Novel Synthetic Method and Insecticidal Evaluation of CF₃-Containing Polycyclic Neonicotinoid Derivatives

The modification of active ingredients with a trifluoromethyl group represents a significant approach for the discovery of highly active pesticides. Herein, we developed a novel [3 + 3] annulation reaction of neonicotinoid precursors and trifluoromethyl-α,β-ynones and synthesized a series of CF₃-containing polycyclic neonicotinoid derivatives in high efficiency. The insecticidal activity results indicated that most of the target compounds showed good insecticidal activities against <i>Aphis craccivora</i> and <i>Nilaparvata lugens</i> at a concentration of 100 mg/L. In particular, compounds <b>3o</b> and <b>4k</b> had LC₅₀ values of 1.53 and 1.47 mg/L against <i>A. craccivora</i>, respectively, which were comparable to that of imidacloprid (LC₅₀ = 1.30 mg/L). The honeybee toxicity predictive model also indicated the potential low honeybee toxicity of target compounds <b>3o</b> and <b>4k</b>. The molecular docking study revealed that the target compounds <b>3o</b> and <b>4k</b> exhibited a favorable binding mode with the <i>Lymnaea stagnalis</i> acetylcholine-binding protein and the R55T-mutated resistant model.