- Design, Synthesis, and Biological Evaluation of Novel 3-Aminomethylindole Derivatives as Potential Multifunctional Anti-Inflammatory and Neurotrophic Agents
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The development of multifunctional molecules that are able to simultaneously interact with several pathological components has been considered as a solution to treat the complex pathologies of neurodegenerative diseases. Herein, a series of aminomethylindole derivatives were synthesized, and evaluation of their application for antineuroinflammation and promoting neurite outgrowth was disclosed. Our initial screening showed that most of the compounds potently inhibited lipopolysaccharide (LPS)-stimulated production of NO in microglial cells and potentiated the action of NGF to promote neurite outgrowth of PC12 cells. Interestingly, with outstanding NO/TNF-α production inhibition and neurite outgrowth-promoting activities, compounds 8c and 8g were capable of rescuing cells after injury by H2O2. Their antineuroinflammatory effects were associated with the downregulation of the LPS-induced expression of the inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Western blotting and immunofluorescence assay results indicated that the mechanism of their antineuroinflammatory actions involved suppression of the MAPK/NF-κB signal pathways. Further studies revealed that another important reason for the high comprehensive antineuroinflammatory activity was the anti-COX-2 capabilities of the compounds. All these results suggest that the potential biochemical multifunctional profiles of the aminomethylindole derivatives provide a new sight for the treatment of neurodegenerative diseases.
- Wang, Wei-Wei,Liu, Ting,Lv, Yu-Meng,Zhang, Wu-Yang,Liu, Zhi-Gang,Gao, Jin-Ming,Li, Ding
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p. 1593 - 1605
(2021/05/31)
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- Mechanosynthesis of N-methyl imines using recyclable imidazole-based acid-scavenger: In situ formed ionic liquid as catalyst and dehydrating agent
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1,1′-(1,4-Butanediyl)bis(imidazole) was prepared by a modified method and its application as an efficient promoter was demonstrated for the mechanosynthesis of N-methyl imines using ball milling as a non-conventional process under solvent-free conditions. In this new protocol design, the bis-imidazole acted as a recyclable acid-scavenging agent. This efficient approach to the N-methyl imines displays a combination of the synthetic virtues of a non-conventional condensation reaction with ecological benefits and convenience of a facile mechanosynthetic process. The current method has advantages such as reduced waste by avoiding solvent, exclusion of hazardous materials during the reaction, elimination of handling an anhydrous gas in an evacuated container or a solution of methylamine in ethanol, good yields for relatively unreactive benzaldehydes containing electron-donating substituents, short reaction times, and metal- and acid-free conditions. Furthermore, the promoter was easily regenerated and reused several times with no significant loss of activity.
- Khaligh, Nader Ghaffari,Ling, Ong Chiu,Mihankhah, Taraneh,Johan, Mohd Rafie,Ching, Juan Joon
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p. 194 - 199
(2018/12/04)
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- Epoxide-Mediated Stevens Rearrangements of α-Amino-Acid-Derived Tertiary Allylic, Propargylic, and Benzylic Amines: Convenient Access to Polysubstituted Morpholin-2-ones
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A new strategy has been established for the synthesis of polysubstituted morpholin-2-ones through Stevens rearrangements of tertiary amines via in situ activation with epoxides. A range of α-amino acid-derived tertiary allylic, propargylic, and benzylic amines reacted with epoxides in the presence of zinc halide catalysts to afford structurally diverse allyl-, allenyl-, and benzyl-substituted morpholin-2-ones, respectively, in moderate-to-good yields with high regioselectivity. The process involves [2,3]- and [1,2]-Stevens rearrangements of quaternary ammonium ylide intermediates and constitutes a very convenient method to prepare polysubstituted morpholin-2-ones through tandem formation of C?N, C?O, and C?C bonds. Moreover, replacing epoxides with aziridines permitted the synthesis of polysubstituted piperazin-2-ones.
- Jin, You-Xiang,Yu, Bang-Kui,Qin, Si-Ping,Tian, Shi-Kai
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supporting information
p. 5169 - 5172
(2019/03/28)
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- Synthesis of N-methyl imines in the presence of poly(N-vinylpyridine) as a reusable solid base catalyst by a mechanochemical process
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The synthesis of N-methyl imines was performed in the presence of catalytic amounts of poly(4-vinylpyridine) in high yields and rapidly at room temperature by a ball milling process. This new method has some advantages including good yields for relatively unreactive carbonyl compounds and short reaction times as well as being green in terms of avoiding the use of toxic reagents and solvents. The major advantage of this process is that the catalyst can be easily regenerated and reused several times without any significant loss of activity.
- Khaligh, Nader Ghaffari,Abbo, Hanna S.,Titinchi, Salam J. J.
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p. 901 - 910
(2017/02/10)
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- Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family
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Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, molecules able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by molecular modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.
- Tintori, Cristina,Brai, Annalaura,Dasso Lang, Maria Chiara,Deodato, Davide,Greco, Antonia Michela,Bizzarri, Bruno Mattia,Cascone, Lorena,Casian, Alexandru,Zamperini, Claudio,Dreassi, Elena,Crespan, Emmanuele,Maga, Giovanni,Vanham, Guido,Ceresola, Elisa,Canducci, Filippo,Ari?n, Kevin K.,Botta, Maurizio
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p. 2747 - 2759
(2016/04/10)
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- Four-Electron Electrocyclic Ring-Opening/Intermolecular [4+2] Cycloadditions of α-Hydroxycyclobutenones: Stereoselective Synthesis of Multiple Substituted δ-Lactams
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A four-electron electrocyclic ring-opening/intermolecular [4+2] cycloaddition of α-hydroxycyclobutenones is reported. The reaction represents the first example for the intermolecular cycloaddition of the extensively studied enol-ketene intermediate, and provides a new synthetic route to multiply substituted δ-lactams in high stereoselectivity.
- Song, Peidong,Li, Qing,Wang, Congcong,Wu, Wenfa,Mao, Xu,Wang, Jiajia,Hu, Xiangdong
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supporting information
p. 1208 - 1212
(2016/04/26)
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- Synergistic effect of dual-frequency ultrasound irradiation in the one-pot synthesis of 3,5-disubstituted isoxazoles
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Herein is reported a one-pot three-step process for the regioselective synthesis of 3,5-disubstituted isoxazoles based on copper(I)-catalyzed cycloaddition reaction between in situ generated nitrile oxides (from the corresponding aldehydes) and alkynes, u
- Koufaki, Maria,Fotopoulou, Theano,Heropoulos, Georgios A.
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- Chemoselective reductive nucleophilic addition to tertiary amides, secondary amides, and N-methoxyamides
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As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide car-bonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor elec-trophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nu-cleophiles to tertiary amides, secondary amides, and N-methoxyamides that uses the Schwartz reagent [Cp2ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.
- Nakajima, Minami,Oda, Yukiko,Wada, Takamasa,Minamikawa, Ryo,Shirokane, Kenji,Sato, Takaaki,Chida, Noritaka
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supporting information
p. 17565 - 17571
(2015/02/19)
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- Simple and efficient one-pot solvent-free synthesis of N-methyl imines of aromatic aldehydes
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A one-pot solvent-free synthesis of N-methyl imines in good to excellent yields was performed by grinding together aromatic aldehydes and methylamine hydrochloride in the presence of a base. The best yields were achieved when an excess of methylamine hydrochloride and inexpensive sodium hydrogen carbonate was used (usually in a molar ratio ArCHO/CH3NH2· HCl/NaHCO3 = 1:5:5), allowing the reaction to proceed for 1 h (in the case of aromatic aldehydes containing electron-withdrawing substituents) or overnight (in the case of electron-rich aldehydes). After a simple work-up (extraction with diethyl ether) the obtained products were mostly pure enough for spectral characterization. In this way, 31 N-methyl imines were prepared, among which eight were synthesized for the first time. Their structures were elucidated by spectral means (1H- and 13C-NMR, IR, MS) whenever it was possible. In the case of salicylaldehyde and 4-chlorobenzaldehyde, the synthesis of the corresponding imines was also conducted on a gram-scale with a 72% and 84% isolated yield, respectively. The present approach not only provides good to high yields, but also eliminates the disadvantages of the traditional synthesis of N-methyl imines, such as the use of hazardous solvents and more or less expensive catalysts and the necessity of work/handling with an anhydrous gas in pressurized containers.
- Radulovi?, Niko S.,Miltojevi?, Ana B.,Vuki?evi?, Rastko D.
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p. 257 - 270
(2013/05/09)
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- 3-Thiolated 2-azetidinones: Synthesis and in vitro antibacterial and antifungal activities
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A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.
- Zarei, Maaroof,Mohamadzadeh, Masoud
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experimental part
p. 5832 - 5840
(2011/08/10)
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- Efficient synthesis of new 4-arylideneimidazolin-5-ones related to the GFP chromophore by 2+3 cyclocondensation of arylideneimines with imidate ylides
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A 2+3 condensation of a wide assortment of Schiff bases, prepared from aromatic aldehydes and primary amines, with methyl (1-ethoxyethylideneamino) acetate allows convenient access to an extensive family of substituted 4-arylideneimidazolin-5-one analogues of the green fluorescent protein (GFP) chromophore. Georg Thieme Verlag Stuttgart · New York.
- Baldridge, Anthony,Kowalik, Janusz,Tolbert, Laren M.
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scheme or table
p. 2424 - 2436
(2010/09/06)
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- Germanium(II)-mediated reductive Mannich-type reaction of α-bromoketones to N-alkylimines
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(Chemical Equation Presented) A versatile metal: Germanium was effectively used in a novel and efficient method for the Mannich-type reaction between α-bromoketones and simple N-alkyl imines (see scheme). Germanium(II) acts as a reducing agent, forming a
- Tanaka, Shin-Ya,Tagashira, Nobuo,Chiba, Kouji,Yasuda, Makoto,Baba, Akio
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supporting information; experimental part
p. 6620 - 6623
(2009/03/12)
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- Synthesis of 2-alkyl-1-aryl-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione derivatives
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A preparative procedure for the synthesis of 2-alkyl-1-aryl-1,2- dihydrochromeno[2,3-c]pyrrole-3,9-diones from methyl 4-(o-hydroxyphenyl)-2,4- dioxobutanoate, aromatic aldehyde, and aliphatic amine is described.
- Vydzhak,Panchishin, S. Ya.
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experimental part
p. 2391 - 2397
(2009/05/30)
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- Efficient microwave-assisted solvent-free synthesis of N-substituted aldimines
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Neat non-volatile amines react with various aromatic aldehydes in the absence of any catalyst, solid support, or solvent, to give imines after a reaction time of eight minutes under microwave irradiation by a clean and very efficient process (yields: 75-100%). In the case of volatile amine, methylamine, 1,3-dimethylurea dispersed on montmorillonite K10 is used as an amine precursor to prepare the corresponding imines. Georg Thieme Verlag Stuttgart.
- Paquin, Ludovic,Hamelin, Jack,Texier-Boullet, Francoise
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p. 1652 - 1656
(2007/10/03)
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- Oxidation of secondary amines by molecular oxygen and cyclohexanone monooxygenase
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Cyclohexanone monooxygenase from Acinetobacter calcoaceticus catalyzed the oxidation of tertiary and secondary amines to N-oxides and nitrones, respectively. The formation of a hydroxylamine intermediate was involved with secondary amines as starting substrates.
- Colonna, Stefano,Pironti, Vincenza,Carrea, Giacomo,Pasta, Piero,Zambianchi, Francesca
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p. 569 - 575
(2007/10/03)
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- Quantitative solid-state reactions of amines with carbonyl compounds and isothiocyanates
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A series of solid-state reactions is reported of gaseous or solid amines with aldehydes to give imines, with solid anhydrides to give diamides (therefrom imides) or amidic carboxylic salts or imides, with solid imides to give diamides, with solid lactones or carbonates to give functionalized carbamic esters, with polycarbonates to give degradative aminolysis, and with solid isothiocyanates to give thioureas. Diamides give imides by solid-state thermolysis or acid catalysis. Various double, two-step, 3-cascade, and sequential reactions are reported in the solid state without melting. The yields are quantitative in 53 reported reaction examples and no workup (except for washings in four cases) is required in the 100% yield reactions. Three initially solid-state reactions but with liquid product were not quantitative. An upscaling to the kg scale shows promise of the technique for large scale applications. Supermicroscopic analyses with AFM elucidate the solid-state mechanism by virtue of far-reaching anisotropic molecular movements in three-step processes. Gas-solid aminolyses of polycarbonates are also studied with AFM. The implications to sustainable chemistry are discussed. (C) 2000 Elsevier Science Ltd.
- Kaupp, Gerd,Schmeyers, Jens,Boy, Juergen
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p. 6899 - 6911
(2007/10/03)
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- Reactions of N-Benzyl- and N-Benzylidene-alkanolamines with Bromine: Formation of 1,3-Oxazolidines, 1,3-Oxazinanes, 4,5-Dihydro-1,3-oxazoles and 5,6-Dihydro-4H-1,3-oxazines
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N-Methylbenzylamines react with bromine in acetonitrile to form N-benzylidenemethylamines.Under similar conditions 2-benzylaminoethanols and 3-benzylaminopropan-1-ols afford 3-benzyl-2-phenyl-1,3-oxazolidines and 3-benzyl-2-phenyl-1,3-oxazinanes, respectively. 2-Benzylidineaminoethanols and 3-benzylideneaminopropan-1-ols likewise give 2-aryl-4,5-dihydro-1,3-oxazoles and 2-aryl-5,6-dihydro-4H-1,3-oxazines, respectively.When N-benzylidenemethylamine is treated with bromine in the presence of alcohols, benzaldehyde acetals are obtained.
- Goosen, Andre,McCleland, Cedric W.,Sipamla, Allworth M.
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p. 2221 - 2232
(2007/10/03)
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- Reactions of N-Chloro-N-alkylbenzylamines with Amines in Acetonitrile. Origin of Steric Effect in Imine-Forming Elimination
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Reaction of N-chloro-N-alkylbenzylamines in which the alkyl group is Me, Et, i-Pr, sec-Bu, and t-Bu with MeNH2 and Et2NH in MeCN have been studied kinetically.The eliminations are quantitative and regiospecific, producing only N-benzylidenealkylamines.The relative rates of elimination for Me/Et/i-Pr/sec-Bu/t-Bu alkyl substituents are 1/0.6/0.4/0.3/0.1 with MeNH2 and 1/0.5/0.3/0.2/0.03 with Et2NH, respectively.Comparison with published data reveals that Charton's value for the imine-forming elimination decreases with the variation of the base-solvent from MeONa-MeOH to MeNH2-MeCN but increases when the base is changed from MeNH2 to Et2NH.For a given base, Hammett ρ and kH/kD values decrease and the ΔH(excit.) and ΔS(excit.) values increase with bulkier alkyl substituents.From these results, the origin of the steric effect in imine-forming elimination is attributed to the repulsive interaction between the alkyl group and the base in the transition state.
- Cho, Bong Rae,Suh, Young Wook
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p. 2855 - 2858
(2007/10/02)
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- Reactions of N-Halogenobenzylmethylamines with Triethylamine in Acetonitrile. Effect of Leaving Group upon the Imine-forming Transition State
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Reactions of N-halogenobenzylmethylamines (1) and (2) with Et3N-MeCN have been investigated kinetically.Eliminations from (1) and (2) were quantitative and regiospecific, producing only benzylidenemethylamines.For the elimination reaction of (1) with Et3N, kH/kD 5.7, ρ 0.88, 9.1 kcal mol-1, and -42.4 cal mol-1 K-1 were determined.The transition-state structure is assessed as being highly symmetric with similar extents of Cβ-H and Nα-Cl bond cleavage, little carbanionic character, and significant ?-bond formation.The structure of the transition state changes only slightly with the change in the leaving group from Cl to Br.
- Cho, Bong Rae,Namgoong, Sung Keon,Kim, Tae Rin
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p. 853 - 856
(2007/10/02)
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- Reactions of N-Chlorobenzylmethylamines with Secondary Amines in Acetonitrile. Effect of Base Strength upon the Imine-Forming Transition State
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Reactions of N-chlorobenzylmethylamines 1 with R2NH in MeCN have been investigated kinetically.Eliminations from 1 were quantitative and regiospecific, producing only benzylidenemethylamines.For the elimination reaction of 1 with Bu2NH, kH/kD = 8.8, ρ = 0.96, ΔH(excit.) = 7.6 kcal/mol, and ΔS(excit.) = -45.1 eu were determined.The transition state structure is assessed as being highly symmetrical with similar extents of Cβ-H and Nα-Cl bond cleavage, little carbanionic character, and significant ? bond formation.The kH/kD and ρ values first increase and then decrease with enhancing amine base strength.Comparison of these results with those for related olefin-forming eliminations provides insight into the transition state differences between imine- and olefin-forming eliminations.
- Cho, Bong Rae,Namgoong, Sung Keon,Bartsch, Richard A.
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p. 1320 - 1324
(2007/10/02)
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- Is Oxygen Abstraction by Nucleophilic Reagents a Characteristic Reaction of Oxaziridines ?
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The reaction of oxaziridines with nucleophilic reagents was studied.The summarized results are as follows. (1) The nucleophilic reactions occur preferentially on the nitrogen atom and the oxaziridine decomposes into a carbonyl compound and an ylide. (2) The reaction site shifts from nitrogen toward oxygen as the bulk of the ring substituents increases. (3) Cis isomers show faster reaction than trans isomers. (4) The carbon atom of the oxaziridine ring is completely inert to nucleophilic reagents.
- Hata, Yoshiteru,Watanabe, Masamichi
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p. 610 - 614
(2007/10/02)
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