Pyrazine with phenyllithium

The reaction of pyrazine with phenyllithium in THF or TMEDA at -45°C leads quantitatively to 102, as shown by the H-NMR spectrum. The assignment of the structure is made possible by comparison with the amino anaIog31. Both H- and l3C-NMR spectra of 102 are rather poorly diagnostic because they consist of broad signals. 

Zoltewicz and Helmick (665) found that, whereas pyrazine reacts with potassium amide to form the anionic o complex (20), methylpyrazine undergoes deprotonation to give the delocalized carbanion (21) and the p.m.r. spectrum shows that pyrazine with phenyllithium at —45° is converted completely into a dihydro adduct analogous to (20) (720a). 

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). 

In contrast to benzene compounds, which undergo ready electrophilic substitution, the highly n-deficient pyrazine and quinoxaline nuclei are susceptible towards nucleophilic attack by a variety of reagents. The direct nucleophilic substitution with organolithium or Grignard reagents to form alkyl or aryl heteroaromatics, however, is rather ineffective, and the dihydro and/or tetrahydro compounds are formed preferentially. For example, reaction of pyrazine with phenyllithium affords... 

Alkylation of pyrazine has been achieved under a variety of conditions. Treatment of pyrazine in ether at — 20° with butyllithium gave a 10% yield of 2-butyl-pyrazine but with phenyllithium only polymeric material or unchanged starting material was obtained (612). Pyrazine is alkylated at the 2-position by the radical MeNHCO(CH2)4CH2 generated from 2-methyl-3,3-pentamethyleneoxazirane and ferrous sulfate (613). Aldehydes and ketones in the presence of a solution of an alkali or alkaline earth metal in liquid ammonia (or a suspension of these metals in other solvents) can be made to alkylate the pyrazine ring in moderate to good yields. Thus from pyrazine and ethyl methyl ketone, a 60% yield of 2-s-butylpyrazine was obtained (614). 

The C nuclear magnetic resonance spectra have been obtained for pyrazine (1504), and 10 monosubstituted pyrazines (1505) and a C n.m.r. study has been made on the adduct of phenyllithium with pyrazine (720a). 

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