Introduction of the Methyl Group into the Pyrazine Ring

Abstract

By the coupling reaction of mono-and dichloropyrazines with trimethylaluminum in the presence of a palladium catalyst, the corresponding mono-and dimethylpyrazines were prepared in excellent yields.Recent investigations have established the utility of palladium catalysts in the diazine chemistry.The palladium catalyzed cross-coupling reaction enabled the introduction of alkenyl and alkynyl groups into the diazines, such as pyrimidines and pyridazinesl.It is also known that the nickel phosphine complexes catalyze 2 the coupling reaction of chloropyrimidines with the Grignard reagents .The pyrazine chemistry has received likewise the benefits from palladium catalysts.Namely, in the presence of palladium catalysts, chloropyrazines undergo the coupling reaction with ethylenic and acetylenic compounds and potassium cyanide3.The present work constitutes a continuation of our investigation on the coupling reaction of chloropyrazines and deals with the introduction of the methyl group as a C1 unit into the pyrazine ring, using trimethylaluminum in the presence of a palladium catalyst.Although chloropyrazines were heated under reflux with trimethylaluminum in dry dioxane, the coupling reaction failed and the starting chloropyrazines were entirely recovered.However, the addition of tetrakis(tripheny1phosphine)palladium accomplished the coupling reaction.Namely, a solution of a chloropyrazine, trimethylaluminum (a 15% hexane solution), and the palladium catalyst in dry dioxane under argon stream was refluxed for 2 h.After cooling, the reaction mixture was diluted with water.The product was extracted with methylene chloride and then purified by chromatography on a silica gel column.The yields are satisfactory as shown in Table 1.