Secondary Hydroxylamines Research Articles

Palladium-Catalyzed Alkenyl C-H Activation/Diamination toward Tetrahydrocarbazole and Analogs Using Hydroxylamines as Single-Nitrogen Sources.

A palladium-catalyzed alkenyl C-H activation/diamination reaction of cycloalkenyl bromoarenes with hydroxylamines is described. A wide range of tetrahydrocarbazoles and analogs has been prepared using fine-tuning bifunctional secondary hydroxylamines as the single-nitrogen sources. Mechanistic investigations suggest that the selective alkenyl C-H activation/diamination cascade process should build the N-heterocycles.

Hydroxylamines As Bifunctional Single-Nitrogen Sources for the Rapid Assembly of Diverse Tricyclic Indole Scaffolds.

Conventional approaches on using hydroxylamine derivatives as single nitrogen sources, for the construction of n-membered (n > 3) N-heterocycles, rely upon two chemical operations by involving sequential nucleophilic and electrophilic C-N bond formations. Here, we report a highly efficient cascade of alkyne insertion/C-H activation/amination for the rapid preparation of a myriad of tricyclic indoles, in a single-step transformation, by using bifunctional secondary hydroxylamines. It is noteworthy that judicious selection of applicable amino agents, for enabling the prior oxidative addition of aryl iodide to initial Pd(0) species and subsequent two C-N bonds formation, was the key to the success of this reaction. Control experiments indicated that a five-membered palladacyclic intermediate played a crucial role in promoting the final aminative ring closure.

Rhodium-catalyzed Electrophilic Amination of Arylboronic Acids with Secondary Hydroxylamines

A rhodium(III)-catalyzed electrophilic amination of arylboronic acids with secondary hydroxylamines has been developed. The rhodium catalysis is compatible with heteroarylboronic acids as well as acyl and alkoxycarbonyl protecting groups on the nitrogen of O-acylhydroxylamines, and the corresponding secondary anilines are obtained in good to excellent yields.

Directional Dynamic Covalent Motion of a Carbonyl Walker on a Polyamine Track

Controlled directional displacement of a molecular group has been achieved based on dynamic covalent motions implementing the reactional features of the imine bond. ortho-Carboxybenzaldehyde derivatives are able to form stable adducts with both primary and secondary amines as imines or as amino lactones, respectively, depending on the acidity of the medium. They may thus perform pH-driven intramolecular "walking" along a non-symmetric polyamine chain, in which an imine serves as the terminus under basic conditions on one end of the chain and a lactone formed on a secondary hydroxylamine nitrogen on the other end serves as the terminal site upon addition of acid. The displacement between the termini occurs stochastically through reversible change in valency at the carbon site of the carbonyl group between imine, aminal, iminium and amino lactone form. On the other hand, the directionality results from the stabilisation of the terminal products under given pH conditions. By its ability to undergo interconversion between C=N and O-C-N moieties, the ortho-carboxybenzaldehyde group extends the realm of dynamic covalent chemistry of imines to secondary amines and opens new perspectives in this field.

Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate

Metabolism-dependent inhibition (MDI) of cytochrome P450 (P450) enzymes has the potential to cause clinically relevant drug-drug interactions. In the case of several alkylamine drugs, MDI of P450 involves formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron to form a metabolic intermediate (MI) complex. The specific metabolites coordinately bound to ferrous iron and the pathways leading to MI complex formation are the subject of debate. We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Ten metabolites formed from lapatinib by CYP3A4-mediated heteroatom dealkylation, C-hydroxylation, N-oxygenation with or without further oxidation, or a combination thereof, were detected by accurate mass spectrometry. The abundance of one metabolite, the N-dealkylated nitroso/oxime lapatinib metabolite (M9), correlated directly with the prevalence or the disruption of the MI complex with CYP3A4. Nitroso/oxime metabolite formation from secondary alkylamines has been proposed to occur through two possible pathways: (1) sequential N-dealkylation, N-hydroxylation, and dehydrogenation (primary hydroxylamine pathway) or (2) N-hydroxylation with dehydrogenation to yield a nitrone followed by N-dealkylation (secondary hydroxylamine pathway). All intermediates for the secondary hydroxylamine pathway were detected but the primary N-hydroxylamine intermediate of the primary hydroxylamine pathway was not. Our findings support the mechanism of lapatinib CYP3A4 inactivation as MI complex formation with the nitroso metabolite formed through the secondary hydroxylamine and nitrone pathway, rather than by N-dealkylation to the primary amine followed by N-hydroxylation and dehydrogenation as is usually assumed.

Inexpensive, multigram-scale preparation of an enantiopure cyclic nitrone via resolution at the hydroxylamine stage

The reduction of the chiral, racemic nitrone MiPNO provides a secondary hydroxylamine. Its O-acylation with O, O’-dibenzoyl- l-tartaric acid anhydride gives two diastereomers, that can be easily separated by selective dissolution in orthogonal solvents. The recovery of the enantiopure nitrone is then carried out in a single step. The process allows the straightforward isolation of ( R) and ( S)-MiPNO in 57% and 38% yield, respectively, from rac-MiPNO.

Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem

Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-FLX], and N-desmethyldiltiazem (MA) undergo N-hydroxylation to the corresponding secondary hydroxylamines [N-hydroxydesipramine, (S)-N-hydroxyfluoxetine, and N-hydroxy-N-desmethyldiltiazem] by cytochromes P450 2C11, 2C19, and 3A4, respectively. The expected primary amine products, N-desmethyldesipramine, (S)-norfluoxetine, and N,N-didesmethyldiltiazem, are also observed. The formation of metabolic-intermediate (MI) complexes from these substrates and metabolites was examined. In each example, the initial rates of MI complex accumulation followed the order secondary hydroxylamine > secondary amine >> primary amine, suggesting that the primary amine metabolites do not contribute to formation of MI complexes from these secondary amines. Furthermore, the primary amine metabolites, which accumulate in incubations of the secondary amines, inhibit MI complex formation. Mass balance studies provided estimates of the product ratios of N-dealkylation to N-hydroxylation. The ratios were 2.9 (DES-CYP2C11), 3.6 [(S)-FLX-CYP2C19], and 0.8 (MA-CYP3A4), indicating that secondary hydroxylamines are significant metabolites of the P450-mediated metabolism of secondary alkyl amines. Parallel studies with N-methyl-d(3)-desipramine and CYP2C11 demonstrated significant isotopically sensitive switching from N-demethylation to N-hydroxylation. These findings demonstrate that the major pathway to MI complex formation from these secondary amines arises from N-hydroxylation rather than N-dealkylation and that the primary amines are significant competitive inhibitors of MI complex formation.

Oxidation of N,N‐Disubstituted Hydroxylamines to Nitrones with Hydrogen Peroxide Catalyzed by Polymer‐Supported Methylrhenium Trioxide Systems

AbstractPoly(4‐vinylpyridine)/methylrhenium trioxide (MTO) compounds IIII and microencapsulated polystyrene/MTO systems IVV are efficient catalysts for the oxidation of secondary hydroxylamines to the corresponding nitrones with H2O2. Complete conversions of substrates and quantitative yields of products are obtained under environmentally friendly experimental conditions and with the use of simple work‐up procedures. Symmetrically substituted hydroxylamines, and non‐symmetrical 3‐substituted and 2‐substituted hydroxypyrrolidines, precursors of nitrones applied in the synthesis of alkaloids and biologically active congeners, have been considered as substrates. The heterogeneous catalysts are stable under the reaction conditions and can be recovered and recycled for at least five times without any appreciable loss in efficiency.

A convenient synthesis of secondary hydroxylamines

The oxidation of a range of β-cyanoethyl tertiary amines with mCPBA gives the corresponding N-oxides, which can be isolated or undergo Cope-elimination to give secondary hydroxylamines in excellent yield.

Acyclic Oxyiminium Ions. Mannich Reactions and Addition of Grignard Reagents

Acyclic oxyiminium ion generation from secondary hydroxylamines ( 4a,b and 6a,b) and formaldehyde in the presence of acetic acid is reported. Trapping these electrophiles with 2-methyl furan, pyrrole or indole affords a series of novel O-benzyl tertiary hydroxylamines in good to excellent yield. Benzotriazole mediated synthetic methodology has also been successfully developed to generate oxyiminium ions which react with Grignard reagents, to give novel O-benzyl tertiary hydroxylamines.

Synthesis of isoxazolidines using polymer supported perruthenate (PSP)

Polymer supported perruthenate (PSP) has been used in mild and selective oxidations of secondary hydroxylamines to give nitrones; in the presence of dipolarophiles isoxazolidines are obtained in one-pot processes in good yields.

Kinetics and Mechanism of the Oxidation of Secondary Hydroxylamines to Nitrones with Hydrogen Peroxide, Catalyzed by Methylrhenium Trioxide

Secondary hydroxylamines, (RCH2)2NOH and (R2CH)2NOH, were converted to nitrones, RCH2N(O)CHR and R2CHN(O)CR2, in >94% yield with hydrogen peroxide as an oxygen donor and methylrhenium trioxide (MTO) as a catalyst. High concentrations of hydrogen peroxide were used so that the methylrhenium diperoxide, CH3Re(O)(η2-O2)2(H2O), was the dominant and reactive form of the catalyst. Representative rate constants are as follows: k/L mol-1 s-1 = 150 (R = Me), 52 (Et), 13.8 (Pri), and 3.33 (PhCH2) in methanol at 25.0 °C. There is no H/D kinetic isotope effect on the rate constant for this step. The data are interpreted to infer the intervention of an oxygenated intermediate, (RCH2)2N(O)OH, which then rapidly dehydrates to yield the nitrone. Two products are formed from unsymmetrical hydroxylamines, the ratio of which establishes the reactivities of the intermediate toward the competing elimination reactions: (RCH2)(R‘CH2)NOH → {(RCH2)(R‘CH2)N(O)OH} → χRCH2N(O)CHR‘ + (1−χ)R‘CH2N(O)CHR.

Chiral oximes in asymmetric synthesis. Addition of organometallic reagents to o-(1-phenylethyl) aldoximes

Addition of Grignard and organolithium reagents to O-(1-phcnylethyl) aldoximes in the presence of boron trifluoride etherate gives secondary hydroxylamines in 21–84% yield with up to 95% diastercomeric excess.

Asymmetric Addition of Organometallic Reagents to O-Phenethyl Aldoximes

Addition of Grignard and organolithium reagents to O-phenethyl aldoximes in the presence of boron trifluoride etherate gives secondary hydroxylamines in 21-84% yield with 38-95% diastereomeric excess.

Current trends in mode of action of Hindered Amine Light Stabilizers

The stabilization mechanisms of Hindered Amine Light Stabilizers (HALS) involving mainly various oxidation products of HALS do not account for the most important experimental facts. Part of these facts pertains to the dependence of HALS performance on their concentration. In polypropylene the performance increases linearly with HALS concentration as long as this concentration is not too high. In high density polyethylene the performance is a linear function of the square root of HALS concentration. Another part of the experimental facts concerns the decrease of the concentration of the light stabilizers on UV exposure of HALS stabilized polyolefins. The decrease is first-order in both PP and PE-HD. However, this decrease, independent of initial HALS concentration in PE-HD, decreases with increasing HALS concentration in PP. The role of the oxidation products of HALS in polyolefin stabilization is discussed in detail. It is found that there is a fundamental difference between the tertiary hydroxylamine ethers mainly formed in polypropylene and the secondary hydroxylamine ethers formed in polyethylene. The latter are postulated to be much more reactive than the former under photooxidative conditions because they contain an α-hydrogen atom prone to attack by peroxy radicals. Various mechanisms are proposed for this reaction. They account for the products found in polymers as well as in model systems. New stabilization mechanisms are proposed to explain the experimental facts. They are based on modified photooxidation mechanisms of unstabilized polymers. Initiation of photooxidation of polyolefins by excited polymeroxygen complexes is of prime importance. This type of initiation remains essential throughout polyethylene photooxidation during which hydroperoxides do not build up. It usually becomes rapidly negligible in polypropylene in comparison with initiation by tertiary hydroperoxides. Initiation of photooxidation in HALS stabilized polyethylene involves HALS-oxygen complexes throughout the useful lifetime of the polymer. Initiation of photooxidation of HALS stabilized PP is attributed to photolysis of tertiary hydroperoxides as long as the concentration of HALS is not too high. The HALS stabilization mechanisms proposed involve quenching of excited polymer-oxygen complexes. Formation of complexes between peroxy radicals and secondary HALS is another important aspect of these mechanisms. The peroxy radical/HALS complex can either react photolytically on absorption of UV light or react with a second peroxy radical. The latter leads to a termination reaction between two peroxy radicals as it is observed in the absence of HALS. The formal kinetics based on the mechanisms envisaged explain the experimental results obtained with HALS stabilized PP and PE-HD. It is postulated that the mechanisms discussed are valid, at least in part, for many polymers other than polyolefins.

Metabolism of chlorpromazine and promazine in vitro: isolation and characterization of N-oxidation products.

1. The syntheses of the secondary hydroxylamines of nor1chlorpromazine and nor1promazine via their corresponding primary hydroxylamines and oximes are described. 2. The N-oxidation products are unstable to analysis by g.l.c. without prior derivatization; the decomposition products and the structures of the trimethylsilyl (TMS) and trifluoroacetyl (TFA) derivatives were characterized by g.l.c.-mass spectrometry. 3. Chlorpromazine, promazine and their demethylated products were shown to undergo metabolic N- and alpha-C-oxidation, to yield hydroxylamines and carboxylic acids, on incubation with fortified 9000 g liver homogenates of male New Zealand white rabbits. 4. A condensation product, an artifact formed by reaction of the metabolically derived primary hydroxylamines with acetaldehyde, an impurity in the extraction solvent, diethyl ether, was identified. 5. N-hydroxynor1- and N-hydroxynor2chlorpromazine undergo metabolic reduction to the parent amines, and the secondary hydroxylamine undergoes N-demethylation to yield the corresponding primary hydroxylamine.

Stereochemistry of the Metabolic Incorporation of Oxygen into (+)- and (-)-N-Benzylamphetamine

1. Both (+)- and (-)-N-benzylamphetamine undergo alpha-carbon and N-oxidation to form N-dealkylated, deaminated and N-oxidized metabolites during incubation with fortified rabbit liver homogenates. 2. Quantitative determination of the metabolites based on specific g.l.c. procedures showed that all activities are localized in the microsomal fraction of rabbit liver. 3. N-Dealkylation, deamination and nitrone and secondary hydroxylamine formation are stereoselective. 4. The characteristics of the enzyme-substrate interactions for both isomers of N-benzylamphetamine indicate that at least two distinct enzyme systems are involved in the N-oxidation and alpha-carbon processes, or a single enzyme possessing an active site with differing conformational requirements for the two oxidative processes.

Oxidation of aliphatic hydroxylamines in aqueous solutions.

The effects of pH, buffer constituents, duration of storage, presence of air, heavy metal ions, extracting solvents and various additives and cofactors on the aerial oxidation of some aliphatic primary and secondary hydroxylamines were investigated. Copper ions were particularly effective catalysts of the oxidation reaction. Conditions to minimize this transformation are described.

Synthetic routes to optical isomers of primary and secondary hydroxylamines of 1-arylisopropylamines

A number of optically pure primary 1-arylisopropylamines were converted to 3-phenyl-2-(1′-arylisopropyl)oxaziridines by the oxidation of the corresponding benzylimines with m-chloroperbenzoic acid. Subsequent acid hydrolysis of the 3-phenyloxaziridines yielded optically pure N-hydroxy-1-arylisopropylamines. The action of m-chloroperbenzoic acid on optically pure secondary 1-arylisopropylamines gave optically pure N-hydroxy derivatives. The optical purity of the hydroxylamines were analysed by GLC utilizing N-trifluoroacetyl- l-prolyl chloride as a reagent.

Metabolism of amphetamines. Identification of N-oxygenated products by gas chromatography and mass spectrometry.

Abstract A sensitive method for the isolation and identification of N-oxygenated metabolites and metabonates of medicinal amines is described. A combination of gas chromatography and mass spectrometry is effective in separating and identifying secondary hydroxylamines, oximes and nitrones, all of which are N-oxygenated products of secondary amines. These products give mass spectra containing diagnostic fragment ions which are of great value in identification. Primary hydroxylamines are oxidized on column to oximes and can be separated and identified as such. This oxidation is avoided if the primary hydroxylamine is introduced by direct inlet into the mass spectrometer. Secondary hydroxylamines are more stable during gas chromatographic examination although some decomposition to nitrone and secondary amine does occur. In contrast, oximes and nitrones show no tendency to decompose when gas chromatographed.