- Synthetic Access to gem-Difluoropropargyl Vinyl Ethers and Their Application to Propargyl Claisen Rearrangement
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With the increasing importance of fluorine to medicinal chemistry and other areas, methods to access various fluorinated compounds are needed. Herein, we report the synthesis of difluoropropargyl vinyl ethers from ketones and aldehydes using difluoropropargyl bromide dicobalt complexes. We applied difluoropropargyl vinyl ethers to the synthesis of difluorodienone or difluoroallene under thermal conditions and trifluoro-pyran under acid-catalyzed conditions.
- Okamura, Toshitaka,Koyamada, Kenta,Kanazawa, Junichiro,Miyamoto, Kazunori,Iwabuchi, Yoshiharu,Uchiyama, Masanobu,Kanoh, Naoki
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p. 1911 - 1924
(2020/12/23)
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- Regioselective, Diastereoselective, and Enantioselective One-Pot Tandem Reaction Based on an in Situ Formed Reductant: Preparation of 2,3-Disubstituted 1,5-Benzodiazepine
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The 1,5-benzodiazepines are important skeletons frequently contained in medicinal chemistry. Herein, we described an unexpected tandem cyclization/transfer hydrogenation reaction for obtaining chiral 2,3-disubstituted 1,5-benzodiazepines. The enolizable aryl aldehydes were chosen as substrates to react with symmetric and unsymmetric o-phenylenediamines. The unforeseen tandem reaction occurred among many possible latent side reactions under chiral phosphoric acid catalysis and affords the corresponding products in moderate yields and regioselectivities, good diastereoselectivities, and enantiomeric ratio (up to 99:1).
- Yang, Gao-Feng,Li, Guang-Xun,Huang, Jin,Fu, Ding-Qiang,Nie, Xiao-Kang,Cui, Xin,Zhao, Jin-Zhong,Tang, Zhuo
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p. 5110 - 5119
(2021/04/12)
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- Kinetic Resolution of Neopentylic Secondary Alcohols by Cu-H-Catalyzed Enantioselective Silylation with Hydrosilanes
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A nonenzymatic kinetic resolution of sterically congested alcohols having a quaternary carbon atom in the β-position is reported. The catalyst system CuCl/NaOtBu/(R,R)-Ph-BPE together with a 3,5-xylyl-substituted tertiary hydrosilane enable enantioselective silylation of the hydroxy group. Several alcohols are obtained with good to excellent selectivity factors, and there are no other known straightforward methods to access these motifs.
- Oestreich, Martin,Papadopulu, Zaneta
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supporting information
p. 438 - 441
(2021/01/13)
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- Rhodium-Catalyzed β-Dehydroborylation of Silyl Enol Ethers: Access to Highly Functionalized Enolates
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An efficient rhodium-catalyzed β-dehydroborylation of aldehyde-derived silyl enol ethers (SEEs) with bis(pinacolato)diboron (B2pin2) is disclosed. The borylation reactions proceeded well with alkyl- and aryl-substituted SEEs, affording a wide array of valuable functionalized β-boryl silyl enolates with high efficiency and excellent stereoselectivity. Moreover, the borylated products, through versatile carbon–boron bond transformations, were readily converted into diverse synthetically useful molecules, including α-hydroxy ketones, functionalized SEEs, and gem-difunctionalized aldehydes.
- Li, Jie,Li, Ruoling,Yang, Wen,Zhao, Pei,Zhao, Wanxiang
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supporting information
p. 9580 - 9585
(2021/12/14)
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- Biomimetic synthesis and anti-inflammatory effects of horsfiequinone A
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Inspired by the oxy-tyrosinase type II copper enzyme, a biomimetic synthesis of the natural product horsfiequinone A (1) has been achieved using CuOTf/DBED/O2 catalyzed oxidation as a key step. The synthetic route furnished 1 in 33% overall yield (64% brsm) from commercially available para-hydroxybenzaldehyde. Moreover, revisiting the biological activity of 1 resulted in the discovery of its in vitro inhibitory activity towards nitric oxide (NO) production in LPS-induced RAW264.7 cells with an IC50 value of 4.42 ± 0.81 μM. The anti-inflammatory effect of 1 was further supported by an iNOS expression inhibition assay and molecular docking simulation.
- Wang, Mei,Liu, Yuan-Lie,Li, Dashan,Xiao, Wen-Wen,Chen, Yang,Zhang, Hong-Lin,Zhan, Rui,Shao, Li-Dong
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supporting information
(2021/02/05)
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- B(C6F5)3-catalyzed tandem protonation/deuteration and reduction of: In situ -formed enamines
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A highly efficient B(C6F5)3-catalyzed tandem protonation/deuteration and reduction of in situ-formed enamines in the presence of water and pinacolborane was developed. Regioselective β-deuteration of tertiary amines was achieved with high chemo- and regioselectivity. D2O was used as a readily available and cheap source of deuterium. Mechanistic studies indicated that B(C6F5)3 could activate water to promote the protonation and reduction of enamines. This journal is
- Wu, Rongpei,Gao, Ke
-
supporting information
p. 4032 - 4036
(2021/05/19)
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- Palladium-Catalyzed Reductive Carbonylation of (Hetero) Aryl Halides and Triflates Using Cobalt Carbonyl as CO Source
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An efficient protocol for the reductive carbonylation of (hetero) aryl halides and triflates under CO gas-free conditions using Pd/Co2(CO)8 and triethylsilane has been developed. The mild reaction conditions, enhanced chemoselectivity and, easy access to heterocyclic and vinyl carboxaldehydes highlights its importance in organic synthesis.
- Dogga, Bhushanarao,Joseph, Jayan T.,Kumar, C. S. Ananda
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supporting information
p. 309 - 313
(2020/12/23)
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- Visible-light-induced oxidative lignin c-c bond cleavage to aldehydes using vanadium catalysts
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Lignin is the largest carrier of aromatics on earth, and its depolymerization can afford value-Added aromatic products. Direct cleavage of the C-C bonds in lignin linkages is significant, but it is challenging to obtain low-molecular-weight aromatic monomers. Herein, using vanadium catalysts under visible light, we selectively cleave the C-C bonds in β-1 and β-O-4 interlinkages occluded in lignin models and extracts by an oxidative protocol. Visible light irradiation triggered single electron transfer between the substrate and the catalyst, which further induced the selective Cα-Cβ bond cleavage and generated the final aromatic products through radical intermediates. Using this photocatalytic chemistry, the reactivity of lignin models and the selectivity of Cα-Cβ bond cleavage were significantly improved. More importantly, this protocol affords aromatic monomers through the fragmentation of organosolv lignins even at room temperature, indicating the potential of photocatalytic C-C bond cleavage of lignin linkages under ambient conditions.
- Liu, Huifang,Li, Hongji,Luo, Nengchao,Wang, Feng
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p. 632 - 643
(2020/01/02)
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- Concurrent Formation of N-H Imines and Carbonyl Compounds by Ruthenium-Catalyzed C-C Bond Cleavage of β-Hydroxy Azides
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A commercial cyclopentadienylrutenium dicarbonyl dimer ([CpRu(CO)2]2) efficiently catalyzes the formation of N-H imines and carbonyl compounds simultaneously from β-hydroxy azides via C-C bond cleavage under visible light. Density functional theory calculations for the cleavage reaction support the mechanism involving chelation of alkoxy azide species and liberation of nitrogen as the driving force. The synthetic utility of the reaction was demonstrated by a new amine synthesis promoted by chemoselective allylation of imine and synthesis of isoquinoline.
- Lee, Jeong Min,Bae, Dae Young,Park, Jin Yong,Jo, Hwi Yul,Lee, Eunsung,Rhee, Young Ho,Park, Jaiwook
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supporting information
p. 4608 - 4613
(2020/06/05)
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- Selective monochlorination of unsymmetrical vicinal diols with chlorinated iminium chlorides
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Chlorinated iminium chlorides have been identified to promote the highly efficient and selective mono-chlorination of unsymmetrical vicinal diols. Vilsmeier reagent, namely, (chloromethylene)dimethyliminium chloride, enables highly reactive and regioselective chlorination of 1,2- and 1,3-diols featured one secondary benzylic hydroxy group and one primary aliphatic hydroxy group to give the corresponding 1,2- and 1,3-chlorohydrins. Viehe's salts (α,α-dichloro iminium salts) exhibit excellent reactivity and good selectivity for vicinal diols to give the corresponding chlorohydrin carbamates via a cyclic intermediate in situ. The chlorination protocols tolerate diverse functional groups, including halogens, naphthalene rings, nitro, and cyano. Moreover, the optical purity of chiral diols could be retained during this chlorination reaction.
- Li, Chengyang,Li, Xiaotong,Wang, Yu,Wu, Xiaoyu,Xie, Xiaomin,Yang, Liqun,Zhang, Zhaoguo
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- Two-way homologation of aliphatic aldehydes: Both one-carbon shortening and lengthening via the same intermediate
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Aliphatic aldehydes can be homologated to both one-carbon shorter and one-carbon longer homologous carbonyl compounds through the 2–4 steps of reactions via the same intermediates, β,γ-unsaturated α-nitrosulfones, prepared from the proline-catalyzed sequential reactions of several aliphatic aldehydes with phenylsulfonylnitromethane. While the oxidative cleavage of the key intermediates gave one-carbon less homologous carbonyl compounds, the reduction of the same key intermediates followed by an oxidation produced one-carbon more homologous carbonyl compounds.
- Yoo, Jae Won,Seo, Youngran,Park, Jong Beom,Kim, Young Gyu
-
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- Oxoiron(v) mediated selective electrochemical oxygenation of unactivated C-H and CC bonds using water as the oxygen source
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An efficient electrochemical method for the selective oxidation of C-H bonds of unactivated alkanes (BDE ≤97 kcal mol-1) and CC bonds of alkenes using a biomimetic iron complex, [(bTAML)FeIII-OH2]-, as the redox mediator in an undivided electrochemical cell with inexpensive carbon and nickel electrodes is reported. The O-atom of water remains the source of O-incorporation in the product formed after oxidation. The products formed upon oxidation of C-H bonds display very high regioselectivity (75:1, 3°:2° for adamantane) and stereo-retention (RC ~99% for cyclohexane derivatives). The substrate scope includes natural products such as cedryl acetate and ambroxide. For alkenes, epoxides were obtained as the sole product. Mechanistic studies show the involvement of a high-valent oxoiron(v) species, [(bTAML)FeV(O)]- formed via PCET (overall 2H+/2e-) from [(bTAML)FeIII-OH2]- in CPE at 0.80 V (vs. Ag/AgNO3). Moreover, electrokinetic studies for the oxidation of C-H bonds indicate a second-order reaction with the C-H abstraction by oxoiron(v) being the rate-determining step.
- Chandra, Bittu,Gupta, Sayam Sen,Hellan, K. M.,Pattanayak, Santanu
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p. 11877 - 11885
(2020/11/18)
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- Magnetically recoverable porphyrin-based nanocatalysts for the effective oxidation of olefins with hydrogen peroxide: A comparative study
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In this paper, preparation, characterization and catalytic applications of metalloporphyrin-based magnetic nanocatalysts were investigated. meso-Tetrakis(4-carboxyphenyl)porphyrinatoiron(iii) chloride (Fe(TCPP)Cl) and meso-tetrakis(4-carboxyphenyl)porphyrinatomanganese(iii) acetate (Mn(TCPP)OAc) were separately immobilized onto the surface of amine functionalized magnetic nanoparticles (Fe3O4/SiO2/NH2) via covalent attachment. The obtained nanocatalysts were characterized using FT-IR and UV-Vis and atomic absorption spectroscopy, X-ray powder diffraction (XRD), vibrating sample magnetometry (VSM), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). The catalytic efficiency of Fe3O4/SiO2/NH2-Fe(TCPP)Cl and Fe3O4/SiO2/NH2-Mn(TCPP)OAc for the green oxidation of alkenes with H2O2 was investigated in a comparative manner. The Mn-porphyrin based magnetic nanocatalyst shows higher catalytic efficiency compared to the Fe-porphyrin. In addition, the prepared magnetic nanocatalyst exhibited excellent reusability and could be reused at least five times without significant leaching or loss of activity. This journal is
- Rayati, Saeed,Moradi, Dana,Nejabat, Fatemeh
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p. 19385 - 19392
(2020/11/23)
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- Deoxygenation of Epoxides with Carbon Monoxide
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The use of carbon monoxide as a direct reducing agent for the deoxygenation of terminal and internal epoxides to the respective olefins is presented. This reaction is homogeneously catalyzed by a carbonyl pincer-iridium(I) complex in combination with a Lewis acid co-catalyst to achieve a pre-activation of the epoxide substrate, as well as the elimination of CO2 from a γ-2-iridabutyrolactone intermediate. Especially terminal alkyl epoxides react smoothly and without significant isomerization to the internal olefins under CO atmosphere in benzene or toluene at 80–120 °C. Detailed investigations reveal a substrate-dependent change in the mechanism for the epoxide C?O bond activation between an oxidative addition under retention of the configuration and an SN2 reaction that leads to an inversion of the configuration.
- Maulbetsch, Theo,Jürgens, Eva,Kunz, Doris
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p. 10634 - 10640
(2020/07/30)
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- Organomagnesium Based Flash Chemistry: Continuous Flow Generation and Utilization of Halomethylmagnesium Intermediates
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The generation of highly unstable chloromethylmagnesium chloride in a continuous flow reactor and its reaction with aldehydes and ketones is reported. With this strategy, chlorohydrins and epoxides were synthesized within a total residence time of only 2.6 s. The outcome of the reaction can be tuned by simply using either a basic or an acidic quench. Very good to excellent isolated yields, up to 97%, have been obtained for most cases (30 examples).
- Von Keutz, Timo,Cantillo, David,Kappe, C. Oliver
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supporting information
p. 7537 - 7541
(2020/10/12)
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- Manganese and rhenium-catalyzed selective reduction of esters to aldehydes with hydrosilanes
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The selective reduction of esters to aldehydes, via the formation of stable alkyl silyl acetals, was, for the first time, achieved with both manganese, -Mn2(CO)10- and rhenium -Re2(CO)10- catalysts in the presence of triethylsilane as reductant. These two methods provide a direct access to a large variety of aliphatic and aromatic alkyl silyl acetals (30 examples) and to the corresponding aldehydes (13 examples) upon hydrolysis. The reactions proceeded in excellent yields and high selectivity at room temperature under photo-irradiation conditions (LED, 365 nm, 40 W, 9 h).
- Wei, Duo,Buhaibeh, Ruqaya,Canac, Yves,Sortais, Jean-Baptiste
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p. 11617 - 11620
(2020/10/19)
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- Synthesis of Arylacetaldehydes by Iridium-Catalyzed Arylation of Vinylene Carbonate with Arylboronic Acids
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The one-step synthesis of arylacetaldehydes by carbon–carbon bond formation between formylmethyl and aryl groups has been realized by the reaction of vinylene carbonate with arylboronic acids in the presence of an iridium/bisphosphine catalyst and a catalytic amount of tetrahydroxydiboron.
- Wang, Zhe,Xue, Fei,Hayashi, Tamio
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supporting information
p. 11054 - 11057
(2019/07/17)
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- Transaminase-Catalyzed Continuous Synthesis of Biogenic Aldehydes
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The physiological role of biogenic aldehydes, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been associated with cardiovascular and neurodegenerative disorders. The availability of these substrates is limited and robust synthetic methodologies would greatly facilitate further biological studies. Herein, a transaminase-mediated single-step process in continuous mode, which leads to excellent product yields (90–95 %), is reported. Coimmobilization of the pyridoxal phosphate (PLP) cofactor eliminated the need for exogenous addition of this reagent without affecting the longevity of the system, delivering a truly self-sufficient process.
- Contente, Martina L.,Paradisi, Francesca
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p. 2830 - 2833
(2019/08/12)
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- Synthesis technology of higenamine and pharmaceutical salt of higenamine
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The invention discloses a synthesis technology of higenamine and pharmaceutical salt of the higenamine, and belongs to the technical field of medicine synthesis. According to the synthesis technology,4-methoxyphenylacetic acid is used as a raw material, and through steps of reduction, oxidation, cyclization, deprotection and the like, the higenamine and the hydrochloride of the higenamine are obtained. Compared with existing technical routes, the synthesis technology has the few steps, and is simple to operate, the raw material is cheap, reaction conditions are mild, a reaction process is easy to control, the total yield and the purity are high, and the synthesis technology is environmentally friendly, safe and suitable for industrial production, and has large industrial prospects.
- -
-
Paragraph 0027-0029; 0034-0036; 0041-0043; 0048-0050
(2019/09/14)
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- Copper-Catalyzed Ring-Opening/Reconstruction of Anthranils with Oxo-Compounds: Synthesis of Quinoline Derivatives
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A copper-catalyzed protocol for the construction of various 2-aryl(alkyl)-3-acylquinolines or 3-arylquinolines using readily available anthranils and 1,3-diketones or aldehydes as starting materials is reported herein. Dioxygen as the sole oxidant and hexafluoroisopropanol as the solvent play an important role in both procedures. This ring-opening/reconstruction strategy involving N-O bond cleavage and C-N/C-C bond formation features high yields and broad substrate scope.
- Zou, Liang-Hua,Zhu, Hao,Zhu, Shuai,Shi, Kai,Yan, Cheng,Li, Ping-Gui
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p. 12301 - 12313
(2019/10/11)
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- α-Amino Diphenyl Phosphonates as Novel Inhibitors of Escherichia coli ClpP Protease
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Increased Gram-negative bacteria resistance to antibiotics is becoming a global problem, and new classes of antibiotics with novel mechanisms of action are required. The caseinolytic protease subunit P (ClpP) is a serine protease conserved among bacteria that is considered as an interesting drug target. ClpP function is involved in protein turnover and homeostasis, stress response, and virulence among other processes. The focus of this study was to identify new inhibitors of Escherichia coli ClpP and to understand their mode of action. A focused library of serine protease inhibitors based on diaryl phosphonate warheads was tested for ClpP inhibition, and a chemical exploration around the hit compounds was conducted. Altogether, 14 new potent inhibitors of E. coli ClpP were identified. Compounds 85 and 92 emerged as most interesting compounds from this study due to their potency and, respectively, to its moderate but consistent antibacterial properties as well as the favorable cytotoxicity profile.
- Moreno-Cinos, Carlos,Sassetti, Elisa,Salado, Irene G.,Witt, Gesa,Benramdane, Siham,Reinhardt, Laura,Cruz, Cristina D.,Joossens, Jurgen,Van Der Veken, Pieter,Br?tz-Oesterhelt, Heike,Tammela, P?ivi,Winterhalter, Mathias,Gribbon, Philip,Windshügel, Bj?rn,Augustyns, Koen
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p. 774 - 797
(2019/01/30)
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- Stereoselective Synthesis of Vinylboronates by Rh-Catalyzed Borylation of Stereoisomeric Mixtures
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The stereoselective preparation of vinylboronates via rhodium-catalyzed borylation of E/Z mixtures of vinyl actetates is described, and this method was also extended to synthesis of vinyldiboronates. These transformations feature high functional group compatibility and mild reaction conditions. Control experiments support a mechanism that involved a Rh-catalyzed borylation-isomerization sequence. The isomerization of (Z)-vinylboronates to (E)-isomers was also demonstrated.
- Li, Shenhuan,Li, Jie,Xia, Tianlai,Zhao, Wanxiang
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supporting information
p. 462 - 468
(2019/03/28)
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- Facile Access to Challenging ortho-Terphenyls via Merging Two Multi-Step Domino Reactions in One-Pot: A Joint Experimental/Theoretical Study
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ortho-Terphenyls are of high interest for medicinal chemistry and materials science, but they are difficult to access. Herein, we demonstrate a straightforward and sustainable synthesis of highly functionalized ortho-terphenyls via joining an organocatalyzed two-step domino reaction (Knoevenagel/vinylogous Michael) with a DABCO/CuBr2 co-catalyzed three-step domino reaction (cyclization/tautomerization/aromatization) in a one-pot process. Overcoming necessity to isolate intermediate products leads to a reduction of energy, costs and waste for a broad scope of reactions. DFT calculations have been performed to investigate the thermodynamics of this one-pot process towards ortho-terphenyls and to study the reaction profile of the vinylogous Michael reaction under inclusion of solvent effects. Role of London dispersion forces in this transformation has been elucidated. It is shown that reaction kinetics and thermodynamics are slightly influenced by dispersion interactions. Furthermore, the addition of dispersion energy donors leads to small changes of reaction energies in some cases.
- Grau, Benedikt W.,B?nisch, Simon,Neuhauser, Alexander,Hampel, Frank,G?rling, Andreas,Tsogoeva, Svetlana B.
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p. 3982 - 3992
(2019/08/08)
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- Application of an electron-transfer catalyst in light-induced aerobic oxidation of alcohols
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The first heterogeneous photocatalysis system including a bipyridinium-based complex as the electron-transfer catalyst was developed for aerobic oxidation of alcohols without the use of any noble-metal, external N-oxide or peroxide co-oxidant. The current work provides an efficient strategy for alcohol oxidation through a cost-effective, convenient and eco-friendly route.
- Guo, Rui-Yun,Sun, Li,Pan, Xin-Yi,Yang, Xiao-Dong,Ma, Shuai,Zhang, Jie
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supporting information
p. 12614 - 12617
(2018/11/20)
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- Regio- and chemoselective rearrangement of terminal epoxides into methyl alkyl and aryl ketones
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The development of the highly active pincer-type rhodium catalyst 2 for the nucleophilic Meinwald rearrangement of functionalised terminal epoxides into methyl ketones under mild conditions is presented. An excellent regio- and chemoselectivity is obtained for the first time for aryl oxiranes.
- Tian, Yingying,Jürgens, Eva,Kunz, Doris
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p. 11340 - 11343
(2018/10/31)
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- Synthesis of Substrates for Aldolase-Catalysed Reactions: A Comparison of Methods for the Synthesis of Substituted Phenylacetaldehydes
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Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydrolysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.
- Al-Smadi, Derar,Enugala, Thilak Reddy,Norberg, Thomas,Kihlberg, Jan,Widersten, Mikael
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supporting information
p. 1187 - 1190
(2018/03/26)
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- Asymmetric synthesis of O-methylneferine
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Diastereoselective Pictet-Spengler reaction of 2-arylethylamine bearing an N-(R)-1-(1-naphthyl)ethylcarbamoyl group with arylacetaldehyde gave 1-benzyltetrahydroisoquinoline in good yield with moderate diastereoselectivity. The reaction was applied to asymmetric synthesis of O-methyl derivative of neferine, an alkaloid of the lotus embryo, Nelumbo nucifera Gaertner.
- Nishimura, Katsumi,Horii, Shinji,Tanahashi, Takao
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p. 865 - 876
(2019/04/26)
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- Iron(III) nitrate-induced aerobic and catalytic oxidative cleavage of olefins
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Microwave-assisted catalytic oxidative cleavage of olefins using Fe(NO3)3·9H2O under O2 is reported. This reaction system is particularly effective when 9-benzylidene-9H-fluorene derivatives are used as substrates even though they are tri- and tetra-substituted olefins.
- Amaya, Toru,Fujimoto, Hayato
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supporting information
p. 2657 - 2660
(2018/06/04)
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- Cobalt-Mediated [2+2+2] Cycloadditions of Alkynes to Benzo-[ b ]furans and Benzo[ b ]thiophenes: A Potential Route toward Morphanoids
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Exploratory studies of the CpCo-mediated [2+2+2] cycloaddition of alkynes to the 2,3-double bond of benzo[ b ]furans (and some benzo[ b ]thiophenes) are presented, with the general aim to access morphinan substructures. The basic feasibility of constructing Co-complexed tetrahydrophenanthro[4,5- bcd ]furans (and -thiophenes) in moderate to good yields is demonstrated, with complete to extensive diastereoselectivity. Limitations are the apparent necessity for bulky (silylated) monoalkynes, the lack of regioselectivity in the cocyclization with unsymmetrical alkynes, and the sensitivity of the ligands, both complexed and uncomplexed, with respect to ring opening and rearrangement.
- Aechtner, Tobias,Barry, David A.,David, Ellen,Ghellamallah, Cédric,Harvey, Daniel F.,De La Houpliere, Alix,Knopp, Monika,Malaska, Michael J.,Pérez, Dolores,Sch?rer, Kaspar A.,Siesel, Brian A.,Vollhardt, K. Peter C.,Zitterbart, Robert
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p. 1053 - 1089
(2017/12/28)
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- Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism
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The direct cyanomethylation of indoles at the 2- or 3-position was achieved via photoredox catalysis. The versatile nitrile synthon is introduced as a radical generated from bromoacetonitrile, a photocatalyst, and blue LED as a light source. The mechanism of the reaction is explored by determination of the Stern-Volmer quenching constants. By combining photophysical data and mass spectrometry to follow the catalyst decomposition, the catalyst ligands were tuned to enable synthetically useful yields of radical coupling products. A range of indole substrates with alkyl, aryl, halogen, ester, and ether functional groups participate in the reaction, affording products in 16-90% yields. The reaction allows the rapid construction of synthetically useful cyanomethylindoles, products that otherwise require several synthetic steps.
- O'Brien, Connor J.,Droege, Daniel G.,Jiu, Alexander Y.,Gandhi, Shivaani S.,Paras, Nick A.,Olson, Steven H.,Conrad, Jay
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p. 8926 - 8935
(2018/07/05)
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- Novel Hypoxia-Inducible Factor 1α (HIF-1α) Inhibitors for Angiogenesis-Related Ocular Diseases: Discovery of a Novel Scaffold via Ring-Truncation Strategy
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Ocular diseases featuring pathologic neovascularization are the leading cause of blindness, and anti-VEGF agents have been conventionally used to treat these diseases. Recently, regulating factors upstream of VEGF, such as HIF-1α, have emerged as a desirable therapeutic approach because the use of anti-VEGF agents is currently being reconsidered due to the VEGF action as a trophic factor. Here, we report a novel scaffold discovered through the complete structure-activity relationship of ring-truncated deguelin analogs in HIF-1α inhibition. Interestingly, analog 6i possessing a 2-fluorobenzene moiety instead of a dimethoxybenzene moiety exhibited excellent HIF-1α inhibitory activity, with an IC50 value of 100 nM. In particular, the further ring-truncated analog 34f, which showed enhanced HIF-1α inhibitory activity compared to analog 2 previously reported by us, inhibited in vitro angiogenesis and effectively suppressed hypoxia-mediated retinal neovascularization. Importantly, the heteroatom-substituted benzene ring as a key structural feature of analog 34f was identified as a novel scaffold for HIF-1α inhibitors that can be used in lieu of a chromene ring.
- An, Hongchan,Lee, Seungbeom,Lee, Jung Min,Jo, Dong Hyun,Kim, Joohwan,Jeong, Yoo-Seong,Heo, Mi Jeong,Cho, Chang Sik,Choi, Hoon,Seo, Ji Hae,Hwang, Seyeon,Lim, Jihye,Kim, Taewoo,Jun, Hyoung Oh,Sim, Jaehoon,Lim, Changjin,Hur, Joonseong,Ahn, Jungmin,Kim, Hyun Su,Seo, Seung-Yong,Na, Younghwa,Kim, Seok-Ho,Lee, Jeewoo,Lee, Jeeyeon,Chung, Suk-Jae,Kim, Young-Myeong,Kim, Kyu-Won,Kim, Sang Geon,Kim, Jeong Hun,Suh, Young-Ger
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p. 9266 - 9286
(2018/10/24)
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- New Stereoselective Biocatalysts for Carboligation and Retro-Aldol Cleavage Reactions Derived from d-Fructose 6-Phosphate Aldolase
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d-Fructose 6-phosphate aldolase (FSA) catalyzes the asymmetric cross-aldol addition of phenylacetaldehyde and hydroxyacetone. We conducted structure-guided saturation mutagenesis of noncatalytic active-site residues to produce new FSA variants, with the goal of widening the substrate scope of the wild-type enzyme toward a range of para- A nd meta-substituted arylated aldehydes. After a single generation of mutagenesis and selection, enzymes with diverse substrate selectivity scopes were identified. The kinetic parameters and stereoselectivities for a subset of enzyme/substrate combinations were determined for the reactions in both the aldol addition and cleavage reaction directions. The achieved collection of new aldolase enzymes provides new tools for controlled asymmetric synthesis of substituted aldols.
- Ma, Huan,Engel, Sarah,Enugala, Thilak Reddy,Al-Smadi, Derar,Gautier, Candice,Widersten, Mikael
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p. 5877 - 5885
(2018/10/05)
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- Biocatalytic Formal Anti-Markovnikov Hydroamination and Hydration of Aryl Alkenes
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Biocatalytic anti-Markovnikov alkene hydroamination and hydration were achieved based on two concepts involving enzyme cascades: epoxidation-isomerization-amination for hydroamination and epoxidation-isomerization-reduction for hydration. An Escherichia coli strain coexpressing styrene monooxygenase (SMO), styrene oxide isomerase (SOI), ω-transaminase (CvTA), and alanine dehydrogenase (AlaDH) catalyzed the hydroamination of 12 aryl alkenes to give the corresponding valuable terminal amines in high conversion (many ≥86%) and exclusive anti-Markovnikov selectivity (>99:1). Another E. coli strain coexpressing SMO, SOI, and phenylacetaldehyde reductase (PAR) catalyzed the hydration of 12 aryl alkenes to the corresponding useful terminal alcohols in high conversion (many ≥80%) and very high anti-Markovnikov selectivity (>99:1). Importantly, SOI was discovered for stereoselective isomerization of a chiral epoxide to a chiral aldehyde, providing some insights on enzymatic epoxide rearrangement. Harnessing this stereoselective rearrangement, highly enantioselective anti-Markovnikov hydroamination and hydration were demonstrated to convert α-methylstyrene to the corresponding (S)-amine and (S)-alcohol in 84-81% conversion with 97-92% ee, respectively. The biocatalytic anti-Markovnikov hydroamination and hydration of alkenes, utilizing cheap and nontoxic chemicals (O2, NH3, and glucose) and cells, provide an environmentally friendly, highly selective, and high-yielding synthesis of terminal amines and alcohols.
- Wu, Shuke,Liu, Ji,Li, Zhi
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p. 5225 - 5233
(2017/08/17)
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- Hypervalent Iodine(III)-Mediated Cascade Cyclization of Propargylguanidines and Total Syntheses of Kealiinine B and C
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An oxidative cascade cyclization of propargylguanidines promoted by phenyliodonium diacetate (PIDA) was developed. The protocol provides an efficient route for the synthesis of the alkaloids kealiinines B and C as well as homologues. The difference in the electronic nature of the acetylene substituent resulted in two ways of the cyclization. A plausible mechanism is proposed based on the experimental results.
- Tian, Guilong,Fedoseev, Pavel,Van der Eycken, Erik V.
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supporting information
p. 5224 - 5227
(2017/04/24)
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- One-Pot Preparation of C1-Homologated Aliphatic Nitriles from Aldehydes through a Wittig Reaction under Metal-Cyanide-Free Conditions
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A one-pot protocol to obtain C1-homologated aliphatic nitriles was achieved by treating aromatic and aliphatic aldehydes with the (methoxymethyl)triphenylphosphonium ylide followed by hydrolysis of the resulting methyl vinyl ethers with pTsOH (Ts = para-toluenesulfonyl) and treatment with molecular iodine and aqueous ammonia under metal cyanide free conditions. Neopentyl-type nitriles, which could not be obtained by conventional methods that involved conversion of the neopentyl alcohol into a tosylate and treatment with metal cyanide, were successfully obtained by using the present method.
- Ezawa, Masatoshi,Togo, Hideo
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p. 2379 - 2384
(2017/05/01)
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- Design and synthesis of neolamellarin a derivatives targeting heat shock protein 90
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In this study, we designed and synthesized a novel family of neolamellarin A derivatives that showed high inhibitory activity toward heat shock protein 90 (Hsp90), a kinase associated with cell proliferation. The 3,4-bis(catechol)pyrrole scaffold and the benzyl group with methoxy modification at N position of pyrrole are essential to the Hsp90 inhibitory activity and cytotoxicity of these compounds. Western blot analysis demonstrated that these compounds induced dramatic depletion of the examined client proteins of Hsp90, and accelerated cancer cell apoptosis. Docking simulations suggested that the binding mode of 9p was similar to that of the VER49009, a potent inhibitor of Hsp90. Further molecular dynamics simulation indicated that the hydrophobic interactions as well as the hydrogen bonds contributed to the high affinity of 9p to Hsp90.
- Jiang, Long,Yin, Ruijuan,Wang, Xueting,Dai, Jiajia,Li, Jing,Jiang, Tao,Yu, Rilei
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supporting information
p. 24 - 33
(2017/04/21)
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- Selective Aerobic Oxidation of Primary Alcohols to Aldehydes
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The 2-azaadamantane- N -oxyl (AZADO)- and 9-azanoradamantane- N -oxyl (nor-AZADO)-catalyzed selective oxidation of primary alcohols to the corresponding aldehydes is described. The use of tert -butyl nitrite as the co-catalyst enables efficient aerobic oxidation in MeCN instead of previously reported AcOH; this is important for the selectivity of the reaction. The addition of a solution of saturated aqueous NaHCO 3 after the completion of the reaction was effective to suppress the overoxidation of the product to the corresponding carboxylic acid during the workup.
- Shibuya, Masatoshi,Furukawa, Keisuke,Yamamoto, Yoshihiko
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p. 1554 - 1557
(2017/08/11)
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- Astemizole analogues with reduced hERG inhibition as potent antimalarial compounds
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Astemizole is a H1-antagonist endowed with antimalarial activity, but has hERG liabilities. Systematic structural modifications of astemizole led to the discovery of analogues that display very potent activity as inhibitors of the growth of the Plasmodium parasite, but show a decreased hERG inhibition, when compared to astemizole. These compounds can be used as starting point for the development of a new class of antimalarials.
- Tian, Junjun,Vandermosten, Leen,Peigneur, Steve,Moreels, Lien,Rozenski, Jef,Tytgat, Jan,Herdewijn, Piet,Van den Steen, Philippe E.,De Jonghe, Steven
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p. 6332 - 6344
(2017/10/23)
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- SmI2(H2O)n Reduction of Electron Rich Enamines by Proton-Coupled Electron Transfer
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Samarium diiodide in the presence of water and THF (SmI2(H2O)n) has in recent years become a versatile and useful reagent, mainly for reducing carbonyl-type substrates. This work reports the reduction of several enamines by SmI2(H2O)n. Mechanistic experiments implicate a concerted proton-coupled electron transfer (PCET) pathway, based on various pieces of evidence against initial outer-sphere electron transfer, proton transfer, or substrate coordination. A thermochemical analysis indicates that the C-H bond formed in the rate-determining step has a bond dissociation free energy (BDFE) of ~32 kcal mol-1. The O-H BDFE of the samarium aquo ion is estimated to be 26 kcal mol-1, which is among the weakest known X-H bonds of stable reagents. Thus, SmI2(H2O)n should be able to form very weak C-H bonds. The reduction of these highly electron rich substrates by SmI2(H2O)n shows that this reagent is a very strong hydrogen atom donor as well as an outer-sphere reductant.
- Kolmar, Scott S.,Mayer, James M.
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supporting information
p. 10687 - 10692
(2017/08/15)
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- Efficient Preparation of Alkaloids Polycarpine and Polycarpaurines A and C
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An efficient method for the preparation of alkaloids polycarpine and polycarpaurines A and C via microwave-assisted three-step one-pot reaction as the key step has been developed. This is the first report about the synthesis of polycarpaurines A and C. Starting from commercially available p-methoxybenzaldehyde, polycarpine and polycarpaurine A were obtained over seven steps with 40 and 24 % overall yield, respectively. Polycarpine could convert to polycarpaurine C in 72% yield in the presence of NaHSO3. The structure of polycarpine and polycarpaurines A and C was confirmed by1H NMR,13C NMR, and HRMS.
- Guo, Pengbin,Yan, Shuang,Hu, Zeliang,Zhuang, Weihui,Xiong, Yan,Zhang, Lanya,Wang, Ziwen,Wang, Qingmin
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p. 121 - 124
(2017/02/05)
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- Synthesis of a novel six membered CNS palladacycle; TD-DFT study and catalytic activity towards microwave-assisted selective oxidation of terminal olefin to aldehyde
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This article documented synthesis of a Schiff base, E-2-(benzylthio)-N-{(2-methoxynaphthalene-1-yl)methylene}benzenamine (HL) by the treatment of 2-meyhoxynaphthaldehyde and 2-(benzylthio)aniline. Reaction of this synthesized Schiff base with Na2PdCl4has been investigated, which gave a novel six membered Pd(II) complex (PdLCl) through C,N,S-donor atom of Schiff base. These two newly synthesized compounds were characterized by1H NMR, FTIR and UV–Vis spectra and structure of the Pd(II) complex was confirmed by X-ray crystallography. The catalyst (PdLCl) displayed considerable reactivity (up to 99% selectivity and 90% yield) in the selective oxidation of terminal [Formula presented] bond in aryl substituted olefin to aldehyde. The method shows good functional groups compatibility, no ketone byproducts and is operationally simple. Time dependent density functional study (TD-DFT) of representative cyclopalladated complex has been undertaken. The simulated optical spectrum of the complex is in good agreement with the experimentally observed spectrum.
- Sarma, Kuladip,Devi, Namita,Sutradhar, Dipankar,Sarma, Bipul,Chandra, Asit K.,Barman, Pranjit
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- Catalyst structure and substituent effects on epoxidation of styrenics with immobilized Mn(tmtacn) complexes
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Monomeric and dimeric complexes of Mn 1,4,7-trimethyl-1,4,7-triazacyclononane (tmtacn) were immobilized under reaction conditions onto solid supports to create heterogeneous catalysts for epoxidation with H2O2. These solid supports consist of activated carbon or silica grafted or co-condensed with benzoic or C3/C4 acids that function both as tethering points and as required co-catalysts. Immobilized catalysts were as much as 50-fold faster than the analogous soluble system, and an immobilized, dimeric Mn(tmtacn) complex with a solid benzoic acid co-catalyst gave the highest yields to epoxide. A Hammett study on the catalytic epoxidation of a series of styrenes showed weak increases in yield for more electron-withdrawing p-substituents reactants for both immobilized complexes, which runs counter to previous observations with analogous homogeneous catalysts, and which appears to reflect a previously unappreciated tradeoff between the intrinsic epoxidation reactivity and strong catalyst inhibition by styrene oxides and glycols. Finally, these catalysts were tested with a variety of solid-co-catalysts, and were successfully utilized in the challenging epoxidation of divinylbenzene to industrially-useful divinylbenzene dioxide using a cascade of two catalyst charges.
- Ignacio-De Leon, Patricia Anne A.,Contreras, Christian A.,Thornburg, Nicholas E.,Thompson, Anthony B.,Notestein, Justin M.
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- Microwave-assisted fast conversion of lignin model compounds and organosolv lignin over methyltrioxorhenium in ionic liquids
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Conversion of a series of lignin β-O-4 model compounds 2-aryloxy-1-arylethanols and organosolv lignin to aromatic chemicals over methyltrioxorhenium (MTO) in ionic liquids without any oxidant and reducing agent under mild conditions was developed. Microwave irradiation accelerates the cleavage of aryl ether bonds and shortens the reaction time to 2 min.
- Zhang, Bo,Li, Changzhi,Dai, Tao,Huber, George W.,Wang, Aiqin,Zhang, Tao
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p. 84967 - 84973
(2015/10/28)
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- Aromatic Monomers by in Situ Conversion of Reactive Intermediates in the Acid-Catalyzed Depolymerization of Lignin
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Conversion of lignin into well-defined aromatic chemicals is a highly attractive goal but is often hampered by recondensation of the formed fragments, especially in acidolysis. Here, we describe new strategies that markedly suppress such undesired pathways to result in diverse aromatic compounds previously not systematically targeted from lignin. Model studies established that a catalytic amount of triflic acid is very effective in cleaving the β-O-4 linkage, most abundant in lignin. An aldehyde product was identified as the main cause of side reactions under cleavage conditions. Capturing this unstable compound by reaction with diols and by in situ catalytic hydrogenation or decarbonylation lead to three distinct groups of aromatic compounds in high yields acetals, ethanol and ethyl aromatics, and methyl aromatics. Notably, the same product groups were obtained when these approaches were successfully extended to lignin. In addition, the formation of higher molecular weight side products was markedly suppressed, indicating that the aldehyde intermediates play a significant role in these processes. The described strategy has the potential to be generally applicable for the production of interesting aromatic compounds from lignin.
- Deuss, Peter J.,Scott, Martin,Tran, Fanny,Westwood, Nicholas J.,De Vries, Johannes G.,Barta, Katalin
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supporting information
p. 7456 - 7467
(2015/06/30)
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- Pd-catalyzed C-N coupling of vinylbromides and sulfonimidamides: A facile synthesis of N′-vinylsulfonimidamides
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N′-Vinyl sulfonimidamides have been synthesized through a Pd-catalyzed C-N cross coupling between the N′-(imine nitrogen) of N′-deprotected sulfonimidamides and vinyl bromides. The hitherto unreported products were obtained in moderate to excellent yield, and the C-C double bond geometry of the vinylic substrates were retained during the course of reaction. Single crystal X-ray crystallographic analysis confirmed the product structure. Furthermore, we demonstrate that the formed N′-vinyl sulfonimidamides could undergo hydrogenation with Pd-C/H2 to provide N′-alkyl sulfonimidamides.
- Nandi, Ganesh C.,Kota, Sudhakar R.,Wakchaure, Prasad B.,Chinthakindi, Praveen K.,Govender, Thavendran,Kruger, Hendrick G.,Naicker, Tricia,Arvidsson, Per I.
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p. 62084 - 62090
(2015/08/03)
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- One-carbon homologation of pyrrole carboxaldehyde via wittig reaction and mild hydrolysis of vinyl ether - Toward the synthesis of a sterically locked phytochrome chromophore
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Mild hydrolysis of vinyl ether derived from a pyrrole carboxaldehyde corresponding to the B,C-ring component of phytochromobilin chromophore was achieved by treatment with oxalyl chloride in chloroform in the presence of water and ethanol to afford a one-carbon homologated aldehyde. This aldehyde was applied to the synthesis of the sterically locked 15E-anti CD-ring component of the chromophore. Furthermore, the aldehyde could be converted to the intermediate for the sterically locked 5Z-anti AB-ring component.
- Sakata, Ryo,Soeta, Takahiro,Ukaji, Yutaka
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p. 593 - 603
(2015/06/25)
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- Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach
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Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
- Zaytsev, Andrey,Dodd, Barry,Magnani, Matteo,Ghiron, Chiara,Golding, Bernard T.,Griffin, Roger J.,Liu, Junfeng,Lu, Xiaohong,Micco, Iolanda,Newell, David R.,Padova, Alessandro,Robertson, Graeme,Lunec, John,Hardcastle, Ian R.
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p. 180 - 189
(2015/02/19)
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- Homogeneous catalytic oxidation of styrene and styrene derivatives with hydrogen peroxide in the presence of transition metal-substituted polyoxotungstates
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The tetrabutylammonium (TBA) salts of the Keggin-type polyoxotungstates with general formula [XW11M(H2O)O39](n-m)-, where X = P, B or Si and M = Mn, Fe or Co, were evaluated as catalysts in the oxidation of styrene, α-methylstyrene, p-methylstyrene, α,p-dimethylstyrene, p-chlorostyrene, p-nitrostyrene, and p-methoxystyrene under mild conditions, using aqueous H2O2 as an eco-sustainable oxidant. In this study, the influence of the catalysts and of the different styrene substituents on the oxidation reaction profile was evaluated in terms of conversion and selectivity. For all the performed catalytic studies, the main product results from the oxidative cleavage of the vinyl double bond, except in the case of the oxidation of p-methoxystyrene catalysed by BW11Mn, for which p-methoxyphenol is the main product. The catalysts BW11Mn and SiW11Co give rise to 100% conversion for almost all of the substrates, excluding p-methoxystyrene and p-nitrostyrene for both catalysts and α,p-dimethylstyrene only in the case of BW11Mn. The selectivity for C=C cleavage products resulting from the oxidative cleavage of the vinyl double bond can be as high as 98%, reaching 98% conversion for p-nitrostyrene when SiW11Co was used as a catalyst. Possible pathways are discussed and the oxidation of a few presumed intermediates was carried out. The systematic study of several substituted styrene derivatives suggests a possible reactivity order for these compounds in the catalytic system considered.
- Duarte, Tiago A. G.,Estrada, Ana C.,Simes, Mrio M. Q.,Santos, Isabel C. M. S.,Cavaleiro, Ana M. V.,Neves, M. Graca P. M. S.,Cavaleiro, Jos A. S.
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p. 351 - 363
(2015/02/18)
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- Ring Expansion of Epoxides under Br?nsted Base Catalysis: Formal [3+2] Cycloaddition of β,γ-Epoxy Esters with Imines Providing 2,4,5-Trisubstituted 1,3-Oxazolidines
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A novel ring-expansion reaction of epoxides under Br?nsted base catalysis was developed. The formal [3+2] cycloaddition reaction of β,γ-epoxy esters with imines proceeds in the presence of triazabicyclodecene (TBD) as a superior Br?nsted base catalyst to afford 2,4,5-trisubstituted 1,3-oxazolidines in a highly diastereoselective manner. This reaction involves the ring opening of the epoxides with the aid of the Br?nsted base catalyst to generate α,β-unsaturated esters having an alkoxide at the allylic position, which would formally serve as a synthetic equivalent of the 1,3-dipole, followed by a cycloaddition reaction with imines in a stepwise fashion. This methodology enables the facile synthesis of enantioenriched 1,3-oxazolidines from easily accessible enantioenriched epoxides.
- Kondoh, Azusa,Odaira, Kenta,Terada, Masahiro
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p. 11240 - 11244
(2016/07/06)
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- Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes
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The combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective α-cyanoalkylation of aldehydes. This synergistic catalysis protocol allows for the coupling of two highly versatile yet orthogonal functionalities, allowing rapid diversification of the oxonitrile products to a wide array of medicinally relevant derivatives and heterocycles. This methodology has also been applied to the total synthesis of the lignan natural product (-)-bursehernin. A combination of photoredox catalysis and enamine catalysis has enabled the development of an enantioselective cyanoalkylation of aldehydes. This synergistic catalysis protocol makes possible the coupling of two highly versatile yet orthogonal functionalities.
- Welin, Eric R.,Warkentin, Alexander A.,Conrad, Jay C.,MacMillan, David W. C.
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supporting information
p. 9668 - 9672
(2015/08/11)
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