Efficient synthesis of 4-pyridone-3-carboxylic acids via the reaction of enaminated diketonates with primary amines

Abstract

A novel approach has been described for the synthesis of 4-pyridones based on enaminated diketonates, which is a green alternative to the widespread transformation of 4-pyrones with amines in organic synthesis. The prepared diketonates, as important polycarbonyl intermediates, were isolated in pure form by simple work-up and used as a convenient platform for the synthesis of bioactive heterocycles. The cyclization of enaminated diketonates under the action of amines is a general and selective pyridonation approach to producing 4-pyridone-3-carboxylic acids and their derivatives, including difficult to access fluorine-containing molecules. Convenient synthesis conditions and easy isolation without the use of column chromatography allowed the introduction of the 4-pyridone-3-carboxylic acid fragment into various classes of amines in high yields. The pyridonation approach can also be implemented under mechanoactivation conditions, which significantly accelerate the reaction. This strategy was applied for the construction of polycyclic 4-pyridone-3-carboxylic acids and a dolutegravir derivative.