Pyrazine → 2,5-Dimethylpyrazine

Participants

Reaction Steps

An alternate pathway for the synthesis of piperazine-2,5-dicarboxylates 64-66 involved reduction of the corresponding pyrazine precursors. Preparation of piperazine-2,5-dicarboxylic acid 64 had been reported in Felder, Von E., Maffei, S., Peitra, S. and Pitre, D., Helv. Chim. Acta. 1960, 43, 888-896, from pyrazine diester 83. Hydrolsis of 83 followed by hydrogenation of the alkaline solution at room temperature was reported to afford trans-64, but no evidence for the geometric assignment was provided. Diacid 64 was prepared from the corresponding pyrazine 82. Synthesis of pyrazine-2,5-dicarboxylic acid 82 had been reported by several authors. See Krems, I. J., and Spoerri, P. E., J. Amer. Chem. Soc. 1946, 68, 527-528; Mager, H. I. X. and Berends, W., Rec. Trav. Chim. 1958, 77, 827-841; Kimura, T., Yamada, S., Kanzahi, K. and Kato, K., Jpn. Patent 1960, 10,510 through Chem. ABs. 1961, 55, 9439; Schut, W. J., Mager, H. I. X., and Berends, W., Rec Trav. Chim. 1961, 80, 391-398 and Fujii, S., Kikucki, R. and Kushida, H., J. Org. Chem. 1966, 31, 2239-2241. Oxidation using SeO2 in refluxing pyridine-water afforded 82 in 65-71% yield from commercially available 2,5-dimethylpyrazine. An alkaline solution of diacid 82 at 50°-60° C. and 40-42 psi H2 pressure using Pd/C catalyst over a period of 12 h afforded an isomeric mixture of 64 in 98% yield. The isomers were separated by crystallization from water under controlled pH. The trans isomer crystallized at pH 5.5-6.5. Further acidification to pH 4.0-5.0 resulted in crystallization of cis-64. Geometric configurations were assigned by [1H]--NMR analysis. ##STR27##

Provenance & Evidence