Direct C–H difluoromethylation of heteroaromatic compounds: emerging methods and developments through 2025

Abstract

Heteroarenes bearing a difluoromethyl (CF₂H) group have emerged as important structural motifs in pharmaceuticals, agrochemicals, and materials science, as the CF₂H unit can fine-tune lipophilicity, strengthen biological interactions, and enhance metabolic stability. Among the available synthetic approaches, direct C–H difluoromethylation of heteroaromatic frameworks stands out as an efficient, step-economical, and atom-economical strategy. In this review, we highlight the most significant advances and developments in the direct C–H difluoromethylation of heteroaromatic compounds reported up to the end of 2025. Catalyst-free reactions are discussed first, followed by metal-catalyzed/mediated and photoredox-catalyzed transformations. Finally, electrocatalytic approaches are covered at the end of the review.