Defluorinative <i>Fluoro</i> ‐Aza‐Nazarov Cyclization

A highly efficient approach toward polysubstituted β-fluoropyrroles is described herein. Starting from α,α-difluoro-β,γ-unsaturated ketone, which is easily available from corresponding difluorinated silyl enol ether, an unprecedented defluorinative fluoro-aza-Nazarov cyclization mediated by TiCl₄ is successfully developed, which enables expedient construction of fluorine-containing tetra-/penta-substituted pyrroles in moderate to excellent yields. The protocol features the use of inexpensive Lewis acid, insensitivity to steric hindrance and compatibility with substrates of different substitution patterns. Furthermore, a two-step sequence and also a one-pot protocol were established for synthesizing tri-substituted pyrroles bearing a 3-fluorine substituent, utilizing a Pd-catalyzed defluorinative fluoro-aza-Nazarov cyclization. This methodology provides a modular solution for the rapid assembly of structurally complex β-fluoropyrrole scaffolds, which are notoriously difficult targets using previous methods. Mechanistic studies indicated a Ti-mediated allylic C─F bond activation pathway, triggering the unprecedented defluorinative Nazarov-type cyclization.