[2 + 3] Cycloaddition of <i>para</i>-Quinamines and <i>para</i>-Quinols with C,N-Cyclic Azomethine Imines: Access to 6/5/6/6-Fused Tetracyclic Pyrazolidines

Presented herein is a catalyst-free cycloaddition of <i>para</i>-quinamines and <i>para</i>-quinols with <i>C</i>,<i>N</i>-cyclic azomethine imines. A variety of 6/5/6/6-fused tetracyclic pyrazolidines featuring four contiguous stereocenters were facilely constructed via unprecedented [2 + 3] cycloaddition of <i>para</i>-quinamines and <i>para</i>-quinols. Such an intriguing cascade reaction pattern not only provided an atom- and step-economical strategy for the synthesis of multinitrogen polycyclic N-heterocycles containing a tertiary amine or alcohol group but also disclosed an unprecedented cycloaddition mode for <i>para</i>-quinamines and <i>para</i>-quinols as a two-atom synthon. Notably, evaluation of the antineuroinflammatory activity of selected pyrazolidines in LPS-treated microglia cells identified compound <b>8</b> as a promising candidate (EC₅₀ = 0.27 μM) with minimal cytotoxicity.