Tetramethylpyrazine, reaction yielding

Pyrazines form diquaternary salts on treatment with triethyloxonium fluoroborate. Using this reagent the 1,4-diethylpyrazinium difluoro-borates of pyrazine, 2,5-dimethyl-, and 2,6-dimethylpyrazines have been obtained in 96, 97, and 46% yield, respectively. The reaction is subject to considerable steric hindrance since the yield of diquaternary salt from tetramethylpyrazine is only 6%. The diquaternary salts are extremely reactive substances and that of the parent compound is shown by ESR measurements to be readily reducible to the radical cation [Eq. (7)].150... 

Tetramethylpyrazine can be converted into its monoanion by the use of sodamide in liquid ammonia or phenyllithium in ether.192 Thus, when phenyllithium, tetramethylpyrazine, and methyl benzoate are reacted in 2 2 1 molar proportion, a 67% yield of the monoacylated product, phenacyltrimethylpyrazine, is formed. A lower yield of monoacylated product is obtained when sodamide and liquid ammonia is used as the condensing agent, but reaction of sodamide, tetramethylpyrazine, and methyl benzoate in 6 1 1 molar proportion gives the optimum yield of diacylated derivative, formulated as 2,6-diphenacyl-3,5-dimethylpyrazine (39), by UV spectral comparison with 2,6-dimethylpyrazine and by the formation of a dioxime. 

Proof of the structure of the pyrazines was established in 1893 by Wolff (22), who converted tetramethylpyrazine to piperazine (8) by the series of reactions shown. The conversion of a-amino ketones to pyrazines requires the loss of hydrogen as well as the loss of water. Gabriel and Pinkus (23) obtained considerably higher yields when oxidizing agents were added to the reaction mixture after the condensation had been allowed to take place. Snape and Brooke (14) in 1897 established that amarone was identical with benzoinimide, ditolanazotide, tetraphenylazine, and tetraphenylpyrazine. 

Dimethyi-l-phenacylpyrazinium bromide (from 2,5-dimethylpyrazine and phenacyl bromide) and dimethyl acetylenedicarboxylate has been shown to give 6-benzoyl-7,8-bis(methoxycarbonyl)-1,4-dimethylpyrroIo[ 1,2-a] pyrazine (25) and 7,8-bis(methoxycarbonyl)-l,4-dimethylpyrrolo[l,2-fl]pyrazine (26) (723), and 1,2,5-trimethylpyrazinium iodide and dimethyl acetylenedicarboxylate also gave a 1% yield of (26). Addition reactions of 2-methyl- (724), 2,6-dimethyl- (724), 2,5-dimethyl- (725), and 2,3,5,6-tetramethylpyrazine (725), with dimethyl acetylenedicarboxylate have also been investigated. 

An interesting end product, tetramethylpyrazine was also presented in the reaction mixture (27.3% of peak area of the total volatiles). Previous study of the model reaction of 2,3-butanedione and ammonium acetate did not yield any tetramethylpyrazine. It is probably due to the reducing environment provided by H2S which reduced 2,3-butanedione to 3-hydroxy-2-butanone. This explained that both 3-hydroxy-2-butanone and 3-mercapto-2-butanone were found in the reaction mixture. This study also supported the mechanism proposed by Elmore and Mottram 10) who observed that, during the reactions of hydroxyketones with aldehydes and ammonium sulfide, the formation of thiazoles was discouraged due to reducing environment provided by H2S derived from ammonium sulfide. It is also interesting to note that con aring to previous a-hydroxyketone series tetramethylpyrazine was present at trace levels whereas in the a-dicarbonyl series it was the major product under comparable tenq)erature conditions. The reason for this observed phenomenon is not obvious. It is possible that in the reaction system of acetoin and ammonium sulfide, the... 

---