Photoredox Catalyzed Radical Fluoroalkylation with Non-Classical Fluorinated Reagents.

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.

Reversal of the Regioselectivity of Iron-Promoted Hydrogenation and Hydrohalogenation of gem-Difluoroalkenes.

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.

Copper-Mediated Oxidative Chloro- and Bromodifluoromethylation of Phenols.

The first oxidative chloro- and bromodifluoromethylation of phenols with (CH3)3SiCF2X and CuX (X = Cl or Br) in the presence of Selectfluor under mild reaction conditions was developed. This protocol provided a practical and efficient method for the synthesis of a diverse range of biologically valuable and synthetically challenging chloro- and bromodifluoromethyl aryl ethers. Preliminary mechanistic studies suggest that this reaction proceeded through a difluorocarbene-involved oxidative coupling process.

N-Trifluoromethoxyphthalimide: A Shelf-Stable Reagent for Nucleophilic Trifluoromethoxylation.

Due to the unique properties of the OCF3 group, trifluoromethyl ether compounds play an important role in pharmaceuticals and agrochemicals. Recently, considerable attention has been focused on the development of practical and convenient reagents for the direct incorporation of the OCF3 group into organic compounds. Herein, we reported a new trifluoromethoxylating reagent N-trifluoromethoxyphthalimide (Phth-OCF3). The reagent was a stable solid and released an OCF3 anion under mild reaction conditions. We demonstrated the application of Phth-OCF3 for the nucleophilic trifluoromethoxylation of various alkyl electrophiles.

Visible-light-induced nickel-catalyzed α-hydroxytrifluoroethylation of alkyl carboxylic acids: Access to trifluoromethyl alkyl acyloins.

A visible-light-induced nickel-catalyzed cross coupling of alkyl carboxylic acids with N-trifluoroethoxyphthalimide is described. Under purple light irradiation, an α-hydroxytrifluoroethyl radical generated from a photoactive electron donor-acceptor complex between Hantzsch ester and N-trifluoroethoxyphthalimide was subsequently engaged in a nickel-catalyzed coupling reaction with in situ-activated alkyl carboxylic acids. This convenient protocol does not require photocatalysts and metal reductants, providing a straightforward and efficient access to trifluoromethyl alkyl acyloins in good yields with broad substrate compatibility. The complex bioactive molecules were also compatible with this catalytic system to afford the corresponding products.

General Synthesis of N-Trifluoromethyl Compounds with N-Trifluoromethyl Hydroxylamine Reagents.

N-CF3 compounds constitute valuable targets in medicinal chemistry. Extensive studies have been reported for the preparation of N-CF3 compounds through fluorination and trifluoromethylation of N-containing compounds. The development of new synthetic methods from abundant and easily available substrates is highly desirable but still challenging. Herein, we report the design and synthesis of novel N-Cbz- and N-Boc-N-trifluoromethyl hydroxylamine reagents by silver-mediated oxidative trifluoromethylation. These reagents have been successfully applied to the direct incorporation of a NCF3 moiety into the commonly used unsaturated substrates under photoredox catalysis. This protocol enables the efficient and regioselective C-H trifluoromethylamination of various (hetero)arenes, including complex bioactive molecules. Furthermore, a variety of alkenes, dienes, and isonitriles undergo tandem trifluoromethylamination/functionalization delivering structurally diverse N-trifluoromethyl aliphatic and heteroaromatic amines. Notably, previously unknown cyclic N-CF3 compounds including N-CF3 oxazolidinones and oxazolones were conveniently prepared with N-Boc-N-trifluoromethyl hydroxylamine reagents. Furthermore, diversification of the resulting α-trifluoromethylamino ketones afforded the largely underexplored N-alkenyl- and N-alkynyl-N-CF3 compounds.

Electrochemical Trifluoromethoxylation of (Hetero)aromatics with a Trifluoromethyl Source and Oxygen.

Trifluoromethoxylated aromatics (ArOCF3 ) are valuable structural motifs in the area of drug discovery due to the enhancement of their desired physicochemical properties upon the introduction of the trifluoromethoxy group (CF3 O). Although significant progress has been made recently in the introduction of CF3 O group into aromatics, current methods either require the use of expensive trifluoromethoxylation reagents or require harsh reaction conditions. We present a conceptually new and operationally simple protocol for the direct C-H trifluoromethoxylation of (hetero)aromatics by the combination of the readily available trifluoromethylating reagent and oxygen under electrochemical reaction conditions. This reaction proceeds through the initial generation of CF3 radical followed by conversion to CF3 O radical, addition to (hetero)aromatics and rearomatization. The utility of this electrochemical trifluoromethoxylation is illustrated by the direct incorporation of CF3 O group into a variety of (hetero)aromatics as well as bio-relevant molecules.

Three-Component Reaction of Pentafluorosulfanyl Chloride, Alkenes and Diazo Compounds and Synthesis of Pentafluorosulfanylfurans.

We report herein the three-component radical addition reaction of SF5 Cl, alkene and diazo compounds for the selective formation of α-alkyl-α-SF5 carbonyl compounds. The three-component addition reaction proceeded through the first reaction of SF5 radical with the diazo compound followed by the addition of the in situ generated carbon radical to alkene. The synthetic useful α-allyl-α-SF5 carbonyl compounds were successfully prepared when allyl trimethylsilanes were used as the alkene substrates. Furthermore, the three-component adducts formed from SF5 Cl, α-diazoacetophenones and vinyl acetates were converted into pentafluorosulfanylfurans. This transformation provided a practical and efficeint method for the synthesis of pentafluorosulfanylfurans.

Light-Induced Divergent Cyanation of Alkynes Enabled by Phosphorus Radicals.

A photochemically induced selective and divergent cyanation reaction of alkynes, enabled by phosphorus radicals, is described. With the use of simple triarylphosphine as a co-catalyst, three cyanation reactions, including di-hydrocyanation, anti-Markovnikov hydrocyanation, and domino hydrocyanation/reduction, can be divergently achieved, furnishing a wide array of alkyl dinitriles, alkenyl nitriles, and alkyl nitriles under mild conditions. Terminal and internal alkynes are applicable with high efficiency and excellent selectivity. Synthetic applications for biologically active agents and preliminary experimental and computational mechanistic studies are reported.

Nucleophilic and Radical Heptafluoroisopropoxylation with Redox-Active Reagents.

The heptafluoroisopropyl group (CF(CF3 )2 ) is prevalent in pharmaceuticals and agrichemicals. However, heptafluoroisopropoxylated (OCF(CF3 )2 ) compounds remain largely underexplored, presumably due to the lack of efficient access to these compounds. Herein, we disclose the practical and efficient heptafluoroisopropoxylation reactions through the invention of a series of redox-active N-OCF(CF3 )2 reagents. These reagents were readily prepared from the oxidative heptafluoroisopropylation of hydroxylamines with AgCF(CF3 )2 . The substitutions on the nitrogen atom significantly affected the properties and reactivities of N-OCF(CF3 )2 reagents. Accordingly, two types of N-OCF(CF3 )2 reagents including N-OCF(CF3 )2 phthalimide A and N-OCF(CF3 )2 benzotriazolium salt O' were used as OCF(CF3 )2 anion and radical precursors, respectively. This protocol enables the direct heptafluoroisopropoxylation of a range of substrates, delivering the corresponding products in moderate to excellent yields.

Chemoselective Hydro(Chloro)pentafluorosulfanylation of Diazo Compounds with Pentafluorosulfanyl Chloride.

Pentafluorosulfanyl chloride (SF5 Cl) is the most prevalent reagent for the incorporation of SF5 group into organic compounds. However, the preparation of SF5 Cl often relies on hazardous reagents and specialized apparatus. Herein, we described a safe and practical synthesis of a bench-stable and easy-to-handle solution of SF5 Cl in n-hexane under gas-reagent-free conditions. The synthetic application of SF5 Cl was demonstrated through the unprecedented reaction with diazo compounds. The chemoselective hydro- and chloropentafluorosulfanylations of α-diazo carbonyl compounds were developed in the presence of K3 PO4 or copper catalyst, respectively. These reactions provide a direct and efficient access to various α-pentafluorosulfanyl carbonyl compounds of high value for potential applications.

Silver-Enabled General Radical Difluoromethylation Reaction with TMSCF2 H.

A silver-mediated oxidative difluoromethylation of styrenes and vinyl trifluoroborates with TMSCF2 H is reported for the first time. This method enables direct and facile access to CF2 H-alkenes from abundant alkenes with excellent functional-group compatibility. Moreover, this Ag/TMSCF2 H protocol could further enable a series of radical difluoromethylation reactions of a wide array of substrates, offering a generic and complementary platform for the construction of diversified C-CF2 H bonds.

Divergent Aminocarbonylations of Alkynes Enabled by Photoredox/Nickel Dual Catalysis.

A metallaphotoredox-catalyzed strategy for the selective and divergent aminocarbonylation of alkynes with amines and 1 atm of CO is reported. This synergistic protocol not only enables the Markovnikov-selective hydroaminocarbonylation of alkynes to afford α,ß-unsaturated amides, but also facilitates a sequential four-component hydroaminocarbonylation/radical alkylation in the presence of tertiary and secondary alkyl boronate esters, which allows for straightforward conversion of alkynes into corresponding amides. Preliminary mechanistic studies disclose that a photoinduced oxidative insertion of aniline and CO into nickel followed by a migratory insertion of (carbamoyl)nickel species could be involved.

Enantioselective Three-Component Fluoroalkylarylation of Unactivated Olefins through Nickel-Catalyzed Cross-Electrophile Coupling.

A nickel-catalyzed, enantioselective, three-component fluoroalkylarylation of unactivated alkenes with aryl halides and perfluoroalkyl iodides has been described. This cross-electrophile coupling protocol utilizes a chiral nickel/BiOx system as well as a pendant chelating group to facilitate the challenging three-component, asymmetric difunctionalization of unactivated alkenes, providing direct access to valuable chiral ß-fluoroalkyl arylalkanes with high efficiency and excellent enantioselectivity. The mild conditions allow for a broad substrate scope as well as good functional group toleration.

Nickel-Mediated Trifluoromethylation of Phenol Derivatives by Aryl C-O Bond Activation.

The increasing pharmaceutical importance of trifluoromethylarenes has stimulated the development of more efficient trifluoromethylation reactions. Tremendous efforts have focused on copper- and palladium-mediated/catalyzed trifluoromethylation of aryl halides. In contrast, no general method exists for the conversion of widely available inert electrophiles, such as phenol derivatives, into the corresponding trifluoromethylated arenes. Reported herein is a practical nickel-mediated trifluoromethylation of phenol derivatives with readily available trimethyl(trifluoromethyl)silane (TMSCF3 ). The strategy relies on PMe3 -promoted oxidative addition and transmetalation, and CCl3 CN-induced reductive elimination. The broad utility of this transformation has been demonstrated through the direct incorporation of trifluoromethyl into aromatic and heteroaromatic systems, including biorelevant compounds.

Cascade trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles.

A cascade oxidative trifluoromethylthiolation and cyclization of N-[(3-aryl)propioloyl]indoles with AgSCF3 is described. This protocol allows for the synthesis of novel bis(trifluoromethylthiolated) or trifluoromethylthiolated pyrrolo[1,2-a]indol-3-ones in moderate to good yields. Mechanistic investigations indicated that radical processes were probably involved in these transformations.

Argentination of Fluoroform: Preparation of a Stable AgCF3 Solution with Diverse Reactivities.

The transformation of a large-volume industrial by-product and stable greenhouse gas fluoroform (HCF3 ) to useful products has recently received significant attention. Now, a simple and scalable preparation of AgCF3 by treatment of HCF3 with t-BuOK and AgOAc is disclosed. The reactivity of the HCF3 -derived AgCF3 has been demonstrated by hydrotrifluoromethylation of alkenes and C-H trifluoromethylation of (hetero)arenes. This work not only provides a new avenue for the utilization of HCF3 , but also presents a reliable and easy-to-execute synthesis of the relatively stable AgCF3 solution.

Hydrotrifluoromethylthiolation of Unactivated Alkenes and Alkynes with Trifluoromethanesulfonic Anhydride through Deoxygenative Reduction and Photoredox Radical Processes.

An ongoing challenge in trifluoromethylthiolation reactions is the use of less expensive and easily available trifluoromethylthio sources. Herein, we disclose an unprecedented usage of trifluoromethanesulfonic anhydride (Tf2 O) as a radical trifluoromethylthiolating reagent. Hydrotrifluoromethylthiolation of unactivated alkenes and alkynes with Tf2 O in the presence of PMePh2 and H2 O under visible-light photoredox catalysis gave the addition products. The trifluoromethylthio radical (. SCF3 ) was first formed from Tf2 O through a photoredox radical processes and deoxygenative reduction of PMePh2 , and H2 O serves as the H-atom donor for the hydrotrifluoromethylthiolation reaction. This reaction provides a new strategy for radical trifluoromethylthiolation.

Direct and Regioselective C-H Oxidative Difluoromethylation of Heteroarenes.

The difluoromethyl group (CF2H) is of great interest in the area of medicinal chemistry. However, the investigation of molecular scaffolds containing this group has been hampered by the limitation of synthetic methods for the introduction of CF2H into heteroarenes. Herein we disclose a new strategy for the direct introduction of a difluoromethyl group into heteroarenes via the copper-mediated C-H oxidative difluoromethylation of heteroarenes with TMSCF2H. This mild and regioselective method enables the convenient synthesis of a range of difluoromethylated heteroarenes in high yields. The usage of 9,10-phenanthrenequinone (PQ) as an oxidant is critical to the success of this new difluoromethylation reaction.

Copper-Catalyzed Sulfenylation, Sulfonylation, and Selenylation of 2,3-Allenoic Acids with Disulfides or Diselenides.

The efficient copper-catalyzed sulfenylation and selenylation of 2,3-allenoic acids with disulfides or diselenides were developed, respectively. These reactions proceeded through tandem radical addition/intramolecular cyclization processes, affording a series of 4-sulfenylated and 4-selenylated butenolides in moderate to excellent yields. Moreover, 4-sulfonylated butenolides could also be obtained by sulfenylation of 2,3-allenoic acids and subsequent oxidation. Further transformation of the sulfur- and selenium-containing butenolides afforded the corresponding furan derivatives in good yields.