derivatives and their use as flavoring agents
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The present invention primarily relates to imidazo[1,2-a]pyridine-ylmethyl-derivatives of Formula (I) wherein R1, R2, X, W e J are as defined in the description, to mixtures thereof and to the use thereof as flavoring agents. The compounds in accordance with the present invention are suitable for producing, imparting, or intensifying an umami flavor. The invention further relates to flavoring mixtures, compositions for oral consumption as well as ready-to-eat, ready-to-use and semifinished products, comprising an effective amount of the compound of Formula (I) and to specific methods for producing, imparting, modifying and/or intensifying specific flavor impressions.
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- Synthesis of novel ligustrazine derivatives as Na+/H+ exchange inhibitors
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A novel series of 3,5,6-trimethylpyrazine-2-methoxy (or methylamino) substituted benzoyl-guanidine derivatives were designed and synthesized as Na+/H+ exchange (NHE) inhibitors. In this study, compounds with electron-withdrawing substituents on the benzene ring seemed to improve NHE-1 inhibitory activities. Compounds 6d, 6k, and 6l were found to be potent inhibitors of NHE-1 (IC50=3.0±1.6, 3.0±1.4, and 1.6±0.4nmol/l, resp.). Furthermore, they showed a remarkable reduction of infarct size in the rat myocardial infarction model in vivo.
- Ren, Mei,Dong, Jin,Xu, Yungen,Wen, Nan,Gong, Guoqing
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experimental part
p. 2727 - 2736
(2011/08/06)
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- LIGUSTRAZINE AROMATIC ACID ETHER DERIVATIVE, ITS PREPARATION METHOD, PHARMACEUTICAL COMPOSITION, AND APPLICATION
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Ligustrazine aromatic acid ether derivative of general formula I, its preparation method, pharmaceutical composition and application, wherein Ar is selected from aryl substituted aryl and substituted styryl, R is selected from hydrogen and alkyl with no more than 6 carbon atoms.
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Page/Page column 6
(2010/08/09)
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- Formation of pyrazines in maillard model systems of lysine-containing dipeptides
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Whereas most studies concerning the Maillard reaction have focused on free amino acids, little information is available on the impact of peptides and proteins on this important reaction in food chemistry. Therefore, the formation of flavor compounds from the model reactions of glucose, methylglyoxal, or glyoxal with eight dipeptides with lysine at the N-terminus was studied in comparison with the corresponding free amino acids by means of stir bar sorptive extraction (SBSE) followed by GC-MS analysis. The reaction mixtures of the dipeptides containing glucose, methylglyoxal, and glyoxal produced 27, 18, and 2 different pyrazines, respectively. Generally, the pyrazines were produced more in the case of dipeptides as compared to free amino acids. For reactions with glucose and methylglyoxal, this difference was mainly caused by the large amounts of 2,5(6)-dimethylpyrazine and trimethylpyrazine produced from the reactions with dipeptides. For reactions with glyoxal, the difference in pyrazine production was rather small and mostly unsubstituted pyrazine was formed. A reaction mechanism for pyrazine formation from dipeptides was proposed and evaluated. This study clearly illustrates the capability of peptides to produce flavor compounds that can differ from those obtained from the corresponding reactions with free amino acids.
- Van Lancker, Fien,Adams,De Kimpe, Norbert
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scheme or table
p. 2470 - 2478
(2010/09/04)
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- Investigations of the reactions of monochloramine and dichloramine with selected phenols: Examination of humic acid models and water contaminants
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The phenols are an important area of investigation because they are substituents in the humic acids and are common contaminants in water. The reactivities and orientations of two common phenols (phenol and m-cresol), and some of their chlorinated intermediates with aqueous monochloroamine and dichloroamine were presented. m-Cresol was more reactive than phenol with both chlorinating agents. NH2Cl and NHCl2 showed extensive reactivity toward the phenols, even the partially chlorinated less reactive intermediates would be expected to fully chlorinate the activated positions in phenolic substituents in the humic acids.
- Heasley, Victor L.,Fisher, Audra M.,Herman, Erica E.,Jacobsen, Faith E.,Miller, Evan W.,Ramirez, Ashley M.,Royer, Nicole R.,Whisenand, Josh M.,Zoetewey, David L.,Shellhamer, Dale F.
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p. 5022 - 5029
(2008/04/18)
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- Preparation of pyrazines
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Alkyl pyrazine compounds are prepared by heating and refluxing an aqueous mixture of an ammonium-containing compound and at least one acyloin compound. Reaction product may be isolated from the reacted mixture by adjusting the pH of the reacted mixture, separating solid material from the pH-adjusted reacted mixture, adding water to the separated solid material to form a solution, allowing product to crystallyze from the solution and then collecting the crystalline product. Alternatively, the reactants may be heated, refluxed and sublimed to collect the pyrazine reaction product on a cooled sublimation collection surface.
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- Electrolytic Oxidation of Ketones in Ammoniacal Methanol in the Presence of Catalytic Amounts of KI
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The indirect electrooxidation of ketones in ammoniacal methanol using iodide ion as a mediator afforded 2,2-dialkyl-2,5-dihydro-1H-imidazoles 3 via an oxidative cyclocoupling of ketimine intermediates formed from ketones and ammonia.The treatment of 3 with dilute HCl gave α-amino ketone hydrochlorides 4 and the parent ketones in good yields.A similar electrooxidation of 3 resulted in the formation of the corresponding 2H-imidazoles 6, which were hydrolyzed to α-diketones and the parent ketones.The same products 6 could also conveniently be obtained by chemical oxidation of 3 with aqueous NaOCl.
- Chiba, Toshiro,Sakagami, Hirotoshi,Murata, Miki,Okimoto, Mitsuhiro
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p. 6764 - 6770
(2007/10/03)
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- Low-Valent Titanium Induced Reductive Cyclization of Nitriles to Symmetrically Substituted Tetraalkylpyrazines
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Reductive cyclization of nitriles 1 induced by titanium tetrachloride/zinc provides an efficient general synthesis of symmetrically substituted tetraalkylpyrazines 2.
- Chen, Wei-xing,Zhang, Jun-hu,Hu, Ming-yang,Wang, Xiao-chun
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p. 701 - 702
(2007/10/02)
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- Highly Selective Aromatic Chlorinations. Part 2. The Chlorination of Substituted Phenols, Anisoles, Anilines, and Related Compounds with N-Chloroamines in Acidic Solution
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Phenols, anisoles, anilines, and related compounds are chlorinated in trifluoroacetic acid at room temperature by N-chlorodialkylamines and N-chlorotrialkylammonium salts.With monsubstituted compounds and their 2- and 3-substituted derivatives the reaction occurs efficiently and selectively at the 4-position.The reactivity of these substrates and the selectivity of their chlorinations are determined by electronic rather than steric effects of the substituent.Blocking the reaction with a substituent at the 4-position generally leads to only poor or moderate yields of the 2-chlorinated product.Evidence for radical and cation radical intermediates has been obtained in the reactions of some of the 4-substituted reactants and the mechanism of chlorination is discussed in the light of these findings.The reactions of selected substrates have been scaled up to give laboratory syntheses.
- Smith, John R. Lindsay,McKeer, Linda C.,Taylor, Jonathan M.
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p. 385 - 392
(2007/10/02)
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- Reactions of Sodium Hydrogentelluride with α-Azido Ketones and α-Azido Bromides
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When treated with sodium hydrogentelluride in ethanol at room temperature, α-azido ketones are easily converted to pyrazines via the self-condensation of initially formed α-amino ketones followed by aerobic oxidation during work-up.On a similar treatment, activated α-azido bromide such as 1,2-diphenyl-1-azido-2-bromoethane suffers E2-type β-elimination to give the corresponding olefin as the sole product, while ordinary α-azido bromides afford complicated mixtures containing amino and olefinic compounds among other products.
- Suzuki, Hitomi,Kawaguchi, Takashi,Takaoka, Koji
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p. 665 - 666
(2007/10/02)
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- INTRODUCTION OF THE METHYL GROUP INTO THE PYRAZINE RING
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By the coupling reaction of mono- and dichloropyrazines with trimethylaluminum in the presence of a palladium catalyst, the corresponding mono- and dimethylpyrazines were prepared in excellent yields.
- Ohta, Akihiro,Inoue, Akira,Watanabe, Tokuhiro
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p. 2317 - 2321
(2007/10/02)
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- HIGH SITE-SELECTIVITY IN THE CHLORINATION OF ELECTRON-RICH AROMATIC COMPOUNDS BY N-CHLORAMMONIUM SALTS.
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N-Chlorammonium salts are efficient and very site-selective monochlorinating agents for electron-rich aromatic compounds.
- Smith, John R. Lindsay,McKeer, Linda C.
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p. 3117 - 3120
(2007/10/02)
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- Studies on the Thermolysis of 2-(2-Hydroxy-2-arylethyl)pyrazines. An Example of a Retro-Ene-Type Reaction
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Several substituted 2-(2-hydroxy-2-arylethyl)pyrazines (1-10) have been prepared and their thermolysis in diglyme and DMF studied.Each of these substrates decomposes to give the parent methylpyrazine and the corresponding aryl aldehyde.Kinetic, isotope effect, and solvent effect studies suggest a mechanism involving a nonpolar concerted six-membered-ring transition state.The degree of proton transfer in the transition state is discussed in detail.Methyl substituents on the pyrazine ring were found to strongly affect the reaction rate.This phenomenon is analyzed interms of the steric and electronic effects induced by the methyl substituents.
- Houminer, Yoram
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p. 999 - 1003
(2007/10/02)
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