NaI-Promoted Synthesis of Dihydroquinolines via an Unusual Azetine Intermediate

Abstract

New approaches to improve Skraup-type reactions for large-scale synthesis of 1,2-dihydroquinolines (1,2-DHQs) are highly desirable yet challenging in synthetic chemistry. Herein, an efficient sodium iodide-promoted Skraup-type reaction of anilines with ketones has been developed at low loading of HBF₄ (0.5 mol%), thus providing a sustainable and economical strategy for the synthesis of 1,2-DHQs. A variety of 1,2-DHQs were obtained in moderate to good isolated yields. The practicality of this strategy was well demonstrated by a hundred-gram-scale synthesis of 6-fluoro-2,2,4-trimethyl-1,2-dihydroquinoline in 68% isolated yield. Intriguingly, an unusual azetine intermediate was successfully isolated and structurally determined by NMR and MS, indicating of an unprecedented mechanism for Skraup-type quinoline synthesis.