Legrand Pierre, Janin Yves L
Synchrotron SOLEIL, L'Orme des Merisiers, 91190 Saint-Aubin, France.
Structure et Instabilité des Génomes (StrInG), Muséum National d'Histoire Naturelle, INSERM, CNRS, Alliance Sorbonne Université, 75005 Paris, France.
Beilstein J Org Chem. 2022 Jul 29;18:935-943. doi: 10.3762/bjoc.18.93. eCollection 2022.
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.
1949年，鲁本·G·琼斯公布了一种2-羟基吡嗪的原创合成方法，该方法涉及在低温下用氢氧化钠处理时，1,2-二羰基化合物与α-氨基酰胺之间的双重缩合反应。这一发现被证明具有重要意义，因为即使在今天，这种制备方法也没有简单的替代方法。多年来，它一直被用于制备2-羟基吡嗪，但其一些局限性，特别是从α-酮醛开始时的区域选择性问题，无疑阻碍了在药物化学中潜在感兴趣的含吡嗪新化学实体的全面产生。本文描述了一些见解和改进，例如前所未有的使用氢氧化四烷基铵，在从苯乙二醛和两种α-氨基酰胺开始时，影响区域选择性和产率的反应参数方面。我们还提出了一种机制，解释了3,5-取代-2-羟基吡嗪作为主要反应产物的反直觉出现情况。
