- Synthesis of β-Keto Esters Promoted by Yttria-Zirconia Based Lewis Acid Catalyst
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A variety of aldehydes react with methyl/ethyl diazoacetate in the presence of yttria-zirconia based catalyst to afford the corresponding β-keto esters in excellent yields.
- Pandey, Rajesh K.,Deshmukh, Anis N.,Kumar, Pradeep
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- Asymmetric reduction of 2-chloro-3-oxo-ester into enantiomerically high pure diltiazem precursor by a Candida ketoreductase
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Methyl (2R,3S)-3-(4-methoxyphenyl)glycidate [(2R,3S)-MPGM] is an advanced chiral synthon for the synthesis of the cardiovascular drug diltiazem. It can be easily accessed by cyclizing the reduction products of methyl 2-chloro-3-(4-methoxyphenyl)-3-oxo-propanoate (1a). Herein, we report an identified carbonyl reductase (CpKR) from Candida parapsilosis that displayed an excellent stereoselectivity toward the keto substituent at the C3-position of the 2-chloro-3-oxo-ester 1a. The engineered Escherichia coli cells harboring CpKR gene were directly applied for the asymmetric reduction of keto ester 1a with a space-time yield of 46 g L?1 d?1, which represents the highest productivity in bio-reduction of 1a reported so far. The isolated chiral alcohol products were then applied to the chemical synthesis of (2R,3S)-MPGM in 99% ee and a total yield of 76% in the two-step chemo-enzymatic reactions, which far exceeded the maximum theoretical yield (50%) of the existing industrial process based on a lipase-catalyzed resolution of racemic MPGM. This work provides a promising eco-friendly and cost-effective route toward industrial synthesis of pharmaceutically relevant diltiazem.
- Chen, Cheng,Chen, Qi,Ni, Guo-Wei,Pan, Jiang,Xu, Jian-He,Xuan, Yang
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- Enantioselective decarboxylative Mannich reaction of β-keto acids withC-alkynylN-BocN,O-acetals: access to chiral β-keto propargylamines
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The chiral keto-substituted propargylamines are an essential class of multifunctional compounds in the field of organic and pharmaceutical synthesis and have attracted considerable attention, but the related synthetic approaches remain limited. Therefore, a concise and efficient method for the enantioselective synthesis of β-keto propargylaminesviachiral phosphoric acid-catalyzed asymmetric Mannich reaction between β-keto acids andC-alkynylN-BocN,O-acetals as easily availableC-alkynyl imine precursors has been demonstrated here, affording a broad scope of β-ketoN-Boc-propargylamines in high yields (up to 97%) with generally high enantioselectivities (up to 97?:?3 er).
- Chen, Li-Jun,Li, Wei,Shen, Bao-Chun,Sun, Zhong-Wen,Xie, Hui-Ding,Zhang, Cong-Cong
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supporting information
p. 8607 - 8612
(2021/10/20)
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- Access to pyridines via cascade nucleophilic addition reaction of 1,2,3-triazines with activated ketones or acetonitriles
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We studied the cascade nucleophilic addition reactions of 1,2,3-triazines with activated acetonitriles or ketones, which were used to construct highly substituted pyridines that are not easily accessed by conventional methods. The strategy addressed some structural diversity issues currently facing medicinal chemistry, and the resulting pyridines could be used as convenient precursors for the synthesis of related pharmaceuticals. In particular, our method was applied to the syntheses of the marketed drug etoricoxib and several biologically important molecules in a few steps.
- Zhang, Yuan,Luo, Han,Lu, Qixing,An, Qiaoyu,Li, You,Li, Shanshan,Tang, Zongyuan,Li, Baosheng
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supporting information
p. 393 - 396
(2020/05/18)
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- Palladium Catalyzed Ring Expansion Reaction of Isoxazolones with Isocyanides: Synthesis of 1,3-Oxazin-6-One Derivatives
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A palladium catalyzed ring expansion reaction of isoxazolones with isocyanides was disclosed. In the reaction, a cascade process involving ring-opening/cyclization was suggested. The reaction features high atomic economy due to no elimination of CO2 occurred. Moreover, products obtained demonstrate aggregation-induced emission properties with relatively high solid-state emission efficiencies. (Figure presented.).
- Zhu, Yi-Ming,Zhang, Wan,Li, Hongkun,Xu, Xiao-Ping,Ji, Shun-Jun
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p. 808 - 818
(2020/12/03)
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- Cu-Catalyzed Synthesis of Benzoxazole with Phenol and Cyclic Oxime
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A Cu-catalyzed straightforward synthesis of benzoxazoles from free phenols and cyclic oxime esters is reported. The mild reaction conditions tolerate various electron-withdrawing and electron-donating functional groups on both substrates, affording benzoxazoles in moderate to good yields. With this protocol, large-scale syntheses of Ezutromid and Flunoxaprofe in one or two steps are demonstrated. A catalytic mechanism, which includes Cu-catalyzed amination via inner-sphere electron transfer and consequent annulation, is proposed.
- Wang, Dong-Hui,Wang, Zheng-Hai
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supporting information
(2022/01/20)
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- Cu-Mediated Expeditious Annulation of Alkyl 3-Aminoacrylates with Aryldiazonium Salts: Access to Alkyl N2-Aryl 1,2,3-Triazole-carboxylates for Druglike Molecular Synthesis
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Alkyl N-aryl 1,2,3-triazole-carboxylates are important molecules or intermediates in medicinal chemistry, but the synthesis of N2-aryl counterparts remains elusive. Herein, we describe a Cu-mediated annulation reaction of alkyl 3-aminoacrylates with aryldiazonium salts, both of which are readily available substrates. Furthermore, alkyl 2-aminoacrylates are also viable substrates. Diverse alkyl N2-aryl 1,2,3-triazole-carboxylates and their analogues can be rapidly prepared under mild conditions. Especially, this protocol allows one to access several druglike variants of carbonic anhydrase inhibitors and celecoxib.
- Liu, Hao-Nan,Cao, Hao-Qiang,Cheung, Chi Wai,Ma, Jun-An
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supporting information
p. 1396 - 1401
(2020/02/22)
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- An efficient route for the synthesis of N-(1H-benzo[d]imidazol-2-yl)benzamide derivatives promoted by CBr4 in one pot
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A metal-free one-pot method for the synthesis of N-(1H-benzo[d]imidazol-2-yl)benzamide derivatives was proposed mediated by CBr4. The reaction went through ring formation and opening processes with only two protons leaving and the thermodynamically favorable products were selectively formed in moderate to good yields.
- Li, Songhua,Li, Yunyi,Ma, Chen,Xie, Caixia
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- Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric Reduction of β-Ketoamides: Application toward (S)-Duloxetine
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High-valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-l-tert-leucine were used as catalysts in asymmetric reduction of N-benzyl-β-ketoamides. Among six different solvents, three different alcohol additives, and two different boranes examined, the use of pinacolborane in tetrahydrofuran (THF) with a t-BuOH additive led to the best results at -20 °C. The corresponding β-hydroxyamides can be furnished with yields up to 92percent and an enantiomeric excess (ee) up to 99percent. We have successfully extended this catalytic protocol for the synthesis of an (S)-duloxetine precursor.
- Chen, Chien-Tien,Maity, Nabin Ch.,Agarwal, Rachit,Lai, Chien-Fu,Liao, Yiya,Yu, Wei-Ru
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supporting information
p. 6408 - 6419
(2020/07/14)
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- Pd-Catalyzed Synthesis of γ-Keto Esters as Key Intermediates for the Synthesis of γ-Hydroxybutenolides
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We herein report a robust and safe palladium catalyzed domino-carbonylation/Suzuki–Miyaura cross-coupling reaction of vinyltosylates with arylboronic acids using Mo(CO)6 as CO-source. The derived γ-keto ester were subsequently cyclized under acidic conditions to obtain γ-hydroxybutenolides, an important structural motif, which occurs in biologically active natural products.
- Schacht, Mathias,Mohammadi, Djawid,Schützenmeister, Nina
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supporting information
p. 2587 - 2591
(2019/02/19)
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- Iron-catalysed 1,2-acyl migration of tertiary α-azido ketones and 2-azido-1,3-dicarbonyl compounds
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Iron-catalysed 1,2-acyl migration of tertiary α-azido ketones and 2-azido-1,3-dicarbonyl compounds provides a simple and atom-economical approach toward enamides and isoquinolones. This paper reports two catalyst systems for these transformations which employ iron(ii) complexes [Fe(dpbz)]Br2 (dpbz = 1,2-bis(diphenylphosphino)benzene) and FeBr2/Et3N, respectively. [Fe(dpbz)]Br2 was found to be highly effective at converting 2-azido-2,3-dihydro-1H-inden-1-ones to isoquinolones. The reagent combination of FeBr2/Et3N, on the other hand, exhibited a broader catalytic scope, owing to the beneficial effect of Et3N. This latter catalyst system enables 2-azido-2-methyl-1,3-dicarbonyl compounds to be converted to the corresponding enamides under mild conditions in good yields.
- Yang, Tonghao,Lin, Yajun,Yang, Chaoqun,Yu, Wei
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supporting information
p. 6097 - 6102
(2019/11/20)
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- Cooperative Catalysis with Coupled Chiral Induction in 1,3-Dipolar Cycloadditions of Azomethine Ylides
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1,3-Dipolar cycloadditions (1,3-DC) between imino esters (as precursors of N-metallated azomethine ylides) and π-deficient alkenes are promoted by cooperative asymmetric Lewis acid/Br?nsted base catalysis. The components of these catalytic pairs are silver salts derived from enantiopure commercially available BINOL-based phosphoric acids and Cinchona alkaloids. Chiral phosphoric silver(I) salts promote HOMO raising of in situ formed 1,3-dipoles, whereas protonated cinchona alkaloids generate a LUMO lowering for the dipolarophiles resulting in a global acceleration of the 1,3-DC. The best results were obtained with BINOL-derived silver phosphate and hydrocinchonine. Matching between both cooperative metallo- and organocatalyst results in an enhanced enantiomeric excess, superior to that reached by both separate components. NOESY experiments and DFT calculations are compatible with a non-covalent interaction (hydrogen bond) between both catalysts, which results in close contacts and mutually coupled chiral environments.
- Cayuelas, Alberto,Larra?aga, Olatz,Selva, Verónica,Nájera, Carmen,Akiyama, Takahiko,Sansano, José M.,de Cózar, Abel,Miranda, José I.,Cossío, Fernando P.
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supporting information
p. 8092 - 8097
(2018/05/30)
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- Reinventing the de Mayo reaction: Synthesis of 1,5-diketones or 1,5-ketoesters via visible light [2+2] cycloaddition of β-diketones or β-ketoesters with styrenes
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A visible light mediated De Mayo reaction between 1,3-diketones and styrenes following a [2+2] cycloaddition pathway via a photosensitization mechanism gives access to 1,5-diketones. The reaction has been applied to substituted styrenes and aryl- and alkyl-substituted ketones. Moreover, the method converts β-ketoesters, β-amido esters, and β-cyano ketones. Seven membered rings, a frequent structural motif of natural products, are also accessible using this methodology.
- Martinez-Haya, Rebeca,Marzo, Leyre,K?nig, Burkhard
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supporting information
p. 11602 - 11605
(2018/10/31)
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- Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic and Bishomoallylic Secondary Alcohols
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We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones bearing a β-stereocenter (up to 95%, 86% ee) but also a concomitant oxidative kinetic resolution of the alcohol substrates (S > 20). In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γ-stereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway with chain walking of the key alkyl-Rh intermediate.
- Huang, Rui-Zhi,Lau, Kai Kiat,Li, Zhaofeng,Liu, Tang-Lin,Zhao, Yu
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supporting information
p. 14647 - 14654
(2018/11/06)
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- SO2F2-Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes
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Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3-sp3 (C-C) bonds to sp-sp (C=C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne-azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).
- Zha, Gao-Feng,Fang, Wan-Yin,Li, You-Gui,Leng, Jing,Chen, Xing,Qin, Hua-Li
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supporting information
p. 17666 - 17673
(2019/01/04)
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- TBHP/AIBN-Mediated Synthesis of 2-Amino-thioazoles from Active Methylene Ketones and Thiourea under Metal-free Conditions
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A new oxidative system of tert-butyl hydroperoxide (TBHP)/azodiisobutyronitrile (AIBN) has been used for the first time for a convenient, metal-free synthesis of substituted 2-aminothioazoles from active methylene ketone derivatives and thiourea. The reaction is postulated to proceed via an oxidative cyclization initiated by a radical process and followed by a condensation reaction.
- Sun, Jiyun,Ge, Huaibin,Zhen, Xiaohua,An, Xuechan,Zhang, Guangtao,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
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p. 2107 - 2114
(2018/03/26)
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- An Aminocatalyzed Stereoselective Strategy for the Formal α-Propargylation of Ketones
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A two-step reaction sequence is described for the asymmetric formal α-propargylation of ketones. This approach takes advantage of an aminocatalyzed conjugate addition of ketones to alkylidene isoxazol-5-ones, followed by a controlled nitrosative degradation event. The target compounds can be accessed in broad scope, in moderate to good yields, perfect diastereocontrol and good to excellent enantioselectivity.
- Jurberg, Igor D.
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supporting information
p. 9716 - 9720
(2017/07/25)
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- Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes
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The first catalytic asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes is described. The method, based on a rhodium-catalyzed cyclopropanation of difluoromethylated olefins, gives access to a broad range of cyclopropanes bearing ester, ketone, or nitro functional groups. By using Rh2((S)-BTPCP)4 as a catalyst, the corresponding products were obtained in high yields and high diastereo- and enantioselectivities (up 20:1 d.r. and 99 % ee). This methodology allowed preparation of enantioenriched difluoromethylcyclopropanes for the first time.
- Bos, Maxence,Huang, Wei-Sheng,Poisson, Thomas,Pannecoucke, Xavier,Charette, André B.,Jubault, Philippe
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supporting information
p. 13319 - 13323
(2017/10/17)
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- Palladium-Catalyzed Enantioselective Narasaka–Heck Reaction/Direct C?H Alkylation of Arenes: Iminoarylation of Alkenes
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A palladium-catalyzed reaction of γ,δ-unsaturated oxime esters with oxadiazoles afforded dihydropyrroles in good to excellent yields through an intramolecular iminopalladation/intermolecular direct heteroarene C?H alkylation cascade. This unprecedented iminoarylation of alkenes was subsequently realized in an enantioselective manner in the presence of a chiral bidentate phosphine ligand (Synphos).
- Bao, Xu,Wang, Qian,Zhu, Jieping
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supporting information
p. 9577 - 9581
(2017/08/01)
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- α-Alkylidene-γ-butyrolactone Formation via Bi(OTf)3-Catalyzed, Dehydrative, Ring-Opening Cyclizations of Cyclopropyl Carbinols: Understanding Substituent Effects and Predicting E/Z Selectivity
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A Bi(OTf)3-catalyzed ring-opening cyclization of (hetero)aryl cyclopropyl carbinols to form α-alkylidene-γ-butyrolactones (ABLs) is reported. This transformation represents different chemoselectivity from previous reports that demonstrated formation of (hetero)aryl-fused cyclohexa-1,3-dienes upon acid-promoted cyclopropyl carbinol ring opening. ABLs are obtained in up to 89% yield with a general preference for the E-isomers. Mechanistically, Bi(OTf)3 serves as a stable and easy to handle precursor to TfOH. TfOH then catalyzes the formation of cyclopropyl carbinyl cations, which undergo ring opening, intramolecular trapping by the neighboring ester group, subsequent hydrolysis, and loss of methanol resulting in the formation of the ABLs. The nature and relative positioning of the substituents on both the carbinol and the cyclopropane determine both chemo- and stereoselective outcomes. Carbinol substituents determine the extent of cyclopropyl carbinyl cation formation. The cyclopropane donor substituents determine the overall reaction chemoselectivity. Weakly stabilizing or electron-poor donor groups provide better yields of the ABL products. In contrast, copious amounts of competing products are observed with highly stabilizing cyclopropane donor substituents. Finally, a predictive model for E/Z selectivity was developed using DFT calculations.
- Sandridge, Matthew J.,McLarney, Brett D.,Williams, Corey W.,France, Stefan
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p. 10883 - 10897
(2017/10/27)
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- Nickel-catalyzed enantioselective hydrogenation of β-(acylamino)acrylates: Synthesis of chiral β-amino acid derivatives
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The nickel-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates has been developed, affording chiral β-amino acid derivatives with excellent yields (95-99% yield) and enantioselectivities (97-99% ee). With the Ni-Binapine system, high enantioselectivities (98-99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl β-(acylamino)acrylates. The synthesis of chiral β-amino acid derivatives on a gram scale has also been achieved with 0.2 mol % catalyst loading.
- Li, Xiuxiu,You, Cai,Li, Shuailong,Lv, Hui,Zhang, Xumu
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supporting information
p. 5130 - 5133
(2017/11/06)
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- Copper-Catalysed Decarboxylative Trifluoromethylation of β-Ketoacids
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An efficient method for Cu-catalyzed decarboxylative trifluoromethylation of β-ketoacids to achieve α-trifluoromethyl ketones was developed. A wide variety of synthetically useful α-trifluoromethyl ketones were obtained in modest to good yields under mild reaction conditions. The present method also exhibits good functional-group compatibility.
- Xu, Xiaolan,Chen, Huanhuan,He, Jianbo,Xu, Huajian
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supporting information
p. 1665 - 1668
(2017/10/05)
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- Geminal Dichlorination of Phenyliodonium Ylides of β-Dicarbonyl Compounds through Double Ligand Transfer from (Dichloroiodo)benzene
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Pre-formed phenyliodonium ylides of cyclic and acyclic β-diketones, β-keto esters and β-diesters were reacted with (dichloroiodo)benzene, resulting in transfer of both chloride ligands onto the ylidic carbon. These two hypervalent iodine(III) compounds exhibit high reactivity towards each other under mild reaction conditions and typically afford the gem-dichloride products in good yield. Upon comparison of these chlorination reactions with those of the analogous diazocarbonyl compounds, reactions of iodonium ylides were unilaterally faster, and often gave the products in higher yield.
- Tao, Jason,Tuck, Tina N.,Murphy, Graham K.
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supporting information
p. 772 - 782
(2016/03/01)
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- Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors
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The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.
- Kavanagh, Madeline E.,Coyne, Anthony G.,McLean, Kirsty J.,James, Guy G.,Levy, Colin W.,Marino, Leonardo B.,De Carvalho, Luiz Pedro S.,Chan, Daniel S. H.,Hudson, Sean A.,Surade, Sachin,Leys, David,Munro, Andrew W.,Abell, Chris
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p. 3272 - 3302
(2016/05/19)
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- Cooperative Indium(III)/Silver(I) System for Oxidative Coupling/Annulation of 1,3-Dicarbonyls and Styrenes: Construction of Five-Membered Heterocycles
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A cooperative indium(III)/silver(I) system for the synthesis of various five-membered heterocycles, including dihydrofurans, pyrroles, spirolactones, and spiroiminolactones, through the sequential oxidative coupling/annulation reaction of 1,3-dicarbonyl compounds with styrenes has been developed. Four different heterocyclic systems were successfully synthesized depending on the substitution pattern of the substrates using readily available starting materials. This system has the advantages of a broad substrate scope, moderate to good chemical yields, an operationally easy and simple procedure, and short reaction times. (Figure presented.) .
- Ko, Tae Yun,Youn, So Won
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supporting information
p. 1934 - 1941
(2016/07/06)
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- Enantioselective hydrogenation of β-aryl-β-ketoester over α-hydroxy acid-modified Raney nickel catalysts: competitive hydrogenation with methyl acetoacetate
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The enantioselective hydrogenation of the aromatic β-ketoesters, methyl 3-phenyl-3-oxypropanoate (1) and its p-methoxy-analogue (2), was studied over tartaric acid-modified Raney nickel catalysts. A competitive hydrogenation approach was used to clarify the catalytic behaviors of the enantio-differentiating hydrogenation of aromatic β-ketoesters over tartaric acid-modified Raney nickel, malic acid-modified Raney nickel, and unmodified Raney nickel in comparison with aliphatic one, represented by methyl acetoacetate. We found that the enantioselectivity could be elucidated by the interaction modes between the surface modifier, Ni metal surface, and the substrate as well as the keto/enol ratio of the substrate. We suggest that the moderate enantioselectivity of 1 over tartaric acid-modified Raney nickel is the result of distorted, weak two-point hydrogen bond interactions with surface tartrate due to unfavorable phenyl–Ni metal surface interactions. The p-methoxy group of 2 suppresses the phenyl–Ni metal surface interactions, resulting in an increase in the enantioselectivity of 2 over tartaric acid-modified Raney nickel. Ligand acceleration effects were observed with methyl acetoacetate and 2 but not with 1.
- Choliq, Azka Azkiya,Watanabe, Junya,Misaki, Tomonori,Okamoto, Yasuaki,Sugimura, Takashi
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p. 657 - 662
(2016/07/11)
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- Trimethylchlorosilane-Mediated Mild α-Chlorination of 1,3-Dicarbonyl Compounds Promoted by Phenyliodonium Diacetate
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Trimethylchlorosilane was used as chlorine source for the α-chlorination of 1,3-dicarbonyl compounds with phenyliodonium diacetate as oxidant at room temperature. The reaction allows the selective synthesis of α-monochlorinated products from different kinds of 1,3-dicarbonyl compounds in good yield. The potential possibility of this conversion for bromination has also been investigated.
- Chong, Siying,Su, Yingpeng,Wu, Lili,Zhang, Weigang,Ma, Junyan,Chen, Xiaowei,Huang, Danfeng,Wang, Ke-Hu,Hu, Yulai
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supporting information
p. 1359 - 1370
(2016/05/02)
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- BUTENOLIDES, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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The present invention relates to: a butenolide-based compound; a stereoisomer thereof; an enantiomer thereof; an in vivo hydrolyzable precursor thereof or a pharmaceutically acceptable salt thereof; and the antibacterial activity, immune disease treatment; and prevention efficacy, the cancer prevention or treatment efficacy, and the preventive activity with respect to the fouling of a medical insertion instrument thereof.
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- Calcium-catalyzed, dehydrative, ring-opening cyclizations of cyclopropyl carbinols derived from donor-acceptor cyclopropanes
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A calcium-catalyzed, dehydrative, ring-opening cyclization of (hetero)aryl cyclopropyl carbinols is reported. The cyclopropyl carbinols are prepared directly from the corresponding donor-acceptor (D-A) cyclopropanes. The calcium catalyst catalyzes the formation of putative (hetero)aryl cyclopropyl carbinyl cations that undergo ring-opening to allylcarbinyl cations. Subsequent intramolecular Friedel-Crafts reaction affords (hetero)aryl-fused cyclohexa-1,3-dienes in up to 97% yield. This approach represents the first example of catalysis for this intramolecular, dehydrative ring-opening cyclization and outperforms the previous reports using stoichiometric Lewis acids.
- Sandridge, Matthew J.,France, Stefan
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supporting information
p. 4218 - 4221
(2016/09/09)
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- Dimethyl malonate/LHMDS system as a new protocol for generating methyl formate anion (-COOMe) in the condensed-phase Dedicated to Professor Charles H. DePuy (1927-2013)
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The treatment of dimethyl malonate with LHMDS in anhydrous THF (condensed-phase) generates, in addition to the expected corresponding lithium enolate, methyl formate anion (or methoxycarbonyl anion, -COOMe) which can react with several electrophiles to give corresponding methoxycarbonyl derivatives by nucleophilic substitution reaction.
- Di Bussolo, Valeria,Princiotto, Salvatore,Martinelli, Elisa,Bordoni, Vittorio,Crotti, Paolo
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supporting information
p. 1644 - 1647
(2016/04/04)
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- PYRAZOLONE DERIVATIVES AS NITROXYL DONORS
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The disclosed subject matter provides pyrazolone derivative compounds, pharmaceutical compositions comprising such compounds, kits comprising such compounds, and methods of using such compounds or pharmaceutical compositions. In particular, the disclosed subject matter provides methods of using such compounds or pharmaceutical compositions for treating heart failure.
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Page/Page column 179; 195; 335
(2016/01/29)
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- The guareschi pyridine scaffold as a valuable platform for the identification of selective PI3K inhibitors
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A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl- 3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity.
- Galli, Ubaldina,Ciraolo, Elisa,Massarotti, Alberto,Margaria, Jean Piero,Sorba, Giovanni,Hirsch, Emilio,Tron, Gian Cesare
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supporting information
p. 17275 - 17287
(2015/12/01)
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- Base initiated aromatization/CO bond formation: A new entry to O-pyrazole polyfluoroarylated ethers
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A base initiated intermolecular SNAr reaction of pyrazolones with polyfluoroarenes was developed. The process involved the isomerization aromatization of pyrazolone followed by the CO bond formation via the selective CF bond cleavage. With this strategy, a wide range of O-pyrazole polyfluoroarylated ethers bearing diverse functional groups were synthesized in mild to good yields. Additionally, our method was also applied to the isoxazol substrates.
- Tang, Xiangyang,Chang, Jing,Liu, Cuibo,Zhang, Bin
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supporting information
p. 6534 - 6537
(2015/01/08)
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- Direct oxidative coupling of enamines and electron-deficient amines: TBAI/TBHP-mediated synthesis of substituted diaminoalkenes under metal-free conditions
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A metal-free cross-coupling of enamines and electron-de fi cient amines through oxidative C(sp2)-N bond formation has been realized by using TBAI as catalyst and TBHP as oxidant. This novel strategy allows for an efficient organocatalytic synthesis of the synthetically useful diaminoalkene derivatives and is highlighted by appealing features such as readily available of the starting materials, wide substrate scope and transition-metal-free characteristics. (Chemical Equation Presented).
- Yuan, Yucheng,Hou, Wenjuan,Zhang-Negrerie, Daisy,Zhao, Kang,Du, Yunfei
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supporting information
p. 5410 - 5413
(2015/01/09)
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- Rhodium-catalyzed enantioseletive hydrogenation of tetrasubstituted α-acetoxy β-enamido esters: A new approach to chiral α-hydroxyl-β-amino acid derivatives
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Asymmetric hydrogenation of tetrasubtitued α-acetoxy β-enamido esters with rhodium catalysts based on chiral diphosphine ligands provides an efficient and concise route to the synthesis of chiral α-hydroxyl-β-amino acid derivatives in excellent enantioselectivities. The products are valuable chiral building blocks in many biologically active compounds and have important applications in organic synthesis.
- Wang, Qingli,Huang, Wenhua,Yuan, Haoquan,Cai, Qin,Chen, Liming,Lv, Hui,Zhang, Xumu
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supporting information
p. 16120 - 16123
(2015/02/18)
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- Cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from N-allyl enamines
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An efficient iodine-mediated cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from easily prepared N-allyl enamines has been developed. The advantages of the reaction include facilitative preparation of substrates 3a-t, good functional group tolerance and transition-metal-free conditions.
- Zhai, Sheng-Xian,Dong, Hong-Ru,Chen, Zi-Bao,Hu, Yi-Ming,Dong, Heng-Shan
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p. 8405 - 8412
(2015/03/04)
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- Studies on the chemoenzymatic synthesis of (R)- and (S)-methyl 3-aryl-3-hydroxypropionates: The influence of toluene-pretreatment of lipase preparations on enantioselective transesterifications
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Two series (para- and meta-substituted) of racemic methyl esters of 3-aryl-3-hydroxypropionic acid were prepared after which the enantiomers were separated by an enzyme-catalyzed transesterification. Several lipases were investigated as the catalyst. The influence of the enzyme pretreatment, as well as substrate concentration, reaction temperature, stirring manner, and substrate conversion on the stereochemical outcome of the biotransformation process were investigated in detail. The best results were achieved by using solvent-pretreated lipase from Pseudomonas fluorescens or Burkholderia cepacia suspended in toluene, and vinyl acetate as the acetyl group donor.
- Borowiecki, Pawel,Bretner, Maria
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p. 925 - 936
(2013/09/23)
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- Phosphodiesterase inhibitors. Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration
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(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl) -5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti- inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.
- Ochiai, Koji,Takita, Satoshi,Kojima, Akihiko,Eiraku, Tomohiko,Iwase, Kazuhiko,Kishi, Tetsuya,Ohinata, Akira,Yageta, Yuichi,Yasue, Tokutaro,Adams, David R.,Kohno, Yasushi
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supporting information
p. 375 - 381
(2013/02/23)
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- Formation of functionalized 2H-azirines through phio-mediated trifluoroethoxylation and azirination of enamines
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A variety of enaminones and enamine carboxylic esters were converted to trifluoroethoxylated 2H-azirines through reactions with PhIO in trifluoroethanol (TFE). The cascade reaction is postulated to proceed via a PhIO-mediated oxidative trifluoroethoxylation and a subsequent azirination of the α-trifluoroethoxylated enamine intermediates.
- Sun, Xiaoqian,Lyu, Youran,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
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supporting information
p. 6222 - 6225
(2014/01/17)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Page/Page column 72
(2012/11/08)
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- HOTf mediated cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes
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The cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes proceed smoothly in freshly distilled HOTf to give the corresponding tetrahydro-5H-benzo[c]fluorene derivatives in good yields along with high stereoselectivities under mild conditions. The Royal Society of Chemistry.
- Chen, Gen-Qiang,Tang, Xiang-Ying,Shi, Min
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supporting information; scheme or table
p. 2340 - 2342
(2012/04/18)
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- Cross-dehydrogenative coupling between enamino esters and ketones: Synthesis of tetrasubstituted pyrroles
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Tetrasubstituted pyrroles have been synthesized via the cross-dehydrogenative coupling between enamino esters and acetone. Silver carbonate proved to be an effective oxidant, and no transition metal catalyst is necessary.
- Zhao, Miao,Wang, Fen,Li, Xingwei
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supporting information; experimental part
p. 1412 - 1415
(2012/05/04)
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- Gold/copper-catalyzed activation of the aci-form of nitromethane in the synthesis of methylene-bridged bis-1,3-dicarbonyl compounds
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Activation of the aci-form of nitromethane using Lewis acids for the attack of carbon nucleophiles was studied. 1,3-Dicarbonyl compounds in the presence of catalytic amounts of AuCl3 or Cu(OTf)2 in nitromethane solvent could be converted into methylene-bridged bis-1,3-dicarbonyl compounds.
- Balamurugan, Rengarajan,Manojveer, Seetharaman
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supporting information; experimental part
p. 11143 - 11145
(2011/11/05)
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- Triclorosilane-mediated stereoselective synthesis of β-amino esters and their conversion to highly enantiomerically enriched β-lactams
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A highly stereoselective trichlorosilane-mediated reduction of N-benzyl enamines was developed; the combination of a low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed to perform the reaction on substrates with different structural features often with total control of the stereoselectivity. By easy deprotection through hydrogenolysis followed by conversion of β-aminoester to 2-azetidinones, the synthesis of enantiomerically pure β-lactams (>98% e.e.) was successfully accomplished.
- Guizzetti, Stefania,Benaglia, Maurizio,Bonsignore, Martina,Raimondi, Laura
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supporting information; experimental part
p. 739 - 743
(2011/04/22)
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- Ambient carboxylation on a supported reversible CO2 carrier: Ketone to β-keto ester
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A reversible CO2 carrier (RCC) has been developed to perform carboxylation of ketone to β-ketoester under ambient CO2 pressure and temperature. RCC has been synthesized by immobilizing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) on methylhydrosiloxane support and reacting with CO2 with 100% degree of functionalisation. RCC is found to be recyclable and shows retention of activity in 5 recycles. CO2 absorption under ambient temperature and desorption at 120°C renders the material suitable for carrying out carboxylation reactions at 25°C with excellent yields. The yield of the reaction can reach up to 100% with TON 200 in 4 h. The extent of the reaction primarily depends upon enol content of the substrate. β-Ketoacid produced during the reaction can be isolated and converted to its corresponding methyl ester derivative by reacting with methyl iodide.
- Beckman, Eric J.,Munshi, Pradip
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experimental part
p. 376 - 383
(2011/04/17)
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- PYRIDAZINONE DERIVATIVE AND PDE INHIBITOR CONTAINING THE SAME AS ACTIVE INGREDIENT
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It is to provide a novel pyridazinone derivative represented by the following general formula (1), which is useful as a pharmaceutical and has a phosphodiesterase inhibitory action: wherein R1 represents H or C1-6 alkyl, each of R2 and R3 represents H, X, C1-6 alkoxy, Z represents O or S, and A represents AA or BB, wherein AA represents: and BB represents: wherein R4 represents H or C1-6 alkyl, and each of R5 and R6 represents C1-6 alkyl.
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Page/Page column 159
(2010/04/25)
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- PYRAZOLONE DERIVATIVE AND PDE INHIBITOR CONTAINING THE SAME AS ACTIVE INGREDIENT
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It is to provide a novel pyrazolone derivative represented by the following general formula (1), which is useful as a pharmaceutical and has a phosphodiesterase inhibitory action: wherein R1,R2: C1-6 alkyl; R3,R4: H, X, C1-6 alkoxy; Z:O, S; A:AA, BB, wherein AA represents wherein BB represents wherein R5: H, C1-6 alkyl ; R6,R7: C1-6 alkyl.
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Page/Page column 109
(2010/04/25)
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- Synthesis and biological activity of new (E)-α-(Methoxyimino) benzeneacetate derivatives containing a substituted pyrazole ring
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Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin analogues with high activity, a series of new strobilurin derivatives containing a substituted pyrazole in the side chain were synthesized and their biological activities were tested. The compounds were identified by 1H nuclear magnetic resonance, infrared, and elemental analysis. The test results indicated that the compounds exhibited strong fungicidal activities against Pyricularia oryzae, Phytophthora infestans, Pseudoperonospora cubenssi, and Erysiphe graminis. The relationship between structure and biological activity is discussed in terms of the effects of the substituents on the pyrazole ring. The present work demonstrates that strobilurin analogues with a 3-(substituted phenyl)-1 H-pyrazol-5-oxy side chain can be used as possible lead compounds for the development of potential agrochemicals.
- Li, Miao,Liu, Chang-Ling,Yang, J.I.-Chun,Zhang, Jin-B.O.,Li, Zhi-Nian,Zhang, Hong,Li, Zheng-Ming
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experimental part
p. 2664 - 2667
(2011/08/05)
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- Iron-catalyzed selective oxidation of N-methyl amines: highly efficient synthesis of methylene-bridged bis-1,3-dicarbonyl compounds
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Methylene-bridged bis-1,3-dicarbonyl derivatives were synthesized efficiently by Iron-catalyzed oxidative reactions of 1,3-dicarbonyl compounds and N,N-dimethylaniline. Blpyrazoles and substituted 1,4-dlhydropyridlne were obtained by the reactions of bis-1,3-dicarbonyl compounds with hydrazines and ammonium acetate, respectively.
- Li, Haijun,He, Zhiheng,Guo, Xingwel,Li, Wenjuan,Zhao, Xuhul,Ll, Zhlplng
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supporting information; experimental part
p. 4176 - 4179
(2009/12/30)
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- Highly enantioselective synthesis of β-amino acid derivatives by the lewis base catalyzed hydrosilylation of β-enamino esters
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A study was conducted to demonstrate highly enantioselective synthesis of β-amino acid derivatives by the Lewis base catalyzed hydrosilylation of βenamino esters. It was found that these catalyst and its analogue displayed excellent activities and enantioselectivities in promoting hydrosilylation of N-aryl β-enamino esters. N-picolinoylpyrrolidine derivatives and N-picolioylephedrine were also evaluated in hydrosilylation of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate. The generality of the Lewis base organocatalyzed hydrosilylation of various β-enamino esters were examined under the optimized conditions. It was observed that the catalytic system exhibited a high sensitivity to the N-substituents, while all the N-aryl β-enamino esters underwent the hydrosilylation smoothly to give corresponding β-amino esters.
- Zheng, Hong-Jie,Chen, Wen-Bing,Wu, Zhi-Jun,Deng, Jin-Gen,Lin, Wen-Qing,Yuan, Wei-Cheng,Zhang, Xiao-Mei
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supporting information; experimental part
p. 9864 - 9867
(2009/10/02)
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- Scope and mechanism of enantioselective michael additions of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by nickel(II)-diamine complexes
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Readily prepared Ni(II)-bis[(R,R)-N,N′-dibenzylcyclohexane-1,2- diamine]Br2 was shown to catalyze the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes at room temperature in good yields with high enantioselectivities. The two diamine ligands in this system each play a distinct role: one serves as a chiral ligand to provide stereoinduction in the addition step while the other functions as a base for substrate enolization. Ligand modification within the catalyst was also investigated to facilitate the reaction of aliphatic nitroalkenes, 1,3-diketones, and β-ketoacids. Ni(II)-bis[(R,R)-N,N′-di-p-bromo-benzylcyclohexane-1,2-diamine]Br 2 was found to be an effective catalyst in these instances. Furthermore, monodiamine complex, Ni(II)-[(R,R)-N,N′-dibenzylcyclohexane- 1,2-diamine]Br2, catalyzed the addition reaction in the presence of water. The proposed model for stereochemical induction is shown to be consistent with X-ray structure analysis.
- Evans, David A.,Mito, Shizue,Seidel, Daniel
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p. 11583 - 11592
(2008/03/15)
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