Emerging Strategies in <i>N</i> ‐Fluoroalkylation: Recent Progress

Abstract The strategic introduction of fluorine to the α ‐carbon of amine compounds enables precise electronic modulation of nitrogen‐centered charge distribution, thereby modifying the molecular spatial configuration and physicochemical properties such as acidity, basicity, lipophilicity, and metabolic stability. These tailored characteristics render N ‐fluoroalkylamines highly advantageous for pharmaceutical applications. However, inherent electronic repulsion between nitrogen and fluorine atoms imposes significant synthetic challenges and compromises the stability of N ‐fluoroalkyl‐substituted architectures. To address these limitations, this review systematically examines state‐of‐the‐art synthetic methodologies for structurally diverse nitrogen‐fluoroalkyl compounds, with emphasis on N ‐difluoromethylamines, N ‐trifluoromethylamines, N ‐perfluoroalkylamines, and related derivatives. By correlating substitution patterns with functional properties, we elucidate structure–activity relationships critical for optimizing drug‐like behavior, providing theoretical guidance for rational drug design and development.