2- Hydroxy-3- pyrazine oxidation

Direct ring syntheses are also available for the preparation of hydroxypyrazines. Thus, haloacylation of an a-aminoketone, followed by reaction with ammonia and oxidation represents a general synthesis of 5,6-disubstituted and 3,5,6-trisubstituted 2-hydroxypyrazines.339 This is illustrated by the preparation of 5,6-dimethyl-2-hydroxy-pyrazine (Scheme 39). Hydroxypyrazines are very conveniently... 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

Bredereck and Schmotzer (1044), from diaminomaleonitrile (DAMN hydrogen cyanide tetramer) and oxalyl chloride, prepared 2,3-dicyano-5,6-dihydroxy-pyrazine but Stetten and Fox (1049) could not prepare 23-diamino-5-hydroxy-pyrazine from glycine amide and oxamide. Section 11.3 lists preparations from a, -diamino or a, -diimino compounds and reagents other than a,0-dicarbonyl compounds (384) with additional data (1050) and oxidation of 23-dichloro-quinoxaline with hot aqueous potassium permanganate gave 23-dicarboxy-5,6-dihydroxypyrazine (1051). 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Pyrido[2,3-6]pyrazine, 8-hydroxy-tautomerism, 3, 250 Pyrido[2,3-h]pyrazine, methyl-acylation, 3, 253 Pyrido[2,3-6]pyrazine, 2-oxo-oxidation, 3, 250-251... 

In [l,2,4]triazolo[4,3-a]pyrazine (174) bromination took place at the 5-position rather than in the triazole ring (77JOC4197). It was not possible to convert the 3-hydroxy derivative into the 3-chloro analogue (68JHC485). The isomeric [1,5-a] compound (175) was also brominated at C-5 (74TL4539), whereas its 7-oxide gave the 8-chloro derivative under Meisenheimer conditions [80JCS(P1)506]. 

Azido-pyrazin-l-oxid reagiert in einer verwandten Reaktion bereits beim Kochen in Benzol in 83% Ausbeute zu 2-Cyan-l-hydroxy-imidazol4 28. 

Heating with phosphoryl chloride converted 1 -hydroxy-3-phenyl-2( 1H )-pyrazinone (52) into the 2,5-dichloro derivative (53) via the 5-monochIoro species. It had been expected that chlorination would take place at C-6, but this occurred only to a minor extent. The observed chloride attack /3 to the oxygen function might be accounted for in terms of the sequence illustrated in Scheme 46 (86JHC149). Reaction mechanisms have been proposed to explain the observed a- and /3-chlorination when 2- and 3-substituted pyrazine Af-oxides are subjected to the Meisenheimer reaction. /3-Chlorination was rationalized in terms of electron withdrawal by the unoxidized nitrogen atom [84JCR(S)318] (Scheme 46). 

It was suggested that a-amino carbonyls such as 3-amino-butane-2-one formed a dihydropyrazine which was subsequently oxidized to a pyrazine (30, 311. The conversion of dihydropyrazine to pyrazine occurs with or without oxygen. There are two possible ways to convert dihydropyrazine into pyrazine without oxygen. One is the disproportionation of dihydropyrazine to give pyrazine and tetrahydropyrazine or piperazine. The other is the dehydration of hydroxy dihydropyrazine (32). Recently, a dialkylpyrazine radical was reported as an intermediate of pyrazine formation (33). However, this simple step from dihydropyrazine to pyrazine is not yet thoroughly understood. 

It should be noted that this mechanism involves a final oxidation. The need for this is avoided when amino acids with an a-hydroxy group in the sidechain (serine, threonine) are involved, as pointed out by Shibamoto and Bernhard234 (see Scheme 5.9). Baltes and Bochmann235 obtained as many as 123 pyrazines, both mono- and bicyclic, by interacting sucrose with serine and threonine under coffee-roasting conditions. 

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. 

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