Pyrazines, hydroxy

The classical route to chloropyrazines is by treatment of a hydroxy-pyrazine with phosphoryl chloride bromopyrazines are similarly prepared by using phosphoryl bromide, phosphorus tribromide, or a mixture of both. Thus, treatment of hydro xypyrazine with phosphoryl chloride gives chloropyrazine in 92% yield,147 and treatment of the hydroxy compound with a mixture of phosphoryl bromide and phosphorus tribromide gives bromopyrazine in 58% yield.266 The use of phosphorus pentahalides frequently leads to substitution products (Scheme 22) for example, when hydroxypyrazine is treated with a mixture of phosphoryl bromide and phosphorus pentabromide both monobromo- and 2,6-dibromopyrazines are formed.287,268 Bromina-tion of hydroxypyrazine with bromine in the presence of small... 

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... 

As already mentioned, hydroxypyrazines exist in tautomeric equilibria with the corresponding pyrazinones which are normally the predominant species in the equilibria. Some of the reactions of hydroxypyrazines are reminiscent of those of phenols they can, for example, be coupled with diazonium salts and brominated and nitrated in either the ortho or para position to the hydroxyl group. Coupling with diazonium salts occurs in neutral or weakly alkaline solution, but if the reaction is carried out in 1 M sodium hydroxide solution, arylation of the pyrazine ring takes place. From hydroxy-pyrazine and benzenediazonium chloride 47% 2-hydroxy-3-phenyl-and 4% 2-hydroxy-3,6-diphenylpyrazine are obtained. 

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... 

Many chloropyrazines have been prepared from hydroxypyrazines by reaction with mixed phosphorus pentachloride-phosphoryl chloride as follows 2-hydroxy-pyrazine to 2-chloropyrazine (818), 2-hydroxy-3-phenylpyrazine to 2-chloro-3-phenylpyrazine (535), 2-hydroxy-6-methyl- and 5-hydroxy-23-[Pg.102]

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). 

The sodium salt of 2-hydroxypyrazine with thiophosphoryl chloride at room temperature gave 2-(dichlorophosphinothioyloxy)pyrazine (1112, 1113) and in N-methyl-2-pyrrolidone with ( ,6)-diethyl phosphorochloridothioate [(EtO)2P(=S)Clj it gave 2-(diethoxyphosphinothioyloxy)pyrazine (1114, 1115), also prepared in the absence of A(-methyl-2-pyrroIidone (1116). The potassium salt of 2-hydroxy-pyrazine in t-butanol-dioxane with 0,0-diphenyl phosphorochloridothioate... 

Supplement (combined with Volumes XXIV and 1936 3458-3793 methane, 25. Pyrimidine, 89. Pyrazine, 91. Nicotine, 110. Dipyridyl, 199. Phenanthroline, 227. Hydroxy compounds, 348 Cinchonine, 424. Quinine, 511. Indigo white, i... 

Conflicting reports on the nitration of phenazine have appeared, but the situation was clarified by Albert and Duewell (47MI21400). The early work suggested that 1,3-dinitroph-enazine could be prepared in 66% yield under standard nitration conditions however, this proved to be a mixture of 1-nitrophenazine and 1,9-dinitrophenazine (24). As with pyrazines and quinoxalines, activating substituents in the benzenoid rings confer reactivity which is in accord with valence bond predictions thus, nitration of 2-methoxy- or 2-hydroxy-phenazine results in substitution at the 1-position. 

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. 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

Protonation of pyrido[2,3-f ]pyrazine occurs normally without covalent hydration, although the 2-hydroxy derivative did show such behaviour (63JCS5737). The pyrido[3,4-f)]pyrazine parent base does show the phenomenon, although the exact structure of the covalent hydrate seemed to be in doubt between protonated (392) and (397). The issue was resolved in favour of the former by NMR (79JHC301, 75AG356). The 3-hydroxy derivative also shows hydration effects, as does the 7-amino cation (63JCS5166). 

Nitro groups have been reduced to amino groups, whilst amino groups in the 3- and 6-positions of pyrido[2,3-f ]pyrazines and in the 5-position of the [3,4-f ] isomers have been hydrolyzed to the corresponding hydroxy derivatives with alkali. Protected amino groups have been liberated by hydrolysis or reduction in deazapteridine syntheses. 

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