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

Abstract 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 TiCl 4 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.