- Analogues of the Herbicide, N-Hydroxy- N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads
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New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of Mycobacterium tuberculosis (Mt) KARI has a Ki value of 19.7 nM, fivefold more potent than IpOHA (Ki = 97.7 nM). This and four other potent analogues are slow- and tight-binding inhibitors of MtKARI. Three compounds were cocrystallized with Staphylococcus aureus KARI and yielded crystals that diffracted to 1.6-2.0 ? resolution. Prodrugs of these compounds possess antimycobacterial activity against H37Rv, a virulent strain of human TB, with the most active compound having an MIC90 of 2.32 ± 0.04 μM. This compound demonstrates a very favorable selectivity window and represents a highly promising lead as an anti-TB agent.
- Kandale, Ajit,Patel, Khushboo,Hussein, Waleed M.,Wun, Shun Jie,Zheng, Shan,Tan, Lendl,West, Nicholas P.,Schenk, Gerhard,Guddat, Luke W.,McGeary, Ross P.
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p. 1670 - 1684
(2021/02/27)
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- Ultrasonic promoted synthesis of Ag nanoparticle decorated thiourea-functionalized magnetic hydroxyapatite: A robust inorganic-organic hybrid nanocatalyst for oxidation and reduction reactions
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In this research, ultrasonic synthesis is applied for the fabrication of a novel catalyst, based on immobilization of silver nanoparticles (AgNPs) on thiourea functionalized magnetic hydroxyapatite. A recoverable Ag nano-catalyst is constructed by decoration of AgNPs on the surface of thiourea modified magnetic hydroxyapatite. Magnetic hydroxyapatite is used as an organic-inorganic hybrid support for the catalyst. The organic-inorganic hybrid support is prepared by co-precipitation, followed by its surface modification through covalent functionalization of 1-(3,5-bis(trifluoromethyl)phenyl)-3-propyl)thiourea. The fabricated catalyst has been characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and Brunauer-Emmett-Teller (BET) analysis. The nanoparticles are mostly tubular in shape and their particle sizes are smaller than 100 nm. This nanocatalyst shows efficient and robust catalytic activity in different reactions, including selective reduction of 4-nitrophenol (4NP) and oxidation of primary amines by applying NaBH4and urea hydrogen peroxide (UHP) as reagents, respectively. The catalyst shows good reusability in 10 sequential reaction runs.
- Bahadorikhalili, Saeed,Arshadi, Hosein,Afrouzandeh, Zahra,Ma'mani, Leila
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p. 8840 - 8848
(2020/06/08)
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- Phyllosilicate-derived Nickel-cobalt Bimetallic Nanoparticles for the Catalytic Hydrogenation of Imines, Oximes and N-heteroarenes
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The development of cost-effective, noble metal-free catalytic systems for the hydrogenation of unsaturated aliphatic, aromatic, and heterocyclic compounds is fundamental for future valorization of general feedstock. With this aim, we report here the preparation of highly dispersed bimetallic Ni/Co nanoparticles (NPs), by a one-pot deposition-precipitation of Ni and Co phases onto mesoporous SBA-15 silica. By adjusting the chemical composition in the starting mixture, three supported catalysts with different Ni to Co weight ratios were obtained, which were further subjected to treatments under reducing conditions at high temperatures. Characterization of the resulting solids evidenced a homogenous distribution of Ni and Co elements forming the NPs, the best results being obtained for Ni/Co-2 : 2 samples, for which 50 wt.percent Ni–50 wt.percent Co NPs are found located on the surface of the residual phyllosilicate. Ni/Co-2 : 2, presenting the best performances for the hydrogenation of 2-methyl-quinoline, was further evaluated in the catalytic hydrogenation of selected imines, oximes and N-heteroarenes. Due to the high dispersion of bimetallic Ni?Co NPs, excellent properties (activity and selectivity) in the conversion of the selected substrates are reported.
- Ciotonea, Carmen,Hammi, Nisrine,Dhainaut, Jérémy,Marinova, Maya,Ungureanu, Adrian,El Kadib, Abdelkrim,Michon, Christophe,Royer, Sébastien
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p. 4652 - 4663
(2020/08/19)
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- B(C6F5)3-catalyzed hydrogenation of oxime ethers without cleavage of the N-O bond
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The hydrogenation of oximes and oxime ethers is usually hampered by N-O bond cleavage, hence affording amines rather than hydroxylamines. The boron Lewis acid B(C6F5)3 is found to catalyze the chemoselective hydrogenation
- Mohr, Jens,Oestreich, Martin
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p. 13278 - 13281
(2015/01/16)
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- Asymmetric α-oxyacylation of cyclic ketones
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Reaction of cyclic ketones with chiral N-alkyl-O-acyl hydroxylamines leads to the corresponding α-oxyacylated carbonyl compound in up to 89% ee. The levels of asymmetric induction were influenced by solvent polarity, acid strength and, to a lesser extent,
- Smithen, Deborah A.,Mathews, Christopher J.,Tomkinson, Nicholas C.O.
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p. 3756 - 3762
(2012/06/01)
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- Minimisation of E-Factor in the synthesis of N-hydroxylamines: The role of silver(i)-based coordination polymers
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Among four different 2-D polymeric silver(i)-bpfb assemblies synthesized, [Ag(μ-bpfb)(N3)]n (4c) having an azide anion was shown to be the best catalyst for the partial oxidation of primary amines to N-monoalkylhydroxylamines with ur
- Sheykhan, Mehdi,Rashidi Ranjbar, Zohreh,Morsali, Ali,Heydari, Akbar
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experimental part
p. 1971 - 1978
(2012/08/14)
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- The mechanism of the α-ketoacid-hydroxylamine amide-forming ligation
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Three-ring circus! Surprisingly complex molecular acrobatics are observed in the mechanism of the α-ketoacid-hydroxylamine amide-forming ligation reaction. Although this remarkable reaction can already be used for the chemoselective union of large, unprotected peptide fragments the elucidated mechanism provides important clues to extending its application to larger and more complex biological targets. Copyright
- Pusterla, Ivano,Bode, Jeffrey W.
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supporting information; experimental part
p. 513 - 516
(2012/03/22)
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- Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide: asymmetric synthesis of β2,2,3-trisubstituted amino acids
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Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to a range of α,β-unsaturated esters gives the corresponding β-amino esters in moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single diastereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-α-methylbenzyl group and the N-O bond within the isoxazolidin-5-one ring in one pot to give the corresponding β2,2,3-trisubstituted amino acids directly.
- Bentley, Scott A.,Davies, Stephen G.,Lee, James A.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.,Toms, Steven M.
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scheme or table
p. 4604 - 4620
(2010/07/05)
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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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- Asymmetric synthesis of N-substituted N-hydroxyureas
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Asymmetric synthesis of (S)-N-(1-arylethyl)-N-hydroxyureas, (S)-N-(6-methoxy)- and (S)-N-(6-benzyloxy-2,3-dihydrobenzofuran-3-yl)-N-hydroxyurea- lipoxygenase inhibitor, is described. Three approaches to the formation of the N-hydroxyurea moiety at the stereogenic center have been used. The first one, via the reaction of (R)-6-benzyloxy-2,3-dihydrobenzofuran-3-ol with N,O-bis(phenoxycarbonyl)hydroxylamine under Mitsunobu conditions, leads to a partially racemized product. Alternatively, the enantioselective reduction of oximes O-benzyl ethers of acetophenone, 4-methoxy- and 4-benzyloxyacetophenone, 6-methoxy- and 6-benzyloxy-2,3-dihydrobenzofuran-3-one with borane/oxazaborolidines can be controlled to produce either the corresponding hydroxylamine O-benzyl ethers or primary amines which have been transformed into N-substituted N-hydroxyureas in 57% to 99% ee.
- Laczkowski, Krzysztof Z.,Pakulski, Marcin M.,Krzeminski, Marek P.,Jaisankar, Parasuraman,Zaidlewicz, Marek
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p. 788 - 795
(2008/09/20)
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- Intermolecular Cope-type hydroamination of alkenes and alkynes using hydroxylamines
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The development of the Cope-type hydroamination as a method for the metal- and acid-free intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxy-lamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes. Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products. A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of various alkenes, alkynes, and hydroxylamines.
- Moran, Joseph,Gorelsky, Serge I.,Dimitrijevic, Elena,Lebrun, Marie-Eve,Bedard, Anne-Catherine,Seguin, Catherine,Beauchemin, Andre M.
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supporting information; experimental part
p. 17893 - 17906
(2009/07/18)
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- Intermolecular cope-type hydroamination of alkenes and alkynes
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(Chemical Equation Presented) Keep it simple! Intermolecular hydroamination can be achieved simply upon heating alkynes and alkenes with aqueous hydroxylamine. Alkynes react to afford oximes in good to excellent yields, and the formation of Markovnikov products is favored. A mechanism involving Cope-type hydroamination followed by bimolecular proton transfer is suggested and supported by DFT studies.
- Beauchemin, Andre M.,Moran, Joseph,Lebrun, Marie-Eve,Seguin, Catherine,Dimitrijevic, Elena,Zhang, Lili,Gorelsky, Serge I.
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p. 1410 - 1413
(2008/12/23)
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- Phase-transfer catalysis for the synthesis of hydroxylamines from oximes using benzyltriethylammonium borohydride in methanol and under solid-phase conditions
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Effective phase-transfer catalysis methodologies for the reduction of oximes to hydroxylamines by a selective and versatile reducing agent, benzyltriethylammonium borohydride (BTEABH), in methanol and under solid-phase conditions are presented.
- Gopalakrishnan, Mannathusamy,Anandabaskaran, Thirunavukkarasu,Sureshkumar, Purusothaman,Thanusu, Jayaraman,Kumaran, Arumugam K.,Kanagarajan, Vijayakumar
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- Oxidation of primary amines to N-monoalkylhydroxylamines using sodium tungstate and hydrogen peroxide-urea complex
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The sodium tungstate-catalyzed (10 mol %) oxidation of primary amines with a urea-hydrogen peroxide complex (UHP) gives the corresponding N-monoalkylhydroxylamines, which are important biologically active compounds, in good to excellent yields. The method is applicable for a wide range of primary amines, including chiral benzylic amines, α-1,2-hydroxylamine and α-amino esters.
- Heydari, Akbar,Aslanzadeh, Saied
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p. 1223 - 1225
(2007/10/03)
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- Asymmetric reduction of ketoxime derivatives and N-alkylketimines with borane-oxazaborolidine adducts
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Oxime ethers of acetophenone, isopropyl methyl ketone, and tert-butyl methyl ketone were reduced to the corresponding hydroxylamine ethers of 45-94% ee with borane-oxazaborolidine 1 derived from (-)-norephedrine. A one-pot reduction of acetophenone oxime with 1 to 1-phenylethylhydroxylamine of 87% ee is described. The reduction of 6-methyl-2,3,4,5-tetrahydropyridine and N-methylimines of the above mentioned ketones with borane-B-methyloxazaborolidine adduct 2, derived from (-)-diphenylprolinol, gave the corresponding amines of 40-74% ee.
- Krzeminski, Marek P.,Zaidlewicz, Marek
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p. 1463 - 1466
(2007/10/03)
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- Process for the selective N-formylation of N-hydroxylamines
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The instant invention provides a process for the selective N-formylation of N-hydroxylamines.
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- BF3-promoted hydrostannation of N-heteroatom-substituted imines for the reduction of C=N bond
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Hydrostannation of N-heteroatom-substituted imines such as oxime ethers, hydrazones, oximes, nitrones, and N-sulfonyl imines using a combination of Bu3SnH and BF3·OEt2 has been systematically studied. Not only aromatic aldimines but also kitimines and aliphatic imines were reduced to give the corresponding amines.
- Ueda, Masafumi,Miyabe, Hideto,Namba, Megumi,Nakabayashi, Toshiki,Naito, Takeaki
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p. 4369 - 4371
(2007/10/03)
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- Process for the selective N-formylation of N-hydroxylamines
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The instant invention provides a process for the selective N-formylation of N-hydroxylamines.
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- A survey of suitable protecting groups for the synthesis of hydroxylamines by Mitsunobu reactions
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A variety of protecting groups, commonly associated with peptide synthesis, are suitable for the N,O-protection of hydroxylamine; the resulting reagents are all suitable for N-alkylhydroxylamine synthesis using the Mitsunobu method.
- Knight, David W.,Leese, Mathew P.
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p. 2593 - 2595
(2007/10/03)
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- Butyltriphenylphosphonium tetraborate (BTPPTB) as a selective reducing agent for the reduction of imines, enamines and oximes and reductive alkylation of aldehydes or ketones with primary amines in methanol or under solid-phase conditions
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Butyltriphenylphosphonium tetraborate (BTPPTB) 1, generated as white solid from butyltriphenylphosphonium bromide and sodium borohydride, is found to be a selective and versatile reducing agent. The reagent in methanol or under solvent-free conditions is very useful for the reduction of imines, enamines and oximes or reductive amination of aldehydes and ketones. Under solvent-free conditions the reactions are faster and the yields of the products are higher.
- Hajipour,Mohammadpoor-Baltork,Noroallhi
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p. 152 - 156
(2007/10/03)
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- Synthesis of N-substituted N-nitrosohydroxylamines as inhibitors of mushroom tyrosinase
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A series of N-substituted N-nitrosohydroxylamines including six new compounds were synthesized and examined for inhibition of mushroom tyrosinase. Corresponding hydroxylamines were reacted with n-butyl nitrite to give substituted nitrosohydroxylamines as their ammonium salt. The N-substituted hydroxylamines were prepared from the primary amines via the oxaziridine, or from the carbonyl compounds via the oxime. Most of the nitrosohydroxylamines tested inhibited mushroom tyrosinase. Among them, N-cyclopentyl-N-nitrosohydroxylamine exhibited the most potent activity (IC50=0.6 μM), as powerful as that of tropolone, one of the most powerful inhibitors. As removal of nitroso or hydroxyl moiety, the enzyme inhibitory activity was completely diminished. Both N-nitroso group and N-hydroxy group were suggested to be essential for the activity, probably by interacting with the copper ion at the active site of the enzyme. Lineweaver-Burk plotting showed that cupferron was a competitive inhibitor but that N-cyclopentyl-N-nitrosohydroxylamine was not.
- Shiino, Mitsuhiro,Watanabe, Yumi,Umezawa, Kazuo
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p. 1233 - 1240
(2007/10/03)
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- A novel transformation of primary amines to N-monoalkylhydroxylamines
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A novel transformation of primary amines to the corresponding N-monoalkylhydroxylamines is described. The three-step protocol involves selective mono-cyanomethylation of primary amines, regioselective formation of nitrones by m-CPBA oxidation, and hydroxylaminolysis of the nitrones with hydroxylamine hydrochloride. The method is applicable for a wide range of primary amines, including alkyl, benzyl, and chiral.
- Tokuyama,Kuboyama,Amano,Yamashita,Fukuyama
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p. 1299 - 1304
(2007/10/03)
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- 1-Benzyl-1-azonia-4-azabicyclo[2.2.2]octane tetrahydroborate (BAAOTB) as a selective reducing agent
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1-Benzyl-1-azonia-4-azabicyclo[2.2.2]octane tetrahydroborate (BAAOTB) 1 generated as white solid from commercially available DABCO and sodium borohydride is found to be a selective and versatile reducing agent. The reagent in t-butanol is very useful for reduction of imines, enamines, oximes, reductive amination of aldehydes and ketones and reductive methylation of amines.
- Hajipour,Mohammadpoor-Baltork,Rahi
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p. 239 - 242
(2007/10/03)
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- DNA gyrase inhibitory and antimicrobial activities of some diphenic acid monohydroxamides
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The synthesis and inhibitory activity against DNA gyrase of a series of diphenic acid Monchydroxamides 4a-f are described. A protocol of two biological assays showed conclusively that inhibition occurs specifically at the DNA-DNA gyrase complex and is not
- Ohemeng, Kwasi A.,Podlogar, Brent L.,Nguyen, Van N.,Bernstein, Jeffrey I.,Krause, Heather M.,Hilliard, Jamese J.,Barrett, John F.
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p. 3292 - 3296
(2007/10/03)
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- ADDITION OF ORGANOLITHIUM COMPOUNDS TO N-THP PROTECTED NITRONE
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A novel synthesis of a-branched primary hydroxylamines by addition of organolithium reagents to N-THP protected nitrone is described.
- Basha, Anwer,Ratajczyk, James D.,Brooks, Dee W.
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p. 3783 - 3786
(2007/10/02)
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- Diastereoselectivity of Organometallic Additions to Nitrones Bearing Sterogenic N-Substituents
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The diastereoselectivity of organometallic additions to nitrones bearing stereogenic α-arylethyl, β-methoxyalkyl, and β-(silyloxy)alkyl substituents on nitrogen has been investigated.High and complementary diastereoselectivity (90-94percent) was observed in the additions of Grignard reagents to nitrones (e.g. 22 and 23) bearing the potentially chelating β-methoxyalkyl group.However, the opposite selectivity resulted from the reaction of methylmagnesium bromide with the corresponding silyl ether (27).The relative stereochemistry of selected hydroxylamine adducts wasestablished by reduction of their phosphate and carbonate derivatives to known amines (37a,b and 39), by periodate cleavage of a β-hydroxy hydroxylamine (41b), and by various correlations (Scheme II).The high facial diastereoselectivity observed with the N-(β-methoxyalkyl)nitrones is explained by a simple chelation model (Scheme III).
- Chang, Zen-Yu,Coates, Robert M.
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p. 3464 - 3474
(2007/10/02)
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- A Fast Procedure for the Reduction of Azides and Nitro Compounds Based on the Reducing Ability of Sn(SR)3-Species
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Tin(II) complexes prepared by treatment of SnCl2 or Sn(SR)2 with appropriate amounts of RSH and Et3N appear to be the best reducing agents for azides (to amines) reported so far.Thes tin(II) complexes also reduce primary and secondary aliphatic nitro compounds to oximes, usually within minutes at r.t. or hours in cold, and tertiary aliphaic as well as aromatic nitro compounds to afford the corresponding hydroxylamines.In general, azides react more rapidly than nitro substituents, whereas carbonyl groups, sulphoxides, sulphones, nitriles, and esters are practically unreactive under the same conditions.Some mechanistic details of the reaction of Sn(SPh)3- with azides and nitro compounds have also been elucidated.
- Bartra, Marti,Romea, Pedro,Urpi, Felix,Vilarrasa, Jaume
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p. 587 - 594
(2007/10/02)
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- THE REACTION OF LiAlH4/HMPA WITH OXIMES: MECHANISM AND SYNTHETIC APPLICATIONS
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Three aspects of the reaction of LiAlH4 in HMPA with oximes have been studied: the mechanism of the conversion of ketoximes into ketones, application of this reaction to the selective reduction of enones to ketones via the ene-oxime, and the conversion of aldoximes to either nitriles or aldehydes as a function of substrate structure.
- Balachander, Natarajan,Wang, Shin-Shin,Sukenik, Chaim N.
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p. 4849 - 4852
(2007/10/02)
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