Diaryldifluoromethanes are valuable structural motifs in medicinal chemistry because they can serve as bioisosteres for diaryl ether, methane, and ketone groups. However, synthetic approaches to these compounds remain limited, particularly those capable of constructing both C-C bonds of the difluoromethylene unit simultaneously. Herein, we developed a straightforward method for the synthesis of diaryldifluoromethanes via nickel-catalyzed cross-coupling of arylboronic acids with difluorodibromomethane (CF2Br2). This protocol features mild reaction conditions, exhibits broad functional group tolerance, and employs readily available starting materials.

The hexafluoroisopropoxy group is a unique and underexplored fluoroalkoxy motif featuring distinctive conformational, electronic, and lipophilic properties. Herein, we report a visible-light-induced C-H hexafluoroisopropoxylation of (hetero)arenes employing a bench-stable N-hexafluoroisopropoxy benzotriazole as the hexafluoroisopropoxy radical precursor. This protocol enables the efficient construction of hexafluoroisopropyl aryl ethers under mild conditions, and is compatible with a broad range of aryl and heteroaryl substrates as well as synthetically and pharmacologically relevant functional groups. Mechanistic studies suggest that photoreductive cleavage of the hexafluoroisopropoxylating reagent by the excited photocatalyst generates the ·OCH(CF3)2 radical.

The fluorinated functional groups represent privileged and irreplaceable motifs in pharmaceuticals and agrochemicals. However, certain fluorinated group-containing compounds, including trifluoromethyl group have recently been classified as per- and polyfluoroalkyl substances (PFAS) due to their high stability, environmental mobility and toxicity. Fortunately, halodifluoromethyl groups (-CF2X, X = Cl, Br, I) can be degraded into nonpersistent compounds and serve as the halogen bond donors, which are distinctive among fluorinated substituents. Despite the importance of these groups, a general method for the installment of halodifluoromethyl groups into aromatics remains underexplored. Here we report a facile and efficient synthesis of chloro(bromo, iodo)difluoromethylarenes through nickel-mediated halodifluoromethylation of (hetero)aryl chlorides(bromides) with TMSCF2Cl or TMSCF2Br. The distinct reaction mechanism involves the insertion of difluorocarbene into the in situ generated aryl nickel(II) halide complex (Ar-Ni(II)-X), followed by oxidant-induced reductive elimination from the resulting aryldifluoromethyl nickel(II) intermediate (ArCF2-Ni(II)-X).

Herein, we report a method for the synthesis of α-aryl-α-trifluoromethyl amines via dual photoredox/nickel-catalysis between aryl bromides and N-trifluoroethyl hydroxylamine under flow conditions. This protocol enables the first direct 1-aminotrifluoroethylation of benzene derivatives under mild conditions in high yields (up to 84%) and with a wide functional group tolerance (32 examples). The transformation proceeds through photoinduced single-electron reduction of N-trifluoroethyl hydroxylamine, followed by 1,2-hydrogen atom transfer, to generate the α-aminotrifluoroethyl radical for cross-coupling of aryl bromides.

Achieving precise stereocontrol when forging two vicinal C(sp³)-C bonds on unsymmetrical internal alkenes remains a formidable challenge. The comparable reactivity of alkyl radicals often compromises chemo- and regioselectivity, while the concurrent induction of diastereo- and enantioselectivity has proven elusive. Here, we show a unified metallaphotoredox strategy that addresses these challenges through two complementary multicomponent difunctionalization protocols. First, a Ni/terpyridine catalyst system enables anti-selective 1,2-dialkylation of both cyclic and acyclic internal alkenes, delivering vicinal C(sp³)-C(sp³) linkages with high levels of chemo-, regio-, and diastereoselectivity. A switch to a chiral biimidazole ligand and replacement of the alkyl halide with a (hetero)aryl bromide unlocks enantioselective 1,2-alkylarylation of cyclic internal alkenes. This transformation affords β-aryl-α-alkylated lactones and related scaffolds bearing two contiguous stereocenters with excellent diastereo- and enantioselective control. This dual strategy offers a rapid and efficient access to drug-like molecular architectures.

A distinctive continuous-flow synthesis of 2,2,2-trifluoro-1-(3 '-methoxy-[1,1 '-biphenyl]-4-yl)ethan-1-ol, an important intermediate for the synthesis of a tryptophan hydroxylase inhibitor LX1031, is described. The pivotal synthetic process involved a photochemically induced nickel-catalysed radical cross coupling of phthalimido trifluoroethanol with 1-bromo-4-(3-methoxyphenyl)benzene. This approach not only enhanced synthetic efficiency but also demonstrated the potential of flow photochemistry for the synthesis of a complicated pharmaceutical intermediate on a gram scale.

The synthesis of chloro- and bromodifluoromethyl alkyl ethers remained a fundamental challenge in synthetic chemistry. Herein we report the efficient and direct synthesis of chloro- and bromodifluoromethyl alkyl ethers through copper-mediated oxidative chrolo- and bromodifluoromethylation of aliphatic alcohols with difluorocarbene-reagents. This difluorocarbene-involved oxidative coupling protocol exhibited broad functional group compatibility and was applicable to a wide range of primary and secondary alcohols.

The incorporation of the pentafluorosulfanyl (SF5) group into organic molecules is highly significant due to its unique physicochemical properties and potential applications in pharmaceuticals and agrochemicals. However, general and efficient methods for the synthesis of benzylic SF5-containing compounds remain unexplored. Herein, we report the synthesis of a series of 2-(pentafluorosulfanyl)methyl benzophenones via the insertion of arynes into the C-C σ-bond of α-pentafluorosulfanyl ketones. This transition-metal-free reaction proceeds under mild conditions with high regioselectivity and good functional group tolerance, as demonstrated by 21 examples.

Comprehensive Summary The pentafluorosulfanyl (SF5) group, characterized by its high electronegativity, lipophilicity and unique octahedral geometry, has the potential to modify the physicochemical properties of both pharmaceuticals and agrochemicals. Recently, pentafluorosulfanyl-containing compounds have garnered increasing attention, and big progress has been made in the development of novel synthetic strategies for these compounds. Central to these advancements is the exploration of synthesis and novel reaction of radical pentafluorosulfanylation reagents. This account provides an overview of the gas-reagent-free practical synthesis and new reaction of pentafluorosulfanyl chloride (SF5Cl) developed by our group.Key Scientists of SF5 Chemistry A partial list of the key scientists' main contributions to the development of pentafluorosulfanyl chemistry

The reaction site of aryl diazonium salt was restricted in the position of diazonium moiety, due to the intrinsic electrophilicity of diazonium moiety. Herein, we described an unprecedented chemoselective alkylation of Csp2-H of aryl diazonium salts with 1-iodo-3-pentafluorosulfanylbicyclo[1,1,1]pentane (SF5-BCP-I). This novel alkylation of aryl diazonium salts provided an efficient access to various SF5-BCP substituted aromatics that might have great potential application in the drug discovery. Mechanistic experiments and theoretical studies revealed that the intrinsic electrophilic SF5-BCP radical resulted in the thermodynamic favorable radical addition on Csp2-H site rather than diazonium moiety of aryl diazonium salt.

The SF5O group has been less explored as a highly fluorinated substituent on an organic framework. In fact, only a few SF5O-containing compounds have been reported, and the preparation of SF5O-containing compounds relied on hazardous reagents and special apparatuses. Herein we describe safe and efficient access to various pentafluoro(aryloxy)-λ6-sulfanes (ArOSF5) through the reaction of hypervalent λ3-chlor(brom)anes with [Et3MeN]+[OSF5]-. The synthetic and application potentials of ArOSF5 moieties were demonstrated by the inertness of OSF5 moieties in the presence of palladium catalysts, alkalis, and nucleophiles.

Herein we reported metal-free oxidative chloro- and bromodifluoromethylation of thiophenols with TMSCF2X in the presence of oxidant N-chloro(bromo)succinimide and nBu4NX (X = Cl or Br), respectively, under mild reaction conditions. This protocol provided a practical and efficient method for synthesizing various biologically valuable and synthetically challenging chloro- and bromodifluoromethyl aryl sulfides. Preliminary mechanistic investigation suggested that the transformation proceeded through a difluorocarbene intermediate.

The fluorosulfonyldifluoromethylation of unactivated alkenes and (hetero)arenes with iododifluoromethanesulfonyl fluoride (ICF2SO2F) under visible light photoredox catalysis was successfully developed. Key to the successful fluorosulfonyldifluoromethylation of aromatic compounds was the usage of AgOTf as an additive to promote the formation of the CF2SO2F radical. The protocol provided a straightforward way to introduce the interesting and useful CF2SO2F group on sp3 and sp2 carbons.

We report an unprecedented Ni-catalyzed direct monofluoromethylthiolation of acyl chlorides, in situ generated from carboxylic acids, with elemental sulfur (S-8) as the S source and fluoroiodomethane (ICH2F) as the CH2F radical source to produce a series of monofluoromethylthioesters in moderate to good yields. This approach features excellent functional group tolerance and broad substrate scope. Additionally, the late-stage monofluoromethylthiolation of complex bioactive molecules can also be accomplished using this method.

Here, we report a photoredox and nickel-catalyzed cross-electrophile coupling strategy for the asymmetric three-component 1,2-alkylarylation of vinyl boronates with (hetero)aryl bromides and (2 degrees, 3 degrees)-alkyl redox-active esters in the presence of Hantzsch ester. With a fluorinated pyridyl-substituted chiral biimidazoline ligand, this reaction enables straightforward access to a wide variety of synthetically valuable chiral alpha-aryl boronates from readily available starting materials. This reaction features mild conditions, broad substrate generality, and good functional group tolerance and proceeds without using metal reductants or alkyl halides. Furthermore, alkenyl halides and other electron-deficient alkenes such as acrylates and vinyl phosphonates can be applied successfully. Preliminary mechanistic studies shed light on the potential reaction pathways and roles of organic amines.

Herein we report a photoredox/nickel-catalyzed cross-coupling of aryl bromides with 1,1,1,3,3,3-hexafluoroisopropanol for the construction of hexafluoroisopropyl aryl ethers. The mild reaction conditions employed allow for the applicability of a wide range of aryl and heteroaryl bromides. Late-stage functionalization and preliminary mechanistic studies have been demonstrated.

We report herein that nickel-mediated trifluoromethylation of chlorinated and brominated phenol derivatives ClArOTs and BrArOTf gave chloro(bromo)trifluoromethylarenes through the chemoselective cleavage of Ar-O bonds. Furthermore, under similar reaction conditions, the chemoselective trifluoromethylation of Ar-Cl and Ar-Br bonds of ClArOPiv and BrArOTs was achieved to give trifluoromethylated phenol derivatives.

The reaction regioselectivity of gem -difluoroalkenes is dependent on the intrinsic polarity. Thus, the reversal of the regioselectivity of the addition reaction of gem -difluoroalkenes remains a formidable challenge. Herein, we described an unprecedented reversal of regioselectivity of hydrogen atom transfer (HAT) to gem -difluoroalkenes triggered by Fe−H species for the formation of difluoroalkyl radicals. Hydrogenation of the in situ generated radicals gave difluoromethylated products. Mechanism experiments and theoretical studies revealed that the kinetic effect of the irreversible HAT process resulted in the reversal of the regioselectivity of this scenario, leading to the formation of a less stable α -difluoroalkyl radical regioisomer. On basis of this new reaction of gem -difluoroalkene, the iron-promoted hydrohalogenation of gem -difluoroalkenes for the efficient synthesis of aliphatic chlorodifluoromethyl-, bromodifluoromethyl- and iododifluoromethyl-containing compounds was developed. Particularly, this novel hydrohalogenation of gem -difluoroalkenes provided an effect and large-scale access to various iododifluoromethylated compounds of high value for synthetic application.

The emergence of photocatalysis has greatly advanced radical fluoroalkylation reactions. Central to this advancement is the introduction and refinement of radical reagents, which play a pivotal role in driving these reactions forward. Intriguingly, some of these reagents, previously not recognized for their radical properties, have emerged as key players in this area. In this Perspective, we provide an overview of four representative reagents pioneered by our laboratory, which have subsequently garnered extensive application in broader research contexts, including difluorocarbene precursors bromodifluoromethylphosphonium bromide, electrophilic sulfonylation reagent triflic anhydride, and nucleophilic trifluoromethylation reagent methyl fluorosulfonyldifluoroacetate (Chen's reagent). The integration of phosphonium reagents, triflic anhydride, and methyl fluorosulfonyldifluoroacetate into photocatalysis has enabled some unexpected reactivities and now notably expanded the capabilities in radical difluoromethylation, trifluoromethylation, and difluoroalkylation. Our discussion highlights how these atypical reagents have enriched the toolkit available for radical fluoroalkylations, offering insights that could inspire future research and application in this area.