One-pot synthesis of 4-pyrimidone-2-thioether through base/acid-mediated condensation of S-alkylisothiourea and β-ketoester

Abstract

4-Pyrimidone-2-thioethers can be useful synthetic precursors to densely functionalized pyrimidines, commonly encountered in bioactive molecules. A convenient one-pot access to 4-pyrimidone-2-thioethers is reported herein, which utilizes a sequential base- and acid-mediated condensation of alkylisothioureas with β-ketoesters. Owing to mild reaction conditions, good to excellent functional group tolerance and yields are achieved. The utility of this approach is demonstrated by the synthesis of the crucial adagrasib intermediate on a 200 gram scale.