2- pyrazine, Hofmann

Despite the fact that one of the first pteridine syntheses was based on an intramolecular Hofmann carboxamide degradation of pyrazine-2,3-dicarboxamide by action of potassium hypobromite and leads to lumazine (equation 104), (07CB4857), pyrazine derivatives in general have not often been used because of availability problems. The reaction of alkyl... 

The amides of pyrazine-2-carboxylic acids and -2,3-dicarboxylic acids undergo the Hofmann reaction. In the case of the conversion of pyrazinamide to aminopyrazine (Scheme 20), the intermediate sodium carbamate can be isolated.219 Pyrazinamides react with phosphoryl chloride to give the corresponding cyanopyra-... 

Aminopyrazines are conveniently prepared from carboxamido-pyrazines by application of the Hofmann reaction (see Section V,B). Thus, Camerino and Palamidessi prepared aminopyrazine in 80% yield from carboxamidopyrazine.312 Aminopyrazine may also be prepared from the reaction of pyrazine with sodamide in liquid ammonia,313 and 3-amino-2,5-dimethylpyrazine is the product of amination of 2,5-dimethylpyrazine with sodamide in dimethyl-aniline.311 The ammonolysis of halopyrazines also represents a useful preparative procedure for aminopyrazines (see Section V,C). This reaction proceeds most easily in the case of fluoro compounds for example, fluoropyrazine is converted into aminopyrazine in 70% yield by treatment with concentrated aqueous ammonia at room temperature for 3 days,299 whereas the corresponding reaction with chloropyrazine has been carried out in a sealed tube at 150°.147 Alkaline hydrolysis of 2,4-dihydroxypteridines followed by decarboxylation yields aminopyrazines 315 thus, high-temperature alkaline hydrolysis of 7-methyl-2,4-dihydroxypteridine (7-methyIlumazine) gives, after decarboxylation of the intermediate pyrazinecarboxylic... 

The isomeric 2-amino-5-methyl- and 2-amino-6-methylpyrazines are obtained by Hofmann degradation of 2-carboxamido-3-hydroxy-5-and 6-methylpyrazines, respectively, followed by phosphoryl chloride treatment and catalytic dechlorination (Scheme 35).324 Two methods for the preparation of 2-aminopyrazine-5-carboxylic acid have been reported. One of these is based on the permanganate oxidation of 2-acetylaminoquinoxaline (see Section V,B), the other on pyrazine 2,5-dicarboxylic acid.325,326 The required transformations are illustrated in Scheme 36. 

Another key intermediate for pteridine synthesis was also seen in 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide which reacts with various amines to form the corresponding amides followed by cyclization with triethyl orthoformate giving 3-alkyl-6-phenyl-4(3/7)pteridinone 8-oxides <87JHC1109>. The synthesis of 2,4-diamino-6-methylpteridine 5-oxide (371) was achieved from 5-methyl-pyrazine-2-carboxamide (366) via the 4-oxide (367), a Hofmann degradation (368), bro-mination (369), and cyanation (370) followed by cyclization with guanidine to give (371) (Scheme 60) <93JHC841>. 

Aminopyrazines may be prepared from carbamoylpyrazines by the Hofmann degradation. Gabriel and Sonn (397) first prepared 2-aminopyrazine from 23-dicarbamoylpyrazine with potassium hypobromite through 2-amino-3-carboxy-pyrazine, which was decarboxylated when heated above its melting point (or in refluxing nitrobenzene) (397, 477). 2,3-Dicarbamoylpyrazine with 2 mol of... 

One only known extranuclear aminopyrazine has been prepared by the Hofmann reaction 2-(2 -carbamoylethyl)pyrazine with sodium hypochlorite gave 2-(2 -aminoethyl)pyrazine (405). 

Bis(azidocarbonyl)pyrazine at reflux with ethanol gave 2,5-bis(ethoxy-carbonylamino)pyrazine (1172) 2-carbamoylpyrazine when subjected to the Hofmann degradation gave the sodium salt of 2-carboxyaminopyrazine (which on acidification gave 2-aminopyrazine) (1171). 

The synthesis has been carried out by Kamal et al. (1962) through an Hofmann exhaustive methylation of the Mannich product obtained by reaction of methylpyrazine with formaldehyde and dimethylamine hydrochloride. Goldman (1963) prepared vinylpyrazine by pyrolysis of pyrazine-ethanol. 

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