- Number and Structure of Solvolysis Intermediates. IV. The Phenolysis of 1-(p-Tolyl)ethyl p-Nitrobenzoate: The Mechanism via a Single Stable Ion-Pair Intermediate with High Selectivity for Nucleophiles
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Optically active 1-(p-tolyl)ethyl p-nitrobenzoate (ROPNB) has been subjected to solvolysis in phenol where the solvolysis was previously found to proceed via a single stable ion-pair intermediate (Int-1) with high selectivity for nucleophiles, i.e., to exhibit the kinetic features expressed by the "B" pattern for the kp-kt profile.On the basis of the absolute configurations and the maximum rotations for the substrate and all of the products which have been chemically established, the stereochemical courses have been disclosed to be partial retention for POPh formation ("retentive phenolysis") and partial inversion for o- and p-RC6H4OH formation with predominant racemization in the solvolysis.These stereochemical outcomes indicate that the key intermediate (Int-1) which provides all of the products should have the structure of a carbocation ion pair shielded at the rear side by a phenol molecule (the rear-side shielded ion-pair intermediate) similarly to the key intermediates which are known for some other phenolysis systems.Consequently, the rear-side shielded ion-pair intermediate plays a key role regarding product formation in all retentive phenolysis systems.
- Kinoshita, Tomomi,Shibayama, Koichi,Takemoto, Masaki,Takeuchi, Ken'ichi
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Read Online
- Functionalization of α-C(sp3)?H Bonds in Amides Using Radical Translocating Arylating Groups
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α-C?H arylation of N-alkylamides using 2-iodoarylsulfonyl radical translocating arylating (RTA) groups is reported. The method allows the construction of α-quaternary carbon centers in amides. Various mono- and disubstituted RTA-groups are applied to the arylation of primary, secondary, and tertiary α-C(sp3)?H-bonds. These radical transformations proceed in good to excellent yields and the cascades comprise a 1,6-hydrogen atom transfer, followed by a 1,4-aryl migration with subsequent SO2 extrusion.
- Radhoff, Niklas,Studer, Armido
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supporting information
p. 3561 - 3565
(2021/01/04)
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- Catalytic α-Deracemization of Ketones Enabled by Photoredox Deprotonation and Enantioselective Protonation
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This study reports the catalytic deracemization of ketones bearing stereocenters in the α-position in a single reaction via deprotonation, followed by enantioselective protonation. The principle of microscopic reversibility, which has previously rendered this strategy elusive, is overcome by a photoredox deprotonation through single electron transfer and subsequent hydrogen atom transfer (HAT). Specifically, the irradiation of racemic pyridylketones in the presence of a single photocatalyst and a tertiary amine provides nonracemic carbonyl compounds with up to 97% enantiomeric excess. The photocatalyst harvests the visible light, induces the redox process, and is responsible for the asymmetric induction, while the amine serves as a single electron donor, HAT reagent, and proton source. This conceptually simple light-driven strategy of coupling a photoredox deprotonation with a stereocontrolled protonation, in conjunction with an enrichment process, serves as a blueprint for other deracemizations of ubiquitous carbonyl compounds.
- Chen, Shuming,Gao, Anthony Z.,Ivlev, Sergei I.,Meggers, Eric,Nie, Xin,Ye, Chen-Xi,Zhang, Chenhao
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supporting information
p. 13393 - 13400
(2021/09/03)
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- Insertion of Diazo Esters into C-F Bonds toward Diastereoselective One-Carbon Elongation of Benzylic Fluorides: Unprecedented BF3Catalysis with C-F Bond Cleavage and Re-formation
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Selective transformation of C-F bonds remains a significant goal in organic chemistry, but C-F insertion of a one-carbon-atom unit has never been established. Herein we report the BF3-catalyzed formal insertion of diazo esters as one-carbon-atom sources into C-F bonds to accomplish one-carbon elongation of benzylic fluorides. A DFT calculation study revealed that the BF3 catalyst could contribute to both C-F bond cleavage and re-formation. This elongation provided α-fluoro-α,β-diaryl esters with a high level of diastereoselectivity. Various benzylic fluorides and diazo esters were applicable. The synthetic utility of this method was demonstrated by the synthesis of a fluoro analogue of a compound that is used as a transient receptor and potential canonical channel inhibitor.
- Wang, Fei,Nishimoto, Yoshihiro,Yasuda, Makoto
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supporting information
p. 20616 - 20621
(2021/11/23)
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- Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters
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A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM. Diastereomeric acylation transition state models are proposed to rationalize the origins of enantiodiscrimination in this process. This KR procedure was also translated to a continuous-flow process using a polymer-supported variant of the catalyst.
- Greenhalgh, Mark D.,Laina-Martín, Víctor,Neyyappadath, Rifahath M.,Qu, Shen,Smith, Andrew D.,Smith, Samuel M.
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supporting information
p. 16572 - 16578
(2020/09/09)
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- 1,3,2-Diazaphospholenes Catalyze the Conjugate Reduction of Substituted Acrylic Acids
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The potent nucleophilicity and remarkably low basicity of 1,3,2-diazaphospholenes (DAPs) is exploited in a catalytic, metal-free 1,4-reduction of free α,β-unsaturated carboxylic acids. Notably, the reduction occurs without a prior deprotonation of the carboxylic acid moiety and hence does not consume an additional hydride equivalent. This highlights the excellent nucleophilic character and low basicity of DAP-hydrides. Functional groups such as Cbz group or alkyl halides which can be problematic with classical transition-metal catalysts are well tolerated in the DAP-catalyzed process. Moreover, the transformation is characterized by a low catalyst loading, mild reaction conditions at ambient temperature as well as fast reaction times and high yields. The proof-of-principle for a catalytic enantioselective version is described.
- Reed, John H.,Cramer, Nicolai
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p. 4262 - 4266
(2020/07/13)
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- Production method of 2-(4-bromomethyl phenyl)propionic acid
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The invention discloses a production method of 2-(4-bromomethyl phenyl)propionic acid. An adopted ionic liquid catalyst can be recycled and used, no molten aluminum trichloride is generated, a material does not need to be washed for multiple times, only layered extraction needs to be conducted, then a required product can be obtained, aluminum trichloride and triethanolamine salt ionic liquid is used, thus environmentally friendliness is achieved, the cost is also saved, and that is, an original cumbersome process is simplified. An original bromination reaction in a glass kettle is changed toa cooling glass pipeline circulation-type bromination reaction in the kettle, through the glass pipeline type reaction, the contact area of the material and light is increased, through circulation, the situation that the material is gathered on the illumination surface, and consequently light illumination is affected is avoided, thus the reaction efficiency is higher, the reaction time is shortened, the occurrence of a side reaction is controlled, and the product purity is higher.
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Paragraph 0017; 0022; 0026; 0027
(2020/03/06)
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- Mechanistic Investigation of the Nickel-Catalyzed Carbonylation of Alcohols
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The carbonylation of alcohols represents a straightforward and atom-efficient methodology for the preparation of carboxylic acids. It is desirable to perform these reactions under precious metal-free and low-pressure conditions, with regioselectivity control. In this work, we present a detailed mechanistic study of a catalytic system based on NiI2, which can carbonylate benzylic alcohols in a highly regioselective manner to the corresponding branched carboxylic acids, core motifs for nonsteroidal drugs. The combination of catalytic amounts of nickel and iodide is crucial for efficient catalytic and regioselective conversion. Quantum-chemical computations were used to evaluate the underlying mechanistic processes. They revealed that a combination of two mechanisms is responsible for the observed reactivity and that the oxidative addition of alkyl halides to the Ni(0) species follows a radical oxidation pathway via two one-electron steps.
- Comba, Peter,Ghosh, Tamal,Hashmi, A. Stephen K.,Krieg, Saskia,Menche, Maximilian,Paciello, Rocco,Rück, Katharina S. L.,Sabater, Sara,Sch?fer, Ansgar,Schaub, Thomas
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supporting information
(2020/03/19)
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- Harnessing Applied Potential: Selective β-Hydrocarboxylation of Substituted Olefins
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The construction of carboxylic acid compounds in a selective fashion from low value materials such as alkenes remains a long-standing challenge to synthetic chemists. In particular, β-addition to styrenes is underdeveloped. Herein we report a new electrosynthetic approach to the selective hydrocarboxylation of alkenes that overcomes the limitations of current transition metal and photochemical approaches. The reported method allows unprecedented direct access to carboxylic acids derived from β,β-trisubstituted alkenes, in a highly regioselective manner.
- Alkayal, Anas,Buckley, Benjamin R.,Malkov, Andrei V.,Montanaro, Stephanie,Tabas, Volodymyr,Wright, Iain A.
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supporting information
(2020/02/13)
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- Exploration of New Biomass-Derived Solvents: Application to Carboxylation Reactions
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A range of hitherto unexplored biomass-derived chemicals have been evaluated as new sustainable solvents for a large variety of CO2-based carboxylation reactions. Known biomass-derived solvents (biosolvents) are also included in the study and the results are compared with commonly used solvents for the reactions. Biosolvents can be efficiently applied in a variety of carboxylation reactions, such as Cu-catalyzed carboxylation of organoboranes and organoboronates, metal-catalyzed hydrocarboxylation, borocarboxylation, and other related reactions. For many of these reactions, the use of biosolvents provides comparable or better yields than the commonly used solvents. The best biosolvents identified are the so far unexplored candidates isosorbide dimethyl ether, acetaldehyde diethyl acetal, rose oxide, and eucalyptol, alongside the known biosolvent 2-methyltetrahydrofuran. This strategy was used for the synthesis of the commercial drugs Fenoprofen and Flurbiprofen.
- Gevorgyan, Ashot,Hopmann, Kathrin H.,Bayer, Annette
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p. 2080 - 2088
(2020/02/20)
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- Preparation method of organic carboxylic acid
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The invention discloses a preparation method of organic carboxylic acid. The preparation method comprises the following steps that catalysts, olefins, water and solvents are added into a reaction container; CO is introduced; heating reaction is performed; after the reaction completion, separation is performed to obtain organic carboxylic acid; the catalysts comprise transition metal catalysts, ligands and catalysis assistants; the catalysis assistants comprise Lewis acid salt. The preparation method has the advantages that the dependency on protonic acid in the prior art is avoided; the Lewisacid salt is used as the catalysis assistant, so that the corrosion of a reaction system on equipment can be effectively prevented; the requirements on equipment are lowered. The preparation method has excellent substrate practicability; the operation steps are simple and fast; the reaction conditions are mild and are easy to control; the raw materials are cheap and can be easily obtained; the product yield and the product purity are high; the preparation method is suitable for large-scale industrial production; the normal/iso ratio of reaction products can be regulated and controlled throughthe catalysis assistants; the defects of regulating and controlling the normal/iso ratio of the reaction products by traditional phosphine ligands are overcome; the reaction progress of the reaction is simplified; the cost is favorably reduced.
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Paragraph 0047-0049
(2019/10/15)
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- Novel synthesizing method of 2-(4-bromomethyl)phenylpropionic acid
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The invention belongs to the field of preparation of intermediates in chemical engineering, and particularly relates to a novel synthesizing method of 2-(4-bromomethyl)phenylpropionic acid. The novelsynthesizing method comprises the following steps of using 4-methyl acetophenone as the raw material; performing reduction, chlorinating and cyaniding, so as to obtain 2-(4-methyl)phenylpropionitrile;hydrolyzing, and brominating, so as to obtain the 2-(4-bromomethyl)phenylpropionic acid. The novel synthesizing method has the advantages that the yield rate is increased, and the cost of raw material is low; the novel synthesizing method is suitable for industrialized production.
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Paragraph 0011
(2019/06/08)
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- Photocarboxylation of Benzylic C-H Bonds
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The carboxylation of sp3-hybridized C-H bonds with CO2 is a challenging transformation. Herein, we report a visible-light-mediated carboxylation of benzylic C-H bonds with CO2 into 2-arylpropionic acids under metal-free conditions. Photo-oxidized triisopropylsilanethiol was used as the hydrogen atom transfer catalyst to afford a benzylic radical that accepts an electron from the reduced form of 2,3,4,6-tetra(9H-carbazol-9-yl)-5-(1-phenylethyl)benzonitrile generated in situ. The resulting benzylic carbanion reacts with CO2 to generate the corresponding carboxylic acid after protonation. The reaction proceeded without the addition of any sacrificial electron donor, electron acceptor or stoichiometric additives. Moderate to good yields of the desired products were obtained in a broad substrate scope. Several drugs were successfully synthesized using the novel strategy.
- Meng, Qing-Yuan,Schirmer, Tobias E.,Berger, Anna Lucia,Donabauer, Karsten,K?nig, Burkhard
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supporting information
p. 11393 - 11397
(2019/08/20)
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- Site-Selective, Remote sp3 C?H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis
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A photoinduced carboxylation of alkyl halides with CO2 at remote sp3 C?H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.
- Sahoo, Basudev,Bellotti, Peter,Juliá-Hernández, Francisco,Meng, Qing-Yuan,Crespi, Stefano,K?nig, Burkhard,Martin, Ruben
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supporting information
p. 9001 - 9005
(2019/06/24)
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- Biocatalytic Parallel Interconnected Dynamic Asymmetric Disproportionation of α-Substituted Aldehydes: Atom-Efficient Access to Enantiopure (S)-Profens and Profenols
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The biocatalytic asymmetric disproportionation of aldehydes catalyzed by horse liver alcohol dehydrogenase (HLADH) was assessed in detail on a series of racemic 2-arylpropanals. Statistical optimization by means of design of experiments (DoE) allowed the identification of critical interdependencies between several reaction parameters and revealed a specific experimental window for reaching an ′optimal compromise′ in the reaction outcome. The biocatalytic system could be applied to a variety of 2-arylpropanals and granted access in a redox-neutral manner to enantioenriched (S)-profens and profenols following a parallel interconnected dynamic asymmetric transformation (PIDAT). The reaction can be performed in aqueous buffer at ambient conditions, does not rely on a sacrificial co-substrate, and requires only catalytic amounts of cofactor and a single enzyme. The high atom-efficiency was exemplified by the conversion of 75 mM of rac-2-phenylpropanal with 0.03 mol% of HLADH in the presence of ~0.013 eq. of oxidized nicotinamide adenine dinucleotide (NAD+), yielding 28.1 mM of (S)-2-phenylpropanol in 96% ee and 26.5 mM of (S)-2-phenylpropionic acid in 89% ee, in 73% overall conversion. Isolated yield of 62% was obtained on 100 mg-scale, with intact enantiopurities. (Figure presented.).
- Tassano, Erika,Faber, Kurt,Hall, Mélanie
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supporting information
p. 2742 - 2751
(2018/07/29)
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- Regioselectivity inversion tuned by iron(iii) salts in palladium-catalyzed carbonylations
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Impactful regioselectivity control is crucial for cost-effective chemical synthesis. By using cheap and abundant iron(iii) salts, the hydroxycarbonylations of both aromatic and aliphatic alkenes were significantly enhanced in both reactivity and selectivity (iso/n or n/iso up to >99:1). Moreover, Pd-catalyzed carbonylation selectivity can be switched from branched to linear by using different Fe(iii) salts. In addition, similar results were obtained for the carbonylation of secondary alcohols.
- Huang, Zijun,Cheng, Yazhe,Chen, Xipeng,Wang, Hui-Fang,Du, Chen-Xia,Li, Yuehui
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supporting information
p. 3967 - 3970
(2018/04/23)
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- Ligand-Controlled Regioselective Hydrocarboxylation of Styrenes with CO2 by Combining Visible Light and Nickel Catalysis
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The ligand-controlled Markovnikov and anti-Markovnikov hydrocarboxylation of styrenes with atmospheric pressure of CO2 at room temperature using dual visible-light-nickel catalysis has been developed. In the presence of neocuproine as ligand, the Markovnikov product is obtained exclusively, while employing 1,4-bis(diphenylphosphino)butane (dppb) as the ligand favors the formation of the anti-Markovnikov product. A range of functional groups and electron-poor, -neutral, as well as electron-rich styrene derivatives are tolerated by the reaction, providing the desired products in moderate to good yields. Preliminary mechanistic investigations indicate the generation of a nickel hydride (H-NiII) intermediate, which subsequently adds irreversibly to styrenes.
- Meng, Qing-Yuan,Wang, Shun,Huff, Gregory S.,Konig, Burkhard
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supporting information
p. 3198 - 3201
(2018/03/13)
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- A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid
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An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2- and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.
- Liu, Wei,Ren, Wenlong,Li, Jingfu,Shi, Yuan,Chang, Wenju,Shi, Yian
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supporting information
p. 1748 - 1751
(2017/04/11)
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- Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed Multiple C(sp3)?H Activation Strategy
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A cobalt-catalyzed dual C(sp3)?H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation-induced methylene C(sp3)?H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp3)?H activation, has also been demonstrated.
- Zhang, Zhuo-Zhuo,Han, Ye-Qiang,Zhan, Bei-Bei,Wang, Sai,Shi, Bing-Feng
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supporting information
p. 13145 - 13149
(2017/09/28)
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- Preparation method of 2-(4-bromomethyl)phenyl propionic acid
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The invention discloses a preparation method of 2-(4-bromomethyl)phenyl propionic acid. The preparation method includes the steps of: performing a reaction to a compound (I) (4-methylstyrene) with hydrogen halide to prepare a compound (II), performing a Grignard reaction and a carboxylation reaction to the compound (II) to obtain a compound (IV), and performing a bromination reaction to obtain a compound (V) (2-(4-bromomethyl)phenyl propionic acid), wherein a byproduct compound (VI) is subjected to a debromination reaction to obtain the compound (V) (2-(4-bromomethyl)phenyl propionic acid). The method is low in cost, has simple operations, is high in yield, is environment-friendly, and is suitable for industrial production.
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- Method for preparing loxoprofen sodium
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The invention relates to the technical field of organic synthesis, in particular to a method for preparing loxoprofen sodium. The invention provides a compound with the structure shown in formula 5 and a preparation method and application of the compound, (the formula is defined in the description). The loxoprofen sodium obtained according to the scheme is high in purity, high in industrialized operation, and good in application prospect.
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Paragraph 0068-0070
(2017/07/12)
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- New Strategy for Forging Contiguous Quaternary Carbon Centers via H 2 O 2 -Mediated Ring Contraction
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Stereospecific construction of contiguous quaternary carbon centers constitutes a major challenge in natural product synthesis. A general protocol that enables stereospecific construction of all stereoisomers of such a moiety remains elusive. In this article, we will discuss the oxidative ring contraction of all-substituted cyclic α-formyl ketones mediated by H 2 O 2, which provides a facile access to the stereospecific construction of contiguous quaternary carbon centers.
- Hu, Jiadong,Yu, Xin,Xie, Weiqing
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p. 2517 - 2524
(2017/09/28)
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- Degradation of ibuprofen by hydrodynamic cavitation: Reaction pathways and effect of operational parameters
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Ibuprofen (IBP) is an anti-inflammatory drug whose residues can be found worldwide in natural water bodies resulting in harmful effects to aquatic species even at low concentrations. This paper deals with the degradation of IBP in water by hydrodynamic cavitation in a convergent-divergent nozzle. Over 60% of ibuprofen was degraded in 60 min with an electrical energy per order (EEO) of 10.77 kWh m-3 at an initial concentration of 200 μg L-1 and a relative inlet pressure pin = 0.35 MPa. Five intermediates generated from different hydroxylation reactions were identified; the potential mechanisms of degradation were sketched and discussed. The reaction pathways recognized are in line with the relevant literature, both experimental and theoretical. By varying the pressure upstream the constriction, different degradation rates were observed. This effect was discussed according to a numerical simulation of the hydroxyl radical production identifying a clear correspondence between the maximum kinetic constant kOH and the maximum calculated OH production. Furthermore, in the investigated experimental conditions, the pH parameter was found not to affect the extent of degradation; this peculiar feature agrees with a recently published kinetic insight and has been explained in the light of the intermediates of the different reaction pathways.
- Musmarra, Dino,Prisciandaro, Marina,Capocelli, Mauro,Karatza, Despina,Iovino, Pasquale,Canzano, Silvana,Lancia, Amedeo
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- Cp2TiCl2-Catalyzed Regioselective Hydrocarboxylation of Alkenes with CO2
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Cp2TiCl2-catalyzed regioselective hydrocarboxylation of alkenes with CO2 to give carboxylic acids in high yields has been developed in the presence of iPrMgCl. The reaction proceeds with a wide range of alkenes under mild conditions. Styrene and its derivatives can transform to α-aryl carboxylic acids, and aliphatic alkenes can transform to form alkanoic acids.
- Shao, Peng,Wang, Sheng,Chen, Chao,Xi, Chanjuan
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supporting information
p. 2050 - 2053
(2016/06/01)
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- Concise Synthesis of 2-Arylpropanoic Acids and Study of Unprecedented Reduction of 3-Hydroxy-2-arylpropenoic Acid Ethyl Ester to 2-Arylpropenoic Acid Ethyl Ester by BH3·THF
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We have developed a concise method of synthesizing racemic arylpropanoic acids, which have been widely used as nonsteroidal anti-inflammatory drugs (NSAIDs). The synthesis involves only four steps from commercially available benzaldehyde. The synthesis incorporates an unprecedented reduction reaction, conversion of 3-hydroxy-2-arylpropenoic acid ethyl ester to 2-arylpropenoic acid ethyl ester by BH3·THF. The reduction reaction has been investigated and optimized.
- Shahid Islam,Ahmad, Syarhabil,Attu, Mary Rose,Foerstering, F. Holger,Mahmun Hossain
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p. 1273 - 1286
(2015/09/22)
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- Hydrocarboxylation of olefins by supported aqueous-phase catalysis
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Pd-TPPTS complexes supported on acidic macro-porous resins (Pd-TPPTS/resin) have been employed for the hydrocarboxylation of 1-hexene and styrene derivatives by supported aqueous phase catalysis (SAPC). Acidic macroporous resins acted as substitutes for both heterogeneous acids and supports of Pd-TPPTS complexes afforded many advantages, such as easy separation from organic products and good reusability. The prepared Pd-TPPTS/resin catalysts were characterized by FT-IR, TG, SEM and N2 physisorption, which demonstrated that the Pd-TPPTS complexes were loaded on the resin. Compared with homogeneous analogue, the present SAP catalyst offered higher total acid yield and selectivity towards linear acid in the hydrocarboxylation of 1-hexene. Moreover, it was found that water had a significant influence on the catalytic activity and selectivity toward linear acid over the SAP catalyst. Optimum water/resin ratio at about 66.7% in the SAP catalyst afforded maximum activity under the given reaction temperature. The present SAP catalyst was highly Pd-leaching resistant and can be reused at least four times without obvious loss in activity.
- He, Zhenhong,Hou, Zhenshan,Zhang, Yagang,Wang, Tianfu,Dilixiati, Yierxiati,Eli, Wumanjiang
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p. 147 - 154
(2015/03/30)
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- Oxidative rearrangement of malondialdehyde: Substrate scope and mechanistic insights
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A novel oxidative rearrangement of malondialdehyde was described. Under the effect of H2O2, malondialdehyde smoothly transferred to carboxylic acid with C-C bond cleavage in good to excellent yields. Mechanistic studies showed that this reaction proceeded via the formation of a 1,2-dioxolane intermediate, followed by concert C-C, O-O, C-H bond cleavage and a hydride shift.
- Yu, Xin,Liu, Zheng,Xia, Zilei,Shen, Zhigao,Pan, Xixian,Zhang, Hui,Xie, Weiqing
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p. 53397 - 53401
(2015/01/16)
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- Laboratory evolution of enantiocomplementary Candida antarctica lipase B mutants with broad substrate scope
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Candida antarctica lipase B (CALB) is a robust and easily expressed enzyme used widely in academic and industrial laboratories with many different kinds of applications. In fine chemicals production, examples include acylating kinetic resolution of racemic secondary alcohols and amines as well as desymmetrization of prochiral diols (or the reverse hydrolytic reactions). However, in the case of hydrolytic kinetic resolution of esters or esterifying kinetic resolution of acids in which chirality resides in the carboxylic acid part of the substrate, rate and stereoselectivity are generally poor. In the present study, directed evolution based on iterative saturation mutagenesis was applied to solve the latter problem. Mutants with highly improved activity and enantioselectivity relative to wild-type CALB were evolved for the hydrolytic kinetic resolution of p-nitrophenyl 2-phenylpropanoate, with the selectivity factor increasing from E = 1.2 (S) to E = 72 (S) or reverting to E = 42 (R) on an optional basis. Surprisingly, point mutations both in the acyl and alcohol pockets of CALB proved to be necessary. Some of the evolved CALB mutants are also efficient biocatalysts in the kinetic resolution of other chiral esters without performing new mutagenesis experiments. Another noteworthy result concerns the finding that enantiocomplementary CALB mutants for α-substituted carboxylic acid esters also show stereocomplementarity in the hydrolytic kinetic resolution of esters derived from chiral secondary alcohols. Insight into the source of stereoselectivity was gained by molecular dynamics simulations and docking experiments.
- Wu, Qi,Soni, Pankaj,Reetz, Manfred T.
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supporting information
p. 1872 - 1881
(2013/08/24)
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- Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2
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The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl2, bis(imino)pyridine 6 (1 mol %), CO 2 (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO2).
- Greenhalgh, Mark D.,Thomas, Stephen P.
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supporting information; experimental part
p. 11900 - 11903
(2012/09/07)
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- Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase- activating protein (FLAP)
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Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl) ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC50 = 0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC50 = 0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.
- Banoglu, Erden,Caliskan, Burcu,Luderer, Susann,Eren, Goekcen,Oezkan, Yagmur,Altenhofen, Wolfram,Weinigel, Christina,Barz, Dagmar,Gerstmeier, Jana,Pergola, Carlo,Werz, Oliver
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p. 3728 - 3741
(2012/08/28)
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- Anchored Pd-complexes in mesoporous supports: Synthesis, characterization and catalysis studies for carbonylation reactions
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Pd(pyca)(PPh3)(OTs) [pyca = 2-picolinate] complex is efficiently anchored inside different mesoporous matrices, such as MCM-41, MCM-48, SBA-15 using a molecular aminopropyl tether moiety employing different synthesis strategies. Thorough characterization of the materials using powder XRD, multinuclear (13C, 29Si, 31P) CP-MAS NMR, XPS, SEM, N2-sorption studies etc. confirmed the successful anchoring of the palladium complex to the walls of the support matrices thus establishing the synthesis protocols unambiguously. The catalysts were found to be highly active and selective for the carbonylation of different aryl olefins and alcohols. Consecutive recycling and successful reuse proved the stability and true heterogeneous nature of all the anchored catalysts, which is a substantial advancement over the existing heterogeneous catalysts for carbonylation.
- Sarkar, Bibhas R.,Chaudhari, Raghunath V.
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p. 154 - 173
(2013/01/15)
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- Synthesis of chiral N-heterocyclic carbene ligands with rigid backbones and application to the palladium-catalyzed enantioselective intramolecular α-arylation of amides
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Chiral N-heterocyclic carbene (NHC) ligands having a 2,2′- bisquinoline-based C2 symmetric skeleton were developed. The ligands exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.
- Liu, Lantao,Ishida, Naoki,Ashida, Shinji,Murakami, Masahiro
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supporting information; scheme or table
p. 1666 - 1669
(2011/05/11)
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- Facile one-pot preparation of 2-arylpropionic and arylacetic acids from cyanohydrins by treatment with aqueous HI
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A novel one-pot two-step procedure has been developed to synthesize highly substituted 2-arylpropionic and arylacetic acids, by treatment with aqueous HI, from cyanohydrins. The hydrogenolytic reduction of α-hydroxy-2-arylpropionic acids was the key step of the process and the optimization of the reaction conditions led to identify aqueous HI as an appropriate and selective reagent for the reductive deoxygenation of cyanohydrins. The synthetic route described a general and efficient strategy for the preparation of large libraries of phenylacetic and phenylpropionic acids derivatives.
- Aramini, Andrea,Sablone, Manolo R.,Bianchini, Gianluca,Amore, Alessia,Fanì, Michela,Perrone, Plinio,Dolce, Alberto,Allegretti, Marcello
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experimental part
p. 2015 - 2021
(2009/07/04)
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- A novel synthetic route to 2-arylalkanoic acids by a ruthenium-catalyzed chemoselective oxidation of furan rings
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An efficient two-step synthesis of 2-arylalkanoic acids from 1-arylalkanols is described. Firstly, 1-arylalkylfuran derivatives were synthesized in high yields by the metal triflate catalyzed Friedel-Crafts alkylation of 2-methylfuran with 1-arylalkanols without employing anhydrous conditions. The chemoselective oxidation of the furan ring in 1-arylalkylfurans to carboxylic acid was then investigated. In a solvent system of hexane-EtOAc/H2O (1:3:4), the furan ring was selectively oxidized with 7 equivalents of NaIO 4 by using 0.5 mol% RuCl3 as catalyst to give 2-arylalkanoic acids in good yields. The selectivity of ruthenium oxidation was controlled by the solvent ratio of hexane-EtOAc. Georg Thieme Verlag Stuttgart.
- Noji, Masahiro,Sunahara, Haruka,Tsuchiya, Ken-Ichi,Mukai, Toru,Komasaka, Ayako,Ishii, Keitaro
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experimental part
p. 3835 - 3845
(2009/07/04)
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- Bulky chiral carbene ligands and their application in the palladium- catalyzed asymmetric intramolecular α-arylation of amides
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(Chemical Equation Presented) Bring on the big cats: New, C 2-symmetric bulky N-heterocyclic carbene ligands bring major improvements in the palladium-catalyzed asymmetric intramolecular α-arylation of amides to give oxindoles (see picture, dba=trans,trans- dibenzylideneacetone), which are formed in high yield and excellent enantiomeric purity.
- Kuendig, E. Peter,Seidel, Thomas M.,Jia, Yi-Xia,Bernardinelli, Gerald
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p. 8484 - 8487
(2008/09/18)
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- Expanding the substrate scope of enzymes: Combining mutations obtained by CASTing
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In a previous paper, the combinatorial active-site saturation test (CAST) was introduced as an effective strategy for the directed evolution of enzymes toward broader substrate acceptance. CASTing comprises the systematic design and screening of focused libraries around the complete binding pocket, but it is only the first step of an evolutionary process because only the initial libraries of mutants are considered. In the present study, a simple method is presented for further optimization of initial hits by combining the mutational changes obtained from two different libraries. Combined lipase mutants were screened for hydrolytic activity against six notoriously difficult substrates (bulky carboxylic acid esters) and improved mutants showing significantly higher activity were identified. The enantioselectivity of the mutants in the hydrolytic kinetic resolution of two substrates was also studied, with the best mutant-substrate combination resulting in a selectivity factor of E=49. Finally, the catalytic profile of the evolved mutants in the hydrolysis of simple nonbranched carboxylic acid esters, ranging from acetate to palmitate, was studied for theoretical reasons.
- Reetz, Manfred T.,Carballeira, Jose Daniel,Peyralans, Jerome,Hoebenreich, Horst,Maichele, Andrea,Vogel, Andreas
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p. 6031 - 6038
(2007/10/03)
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- Synthesis of 1,4:3,6-dianhydro-d-mannitol 2,5-(hydrogenphosphate) and its usage in palladium-catalyzed hydroxycarbonylation of styrene
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Phosphorylation of 1,4:3,6-dianhydro-d-mannitol by phosphorus oxychloride in the presence of triethylamine followed by hydrolysis gave a cyclie hydrogen phosphate, which has the crystal structure of 6-hydroxy-6-oxo-2,5,7,10-tetraoxa-6-phospha-tricyclo[6.3.0.04,11]undecane. It was used as a chiral ligand in palladium-catalyzed hydroxycarbonylation of styrene. The regioselectivity was good, but the optical yield was limited.
- Jiang, Biao,Huang, Zuo-Gang,Cheng, Ke-Jun
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p. 2797 - 2803
(2007/10/03)
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- Anchored Pd complex in MCM-41 and MCM-48: Novel heterogeneous catalysts for hydrocarboxylation of aryl olefins and alcohols
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We report here, for the first time, synthesis of anchored Pd complexes in mesoporous supports such as MCM-41 and MCM-48 as true heterogeneous catalysts for hydrocarboxylation of aryl olefins and alcohols to give excellent conversion (~100%) and regioselectivity (~99%) for 2-arylpropionic acids. The catalysts were characterized by powder-XRD, 31PCP-MAS NMR, FT-IR, TEM, XPS and ICP-AES. Recycle studies with these anchored Pd mesoporous catalysts were performed to confirm true heterogeneity. Copyright
- Mukhopadhyay, Kausik,Sarkar, Bibhas R.,Chaudhari, Raghunath V.
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p. 9692 - 9693
(2007/10/03)
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- Carbonylation of vinyl aromatics: Convenient regioselective synthesis of 2-arylpropanoic acids
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(equation presented) Various substituted and nonsubstituted 2-arylpropanoic acids have been synthesized in high turnovers with high regioselectivity by palladium-catalyzed carbonylation of vinyl aromatics. Both terminal and internal olefins are carbonylated, though hindered olefins are less reactive. In all the cases high yields and high selectivity are observed. Olefins with electron-withdrawing para substituents gave the highest regioselectivity in the formation of the corresponding 2-arylpropanoic acids.
- Seayad,Jayasree,Chaudhari
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p. 459 - 461
(2008/02/11)
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- Systematic study of chiral discrimination upon crystallisation. Part 2.1 Chiral discrimination of 2-arylalkanoic acids by (1R,2S)-2-amino-1,2-diphenylethanol
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The resolution of 2-arylalkanoic acids by (1R,2S)-2-amino-1,2-diphenylethanol has been studied. It has been found that the position of a substituent on the aromatic group of the acids affects resolution efficiency to a considerable extent. Crystal structu
- Kinbara, Kazushi,Kobayashi, Yuka,Saigo, Kazuhiko
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p. 1767 - 1775
(2007/10/03)
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- An efficient synthesis of α-Cuparenone
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Synthesis of α-Cuparenone is described. The key step involved are photorearrangement of α-halo arylketone (4) to 1-methyl-1-(p-tolyl)acetic acid (5) and extremely mild, essentially neutral, room temperature/3-aza-claisen reaction of N-allylamide (6).
- Chavan, Subhash P.,Ravindranathan,Patil, Sachindra S.,Dhondge, Vijay D.,Dantale, Shuhhada W.
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p. 2629 - 2630
(2007/10/03)
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- Photochemical Rearrangement of α-Chloro-Propiophenones to α-Arylpropanoic Acids: Studies on Chirality Transfer and Synthesis of (S)-(+)-Ibuprofen and (S)-(+)-Ketoprofen
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A new single-step efficient photochemical approach for α-arylpropanoic acids (4) from α-chloro-propiophenones (5) is described.It involves carbonyl triplet excited state directed 1,2-aryl migration of the aryl group which has been found to be highly dependent upon the nature of the aryl substituent.The mode of the rearrangement is probed by the study of the photobehaviour of a set of optically active α-chloro-propiophenones.The results suggest that the nature of the carbonyl triplets (n, ?*/ ?, ?*) plays an important role in the chirality transfer.This method finds application in the synthesis of optically active ibuprofen (4e) and ketoprofen (26), though in moderate optical yields.
- Sonawane, Harikisan,Bellur, Nanjundiah S.,Kulkarni, Dilip G.,Ayyangar, Nagaraj R.
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p. 1243 - 1260
(2007/10/02)
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- A new method for the preparation of 2-aryl propionic acids using low-valent titanium
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The addition of dihalocarbenes to arylmethylketones in the presence of low-valent titanium yields 2-aryl propionic acids in acceptable yield by one pot reaction. The reaction conditions were optimized. The TiCl4/LiAlH4 ratio is one variable that controls the selectivity of the process.
- Garcia, Mariano,Del Campo, Carmen,Sinisterra, Jose V.,Llama, Emilio F.
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p. 7973 - 7974
(2007/10/02)
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- Chemoenzymatic synthesis of pure enantiomeric 2-aryl propionic acids
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A new chemoenzymatic procedure to obtain pure enantiomeric 2-arylpropionic acids is described. The one pot synthesis of (±)-2-arylpropionic acids is carried out by addition of dichlorocarbene to the C=O bond of arylmethylketones and hydrogenolysis of the additon product. The racemic mixture is resolved by enantiospecific hydrolysis of the racemic ethyl esters using native lipase from Candida rugosa. The good yields, the accessibility of the starting arylmethylketones and the stereospecificity of the enzymatic hydrolysis make the process interesting in order to obtain the same non steroidal antiinflammatory drugs such as Ibuprofen or Naproxen.
- Garcia,Del Campo,Llama,Sanchez-Montero,Sinisterra
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p. 8433 - 8440
(2007/10/02)
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- The enantioselective metabolism of p-cymene in rabbits
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p-Cymene (1) was metabolized in rabbits and the following four optically active metabolites, 2-(p-tolyl)-1-propanol (3': R/S = 65:35), 2-(p-tolyl)propanoic acid (5': R/S = 0:100), p-(2-hydroxy-1-methylethyl)benzoic acid (6': R/S = 91:9) and p-(1-carboxyethyl)benzoic acid (8': R/S = 30:70), were isolated in addition to three optically inactive metabolites, 2-(p-tolyl)-2-propanol (2), p-isopropylbenzoic acid (4'), and p-(1-hydroxy-1-methylethyl)benzoic acid (7'). The presumed metabolic pathways of p-cymene in rabbits were confirmed by the administration of the intermediate metabolites (2, 3', 4', and 5'). The enantiomeric ratios of the metabolites, 3' and 6', suggested that ω-hydroxylations of the isopropyl group in 1 and 4' occurred preferentially at the pro-S methyl group. In the metabolism of 1, the S-isomers are predominant in the propanoic acid derivatives, but the R-isomers are rich in the propanol derivatives. It is of interest that the metabolism of 4', however, produced predominantly the corresponding propanol derivative (6'; R/S = 91:9) and propanoic acid derivative (8'; R/S = 80:20) possessing the same R-configuration. Some optically active p-cymene derivatives were also synthesized as standard compounds.
- Matsumoto,Ishida,Yoshida,Terao,Takeda,Asakawa
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p. 1721 - 1726
(2007/10/02)
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- DIRECT, REGIOSELECTIVE HYDROCARBOXYLATION OF ALKYNES TO SATURATED ACIDS BY COBALT AND NICKEL CATALYSTS UNDER PHASE TRANSFER CONDITIONS
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Phase transfer catalyzed carbonylation of alkynes in the presence of cobalt chloride, potassium cyanide, and nickel cyanide affords saturated carboxylic acids, with good selectivity observed for the branched-chain isomer.
- Lee, Jong-Tae,Alper, Howard
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p. 1769 - 1770
(2007/10/02)
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- Light-mediated direct transformation of 2-chloropropiophenones into 2-arylpropionic acids
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A strategy based on photochemical 1,2-aryl migration as the pivotal step allows efficient transformation of 2-chloro-propiophenones into 2-arylpropionic acids. A noticeable substituent-directed excited state control on the rearrangement process has been observed.
- Sonawane, Harikisan R.,Kulkarni, Dilip G.,Ayyangar, Nagaraj R.
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p. 7495 - 7496
(2007/10/02)
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