Aminopyrazines from amides

Methyl 3-aminopyrazine-2-carhoxylate [16298-03-6] M 153.1, m 169-172°, 172°. Forms yellow needles from H2O (100 parts using charcoal). If it contains the free acid then dissolve in CH2CI2 wash with saturated aqueous Na2C03, brine, dry over MgS04 filter, evaporate and recrystallise the residue. Th free acid has m 203-204° (dec) [UV Brown and Mason J Chem Soc 3443 7956] and pK <1 and pK2 3.70. The ammonium salt has m 232° (dec) (from aq Me2CO) and the amide has m 239.2° (from H2O) [Ellingson et al. J Am Chem Soc 67 1711 1945 ]. 

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>. 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

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