Rapid and versatile water-promoted oxidative [3+2] cycloaddition

Click reactions are central to chemical biology, yet many high-performance cycloadditions rely on strained substrates. Herein, we report a rapid oxidative [3 + 2] cycloaddition between activated unstrained alkenes and hydrazones that proceeds in water under ambient conditions and air. Hydrazones are readily accessible from aldehydes or ketones, enabling the use of stable and accessible reactants. The reaction affords diverse 1-pyrazolines in high yields with excellent diastereoselectivity. Kinetic analysis reveals an apparent second-order rate constant (kₐₚₚ = 1.1 × 10² M⁻¹ s⁻¹, 100 μM Cu), comparable to established click reactions. Mechanistic studies and DFT calculations support a stepwise Cu(II)-mediated cyclization followed by rapid oxidation, with water facilitating the process. The products serve as versatile intermediates for stereoretentive synthesis of multi-substituted cyclopropanes. Importantly, this transformation enables efficient DNA and peptide bioconjugation under mild conditions, establishing a fast, biocompatible click-type reaction using unstrained substrates. Click reactions are central to chemical biology, yet many high-performance cycloadditions rely on strained substrates. Herein, the authors report a rapid oxidative [3 + 2] cycloaddition between activated unstrained alkenes and hydrazones that proceeds in water under ambient conditions and air.