Hydroxylamines secondary, oxidation

Preparation of hydroxylamines through oxidation of an amino group is an attractive approach since a variety of primary and secondary amines are commercially available, including compounds with high enantiomeric purity. A number of reagents have been suggested for the oxidation. However, yields are variable and sometimes are difficult to predict, since primary hydroxylamines can undergo further oxidation into nitroso and nitro compounds. The overoxidation is less a problem for A,iV-disubstituted hydroxylamines... 

Figure 34 Oxidative reactions of amines. Formation of N-oxides from oxidation of tertiary amines and formation of hydroxylamines from oxidation of primary and secondary amines.

Tertiary amines are transformed into A-oxides (generally less toxic), but primary and secondary amines are oxidized into hydroxylated derivatives (hydroxylamines). This oxidation is responsible for the hepatotoxicity and mutagenicity of acetamino-2-fluorene (Figure 33.11). ... 

Oxidation of amines and hydroxylamines. Secondary amines undergo dehydrogenation to afford imines, whereas (V,)V-dialkylhydroxylamines are converted to nitrones at room temperature. 

Forsyth et al. found that gelsemicine contains three active hydrogen atoms (Zerewitinov determination), yields a non-basic, monobenzoyl derivative, m.p. 232°, and behaves as a secondary base giving JV-methyl-gelsemicine hydriodide, m.p. 227°, on treatment with methyl iodide. It does not react with either hydroxylamine or 2 4-dinitrophenylhydrazine. On hydrogenation in dry acetic acid in presence of Adams s platinic oxide catalyst it absorbs three molecules of hydrogen. 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

Secondary amines (R2NH) are oxidized to hydroxylamines (R2NHOH), which are resistant to further oxidation, by dimethyldioxirane and by benzoyl peroxide and NajHPOa. " ... 

TS-1 is a material that perfectly fits the definition of single-site catalyst discussed in the previous Section. It is an active and selective catalyst in a number of low-temperature oxidation reactions with aqueous H2O2 as the oxidant. Such reactions include phenol hydroxylation [9,17], olefin epoxida-tion [9,10,14,17,40], alkane oxidation [11,17,20], oxidation of ammonia to hydroxylamine [14,17,18], cyclohexanone ammoximation [8,17,18,41], conversion of secondary amines to dialkylhydroxylamines [8,17], and conversion of secondary alcohols to ketones [9,17], (see Fig. 1). Few oxidation reactions with ozone and oxygen as oxidants have been investigated. 

As shown in Fig. 6.4, primary amines are converted to oximes, secondary amines to hydroxylamines, and tertiary amines to N-oxides.34... 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64... 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

Study of the kinetics of the oxidation of asymmetric secondary hydroxylamines to nitrones with H2O2, catalyzed by methylrhenium trioxide, has led to the elucidation of the mechanism of the reaction (104). Full transformation of N,N -disubstituted hydroxylamines into nitrones upon treatment with H2O2 occurs on using polymeric heterogeneous catalysts such as polymer-supported methylrhenium trioxide systems (105). 

Alkyl and aryl C-nitroso compounds contain a nitroso group (-N=0) directly attached to an aliphatic or aromatic carbon. As compounds with a nitroso group attached to a primary or secondary carbon exist primarily as the oxime tautomer, the stable examples of C-nitroso compounds contain nitroso groups attached to tertiary carbons, such as 2-methyl-2-nitroso propane (1, Fig. 7.1) or nitroso groups attached to carbons bearing an electron-withdrawing group (-CN, -N02, -COR, -Cl, -OAc, Fig. 7.1). Oxidation of alkyl and aryl hydroxylamines provides the most direct route to alkyl and... 

The actual oxidant may be peroxyseleninic acid, H0Se(0)00H, which is known to oxidize secondary amines to hydroxylamines. 

FMO also oxidizes primary and secondary amines. For example, it N-hydroxylates both amphetamine and methamphetamine to generate the corresponding hydroxylamines (Fig. 4.27) (70). It then catalyzes a second N-hydroxylation of both metabolites. The two A, A -dihydroxy intermediates eliminate water to generate the oxime in the case of amphetamine and the nitrone in the case of methamphetamine. 

FIGURE 4.86 Oxidation of a secondary amine to a hydroxylamine followed by nitrone formation. 

The first product in the oxidation of secondary amines is also a hydroxylamine (Fig. 4.86). Further oxidation requires the involvement of an adjacent carbon atom to form a nitrone. If there is more than one adjacent carbon with a hydrogen atom, the major product will usually involve the most substituted carbon atom (assuming at least one hydrogen such that a new bond can be formed) or one in which the nitrone is conjugated with other double bonds as shown in Figure 4.86. 

Polymer-supported permthenate has also been used in two convergent pathways for the synthesis of isoxazoUdines with each route employing different starting materials in order to create the maximum structural diversity [73]. In the first route secondary hydroxylamines, readily prepared from amines by in situ treatment with dimethyldioxirane, were oxidized directly to nitrones using polymer-supported permthenate (PSP). Alternatively, primary alcohols were used as the... 

The partial leach protocol used a 2-h leach, using 40 ml of 0.25 M hydroxylamine hydrochloride in 0.1 M HCI at 60°C, on 1 g of the <63- j.m fraction (Cameron et al. 2004). This hydroxylamine leach is designed to dissolve secondary iron and manganese oxides. This relatively aggressive leach protocol will also dissolve phosphatic, calcareous and amorphous clay components, and will likely desorb any ions weakly bonded to other components. 

Direct oxidation of primary amines with peroxide oxidants does not provide appreciable yield of hydroxylamines. As was mentioned above, oxidation of secondary amines usually proceeds smoothly giving moderate to good yields of iV,iV-disubstituted hydroxylamines. Oxidation of sterically hindered secondary amines such as 125 (equation 88) can also be done with peracids . Further oxidation of the resulting Af,A-disubstituted hydroxylamines 126 with an excess of m-chloroperbenzoic acid is known to end up with the corresponding nitroxyl radicals of type 127 (equation 88) ° although the reaction can be stopped at the hydroxylamine stage. 

In an analogous way, secondary amines can be protected through attachment of / -cyanoethyl or a similar function. The cyanoethyl group undergoes facile Cope elimination from initially formed A-oxide (e.g. 137, equation 91) thus giving the corresponding hydroxylamine 138 in a good yield . ... 

An alternative strategy preventing fnrther oxidation of hydroxylamines is based on concomitant O-protection of the hydroxyamino gronp. Reaction of primary amines with benzoyl peroxide affords O-benzoyl hydroxylamines of type 139 (equation 92) that can be deprotected under mildly basic conditions. The oxidation is compatible with a number of functionalities and does not interfere with other functionalities snch as an isolated double bond in the molecule of amine. This reaction is versatile and a number of hydroxylamines has been prepared in this way, although yields are only moderate in most cases . Oxidation of secondary amines with benzoyl peroxide is also possible and usually proceeds in better yields. 

Oxidation of secondary amines with oxaziridine 144 provides moderate yields of hydroxylamines 145, although overoxidation invariably results in formation of nitrones 146 (equation 96). ... 

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