Amidation of pyrazine

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-... 

Homolytic amidation of pyrazine to 2-carbamoylpyrazine can be effected in > 80% yield by using concentrated sulfuric acid with carbamoyl radicals ( CONH2) generated from the action of hydrogen peroxide and ferrous sulfate on formamide (611). 

Amidation of pyrazine 2-amino-3-carboxylic acid (28) with r-BuNH2 using DEPC provides amide 29 in the presence of NEt3 but failed with base diazabicycloundecane (DBU).12 DEPC effectively coupled amino ester 30 with 28 to give amide 31 in 95% yield but the coupling reaction failed with DCC.13,14 DEPC served as an effective coupling agent for the preparation of amide 33 from methyl pyrrolidine carboxylate (32) and pyrazine carboxylic acid 28.13... 

It should be noted that, as all carbon positions in pyrazine are identical, the locant 2- in a monosubstituted derivative is unnecessary. All possible reduced derivatives of pyrazine 1, and several of those of its benzo analogues quinoxaline 2 and phenazine 3, are known. There are four dihydropyrazines, the 1,2-, 2,3-, 1,4-, and 2,5-isomers, two tetrahydropyrazines, the 1,2,3,4- and 1,2,3,6-, and hexahydropyrazine or piperazine, the last of which is omitted in this chapter. The reduced quinoxalines are the 1,2- and 1,4-dihydro compounds and 1,2,3,4-tetrahydroquinoxaline. The only known reduced phenazine is 1,4-dihydrophenazine. Hydroxypyrazine 4 and hydroxyquinoxaline 6 have been shown to exist in the tautomeric amide form by spectral studies, and therefore they are formulated as 2(1//)-pyrazinone 5 and 2(l//)-quinoxalinone, respectively. In contrast, aminopyrazine and aminoquinoxaline exist as described in the amino rather than the imino forms (Figure 1). 

Construction of pyrazine rings from a-amino nitriles has been sometimes completed through multistep reactions. For example, 2-aminopyrazine 1-oxide 163 is synthesized via amide intermediate 162 formed by reaction of methyl a-aminocyanoacetate with a-oximino carboxylic acid (Scheme 45) <1994H(38)1581>. 

Two examples were reported for the synthesis of the pyrido[2,3-, ]pyrazine moiety using pyrazine precursors. Thus, amidation of methyl 2-aminopyrazine-3-carboxylate 670 with a substituted acetyl chloride followed by heterocycliza-tion of the formed amide 671 gave 6,8-dihydroxy pyridopyrazine 672 <2004W02004056825>. 

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 ... 

This reaction gives good results for a variety of activated and unactivated alkyl halides [112] Oxidation of 2-bromoketones with iV-phenyltrifl amide was used in a one pot synthesis of pyrazines by the sequence of reactions shown in equaUon 57... 

There is one report describing the oxidative amination of pyrazine, using potassium amide as nucleophile, liquid ammonia at — 35°C as solvent and... 

The lone set of dimers in Table II, [M(C5Me5)2]2(M Pyraz ne) (Fig. 20 M = Ba), were synthesized from the base-free metallocenes by addition of pyrazine to MCp (1 2), analogous to the dioxane reaction for the amide compounds (Fig. 8).103 The pyrazine compounds are intensely colored owing to both charge transfer and intraligand electronic transitions. The pyrazine ligand has been shown to be labile by uv-vis spectroscopy. 

An improved dissymmetrization of imidazole-4,5-dicarboxylic acid 869 for the synthesis of Ar,AT -disubstituted dicarboxamides 872 involves the preparation of pyrazine-dione diphenyl ester 870. Selective amide formation at the pyrazine carbonyl at low temperatures affords the mixed amide ester 871, which is subsequently converted into 872 (Scheme 213) <2002JOC7151>. 

Pyrazine is aminated to 2-aminopyrazine with sodium amide in liquid ammonia at room temperature (606), in solvents such as dioxane or pyridine at room temperature or above (yields to 16%), or in the absence of added solvent at 50-55 (yields 36-60%) (607). N.m.r. evidence has been obtained for the anionic a complex (2) in the amination of pyrazine (608). 3-Substituted 1-methylpyrazinium ions... 

Renilla (sea pansy) luciferin (and certain of its synthetic analogues) produces a brilliant blue chemiluminescence when dissolved in organic solvents such as dimethylformamide and involves the anion of 2-acetamido-3-benzyl-5-(p-hydroxy-phenyl)pyrazine (21) (1191). 5-Hydrazino-2-hydrazinocarbonylpyrazine is effective against mycobacterium tuberculosis and m. kansasii in vitro (1098). Aminonitro-pyrazines have been claimed as useful yellow dyes for wool (1180) and tetraamino-pyrazine (1180) and A -substituted amides of 2-carboxy-3,5-bismethylamino-6-(A -methylcarbamoyl)pyrazines (1192) as fluorescent brighteners (or optical bleaching agents) for textiles. 

The reactions of pyrazine with sodium amide in liquid ammonia to give the anion of 2-amino-1,2-dihydropyrazine (608), and of 3-substituted 1-methylpyrazinium ions with liquid anunonia to give 3(or 5)-substituted 2-amino-1-methyl-1,2-dihydro-pyrazines (609) have been described in Section IV. 1C. Similar reactions of pyrazine with phenyllithium at —45° in tetrahydrofuran (720a) and of 1,2,5-trimethyl-pyrazinium salts in liquid ammonia with nitromethide and ethanethiolate anions (721) have been described in Section IV.2C(8). 

The first direct evidence for the existence of anionic cr-adducts was presented by Zoltewicz and Helmick (72JA682). They identified anionic (T-adducts 18, 19, and 20 by the addition of pyrazine, pyrimidine, and pyr-idazine, respectively, to excess sodium or potassium amide in liquid ammonia. Identification was made possible by H-NMR spectroscopy. 

Direct zincation of each of the diazines can be achieved using a zinc diamide/lithium amide mixture, pyrazine and pyrimidine (at C-4) in THF at room temperature, pyridazine (at C-3) requiring reaction at reflux. Pyridazine and pyrimidine can also be directly zincated using a phosphazene base (t-Bu-P4) with zinc iodide. ... 

One of the classical methods for the synthesis of pyrazines involves dimerization of an a-amino carbonyl compound and subsequent aromatization. Oximes have often been used as the latent functionality to generate the amine by a variety of reductive processes. 3-Oxo-2-oximinobutanoic esters or the amides (146), which are formed by nitrosation of acetoacetic acid derivatives, are reduced by catalytic hydrogenation <82CPB3424, 91JHC1731> or titanium(III)-induced reduction <88H(27)il23> to give the tetrasubstituted pyrazines (147) (Equation (17)). 

The same principles apply to the synthesis of pyrazines such as (85), the odour principle of green peppers. The eno ether must be made from amide (86) and we can then disconnect into available (Chapter 23) glyoxal (88) and compound... 

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