Modular Synthesis of Fluoro‐ and Polyfluoroalkyl‐Substituted <i>N</i> ‐Heterocycles via Photocatalytic Radical‐Polar Crossover [3 + 2 + 1] Cyclization

Comprehensive Summary Due to the unique physicochemical properties of fluorine atom, the introduction of fluorine or polyfluoroalkyl group has emerged as a pivotal strategy in pharmaceutical and agrochemical design. Radical fluoroalkylation reactions stand out as a particularly efficient and innovative synthetic platform, enabling the construction of a vast array of valuable organofluorine compounds. However, a major synthetic challenge persists─the development of a unified, generalizable methodology capable of selectively forging fluorinated or fluoroalkylated molecular architectures from simple precursors remains highly desirable and challenging. Emerging strategies aim to leverage C–F bond activation, which allows for the transformation of readily available, yet often inert, polyfluorinated feedstocks into versatile fluorinated products. Described herein is a photocatalytic radical‐polar crossover [3 + 2 + 1] cyclization reaction from easily available polyfluoroalkyls, enamines and 3‐aminoindazole or 3‐aminopyrazoles derivatives under mild conditions. Detailed mechanistic investigations reveal a sophisticated cascade pathway involving initial radical fluoroalkylation of the enamine, followed by a defluorination, and culminating in a cyclization sequence. To the best of our knowledge, this platform represents one of the very few examples for the construction of biologically important fluorine or fluoroalkyl‐containing fused‐ring systems under a uniform reaction condition with high efficiency and compatibility. Key to this methodology is the in‐situ generation of a reactive α,β ‐unsaturated iminium intermediate while enabling subsequent cascade multicomponent cyclization reactions. This transformation proceeds efficiently in simple one‐pot protocol with broad substrate scopes, including perfluoroalkyl halides with varying chain lengths and substitution patterns, as well as diverse nucleophilic partners. We anticipate that this transformation will establish a versatile and powerful platform for the highly efficient synthesis of diverse fluorinated scaffolds. By merging radical reactivity with polar crossover and cascade cyclization in a simple operational protocol, it opens practical and streamlined avenues for the discovery and development of diverse fluorinated compounds in medicinal and agricultural chemistry.