Pyrazines preparations

Another method for pyrazine preparation is the cycloaddition of oxadiazinones with dienophiles. The oxadiazinone 208 undergoes cycloadditions with electron rich dienophiles such as 2,3-dihydrofuran to produce lumazines 209 <00JHC419>. 

Table 14 [1,2,4]Triazolo[4,3-a]pyrazines prepared from 2-hydrazinopyrazines or their derivatives Entry Product Yield (%) Reference...

Table 6 Tetrazolopyridazines, -pyrimidines, and -pyrazines prepared by nucleophilic substitution of haloazines by azide anion...

Trichloropyrazine may also be prepared by chlorination of 2,3-dichloro-pyrazine296 or, as previously mentioned, from triketopiperazine,273 296 but A-oxide rearrangement is probably the laboratory method of choice. A further application of A-oxide rearrangement for chloro-pyrazine preparation is taken from the work of Cragoe and his colleagues (Scheme 28).265... 

TABLE II.2 PYRAZINES PREPARED BY REDUCTION OF a-HYDROXYIMINO KETONES... 

Attempted preparations of the parent compound, pyrazine, from halogeneoacetal-dehyde and ammonia were not very successful (23, 237). Tschitschibabin and Schtschukina (237) made a careful study of this reaction their best yield, after oxidation with mercuric salts, was not higher than 11%. Some pyrazines prepared by this method are listed in Table 11.3 (3,10, 23,31,166,193, 209,236-247). 

TABLE II.3 PYRAZINES PREPARED BY AMMONOLYSIS OF a-HALOGENO CARBONYL COMPOUNDS... 

Some pyrazines prepared by this method are listed in Table II.4 (3,11,12,205, 257-267). 

TABLE II.4 PYRAZINES PREPARED FROM a-HYDROXY CARBONYL COMPOUNDS AND AMMONIA, AMMONIUM SALTS, OR FORMAMIDE... 

TABLE 11.5 PYRAZINES PREPARED FROM AMINO ACIDS BY THE AimON OF ACETIC ANHYDRIDE AND PYRIDINE FOLLOWED BY HYDROLYSIS... 

Pyrazines have been prepared by heating 1,2-dicarbonyl compounds with a-amino acids. Thus Rizzi (308) observed that under the conditions of the Strecker degradation, equimolar amounts of DL-valine (44) and butane-2,3-dione in refluxing bis(2-methoxyethyl) ether, diglyme, gave isobutyraldehyde, tetra-methylpyrazine (9%), and a mixture of cis- and trans-2-isopropyl-4,5-dimethyl-3-oxazoline (4%). He proposed a reductive amination mechanism in which butane-23-dione was converted to 2-aminobutan-3-one which underwent self-condensation to the pyrazine. Tetramethylpyrazine was also prepared when the same reactants were heated in dimethylformamide at 123° for 5 hours (and other pyrazines prepared similarly) (308a). 

The condensation of a, dicarbonyl compounds (49) with aj3-diamino compounds (50), which proceeds through the dihydropyrazine (51), has been much used for the synthesis of alkyl- and arylpyrazines (52). These reactions are usually carried out in methanol, ethanol, or ether in the presence of sodium or potassium hydroxide. The dihydropyrazines may be isolated, or oxidized directly to the pyrazine. Dehydrogenating agents that have been employed include oxygen in aqueous alkali (329), air in the presence of potassium hydroxide (330), sodium amylate in amyl alcohol (330a), alcoholic ferric chloride (24), and copper chromite catalyst at 300° (331) (see also Section 1). Pyrazines prepared by this method and modifications described below are listed in Table II.8 (2, 6, 24, 60, 80,195, 329-382) and some additional data are provided in Sections VI. 1 A, VlII.lA(l), and IX.4A(1). 

The pyrazine ring is relatively stable to oxidation, and many pyrazine-carboxylic acids have been prepared from quinoxalines, phenazines, and other fused pyrazines by oxidation with potassium permanganate. This reaction has been most used for the oxidation of quinoxalines, for example, 77 -> 78. The oxidations are usually carried out with potassium permanganate in alkali (397), but may also be effected without added base (398). Crippa and Perroncito (399) have also used chromic oxide in acetic acid-acetic anhydride to oxidize benzo(/]quinoxalines (79). Pyrazines prepared by this method are summarized in Table 11.9 (397-419). 

The reactions of various dipeptides with glyoxal at 100° and pH 5 have been studied and, besides other products, gave a series of new l-(l proposed mechanism involved an intermediate of type (109) in the formation of the pyrazine. Pyrazines prepared from dipeptides in this manner are listed in Table 11.12 (380, 381). The study has been extended to tri- and tetrapeptides (382). Some additional data are recorded in Section VI.9A(1). 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

Reaction of 3,4-diaminopyridine with pyruvaldehyde (MeCOCHO) under neutral conditions gives the expected 2-methyl compound 23, identical with a sample obtained from the 2-methyl-3-thioxo derivative 24. The infrared spectrum of the compound is different to that of 3-methylpyrido[3,4-h]pyrazine prepared by an unambiguous route (see... 

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