Pyrazine sulfones,

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Nucleophilic substitution with heteroaryl halides is a particularly useful and important reaction. Due to higher reactivity of heteroaryl halides (e.g. 35, equation 24) in nucleophilic substitution these reactions are widely employed for synthesis of Al-heteroaryl hydroxylamines such as 36. Nucleophilic substitution of halogen or sulfonate functions has been performed at positions 2 and 4 of pyridine , quinoline, pyrimidine , pyridazine, pyrazine, purine and 1,3,5-triazine systems. In highly activated positions nucleophilic substitutions of other than halogen functional groups such as amino or methoxy are also common. 

Racemic piperazine-2-carboxylic acid (4-azapipecolic acid, 22) is obtained by hydrogenation of pyrazine carboxylic acid salts/236 For its enantiomeric resolution several methods have been described, e.g. fractional crystallization of its S-camphor-10-sulfonic add salt/236,237 fractional crystallization of l,4-dibenzylpiperazine-2-carboxylic add menthyl ester/238 or selective digestion of racemic piperazine-2-carboxylic add amide by leucine aminopeptidase/239 ... 

By aminolysis of pyrazine sulfoxides or sulfones (nuclear primary, secondary, tertiary) Section 6.4. 

Pyrazine derivatives were again popular as ligands in crystallographic studies of transition metal complexes. These complexes included silver(I) alkylpyrazine sulfonates 83 <07IC7299>, tetrakis[3-(pyrazin-2-yloxy)pyridinc-AiVJdithiocyanatomanganese <07AX(E)m441>,... 

Pyrazine with hydroxylamine-O-sulfonic acid underwent (V-amination to give A -aminopyrazinium derivatives (610). 

R = Me) have been synthesized by A/-amination of pyrazine derivatives with hydroxylamine-D-sulfonic acid (H2NOSO2H) as the potassium salt, and later addition of hydriodic acid (610). 

A -Amination of pyrazine 1-oxide and 2,5-dimethylpyrazine 1-oxide has been effected with hydroxylamine-O-sulfonic acid and hydriodic acid to give 4-aminopyrazinium 1-oxide iodide (40, R = = H) and 4-amino-2,5-dimethyl-... 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

Mercaptopyrazine in aqueous hydrochloric or acetic acids was chlorinated to give the sulfonyl chloride which with excess liquid ammonia gave 2-sulfamoyl-pyrazine (1006, 1153). Direct sulfonation of the pyrazine ring has never been reported (819) but 2-sulfopyrazine (17) has been prepared from 2-chloropyrazine and aqueous sodium sulfite at 150° (819), and from 2-fluoropyrazine and aqueous sodium sulfite at reflux for 2 hours (882, 884). 2-Amino-3-mercaptopyrazine in aqueous sodium hydroxide with concentrated ammonia and sodium hypochlorite has been shown to give 2-amino-3-sulfamoylpyrazine (1101). 

Formylpyrazines have been isolated from acetals by hydrolysis. Thus 2-acetamido-3-dimethoxymethylpyrazine refluxed with aqueous pyridine hydrochloride gave 2-acetamido-3-formylpyrazine (1075), and 2-dimethoxymethyl-3-ethoxycarbonyl-aminopyrazine was hydrolyzed similarly (1075) 2-dimethoxymethyI-3-formamido-pyrazine with toluene-j9-sulfonic acid monohydrate and sodium sulfate in acetone at room temperature gave 2-formamido-3-formylpyrazine (1075), and 2-dimethoxy-methyl-3-ethoxalylaminopyrazine refluxed with the same reagents gave 2-ethoxalyl-amino-3-formylpyrazine (1075). 

The major intermediate of the Maillard reaction 38, having an ally lie system, seems to furnish a cytotoxic ester on metabolic sulfonation [298]. In contrast to the above findings, some Amadori products, such as pyrazines have antimutagenicity [299,300,301]. Enkastines, the Amadori products of 33 and dipeptides, beneficially prolong the action of enkephaline by inhibiting enkephalinase [302]. 

---