- SUBSTITUTED 3,4,12,12A-TETRAHYDRO-1H-[1,4]OXAZINO[3,4-C]PYRIDO[2,1-F][1,2,4]TRIAZINE-6,8-DIONE, PHARMACEUTICAL COMPOSITION, AND METHODS FOR PREPARING AND USING SAME
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Influenza is an acute infectious respiratory disease caused by the influenza virus. It is part of the group of Acute Respiratory Viral Infections (ARVI). It occasionally spreads in the form of epidemics and pandemics. Currently, more than 2000 variants of the influenza virus differing in the antigen spectrum have been identified. Given that influenza is a serious threat to public health (worldwide, these annual epidemics lead to 3-5 million cases of severe illness, millions of hospitalizations, and up to 650,000 deaths), it seems appropriate to search for new anti-influenza drugs with improved characteristics. The inventors surprisingly found out that the previously unknown substituted 3,4,12,12a-tetrahydro-1 H-[1,4] oxazino[3,4-c]pyrido[2,1-f] [1,2,4]triazine-6,8-dione of general formula 1, its stereoisomer, their prodrug, pharmaceutically acceptable salt, solvate, hydrate, and a crystalline or polycrystalline form thereof are effective agents for prophylaxis and treatment of viral diseases, including influenza where R1 is (6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, (7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)-methyl; R2 is hydrogen or a protective group selected from a series comprising (C1-C3 alkyl) oxycarbonyloxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, {[2-(C1-C3 alkyl) oxyethoxy]carbonyl}oxy, ({[(1R)-2-[(C1-C3alkyl)oxy]-1-methylethoxy}carbonyl)oxy, {[(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy)carbonyl]oxy,{[(1-acetylazetidine)-3-yloxy]carbonyl}oxy, {[(C1-C3alkyl) oxycarbonyl] -oxy}methoxy, ({[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy) methoxy.
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Paragraph 0055; 0092
(2021/01/21)
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- Modulation of photochemical oxidation of thioethers to sulfoxides or sulfones using an aromatic ketone as the photocatalyst
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We have developed an eco-friendly and chemo-selective photocatalytic synthesis of sulfoxides or sulfones via oxidation of sulfides (thioethers) at ambient temperature using air or O2 as the oxidant. An inexpensive thioxanthone was used as the photocatalyst. Our method offers excellent chemical yields and good functional group tolerance. The hydrogen bonding between hexafluoro-2-propanol (HFIP) and sulfoxides may play an important role in minimizing the over-oxidization of sulfoxides.
- Zhao, Bin,Hammond, Gerald B.,Xu, Bo
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supporting information
(2021/09/13)
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- t-BuOK-promoted methylthiolation of aryl fluorides with dimethyldisulfide under transition-metal-free and mild conditions
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In the presence of potassium tert-butoxide (t-BuOK), the cross-coupling reaction between aryl fluorides and dimethyldisulfide was developed. A series of aryl methyl sulfides were obtained in moderate to good yields under transition-metal-free and mild conditions.
- Huang, Dayun,Wu, Xiangmei
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- Scalable electrochemical reduction of sulfoxides to sulfides
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A scalable reduction of sulfoxides to sulfides in a sustainable way remains an unmet challenge. This report discloses an electrochemical reduction of sulfoxides on a large scale (>10 g) under mild reaction conditions. Sulfoxides are activated using a substoichiometric amount of the Lewis acid AlCl3, which could be regeneratedviaa combination of inexpensive aluminum anode with chloride anion. This deoxygenation process features a broad substrate scope, including acid-labile substrates and drug molecules.
- Kong, Zhenshuo,Pan, Chao,Li, Ming,Wen, Lirong,Guo, Weisi
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supporting information
p. 2773 - 2777
(2021/04/21)
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- Reduction of CO2 with NaBH4/I2 for the Conversion of Thiophenols to Aryl Methyl Sulfides
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We report a tandem reaction to realize reduction of carbon dioxide with thiophenols to generate aryl methyl sulfides under the NaBH4/I2 system with 18-crown-6 as the solvent. Thiophenols bearing electron-donating and electron-withdrawing groups are feasible in this reaction. Controlled experiment results indicate that 18-crown-6 plays a critical role in six-electron reduction of carbon dioxide.
- Zhang, Bo,Fan, Zhengning,Guo, Zhiqiang,Xi, Chanjuan
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p. 8661 - 8667
(2019/07/03)
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- A visible-light photocatalytic thiolation of aryl, heteroaryl and vinyl iodides
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The general catalytic synthesis of aryl and vinyl thioethers from readily available halides remains a challenge. Herein we report a unified method for the thiolation of aryl and vinyl iodides with dialkyl disulfides using visible light photoredox catalysis. A range of thioether products bearing diverse functional groups can be accessed in high yield and with excellent chemoselectivity. We demonstrate the versatility of this method through the expedient synthesis of a family of thioether-rich natural products. A detailed investigation of the photocatalytic mechanism is presented from both steady-state and time-resolved luminescent quenching as well as transient absorption spectroscopy experiments.
- Czyz,Weragoda,Monaghan,Connell,Brzozowski,Scully,Burton,Lupton,Polyzos
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supporting information
p. 1543 - 1551
(2018/03/08)
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- Environmentally benign indole-catalyzed position-selective halogenation of thioarenes and other aromatics
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Halogenated aromatic compounds are the cores of many pharmaceutical, agricultural and chemical products but they are commonly prepared using electrophilic halogenation reactions in non-green chlorinated solvents under harsh conditions. A separate problem happens in the aromatic halogenation of thioarenes because they readily undergo oxidative side-reactions. Herein we report an environmentally benign electrophilic bromination of aromatics using an indole-catalytic protocol, which is suitable for a wide range of substrates including thioarenes.
- Shi, Yao,Ke, Zhihai,Yeung, Ying-Yeung
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p. 4448 - 4452
(2018/10/17)
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- METHOD FOR PRODUCING SULFIDE
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PROBLEM TO BE SOLVED: To provide a method that performs a deoxygenation reaction of a sulfoxide using hydrogen as a reductant, and produces a corresponding sulfide. SOLUTION: A method for producing a sulfide is characterized by performing a deoxygenation reaction of a sulfoxide in the presence of a platinum-carrying molybdenum trioxide catalyst in which a platinum particle is immobilized to a molybdenum trioxide, and hydrogen, to obtain a corresponding sulfide. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPO&INPIT
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Paragraph 0075-0077; 0080; 0083
(2018/06/07)
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- Mild Deoxygenation of Sulfoxides over Plasmonic Molybdenum Oxide Hybrid with Dramatic Activity Enhancement under Visible Light
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Harvesting solar light to boost commercially important organic synthesis still remains a challenge. Coupling of conventional noble metal catalysts with plasmonic oxide materials which exhibit intense plasmon absorption in the visible light region is a promising option for efficient solar energy utilization in catalysis. Herein, we for the first time demonstrate that plasmonic hydrogen molybdenum bronze coupled with Pt nanoparticles (Pt/HxMoO3-y) shows a high catalytic performance in the deoxygenation of sulfoxides with 1 atm of H2 at room temperature, with dramatic activity enhancement under visible light irradiation relative to dark conditions. The plasmonic molybdenum oxide hybrids with strong plasmon resonance peaks pinning at around 556 nm are obtained via a facile H-spillover process. Pt/HxMoO3-y hybrid provides excellent selectivity for the deoxygenation of various sulfoxides as well as pyridine N-oxides, in which drastically improved catalytic efficiencies are obtained under the irradiation of visible light. Comprehensive analyses reveal that oxygen vacancies massively introduced via a H-spillover process are the main active sites, and the reversible redox property of Mo atoms and strong plasmonic absorption play key roles in this reaction. The catalytic system works under extremely mild conditions and can boost the reaction by the assistance of visible light, offering an ultimately greener protocol to produce sulfides from sulfoxides. Our findings may open up a new strategy for designing plasmon-based catalytic systems that can harness visible light efficiently.
- Kuwahara, Yasutaka,Yoshimura, Yukihiro,Haematsu, Kohei,Yamashita, Hiromi
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p. 9203 - 9210
(2018/06/25)
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- METHOD FOR PRODUCING PHENOTHIAZINE DERIVATIVE
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PROBLEM TO BE SOLVED: To provide a method for producing a phenothiazine derivative that has reduced limitations on the number of functional groups that can be arranged to it, prevents the occurrence of by-products, and secures high yields. SOLUTION: A method for producing a phenothiazine derivative includes the step of reacting a benzyne precursor with a compound represented by formula (A) (RA1-RA5 independently represent H, a hydroxy group or an organic group, RA1 and RA2, RA2 and RA3, RA3 and RA4 may together form, with an adjacent atom, a 5-8 membered ring; RA6 is H or an optionally substituted C1-C20 hydrocarbon group; X is a halogen atom). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0053
(2018/03/31)
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- Synthesis of diverse phenothiazines by direct thioamination of arynes with S-(o-bromoaryl)-S-methylsulfilimines and subsequent intramolecular BuchwaldHartwig amination
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A facile method for the synthesis of diverse phenothiazines has been achieved by direct thioamination of aryne intermediates with S-(o-bromoaryl)-S-methylsulfilimines and subsequent intramolecular BuchwaldHartwig amination. Since various sulfilimines could be prepared easily by odorless copper-catalyzed ipso-thiolation of readily available o-bromoarylboronic acids followed by imination and hydrolysis, this approach enables the synthesis of a wide variety of multisubstituted phenothiazines.
- Matsuzawa, Tsubasa,Uchida, Keisuke,Yoshida, Suguru,Hosoya, Takamitsu
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supporting information
p. 825 - 828
(2018/07/05)
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- Lewis Acid–Base Interaction-Controlled ortho-Selective C?H Borylation of Aryl Sulfides
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An iridium/bipyridine-catalyzed ortho-selective C?H borylation of aryl sulfides was developed. High ortho-selectivity was achieved by a Lewis acid–base interaction between a boryl group of the ligand and a sulfur atom of the substrate. This is the first example of a catalytic and regioselective C?H transformation controlled by a Lewis acid–base interaction between a ligand and a substrate. The C?H borylation reaction could be conducted on a gram scale, and with a bioactive molecule as a substrate, demonstrating its applicability to late-stage regioselective C?H borylation. A bioactive molecule was synthesized from an ortho-borylated product by converting the boryl and methylthio groups of the product.
- Li, Hong Liang,Kuninobu, Yoichiro,Kanai, Motomu
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p. 1495 - 1499
(2017/02/05)
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- Metal-free radical thiolations mediated by very weak bases
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Aromatic thioethers and analogous heavier chalcogenides were prepared by reaction of arene-diazonium salts with disulfides in the presence of the cheap and weak base NaOAc. The mild and practical reaction conditions (equimolar reagents, DMSO, r.t., 8 h) tolerate various functional groups (e.g. Br, Cl, NO2, CO2R, OH, SCF3, furans). Mechanistic studies indicate the operation of a radical aromatic substitution mechanism via aryl, acetyloxyl, thiyl, and dimsyl radicals.
- Koziakov, Denis,Majek, Michal,Jacobi Von Wangelin, Axel
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supporting information
p. 11347 - 11352
(2016/12/16)
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- FUSED TRICYCLIC BENZIMIDAZOLES DERIVATIVES AS MODULATORS OF TNF ACTIVITY
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A series of tricyclic benzimidazole derivatives, in particular dihydro-1H- imidazo [1,2-a]benzimidazo le, dihydro-1H-pyrrolo [1,2-a]benzimidazo le, dihydro-1H- pyrazino[1,2-a]benzimidazole, dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole and dihydrothiazolo[3,4-a]benzimidazolem, and analogues thereof, being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
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Page/Page column 127
(2015/06/25)
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- N-Imidazolylation of Sulfoximines from N-Cyano Sulfoximines, 1-Alkynes, and N-Sulfonyl Azides
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The rhodium-catalyzed N-imidazolylation of N-sulfonyl-1,2,3-triazoles with a variety of N-cyano sulfoximines has been developed for the synthesis of N-imidazolyl sulfoximines via elimination of molecular nitrogen. Copper-catalyzed [3+2] cycloaddition followed by rhodium-catalyzed N-imidazolylation from 1-alkynes, N-sulfonyl azides, and N-cyano sulfoximines is also demonstrated for the synthesis of N-imidazolyl sulfoximines in a one-pot procedure.
- Kim, Sanghyuck,Kim, Ji Eun,Lee, Jinsub,Lee, Phil Ho
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supporting information
p. 3707 - 3717
(2016/01/25)
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- Sulfoxide-to-sulfilimine conversions: Use of modified Burgess-type reagents
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Sulfoxides can directly be converted into N-cyanosulfilimines using a new Burgess-type reagent. By applying this strategy with a related reagent variant, synthetically valuable NH-sulfoximines have been prepared from sulfoxides via N-protected sulfilimines. The practical three-step reaction sequence is generally high yielding and applicable to a wide range of substrates. The sulfoxide-to-sulfilimine conversion can also be performed under solvent-reduced conditions in a ball mill. Copyright
- Hendriks, Christine M. M.,Lamers, Philip,Engel, Julien,Bolm, Carsten
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supporting information
p. 3363 - 3368
(2013/12/04)
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- Tert-Butanesulfinylthioether ligands: Synthesis and application in palladium-catalyzed asymmetric allylic alkylation
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A class of novel chiral SO-S-type bidentate ligands based on the tert-butylsulfinyl moiety as the sole chiral source were designed and synthesized through a simple and efficient pathway. These ligands are effective catalyst precursors for the palladium-catalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate and moderate to good stereoselectivities (up to 84% ee) were obtained.
- Liu, Jibing,Chen, Guihua,Xing, Junwei,Liao, Jian
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experimental part
p. 575 - 579
(2011/06/21)
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- New synthesis of benzothiazines and benzoisothiazoles containing a sulfoximine functional group
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(Chemical Equation Presented) The reaction of S-2-bromophenyl-S- methylsulfoximine with terminal alkynes in the presence of a palladium catalyst resulted in the formation of both 1,2-benzothiazines and 1,2-benzoisothiazoles. A preference for the former was seen with alkylalkynes, while the latter were preferentially formed with alkynylarenes.
- Harmata, Michael,Rayanil, Kanok-On,Gomes, Maria G.,Zheng, Pinguan,Calkins, Nathan L.,Kim, Soo-Yeun,Fan, Yimin,Bumbu, Valentina,Dong, Reyoul Lee,Wacharasindhu, Sumrit,Hong, Xuechuan
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p. 143 - 145
(2007/10/03)
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- Synthetic routes to polyheteroacenes: Characterization of a heterocyclic ladder polymer containing phenoxathiinium-type building blocks
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The synthetic routes to ladder polymers that consist of benzenetetrayl subunits with oxo and methylsulfonio linkages are described. As the key intermediate, poly(phenylene oxide)s having pendant methylsulfenyl groups are prepared by copper-catalyzed oxidative polymerization of the corresponding phenols with O2. The oxidation of the polymer with an equimolar amount of H2O2 in the presence of acetic acid effects the high-yielding conversion of methylsulfenyl to methylsulfinyl groups without the formation of the undesired methylsulfonyl groups. The superacidified condensation of the resulting polymer (Swern reaction of aryl sulfoxides) under dilution conditions induces the polymer-analogous intramolecular electrophilic ring-closing reaction of the hydroxymethylphenylsulfonium cation onto the adjacent benzene ring to yield the required ladder polymer, which has proved to be a semiconductor with an intrinsic electric conductivity of 2 × 10-5 S/cm. A comparison of the spectroscopic properties of the ladder polymer with those of the model compounds such as 5-methylphenoxathiinium triflate and phenoxathiin discloses π-electron delocalization over the methylsulfonio linkages, demonstrating the efficacy of the ladderization for p-π/d-π interactions in arylsulfonium moieties. This synthetic approach permits the thio and alkylsulfonio ladder linkages for a variety of phenyl ethers to form in high yields.
- Oyaizu, Kenichi,Mikami, Takefumi,Mitsuhashi, Fumio,Tsuchida, Eishun
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- Alkyl- and Arylthiodediazoniations of Dry Arenediazonium o-Benzenedisulfonimides. Efficient and Safe Modifications of the Stadler and Ziegler Reactions to Prepare Alkyl Aryl and Diaryl Sulfides
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The reaction between dry arenediazonium o-benzenedisulfonimides 1 and sodium thiolates in anhydrous methanol represents an efficient and safe procedure, of general validity, for the preparation of unfunctionalized or variously functionalized alkyl aryl and diaryl sulfides. As a rule, the reaction temperature was maintained at 0-5°C for the alkylthiodediazoniations and at room temperature (20-25°C) for the arylthiodediazoniations. The sulfide yields are generally high; of the 63 considered examples, 43 gave yields greater than 80% and 13 were between 70% and 80%. Lower yields were obtained only when sterically hindered diazonium salts or thiols were used. A good amount of the o-benzenedisulfonimide (8) was always recovered from the reactions and could be reused to prepare salts 1. The copious experimental data collected in homogeneous conditions have offered several starting points for the study of the mechanism of these reactions.
- Barbero, Margherita,Degani, Iacopo,Diulgheroff, Nicola,Dughera, Stefano,Fochi, Rita,Migliaccio, Mara
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p. 5600 - 5608
(2007/10/03)
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- Preparation of optically active ortho-chloro- and ortho-bromophenyl sulfoxides
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The preparation of the diastereomerically pure menthyl (S)-2-chloro- and (S)-2-bromophenyl sulfinates by esterification of the corresponding sulfinic acids with (1R,2S,5R)-(-)-menthol and recrystallization/epimerization is reported. The two sulfinates have been converted into enantiomerically pure aryl, vinyl and alkyl sulfoxides by reaction with organomagnesium reagents. These sulfoxides are useful chiral auxiliaries to control the stereochemical outcome of radical reactions.
- Imboden, Christoph,Renaud, Philippe
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p. 1051 - 1060
(2007/10/03)
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- 2-Halo-2-cyclohexenols from 6,6-dihalobicyclo-[3.1.0]hexanes and dimethyl sulfoxide. Studies towards a non-basic hydroxide equivalent
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A practical, high yielding, cheap and mild method for the synthesis of 2-halo-2-cycloalkenols, especially 2-bromo-2-cyclohexenol, is reported. Direct conversion from a variety of thermally labile n,n-dihalobicyclo[n-3.1.0]alkanes to 2-halo-2-cycloalkenols can be achieved without using silver salts by simple heating in DMSO. The intermediate 1,n-dihalocycloalkenes immediately undergo indirect allylic substitution with DMSO to yield the corresponding halocycloalkenols. A possible mechanism for the substitution step comprises nucleophilic attack by DMSO followed by a Pummerer rearrangement and hydrolytic decomposition. Kinetic and mechanistic experiments to verify the course of the reaction are presented. Acta Chemica Scandinavica 1997.
- Wessjohann, Ludger A.,Muehlbauer, Andrea,Sinks, Udo
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p. 1112 - 1115
(2007/10/03)
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- Electroreduction of Organic Compounds, 19. Formation of Benzoanellated Sulfur Heterocycles by Intramolecular Cathodic Cyclization of Dithiocarboxylic Esters
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Cathodic reduction of aryl (3) and benzyl (5) dithiopivaloates and related dithioesters with leaving groups at the benzene ring or a side chain yield the sulfur heterocycles 23, 30 - 32, and 34 depending on the nature of the starting material and the reaction conditions.In the case of the α-oxo-dithioester 22, thioindigo (44) is formed. - The corresponding thioamides 14, 16, and 18 show a strong tendency to reductive dehalogenation but the S,N-heterocycles 38 and 39 are also formed in minor amounts. - The formation of the rearranged products 29 - 32, and 34 isdiscussed in terms of C,S-splitting in the primarily formed radical anion and subsequent C,C-coupling of the fragments and follow-up reactions.Key Words: Dithiopivaloates, S-aryl, S-benzyl / Electroreduction
- Gade, Thomas,Streek, Michael,Voss, Juergen
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p. 127 - 142
(2007/10/02)
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- Synthesis of Mercapturic Acid Derivatives of Putative Toxic Metabolites of Bromobenzene
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The synthesis and characterization of nine isomerically defined S-arylmercapturic acids of interest in connection with the metabolism of the model hepatotoxin bromobenzene is described.Included are three S-(bromophenyl)-, two S-(bromohydroxyphenyl)-, and three S-(bromodihydroxyphenyl)mercapturic acids of defined substitution pattern.In addition, several related compounds with two or no bromine atoms are described.These syntheses depend on two basic methods, 1,4-addition of various arene thiols to acetamidoacrylic acid or the 1,4-addition of N-acetyl-L-cysteine to various benzoquinone derivatives.In addition, we describe a method for efficient conversion of the mercapturic acids to thioanisole derivatives, regioisomers of which can be separed and detected at low levels by capillary gas-liquid chromatography.
- Hanzlik, Robert P.,Weller, Paul E.,Desai, Jayant,Zheng, Jiang,Hall, Larry R.,Slaughter, Donald E.
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p. 2736 - 2742
(2007/10/02)
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- Electroreduction of Organic Compounds, 13. - Coelectroreduction of Methyl Dithiocarboxylates with Halogenoarenes
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Coelectroreduction of methyl dithiopivalate (1) or dithiobenzoate (11) with a monohalogenobenzene does not result in any characteristic products.However, the aryl methyl dithioacetals 7 and 8 are formed on cathodic reduction of 1 in the presence of the o-dihalogenobenzenes 4 and 5, respectively. - An SNAr mechanism is proposed, which is also in accordance with the formation of 2-bromobenzenethiolate (9) from 1 and 4 or 5.
- Streek, Michael,Voss, Juergen
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p. 2251 - 2254
(2007/10/02)
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