Oxidation of Tertiary Amines to N-Oxides

Previous reviews have dealt with metal-catalyzed [93] and stoichiometric [94] oxidation of amines in a broad sense. This section will be limited to the selective oxidation of tertiary amines to N-oxides. Amine N-oxides are synthetically useful compounds [95, 96] and are frequently used as stoichiometric oxidants in osmium-[97-99] manganese- [100] and ruthenium-catalyzed [101,102] oxidations, as well as in other organic transformations [103-105]. Aliphatic tert-amine N-oxides are usefid surfactants [96] and are essential components in hair conditioners, shampoos, toothpaste, cosmetics, and so on [106]. Chiral N-oxides have been used in asymmetric catalysis involving metal-free catalytic transformations [107] as well as metal-catalyzed reactions where the N-oxide serves as a ligand [107, 108]. Chiral tertiary amine N-oxides were recently used as reagents in asymmetric epoxidation of a,(3-unsaturated ketones [109]. 

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Other mono-oxygenases are not cytochrome P450 dependent, such as flavoproteins located in the endoplasmic reticulum that are involved in the oxidation of tertiary amines to N-oxides and of various sulfur compounds. Yet other oxidative enzymes, including alcohol and aldehyde dehydrogenases and monoamine oxidases, are located in the mitochondria or cytosol. 

Because of their importance, various methods have been reported for the oxidation of tertiary amines to N-oxides. The oxidations of amines are discussed below under the following headings (i) stoichiometric reactions, (ii) chemocatalytic reactions, and (iii) biocatalytic reactions. Finally we provide some examples where N-oxides are generated in situ as catalytic oxotransfer species in catalytic transformations. 

Selective oxidation of tertiary amines to N-oxides by H0F-CH3CN was reported by Rozen and coworkers [115]. The reaction is rapid, and amine N-oxides were isolated in high yields (Eq. (8.23)). The HOF-CH3CN complex was also employed to oxidize a number of substituted pyridines to their corresponding N-oxides (Eq. (8.24)). 

Aerobic oxidation of tertiary amines to N-oxide on a heterogeneous gold catalyst (Au/C) was reported to give high yields and selectivity in aqueous solution [122]. 

Only a limited number of examples of the biocatalytic oxidation of tertiary amines have been reported. Colonna et td. used bovine serrmi albumin (BSA) as a biocatalyst for the asymmetric oxidation of tertiary amines to N-oxides [127]. Oxone, NaI04, H2O2, and MCPBA were tested as oxidants, and the best results were obtained with NaI04 and H2O2 (Eq. (8.30)). Thus, BSA-catalyzed N-oxidation of 36 with these oxidants afforded N-oxide 37 in high yield in 64—67% ee. The reaction is formally a dynamic kinetic resolution, since the enantiomers of the starting material are in rapid equilibrium. 

An aerobic oxidation of tertiary amines to N-oxides catalyzed by Cobalt Schiff-base complexes was recently reported [98]. The reaction was run at room temperature with 0.5 mol% of the cobalt catalyst [Eq. (26)]. The presence of molecular sieves (5 A) enhanced the rate of the reaction. With this procedure various pyridines were oxidized to their corresponding N-oxides in yields ranging from 50 to 85 %. Electron-deficient pyridines such as 4-cyanopyridine gave a slow reaction with only 50% yield. 

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