- 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
-
supporting information
p. 20616 - 20621
(2021/11/23)
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- COMPOUNDS AND METHODS FOR TREATMENT OF HEDGEHOG PATHWAY ASSOCIATED CONDITIONS
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Provided herein is novel compounds of formula (I), (II), (III), (IV), and (V) as described in the specification, and pharmaceutically acceptable salts, solvates, and prodrugs and compositions thereof, and methods of measuring hedgehog pathway activation in tumor cells, examining tumor cell proliferation, differentiation and apoptosis and using the compounds and pharmaceutical compositions disclosed for treatment of diseases and disorders associated with the hedgehog signaling pathway.
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Page/Page column 69; 70; 71
(2020/01/24)
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- Preparation of optically pure flurbiprofen via an integrated chemo-enzymatic synthesis pathway
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In the synthesis of chiral molecules, the incorporation of enantioselective enzymatic conversions within the synthetic route often presents a useful approach. For the substitution of a chemical step with an enzymatic reaction, however, the complete synthetic route leading to and from this reaction needs to be considered carefully. An integrated approach, taking the possibilities and challenges of both types of conversions into account, can give access to chemo-enzymatic processes with great potential for effective synthesis strategies. We here report on the synthesis of enantiopure flurbiprofen using arylmalonate decarboxylase (AMDase, EC 4.1.1.76) in a chemo-enzymatic approach. Interestingly, practical considerations required shifting the enzymatic step to an earlier position in the synthetic route than previously anticipated. Engineered enzyme variants made it possible to obtain both (R)- and (S)-enantiomers of the target compound in excellent optical purity (>99%ee). The presented results underline that enzymes are most useful when they fit in a synthetic route, and that the optimization of biocatalytic steps and the planning of synthetic routes should be an integrated process.
- Enoki, Junichi,Linhorst, Max,Busch, Florian,Baraibar, álvaro Gomez,Miyamoto, Kenji,Kourist, Robert,Mügge, Carolin
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p. 135 - 142
(2019/02/14)
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- Total synthesis of carbazole alkaloids
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A Suzuki-Miyaura cross coupling, followed by triphenylphosphine mediated Cadogan reductive cyclization sequence provided efficient access to a series of carbazole alkaloids. In the present work, this approach was applied to the total synthesis of mukonine, clauszoline K, koenoline, murrayanine, murrayafoline A, mukoeic acid, glycoborine, glycozolicine, mukolidine, mukoline, glycozoline, 3-methoxy-9H-carbazole-1-carboxylic acid methyl ester, (3-methoxy-9H-carbazol-1-yl)-methanol, 3-methoxy-9H-carbazole-1-carbaldehyde, 3-methoxy-9H-carbazole-1-carboxylic acid, 2-methyl-9H-carbazole and nonsteroidal anti-inflammatory drug (NSAID) carprofen and its derivatives.
- Bhatthula, Bharath kumar goud,Kanchani, Janardhan reddy,Arava, Veera reddy,Subha
-
supporting information
p. 874 - 887
(2019/01/11)
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- ANTITUMOR COMPOUND TARGETING IDH2 MUTATION AND METHOD OF USE THEREOF
-
The present application relates to compounds represented by general formula (I), general formula (II) or general formula (III), and pharmaceutically acceptable salts or hydrates thereof, preparation methods thereof, and pharmaceutical compositions thereof. The compounds represented by general formula (I), general formula (II) or general formula (III) have inhibitory activities against isocitrate dehydrogenase 2 (IDH2), thereby being capable of treating IDH2 mutation-induced cancers.
- -
-
Paragraph 0128; 0129
(2018/06/15)
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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
-
supporting information
p. 3967 - 3970
(2018/04/23)
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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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p. 2742 - 2751
(2018/07/29)
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- New Strategy for Forging Contiguous Quaternary Carbon Centers via H 2 O 2 -Mediated Ring Contraction
-
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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- 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
-
supporting information
p. 13145 - 13149
(2017/09/28)
-
- Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis
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The merger of photoredox catalysis with asymmetric copper catalysis have been realized to convert achiral carboxylic acids into enantiomerically enriched alkyl nitriles. Under mild reaction conditions, the reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.
- Wang, Dinghai,Zhu, Na,Chen, Pinhong,Lin, Zhenyang,Liu, Guosheng
-
supporting information
p. 15632 - 15635
(2017/11/14)
-
- TYK2 INHIBITORS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
- -
-
Paragraph 0682; 0685; 0686
(2016/09/26)
-
- Modulators of methyl modifying enzymes, compositions and uses thereof
-
Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.
- -
-
Page/Page column 230; 232; 260; 261; 262
(2015/12/26)
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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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- MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
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Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein
- -
-
Paragraph 00508; 00511; 00586; 00589
(2013/06/05)
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- Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones - A new strategy to combat malarial parasites
-
Our work on targeting redox equilibria of malarial parasites propagating in red blood cells has led to the selection of six 1,4-naphthoquinones, which are active at nanomolar concentrations against the human pathogen Plasmodium falciparum in culture and a
- Mueller, Tobias,Johann, Laure,Jannack, Beate,Brueckner, Margit,Lanfranchi, Don Antoine,Bauer, Holger,Sanchez, Cecilia,Yardley, Vanessa,Deregnaucourt, Christiane,Schrevel, Joseph,Lanzer, Michael,Schirmer, R. Heiner,Davioud-Charvet, Elisabeth
-
supporting information; experimental part
p. 11557 - 11571
(2011/09/16)
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- The discovery of MK-0674, an orally bioavailable cathepsin K inhibitor
-
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies
- Isabel, Elise,Bateman, Kevin P.,Chauret, Nathalie,Cromlish, Wanda,Desmarais, Sylvie,Duong, Le T.,Falgueyret, Jean-Pierre,Gauthier, Jacques Yves,Lamontagne, Sonia,Lau, Cheuk K.,Leger, Serge,LeRiche, Tammy,Levesque, Jean-Francois,Li, Chun Sing,Masse, Frederic,McKay, Daniel J.,Mellon, Christophe,Nicoll-Griffith, Deborah A.,Oballa, Renata M.,Percival, M. David,Riendeau, Denis,Robichaud, Joel,Rodan, Gideon A.,Rodan, Sevgi B.,Seto, Carmai,Therien, Michel,Truong, Vouy Linh,Wesolowski, Gregg,Young, Robert N.,Zamboni, Robert,Black, W. Cameron
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scheme or table
p. 887 - 892
(2010/08/22)
-
- ANTAGONISTS OF LYSOPHOSPHATIDIC ACID RECEPTORS
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Described herein are compounds that are antagonists of lysophosphatidic receptor(s). Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such antagonists, alone and in combination with other compounds, for treating LPA-dependent or LPA-mediated conditions or diseases.
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Page/Page column 27
(2010/06/22)
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- Modulators of 11-beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
-
The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1 and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of
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-
Page/Page column 28
(2010/11/28)
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- REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE A AND B
-
The instant invention relates to compounds of formula I, diagrammed below, wherein R3, E, D and Y are defined in the application, which are useful as reversible inhibitors of monoamine oxidase-B and/or monoamine oxidase-A, and therefore useful to treat or prevent neurological diseases or conditions in mammals, preferably humans.
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-
Page/Page column 31
(2008/06/13)
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- CATHEPSIN CYSTEINE PROTEASE INHIBITORS
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This invention relates to a novel class of compounds, represented by the formula below, wherein the meanings of G, E, E, n, R1, R2, R3 et R4 are indicated therein, which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
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Page/Page column 64
(2010/02/11)
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- Amide, carbamate, and urea derivatives
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The present invention provides certain amide, carbamate and urea derivatives useful for potentiating glutamate receptor function in a mammal and therefore, useful for treating a wide variety of conditions, such as psychiatric and neurological disorders.
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- An interesting synthetic application of S-alkyl (aryl)bis(alkylsulfanyl)thioacetates: General procedure for the preparation of (±)-α-arylpropionic acids
-
Reported here is a new procedure for the synthesis of α-arylpropionic acids 1 in the racemic form, starting from derivatives of aromatic carboxylic acids 2 (i.e., esters), via 1-aryl-2,2,2-tris(alkylsulfanyl)ethanones 4-6, S-alkyl (aryl)bis(alkylsulfanyl)thioacetates 7-9, S-alkyl α-aryl-α-(alkylsulfanyl)thiopropionates 10-12 and S-alkyl α-arylthiopropionates 13-15. Each stage takes place easily and yields are always high.
- Clericuzio, Marco,Degani, Iacopo,Dughera, Stefano,Fochi, Rita
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p. 921 - 927
(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
-
p. 459 - 461
(2008/02/11)
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- Oxidative Rearrangement of Aryl Ethyl Ketones to Alkyl 2-Arylpropanoates by Lead(IV) Acetate
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Treatment of the propiophenones p-R'C6H4COCH2Me (1; R' = H, Me, Bui, Ph, Br) with lead(IV) acetate in trialkyl orthoformate in the presence of acid catalyst is found to give alkyl esters of 2-arylpropanoic acids (2) in good to excellent yields via 1,2-aryl migration in (1).Hydrolysis of (2) leads to the corresponding acids, some of which are important pharmaceutical compounds.The rate of aryl migration increases when the substituent R' is an electron-releasing group such as methyl, isobutyl, or phenyl.The rate of rearrangement of the dimethyl acetals of (1); R' = H, Bui, Ph) is nearly the same as that of (1).Such rearrangement hardly occurs in the absence of acid catalyst.A reaction pathway involving the formation of a monoalkoxylead(IV) compound, and its decomposition accompanied with aryl migration is discussed.
- Yamauchi, Takayoshi,Nakao, Kenji,Fujii, Kyoichi
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p. 1433 - 1436
(2007/10/02)
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- Thallium(III) Nitrate-mediated Efficient Synthesis of 2-Arylpropionic Acids from 1-Halogenoethyl Aryl Ketones
-
Treatment of 1-halogenoethyl aryl ketones (1; R = H, iBu, OMe, Me, Ph, or Br; X = Br or Cl) with Tl(NO3)3*3H2O and perchloric acid in a trialkyl orthoformate at 25-50 deg C affords alkyl esters (3) of 2-arylpropionic acid in good-to-excellent yields via 1,2-aryl migration in substrates (1).The hydrolysis of esters (3) leads to the corresponding acids, some of which are pharmaceutically important compounds.The reaction hardly occurs in methanol.The key step of the reaction is the in situ acetal formation of the starting ketone.The thallium(III) salt acts as an effective Lewis acid catalyst for both acetal formation and halide abstraction.
- Yamauchi, Takayoshi,Nakao, Kenji,Fujii, Kyoichi
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p. 1255 - 1258
(2007/10/02)
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- Application of Oxidative Aryl Migration in Organo-selenium and -tellurium Compounds to the Synthesis of 2-Arylpropanoic Acids
-
The ethylene acetals of aryl α-phenylseleno- and α-phenyltelluro-ethyl ketones i, Ph, Br) and 5-bromo-6-methoxy-2-naphthyl> have been prepared in 12-83percent yields by treating the corresponding α-bromo compounds with diphenyl diselenide-sodium or diphenyl ditelluride-sodium, respectively, in tetrahydrofuran-dimethylformamide under reflux for 6-10 h, during which the bromine is substituted by the PhSe or PhTe group.This substitution is not observed when the (PhM)2-NaBH4-EtOH (M=Se, Te) system which is known as a source of PhM- anion is used.Oxidation of the acetals thus formed with an excess of meta-chloroperbenzoic acid at 20-25 deg C for 1 h affords hydroxy-ethyl 2-arylpropanoates in 56-86percent yields via aryl group migration which are hydrolysed to 2-arylpropanoic acids, some of which are pharmaceutically important compounds.Overall isolated yields of 2-arylpropanoic acids are around 30-42percent based on the starting propiophenones over 5 steps.
- Uemura, Sakae,Fukuzawa, Shin-ichi,Yamauchi, Takayoshi,Hattori, Kaneaki,Mizutaki, Shoichi,Tamaki, Kentaro
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p. 1983 - 1987
(2007/10/02)
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- New Preparative Method for 2-Arylpropanoic Acids by Oxidative Aryl Migration in Aryl α-Seleno- and Aryl α-Telluro-ethyl Ketones
-
Oxidation with m-chloroperbenzoic acid of the ethylene acetals of aryl α-phenylseleno- or aryl α-phenyltelluro-ethyl ketones prepared by treating the corresponding α-bromo compounds with diphenyl diselenide-sodium or diphenyl ditelluride-sodium, respectively, affords hydroxyethyl 2-arylpropanoates in moderate to good yields via aryl group migration.
- Uemura, Sakae,Fukuzawa, Shin-ichi,Yamauchi, Takayoshi,Hattori, Kaneaki,Mizutaki, Shoichi,Tamaki, Kentaro
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p. 426 - 427
(2007/10/02)
-