- Catalytic enantioselective desymmetrization of cyclobutane-1,3diones by carbonyl-amine condensation
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A chiral phosphoric acid-catalyzed enantioselective condensation of 2,2-disubstituted cyclobutane-1,3-diones with a primary amine is described. This reaction offered a mild and efficient protocol for constructing quaternary carbon-containing cyclobutanes
- Wen, Kai-Ge,Liu, Chao,Wei, Dong-Hui,Niu, Yan-Fei,Peng, Yi-Yuan,Zeng, Xing-Ping
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supporting information
p. 1118 - 1122
(2021/02/16)
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- Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2-Amino Acids
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The asymmetric synthesis of β2,2-amino acids remains a formidable challenge in organic synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β2,2-amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amount of chiral phosphoric acid. Typically, this transformation probably proceeds through an asymmetric counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β2,2-amino acids has been developed.
- Shao, Ying,Sun, Jiangtao,Tang, Shengbiao,Wang, Kai,Yu, Jianliang
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supporting information
p. 23516 - 23520
(2020/10/21)
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- Selective Inhibitors of a Human Prolyl Hydroxylase (OGFOD1) Involved in Ribosomal Decoding
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Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. We report a structurally informed template-based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2.
- Thinnes, Cyrille C.,Lohans, Christopher T.,Abboud, Martine I.,Yeh, Tzu-Lan,Tumber, Anthony,Nowak, Rados?aw P.,Attwood, Martin,Cockman, Matthew E.,Oppermann, Udo,Loenarz, Christoph,Schofield, Christopher J.
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supporting information
p. 2019 - 2024
(2019/01/11)
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- 2-Amino-5,6-difluorophenyl-1 H-pyrazole-Directed PdII Catalysis: Arylation of Unactivated β-C(sp3)-H Bonds
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Palladium-catalyzed arylation of unactivated β-C(sp3)-H bonds in carboxylic acid derivatives with aryl iodides is described for the first time using 2-amino-5,6-difluorophenyl-1H-pyrazole as an efficient and readily removable directing group. Two fluoro groups are installed at the 5- and 6-position of the anilino moiety in 2-aminophenyl-1H-pyrazole, clearly enhancing the directing ability of the auxiliary. In addition, the protocol employs Cu(OAc)2/Ag3PO4 (1.2/0.3) as additives, evidently reducing the stoichiometric amount of expensive silver salts. Furthermore, this process exhibits high β-site selectivity, compatibility with diverse substrates containing α-hydrogen atoms, and excellent functional group tolerance.
- Yang, Jinyue,Fu, Xiaopan,Tang, Shibiao,Deng, Kezuan,Zhang, Lili,Yang, Xianjin,Ji, Yafei
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p. 10221 - 10236
(2019/08/20)
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- Palladium-Catalyzed Carbon Isotope Exchange on Aliphatic and Benzoic Acid Chlorides
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An operationally simple protocol for a palladium-catalyzed 13CO and 14CO exchange with activated aliphatic and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, an
- Gauthier, Donald R.,Rivera, Nelo R.,Yang, Haifeng,Schultz, Danielle M.,Shultz, C. Scott
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supporting information
p. 15596 - 15600
(2018/11/23)
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- Preparation method for indanone compound
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The invention especially relates to a preparation method for an indanone compound, belonging to the field of organic synthesis. The preparation method for the indanone compounds comprises the following steps: 1) subjecting a compound as shown in a formula I and a compound as shown in a formula II to a condensation reaction so as to prepare a compound as shown in a formula III; 2) subjecting the compound as shown in the formula III to hydrolysis in the presence of alkali so as to prepare a compound as shown in a formula IV; and 3) carrying out acylation and ring closure on the compound as shownin the formula IV so as to prepare the as shown in a formula V. Compared with the prior art, the preparation method for the indanone compound in the invention has the advantages of low raw material cost, simple operation, low production of waste water, waste gas and industrial residues, high yield and the like, and is more suitable for industrial production; and compared with various traditionalpreparation methods for the indanone compound, the preparation method of the invention has obvious advantages and shows good industrialization prospects.
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- Ligand-Enabled Alkynylation of C(sp3)?H Bonds with Palladium(II) Catalysts
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The palladium(II)-catalyzed β- and γ-alkynylation of amide C(sp3)?H bonds is enabled by pyridine-based ligands. This alkynylation reaction is compatible with substrates containing α-tertiary or α-quaternary carbon centers. The β-methylene C(sp
- Fu, Haiyan,Shen, Peng-Xiang,He, Jian,Zhang, Fanglin,Li, Suhua,Wang, Peng,Liu, Tao,Yu, Jin-Quan
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supporting information
p. 1873 - 1876
(2017/02/05)
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- 3-Phenylalkyl-2H-chromenes and -chromans as novel rhinovirus infection inhibitors
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Following our studies on structure-activity relationships of anti-rhinovirus chromene and chroman derivatives, we designed and synthesized new series of 3-phenylalkyl-2H-chromenes and -chromans bearing differently sized, aliphatic linker chains between the two cycles. The cytotoxicity and the antiviral activity of the new compounds on human rhinovirus (HRV) serotype 1B and 14 infection were evaluated in HeLa cell cultures. Most of the tested compounds interfered with HRV1B multiplication in the micromolar or submicromolar concentrations while HRV14 was less susceptible. 3-[3-(4-Chlorophenyl)propyl]chroman (9c) was selected for preliminary mechanism of action studies due to its potent activity against both serotypes (IC50 of 0.48?μM and 1.36?μM towards HRV1B and 14, respectively) coupled with high selectivity (SI?=?206.18 and 73.26, respectively). Results of time of addition/removal studies suggest that 9c, similarly to related derivatives, behaves as a capsid binder interfering with some early events of the HRV1B infectious cycle.
- Conti, Cinzia,Proietti Monaco, Luca,Desideri, Nicoletta
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p. 2074 - 2083
(2017/03/23)
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- Photoinduced, Copper-Catalyzed Decarboxylative C-N Coupling to Generate Protected Amines: An Alternative to the Curtius Rearrangement
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The Curtius rearrangement is a classic, powerful method for converting carboxylic acids into protected amines, but its widespread use is impeded by safety issues (the need to handle azides). We have developed an alternative to the Curtius rearrangement that employs a copper catalyst in combination with blue-LED irradiation to achieve the decarboxylative coupling of aliphatic carboxylic acid derivatives (specifically, readily available N-hydroxyphthalimide esters) to afford protected amines under mild conditions. This C-N bond-forming process is compatible with a wide array of functional groups, including an alcohol, aldehyde, epoxide, indole, nitroalkane, and sulfide. Control reactions and mechanistic studies are consistent with the hypothesis that copper species are engaged in both the photochemistry and the key bond-forming step, which occurs through out-of-cage coupling of an alkyl radical.
- Zhao, Wei,Wurz, Ryan P.,Peters, Jonas C.,Fu, Gregory C.
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supporting information
p. 12153 - 12156
(2017/09/12)
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- Unactivated C(sp3)-H hydroxylation through palladium catalysis with H2O as the oxygen source
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A novel palladium catalyzed hydroxylation of unactivated aliphatic C(sp3)-H bonds was successfully developed. Different from conventional methods, water serves as the hydroxyl group source in the reaction. This new reaction demonstrates good reactivity and broad functional group tolerance. The C-H hydroxylated products can be readily transformed into various highly valuable chemicals via known transformations. Based on experimental and theoretical studies, a mechanism involving the Pd(ii)/(iv) pathway is proposed for this hydroxylation reaction.
- Hu, Jiantao,Lan, Tianlong,Sun, Yihua,Chen, Hui,Yao, Jiannian,Rao, Yu
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p. 14929 - 14932
(2015/10/06)
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- Memory of chirality in rebound cyclizations of α-amide radicals
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Reduction of (S)-N-(2-bromoallyl)-N-(tert-butyl)-2-methyl-3- phenylpropanamide with tributyltin hydride provides (3S,4S)-3-benzyl-1-(tert- butyl)-3,4-dimethylpyrrolidin-2-one with about 80% retention of chirality at the stereocenter adjacent to the amide carbonyl group. This memory of chirality is suggested to occur by transfer of chirality from a stereocenter to an axis, then from the axis back to a new stereocenter.
- Sasmal, Aniruddha,Taniguchi, Tsuyoshi,Wipf, Peter,Curran, Dennis P.
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supporting information
p. 1 - 5
(2013/03/13)
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- On the origins of diastereoselectivity in the alkylation of enolates derived from N-1-(1′-Naphthyl)ethyl-O-tert-butylhydroxamates: Chiral Weinreb amide equivalents
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(Chemical Equation Presented) The stereochemical outcome observed upon alkylation of enolates derived from N-1-(1′-naphthyl)ethyl-O-tert- butylhydroxamates (chiral Weinreb amide equivalents) may be rationalized by a chiral relay mechanism. Deprotonation withKHMDS leads to a nonchelated (Z)-enolate inwhich the oxygen atoms adopt an anti-periplanar conformation. The configuration of the N-1-(1′-naphthyl)ethyl group dictates the conformation of the O-tert-butyl group and the configuration adopted by the adjacent pyramidal nitrogen atom. Highly diastereoselective enolate alkylation then proceeds anti to both the bulky tert-butyl group (sterically driven) and the N-lone pair (stereoelectronically driven).
- Davies, Stephen G.,Goodwin, Christopher J.,Hepworth, David,Roberts, Paul M.,Thomson, James E.
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supporting information; experimental part
p. 1214 - 1227
(2010/04/26)
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- Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8- (trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury
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Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the α position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
- Huang, Adrian,Moretto, Alessandro,Janz, Kristin,Lowe, Michael,Bedard, Patricia W.,Tam, Steve,Di, Li,Clerin, Valerie,Sushkova, Natalia,Tchernychev, Boris,Tsao, Desiree H. H.,Keith Jr., James C.,Shaw, Gray D.,Schaub, Robert G.,Wang, Qin,Kaila, Neelu
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supporting information; experimental part
p. 6003 - 6017
(2010/11/19)
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- Indene-based scaffolds. Design and synthesis of novel serotonin 5-HT 6 receptor ligands
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A series of novel indene derivatives designed by a scaffold selection gave access to several examples of (Z)-arylmethylideneindenes and indenylsulfonamides that acted as serotonin 5-HT6 receptor ligands. Different synthetic multistep routes could be applied to these target compounds, each with their own complexity and limitations. A reasonable route involved the (3-indenyl)acetic acids as the key intermediates, and two alternatives were also examined. The first protocol used was a two-step sequence employing a modified Horner-Wadsworth-Emmons reaction, but better results were obtained with a procedure based on the condensation of indanones with the lithium salt of ethyl acetate, followed immediately by dehydration with acid and hydrolysis/ isomerization under basic catalysis. (3-Indenyl)acetic acids were transformed to the corresponding acetamides, which were effectively reduced to indenylsulfonamides 13-17 using an optimized procedure with AlH 3-NMe2Et. The binding at the 5-HT6 receptor was with moderate affinity (Ki = 216.5 nM) for the (Z)- benzylideneindenylsulfonamide 12 and enhanced affinity for the simple indenylsulfonamide counterpart 13 (Ki = 50.6 nM). Selected indenylsulfonamides 14-17 were then tested, showing Ki values as low as 20.2 nM. The Royal Society of Chemistry 2008.
- Alcalde, Ermitas,Mesquida, Neus,Frigola, Jordi,Lopez-Perez, Sara,Merce, Ramon
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experimental part
p. 3795 - 3810
(2009/02/04)
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- Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors
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Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4′-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based
- Joseph-McCarthy, Diane,Parris, Kevin,Huang, Adrian,Failli, Amedeo,Quagliato, Dominick,Dushin, Elizabeth Glasfeld,Novikova, Elena,Severina, Elena,Tuckman, Margareta,Petersen, Peter J.,Dean, Charles,Fritz, Christian C.,Meshulam, Tova,DeCenzo, Maureen,Dick, Larry,McFadyen, Iain J.,Somers, William S.,Lovering, Frank,Gilbert, Adam M.
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p. 7960 - 7969
(2007/10/03)
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- Radical Chain Reaction or Benzenethiol with Pentynylthiol Esters: Production of Aldehydes under Stannane/Silane-Free Conditions
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The radical chain reaction of benzenethiol with accessible 4-pentynylthiol esters provides a new stannane/silane-free protocol for the production of aromatic and aliphatic aldehydes. The procedure is especially useful for the aryl and primary aldehydes, even in the presence of substituents highly sensitive to reductive conditions, and is also of some utility for the vinylic and secondary ones, The protocol is instead not applicable to the tertiary aldehydes, owing to preferential alkane-forming decarbonylation, although the tertiary ones derived from bridgehead precursors can still be usefully produced.
- Benati, Luisa,Leardini, Rino,Minozzi, Matteo,Nanni, Daniele,Scialpi, Rosanna,Spagnolo, Piero,Zanardi, Giuseppe
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p. 985 - 990
(2007/10/03)
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- A direct and mild conversion of tertiary aryl amides to methyl esters using trimethyloxonium tetrafluoroborate: A very useful complement to directed metalation reactions
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The scope and generality of a direct process for the conversion of tertiary amides directly to methyl esters has been investigated. The process involves a two-step, one pot procedure in which a tertiary amide is first treated with trimethyloxonium tetrafluoroborate to generate an imidate intermediate which is then hydrolyzed, generally by the addition of saturated aqueous sodium bicarbonate solution. Although this process fails for aliphatic amides, very good yields are realized for a variety of amides derived from aromatic carboxylic acids. Steric hindrance at the N-alkyl group is well tolerated; thus N,N-dimethyl, -diethyl, and -diisopropyl amides can all be utilized successfully. (C) 2000 Elsevier Science Ltd.
- Keck, Gary E,McLaws, Mark D,Wager, Travis T
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p. 9875 - 9883
(2007/10/03)
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- Optically active 3-amino-2H-azirines as synthons for enantiomerically pure α,α-disubstituted α-amino acids: Synthesis of the α-methylphenylalanine synthons and some model peptides
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The synthesis of a novel 2-benzyl-2-methyl-3-amino-2H-azirine derivative with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers 9a and 9b which are the D- and L-2-methylphenylalanine ((α-Me)Phe) synthons, respectively. The reaction of 9a and 9b with thiobenzoic acid and with Z-leucine yielded the monothiodiamides 10a and 10b and the dipeptide derivatives 11a and 11b, respectively. Methanolysis of 11b yielded 12b. The absolute configuration of 10a was established by X-ray crystallography. The absolute configuration of (α-Me)Phe in 12b has been deduced from the known configuration of L-leucine.
- Bucher,Linden,Heimgartner
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p. 935 - 946
(2007/10/02)
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- Intramolecular Nucleophilic Acyl Substitution Reactions Mediated by Samarium(II) Iodide: A Convergent Approach to the Preparation of Enantiomerically Enriched 4-Hydroxy Ketones from 3-Iodopropyl Carboxylates
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Intramolecular nucleophilic acyl substitution (I NAS) reactions of substituted δ-iodopropylcarboxylates have been achieved using samarium(II) iodide (SmI2) in the presence of an iron(III) catalyst.Diverse ester starting materials containing stereogenic centers placed in varying postions on the substrates have been converted to acyclic 4-hydroxy ketone derivatives in good yields using this method.No racemization of stereogenic centers α to the carbonyl was observed in any of the reactions examined.Consequently, the method serves as a convenient, high-yield synthesis of functionalized, enantiomerically enriched acyclic ketones possesing stereogenic centers far removed from one another.
- Molander, Gary A.,Shakya, Sagar R.
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p. 3445 - 3452
(2007/10/02)
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- Convenient Synthetic Sequence for the Preparation of Indanones
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A convenient and general methods is reported for the synthesis of indanones from aryl ketones or aldehydes.
- Smonou, Ioulia,Orfanopoulos, Michael
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p. 1387 - 1397
(2007/10/02)
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- Radical Cyclizations of Alkenyl-Substituted 4,5-Dihydro-1,3-thiazole-5-thiols
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Heating of 5-alkenyl- or 5-alkinyl-4,5-dihydro-1,3-thiazole-5-thiols of type 5 in the presence of a radical initiator gave dithiaspirobicycles in fair-to-excellent yield (Scheme 3).Under analogous conditions, the 4,5-dihydro-4-vinyl-1,3-thiazole-5-thiol 5d underwent a cyclization to give the annellated dithiabicycle 7 (Scheme 4).In this reaction, a minor product 8 was formed by an unknown reaction mechanism.The structure of 8 was established by X-ray crystallography.The starting 1,3-thiazole-5-thiols 5 have been synthesized by carbophilic alkylation of the C=S group of 1,3-thiazole-5(4H)-thiones with Grignard-reagents or alkylcuprates.The thiazolethiones were obtained by the reaction of 3-amino-2H-azirines with thiobenzoic acid followed by sulfurization and cyclization.The 4-benzyl derivative 1b was thermally rearranged via 1,3-benzyl migration to yield the benzyl (1,3-thiazol-5-yl) sulfide 11 (Scheme 5).
- Jenny, Christjohannes von,Wipf, Peter,Heimgartner, Heinz
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p. 838 - 846
(2007/10/02)
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- SYNTHESIS OF ARYLALKYLHYDROXAMIC ACIDS WITH AN α-ASYMMETRICAL CARBON ATOM
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Optically active hydroxamic acids have been obtained by two routes from (-)-2-phenylpropanoic, (-)-2-methyl-3-phenylpropanoic, and (-)-2-methyl-4-phenylbutanoic acids.It has been shown that the hydroxamic acids obtained by reaction of the acids with hydro
- Potapov, V. M.,Dem'yanovich, V. M,Vendrova, O. E.,Khlebnikov, V. A.
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p. 1041 - 1043
(2007/10/02)
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