Dehydroxy-Perfluoro-tert-butylation of alcohols with PhSOC(CF) and insights into the structure of the [C(CF)] anion.

Branched PFOA and PFOS have shorter half-lives, lower toxicity, and weaker serum protein binding than linear ones, offering better environmental and health safety. Yet methods to access such branched motifs remain under developed. We now introduce a one-step dehydroxy-perfluoro-tert-butylation of alcohols, in which perfluoro-tert-butyl phenyl sulfone serves both to activate the C-O bond and to deliver the perfluoro-tert-butyl group.

Modular synthesis of CF-containing compounds with PhSOCFH reagent through difluoromethylene radical anion synthon strategy.

Difluoromethylene moiety has gained widespread applications in pharmaceuticals, agrochemicals, and materials owing to its augmented lipophilicity and being bioisosteric to ethereal oxygen. Possessing two orthogonal reactivity modes for bridging an electrophile and a radical acceptor to give gem-difluorides (R-CF-R), the efficient difluoromethylene radical anion synthon (diFRAS) has been long sought after. In this work, we successfully utilize the readily available difluoromethyl phenyl sulfone (PhSOCFH) to couple with electrophiles and radical acceptors, thereby enabling PhSOCFH to serve as a novel diFRAS in organic synthesis.

Synthesis of Perfluoro--butyl Triazoles via Decarboxylative CuAAC of (Perfluoro--butyl)propiolic Acid with Azides.

A copper-catalyzed decarboxylative cycloaddition of (perfluoro--butyl)propiolic acid (PFtPA) with azides under mild conditions was developed, enabling the facile synthesis of perfluoro--butyl (PFtB) triazoles. The strong electron-withdrawing nature of the PFtB group facilitates efficient decarboxylative cycloaddition at 30 °C using catalytic copper acetate, avoiding the requirement of traditional harsh conditions. This method provides high yields of products and is compatible with a wide range of azides (including bioactive molecules).

-Activation of 2-PySOCFH for Electrophilic Difluoromethylthiolation of Electron-Rich Heteroarenes.

Difluoromethyl 2-pyridyl sulfone (2-PySOCFH) is a readily accessible, cost-effective, and versatile reagent with broad applications in fluoroalkylation and fluoroolefination. Here, we unveil a novel application of 2-PySOCFH in electrophilic difluoromethylthiolation. Key to this advance is the strategic -activation of 2-PySOCFH to generate stable -methylpyridinium salt and pyridine -oxide derivatives.

From -Fluoroalkylation to Fluoroalkylation-Thiolation: Difunctionalization of Alkenes with Fluoroalkyl Phenyl Sulfones and Thiophenols Enabled by Photoredox Copper Catalysis.

Molecules containing fluoroalkyl and arylthio groups play a pivotal role in pharmaceutical and agrochemical development. The simultaneous introduction of these functional groups through the 1,2-difunctionalization of alkenes is an efficient strategy. Fluoroalkyl phenyl sulfones serve as accessible fluoroalkyl radical precursors; however, their tendency to interact with thiophenol via the electron donor-acceptor interaction mechanism can impede the desired transformation.

1,6-Nucleophilic Di- and Trifluoromethylation of -Quinone Methides with MeSiCFH/MeSiCF Facilitated by CsF/18-Crown-6.

The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of -quinone methides (-QMs) with MeSiRf (Rf = CFH, CF, CFCF, CFCOOEt, and CFSPh) under mild conditions are described. Although MeSiCFH shows lower reactivity than MeSiCF, it can react with -QMs promoted by CsF/18-Crown-6 to give structurally diverse difluoromethyl products in good yields. The products can then be further converted into fluoroalkylated -quinone methides and -fluoroalkylated diarylmethanes.

N-Heteroaromatic Fluoroalkylation through Ligand Coupling Reaction of Sulfones.

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N-heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N-heteroaryl sulfur(IV) and N-heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N-heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis.

Controllable Double Difluoromethylene Insertions into S-Cu Bonds: (Arylthio)tetrafluoroethylation of Aryl Iodides with TMSCFBr.

A new method of constructing "ArSCFCFCu" from ArSCu and TMSCFBr (TMS=trimethylsilyl) has been developed. The cross-coupling reactions of the obtained "ArSCFCFCu" with diverse aryl iodides (Ar'I) provide an efficient access to Ar'CFCFSAr. Mechanistic studies demonstrate that the "ArSCFCFCu" species were generated through controllable double difluoromethylene insertions into ArS-Cu bonds rather than the 1,2-addition of ArSCu to tetrafluoroethylene.

Divergent Generation of the Difluoroalkyl Radical and Difluorocarbene via Selective Cleavage of C-S Bonds of the Sulfox-CFSOPh Reagent.

A new difluoroalkylation reagent Sulfox-CFSOPh bearing both sulfoximine and sulfone moieties was prepared from commercially available SulfoxFluor and PhSOCFH. On one hand, the Sulfox-CFSOPh reagent could act as a (phenylsulfonyl)difluoromethyl radical source under photoredox catalysis, in which the arylsulfoximidoyl group is selectively removed. On the other hand, under basic conditions, Sulfox-CFSOPh could serve as a difluorocarbene precursor for S- and O-difluoromethylations with S- and O-nucleophiles, respectively, in which the phenylsulfonyl group in Sulfox-CFSOPh is selectively removed (followed by α-elimination of the arylsulfoximidoyl group).

Controllable Fluorocarbon Chain Elongation: TMSCFBr-Enabled Trifluorovinylation and Pentafluorocyclopropylation of Aldehydes.

Controllable fluorocarbon chain elongation (CFCE) is a promising yet underdeveloped strategy for the well-defined synthesis of structurally novel polyfluorinated compounds. Herein, the direct and efficient trifluorovinylation and pentafluorocyclopropylation of aldehydes are described by using TMSCFBr (TMS = trimethylsilyl) as the sole fluorocarbon source, accomplishing the goals of CFCE from C to C and from C to C, respectively. The key to the success of these CFCE processes lies in the unique and diversified chemical reactivity of TMSCFBr, which can serve as two different precursors, namely, a TMSCF radical precursor and a difluorocarbene precursor.

Transition-Metal-Free Controllable Single and Double Difluoromethylene Formal Insertions into C-H Bonds of Aldehydes with TMSCF Br.

We have developed a new strategy for controllable single and double difluoromethylene (CF ) formal insertions into C-H bonds of aldehydes with nearly full selectivity under transition-metal-free conditions. The key to the success of controllable CF insertions lies in the well-defined formation of 2,2-difluoroenolsilyl ether and 2,2,3,3-tetrafluorocyclopropanolsilyl ether intermediates using difluorocarbene reagent TMSCF Br (TMS=trimethylsilyl). These two intermediates can react with various electrophiles including proton sources and various halogenation reagents, allowing for the access to diverse arrays of ketones containing difluoromethylene (CF ) and tetrafluoroethylene (CF CF ) units.

Reagent-Controlled Highly Stereoselective Difluoromethylation: Efficient Access to Chiral α-Difluoromethylamines from Ketimines.

A reagent-controlled highly stereoselective reaction between (S)-difluoromethyl phenyl sulfoximine and imines is reported, and this synthetic method provides a variety of enantiomerically enriched α-difluoromethyl amines. The main pros of this approach include high efficiency, high stereoselectivity, and a broad substrate scope, which is probably achieved through a non-chelating transition state.

Visible-light-promoted -trifluoromethylation of thiophenols with trifluoromethyl phenyl sulfone.

Trifluoromethyl phenyl sulfone is traditionally a nucleophilic trifluoromethylating agent. Herein, we report the first example of the use of trifluoromethyl phenyl sulfone as a trifluoromethyl radical precursor. Arylthiolate anions can form electron donor-acceptor (EDA) complexes with trifluoromethyl phenyl sulfone, which can undergo an intramolecular single electron transfer (SET) reaction under visible light irradiation, thus realizing the -trifluoromethylation of thiophenols under photoredox catalyst-free conditions.

Dynamic Kinetic Resolution-Enabled Highly Stereoselective Nucleophilic Fluoroalkylation to Access Chiral β-Fluoro Amines.

β-Fluorinated amine is highly desirable for biological and pharmaceutical science, because replacing a C-H bond with a C-F bond can change the physical and chemical properties of the parent molecule to a large extent but not significantly alter its overall geometry. Herein, the highly stereoselective nucleophilic monofluoromethylation of imines have been developed. It is proposed that the chelated transition state enables the chiral induction by the dynamic kinetic resolution of the chiral α-fluoro carbanions.

Controllable Single and Double Difluoromethylene Insertions into C-Cu Bonds: Copper-Mediated Tetrafluoroethylation and Hexafluoropropylation of Aryl Iodides with TMSCFH and TMSCFBr.

The selective difluoromethylene insertion into a C-Cu bond is a challenging task and is currently limited to either a single CF insertion into CuCF or double CF insertions into CuCF (or ()-CFCF = CFCu). Achieving both selective single and double CF insertions into the same C-Cu bond is even more difficult. Herein, highly controllable single and double CF insertions into CuCFH species with a TMSCFBr reagent have been described, affording two previously unknown fluoroalkylcopper species "Cu(CF)CFH" ( = 1 and 2) independently under different reaction conditions.

SulfoxFluor-enabled deoxyazidation of alcohols with NaN.

Direct deoxyazidation of alcohols with NaN is a straightforward method for the synthesis of widely used alkyl azides in organic chemistry. However, known methods have some limitations such as high reaction temperatures and narrow substrate scope. Herein, a general and practical method for the preparation of alkyl azides from alcohols using NaN has been developed.

Copper-mediated pentafluoroethylation of organoboronates and terminal alkynes with TMSCF.

The TMSCF-derived CuCFCF species has been successfully applied in pentafluoroethylation of organoboronates and terminal alkynes. By using 1,10-phenanthroline as a ligand, a broad range of (hetero)arylboronates and alkenylboronates were smoothly pentafluoroethylated under aerobic conditions. Furthermore, terminal alkynes can undergo aerobic cross-coupling with the TMSCF-derived CuCFCF species in the absence of additional ligands.

S-(Trifluoromethyl)Benzothioate (TFBT): A KF-Based Reagent for Nucleophilic Trifluoromethylthiolation.

Invited for the cover of this issue is Jinbo Hu and co-workers at Shanghai Institute of Organic Chemistry and Chongqing University. The image depicts TFBT (S-(trifluoromethyl) benzothioate), which is easily synthesized using KF, as an inexpensive, bench-stable and user-friendly trifluoromethylthiolation reagent. Read the full text of the article at 10.

S-(Trifluoromethyl)Benzothioate (TFBT): A KF-Based Reagent for Nucleophilic Trifluoromethylthiolation.

S-(Trifluoromethyl)benzothioate (TFBT) has been developed as an inexpensive, bench-stable, and user-friendly trifluoromethylthiolation reagent, which can be easily synthesized by using KF as the only fluorine source. By using TFBT, trifluoromethylthiolates with various counterions can be readily obtained. The synthetic application of TFBT was demonstrated by trifluoromethylthiolation-halogenation of arynes, bis(trifluoromethylthiolation)-halogenation of 1,2-benzdiynes, nucleophilic substitution of alkyl halides, deoxytrifluoromethylthiolation of alcohols, and cross-coupling with aryl and vinyl boronic acids.

TMSCF Br-Enabled Fluorination-Aminocarbonylation of Aldehydes: Modular Access to α-Fluoroamides.

A protocol for the modular assembly of the α-fluoroamide motif has been developed, which provides a practical method for the efficient synthesis of structurally diverse α-fluoroamides from easily available aldehydes and tertiary amines through a three-component fluorination-aminocarbonylation process. The key to the success of this process is taking advantage of the multiple roles of the unique difluorocarbene reagent TMSCF Br (TMS=trimethylsilyl). The mechanism of the process involves the 1,2-fluorine and oxygen migrations of the in situ formed TMS-protected α-aminodifluoromethyl carbinol intermediates, which represents a new type of deoxyfluorination reaction.

Fluorination Triggers Fluoroalkylation: Nucleophilic Perfluoro-tert-butylation with 1,1-Dibromo-2,2-bis(trifluoromethyl)ethylene (DBBF) and CsF.

Perfluoro-tert-butylation reaction has long remained a challenging task. We now report the use of 1,1-dibromo-2,2-bis(trifluoromethyl)ethylene (DBBF) as a practical reagent for perfluoro-tert-butylation reactions for the first time. Through a consecutive triple-fluorination process with DBBF and CsF, the (CF ) C species can be liberated and observed, which is able to serve as a robust nucleophilic perfluoro-tert-butylating agent for various electrophiles.

Divergent S- and C-Difluoromethylation of 2-Substituted Benzothiazoles.

Two unprecedented and complementary synthetic strategies for S- and C-difluoromethylation of 2-substituted benzothiazoles have been developed by taking advantage of the remarkably different reactivity of CFH and 2-PySOCF nucleophiles. A variety of structurally diverse difluoromethyl 2-isocyanophenyl sulfides and 2-difluoromethylated benzothiazoles were synthesized with these two new synthetic protocols.

Difluorocarbene-Induced Ring-Opening Difluoromethylation-Halogenation of Cyclic (Thio)Ethers with TMSCF X (X=Br, Cl).

The ring-opening difluoromethylation-halogenation of cyclic (thio)ethers is reported through a simple strategy relying on carbon-chalcogen bond activation with difluorocarbene. The reaction proceeds through in situ protonation of the previously little-known difluoromethylene oxonium or sulfonium ylide intermediate followed by ring-opening with halide ion to afford halogenated acyclic difluoromethyl (thio)ethers that can then be employed for further elaboration. TMSCF X (X=Br, Cl) are unique reagents to achieve this synthetic purpose, which serve as both the difluorocarbene source and the halide ion source.

Copper-Mediated Cross-Coupling of Diazo Compounds with Sulfinates.

A copper-mediated cross-coupling reaction between a diazo compound and a sodium alkane(arene)sulfinate gives a sulfone as the product. This reaction proceeds under mild conditions and features excellent functional group compatibility. A wide range of sodium alkane(arene)sulfinates were successfully applied in this chemistry.

Electrochemical reduction of fluoroalkyl sulfones for radical fluoroalkylation of alkenes.

Radical fluoroalkylation of alkenes has been developed by electrochemical reduction of fluoroalkyl sulfones. A series of electron-deficient alkenes readily undergo hydrofluoroalkylation in good to excellent yields. This chemistry represents the first example of electrochemical generation of fluoroalkyl radicals from sulfones, which are used for practical radical fluoroalkylation of organic compounds.