- Oxidation-Cope elimination: A REM-resin cleavage protocol for the solid-phase synthesis of hydroxylamines
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We have established that using an oxidation-Cope elimination cleavage protocol allows for the synthesis of N,N-disubstituted hydroxylamines from REM resin (polymer-bound benzyl acrylate). Michael addition of a secondary amine or addition of a primary amine followed by reductive alkylation provides polymer-bound tertiary amines. Oxidation of these resin-bound tertiary amines with MCPBA is followed by concomitant Cope elimination to regenerate the polymer-bound acrylate and provide the cleaved hydroxylamines.
- Sammelson, Robert E,Kurth, Mark J
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- Synthesis of N,N,O-Trisubstituted Hydroxylamines by Stepwise Reduction and Substitution of O-Acyl N,N-Disubstituted Hydroxylamines
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Diverse N,N,O-trisubstituted hydroxylamines, an under-represented group in compound collections, are readily prepared by partial reduction of N-acyloxy secondary amines with diisobutylaluminum hydride followed by acetylation and reduction of the so-formed O-acyl-N,N-disubstituted hydroxylamines with triethylsilane and boron trifluoride etherate. Use of carbon nucleophiles in the last step, including allyltributylstannane, silyl enol ethers, and 2-methylfuran, gives N,N,O-trisubstituted hydroxylamines with branching α- to the O-substituent. N,N-Disubstiuted hydroxylamines are conveniently prepared by reaction of secondary amines with dibenzoyl peroxide followed by diisobutylaluminum hydride reduction.
- Dhanju, Sandeep,Crich, David
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p. 1820 - 1823
(2016/05/19)
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- The Reactivity of Difluorocarbene with Hydroxylamines: Synthesis of Carbamoyl Fluorides
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Carbamoyl fluorides are formed in reactions of hydroxylamines with difluorocarbene generated from sodium bromodifluoroacetate as readily available and non-toxic carbene precursor. The process shows a high functional group tolerance, and the reaction path has been rationalized by computational calculations. (Figure presented.) .
- Baars, Hannah,Engel, Julien,Mertens, Lucas,Meister, Daniela,Bolm, Carsten
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p. 2293 - 2299
(2016/07/29)
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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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- Oxidation of amines catalyzed by cyclohexanone monooxygenase
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Cyclohexanone monooxygenase catalyzed the oxidation of tertiary, secondary and hydroxylamines to N-oxides, hydroxylamines and nitrones respectively.
- Colonna, Stefano,Pironti, Vincenza,Pasta, Piero,Zambianchi, Francesca
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p. 869 - 871
(2007/10/03)
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- A novel oxidative transformation of α-aminonitriles to amides
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A novel oxidative transformation of α-aminonitriles to amides is reported. Oxidation of α-aminonitriles with peracid, followed by basic treatment affords, amides in good yields. A mechanistic aspect of this transformation is also discussed.
- Yokoshima, Satoshi,Kubo, Tetsuji,Tokuyama, Hidetoshi,Fukuyama, Tohru
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p. 122 - 123
(2007/10/03)
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- Nitrogen inversion and N-O bond rotation in some hydroxylamine and isoxazolidine derivatives
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A series of trisubstituted hydroxylamine derivatives, both cyclic and acyclic, has been prepared. The energy barriers in these hydroxylamines are found to be dominated either by nitrogen inversion or N-O bond rotation depending on the nature of the substi
- Hassan, Azfar,Wazeer, Mohamed I. M.,Perzanowski, Herman P.,Ali, Sk. Asrof
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p. 411 - 418
(2007/10/03)
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- Origin of "Hetero Effect" on Nitrogen Inversion. Comparison of Hydroxylamines and Aminoxide Anions
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Rate constants for nitrogen inversion in N-benzyl-N-methylhydroxylamine, N,N-diethylhydroxylamine, 1-hydroxy-2,2,4,4-tetramethylpyrrolidine, their conjugate bases, and their O-acetyl derivatives in dimethylformamide-d7 were determined based on the 1H NMR
- Perrin, Charles L.,Thoburn, John D.,Elsheimer, Seth
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p. 7034 - 7038
(2007/10/02)
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- Metalloenzyme Models. Divalent Metal Ion Catalyzed Hydrolysis of p-Nitrophenyl Picolinate in the Presence of Imidazoles and Pyridines Having Hydroxyl Groups in Their Side Chains
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Rate constants for hydrolysis of p-nitrophenyl picolinate at 25 deg C in the pH range 6.5-8.5 were measured in the absence and presence of divalent metal ions (Ni(II), Zn(II), Co(II), Ca, Mg) and substituted imidazoles or pyridines as ligands having alcoholic hydroxyl groups in their side chains. In the presence of either metal ion or ligand, the rate is slow and the pseudo-first-order rate constant (kobsd) increases linearly in a first-order manner with respect to the concentration of metal ion or ligand until it gives the second-order rate constant, kM or kL, respectively. In the presence of both a metal ion (Ni(II) or Zn(II)) and a ligand, rate increase is remarkable for some ligands and the increase in kobsd values constructs saturation curves with respect to increase in either metal ion or ligand concentration. The saturation curves were analyzed based upon rate equations formulated by assuming the formation of 1:1 complex of metal ion and ligands as the catalyst, leading to evaluation of the association constant K for complexes and the second-order rate constant kc for the reaction of complex with substrate. Values of kobsd, kc, and K are dependent greatly upon the structure of ligands and pH. The ligands complexed with Zn(II) ion appear to be simple but highly active models of hydrolytic metalloenzymes.
- Ogino, Kenji,Shindo, Katsuhiko,Minami, Tooru,Tagaki, Waichiro,Eiki, Toshio
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p. 1101 - 1106
(2007/10/02)
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- The Chemistry of 1-Carba-1-deaza-N5-ethyl-N3-methyllumiflavins. Influense of the N1 upon the Reactivity of Flavin 4a-Hydroperoxides
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N5-ethyl-N3-methyl-1,5-dihydro-1-deazalumiflavin (C1-FlEtH) has been synthetized and characterized.In aqueous solution (pH 3) C1-FlEtH reacts with 1 eqiv of 3O2 to provide N5-ethyl-N3-methyl-1-deazalumiflavinium cation (C1-Flox+Et).C1-Flox+Et may be reduced to C1-FlEtH by ascorbate, dithionite, or H2/Pd.C1-Flox+Et is not photoreducible by EDTA as is Flox+Et.This is due to direct photolysis of C1-Flox+Et with the accompanying loss of the N5-ethyl substituent as acetaldehyde.The spectral properties of C1-FlEtH2+, C1-FlEtH, and C1-FlEt- and associated pKa's have been determined and compared to the analogous constants for FlEtH2+, FlEtH, and FlEt-.A comparison of the spectral properties of Flox+Et and C1-Flox+Et has been made.The pKa values and the pH dependences of the rate constants for the formation and dissociation of the pseudobases (i.e.C1-4a-FlEtOH and 4a-FlEtOH) of Flox+Et and C1-Flox+Et have also been determined as have the rate constants (pH 3.0) for addition of β-mercaptoethanol to the 4a-position of Flox+Et and C1-Flox+Et (providing 4a-FlEt-SCH2CH2OH and C1-4a-FlEt-SCH2CH2OH).Partial oxidation of C1-FlEtH by 3O2 in H2O produces the radical C1-FlEt. through comproportionation of C1-Flox+Et and C1-FlEtH.Evidence is presented, suggesting that the radical C1-FlEt. possesses a higher free-energy content than does FlMe..The oxidation of C1-FlEtH in H2O or t-BuOH with excess 3O2 is autocatalytic in nature.The initial rate for reaction of C1-FlEtH with 3O2 is substantially greater than the initial rate for reaction of FlMeH with 3O2.This observation is discussed in terms of the mechanism of reaction of FlRH with O2.In DMF, C1-FlEtH reacts with 3O2 to form a 4a-hydroperoxide (i.e.C1-4a-FlEtOOH) which is quite stable.The rate constants for solvolysis of C1-4a-FlEtOOH and 4a-FlEtOOH in DMF have been compared.The second-order rate constants for the (a) oxidation of I- in 95percent EtOH/DMF, (b) N-oxidation of N,N-dimethylbenzylamine, N-methylbenzylamine, and morpholine in DMF, and (c) the S-oxidation of thioxane in DMF by C1-4a-FlEtOOH and α-FlEtOOH have been determined.The flavin products for the N- and S-oxygenation reactions are the pseudobases C1-4a-FlEtOH and 4a-FlEtOH.These reactions are quantitative.Comparison of the various rate constants indicates that C1-4a-FlEtOOH is from 3- to 17-fold a poorer oxidizing agent than is 4a-FlEtOOH.This can be explained by the somewhat less electronegative character of the 4a-position of the 1-deazaflavin hydroperoxide.The equilibrium constants for 4a-additions and retroadditions to C1-Flox+Et and Flox+Et are comparable, and this leads to the conclusion that the difference in free-energy contents of C1-Flox+Et and Flox+Et (starting states) and C1-4a-FlEtX and 4a-FlEtX (products) is the same.Due to this feature, the decrease in ΔG* for 4a additions to Flox+Et, as compared to C1-Flox+Et ...
- Ball, Sheldon,Bruice, Thomas C.
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p. 5494 - 5503
(2007/10/02)
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- Oxidation of Amines by a 4a-Hydroperoxyflavin
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Kinetic and product studies have been carried out for the reaction of 12 tertiary amines, secondary amines, and secondary hydroxylamines with the 4a-hydroperoxide of N5-ethyl-3-methyllumiflavin (4a-FlEtOOH).All reactions were found to be first order in 4a-FlEtOOH and amine in t-BuOH solvent.Transfer from t-BuOH to the aprotic solvent dioxane decreases the second-order rate constant by ca. threefold, but does not change the kinetic order in reactants (i.e., no external proton source is required).The reactions with the secondary and tertiary amines are quantitative, yielding secondary hydroxylamines and tertiary amine oxides along with the flavin pseudobase (4a-FlEtOH).Secondary hydroxylamines yield with 4a-FlEtOOH nitrones and 4a-FlEtOH.The free radical trap 2,6-di-tert-butyl-4-methylphenol does not influence the rate constants or product yields.This finding, along with the observation that rate constants are not related to the stability of cation radicals derived from amine, establishes that free radical processes are not involved in the N-oxidation reactions.The N-oxidation reactions are best explained as occurring through nucleophilic attack of amine nitrogen upon the terminal oxygen of the 4a-FlEtOOH molecule with back donation of the hydroperoxy hydrogen to the internal peroxy oxygen.Comparison of the second-order rate constants ( on the basis of the amine pKa's in H2O) provides the nucleophilic order secondary hydroxylamines > tertiary amines > secondary amines.The disappearance of 4a-FlEtOOH from solution in the presence of primery amines is much slower than with secondary amines and the reaction does not follow a simple rate law nor is 4a-FlEtOH a major product.In t-BuOH the spontaneous first-order rate constant for decomposition of 4a-FlEtOOH exceeds that for the decomposition of H2O2 by more than 400-fold while the second-order rate constant for N-oxidation of N,N-dimethylbenzylamine by 4a-FlEtOOH exceeds that for N-oxidation by H2O2 by 36000-fold (and N-oxidation by t-BuOOH by > 400000).These results are discussed in terms of the involvement of 4a-hydroperoxyflavin cofactor in the metabolism of amines by the hepatic flavoprotein microsomal oxidase.
- Ball, Sheldon,Bruice, Thomas C.
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p. 6498 - 6503
(2007/10/02)
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