A Novel Route for the Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones via the Stephen-Biginelli Reaction

Introduction: Dihydropyrimidin-2(1H)-ones are privileged heterocycles present in natural products and bioactive molecules, including calcium channel blockers, antihypertensives, antivirals, and anticancer agents. Their broad pharmacological relevance has spurred sustained interest in developing efficient and environmentally benign methods for the synthesis of 3,4-dihydropyrimidin- 2(1H)-ones, which offer structural diversity and scope for further functionalization. Methods: The Stephen reduction involves the conversion of benzonitriles to benzaldehydes in the presence of HCl using stoichiometric reductants, such as SnCl₂·2H₂O. This method can be applied to synthesize dihydropyrimidinone analogues; the aldehydes formed from the Stephen reduction react with urea and ethyl acetoacetate in the Stephen–Biginelli reaction. Additionally, SnCl₄, generated in situ during the Stephen reduction, accelerates the reaction. Results: A series of dihydropyrimidin-2(1H)-one derivatives was efficiently synthesized through an in situ Stephen’s reduction combined with the Biginelli reaction, commonly referred to as the Stephen– Biginelli reaction. This protocol offers notable advantages, including excellent yields, short reaction times, and the absence of any catalyst requirement. Discussion: The in-situ generated SnCl4 formed during the Stephen reduction acts as a catalyst for the one-pot Biginelli reaction, thereby combining both transformations to afford 3,4- dihydropyrimidin-2(1H)-one derivatives efficiently. Conclusion: In summary, an efficient and sustainable Stephen–Biginelli strategy has been established for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives, offering high yields, rapid access, and catalyst-free conditions.