Multifaceted reactions of difluorocarbene with amines: synthesis and mechanistic insights

Difluorocarbene (:CF₂), a highly reactive fluorine-containing intermediate, has emerged as a central research subject in the interdisciplinary domain of modern fluorine chemistry and synthetic methodology, owing to its unique electronic structure and diverse reactivity. The application scope of this intermediate as a versatile "carbon source" is not limited to conventional fluorination reactions but also includes non-traditional transformations. In organic synthesis, difluorocarbene exhibits a remarkable diversity of reactivity with amines. For instance, primary amines undergo nucleophilic attack to form fluoroimine and isocyanide intermediates, which can be further converted into fluorinated heterocyclic compounds, other heterocycles, and nitriles. Secondary amines, in turn, follow nucleophilic substitution pathways to achieve nitrogen-centered difluoromethylation or formylation. Tertiary amines, on the other hand, evolve into ammonium ylides through N-difluoromethylation, subsequently triggering cascade reactions, including cyclization, fluorination, C-N bond cleavage, and coupling processes. Herein, this review systematically summarizes the multifaceted reactivity of difluorocarbene with amines and highlights recent breakthroughs in this rapidly evolving field.