Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel-catalyzed hydromonofluoroalkylation of unactivated alkenes and copper-catalyzed CÀ C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro-alkoxy, -alkylamino motifs with commercially available heteroatom-based coupling partners.

No abstract

Fluorinated motifs are frequently encountered in drugs and agrochemicals. Incorporating fluorine-containing motifs in drug candidates for lead optimization in pharmaceutical research and development has emerged as a powerful tool. The construction of molecules that feature a trifluoromethyl (CF3−) group on a stereogenic carbon has accumulated broad research efforts. Unlike its well-explored, biologically active methyl counterpart, asymmetric construction of β-trifluoromethylated alcohols bearing adjacent stereocenters still remains elusive. Through retrosynthetic analysis, we posited that followed by sequential reduction of carbonyl, the initial construction of chiral α-trifluoromethylated ketones could render the desired product in a facile, one-pot fashion. Herein, we developed the first example of nickel-catalyzed asymmtric reductive cross-coupling trifluoroalkylation of acyl chlorides for enantioselective synthesis of diverse α-trifluoromethylated ketones. The one-pot reduction of these α-trifluoromethylated ketones furnished corresponding alcohols bearing β-CF3-substituted stereogenic carbons with excellent diastereoselectivity and complete enantioselective retention. High yields/enantioselectivity, mild conditions, and good functional group compatibility are shown in the system. Utilities of the method are also illustrated by applying asymmetric, late-stage trifluoroalkylation of biologically active complex molecules, revealing tremendous potential for development of CF3-containing chiral drugs.

A photoinduced copper-catalyzed strategy for the monofluoroalkylation of alkynes with readily available monofluoroalkyl triflates was developed. It provides a new protocol to access valuable propargyl fluoride compounds via C−C bond formation by avoiding the use of highly toxic fluorination reagents. This reaction proceeded under mild conditions to afford propargyl monofluorides in moderate to high yields. Preliminary mechanistic studies reveal that a ligand-matched alkynyl copper complex might be the key photoactive substance.

Monofluoroalkanes are important in many pharmaceuticals, agrochemicals and functional materials. However, the lack of easily available and transformable monofluoroalkylating reagents that facilitate a broad array of transformations has hampered the application of monofluoroalkylation. Herein, we report a general and efficient method of preparing diverse aliphatic monofluorides with monofluoroalkyl triflate as the synthetic scaffold. Using both nickel-catalyzed hydromonofluoroalkylation of unactivated alkenes and copper-catalyzed CÀ C bond formation, the general diversification of the monofluoroalkylating scaffold has been exhibited. The broad utility of this monofluoroalkylating reagent is shown by concise conversion into various conventional fluoroalkylating reagents and construction of monofluoro-alkoxy, -alkylamino motifs with commercially available heteroatom-based coupling partners.