- Methyl group transfer upon gas phase decomposition of protonated methyl benzoate and similar compounds
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Gas phase decompositions of protonated methyl benzoate and its conjugates have been studied by using electrospray ionization-collision induced dissociation-tandem mass spectrometry. Loss of CO2 molecule, thus transfer of methyl group, has been observed. In order to better understand this process, the theoretical calculations have been performed. For methyl benzoate conjugates, it has been found that position of substituent affects the loss of CO2 molecule, not the electron donor/withdrawing properties of the substituent. Therefore, electrospray ionization-mass spectrometry in positive ion mode may be useful for differentiation of isomers of methyl benzoate conjugates.
- Frański, Rafa?,Gierczyk, B?a?ej,Zalas, Maciej,Jankowski, Wojciech,Hoffmann, Marcin
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Read Online
- Intramolecular rearrangements of but-3-enoic esters
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Support for the proposal by Khalafy and Prager1 of a cheletropic rearrangement of a 6-methylidenecyclohexa-2,4-diene-1-carboxylate under flash vacuum pyrolysis (f.v.p.) conditions has been obtained by a study of the f.v.p. products obtained from methyl 1-methyl-6-methylidenecyclohexa-2,4-diene-1-carboxylate and methyl 2,2-dimethylbut-3-enoate. A significant product in each case arises from a reaction involving decarbonylation and transfer of a methoxy group to C4 (but-3-enoate numbering). CSIRO 2000.
- Tsaconas, Michael,Prager, Rolf H.,Millan, David S.
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Read Online
- GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes
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GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 μM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.
- Wang, Congcong,Zhang, Yu-Fang,Guo, Shimeng,Zhao, Quan,Zeng, Yanping,Xie, Zhicheng,Xie, Xin,Lu, Boxun,Hu, Youhong
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p. 941 - 957
(2020/11/30)
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- Milled Dry Ice as a C1 Source for the Carboxylation of Aryl Halides
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The use of carbon dioxide as a C1 chemical feedstock remains an active field of research. Here we showcase the use of milled dry ice as a method to promote the availability of CO 2in a reaction solution, permitting practical synthesis of arylcarboxylic acids. Notably, the use of milled dry ice produces marked increases in yields relative to those obtained with gaseous CO 2, as previously reported in the literature.
- O'Brien, Connor J.,Nicewicz, David A.
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supporting information
p. 814 - 816
(2021/03/01)
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- Robust synthesis of NIR-emissive P-rhodamine fluorophores
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P-Rhodamines were accessed by implementing a robust three step sequence consisting of (i) addition of m-metallated anilines to dichlorophosphine oxides, (ii) selective dibromination, and (iii) cyclization of the diaryllithium reagents derived from the dib
- Arndt, Hans-Dieter,Nasufovic, Veselin,Sauer, Maria,Vilotijevic, Ivan
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supporting information
p. 1567 - 1571
(2020/03/06)
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- Synthesis and Characterization of Acridinium Dyes for Photoredox Catalysis
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Photoredox catalysis is a rapidly evolving platform for synthetic methods development. The prominent use of acridinium salts as a sustainable option for photoredox catalysts has driven the development of more robust and synthetically useful versions based on this scaffold. However, more complicated syntheses, increased cost, and limited commercial availability have hindered the adoption of these catalysts by the greater synthetic community. By utilizing the direct conversion of a xanthylium salt into the corresponding acridinium as the key transformation, we present an efficient and scalable preparation of the most synthetically useful acridinium reported to date. This divergent strategy also enabled the preparation of a suite of novel acridinium dyes, allowing for a systematic investigation of substitution effects on their photophysical properties.
- White, Alexander R.,Wang, Leifeng,Nicewicz, David A.
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supporting information
p. 827 - 832
(2019/04/25)
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- APELIN RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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Provided herein are agonists of the apelin receptor for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.
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Paragraph 0478-0479
(2019/02/25)
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- Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations
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From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.
- Nicolaou,Wang, Yanping,Lu, Min,Mandal, Debashis,Pattanayak, Manas R.,Yu, Ruocheng,Shah, Akshay A.,Chen, Jason S.,Zhang, Hongjun,Crawford, James J.,Pasunoori, Laxman,Poudel, Yam B.,Chowdari, Naidu S.,Pan, Chin,Nazeer, Ayesha,Gangwar, Sanjeev,Vite, Gregory,Pitsinos, Emmanuel N.
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supporting information
p. 8235 - 8246
(2016/07/15)
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- Iron-Catalyzed Ortho C-H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand
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Iron-catalyzed C-H functionalization of aromatics has attracted widespread attention from chemists in recent years, while the requirement of an elaborate directing group on the substrate has so far hampered the use of simple aromatic carbonyl compounds such as benzoic acid and ketones, much reducing its synthetic utility. We describe here a combination of a mildly reactive methylaluminum reagent and a new tridentate phosphine ligand for metal catalysis, 4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me2N-TP), that allows us to convert an ortho C-H bond to a C-CH3 bond in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions. The reaction is powerful enough to methylate all four ortho C-H bonds in benzophenone. The reaction tolerates a variety of functional groups, such as boronic ester, halide, sulfide, heterocycles, and enolizable ketones.
- Shang, Rui,Ilies, Laurean,Nakamura, Eiichi
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supporting information
p. 10132 - 10135
(2016/08/31)
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- Compounds for the treatment of metabolic disorders
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Compounds useful for the treatment of various metabolic disorders, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, cachexia, obesity, atherosclerosis and arteriosclerosis, are disclosed.
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Page/Page column 93; 94; 96-98; 100; 103; 104; 106-110
(2016/03/12)
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- Upgrading malic acid to bio-based benzoates via a Diels-Alder-initiated sequence with the methyl coumalate platform
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The conversion of naturally-occurring malic acid to the 2-pyrone methyl coumalate was optimized using a variety of acid catalysts. Coupling methyl coumalate with electron-rich dienophiles in an inverse electron-demand Diels-Alder (IEDDA)/decarboxylation/elimination domino sequence resulted in an investigation of the scope and limitations of the methodology. The thermal, metal-free, and one-pot procedure allows regioselective access to diverse aromatic compounds including tricyclic, biphenyl, and pyridinyl systems for elaboration. A comparison with analogous pyrones demonstrates the striking efficacy of methyl coumalate as a versatile platform for the generation of biorenewable functionalized benzoates. This journal is
- Lee, Jennifer J.,Pollock Iii, Gerald R.,Mitchell, Donald,Kasuga, Lindsay,Kraus, George A.
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p. 45657 - 45664
(2015/02/19)
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- Isosteric analogs of lenalidomide and pomalidomide: Synthesis and biological activity
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A series of analogs of the immunomodulary drugs lenalidomide (1) and pomalidomide (2), in which the amino group is replaced with various isosteres, was prepared and assayed for immunomodulatory activity and activity against cancer cell lines. The 4-methyl and 4-chloro analogs 4 and 15, respectively, displayed potent inhibition of tumor necrosis factor-α (TNF-α) in LPS-stimulated hPBMC, potent stimulation of IL-2 in a human T cell co-stimulation assay, and anti-proliferative activity against the Namalwa lymphoma cell line. Both of these analogs displayed oral bioavailability in rat.
- Ruchelman, Alexander L.,Man, Hon-Wah,Zhang, Weihong,Chen, Roger,Capone, Lori,Kang, Jian,Parton, Anastasia,Corral, Laura,Schafer, Peter H.,Babusis, Darius,Moghaddam, Mehran F.,Tang, Yang,Shirley, Michael A.,Muller, George W.
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p. 360 - 365
(2013/02/23)
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- Methylation using dimethylcarbonate catalysed by ionic liquids under continuous flow conditions
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The ionic liquid, tributylmethylammonium methylcarbonate, has been employed as a catalytic base for clean N-methylation of indole with dimethylcarbonate. The reaction conditions were optimised under microwave heating to give 100% conversion and 100% selectivity to N-methylindole, and subsequently transferred to a high temperature/high pressure (285 °C/150 bar) continuous flow process using a short (3 min) residence time and 2 mol% of the catalyst to efficiently methylate a variety of different amines, phenols, thiophenols and carboxylic acid substrates. The extremely short residence times, versatility, and high selectivity have significant implications for the synthesis of a wide range of pharmaceutical intermediates, as high product throughputs can be obtained via this scalable continuous flow protocol. It has also been shown that the ionic liquid can be generated in situ from tributylamine, which has the net effect of transforming an ineffective stoichiometric base into a highly efficient catalyst for this broad class of reactions.
- Glasnov, Toma N.,Kappe, C. Oliver,Holbrey, John D.,Seddon, Kenneth R.,Yan, Ting
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p. 3071 - 3076,6
(2020/09/16)
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- Substituted Indole Compounds
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Substituted indole compounds corresponding to the formula I: In which R8, R9a, R9b, R10, R11, R200, R210, A, D, T, q, s and t have defined meanings, processes for the preparation thereof, pharmaceutical compositions containing such compounds and the use of substituted indole compounds for the treatment or inhibition of pain and other conditions which are at least partly mediated by Bradykinin 1 receptors (B1R).
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Page/Page column 44-45
(2010/09/07)
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- A Simple, efficient, green, cost effective and chemoselective process for the esterification of carboxylic acids
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Carboxylic acids have been esterified under mild and solvent-free conditions in high yield and purity using the green reagents, dimethyl carbonate and diethyl carbonate, under acid catalysis. The present methodology is free of the disadvantages of base catalysis described earlier, such as high temperatures, use of autoclaves, use of the expensive DBU as base in stoichiometric amounts and the carbonate as solvent. High chemoselectivity is observed in the case of hydroxybenzoic acids.
- Rekha,Ramani, Modukuri V.,Ratnamala,Rupakalpana, Vempati,Subbaraju, Gottumukkala V.,Satyanarayana, Chava,Rao, C. Someswara
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experimental part
p. 769 - 773
(2010/04/22)
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- Carbonylation of aryl halides: Extending the scope of the reaction
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Carbonylation reactions are being increasingly favoured in pharmaceutical chemistry for the atom-efficient introduction of carbonyl centres in aldehydes, acids, esters, and amides. Convenient procedures for simple aryl iodides and bromides are well established, and now the need is to develop improved conditions to allow the reactions to be extended to the more unreactive substrates, such as sterically hindered compounds and aryl chlorides. Sterically hindered compounds such as 2-iodo- or 2-bromo-m-xylenes can be converted using alkoxy and aminocarbonylation, while dehalogenation becomes a significant side reaction for reductive carbonylation. Less hindered compounds such as 2-iodo- or bromotoluene can be reacted successfully. Changing the aryl ligands of PdCl2{Ph2P(CH2)3PPh2} to alkyl groups improves the rate of oxidative addition but slows the carbonyl insertion step such that rates for the majority of aryl bromides are not improved by this change. Complexes such as PdCl2{Cy 2P(CH2)3PCy2} offer better performance for alkoxy and aminocarbonylation of aryl chlorides. However, for reductive carbonylation dehalogenation is a significant side reaction. Increasing CO pressure results in additional CO coordination to the catalytic intermediates and slows the reaction, while the dehalogenation is little affected, so reaction selectivity suffers. Thus, CO pressure is a critical parameter, particularly for reductive carbonylation, in achieving the optimum performance.
- Barnard, Christopher F.J.
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p. 566 - 574
(2013/01/03)
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- Electronic effects in the Pt-catalyzed cycloisomerization of propargylic esters: Synthesis of 2,3-disubstituted indolizines as a mechanistic probe
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(Chemical Equation Presented) The initial 5-exo versus 6-endo cyclization of the acyl group onto the activated alkyne of propargylic esters has been found to be dependent on electronic effects of the acyl, alkyne, and propargylic carbon substituents. Thes
- Hardin, Alison R.,Sarpong, Richmond
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p. 4547 - 4550
(2008/03/13)
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- Therapeutic uses of tri-aryl acid derivatives
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The use of triaryl acid derivatives of formula (I) and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.
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Page/Page column 150
(2010/10/20)
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- 13C and 1H nuclear magnetic resonance of methyl-substituted acetophenones and methyl benzoates: Steric hindrance and inhibited conjugation
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The 1H and 13C NMR spectra of 14 methyl-substituted acetophenones and 14 methyl-substituted methyl benzoates were assigned and interpreted with respect to the conformation of the Car - C(O) bond. The substituent effects are proportional in the two series and can be divided into polar and steric: each has different effects on the 13C SCS of the individual atoms. In the case of C atoms C(O), C(1) and CH3(CO), the steric effects were quantitatively separated by comparing SCS in the ortho and para positions. The steric effects are proportional for the individual C atoms and also to steric effects estimated from other physical quantities. However, they do not depend simply on the angle of torsion φ of the functional group as anticipated hitherto. A better description distinguishes two classes of compounds: sterically not hindered or slightly hindered planar molecules and strongly sterically hindered, markedly non-planar. In order to confirm this reasoning without empirical correlations, the J(C,C) coupling constants were measured for three acetophenone derivatives labeled with 13C in the acetyl methyl group. The constants confirm unambiguously the conformation of 2-methylacetophenone; their zero values are in accord with the conformation of 2,6-dimethylacetophenone. The zero values in the unsubstituted acetophenone are at variance with previous erroneous report but all J(C,C) values are in accord with calculations at the B3LYP/6-311++G(2d,2p)// B3LYP/6-311+G(d,p) level. Copyright
- Budesinsky, Milos,Kulhanek, Jiri,Boehm, Stanislav,Cigler, Petr,Exner, Otto
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p. 844 - 851
(2007/10/03)
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- Therapeutic uses of di-aryl acid derivatives
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The use of diaryl acid derivatives of formula (I) or pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof, wherein the variables shown are defined in the disclosure, and their pharmaceutical compositions as PPAR ligand receptor binders. The PPAR ligand receptor binders of this invention are useful as agonists or antagonists of the PPAR receptor.
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- Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine
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We designed and synthesized a new class of peptidomimetic human immunodeficiency virus (HIV) protease inhibitors containing a unique unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy- 4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure - activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to the delineation of a set of structural characteristics that appear to afford an orally available HIV protease inhibitor. Optimum structures, exemplified by 21f (JE-2147), incorporated 3-hydroxy-2- methylbenzoyl groups as the P2 ligand, (R)-5,5-dimethyl-1,3-thiazolidine-4- carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present study demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.
- Mimoto, Tsutomu,Kato, Ryohei,Takaku, Haruo,Nojima, Satoshi,Terashima, Keisuke,Misawa, Satoru,Fukazawa, Tominaga,Ueno, Takamasa,Sato, Hideharu,Shintani, Makoto,Kiso, Yoshiaki,Hayashi, Hideya
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p. 1789 - 1802
(2007/10/03)
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- Aromatic Spiranes XX [1]: Syntheses of Dimethylsubstituted 2-Carboxymethyl-indan-1-ones and Benzylchlorides as Synthones for Syntheses of di- to tetramethylsubstituted Spirobiindandiones
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The isomeric dimethyl methylbenzoates 5, obtained from the bromides via Grignard reactions with dimethylcarbonate, were reduced with LiAlH4 to the hydroxymethyl derivatives 6. The latter were then transformed both to the benzylchlorides 7 (with SOCl2) and to the aldehydes 8 (with pyridinium chlorochromate). Knoevenagel-Doebner reaction of 8 afforded the acrylic acids 9 which (after hydrogenation to 11) were cyclized to the desired indanones 12 with polyphosphoric acid. On the other hand, 12c and 12e were prepared from dimethyl 3-chloropropiophenone (14) by warming with sulfuric acid. After NaH-catalyzed reaction with dimethylcarbonate, the indanones 12 gave the ketoesters 15 which then could be hydrogenated to the indanes 16. All reactions proceeded with satisfactory to excellent yields (60-90%).
- Neudeck
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p. 185 - 200
(2007/10/03)
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- Concepts of sterically hindered resonance and buttressing effect: Gas-phase acidities of methyl-substituted benzoic acids and basicities of their methyl esters
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Two classical terms "Steric Hindrance to Resonance" and "Buttressing Effect" are revisited on the basis of the gas-phase acidities of nine methyl-substituted benzole acids and of the gas-phase basicities of their methyl esters, measured using FT- ICR spectrometry. By combining these data with published heats of formation of the neutrals and by using the principle of isodesmic reactions, relative enthalpies of formation were evaluated separately for the acid molecules, their anions (deprotonated), and their protonated cations (substituted by the protonated forms of the corresponding methyl esters). Energies of all species were also calculated at the semiempirical level (AMI). Substituent effects on the gas-phase acidity are similar to those on the acidity in water. All the methyl groups have a stabilizing polar effect, and o-methyl groups have a destabilizing steric effect, both effects increasing from the deprotonated forms to the acid molecules and then to the protonated forms. Separation of the two effects was attempted, assuming equal polar effects in the ortho and para positions. The results are internally consistent: their detailed analysis is in favor of a primary steric effect rather than a steric inhibition of resonance. The latter must be relatively weaker and operating only in 2,6-dimethyl derivatives, which are certainly nonplanar. In the literature this concept has been used too broadly, even for compounds for which the nonplanar conformation has not been proven. The concept of buttressing effect has been confirmed for methyl-substituted benzoic acids, but it is formulated more generally and more exactly. According to the new definition, it can be observed even for nonadjacent substituants.
- Decouzon, Michèle,Ertl, Peter,Exner, Otto,Gal, Jean-Fran?ois,Maria, Pierre-Charles
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p. 12071 - 12078
(2007/10/02)
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- Palladium Catalysed Alkoxycarbonylation of Phenols to Benzoate Esters
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The methoxycarbonylation of aryl trifluoromethanesulphonates with CO and aliphatic alcohols is catalysed by Pd(OAc)2-1,3-bis(diphenylphosphino)propane in high yield at 70 deg C and ambient CO pressure.
- Dolle, Roland E.,Schmidt, Stanley J.,Kruse, Lawrence I.
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p. 904 - 905
(2007/10/02)
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- Synthetic Approach to Aklavinone Using 2-Oxo-2H-pyran-5-carboxylate (Coumalate) Intermediates
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A novel approach for the preparation of aklavinone 5 is described in which the key step is the cycloaddition of a substituted coumalate with a ketene acetal to produce a masked A ring with the C and D rings attached.The 4-(arylmethyl)coumalate 53 was prepared from naphthalene-1,5-diol (6) by a seven step route involving as the key step the cyclocondensation of the methyl (arylmethyl)propiolate 52 with methyl 3-oxopentanoate 10.Cycloaddition of 53 with dimethyl ketene acetal 12 produced the potential A-ring precursor 67, which could not be cleanly reduced, thereby ending this scheme.The preparation of functionalized 4,6-dialkylpyrone-5-carboxylates and their use in the synthesis of bicyclic lactones and substituted benzoates via cycloaddition reactions are also described.
- Jung, Michael E.,Hagenah, Jeffrey A.
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p. 1889 - 1902
(2007/10/02)
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- PREPARATION AND CYCLOADDITION OF FUNCTIONALIZED 4,6-DIALKYLPYRONE-5-CARBOXYLATES. SYNTHESIS OF BICYCLIC LACTONES AND SUBSTITUTED BENZOATES
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Several alkyl pyrone-5-carboxylates (coumalates) with alkyl and functionalized alkyl substituents at C4 and C6 have been prepared by a general route; their cycloadditions with electron-rich olefins have been carried out to provide aromatic and non-aromati
- Jung, Michael E.,Hagenah, Jeffrey A.
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p. 117 - 121
(2007/10/02)
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- Novel benzylsulfonylureas and arylsulfamoylureas N-[(substituted pyrimidin-2-yl)aminocarbonyl]-1-oxo-fused benzyl-7-methanesulfonamides useful as herbicides and plant growth regulants
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Benzylsulfonylureas and arylsulfamoylureas are useful as pre-emergent and post-emergent herbicides and as plant growth regulants.
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- THE METHYLATION OF CARBOXYLIC ACIDS USING METHYL TRICHLOROACETATE
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Metyl trichloroacetate has been shown to methylate carboxylic acids with the loss of chloroform and carbon dioxide.
- Renga, James M.,Wang, Pen-Chung
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