- Preparations of anthraquinone and naphthoquinone derivatives and their cytotoxic effects
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Chrysophanol and 1,8-di-O-hexylchrysophanol derivatives having nucleic acid bases at position 5 were synthesized. Furthermore, derivatives of menadione substituted at position 11 (type A naphthoquinone derivatives) or methylmenadione substituted at position 7 (type B naphthoquinone derivatives) modified with nucleic acid bases, amines and thiocyano, selenocyano or thioacetyl groups were synthesized. The cytotoxic effects of these derivatives on HCT 116 cells, which poorly express P-glycoprotein (P-gp), and Hep G2 cells, which stably express P-gp, were evaluated by performing 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results were compared with those obtained using 5-fluorouracil (5-FU), which has been used clinically. Several of these derivatives exhibited markedly higher potent cytotoxic effects not only on HCT cancer cells but also Hep G2 cancer cells as compared with 5-FU.
- Cui, Xing-Ri,Saito, Ryota,Kubo, Takatsugu,Kon, Daijiro,Hirano, Yuich,Saito, Setsuo
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- Detection and quantification of vitamin K1 quinol in leaf tissues
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Phylloquinone (2-methyl-3-phytyl-1,4-naphthoquinone; vitamin K1) is vital to plants. It is responsible for the one-electron transfer at the A1 site of photosystem I, a process that involves turnover between the quinone and semi-quinone forms of phylloquinone. Using HPLC coupled with fluorometric detection to analyze Arabidopsis leaf extracts, we detected a third redox form of phylloquinone corresponding to its fully reduced - quinol-naphthoquinone ring (PhQH2). A method was developed to quantify PhQH2 and its corresponding oxidized quinone (PhQ) counterpart in a single HPLC run. PhQH2 was found in leaves of all dicotyledonous and monocotyledonous species tested, but not in fruits or in tubers. Its level correlated with that of PhQ, and represented 5-10% of total leaf phylloquinone. Analysis of purified pea chloroplasts showed that these organelles accounted for the bulk of PhQH2. The respective pool sizes of PhQH2 and PhQ were remarkably stable throughout the development of Arabidopsis green leaves. On the other hand, in Arabidopsis and tomato senescing leaves, PhQH2 was found to increase at the expense of PhQ, and represented 25-35% of the total pool of phylloquinone. Arabidopsis leaves exposed to light contained lower level of PhQH2 than those kept in the dark. These data indicate that PhQH2 does not originate from the photochemical reduction of PhQ, and point to a hitherto unsuspected function of phylloquinone in plants. The putative origin of PhQH2 and its recycling into PhQ are discussed.
- Oostende, Chloe van,Widhalm, Joshua R.,Basset, Gilles J.C.
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- One-pot hydroacetylation of menadione (vitamin K3) to menadiol diacetate (vitamin K4) by heterogeneous catalysis
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Vitamin K4 (menadiol diacetate, MDD) can be easily synthesized through cleaner and more efficient catalytic alternatives following the green chemistry principles. Ionic gold-based hydroxylated fluorides are active bi-functional catalysts for the one-pot hydroacetylation of menadione leading to MDD with 77% selectivity. Unprecedent results were obtained in the presence of oxide-fluoride catalysts by using a microwave-assisted hydrogen-transfer (Meerwein-Ponndorf-Verley reaction) coupled with an acetylation approach, yielding very high selectivities for the target product (95%). Copyright
- Dobrinescu, Claudiu,Iorgulescu, Elena E.,Mihailciuc, Constantin,MacOvei, Dan,Wuttke, Stefan,Kemnitz, Erhard,Parvulescu, Vasile I.,Coman, Simona M.
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- Reduction of quinones by NADH catalyzed by organoiridium complexes
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One electron at a time: Half-sandwich organometallic cyclopentadienyl- IrIII complexes containing N,N-chelated ligands can catalyze the reduction of quinones (Q), such as vitaminK3, to semiquinones (Q .-) by coenzyme NADH (see picture). DFT calculations suggest that the mechanism involves hydride transfer followed by two one-electron transfers and the unusual IrII oxidation state as a key transient intermediate. Copyright
- Liu, Zhe,Deeth, Robert J.,Butler, Jennifer S.,Habtemariam, Abraha,Newton, Mark E.,Sadler, Peter J.
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- Synthesis of Novel Synthetic Vitamin K Analogues Prepared by Introduction of a Heteroatom and a Phenyl Group That Induce Highly Selective Neuronal Differentiation of Neuronal Progenitor Cells
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We synthesized novel vitamin K2 analogues that incorporated a heteroatom and an aromatic ring in the side chain and evaluated their effect on the selective differentiation of neuronal progenitor cells into neurons in vitro. The results showed that a menaquinone-2 analogue bearing a p-fluoroaniline had the most potent activity, which was more than twice as great as the control. In addition, the neuronal selectivity was more than 3 times greater than the control.
- Kimura, Kimito,Hirota, Yoshihisa,Kuwahara, Shigefumi,Takeuchi, Atsuko,Tode, Chisato,Wada, Akimori,Osakabe, Naomi,Suhara, Yoshitomo
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- Synthesis of novel vitamin K derivatives with alkylated phenyl groups introduced at the ω-terminal side chain and evaluation of their neural differentiation activities
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Vitamin K is an essential cofactor of γ-glutamylcarboxylase as related to blood coagulation and bone formation. Menaquinone-4, one of the vitamin K homologues, is biosynthesized in the body and has various biological activities such as being a ligand for steroid and xenobiotic receptors, protection of neuronal cells from oxidative stress, and so on. From this background, we focused on the role of menaquinone in the differentiation activity of progenitor cells into neuronal cells and we synthesized novel vitamin K derivatives with modification of the ω-terminal side chain. We report here new vitamin K analogues, which introduced an alkylated phenyl group at the ω-terminal side chain. These compounds exhibited potent differentiation activity as compared to control.
- Sakane, Rie,Kimura, Kimito,Hirota, Yoshihisa,Ishizawa, Michiyasu,Takagi, Yuta,Wada, Akimori,Kuwahara, Shigefumi,Makishima, Makoto,Suhara, Yoshitomo
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- A Synthetic Isoprenoid Lipoquinone, Menaquinone-2, Adopts a Folded Conformation in Solution and at a Model Membrane Interface
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Menaquinones (naphthoquinones, MK) are isoprenoids that play key roles in the respiratory electron transport system of some prokaryotes by shuttling electrons between membrane-bound protein complexes acting as electron acceptors and donors. Menaquinone-2 (MK-2), a truncated MK, was synthesized, and the studies presented herein characterize the conformational and chemical properties of the hydrophobic MK-2 molecule. Using 2D NMR spectroscopy, we established for the first time that MK-2 has a folded conformation defined by the isoprenyl side-chain folding back over the napthoquinone in a U-shape, which depends on the specific environmental conditions found in different solvents. We used molecular mechanics to illustrate conformations found by the NMR experiments. The measured redox potentials of MK-2 differed in three organic solvents, where MK-2 was most easily reduced in DMSO, which may suggest a combination of solvent effect (presumably in part because of differences in dielectric constants) and/or conformational differences of MK-2 in different organic solvents. Furthermore, MK-2 was found to associate with the interface of model membranes represented by Langmuir phospholipid monolayers and Aerosol-OT (AOT) reverse micelles. MK-2 adopts a slightly different U-shaped conformation within reverse micelles compared to within solution, which is in sharp contrast to the extended conformations illustrated in literature for MKs.
- Koehn, Jordan T.,Magallanes, Estela S.,Peters, Benjamin J.,Beuning, Cheryle N.,Haase, Allison A.,Zhu, Michelle J.,Rithner, Christopher D.,Crick, Dean C.,Crans, Debbie C.
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- NAPHTHOQUINONE-BASED CHALCONE DERIVATIVES AND USES THEREOF
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The present disclosure provides compounds of formula 1 to inhibit or prevent mitochondrial dysfunction by augmenting mitochondrial function. Mitochondrial dysfunction is the hallmark of a wide range of diseases and disorders. Mitochondria are a promising therapeutic target for the detection, prevention and treatment of various human diseases such as cancer, neurodegenerative diseases, ischemia-reperfusion injury, diabetes and obesity.
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Paragraph 00175
(2021/09/04)
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- Quinone Reduction by Organo-Osmium Half-Sandwich Transfer Hydrogenation Catalysts
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Organo-osmium(II) 16-electron complexes [OsII(η6-arene)(R-PhDPEN)] (where η6-arene =para-cymene or biphenyl) can catalyze the reduction of prochiral ketones to optically pure alcohols in the presence of a hydride source. Such complexes can achieve the conversion of pyruvate to unnatural http://www.w3.org/1999/xlinkd-lactate in cancer cells. To improve the catalytic performance of these osmium complexes, we have introduced electron-donor and electron-acceptor substituents (R) into thepara(R1) ormeta(R2) positions of the chiral R-phenyl-sulfonyl-diphenylethylenediamine (R-PhDPEN) ligands and explored the reduction of quinones, potential biological substrates, which play a major role in cellular electron transfer chains. We show that the series of [OsII(η6-arene)(R-PhDPEN)] derivatives exhibit high turnover frequencies, enantioselectivities (>92%), and conversions (>93%) for the asymmetric transfer hydrogenation (ATH) of acetophenone-derived substrates and reduce duroquinone and menadione to their di-alcohol derivatives. Modeling of the catalysis using density functional theory (DFT) calculations suggests a mechanism involving formic acid deprotonation assisted by the catalyst amine groups, phenyl-duroquinone stacking, hydride transfer to OsII, possible CO2coordination, and tilting of the η6-arene ring, followed by hydride transfer to the quinone. These findings not only reveal subtle differences between Ru(II) and Os(II) catalysts, but also introduce potential biological applications.
- Bolitho, Elizabeth M.,Coverdale, James P. C.,Sadler, Peter J.,Schünemann, Volker,Wolny, Juliusz A.,Worby, Nathan G.
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p. 3012 - 3023
(2021/09/13)
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- Stereoselective [4+2] cycloaddition of singlet oxygen to naphthalenes controlled by carbohydrates
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Stereoselective reactions of singlet oxygen are of current interest. Since enantioselective photooxygenations have not been realized efficiently, auxiliary control is an attractive alternative. However, the obtained peroxides are often too labile for isolation or further transformations into enantiomerically pure products. Herein, we describe the oxidation of naphthalenes by singlet oxygen, where the face selectivity is controlled by carbohydrates for the first time. The synthesis of the precursors is easily achieved starting from naphthoquinone and a protected glucose derivative in only two steps. Photooxygenations proceed smoothly at low temperature, and we detected the corresponding endoperoxides as sole products by NMR. They are labile and can thermally react back to the parent naphthalenes and singlet oxygen. However, we could isolate and characterize two enantiomerically pure peroxides, which are sufficiently stable at room temperature. An interesting influence of substituents on the stereoselectivities of the photooxygenations has been found, ranging from 51:49 to up to 91:9 dr (diastereomeric ratio). We explain this by a hindered rotation of the carbohydrate substituents, substantiated by a combination of NOESY measurements and theoretical calculations. Finally, we could transfer the chiral information from a pure endoperoxide to an epoxide, which was isolated after cleavage of the sugar chiral auxiliary in enantiomerically pure form.
- Bauch, Marcel,Fudickar, Werner,Linker, Torsten
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- Rational designed highly sensitive NQO1-activated near-infrared fluorescent probe combined with NQO1 substrates in vivo: An innovative strategy for NQO1-overexpressing cancer theranostics
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Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.
- Gong, Qijie,Yang, Fulai,Hu, Jiabao,Li, Tian,Wang, Pengfei,Li, Xiang,Zhang, Xiaojin
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- Bioinspired Photoredox Benzylation of Quinones
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3-Benzylmenadiones were obtained in good yield by using a blue-light-induced photoredox process in the presence of Fe(III), oxygen, and γ-terpinene acting as a hydrogen-atom transfer agent. This methodology is compatible with a wide variety of diversely substituted 1,4-naphthoquinones as well as various cheap, readily available benzyl bromides with excellent functional group tolerance. The benzylation mechanism was investigated and supports a three-step radical cascade with the key involvement of the photogenerated superoxide anion radical.
- Donzel, Maxime,Elhabiri, Mourad,Davioud-Charvet, Elisabeth
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supporting information
p. 10055 - 10066
(2021/07/31)
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- NAPHTHOQUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISORDERS
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Disclosed herein are naphthoquinone derivative compounds of the formula shown below, compositions thereof, and methods of using such compounds and compositions for treating or suppressing oxidative stress disorders and/or neurodegenerative disorders and/or for inhibiting ferroptosis.
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Paragraph 00125
(2020/12/30)
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- Synergistic factors ensue high expediency in the synthesis of menaquinone [K2] analogue MK-6: Application to access an efficient one-pot protocol to MK-9
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Here we report a practical and efficient method for the synthesis of menaquinone vitamin (K2) analog MK-6 in all trans forms through “1 + 5 convergent synthetic approach” of pentaprenyl chloride with monoprenyl menadione derivative. In the synergistic factors, less efficient leaving group/more efficient nucleophile (Cl) in the substrate makes it more prominent reaction by eliminating all Sn2’ side reaction products. Further, the addition of acetic acid in the last step (desulfonation) of reaction sequence removes the limitations of the reactions in terms of cyclized side product (multiple reactions of pentaprenyl alcohol with Et3B), byproduct (Et3B, incendiary compound) formations and their interruption in the tricky purification processes. The utility of this method was further extended to find an efficient one-pot synthesis to MK-9 to the gram scale synthesis. This approach is economical and efficient and avoids the awkward chromatographic separation processes.
- Yerramsetti, Nanaji,Dampanaboina, Lavanya,Mendu, Venugopal,Battula, Satyanarayana
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supporting information
(2020/11/12)
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- Synthesis and antitubercular activity of 1- and 3-substituted benzo[: G] isoquinoline-5,10-diones
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In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity. The anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 μM and 1.05 μM, and acute cytotoxic concentrations of >128 μM and 34.85 μM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.
- Smets, Robert J.,Torfs, Eveline,Lemière, Filip,Cos, Paul,Cappoen, Davie,Abbaspour Tehrani, Kourosch
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p. 2923 - 2939
(2019/03/21)
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- Direct Synthesis of Hydroquinones from Quinones through Sequential and Continuous-Flow Hydrogenation-Derivatization Using Heterogeneous Au–Pt Nanoparticles as Catalysts
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Pt–Au bimetallic nanoparticle catalysts immobilized on dimethyl polysilane (Pt–Au/(DMPSi-Al2O3)) have been developed for selective hydrogenation of quinones to hydroquinones. High reactivity, selectivity, and robustness of the catalysts were confirmed under continuous-flow conditions. Various direct derivatizations of quinones, such as methylation, acetylation, trifluoromethanesulfonylation, methacrylation, and benzoylation were successfully performed under sequential and continuous-flow conditions to afford the desired products in good to excellent yields. Especially, air-sensitive hydroquinones, such as anthrahydroquinones and naphthohydroquinones, could be successfully generated and derivatized under closed sequential and continuous-flow conditions without decomposition.
- Miyamura, Hiroyuki,Tobita, Fumiya,Suzuki, Aya,Kobayashi, Shū
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supporting information
p. 9220 - 9224
(2019/06/13)
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- Directed Remote Lateral Metalation: Highly Substituted 2-Naphthols and BINOLs by In Situ Generation of a Directing Group
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A general synthesis of highly substituted 2-naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt2 or LiNiPr2 into Z-cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2-naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one-pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z-cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3′-diaryl BINOL ligands is also reported.
- Patel, Jignesh J.,Laars, Marju,Gan, Wei,Board, Johnathan,Kitching, Matthew O.,Snieckus, Victor
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supporting information
p. 9425 - 9429
(2018/07/29)
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- Catalytic Electrophilic Alkylation of p-Quinones through a Redox Chain Reaction
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Allylation and benzylation of p-quinones was achieved through an unusual redox chain reaction. Mechanistic studies suggest that the existence of trace hydroquinone initiates a redox chain reaction that consists of a Lewis acid catalyzed Friedel–Crafts alkylation and a subsequent redox equilibrium that regenerates hydroquinone. The electrophiles could be various allylic and benzylic esters. The addition of Hantzsch ester as an initiator improves the efficiency of the reaction.
- Xu, Xiao-Long,Li, Zhi
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supporting information
p. 8196 - 8200
(2017/06/30)
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- Convergent Synthesis of Menaquinone-7 (MK-7)
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A practical synthesis of menaquinone-7 (MK-7, Vitamin K2) in the all-trans form was designed. Stereoselective synthesis of MK-7 was achieved through a "1 + 6" convergent strategy by condensation of two building blocks, menadione monoprenyl derivative (fragment "1") with hexaprenyl bromide (fragment "6", 82%). Pd-catalyzed desulfonation with LiEt3BH (78%) was followed by oxidation of the hydroquinone moiety using ammonium cerium(IV) nitrate (72%). The major challenge in our methodology was the preparation of all-trans hexaprenyl bromide by coupling of two triprenyl units derived from trans, trans-farnesol. Manufacturing on a pilot scale was accomplished through our approach. The scalable method was designed especially for a large, kilogram-scale production from easily available intermediates. Furthermore, the proposed methodology avoids many chromatographic purifications and allows for a relatively cost-effective manufacturing. Moreover, our synthesis yielded high-purity (99.9%) final product MK-7, which can be used as a dietary supplement as well as an active pharmaceutical ingredient.
- Baj, Aneta,Wa?ejko, Piotr,Kutner, Andrzej,Kaczmarek, ?ukasz,Morzycki, Jacek W.,Witkowski, Stanis?aw
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p. 1026 - 1033
(2016/11/11)
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- Homolytic Cleavage of a B-B Bond by the Cooperative Catalysis of Two Lewis Bases: Computational Design and Experimental Verification
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Density functional theory (DFT) investigations revealed that 4-cyanopyridine was capable of homolytically cleaving the B-B σ bond of diborane via the cooperative coordination to the two boron atoms of the diborane to generate pyridine boryl radicals. Our experimental verification provides supportive evidence for this new B-B activation mode. With this novel activation strategy, we have experimentally realized the catalytic reduction of azo-compounds to hydrazine derivatives, deoxygenation of sulfoxides to sulfides, and reduction of quinones with B2(pin)2 at mild conditions. Breaking good: The diborane B-B bond can be homolytically cleaved via the cooperative catalysis of two 4-cyanopyridine molecules. Using this combination of a diborane (B2(pin)2) and 4-cyanopyridine also allows the catalytic reduction of the N=N double bond of azo-compounds to hydrazine derivatives, deoxygenation of sulfoxides to sulfides, and reduction of quinones under mild conditions.
- Wang, Guoqiang,Zhang, Honglin,Zhao, Jiyang,Li, Wei,Cao, Jia,Zhu, Chengjian,Li, Shuhua
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p. 5985 - 5989
(2016/05/19)
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- Convergent synthesis of menaquinone-7 (MK-7)
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A practical synthesis of menaquinone-7 (MK-7, vitamin K2) in the all-Trans form was designed. Stereoselective synthesis of MK-7 was achieved through a "1 + 6" convergent strategy by condensation of two building blocks, menadione monoprenyl derivative (fragment "1") with hexaprenyl bromide (fragment "6", 82%). Pd-catalyzed desulfonation with LiEt3BH (78%) was followed by oxidation of the hydroquinone moiety using ammonium cerium(IV) nitrate (72%). The major challenge in our methodology was the preparation of all-Trans hexaprenyl bromide by coupling of two triprenyl units derived from trans,trans-farnesol. Manufacturing on a pilot scale was accomplished through our approach. The scalable method was designed especially for a large, kilogram-scale production from easily available intermediates. Furthermore, the proposed methodology avoids many chromatographic purifications and allows for a relatively cost-effective manufacturing. Moreover, our synthesis yielded high-purity (99.9%) final product MK-7, which can be used as a dietary supplement as well as an active pharmaceutical ingredient.
- Baj, Aneta,Wa?ejko, Piotr,Kutner, Andrzej,Kaczmarek, L?ukasz,Morzycki, Jacek W,Witkowski, Stanisl?aw
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p. 1026 - 1033
(2017/01/16)
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- Method for synthesizing vitamin K1
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The invention relates to a method for synthesizing vitamin K1, relating to the technical field of synthesis of organic matters. The method comprises the following steps: reducing 2-methyl1,4-naphthoquinone to 2-methyl-1,4-naphthalenediol in certain solvents by virtue of a reducing agent under certain conditions, then adding phytol, reacting by using an appropriate catalyst under certain conditions to synthesize 2-methyl3-phytyl1,4-naphthalenediol, then oxidizing the 2-methyl3-phytyl1,4-naphthalenediol by using an appropriate oxidizing agent to obtain vitamin K1, and decompressing and concentrating to obtain the vitamin K1. According to the method for synthesizing the vitamin K1, the 2-methyl1,4-naphthoquinone is used as a raw material, and the hydroxyl groups are not required to be protected, so that the method has the characteristics of simple process, moderate reaction conditions, high productivity, high product purity and high yield; moreover, the method is low in production cost and very suitable for industrialized production.
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Paragraph 0023; 0025
(2017/02/23)
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- Method of preparation of stereospecific quinone derivatives
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A novel process for the regio- and stereospecific synthesis of polyprenylated quinone derivatives, such as Vitamin K1, K2 and Ubiquinone, has been achieved exploiting dithioacetal-, especially 1,3-dithiane-, mediated Umpolung chemistry which works along a new concept "Inhibiting resonance delocalization (IRD)" to overcome isomerization generated due to delocalization of allylic carbanions on the π-electron cloud of an allylic system. The present novel synthesis of all-trans Vitamins K1, K2 and Ubiquinone is achieved by coupling of a quinone group with a polyprenyl side chain where either of the two moieties may have 1,3-dithiane as a terminal group while undergoing umpolung chemistry. Similarly while coupling two polyprenyl fragments to each other in building of the all-trans side chain. A stereospecific synthesis of vitamin K1 was also achieved along the same synthetic outline using a chiral hexahydrofarnesyl derivative retaining optical and geometrical isomeric properties equivalent to those of the natural K1.
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Paragraph 0051-0052
(2015/05/19)
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- METHOD OF PREPARATION OF STEREOSPECIFIC QUINONE DERIVATIVES
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The description provides processes for the regio and stereospecific synthesis of polyprenylatedquinone derivatives, such as Vitamin K1, K2 and Ubiquinone, exploiting dithioacetals, especially 1,3-dithiane, mediated Umpolung chemistry which works along a new concept “Inhibiting resonance delocalization (IRD)” to overcome isomerization generated due to delocalization of allyliccarbanion on the π-electron cloud of an allylic systems by the conventional synthesis.
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Paragraph 0147-0148
(2015/05/13)
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- Stereoselective heck reactions with vinyl sulfoxides, sulfides and sulfones
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We report the Heck cross-coupling of notoriously unreactive, but synthetically valuable olefins: vinyl sulfoxides, vinyl sulfones, and vinyl sulfides. Key findings include the importance of the sterically hindered (tri-tert-butyl)phosphine ligand and the unique effectiveness of triethylamine as the base. The method is general, E-selective, and can be used to synthesize disubstituted or trisubstituted olefins through simple adjustments of stoichiometry. Copyright
- Bachmann, Daniel G.,Wittwer, Christopher C.,Gillingham, Dennis G.
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supporting information
p. 3703 - 3707
(2014/01/06)
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- Evidence for NQO1 and NQO2 catalyzed reduction of ortho-and para-quinone methides
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NAD(P)H:quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinones and thereby prevent generation of toxic radicals. Quinone methides (QMs) covalently react with cellular macromolecules to form DNA adducts and/or protein conjugates resulting in toxicity and carcinogenesis. Based on similar structural features of quinones and QMs, it is logical to assume that NQO1 and/or NQO2 could also catalyze the two-electron reduction of QMs. However, hitherto the reduction of QMs, as both endogenous and/or exogenous biological substrates, by either NQO1/NQO2 has never been demonstrated. Here we show for the first time that both NQO1 and NQO2 can catalyze the reduction of electrophilic ortho-/para-QMs. The involvement of the enzyme in the reduction of p-cresol quinone methide (PCQM) and o-cresol quinone methide (OCQM) was demonstrated by reappearance of NQO1/NQO2-FAD peak at 450 nm after addition of the QMs to the assay mixture. Further reduction of methides by NQO1/NQO2 was confirmed by analyzing the assay mixture by tandem mass spectrometry. Preliminary kinetic studies show that NQO2 is faster in reducing QMs than its homolog NQO1, and moreover, ortho-QMs are reduced faster than para-QMs. Enzyme-substrate docking studies showed results consistent with enzyme catalysis. Thus, NQO1/NQO2 can play a significant role in deactivation of QMs.
- Kucera,Livingstone,Moscoso,Gaikwad
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p. 1016 - 1026
(2013/12/04)
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- Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/Ref-1)
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The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 μM range.
- Nyland II, Rodney L.,Luo, Meihua,Kelley, Mark R.,Borch, Richard F.
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experimental part
p. 1200 - 1210
(2010/07/18)
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- Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors
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Plasmodium falciparum NDH2 (pfNDH2) is a non-proton pumping, rotenone-insensitive alternative enzyme to the multi-subunit NADH:ubiquinone oxidoreductases (Complex I) of many other eukaryotes. Recombinantly expressed pfNDH2 prefers coenzyme CoQ0 as an acceptor substrate, and can also use the artificial electron acceptors, menadione and dichlorophenol-indophenol (DCIP). Previously characterized NDH2 inhibitors, dibenziodolium chloride (DPI), diphenyliodonium chloride (IDP), and 1-hydroxy-2-dodecyl-4(1H)quinolone (HDQ) do not inhibit pfNDH2 activity. Here, we provide evidence that HDQ likely targets another P. falciparum mitochondrial enzyme, dihydroorotate dehydrogenase (pfDHOD), which is essential for de novo pyrimidine biosynthesis.
- Dong, Carolyn K.,Patel, Vishal,Yang, Jimmy C.,Dvorin, Jeffrey D.,Duraisingh, Manoj T.,Clardy, Jon,Wirth, Dyann F.
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supporting information; experimental part
p. 972 - 975
(2009/08/15)
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- NOVEL SUBSTITUTED NAPHTHOPYRANS
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Described are novel reversible photochromic 2H-naphtho[1,2-b]pyran compounds, examples of which are compounds having certain substituents at the number 5 carbon atom of the naphtho-portion of the naphthopyran and at the 2-position of the pyran ring. Certain substituents may also be present at the number 6, 7, 8, 9 or 10 carbon atoms of the naphtho portion of the naphthopyran. Also described are organic host materials that contain or that are coated with such compounds. Articles such as ophthalmic lenses or other plastic transparencies that incorporate the novel naphthopyran compounds or combinations thereof with complementary photochromic compounds, e.g., spiro(indoline) type compounds, are also described.
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Page/Page column 14
(2010/11/08)
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- 2,3-Dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4-naphthoquinones: Glycation inhibitors with lipid peroxidation activity
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Anti-glycation activity of our anti-oxidant quinone library was measured and several 2,3-dimethoxy-5-methyl-1,4-benzoquinones and 2-methyl-1,4- naphthoquinones were identified as novel inhibitors of glycation, of which 2,3-dimethoxy-5-methyl-1,4-benzoquinones 13b is the most potent glycation inhibitor with around 50 μM of the IC50 value.
- Jung, Young-Sik,Joe, Bo-Young,Cho, Sung Ju,Konishi, Yasuo
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p. 1125 - 1129
(2007/10/03)
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- Practical synthesis of (R)-(+)-6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4- hydroxyphenyl)hexanoic acid: A key intermediate for a therapeutic drug for neurodegenerative diseases
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A practical method for the preparation of (R)-(+)-6-(1,4-dimethoxy-3- methyl-2-naphthyl)-6-(4-hydroxyphenyl)hexanoic acid (R)-2, a key intermediate for a therapeutic drug for neurodegenerative diseases, has been developed. rac-Methyl 6-(1,4-dimethoxy-3-methyl-2-naphthyl)-6-(4-(propionyloxy)phenyl) hexanoate rac-9b was synthesized from 2-methylnaphthoquinone in seven steps. An optically active ester (R)-9b was readily obtained from the corresponding racemic ester by lipase-catalyzed resolution, followed by sulfation or phosphorylation. Sulfation by a sulfur trioxide pyridine complex or phosphorylation by phosphoryl chloride enabled facile isolation of the optically active ester simply by extraction. Optically active acid (R)-2 was synthesized in excellent enantiomeric excess by hydrolysis of (R)-9b followed by recrystallization. The present synthesis of (R)-2 was accomplished in 10 steps without requiring chromatographic purification.
- Ito, Tatsuya,Ikemoto, Tomomi,Yamano, Toru,Mizuno, Yukio,Tomimatsu, Kiminori
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p. 3525 - 3531
(2007/10/03)
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- Synthesis of 2-alkoxymethyl-3-trifluoromethyl-1,4-naphthoquinones
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2-Alkoxymethyl-3-trifluoromethyl-1,4-naphthoquinones were conveniently synthesized in two steps by treatment of 2-substituted-3-bromo-1,4-dimethoxynaphthalene with CF3COONa/CuI and subsequent dealkylative oxidation by treatment with cerium(IV) ammonium nitrate.
- Van Tuyen, Nguyen,Kesteleyn, Bart,De Kimpe, Norbert
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p. 121 - 127
(2007/10/03)
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- Reductive and Bioreductive Activation is Controlled by Electronic Properties of Substituents in Conformationally-Constrained Anticancer Drug Delivery Systems
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Conformationally-constrained, anticancer drug delivery systems (TDDS) containing the methyl ester of melphalan (as a model drug) were synthesized using electron-withdrawing or electron-donating functional groups to modulate reductive and bioreductive activation. The electronic nature of substituents in TDDS was found to control reductive and bioreductive activation of TDDS, thus influencing drug delivery from TDDS.
- Weerapreeyakul, Natthida,Visser, Petra,Brummelhuis, Mathijn,Gharat, Laxmikant,Chikhale, Prashant J.
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p. 148 - 163
(2007/10/03)
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- Chemistry of L-ascorbic acid. Part 3.1 Photoreduction of quinones with 5,6-O-isopropylidene-L-ascorbic acid
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Upon irradiation with UV light, instead of undergoing the Paterno-Buechi reaction, 5,6-O-isopropyIidene-L-ascorbic acid reduced quinones quite efficiently and rapidly to the corresponding hydroquinones. The Royal Society of Chemistry 2000.
- Kulkarni, Mukund G.,Kate, Sandesh D.
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p. 4242 - 4244
(2007/10/03)
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- Synthesis of quinones from hydroquinone dimethyl ethers. Oxidative demethylation with cobalt(III) fluoride
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The oxidative demethylation of 1,4-dimethoxynaphthalene and 1,4- dimethoxybenzene derivatives with cobalt(III) fluoride proceeded in good to excellent yield to afford the corresponding naphthoquinone and benzoquinone derivatives.
- Tomatsu, Ayumi,Takemura, Syunji,Hashimoto, Kimiko,Nakata, Masaya
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p. 1474 - 1476
(2007/10/03)
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- Reductive activation of conformationally-constrained, anticancer drug delivery systems
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Redox-active substituents were used to modulate reduction potentials in conformationally-constrained, drug delivery systems. The extent of drug delivery was proportional to the degree of reductive activation, which was influenced by the electronic properties of the substituents. Such reductively-activated carrier systems can be used to achieve controlled drug delivery to bioreductive regions in hypoxic solid tumors.
- Gharat, Laxmikant,Visser, Petra,Brummelhuis, Mathijn,Guiles, Ronald,Chikhale, Prashant
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p. 444 - 456
(2007/10/03)
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- Thermodynamics of semiquinone disproportionation in aqueous buffer
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The thermodynamic parameters, Kdisp, ΔH° and ΔS°, controlling the disproportionation of semiquinones derived from 1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 2-methylbenzoquinone (MBQ), menadione (MNQ), naphthazarin (NZQ) and quinizarin (QNZ), have been determined. Smaller disproportionation constants, Kdisp, are observed upon addition of a fused benzene ring to the semiquinone structure. Negative enthalpies and positive entropies of disproportionation govern the disproportionation equilibria. Addition of OH groups to the 5 and 8 positions in NQ?- displaces the disproportionation equilibrium to the semiquinone probably due to intramolecular hydrogen bonding.
- Alegria, Antonio E.,Lopez, Marcos,Guevara, Norberto
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p. 4965 - 4968
(2007/10/03)
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- Kinetics and mechanism of photochemical decomposition of menadiole sodium sulphate in solutions
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Photochemical decomposition of Menadiole Sodium Sulphate [I] in an atmosphere of air in aqueous solutions UV irradiated at 254 nm is a composite consecutive first order reaction of the type A → B → C → D where in the first step occur two parallel photohydrolysis ractions, leading to the isomeric hemiesters: 2-methyl-1-hydroxy-4-naphtohydroquinone sulphate ester [II] and 2-methyl-4-hydroxy-1-naphtohydroquinone sulphate ester [III]. In the second step of the reaction, these esters hydrolyse to 2-methyl-1,4-naphtohydroquinone [IV]. The third, last step consists in an oxidation reaction leading to 2-methyl-1,4-naphtoquinone [V]. The quantum yields φ of the individual steps were amounted to 13.6·10-2, 17.1·10-3 and 6.5·10-5, respectively, with a temperature coefficient of 0.91. The rate of all the steps of the reaction increase with decreasing dielectric coefficient of the solvent. The first and second steps were found to fulfil the functions 1g k(1obs·) = f (1g D) and 1g k(2obs·) = f (1g D).
- Marciniec, Barbara,Jaskula-Begol, Jolanta
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p. 187 - 191
(2007/10/03)
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- Thermal decomposition of menadiole sodium sulphate in the solid state
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By kinetic (accelerated ageing test) and instrumental (UV, IR, TLC, DTA, MS, EPR) methods, decomposition of Menadiole Sodium Sulphate (MSS) in the solid phase is found to proceed by a composite consecutive reaction of the order conforming to the Prout-Thompkins model, at a rate dependent on temperature and humidity. The first stage of the reaction consists in dehydratation, the second - in oxidating desulfonation following a free-radical path, and the third - in dimerisation, in the presence of humidity, moreover, a parallel reaction of hydrolysis and a consecutive reaction of reduction take place. Thermal decomposition products of MSS in solid state are successively: the anhydrate, the free radical, menadion (MD), and dimer (MDD) arisen from two MD molecules, under conditions of humidity, menadiol (MDH) arises too.
- Marciniec, Barbara,Szukowska, Beata,Wieckowski, Andrzej
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p. 263 - 268
(2007/10/03)
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- A novel electrochemical proton pump
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Protons are transported electrochemically from one aqueous phase to the other phase via an oil phase containing a hydrophobic quinone compound (vitamin K3) using a pair of solid polymer electrodes set at the oil/water boundaries
- Matsumura, Michio,Nohara, Masahiro,Ohno, Teruhisa
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p. 1949 - 1952
(2007/10/03)
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- THE GENERATION OF C,O,O-TRILITHIATED DERIVATIVES OF DIHYDRIC PHENOLS
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Halogenated dihydric phenols (hydroquinones and resorcinols) undergo halogen metal exchange with nBuLi/TMEDA/THF or ether (inverse addition) under sonication, thereby generating a C,O,O-trilithiated species which can be trapped with electrophiles.
- Saa, Jose M.,Morey, Jeroni,Suner, Guillem,Frontera, Antoni,Costa, Antoni
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p. 7313 - 7316
(2007/10/02)
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- Reactivity of some Quinones with Alkylaluminium Compounds
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The reactions of 2-methyl-1,4-naphthoquinone with triethylaluminium and 2,5-di-t-butyl-1,4-benzoquinone with triisobutylaluminium were studied.In each of these reactions three different products were obtained and characterized by n.m.r. and i.r.U.V. spectrophotometry showed that 2-methyl-1,4-naphthoquinone behaves as a weak base and the ionization constants pK1 = -0.922 and pK2 = -4.065 were reported in aqueous HClO4.This is a useful information for elucidating the mechanism of the first reaction studied, based on the different basicity of the carbonyl groups.
- Leal, J. M.,Arcos, J.,Garcia, B.
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p. 887 - 896
(2007/10/02)
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- New Reduction Method of α-Diketones, Oxo amides, and Quinones with Zn-EtOH in the Presence of a Salt
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The reagent, Zn-Salt-EtOH effectively reduces α-diketones, oxo amides, and quinones to hydroxy ketones, hydroxy amides, and hydroquinones, respectively.
- Toda, Fumio,Tanaka, Koichi,Tange, Hiroshi
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p. 1555 - 1556
(2007/10/02)
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- Clusters 2- as Novel Catalysts in Organic Reductions
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The cluster 2- catalyzed the redudtions of nitro compounds, quinones and N-oxide compounds to amines, hydroquinones, and deoxygenated compounds, respectively, in the presence of thiols in CH3CN solution.The reaction mechanism was also investigated by electron spin resonance spectroscopy, and it was concluded that these reactions proceed via one-electron transfer from the cluster to the substrates.Keywords - ferredoxin; cluster; electron transfer; iron-sulfur protein; reduction; superoxidized cluster
- Itoh, Takashi,Nagano, Tetsuo,Hirobe, Masaaki
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p. 2013 - 2017
(2007/10/02)
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- Synthesis of Menadione
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New methods conceptually different from previous approaches are described for the preparation of 2-methyl-1,4-naphthoquinone (menadione), an antihemorrhagic agent.Recently the bisulphite adduct of menadione has been shown to be a promising plant growth regulator.
- Rao, A. V. Rama,Deshpande, V. H.,Ravichandran, K.
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p. 233 - 235
(2007/10/02)
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- Dimeric Naphthoquinones, 13. Synthesis of m-Substituted 4-Methoxy-1-naphthols - β-Haloalkyl Ethers as Protective Groups in Phenols
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m-Substituted naphthohydroquinone monoethers are difficult to synthesize by direct alkylation.They are conveniently obtainable now in the following way: Acid-catalyzed reaction of naphthohydroquinones with β-haloethyl alcohols affords monoesters 5 in high yield which are conventionally alkylated forming 6.In 6 the protective group is cleaved off via the vinyl ether or, under milder conditions, by bromine/iodine exchange and fragmentation with zink. - Key words: Naphthols, Protective Groups, Haloalkyl Ethers
- Laatsch, Hartmut
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p. 534 - 542
(2007/10/02)
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