Emerging Strategies in N-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.