Discovery of Novel Neonicotinoids with Conjugated Diene Enabled by Cascade Allylation/Isomerization Synthetic Methodology

As one of the most significant insecticides, neonicotinoids have played a pivotal role in crop protection and public sanitation. However, the high resistance and bee toxicity of neonicotinoid insecticides have attracted considerable attention. Herein, a series of neonicotinoid compounds with conjugated diene moieties were synthesized through the cascade allylation/isomerization reaction. Most of the target compounds exhibited excellent insecticidal activities against <i>Aphis craccivora</i>, and some compounds exhibited good insecticidal activities against <i>Mythimna separata</i>. In particular, compound <b>A15</b> showed outstanding insecticidal activity against <i>A. craccivora</i> (LC₅₀ = 0.15 mg/L), which was superior to that of imidacloprid (LC₅₀ = 0.36 mg/L). In addition, this candidate exhibited minimal cross-resistance to imidacloprid. The acute contact toxicity tests on <i>Apis mellifera</i> suggested that compound <b>A15</b> was 10 times less toxic than imidacloprid. Electrophysiological experiments and molecular docking studies indicated that compound <b>A15</b> exerted its insecticidal effects by interfering with nicotinic acetylcholine receptors. This work identifies a novel conjugated diene neonicotinoid candidate with significant potential for further development.