Mercuric acetate, oxidation of tertiary amines

Enamines via Mercuric Acetate Oxidation of Tertiary Amines. 

The preceding section described the preparation of enamines by mercuric acetate oxidation of tertiary amines. The initial product in these oxidations is the ternary iminium salt, which is converted to the enamine or mixture of enamines by reaetion with base. Thus iminium salts synthesized by methods other than the oxidation of tertiary amines or the protonation of enamines are potential enamine sources. 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

The most general method for synthesis of cyclic enamines is the oxidation of tertiary amines with mercuric acetate, which has been investigated primarily by Leonard 111-116) and applied in numerous examples of structural investigation and in syntheses of alkaloids 102,117-121). The requirement of a tram-coplanar arrangement of an a proton and mercury complexed on nitrogen, in the optimum transition state, confers valuable selectivity to the reaction. It may thus be used as a kinetic probe for stereochemistry as well as for the formation of specific enamine isomers. 

The key step in syntheses of if/-quebrachamine (122-127) and if/-dihydro-cleavamine (12S) is the oxidation of tertiary amines with mercuric acetate to cyclic imonium salts, which give rise to an intramolecular electrophilic attack on an indole. 

Leonard and coworkers " have developed the mercuric acetate oxidation of cyclic tertiary amines into a eneral method for the synthesis of heterocyclic enamines. This method has been used by other authors , A solution of the amine with a four-molar excess of mercuric acetate in 95% aqueous acetic add was refluxed on a steam bath and, after 1.5 hours, the mercurous acetate had precipitated and the amine obtained in 60-80% yield. It was assumed that 1,2-elimination, which requires an antiperiplanar arrangement of the nitrogen-electron pair and the eliminated hydrogen atom, took place, and that elimination of the hydrogen atom on the tertiary carbon atom is preferred, Oyeroxidation can be avoided by adding disodium ethylenediamine-tetraacetate to the reaction mixture . 

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]. 

As a means of decreasing side reactions in the dehydrogenation of tertiary amines with mercuric acetate, Knabe studied the oxidation of alkaloids of the type of papaverine (1) in the presence of an equivalent amount of the sequestering agent ethylenediamine tetraacetic acid (EDTA) as the disodium salt. The products were the papaverinium salt (2) and the dihydro salt (3) in the yields noted- In the absence of the complexing agent, papaverine is cleaved at the methylene bridge. 

Dehydrogenation of tertiary amines. Leonard found that cyclic tertiary amines can be oxidized to enamines with 4 mole equivalents of mercuric acetate in 5% aqueous acetic acid at steam-bath temperature. When quinolizidine was treated in... 

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

The oxidation of unsymmetrical tertiary amines with mercuric acetate may also lead to isomeric enamines. In such cases, structures can often be established by NMR and IR spectra of the enamines and their corresponding imonium salts, through comparison with model systems (202-205). 

In 1955, Leonard described a general method for the oxidation of cyclic tertiary amines to give enamines. Quinolizidine was dehydrogenated using mercuric acetate in 5 % aqueous acetic acid by heating on the steam bath for hr to give 92% mercurous acetate and 60% dehydroquinolizidine. 

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