- Catalytic Asymmetric Synthesis of Unprotected β2-Amino Acids
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We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. A newly developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a silylated aminomethyl ether, followed by hydrolytic workup, to give free β2-amino acids in high yields, purity, and enantioselectivity. Importantly, both aromatic and aliphatic β2-amino acids can be obtained using this method. Mechanistic studies are consistent with the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to explain the enantioselectivity is suggested on the basis of density functional theory calculation.
- Zhu, Chendan,Mandrelli, Francesca,Zhou, Hui,Maji, Rajat,List, Benjamin
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p. 3312 - 3317
(2021/04/07)
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- Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
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The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modification of the obtained cysteine mutants with maleimides, followed by computational elucidation of the possible binding modes. In infected cells, antiviral activity against Dengue virus serotype 2 using prodrugs of the inhibitors was observed. In summary, a novel inhibitor scaffold targeting an allosteric site shared between flaviviral NS2B/NS3 proteases is presented whose efficacy is demonstrated in vitro and in cellulo.
- Millies, Benedikt,Von Hammerstein, Franziska,Gellert, Andrea,Hammerschmidt, Stefan,Barthels, Fabian,G?ppel, Ulrike,Immerheiser, Melissa,Elgner, Fabian,Jung, Nathalie,Basic, Michael,Kersten, Christian,Kiefer, Werner,Bodem, Jochen,Hildt, Eberhard,Windbergs, Maike,Hellmich, Ute A.,Schirmeister, Tanja
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p. 11359 - 11382
(2019/12/24)
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- AN ECO-FRIENDLY PROCESS FOR HYDROGENATION OR/AND HYDRODEOXYGENATION OF ORGANIC COMPOUND USING HYDROUS RUTHENIUM OXIDE CATALYST
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The invention discloses aneco-friendly process for hydrogenation (alkenealkene, carbonyl compound and aromatic) and hydrodeoxygenation (methoxy phenols) of organic compound using hydrous ruthenium oxide (HRO) and its supported form as a recyclable heterogeneous catalyst in aqueous medium with good yield of desired compounds (70-100%) under mild reaction conditions. The invention also discloses hydrogenation of organic compound such as alkene, carbonyl compound and substituted aromatic and also for the processes that involve hydrodeoxygenation, for example, lignin derived aromatic (methoxy phenols).
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Page/Page column 15; 22
(2017/08/01)
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- Method for preparing (S)-3-piperidinecarboxylic acid
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The invention discloses a method for preparing (S)-3-piperidinecarboxylic acid. The method includes steps of carrying out reaction on 3-piperidinecarboxamide or salt of the 3-piperidinecarboxamide in concentrated hydrochloric acid to obtain (S)-3-piperidinecarboxylic acid salt; converting the (S)-3-piperidinecarboxylic acid salt to obtain the (S)-3-piperidinecarboxylic acid. The method has the advantages that the reaction is carried out on the 3-piperidinecarboxamide or the salt of the 3-piperidinecarboxamide in the concentrated hydrochloric acid, accordingly, chiral resolution effects can be realized while hydrolysis is carried out, and resolution on the 3-piperidinecarboxamide or 3-piperidinecarboxylic acid by the aid of chiral resolving agents can be omitted; preparation processes are simple in post-treatment operation, N protection and de-protection processes are omitted, accordingly, the method is high in atomic economy and low in cost, and a simple, feasible and low-cost production method can be provided for synthesizing the (S)-3-piperidinecarboxylic acid.
- -
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Paragraph 0025-0030; 0036; 0039; 0041
(2017/08/29)
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- Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)
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The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors of diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification of the pyrrolidine amide group for a significant LipE improvement, and (2) insertion of a sp3-hybridized carbon center in the core of the molecule for simultaneous improvement of N-glucuronidation metabolic liability and off-target pharmacology. The preclinical candidate 9 (PF-06424439) demonstrated excellent ADMET properties and decreased circulating and hepatic lipids when orally administered to dyslipidemic rodent models.
- Futatsugi, Kentaro,Kung, Daniel W.,Orr, Suvi T. M.,Cabral, Shawn,Hepworth, David,Aspnes, Gary,Bader, Scott,Bian, Jianwei,Boehm, Markus,Carpino, Philip A.,Coffey, Steven B.,Dowling, Matthew S.,Herr, Michael,Jiao, Wenhua,Lavergne, Sophie Y.,Li, Qifang,Clark, Ronald W.,Erion, Derek M.,Kou, Kou,Lee, Kyuha,Pabst, Brandon A.,Perez, Sylvie M.,Purkal, Julie,Jorgensen, Csilla C.,Goosen, Theunis C.,Gosset, James R.,Niosi, Mark,Pettersen, John C.,Pfefferkorn, Jeffrey A.,Ahn, Kay,Goodwin, Bryan
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supporting information
p. 7173 - 7185
(2015/10/05)
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- Characterization of an enantioselective amidase from Cupriavidus sp. KNK-J915 (FERM BP-10739) useful for enzymatic resolution of racemic 3-piperidinecarboxamide
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A novel amidase (CsAM) acting on (R,S)-N-benzyl-3-piperidinecarboxamide was purified from Cupriavidus sp. KNK-J915 (FERM BP-10739) and characterized. The enzyme acts on (R,S)-N-benzyl-3-piperidinecarboxamide S-selectively to yield (R)-N-benzyl-3-piperidinecarboxamide. Analytical gel filtration column chromatography and SDS-PAGE revealed that the enzyme is a tetramer with a subunit of approximately 47 kDa. It has a broad substrate spectrum against nitrogen-containing heterocyclic amides. Its optimal pH and temperature are 8.0-9.0 and 50 °C, respectively. The CsAM gene was cloned and sequenced, and it was found to comprise 1341 bp and encode a polypeptide of 46,388 Da. The deduced amino acid sequence exhibited 78% identity to that of a putative amidase (CnAM) from Cupriavidus necator JMP134. The cultured cells of recombinant Escherichia coli producing CnAM could be used for the S-selective hydrolysis of (R,S)-N-benzyl-3-piperidinecarboxamide but could not be used for the S-selective hydrolysis of (R,S)-3-piperidinecarboxamide because of its very low level of selectivity. In contrast, the cultured cells of recombinant E. coli producing CsAM could hydrolyze both (R,S)-N-benzyl-3-piperidinecarboxamide and (R,S)-3-piperidinecarboxamide with high S-selectivity.
- Nojiri, Masutoshi,Taoka, Naoaki,Yasohara, Yoshihiko
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p. 136 - 142
(2014/12/10)
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- PROCESS FOR PRODUCING SOLID AMINO ACID
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The problem to be solved by the present invention is to ea lily and efficiently produce an amino acid having 2 to 7 carbon atoms as a high-purity solid without complicated operation, which is useful as a synthetic intermediate for medicines or agrochemicals. The present invention is characterized in comprising a step of precipitating solid amino acid with high purity. In the present invention, the by-produced salt composed of the sulfonic acid and the amine was removed to the mother liquor by reacting an amine with a sulfonic acid salt of amino acid in an aprotic polar solvent, or by reacting a sulfonic acid with an amine salt of amino acid in an aprotic polar solvent. The sulfonic acid salt of amino acid, for example, may be produced by reacting a N-(tert-butoxycarbonyl) amino acid with a sulfonic acid, or by reacting an amino acid tert-butyl ester with a sulfonic acid.
- -
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Paragraph 0057-0060
(2014/12/09)
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- DIACYLGLYCEROL ACYLTRANSFERASE 2 INHIBITORS
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Derivatives of purine, 3H-imidazo[4,5-b]pyrimidine and 1H- imidazo[4,5-d]pyrazine of Formula I that inhibit the activity of the diacylglycerol acyltransferase 2 (DGAT2) and their uses in the treatment of diseases linked thereto in animals are described herein.
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Page/Page column 138
(2013/10/22)
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- Iridium-catalyzed enantioselective hydrogenation of unsaturated heterocyclic acids
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Spiral binding: A highly enantioselective hydrogenation of unsaturated heterocyclic acids has been developed by using chiral iridium/spirophosphino oxazoline catalysts (see scheme; BArF-=tetrakis[3,5- bis(trifluoromethyl)phenyl]borate, Boc=tert-butoxycarbonyl). This reaction provided an efficient method for the preparation of optically active heterocyclic acids with excellent enantioselectivities. Copyright
- Song, Song,Zhu, Shou-Fei,Pu, Liu-Yang,Zhou, Qi-Lin
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p. 6072 - 6075
(2013/07/05)
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- METHOD FOR PRODUCING OPTICALLY ACTIVE 3-AMINOPIPERIDINE OR SALT THEREOF
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The present invention relates to a method for producing an optically active 3-aminopiperidine or salt thereof. In the method, a racemic nipecotamide is stereoselectively hydrolyzed to obtain an optically active nipecotamide and an optically active nipecotic acid in the presence of an enzyme source derived from an organism, and then the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by aroylation, Hofmann rearrangement, deprotection of the amino group and further deprotection; or the optically active nipecotamide is derived into an optically active aminopiperidine or salt thereof by selective protection with BOC, Hofmann rearrangement and further deprotection. It is possible by the present invention to produce an optically active 3-aminopiperidine or salt thereof useful as a pharmaceutical intermediate from an inexpensive and easily available starting material by easy method applicable to industrial manufacturing.
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Page/Page column 15-16
(2010/05/13)
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- Microwave-assisted hydrogenation of pyridines
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Using a commercially available device for controlled introduction of hydrogen in a vial for reactions under microwave dielectric heating, we developed a protocol for the transformation of substituted pyridines into the corresponding piperidines. Complete reduction occurred in 40 minutes, or even less, on substrates that require 24-48 hours to be reduced under standard conditions. Moreover, the reduction proved to be as stereoselective as the corresponding reaction carried out at room temperature. Georg Thieme Verlag Stuttgart.
- Piras, Leonarda,Genesio, Eva,Ghiron, Chiara,Taddei, Maurizio
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body text
p. 1125 - 1128
(2009/04/04)
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- Preparation of β2-amino acid derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys, pyrrolidine-3-carboxylic acid) by using DIOZ as chiral auxiliary
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The title compounds were prepared from valine-derived N-acylated oxazolidin-2-ones, 1-3, 7, 9, by highly diastereoselective (≥ 90%) Mannich reaction (→ 4-6; Scheme 1) or aldol addition (→ 8 and 10; Scheme 2) of the corresponding Ti- or B-enolates as the key step. The superiority of the '5,5-diphenyl-4-isopropyl-1,3-oxazolidin-2-one' (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t-Bu-, Boc-, Fmoc-, and Cbz-protected β2-homoamino acid derivatives 11-23 (Schemes 3-6). The use of ω-bromo-acyl-oxazolidinones 1-3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic-acid derivatives.
- Gessier, Francois,Schaeffer, Laurent,Kimmerlin, Thierry,Floegel, Oliver,Seebach, Dieter
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p. 2235 - 2249
(2007/10/03)
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- Enantioselective homogeneous hydrogenation of monosubstituted pyridines and furans
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The first case of an enantioselective hydrogenation of monosubstituted pyridines and furans with homogeneous rhodium diphosphine catalysts with low but significant enantioselectivities and catalyst activities is reported. Best enantioselectivities (ees of 24-27%) were obtained for the hydrogenation of 2-and 3-pyridine carboxylic acid ethyl ester and 2-furan carboxylic acid with catalysts prepared in situ from [Rh(nbd)2]BF4 and the chiral ligands diop, binap, or ferrocenyl diphosphines of the josiphos type. Turnover numbers (ton) were in the order of 10-20, turnover frequencies (tof) usually 1-2 h-1. Diphosphines giving 6-or 7-ring chelates led to higher ees than 1,2-diphosphines; otherwise, no clear correlation between ligand properties and catalytic performance was found. In some experiments black precipitates were observed at the end of the reaction, indicating the decomposition of the homogeneous catalysts for certain ligand/metal/ substrate combinations.
- Studer, Martin,Wedemeyer-Exl, Christina,Spindler, Felix,Blaser, Hans-Ulrich
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p. 1335 - 1343
(2007/10/03)
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- Stereochemical control of hairpin formation in β-peptides containing dinipecotic acid reverse turn segments
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We examine the relationship between covalent structure and conformational propensity among a series of β-amino acid tetramers. These experiments focus on the hairpin folding motif. Among conventional peptides, the minimum increment of β-sheet secondary structure is a 'β-hairpin,' in which two strands are connected via a short loop. The present studies are aimed at optimizing hairpin stability among β-peptides. Previous work from our laboratory has identified optimal substitution patterns for residues that form strands in an antiparallel β-peptide sheet (Krauthauser et al. J. Am. Chem. Soc. 1997, 119, 11719), and we have shown that a dinipecotic acid segment can promote sheet-type interactions between attached strand residues (Chung et al. J. Am. Chem. Soc. 1998, 120, 10555). Here we compare all four possible configurations of the dinipecotic acid segment, (R,S), (S,R), (R,R) and (S,S), for the ability to induce sheet formation with a constant set of enantiomerically pure strand residues. We show that both heterochiral dinipecotic acid segments promote hairpin formation, although one is distinctly superior. Neither of the homochiral dinipecotic acid supports hairpin folding. When the strand residues are β-alanine (achiral), the heterochiral dinipecotic acid segment is again superior to the homochiral segment, but we find a difference between hairpin conformations in solution and in the solid state.
- Chung, Yong Jun,Huck, Bayard R.,Christianson, Laurie A.,Stanger, Heather E.,Krauthaeuser, Susanne,Powell, Douglas R.,Gellman, Samuel H.
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p. 3995 - 4004
(2007/10/03)
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- Pd-catalyzed asymmetric allylic alkylation of 3-acetoxy-N-(tert- butyloxycarbonyl)-1,2,3,6-tetrahydropyridine - Preparation of key intermediates for natural product synthesis
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A convenient synthesis of racemic tetrahydropyridine 1 was developed. Pd-catalyzed allylic alkylation of 1 with malonate and dimethylacetoxymalonate as nucleophiles with the phosphanylcarboxylic acid L1 and the dihydrooxazol L2 as ligands, were carried out and gave enantiomeric excesses of up to 98%. Absolute configurations were determined for all compounds described. From the alkylation products (+)- and (-)-2a, and (+)- and (-)-2b a variety of versatile, nonracemic chiral intermediates were prepared.
- Schleich, Simone,Helmchen, Guenter
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p. 2515 - 2521
(2007/10/03)
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- Polymerization- and solvent-triggered cooperativity between copper(II) ions in the catalysis of the hydrolysis of amino esters by pyridine-based ligands
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Polymeric (2) and oligomeric (4, 5) materials made of repeating units of 2,6-diaminomethylpyridine and 4,4′-diphenylmethane have been synthesized with the number of monomeric units (n) ranging from 2 to 29. In 1:1 DMSO/water solutions, these materials are fully soluble and strongly bind CuII ions. The complexes catalyze to different extents the hydrolysis of the p-nitrophenyl esters of α-, β-, and γ-amino acids. Only CuII complexes of polymeric 2 (n ≥ 10) are more effective catalysts than free CuII ions in the cleavage of β-amino esters. Such enhanced reactivity, which in the case of β-alanine p-nitrophenyl ester (β-AlaPNP) amounts to almost two orders of magnitude when the comparison is made with the CuII complex of monomeric ligand (N,N'-benzyl)-2,6-aminomethylpyridine (3), is observed in 1:1 (v/v) DMSO/H2O only when a certain degree of polymerization is reached (6 3CH2OH/H2O the kinetic benefits of the complexes of polymer 2 (n = 10) diminishes and vanishes in 9:1 (v/v) CH3CH2OH/H2O. Analysis of rate data suggests that two neighboring CuII ions bound to the polymeric ligands cooperate for the occurrence of the hydrolytic process: one of them coordinates the amino group of the substrate so that the carbonyl of the carboxylate faces the second metal ion which delivers a bound hydroxyl acting as the nucleophilic species. The selectivity toward β-amino ester is likely associated with a rather rigid conformation of these metallopolymers which places two metal centers at the appropriate distance one from the other. It is suggested that the onset of the metal ion cooperativity is connected to a conformational change of the metallopolymer from an extended to a globular structure, likely triggered by hydrophobic forces.
- Scrimin, Paolo,Tecilla, Paolo,Tonellato, Umberto
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p. 1143 - 1153
(2007/10/03)
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- Chemoselective deprotection of benzyl esters in the presence of benzyl ethers, benzyloxymethyl ethers and N-benzyl groups by catalytic transfer hydrogenation
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-COOBn, -PO(OH)OBn, -O-CBz and N-CBz groups are efficiently and chemoselectively deprotected in the presence of Bn and BOM ethers and N-Bn groups by hydrogenolysis under catalytic transfer hydrogenation using 10% palladium on carbon as the catalyst and cyclohexadiene as the hydrogen donor.
- Bajwa
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p. 2299 - 2302
(2007/10/02)
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- Various N-substituted 3-piperidine carboxylic acids or N-substituted 3-pyridinecarboxylic acids and derivatives thereof
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Selected analogs of nipecotic acid are the novel compounds of the present invention. The analogs are GABA uptake inhibitors for use to treat epilepsy and, thus, the invention is also pharmaceutical compositions and methods of use therefor.
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- Hydrolysis of nipecotic acid phenyl esters
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The synthesis and anticonvulsant activity of nipecotic acid esters (1a-1f) have been previously reported. It was thought that these prodrug esters underwent hydrolytic conversion to 1 which inhibited GABA uptake, and that both 1 and an intact ester may ha
- Gokhale,Crider,Gupte,Wood
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- Various N-substituted 3-piperidine carboxylic acids or N-substituted 3-pyridinecarboxylic acids and derivatives thereof
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Analogs of nipecotic acid are the novel compounds of the present invention. The analogs are GABA uptake inhibitors for use to treat epilepsy and, thus, the invention is also pharmaceutical compositions and methods of use therefor.
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- ORIENTATION OF CARBOXYLATION REACTION BY CONTACT GLOW DISCHARGE ELECTROLYSIS
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The carboxylation reaction of aliphatic amines and cyclic imines in aqueous formic acid by contact glow discharge electrolysis (CDGE) was studied and the orientation of the carboxylation reaction was investigated.It was found that orientation of the reaction was controlled by the effect of the charged and uncharged nitrogen atom.
- Terasawa, Jun-ichi,Harada, Kaoru
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-