Synthesis of Spiro-β-lactam-pyrroloquinolines as Fused Heterocyclic Scaffolds through Post-transformation Reactions

Abstract

A sequential post-transformation of Ugi four-component reaction/nucleophilic substitution was developed for the synthesis of spiro-β-lactam-pyrroloquinolines. This method involves the Ugi-4CR of 2-chloro-3-formyl quinolines <b>1a</b>-<b>h</b>, amines <b>2a</b>-<b>d</b>, 2-chloroacetic acid <b>3</b>, and isocyanides <b>4a</b>, <b>4b</b> for the synthesis of versatile precursors <b>5a</b>-<b>v</b>. The Ugi adducts were intramolecularly cyclized under basic conditions through the sequential nucleophilic aromatic substitution (S_NAr)/second-order nucleophilic substitution (S_N2) reaction to give spiro-β-lactam-pyrroloquinoline scaffolds <b>6a</b>-<b>t</b>. This approach is an efficient method for the synthesis of fused bioactive heterocyclic backbones containing quinoline, pyrrolidone, and β-lactam with high bond-forming efficiency.