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Emerging as a powerful tool for lead optimization in pharmaceutical research and development, to develop the facile, general protocols that allows the incorporation of fluorine-containing motif in drug candidates has accumulated enormous research interest in recent years. Among these important motifs, the incorporation of strategic motif CF 3 on aliphatic chain especially with the concomitant construction of trifluoromethylated alkanes bearing a CF 3 -substituted stereogenic carbon, is of paramount importance. Herein, we disclose an asymmetric nickel-catalyzed reductive trifluoroalkylation of alkenyl halides for enantioselective syntheses of diverse α -trifluoromethylated allylic alkanes, offering a general protocol to access the trifluoromethyl analogue to chiral α -methylated allylic alkanes, one of the most prevalent key components among natural products and pharmaceuticals. Utilities of the method including the application of the asymmetric trifluoroalkylation on multiple biologically active complex molecules, derivatization of transformable alkenyl functionality were demonstrated, providing a facile method in the diversity-oriented syntheses of CF 3 -containing chiral drugs and bioactive-molecules. The efficient construction of trifluoromethylated alkanes bearing a CF 3 chiral center is of great importance in organic synthesis. Here, the authors disclose the enantioselective syntheses of α-trifluoromethylated allylic alkanes via reductive trifluoroalkylation.

The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules. The difluoromethyl group is a crucial fluorinated moiety, and the synthesis of chiral CF₂H-containing analogs is a powerful strategy in drug design and screening. Here, the authors report a strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling.

Sulfur hexafluoride (SF6), a chemically inert and stable gas essential to the electric power industry, poses severe environmental risks due to its persistence and high global warming potential. While traditional degradation methods are inefficient, photocatalytic single electron reduction (SER) enables SF6 activation into SF5 radicals, creating opportunities for both degradation and reutilization. The SF5 group, renowned for its strong electron-withdrawing, lipophilic, and bioisosteric features, has great potential in drug discovery, while efficient methods for synthesizing alkyl- or BCP-SF5 motifs remain scarce. As a safe, inexpensive, and atom-economical alternative to conventional SF5 reagents, SF6 serves as an ideal yet underexplored SF5 source. Herein, we present a photocatalytic strategy for the direct synthesis of diverse SF5-containing scaffolds, including ketones, acetals, and bicyclo[1.1.1]pentane derivatives. Derivatization studies demonstrate its synthetic versatility, particularly in accessing α-SF5-substituted acetaldehydes. Mechanistic and density functional theory (DFT) studies confirm the single electron reduction of SF6, highlighting a mild, efficient, and broadly applicable route for constructing SF5-functionalized architectures in fluorinated drug development.Sulfur hexafluoride (SF6), a chemically inert and stable gas essential to the electric power industry, poses severe environmental risks due to its persistence and high global warming potential. While traditional degradation methods are inefficient, photocatalytic single electron reduction (SER) enables SF6 activation into SF5 radicals, creating opportunities for both degradation and reutilization. The SF5 group, renowned for its strong electron-withdrawing, lipophilic, and bioisosteric features, has great potential in drug discovery, while efficient methods for synthesizing alkyl- or BCP-SF5 motifs remain scarce. As a safe, inexpensive, and atom-economical alternative to conventional SF5 reagents, SF6 serves as an ideal yet underexplored SF5 source. Herein, we present a photocatalytic strategy for the direct synthesis of diverse SF5-containing scaffolds, including ketones, acetals, and bicyclo[1.1.1]pentane derivatives. Derivatization studies demonstrate its synthetic versatility, particularly in accessing α-SF5-substituted acetaldehydes. Mechanistic and density functional theory (DFT) studies confirm the single electron reduction of SF6, highlighting a mild, efficient, and broadly applicable route for constructing SF5-functionalized architectures in fluorinated drug development.

The incorporation of fluoroalkyl groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to their ability to modulate lipophilicity, permeability, metabolic stability, and binding affinity. Despite significant advances realized, the means to introducing fluoroalkyl groups such as ─CF2H or ─CF3 in an enantioselective manner remain scarce. Herein, we report a Ni‐catalyzed enantioselective reductive alkenylation of α‐CF2H or ─CF3 amino chlorides with vinyl iodides. This method provides an efficient and modular technique for constructing stereocenters bearing a fluoroalkyl group. A key to success was the incorporation of an arylamide moiety with the substrates, which stabilizes the α‐fluoroalkyl radical intermediate, thus offering a de novo approach to access enantioenriched α‐CF2H (─CF3) allylamines. Our protocol is characterized by its mild reaction conditions, broad substrate scope, as well as excellent enantio—and chemo‐selectivity, even in the context of late‐stage functionalization. Difluoromethyl (CF2H) group, the bioisostere of hydroxyl thiol methyl or amide is privileged in medicinal chemistry due to hydrogen‐binding ability and lipophilic, metabolically stable, and chemical inert nature. However, enatioseleceive CF2H introduction remains challenging. We report a modular approach for the constructing stereocenters bearing CF2H or CF3 groups via Ni‐catalyzed asymmetric reductive alkenylation of α‐CF2H or ‐CF3 amino chlorides with vinyl iodides.

Sulfur hexafluoride (SF 6 ), a chemically inert and stable gas essential to the electric power industry, poses severe environmental risks due to its persistence and high global warming potential. While traditional degradation methods are inefficient, photocatalytic single electron reduction (SER) enables SF 6 activation into SF 5 radicals, creating opportunities for both degradation and reutilization. The SF 5 group, renowned for its strong electron‐withdrawing, lipophilic, and bioisosteric features, has great potential in drug discovery, while efficient methods for synthesizing alkyl‐ or BCP‐SF 5 motifs remain scarce. As a safe, inexpensive, and atom‐economical alternative to conventional SF 5 reagents, SF 6 serves as an ideal yet underexplored SF 5 source. Herein, we present a photocatalytic strategy for the direct synthesis of diverse SF 5 ‐containing scaffolds, including ketones, acetals, and bicyclo[1.1.1]pentane derivatives. Derivatization studies demonstrate its synthetic versatility, particularly in accessing α‐SF 5 ‐substituted acetaldehydes. Mechanistic and density functional theory (DFT) studies confirm the single electron reduction of SF 6 , highlighting a mild, efficient, and broadly applicable route for constructing SF 5 ‐functionalized architectures in fluorinated drug development.

The incorporation of fluoroalkyl groups into drug candidates has garnered increasing attention in the pharmaceutical industry due to their ability to modulate lipophilicity, permeability, metabolic stability, and binding affinity. Despite significant advances realized, the means to introducing fluoroalkyl groups such as ─CF 2 H or ─CF 3 in an enantioselective manner remain scarce. Herein, we report a Ni‐catalyzed enantioselective reductive alkenylation of α‐CF 2 H or ─CF 3 amino chlorides with vinyl iodides. This method provides an efficient and modular technique for constructing stereocenters bearing a fluoroalkyl group. A key to success was the incorporation of an arylamide moiety with the substrates, which stabilizes the α‐fluoroalkyl radical intermediate, thus offering a de novo approach to access enantioenriched α‐CF 2 H (─CF 3 ) allylamines. Our protocol is characterized by its mild reaction conditions, broad substrate scope, as well as excellent enantio—and chemo‐selectivity, even in the context of late‐stage functionalization.

The difluoromethyl group is a crucial fluorinated moiety with distinctive biological properties, and the synthesis of chiral CF₂H-containing analogs has been recognized as a powerful strategy in drug design. To date, the most established method for accessing enantioenriched difluoromethyl compounds involves the enantioselective functionalization of nucleophilic and electrophilic CF₂H synthons. However, this approach is limited by lower reactivity and reduced enantioselectivity. Leveraging the unique fluorine effect, we design and synthesize a radical CF₂H synthon by incorporating isoindolinone into alkyl halides for asymmetric radical transformation. Here, we report an efficient strategy for the asymmetric construction of carbon stereocenters featuring a difluoromethyl group via nickel-catalyzed Negishi cross-coupling. This approach demonstrates mild reaction conditions and excellent enantioselectivity. Given that optically pure difluoromethylated amines and isoindolinones are key structural motifs in bioactive compounds, this strategy offers a practical solution for the efficient synthesis of CF₂H-containing chiral drug-like molecules.