Demethylation of tertiary amines

The Ru(II)/ROOH system can also be used to oxidize tertiary amines. The intermediate iminium ion is formed, as described earlier for secondary amines, and can be trapped by nucleophiles. Thus, the ruthenium-catalysed oxidation of tertiary amines with hydrogen peroxide in methanol can be performed to give the corresponding a-methoxyamines with high efficiency as illustrated in Fig. 24 [ 137]. Another example is the selective demethylation of tertiary amines in methanol with a combination of Ru(II) and H202, followed by hydrolysis of the intermediate a-methoxylated amines. For example, the methoxylation of N,N-dimethyl-p-toluidine followed by treatment with 2 N HC1 solution gave N-methyl-p-toluidine in 75% yield (Eq. 35) [137]. 

The oxidation of N-methylamines provides various useful methods for organic synthesis. Selective demethylation of tertiary methylamines can be carried out by the ruthenium-catalyzed oxidation and subsequent hydrolysis (Eq. 3.71). This is the first synthetically practical method for the N-demethylation of tertiary amines. The methyl group is removed chemoselectively in the presence of various alkyl groups. 

Such demethylation takes place often without interception of the form-amide. Dicyclohexylmethylamine, on treatment with potassium ferricya-nide in potassium hydroxide at room temperature overnight, is converted into dicyclohexylamine in 87% yield [926]. Other oxidants suitable for the demethylation of tertiary amines are mercuric acetate in 5% aqueous acetic acid at 100 °C [403], manganese dioxide in cyclohexane at 20 °C [812], and even oxygen, which, under irradiation at 20 °C in the presence of rose bengal in aqueous rm-butyl alcohol, converts codeine into norcodeine in 75% yield [46]. 

N-Demethylation of tertiary amines. Tertiary amines are converted into N-demethyl-N-nitrosamines (40-80% yield) by treatment with AgN02 (4-8 molar eq.) in DMF (70°, 2-24 hr.). N-Nitrosamines are readily hydrolyzed to secondary amines by acid. ... 

An improved procedure for the A-demethylation of tertiary amines, which was applied in the morphine series, utilizes phenyl chloroformate to obtain an intermediate carbamate which is then easily cleaved with a 1 1 mixture of 64 and 95% hydrazine. / -Nitrophenyl chloroformateor the milder vinyl chloroformate are sometimes preferred over phenyl chloroformate. 

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