Pyrazine acid, ring synthesis

Several approaches, apart from those already considered, have provided partially or fully reduced derivatives of this ring system. Heating 2-acetylfuran (48) with ethylenediamine gave the 3,4-dihydro compound 49 in 45% yield. N-Tetrahydrofurfurylethylenediamine (50) has been cyclized to the perhydro compound 51 at 300° over alumina. 1-Oxoperhydro derivatives are obtained on reaction of ethylenediamine with a,S-dihalocarboxylic acids. " " This synthesis has been extended using suitable dihalo acids to a variety of diazabicyclic systems including pyrido[l,2-a]pyrazine (see Chapter XXVII). 

In the case of phenazine, substitution in the hetero ring is clearly not possible without complete disruption of the aromatic character of the molecule. Like pyrazine and quinoxa-line, phenazine is very resistant towards the usual electrophilic reagents employed in aromatic substitution reactions and substituted phenazines are generally prepared by a modification of one of the synthetic routes employed in their construction from monocyclic precursors. However, a limited range of substitution reactions has been reported. Thus, phenazine has been chlorinated in acid solution with molecular chlorine to yield the 1-chloro, 1,4-dichloro, 1,4,6-trichloro and 1,4,6,9-tetrachloro derivatives, whose gross structures have been proven by independent synthesis (53G327). 

The cleavage of fused pyrazines represents an important method of synthesis of substituted pyrazines, particularly pyrazinecarboxylic acids. Pyrazine-2,3-dicarboxylic acid is usually prepared by the permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring resembles the pyridine ring in its stability rather than the other diazines, pyridazine and pyrimidine. Fused systems such as pteridines may easily be converted under either acidic or basic conditions into pyrazine derivatives (Scheme 75). 

Selective reduction of the 7-oxo group in pyrido[23-synthetic approach to 5,10-dideazatetrahydrofolic acid <00H(53)1207>. Cycloaddition of pyrimido[4,5-c][l,2,5]oxadiazine 96 with 2,3-dihydrofuran affords a new synthesis of dimethyllumazine derivative 97 which undergoes a ring-opening reaction to give pyrazine derivative 98 <00JHC419>. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

The established procedure for the synthesis of the fused pyrazine ring involves condensation of the oxadiazole diamine with 1,2-dicarbonyl compounds <1978JOC341>. The latter procedure was used by Beebe et al. to make a series of [l,2,5]oxadiazolo[3,4-/ ]pyrazines for evaluation as antibacterial agents <2003BML3133>. An example is shown in Scheme 52, which involved heating the diamine with (3-bromophenyl)oxoacetic acid in glacial acetic acid at 110°C to give the [l,2,5]oxadiazolo[3,4- ]pyrazine. 

Stepwise pyrazine ring-formation using 5-nitropyrimidine was applied to the synthesis of 4a-hydroxytetrahydrobiopterin (95), which is an interesting intermediate in the metabolism of aromatic amino acids (see Sect. 5.2). As illustrated in Scheme 18, the 5-aminopyrimidine 97 prepared from chloroni-tropyrimidine 96 by nucleophilic substitution followed by catalytic hydrogenation was oxidized under acidic conditions to o-quinone derivative 98. 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

The most useful synthesis of this ring system involves conversion of 2-aminomethyl-pyrazines (470) by means of carboxylic acids or anhydrides into the amides (471), which are cyclized to 3-substituted imidazo[l,5-a]pyrazines (472) (73KX 2049, 75JHC207, 75JHC211, 75JOC3379). 

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