Controllable Fluorocarbon Chain Elongation: TMSCF2Br-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 TMSCF2Br (TMS = trimethylsilyl) as the sole fluorocarbon source, accomplishing the goals of CFCE from C1 to C2 and from C1 to C3, respectively. The key to the success of these CFCE processes lies in the unique and diversified chemical reactivity of TMSCF2Br, which can serve as two different precursors, namely, a TMSCF2 radical precursor and a difluorocarbene precursor. Various functional groups are amenable to this new synthetic protocol, providing streamlined access to a broad range of alcohols containing trifluorovinyl or pentafluorocyclopropyl moieties from abundantly available aldehydes. The potential utility of these methods is further demonstrated by the gram-scale synthesis, derivatization, and measurement of log P values of the products.

1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6.

The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of para-quinone methides (p-QMs) with Me3SiRf (Rf = CF2H, CF3, CF2CF3, CF2COOEt, and CF2SPh) under mild conditions are described. Although Me3SiCF2H shows lower reactivity than Me3SiCF3, it can react with p-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 para-quinone methides and α-fluoroalkylated diarylmethanes.

Controllable Double Difluoromethylene Insertions into S-Cu Bonds: (Arylthio)tetrafluoroethylation of Aryl Iodides with TMSCF2Br.

A new method of constructing "ArSCF2CF2Cu" from ArSCu and TMSCF2Br (TMS=trimethylsilyl) has been developed. The cross-coupling reactions of the obtained "ArSCF2CF2Cu" with diverse aryl iodides (Ar'I) provide an efficient access to Ar'CF2CF2SAr. Mechanistic studies demonstrate that the "ArSCF2CF2Cu" species were generated through controllable double difluoromethylene insertions into ArS-Cu bonds rather than the 1,2-addition of ArSCu to tetrafluoroethylene.

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. Here we present a ligand coupling-enabled formal SO2 extrusion of fluoroalkyl 2-azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N-heteroaromatic fluoroalkylation.

Transition-Metal-Free Controllable Single and Double Difluoromethylene Formal Insertions into C-H Bonds of Aldehydes with TMSCF2 Br.

We have developed a new strategy for controllable single and double difluoromethylene (CF2 ) formal insertions into C-H bonds of aldehydes with nearly full selectivity under transition-metal-free conditions. The key to the success of controllable CF2 insertions lies in the well-defined formation of 2,2-difluoroenolsilyl ether and 2,2,3,3-tetrafluorocyclopropanolsilyl ether intermediates using difluorocarbene reagent TMSCF2 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 (CF2 ) and tetrafluoroethylene (CF2 CF2 ) units. The first synthesis of relatively stable 2,2,3,3-tetrafluorocyclopropanolsilyl ethers has been achieved, which offers a new platform to explore other unknown chemical space.

Controllable Single and Double Difluoromethylene Insertions into C-Cu Bonds: Copper-Mediated Tetrafluoroethylation and Hexafluoropropylation of Aryl Iodides with TMSCF2H and TMSCF2Br.

The selective difluoromethylene insertion into a C-Cu bond is a challenging task and is currently limited to either a single CF2 insertion into CuCF3 or double CF2 insertions into CuC6F5 (or (Z)-CF3CF = CFCu). Achieving both selective single and double CF2 insertions into the same C-Cu bond is even more difficult. Herein, highly controllable single and double CF2 insertions into CuCF2H species with a TMSCF2Br reagent have been described, affording two previously unknown fluoroalkylcopper species "Cu(CF2)nCF2H" (n = 1 and 2) independently under different reaction conditions. This work represents the first example of both single and double CF2 insertions into the same C-Cu bond in a highly selective manner. The synthetic value of the obtained "Cu(CF2)nCF2H" (n = 1 and 2) species is demonstrated by their reactions with aryl iodides, halogenation agents, and cinnamyl chloride, which enables the direct transfer of HCF2CF2 and HCF2CF2CF2 moieties into organic molecules. The key to controllable fluorocarbon chain elongation from C1 to C2 and from C1 to C3 is presumably attributed to the different reactivities of "Cu(CF2)nCF2H" species (n = 0, 1, 2 and 3) and the loading of the TMSCF2Br reagent.

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.

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 10.1002/chem.202104395.

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

A reagent-controlled highly stereoselective reaction between (S)-difluoromethyl phenyl sulfoximine 1 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.

TMSCF2 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 TMSCF2 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.

Difluorocarbene-Induced Ring-Opening Difluoromethylation-Halogenation of Cyclic (Thio)Ethers with TMSCF2 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. TMSCF2 X (X=Br, Cl) are unique reagents to achieve this synthetic purpose, which serve as both the difluorocarbene source and the halide ion source.

Iron-Catalyzed Fluoroalkylation of Arylborates with Sulfone Reagents: Beyond the Limitation of Reduction Potential.

The iron-catalyzed alkyl-aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron-catalyzed radical difluoroalkylation of arylborates with N-heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N-heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single-electron-transfer process, which enables both fluoroalkyl N-heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N-heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents.

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 (CF3 )3 C- species can be liberated and observed, which is able to serve as a robust nucleophilic perfluoro-tert-butylating agent for various electrophiles. The power of this synthetic protocol is evidenced by the efficient synthesis of structurally diverse perfluoro-tert-butylated molecules. Multiple applications demonstrate the practicability of this method, as well as the superiority of perfluoro-tert-butylated compounds as sensitive probes. The perfluoro-tert-butylated product was successfully applied in 1 H- and 19 F-magnetic resonance imaging (MRI) experiment with an ultra-low field (ULF) MRI system.

From C1 to C3 : Copper-Catalyzed gem-Bis(trifluoromethyl)olefination of α-Diazo Esters with TMSCF3.

A Cu-catalyzed gem-bis(trifluoromethyl)olefination of α-diazo esters, using TMSCF3 as the only fluorocarbon source, has been developed and provides an exquisite method to access gem-bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into "CuCF3 " to generate the α-CF3 -substituted organocopper species, which then undergoes ß-fluoride elimination and two consecutive addition-elimination processes to give the desired products. The key to this efficient one-pot C1 -to-C3 synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem-difluoroalkene intermediates.

Rapid Deoxyfluorination of Alcohols with N-Tosyl-4-chlorobenzenesulfonimidoyl Fluoride (SulfoxFluor) at Room Temperature.

The deoxyfluorination of alcohols is a fundamentally important approach to access alkyl fluorides, and thus the development of shelf-stable, easy-to-handle, fluorine-economical, and highly selective deoxyfluorination reagents is highly desired. This work describes the development of a crystalline compound, N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor), as a novel deoxyfluorination reagent that possesses all of the aforementioned merits, which is rare in the arena of deoxyfluorination. Endowed by the multi-dimensional modulating ability of the sulfonimidoyl group, SulfoxFluor is superior to 2-pyridinesulfonyl fluoride (PyFluor) in fluorination rate, and is also superior to perfluorobutanesulfonyl fluoride (PBSF) in fluorine-economy. Its reaction with alcohols not only tolerates a wide range of functionalities including the more sterically hindered alcoholic hydroxyl groups, but also exhibits high fluorination/elimination selectivity. Because SulfoxFluor can be easily prepared from inexpensive materials and can be safely handled without special techniques, it promises to serve as a practical deoxyfluorination reagent for the synthesis of various alkyl fluorides.

Fluoroalkylation of Various Nucleophiles with Fluoroalkyl Sulfones through a Single Electron Transfer Process.

The fluoroalkylation of various nucleophilic reagents with (phenylsulfonyl)difluoromethyl (PhSO2CF2)-substituted phenanthridines was achieved to give fluorinated phenanthridine derivatives, which enables the construction of both carbon-heteroatom and carbon-carbon bonds via the substitution of the phenylsulfonyl group. Mechanistic studies indicated that these reactions proceed through a unimolecular radical nucleophilic substitution (SRN1) mechanism. It is worthwhile noting that in the cases of O-nucleophiles ( t-BuO- and PhO-), the addition of t-BuOK/PhCHO could significantly promote the reactions, due to the in situ formation of a highly reactive electron donor species through the interaction of t-BuOK, PhCHO, and the solvent DMF, which can effectively initiate the single electron transfer process.

A General Protocol for C-H Difluoromethylation of Carbon Acids with TMSCF2 Br.

An efficient method for the selective C-difluoromethylation of carbon acids with the reagent TMSCF2 Br has been developed. A variety of structurally diverse sp3 - and sp-hybridized carbon nucleophiles, including esters, amides, fluorenes, terminal alkynes, ß-ketoesters, malonates, and other activated C-H nucleophiles, could be efficiently and selectively transformed into the corresponding C-difluoromethylated products under mild conditions. This protocol is also effective for the late-stage difluoromethylation of pharmaceutically relevant molecules and can be readily scaled up. Moreover, ambident substrates with more than one reactive site towards difluorocarbene can be difluoromethylated orthogonally using TMSCF2 Br.

Trifluoromethyl Benzoate: A Versatile Trifluoromethoxylation Reagent.

Trifluoromethyl benzoate (TFBz) is developed as a new shelf-stable trifluoromethoxylation reagent, which can be easily prepared from inexpensive starting materials using KF as the only fluorine source. The synthetic potency of TFBz is demonstrated by trifluoromethoxylation-halogenation of arynes, nucleophilic substitution of alkyl (pseudo)halides, cross-coupling with aryl stannanes, and asymmetric difunctionalization of alkenes. The unprecedented trifluoromethoxylation-halogenation of arynes proceeds smoothly at room temperature with the aid of a crown ether-complexed potassium cation, which significantly stabilizes the trifluoromethoxide anion derived from TFBz.

Iron-Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-Pyridyl Sulfone.

We report the first iron-catalyzed difluoromethylation of arylzincs with difluoromethyl 2-pyridyl sulfone via selective C-S bond cleavage. This method employs the readily available, bench-stable fluoroalkyl sulfone reagent and inexpensive iron catalyst, allowing facile access to structurally diverse difluoromethylated arenes at low temperatures. The experiment employing a radical clock indicates the involvement of radical species in this iron-catalyzed difluoromethylation process.

Hypervalent Iodine(III)-Catalyzed Balz-Schiemann Fluorination under Mild Conditions.

An unprecedented hypervalent iodine(III) catalyzed Balz-Schiemann reaction is described. In the presence of a hypervalent iodine compound, the fluorination reaction proceeds under mild conditions (25-60 °C), and features a wide substrate scope and good functional-group compatibility.