- A FACILE SYNTHESIS OF 1,3-CYCLOALKADIONES
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1,3-Cycloalkadiones were prepared by the reaction of 1,2-bis(trimethylsiloxy)cycloalkenes with chloromethyl methyl ether followed by treatment of the resulting 2-hydroxy-2-methoxymethyl cycloalkanones with potassium hydrogen sulfate.The first step of the reactions was effectively catalyzed by active zinc reagents prepared from zinc-copper and alkyl iodides.
- Nishiguchi, Ikuzo,Hirashima, Tsuneaki,Shono, Tatsuya,Sasaki, Manji
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- Investigation of methods for seven-membered ring synthesis: A practical synthesis of 4-oxo-5,6,7,8-tetrahydro-4h-cyclohepta[b]furan-3-carboxylic acid
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Several synthetic routes to 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid (1) are described, and the scale-up issues with each route are discussed. Seven-membered ring formation is a key issue with these syntheses, and several strategies are presented, including preparation from cycloheptane-1,3-dione, ring-expansion routes, Dieckmann cyclization, acetylene-furan [4 + 2] cycloaddition, and Friedel-Crafts cyclization. Two of the routes were scaled in the pilot plant to provide kilogram quantities of the title compound. The first scale-up route is outlined in Scheme 2 and utilizes a ring-expansion strategy to prepare cycloheptane-1,3-dione from cyclopentanone, via a [2 + 2] cycloaddition between dichloroketene and the silyl enol ether of cyclopentanone. The diketone is converted to the title compound by condensation with ethyl bromopyruvate and base, followed by acid hydrolysis. This route was efficient on laboratory scale but encountered problems upon scale-up due to a competing fragmentation pathway in the Zn/AcOH-mediated retro-aldol of cyclobutanone 11. The second, more successful scale-up route is described in Scheme 15, and involves Friedel-Crafts acylation of 3-carboethoxyfuran selectively at the 5-position. Reduction, lactonization, and hydrogenolysis provide acid 43, which is cyclized via a second Friedel-Crafts reaction to form the seven-membered ketone.
- Ragan, John A.,Murry, Jerry A.,Castaldi, Michael J.,Conrad, Alyson K.,Jones, Brian P.,Bryan, Li,Makowski, Teresa W.,McDermott, Ruth,Sitter, Barb J.,White, Timothy D.,Young, Gregory R.
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- Ambident Reactivity of Medium-Ring Cycloalkane-1,3-dione Enolates
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Cycloalkane-1,3-diones with ring sizes 7-10 have been converted to their enolates and subjected to a variety of ethylation and methylation reagent/solvent systems. The greatest amount of O-alkylation was encountered using ethyl tosylate in HMPA. The O/C alkylation ratios decreased with almost every reagent/solvent system as the ring size was increased. This trend is consistent with greater steric strain in the conjugated enolate resonance contributor, resulting in diminished O-attack as the ring size is increased.
- Thompson, Glenn S.,Hirsch, Jerry A.
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- A practical synthesis of cycloheptane-1,3-dione
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A three-step synthesis of cycloheptane-1,3-dione has been developed which avoids the use of heavy metal or explosive reagents and provides access to multigram quantities of this material.
- Ragan, John A.,Makowski, Teresa W.,Amende, David J.,Clifford, Pamela J.,Young, Gregory R.,Conrad, Alyson K.,Eisenbeis, Shane A.
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- Reductive Electrochemical Activation of Molecular Oxygen Catalyzed by an Iron-Tungstate Oxide Capsule: Reactivity Studies Consistent with Compound i Type Oxidants
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The reductive activation of molecular oxygen catalyzed by iron-based enzymes toward its use as an oxygen donor is paradigmatic for oxygen transfer reactions in nature. Mechanistic studies on these enzymes and related biomimetic coordination compounds designed to form reactive intermediates, almost invariably using various "shunt" pathways, have shown that high-valent Fe(V)=O and the formally isoelectronic Fe(IV) =O porphyrin cation radical intermediates are often thought to be the active species in alkane and arene hydroxylation and alkene epoxidation reactions. Although this four decade long research effort has yielded a massive amount of spectroscopic data, reactivity studies, and a detailed, but still incomplete, mechanistic understanding, the actual reductive activation of molecular oxygen coupled with efficient catalytic transformations has rarely been experimentally studied. Recently, we found that a completely inorganic iron-tungsten oxide capsule with a keplerate structure, noted as {Fe30W72}, is an effective electrocatalyst for the cathodic activation of molecular oxygen in water leading to the oxidation of light alkanes and alkenes. The present report deals with extensive reactivity studies of these {Fe30W72} electrocatalytic reactions showing (1) arene hydroxylation including kinetic isotope effects and migration of the ipso substituent to the adjacent carbon atom ("NIH shift"); (2) a high kinetic isotope effect for alkyl C - H bond activation; (3) dealkylation of alkylamines and alkylsulfides; (4) desaturation reactions; (5) retention of stereochemistry in cis-alkene epoxidation; and (6) unusual regioselectivity in the oxidation of cyclic and acyclic ketones, alcohols, and carboxylic acids where reactivity is not correlated to the bond disassociation energy; the regioselectivity obtained is attributable to polar effects and/or entropic contributions. Collectively these results also support the conclusion that the active intermediate species formed in the catalytic cycle is consistent with a compound I type oxidant. The activity of {Fe30W72} in cathodic aerobic oxidation reactions shows it to be an inorganic functional analogue of iron-based monooxygenases.
- Bugnola, Marco,Shen, Kaiji,Haviv, Eynat,Neumann, Ronny
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p. 4227 - 4237
(2020/05/05)
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- Constrained bithiazoles: Small molecule correctors of defective δf508-CFTR protein trafficking
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Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the δF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using δF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7-versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7-and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.
- Coffman, Keith C.,Nguyen, Huy H.,Phuan, Puay-Wah,Hudson, Brandi M.,Yu, Gui J.,Bagdasarian, Alex L.,Montgomery, Deanna,Lodewyk, Michael W.,Yang, Baoxue,Yoo, Choong L.,Verkman,Tantillo, Dean J.,Kurth, Mark J.
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p. 6729 - 6738
(2014/10/15)
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- Combined effects on selectivity in Fe-catalyzed methylene oxidation
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Methylene C-H bonds are among the most difficult chemical bonds to selectively functionalize because of their abundance in organic structures and inertness to most chemical reagents. Their selective oxidations in biosynthetic pathways underscore the power of such reactions for streamlining the synthesis of molecules with complex oxygenation patterns. We report that an iron catalyst can achieve methylene C-H bond oxidations in diverse natural-product settings with predictable and high chemo-, site-, and even diastereoselectivities. Electronic, steric, and stereoelectronic factors, which individually promote selectivity with this catalyst, are demonstrated to be powerful control elements when operating in combination in complex molecules. This small-molecule catalyst displays site selectivities complementary to those attained through enzymatic catalysis.
- Chen, Mark S.,White, M. Christina
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scheme or table
p. 533 - 571
(2010/10/05)
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- Fragmentation of tertiary cyclopropanol compounds catalyzed by vanadyl acetylacetonate
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Tertiary cyclopropanol compounds react with a catalytic amount of vanadyl acetylacetonate in the presence of oxygen affording β-hydroxyketones and β-diketones. For 3-substituted-bicyclo[4.1.0]alkanols, peroxides are obtained, as are the β-hydroxyketones. Conversely, 2- ethoxycarbonylcyclopropyl silyl ethers produce ethyl γ-oxocarboxylate derivatives given the same reaction conditions.
- Kirihara, Masayuki,Kakuda, Hiroko,Ichinose, Motohiro,Ochiai, Yuta,Takizawa, Shinobu,Mokuya, Asuka,Okubo, Kumiko,Hatano, Akihiko,Shiro, Motoo
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p. 4831 - 4839
(2007/10/03)
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- Synthetic Applications in Radical/Radical Cationic Cascade Reactions
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Oxidative photoinduced electron transfer (PET) reactions have been performed with various cyclic cyclopropyl(vinyl) silyl ethers bearing an olefinic or acetylenic side chain. The reactions result in bi- to tetracyclic ring systems via a fragmentation-radical/radical cationic addition reaction pathway with well defined ring juncture. The mode of cyclisation (endo/exo) can be partially controlled by addition of nucleophiles due to the suppression of radical cationic reaction pathways. Quantum chemical calculation of the cyclisation transition states underline the experimentally found selectivities. Additional mechanistic studies concerning the saturation step reveal that the final radical is saturated mostly by the solvent and traces of water in the solvent.
- Rinderhagen, Heiko,Mattay, Jochen
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p. 851 - 874
(2007/10/03)
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Asymmetric hydrogenation method of a ketonic compound and derivative
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The present invention relates to a process for the asymmetric hydrogenation of a ketonic compound and derivative. The invention relates to the use of optically active metal complexes as catalysts for the asymmetric hydrogenation of a ketonic compound and derivative. The process for the asymmetric hydrogenation of a ketonic compound and derivative is characterized in that the asymmetric hydrogenation of said compound is carried out in the presence of an effective amount of a metal complex comprising as ligand an optically active diphosphine corresponding to one of the following formulae: STR1
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- Tertiary cyclopropanol systems as synthetic intermediates: Novel ring-cleavage of tertiary cyclopropanol systems using vanadyl acetylacetonate
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Tertiary cyclopropanol systems react with a catalytic amount of vanadyl acetylacetonate under an oxygen atmosphere to afford β-hydroxyketones and β-diketones.
- Kirihara, Masayuki,Ichinose, Motohiro,Takizawa, Shinobu,Momose, Takefumi
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p. 1691 - 1692
(2007/10/03)
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- CERTAIN FUSED PYRROLECARBOXAMIDES A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS
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Disclosed are compounds of formula I: STR1 wherein R 8 and R. sub.9 independently represent hydrogen or organic substituents; W represents optionally substituted thiazolyl or quinoxalinyl; X is hydrogen, hydroxy or lower alkyl; andT is hydrogen, halogen, hydroxy, nitro, amino or alkyl,which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptor. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
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- CERTAIN PYRROLO PYRIDINE-3-CARBOXAMIDES; A NEW CLASS OF GABA BRAIN RECEPTOR LIGANDS
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The present invention encompasses structures of the formula: STR1 or the pharmaceutically acceptable non-toxic salts thereof wherein: STR2 wherein: W represents substituted or unsubstituted phenyl;X is hydrogen, hydroxy or lower alkyl; T is hydrogen, halogen, hydroxy, nitro, amino or alkyl; R. sub.3 is hydrogen or an organic group;R 4 is hydrogen or substituted or unsubstituted organic substituent;R 5 and R 6 represent organic, and inorganic substituents; andn is 1, 2, 3, or 4, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.
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- Cascade reactions of methyl-2-chloro-2-cyclopropylideneacetate with five- and seven-membered cyclic dienolates: A novel approach to the bicyclo[4.2.1]nonane segment of the skeleton of mediterraneols
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The MIMIRC (Michael-Michael-Ring Closure) reaction of methyl 2-chloro-2-cyclopropylideneacetate (5) with the cyclic dienolates 6a, 6c, and the one derived from 11-R under aprotic conditions gave the tricyclic adducts 7a, 7c, and 10-R, respectively, in moderate to good yield. Compound 10-R is conceived as a potential intermediate for the synthesis of the biologically active marine diterpenes mediterraneol 1.
- Hadjiarapoglou,Klein,Spitzner,De Meijere
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p. 525 - 528
(2007/10/03)
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- Radical tandem cyclizations by anodic decarboxylation of carboxylic acids
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Radical tandem cyclizations are initiated by the Kolbe electrolysis of unsaturated carboxylic acids 4, 18, 23-25 which are prepared in a few steps. The efficiency of the radical tandem cyclization provides a short synthetic sequence to tricyclic products, e.g. angular triquinanes 7, 8, 11, 26-28. In this anodic tandem cyclization, three C-C bonds are formed regio- and stereoselectively in a one-pot reaction by intramolecular addition and intermolecular coupling. The use of different carboxylic acids as starting materials and various coacids gives versatile access to substituted tricyclic compounds.
- Matzeit,Schafer,Amatore
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p. 1432 - 1444
(2007/10/02)
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- Chiral acetals in organic synthesis: Regioselective synthesis of 2-and 3-hydroxy acetals from 2,3-olefinic acetals. Reinvestigation and further applications
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Achiral as well as chiral 2,3-olefinic acetals are converted into 2- and 3- hydroxy acetals via LAH reduction of the corresponding epoxides and via bromohydrins followed by TBTH reductions respectively. Synthesis of 1,3-diones is described. Compounds from chiral systems are further utilized for asymmetric synthesis.
- Vankar, Yashwant D.,Reddy, M. Venkatram,Chaudhuri, Narayan C.
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p. 11057 - 11078
(2007/10/02)
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- Palladium(0)-catalyzed isomerization of α,β-epoxy ketones to β-diketones
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In the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium(0) and 1,2-bis(diphenylphosphino)ethane, α,β-epoxy ketones isomerize to the corresponding β-diketones in high yields.Both open-chain and cyclic substrates can be used.Possible reaction mechanisms are discussed.
- Suzuki, M.,Watanabe, A.,Noyori, R.
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p. 230 - 236
(2007/10/02)
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- REGIOSELECTIVE REDUCTIONS OF 2,3-EPOXY ACETALS WITH ZINC-CHLOROTRIMETHYLSILANE AND LITHIUM ALUMINIUM HYDRIDE: CONVENIENT SYNTHESIS OF 1,2 AND 1,3-DIONES
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A variety of 2,3-epoxy acetals have been found to undergo regioselective reductions with zinc-chlorotrimethylsilane and lithium aluminium hydride to give 2-hydroxy and 3-hydroxy acetals respectively.Their oxidation followed by hydrolysis furnished the corresponding 1,2- and 1,3-diones in good yields.
- Vankar, Yashwant D.,Chaudhuri, Narayan C.,Rao, C. Trinadha
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p. 551 - 554
(2007/10/02)
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- 2-Hydroxy-4-(substituted) phenyl cycloalkanes and derivatives
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Compounds having the formula STR1 R1 is hydrogen, benzyl or an ester moiety; Y is --CH(R2 ")CH(R2)-- or--CH(R3)CH2 --; R2 " is hydrogen or methyl; R2 is OH or X-substituted (C1-6)alkyl; R3 is OH, cyano or X-substituted (C1-3) alkyl; X is --OR6, --SR6, --S(O)R6, --S(O)2 R6, --NR6 R7, --COOR7, --CONR7 R8 or oxo; with the proviso that when X is --NR6 R7, --COOR7 or --CONR7 R8, said group is located on the terminal carbon atom of R2 or R3 ; R6 is hydrogen, (C1-6)alkyl or acetyl; each of R7 and R8 is hydrogen or (C1-6)alkyl; s is an integer of 1 or 2; with the proviso that when R6 is acetyl, R7 is hydrogen and X is other than S(O)R6 or S(O)2 R6 ; Z--W is alkyl, phenylalkyl or pyridylalkyl which can have an oxygen atom as part of the alkyl chain, and their use as CNS agents, antidiarrheals and antiemetics. Processes for their preparation and intermediates therefor are described.
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