2.2 Synthesis of Monofluoromethylated Compounds

Abstract The incorporation of monofluoromethyl groups into organic scaffolds has emerged as a prominent area of interest since the mid-20th century, driven by the unique biological properties these groups impart. This substituent functions as a versatile bioisostere for methyl and hydroxymethyl groups, with the capacity to form subtle hydrogen bonds that significantly impact molecular recognition and pharmacological behavior. In contrast to the well-established di- and trifluoromethylation reactions, monofluoromethylation remains synthetically challenging due to the inherent instability and high reactivity of monofluoromethyl reagents. Since the early 1980s, substantial efforts have been dedicated to developing reliable, cost-effective, and practical methodologies for monofluoromethyl group introduction. This review summarizes recent advances in reagent design and synthetic strategies for achieving selective and efficient monofluoromethylation, underscoring its growing importance in drug discovery and functional materials.