Practical Synthesis of 3-Substituted Pyrimidin-4-ones and 4(3H)-Quinazolinones from Nitriles: Mechanistic Insights, Scope, and Scale-Up

Abstract

Pyrimidin-4-ones and (3H)-quinazolin-4-ones are widely occurring heterocyclic motifs found in biologically active substances. This report presents a practical and scalable three-step, two-pot synthesis of 2-unsubstituted-3-alkyl/aryl derivatives of these heteroaromatics. During the mechanistic investigation of the hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU)-mediated coupling of 4-hydroxyquinazolines with amines, we found that the N-activated heterocycle underwent nucleophilic attack on the methine atom with subsequent ring opening and ring closing (ANRORC mechanism). Building on the new mechanistic insight, we designed and developed an efficient synthesis of 2-unsubstituted-3-substituted pyrimidin-4-ones through the condensation of β-aminoacrylates with dimethylformamide dimethylacetal (DMF-DMA), followed by cyclization with primary amines. The required β-aminoacrylates were easily obtained in a single step via ZnCl₂-mediated decarboxylative Blaise–Reformatsky reaction of nitriles, which was extended to aliphatic substrates using an improved protocol. The methodology described herein is particularly suited to execution on a large scale as it requires no chromatography, utilizes no solvents of very high concern, and has been successfully demonstrated on the liter scale.