On Reuben G. Jones synthesis of 2-hydroxypyrazines

In 1949, Reuben G. Jones disclosed an original synthesis of 2-hydroxypyrazines involving a double condensation between 1,2dicarbonyls and alpha-aminoamides upon treatment with sodium hydroxide at low temperature. This discovery turned out to be of importance as even today there are no simple alternatives to this preparation. Across the years, it was employed to prepare 2-hydroxypyrazines but some of its limits, notably regioselectivity issues when starting from alpha-ketoaldehydes, certainly hampered a full-fledged generation of pyrazine-containing new chemical entities of potential interest in medicinal chemistry. The present text describes some insights and improvements, such as the unprecedented use of tetraalkylammonium hydroxide, in the reaction parameters affecting the regioselectivity and yield when starting from phenylglyoxal and two alpha-aminoamides. We also suggest a mechanism explaining the counterintuitive occurrence of 3,5-substituted-2-hydroxypyrazine as the major reaction product.

Automated summary

This article reports an improved method for the synthesis of 2-hydroxypyrazines, which can enhance the regioselectivity and yield of the product. By using tetraalkylammonium hydroxide as the reaction parameter, starting from phenylglyoxal and alpha-aminoamides, pyrazine-containing new chemical entities of potential interest in medicinal chemistry were obtained.