2.3.5.6- Tetramethylpyrazine reduction

Polarographic studies on pyrazine and methylpyrazines indicate that 1 4-dihydropyrazines are the products of reduction. The reduction of pyrazine itself at the dropping mercury electrode proceeds reversibly. The substitution of methyl groups makes the reduction more difficult with an increased number of methyl groups an increased tendency toward irreversible reduction is noted.102-104 The half-wave reduction potentials for pyrazine, methylpyrazine, 2,6-dimethyl-pyrazine, and tetramethylpyrazine are 2.17, 2.23, 2.28, and 2.50 eV, respectively. Pyrazine is thus more easily reduced than pyridine which has a half-wave potential of 2.76 eV, and less easily reduced than quinoxaline which has a half-wave potential of 1.80 eV.105... 

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). 

Polarographic studies have been made on pyrazine and methylpyrazines they indicate that 1,4-dihydropyrazines are produced, and that substitution (by methyl groups) makes the reduction more difficult. The reduction of the parent pyrazine proceeds reversibly (125, 586-588). The experimental half-wave reduction potentials [pyrazine (2.17 eV), methylpyrazine (2.23) 2,6-dimethylpyrazine (2.28), tetramethylpyrazine (2.50), pyridine (2.76), and quinoxaline (1.80)] also revealed that pyrazine was more easily reduced than pyridine but less easily reduced than quanoxaline (589). 

The polarographic behavior of the 1-oxides and 1,4-dioxides of pyrazine, 2,5-dimethylpyrazine, and tetramethylpyrazine at various pH values has been investigated. It was assumed that at lower pH values, the A -oxide group was reduced in its protonated form. In acid media the 1-oxides exhibited double waves, the first of which is attributable to the reduction of jV-oxide groups and the second to that of the pyrazine nucleus (production of 1,4-dihydro compounds). Reduction of both A -oxide groups of pyrazine-1,4-dioxide proceeded simultaneously (588). Half-wave potentials of the voltammetric oxidation and reduction of pyrazine mono- and di-A -oxides have been measured in dimethylformamide, and in acetonitrile by the technique of a rotating platinum electrode (750). 

A dose-dependent reduction in plasma glucose levels was observed in diabetic mice intraperitoneally administered 10, 25, or 50 mg/kg of the compound tetramethylpyrazine (Lee et al. 2002). 

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