On Reuben G. Jones synthesis of 2-hydroxypyrazines

Abstract

In 1949, Reuben G. Jones disclosed an original synthesis of 2-hydroxypyrazines involving a double condensation between 1,2-dicarbonyls and α-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 α-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 α-aminoamides. We also suggest a mechanism explaining the counterintuitive occurrence of 3,5-substituted-2-hydroxypyrazine as the major reaction product.

l‐Serine is the Direct Precursor for the Pyrazine Ring Construction in the Biosynthesis of 3‐Isobutyl‐2‐Methoxypyrazine in Bell Pepper Fruits (Capsicum annuum L.)

“…Prior investigations clearly demonstrated that glycine (5) and glyoxylic acid (8) do not serve as direct precursors to 3-isobutyl-2-methoxypyrazine (IBMP, 1). Instead, they are deemed to act as C 1 -building blocks, suggesting that they are first metabolized before they are incorporated into 1.…”

“…As many pesticides, pharmaceuticals and flavorings are pyrazine‐based, they are also synthesized chemically in industry [4–6] . The pyrazine ring can be synthesized using various routes mainly by direct ring closure such as the two‐step synthesis starting with a condensation of a 1,2‐diketone with a 1,2‐diamine (Scheme 1A) or the spontaneous intramolecular α‐aminoketone‐cyclization (Scheme 1B) [4,5,7,8] …”

“…[4][5][6] The pyrazine ring can be synthesized using various routes mainly by direct ring closure such as the two-step synthesis starting with a condensation of a 1,2-diketone with a 1,2-diamine (Scheme 1A) or the spontaneous intramolecular α-aminoketone-cyclization (Scheme 1B). [4,5,7,8] Pyrazines contribute to different aromas; their aroma properties depend on their substitution pattern. Alkyl-substituted pyrazines have a roasted, nutty, or earthy flavour.…”