Heterocyclic aromatic amines bromination

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

Oxidation of the parent aromatic heterocycle with hydrogen peroxide at room temperature yields the dioxo compound 8, in line with the susceptibility of the ring system to covalent dihydration. The bromine atom in compound 15 is readily displaced by amines in refluxing ethanol to give... 

The first retrosynthetic step introduces a great simplification of TM 8.3 by disconnection of the C-N bond in a refro-Michael mode resulting in 3-aminopyridine TM 8.3a and ethyl methacrylate. The heterocyclic amine is not available by either the nitration of pyridine and reduction or bromination and ammonolysis. In both cases the pyridine nucleus proves resistant to electrophilic aromatic substitution. 

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