Oxidation nitrogen, peracid

Xanthines substituted at the 8-position with an oxygen or nitrogen atom are oxidized with peracids to 4,5-dihydro-1,2,4-oxadiazoles (200) (Scheme 87) <940PP353>. 

Most cyclic a-diazoketones are oxidized by peracids to a-diketones in good yield, but low yields were obtained for oxidation of a-diazocyclo-octanone and a-diazo-cyclononanone because of further oxidation to suberic and azelaic anhydrides, respectively. Since the rate of oxidation is only slightly dependent upon ring size, the conformation of the transition state must be similar to that of the ground state a concerted nitrogen extrusion-oxygen addition mechanism has been proposed. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

Among the oxidative procedures for preparing azo compounds are oxidation of aromatic amines with activated manganese dioxide oxidation of fluorinated aromatic amines with sodium hypochlorite oxidation of aromatic amines with peracids in the presence of cupric ions oxidation of hindered aliphatic amines with iodine pentafluoride oxidation of both aromatic and aliphatic hydrazine derivatives with a variety of reagents such as hydrogen peroxide, halogens or hypochlorites, mercuric oxide, A-bromosuccinimide, nitric acid, and oxides of nitrogen. 

Pyridine A-oxides are formed by the treatment of pyridines with peracids (74)— (75). Typical conditions are MeC02H/H202 at 100°C or m-ClC6H4C03H/CHCl3 at 0°C. The pyridine nitrogen atom reacts less readily with peracids than do aliphatic tertiary amines, as expected. Large a-substituents and any electron-withdrawing substituents slow the reaction thus the A-oxidation of 2,6-diphenylpyr-idine proceeds in poor yield, and efficient conversion of pentachloropyridine to the A-oxide requires a powerful oxidant such as peroxytrifluoroacetic acid. 

N-Oxidation may be formally considered as quatemization of pyridine-like nitrogen atom by the HO+ cation, formed by heterolysis of 0-0 bond in the peracid molecule. Indeed, common features exist between N-alkylation and N-oxidation both reactions are second order (first order at each reagent). The reaction constant, p, for oxidation of 3- and 4-substituted pyridines by PhC03H in aqueous dioxane is -2.35, Close to the p value for N-alkylation (Chem. of the Heterocyclic N-oxides, N-Y, Acad. Press, 197l). 

The oxidation rate with excess peracid decreases in the order > 7ji > 71) >> 6a the first three compounds react readily below -30°C whereas 6a requires > 10°C for significant reaction in 24 hr. The nitrogen free electrons of 7ji and 7j) may facilitate their oxidation by increasing the polarizability of the sulfur. 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

Electrophilic substitution at nitrogen can occur in either ring depending on the nature of the substituents present. Electrophilic substitution at carbon proceeds readily in the presence of electron-releasing substituents. A wide variety of electrophiles have been studied. Mesoionic systems are readily substituted and cationic structures may become very reactive when conditions are chosen so as to promote intermediate formation of a pseudo-or anhydro-base. Sulfoxides are formed in the peracid oxidation of fused dihydrothiazoles. 

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