Oxidation Of Tertiary Amines Research Articles

The highly stereoselective formation of pipecolic acid N-oxide and related derivatives

N-Alkylated derivatives of pipecolic acid are shown to undergo highly stereoselective oxidation to give stable tertiary amine N-oxides. The ester derivatives show a high degree of stability compared to their proline analogues.

Chiral t-butylphenylphosphinothioic acid in NMR analysis of tertiary amine oxides with a stereogenic nitrogen atom

The enantiomers of tertiary amine oxides 3 show NMR spectral nonequivalence in the presence of (−)-( S)- or (+)-( R)- t-butylphenylphosphinothioic acid 4. It is observed even for the ε-methyl protons and is large enough to determine the ee values of 3 having long alkyl chains. The enantiomeric thioacids 4 induce also an extremely large magnetic nonequivalence of the geminal N-methylene protons in 3.

Menadione-dependent reduction of tertiary amine N-oxide by rat liver cytosol.

This study demonstrates the menadione-dependent reduction of imipramine N-oxide, a tertiary amine N-oxide, to imipramine by rat liver cytosol in the presence of NADH or NADPH. A mechanism for the cytosolic reduction of the tertiary amine N-oxide is proposed. Menadione is converted to its reduced form by a menadione-reducing enzyme such as DT-diaphorase and the reduced pyridine nucleotide, followed by reduction of the tertiary amine N-oxide to the amine by the heme group of catalytic hemoproteins in the presence of reduced menadione as an electron donor.

A New Cycloisomerization Reaction: Formation of Eight-Membered-Ring Compounds from 3-Sila 1,7-Enynes

An intramolecular cycloisomerization occurred upon adding a tertiary amine N-oxide to alkyne−cobalt complexes, derived from 3-sila 1,7-enynes and dicobalt octacarbonyl. As a result, eight-membered ...

Mild and efficient preparation of alkynepentacarbonyldicobalt complexes containing the chiral ( R) -(+) -Glyphos ligand

A range of diastereomeric alkynepentacarbonyldicobalt complexes containing the ( R)-(+)-Glyphos ligand have been prepared in moderate to good yields under standard thermal conditions. Additionally, novel tertiary amine N-oxide mediated reactions have been developed which allow the synthesis of the same range of complexes at room temperature with good selectivity in consistently high yields. Optically pure ( R)-(+)-Glyphos containing complexes have been obtained by preparative HPLC separation of the sets of diastereomeric compounds. Finally, the amine N-oxide techniques allow the rapid and clean preparation of alkynepentacarbonyltriphenylphosphinedicobalt complexes in good to high yields at room temperature.

The crystal structures of [NMe4][(Me2AsO2){MoO(O2)2}2], [NMe4][(Ph2PO2){MoO(O2)2}2], [NBun 4][(Ph2PO2){WO(O2)2}2] and [NH4][(Ph2PO2){MoO(O2)2(H2O)}] and their use as catalytic oxidants

The new heteropolyperoxometalate compounds [NMe4][(Me2AsO2){MoO(O2)2}2]1, [NMe4][(Ph2PO2){MoO(O2)2}2]2, [NBun4][(Ph2PO2){WO(O2)2}2]3 and [NH4][(Ph2PO2){MoO(O2)2(H2O)}]4 have been isolated and their crystal structures determined. Compounds 1–3 are dinuclear, whilst compound 4 is mononuclear; in all four structures the metal centre(s) have essentially identical pentagonal-bipyramidal co-ordination geometries with a weak axial ligand trans to an oxo group. The utility of 3 as a catalyst for the oxidation of alkenes, alcohols and tertiary amines with hydrogen peroxide as cooxidant has been studied.

The molecular biology of the flavin-containing monooxygenases of man

cDNA clones encoding five distinct members of the FMO family of man (FMOs 1,2, 3, 4 and 5) were isolated by a combination of library screening and reverse transcription-polymerase chain reaction techniques. The deduced amino acid sequences of the human FMOs have 82–87% identity with their known orthologues in other mammals but only 51–57% similarity to each other. The hydropathy profiles of the proteins are very similar. From the calculated rate of evolution of FMOs (a 1% change in sequence per 6 million years) it would appear that individual members of the FMO gene family arose by duplication of a common ancestral gene some 250–300 million years ago. Each of the FMO genes was mapped by the polymerase chain reaction to the long arm of human chromosome 1. The localization of the FMO1 gene was further refined to 1q23–q25 by in situ hybridization of human metaphase chromosomes. RNase protection assays demonstrated that in man each FMO gene displays a distinct developmental and tissue-specific pattern of expression. In the adult, FMO1 is expressed in kidney but not in liver, whereas in the foetus its mRNA is abundant in both organs. FMO3 expression is essentially restricted to the liver in the adult and the mRNA is either absent, or present in low amounts, in foetal tissues. FMO4 is expressed more constitutively. Human FMO1 and FMO3 cDNAs were functionally expressed in prokaryotic and eukaryotic cells. FMO1 and FMO3, expressed in either system, displayed product stereoselectivity in their catalysis of the N-oxidation of the pro-chiral tertiary amines, N-ethyl- N-methylaniline (EMA) and pargyline. Both enzymes were stereoselective with respect to the production of the (−)- S-enantiomer of EMA N-oxide. But in the case of pargyline, the enzymes displayed opposite stereoselectivity, FMO1 producing solely the (+)-enantiomer and FMO3 predominantly the (−)-enantiomer of the N-oxide.

Role of hepatic flavin-containing monooxygenase 3 in drug and chemical metabolism in adult humans

In conjunction with asymmetric chemical syntheses and spectral, chiroptical, Chromatographic and stereochemical correlation methods, we have developed procedures for the quantification of sulfoxide enantiomers and tertiary amine N-oxide diastereomer metabolites arising from the action of the adult human liver and other flavin-containing monooxygenases (FMOs). The parallel nature of the metabolic in vitro-in vivo studies and the use of chemical model oxidation systems allowed us to identify the FMO isoform involved. We investigated the enantioselective S-monooxygenation of cimetidine and the diastereoselective tertiary amine N-1′-oxygenation of ( S)-nicotine as stereoselective functional probes of adult human liver FMO action. In both cases, the majority of evidence points to adult human liver FMO3 as the principal enzyme responsible for cimetidine S-oxygenation and ( S)-nicotine N-1′-oxygenation in vitro and in vivo. The excellent agreement between the absolute configuration of the major cimetidine S-oxide and ( S)-nicotine N-1′-oxide metabolites isolated from human urine and the major metabolite formed in the presence of adult human liver microsomes suggests that in vitro hepatic preparations may serve as a useful model for the in vivo condition. Further, that adult human liver cDNA-expressed FMO3 in Escherichia coli also gave the same absolute stereoselectivity (i.e. for ( S)-nicotine N-1′-oxygenation) confirms the identity of the monooxygenase in vivo. Although we cannot rule out the involvement of minor contributions of cytochrome P-450 monooxygenases in cimetidine and ( S)-nicotine oxidation, the majority of the data support the fact that cimetidine S-oxygenation and ( S)-nicotine N-1′-oxygenation are stereoselective functional probes of adult human liver FMO3 activity. Finally, because the stereochemistry of the principal metabolite of cimetidine and ( S)-nicotine in small experimental animals is distinct from that observed in humans, it is likely that species variation in predominant FMO isoforms exist and this may have important consequences for the choice of experimental animals in human preclinical drug design and development programs.

Non-metallocatalyzed epoxidation of chiral unsaturated lactams by tertiary amine N-oxides

Tertiary amine N-oxides were used to stereospecifically epoxidize chiral unsaturated bicyclic lactams in high yields (90–99%) at room temperature. This appears to be the first reported example of tertiary amine N-oxides acting as epoxidizing agents in the absence of a metal catalyst.

Heteropolyperoxo- and isopolyperoxo-tungstates and-molybdates as catalysts for the oxidation of tertiary amines, alkenes and alcohols

The catalytic oxidation of tertiary amines to the corresponding N-oxides by [XO4{MO(O2)2}4]3–(X = P or As, M = Mo or W) and by [M2O3(O2)4]2– with H2O2 as co-oxidant has been studied. Epoxidation of alkenes and oxidation of alcohols by [M2O3(O2)4]2– with H2O2 as co-oxidant has also been examined and compared with that effected by [XO4{MO(O2)2}4]3–. A possible structure for [M2O3(O2)4]2– is suggested.

Use of dioxiranes for the chemoselective oxidation of tertiary amines bearing alkene moieties

A neat and high yield chemoselective epoxidation of alkene moieties present in tertiary amines is accomplished by treatment of the corresponding amine–boron trifluoride adduct with dimethyldioxirane or methyl(trifluoromethyl)dioxirane.

Final Report on the Safety Assessment of Lauramine Oxide and Stearamine Oxide

Lauramine Oxide and Stearamine Oxide are aliphatic tertiary amine oxides that are used mostly in hair care products as foam builders and stabilizers, viscosity enhancers, emollients, conditioners, emulsifiers, antistatic agents, and wetting agents. Both compounds are susceptible to nitrosation and can form nitrosamines in the presence of nitrosating agents. In rats, up to 40% of Lauramine Oxide applied to the skin was absorbed. In two human volunteers, 92% of the dose applied to the skin was recovered from the skin. The oral LD50 in rats for a formulation containing 0.3% Lauramine Oxide was estimated to be >20 g/kg. At a concentration of 30%, Lauramine Oxide produced severe dermal reactions in rabbits, but at 0.3% only slight to moderate erythema with slight edema, Assuring, and slight to moderate epithelial desquamation were found. Stearamine Oxide applied to rabbit skin at 5% did not cause irritation. Both ingredients caused mild, transient ocular irritation in rabbits. Clinical data showed dermal exposure to 3.7% Lauramine Oxide to be a mild irritant, with a slight potential for mild cumulative skin irritation at concentrations as low as 2%. At 0.3%, Lauramine Oxide was not a sensitizer in clinical studies. Lauramine Oxide was nonmutagenic in the Ames assay, but was mutagenic after nitrosation. Lauramine Oxide at 0.1% in drinking water was not carcinogenic in rats, but at 0.1% with 0.2% sodium nitrate did increase the incidence of liver neoplasms. Based on this animal data, neither ingredient should contain N-ni-troso compounds nor be used in formulations containing nitrosating agents. On the basis of the available animal and clinical data, it is concluded that Lauramine Oxide and Stearamine Oxide are safe as cosmetic ingredients for rinse-off products, but that the concentration in Lauramine Oxide leave-on products should be limited to 3.7% and that of Stearamine Oxide limited to 5%.

An analysis of the relative occurrence of N-demethylation and N-oxidation in xenobiotic metabolism using structure-reactivity maps.

The relative occurrence of N-demethylation and N-oxidation in a structurally diverse set of N-methyl tertiary amines was examined using structure-reactivity maps. A structure-reactivity map of the data indicated important structural features useful for predicting the relative occurrence of these reactions. A steric index which describes the degree of steric hinderance at the N-methyl reaction site is defined. A QSAR between the relative occurrence of N-demethylation and N-oxidation of N-methyl tertiary amines and the steric index was developed.

Potentiometric titration of long chain tertiary amine oxides and tertiary amines using a poly(vinyl chloride) membrane electrode

Two separate potentiometric titrations are used to quantify mixtures of long chain tertiary amine oxide and tertiary amine as their cations. A direct titration of the mixture in water at pH 2 against a standard sodium lauryl sulfate solution, using a poly(vinyl chloride) membrane sensing electrode, determines the total surfactant content, reported as % m/m tertiary amine oxide. A simple extraction is used to separate the tertiary amine, which is subsequently titrated under the same conditions. This titration is quantitative for dimethylalkylamine oxides and their corresponding amines (where alkyl = C10–C16). Seven analyses are performed on an aqueous mixture and give the following results: tertiary amine oxide, 23.8 ± 0.1% m/m and tertiary amine, 1.0 ± 0.1% m/m, at a 95% confidence level. This method is capable of determining tertiary amine at 0.1% m/m in the presence of 25% m/m tertiary amine oxide with no interference. The same aqueous mixture is spiked with tertiary amine to test the quantitative recovery of the amine. The recovery is 3.1% m/m compared with an expected value of 3.2% m/m amine.

Effect of coordinating ligands on the Pauson-Khand cycloaddition: trapping of an intermediate

The Pauson-Khand cobalt-mediated cycloaddition has become a synthetically important reaction. Several modifications have increased the utility of the reaction, including reports that tertiary amine N-oxides greatly accelerate the rate of cycloaddition in both intra- and some intermolecular reactions. To date, there has been no direct evidence to support the mechanistic hypothese for either the thermal or amine oxide promoted reactions beyond complete identification of the hexacarbonyl alkyne complex. While the amine oxide promoted reaction is normally greatly accelerated over the analogous thermal one, in the presence of amine oxides, the rate of cycloaddition of a 1,6-enyne may be enhanced even further by the presence of sulfur, nitrogen, or oxygen in the homopropargylic or bishomopropargylic position

ChemInform Abstract: Ruthenium‐Catalyzed Oxidation of Tertiary Amines with Hydrogen Peroxide in the Presence of Methanol.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthetic Utility of AmineN-Oxides

Tertiary amine N-oxides undergo preparatively useful reactions, namely, rearrangement to trisubstituted hydroxylamines (including 1,2-oxazaheterocycles), thermal cleavage to alkenes and hydroxylamines, addition and rearrangement reaction via iminium cation and azomethine ylide. Furthermore, these compounds are selective oxidants (inter alia for the «activation» of organometallics), and N-oxidation can be also used for protective purposes

Visualizing relative occurrences in metabolic transformations of xenobiotics using structure-activity maps.

Structure maps are presented as an efficient means of indicating structure-reactivity relationships in metabolic pathway databases. The relative occurrence of N-demethylation and N-oxidation of N-methyl tertiary amines was examined using the structure map methodology. A new family of reaction site representations, the n-level representations, was developed to describe the N-methyl reaction sites of the compounds in the data set. It was possible to differentiate N-demethylation and N-oxidation reaction sites using a structure map constructed from a 3-level representation of the reaction sites.

Ruthenium-catalyzed oxidation of tertiary amines with hydrogen peroxide in the presence of methanol

α-Methoxylation of tertiary amines can be performed by the ruthenium-catalyzed oxidation of tertiary amines with hydrogen peroxide in the presence of methanol. The reaction provides an efficient method for selective N-demethylation of tertiary methylamines and construction of quinoline skeletons.

XYZH systems as potential 1,3-dipoles. Part 36. 1,5-Electrocyclisation processes via oxidation of tertiary amines. Pyrrolo-dihydroisoquinolines and -dihydro-β-carbolines.

A range of tertiary N-allylamines derived from 1,2,3,4-tetrahydroisoquinoline undergo oxidative cyclisation, induced by Ag 2CO 3, to pyrrolo-dihydroisoquinolines in moderate to good yield. Analogous oxidative cyclisations are reported for N-allyl-tetrahydro-β-carbolines and a pyrrolidine. The reactions proceed via formation of a 1,5-dipole followed by an electrocyclisation and subsequent aromatisation.