Oxidation of secondary amines

METHYLTRIOXORHENIUM CATALYZED OXIDATION OF SECONDARY AMINES TO NITRONES TV-BENZYLIDENE-... 

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). 

Oxidation of secondary amines into nitrones has been extensively studied and a variety of well-known efficient oxidants and catalysts which can be employed in this process are available. Catalytic oxidation by hydrogen peroxide at room temperature is carried out by using sodium tungstate (Fig. 2.1) (28-47). 

In recent years, the use of heterogeneous catalysts Mg-Al LDH (66, 67) and Mg-Al-0 - Bu hydrotalcite (HT-O- Bu), in the oxidation of secondary amines with hydrogen peroxide, has been reported (68). The reaction appears to proceed quickly at room temperature, affording high yields. Similarly, it has been found... 

The most effective and frequently used oxidant of secondary amines in organic solvents (CH2CI2, CH3CN, MeOH) is m-chloroperbenzoic acid (m-CPBA). Oxy-dation with m-CPBA of seco-curane type indoline alkaloids of strychnobrasiline (32), in deacetylated form, gives the corresponding nitrones (33), (34), and (35) (Scheme 2.12) (86). 

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. 

Anodic oxidations of secondary amines can provide radicals or radical cations. 

Colonna, S., Pironti, V., Carrea, G., Pasta, P. and Zambianchi, F., Oxidation of secondary amines by molecular oxygen and cyclohexanone monooxygenase. Tetrahedron, 2004,60, 569. 

Oxidation of Secondary Amines to Nitrones 6-Methy1-2,3,4,5-Tetrahydropyridine N-Oxide... 

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. 

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). ... 

Oxidation of secondary amines with H2O2 in the presence of Na2W04 gave the corresponding nitrones in good to excellent yields (40-90%) . Cyclic and acyclic amines are converted in mild conditions, room temperature, 3 h, using MeOH or H2O as solvents. 

Alkyl hydroperoxides in association with V- and Mo-based catalysts were reported to efficiently convert tertiary amines to N-oxides . Lower or trace product yields are observed in the oxidation of secondary amines employing similar oxidizing systems . 

The oxidation of secondary amines with no a-hydrogen atoms leads to hydroxy-lamines, but excessive dioxirane may further oxidize the hydroxylamines to the corresponding nitroxyl radical. For example, when a slight excess of isolated DMD is employed, 2,2,6,6-tetramethylpiperidin-4-ol (15) is quantitatively transformed into the hydroxylamine... 

Oxidation of aminesTertiary amines are oxidized by this reagent (2 equivalents) to amides in 70 95% yield. The oxidation of secondary amines is less selective amides are obtained in 35 50% yield accompanied by carboxylic acids and esters. 

Buonomennna, M.G., Lopea, L.C., Barbieri, G., Favia, P., d Agostino, R. and Drioli, E. (2007) Sodium tungstate immobilized on plasma-treated PVDF membranes new efficient heterogeneous catalyst for oxidation of secondary amines to nitrones. Journal of Molecular Catalysis. A, Chemical, 273, 32-38, 10.1016/... 

Secondary amines can be oxidized at the N-H bond to hydroxylamines and nitroxides, and via nitrones via C-N oxidation. Nitrones are valuable intermediates in the production of isoxazolines. Initial C-N oxidation of secondary amines gives imines which can react further to oxaziridines. The latter can be converted to nitrones, and both to amides. Primary amines are oxidized at the N-H bond to mono-substituted hydroxylamines, which are readily converted further to nitroso and nitro compounds by the more activated peroxygen... 

The oxidation of secondary amines can produce the corresponding hydroxyl-amines and nitrones (Equation 18.15) [134, 135]. TS-1 and TS-2 catalyzed the production of the former, at H202/amine molar ratios below unity. The addition of alkali metal additives improved the selectivity up to 90% [136]. High yields of nitrones could be obtained at greater H202/amine ratios. 

Table 13 Oxidation of secondary amines with A/-suifonyioxaziridine 33...

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