Efficient synthesis of novel arylidene cyanoacetamide derivatives via Knoevenagel condensation

The widespread utility of unsaturated 2-cyanoacetamide derivatives in medicinal chemistry is fixed, as they serve as essential building blocks for synthesizing bioactive compounds, thereby facilitating the development of innovative pharmaceutical agents. This study presents an efficient and high-yielding synthetic approach to novel arylidene cyanoacetamide derivatives via Knoevenagel condensation. A series of N-substituted cyanoacetamides (2, 3, 4, and 5) were first prepared by reacting ethyl cyanoacetate (1) with cyclohexylamine, morpholine, piperidine, and piperazine. These intermediates were subsequently condensed with various aromatic aldehydes including cinnamaldehyde (6), 3-(4-dimethylamino) phenyl acrylaldehyde (7), and 4-(dimethylamino) benzaldehyde (8) using trimethylamine as a base catalyst. The reaction afforded the target arylidene derivatives (I-VI) excellent yields (70.0-90.0%) under mild and straightforward conditions. All compounds were fully characterized by ¹H NMR, ¹³C NMR, and mass spectrometry. This method provides a practical and scalable route to structurally diverse arylidene cyanoacetamides, which hold potential for applications in medicinal chemistry (e.g., as bioactive scaffolds) and materials science (e.g., as optoelectronic materials).