Difluoromethyl Group Research Articles

Divergent Generation of the Difluoroalkyl Radical and Difluorocarbene via Selective Cleavage of C-S Bonds of the Sulfox-CF2SO2Ph Reagent.

A new difluoroalkylation reagent Sulfox-CF2SO2Ph bearing both sulfoximine and sulfone moieties was prepared from commercially available SulfoxFluor and PhSO2CF2H. On one hand, the Sulfox-CF2SO2Ph 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-CF2SO2Ph could serve as a difluorocarbene precursor for S- and O-difluoromethylations with S- and O-nucleophiles, respectively, in which the phenylsulfonyl group in Sulfox-CF2SO2Ph is selectively removed (followed by α-elimination of the arylsulfoximidoyl group).

Electrochemical synthesis of β-difluoromethylamide compounds by N-benzenesulfonylacrylamide with difluorine reagents.

A mild and efficient electrochemical method for radical addition, cyclization, and migration reaction was described in this work. A difluoromethyl radical was produced by anodizing CF2HSO2Na. The resulting product was then added to olefin, underwent Smiles cyclization, and migrated to form β-difluoromethamide compounds after the release of SO2. The process was free from metals and catalysts, gram-grade, and resistant to a variety of electron-rich substrates.

Ligand-assisted manganese-enabled direct C–H difluoromethylation of arenes

The incorporation of a difluoromethyl group within an aromatic ring is highly desirable.

SYNTHESIS OF 1-ALKYLSULPHONYL-4-X-2,3,5,6-TETRAFLUOROBENZENES FROM SULPHANYL DERIVATIVES

The interaction of alkyl(4-X-2,3,5,6-tetrafluorophenyl)sulphanes (X = H, CF3) containing difluoromethyl and benzyl groups as alkyl components with hydrogen peroxide in acetic or trifluoroacetic acid gave the corresponding sulphonyl derivatives. The effect of the acid used on the reaction result was established in the case of (difluoromethyl)[4-(trifluoromethyl)-2,3,5,6-tetrafluorophenyl]sulphane. The synthesis of 1-alkylsulphonyl-2,3,5,6-tetrafluorobenzenes scaling possibility to tens of grams was demonstrated. Product yields were 84-97%.

Difluoromethylation-Carboxylation and -Deuteration of Alkenes Triggered by Electroreduction of Difluoromethyltriphenylphosphonium Bromide.

It is significant to develop novel difluoromethylation methods because of the important roles of difluoromethyl groups in the medicinal chemistry and material industries. Here, we developed a novel difluoromethylation-carboxylation and difluoromethylation-deuteration method triggered by a difluoromethyl radical generated by electroreduction of stable and easily available difluoromethyltriphenylphosphonium bromide. Various molecules containing difluoromethyl and carboxyl or deuterium groups can be synthesized through this method. The establishment of this method will provide an alternative to radical difluoromethylation reactions.

Efficient Synthesis of Fused Heterocycles Incorporating Pyrazole/Thiadiazine or Pyrazole/Thiadiazepine Fragments Using N‐Chlorosulfonyltrihaloacetimidoyl Chlorides

AbstractA novel simple and effective method has been developed for constructing pyrazolothiadiazine and pyrazolothiadiazepine fused heterocycles incorporating an endocyclic sulfonamide fragment. The cyclocondensation of readily available N‐(chlorosulfonyl)imidoyl chlorides, RC(Cl)=NSO2Cl (R=CCl3, CF2Br), with N‐methyl‐substituted 4‐ or 5‐aminopyrazoles results in the formation of isomeric pyrazolothiadiazine‐S,S‐dioxides. Additionally, when 5‐ or 3‐aminoalkyl‐substituted pyrazoles are employed, they serve as 1,4‐N−C−C−C binucleophiles, leading to the synthesis of novel pyrazolothiadiazepine heterocycles. Notably, the trichloromethyl and bromodifluoromethyl substituents in these compounds can be converted into dichloromethyl and difluoromethyl groups, providing enhanced functionalization options.

Visible‐Light‐Induced Multicomponent Reaction of Aromatic Aldehydes, Amines and Sodium Difluoromethanesulfinate: Synthesis of CF2H‐Substituted Secondary Amines

AbstractA visible‐light induced multicomponent reaction of aromatic aldehydes, amines and sodium difluoromethanesulfinate for the synthesis of fluorinated secondary amines has been investigated. The protocol affords a convenient pathway for the introduction of difluoromethyl group into imines, which generated in situ by the reaction of aldehydes and amines. A diverse range of fluorinated secondary amines were synthesized in 43%–79% yields under room temperature. In addition, a plausible mechanism was proposed based on several control experiments.

Ir-Catalyzed Ortho-Selective C-H Borylation of Difluoromethyl Arenes.

The difluoromethyl group (CF2H) has received great attention due to its distinct properties in recent years. Herein, we report a new strategy for postmodification of difluoromethyl compounds. Ortho-selective C-H borylation of difluoromethyl arenes is achieved by a cyclometalated mesoionic carbene-Ir complex. The regioselectivity is controlled by a hydrogen bond between CF2H and the boryl group via the outer-sphere direction.

Photoredox Catalysis-Enabled C-H Difluoromethylation of Heteroarenes with Pentacoordinate Phosphorane as the Reagent.

Difluoromethylated heterocyclic compounds have found broad applications in numerous bioactive molecules. Herein, we report photoredox catalysis-induced direct C-H difluoromethylation of heterocycles by using bis(difluoromethyl) pentacoordinate phosphorane (PPh3(CF2H)2, 1) as the reagent. A variety of heterocycles, such as quinoxalin-2(1H)-one, thiophene, indole, and coumarin, are readily tailored with a difluoromethyl group. The method is featured as transition-metal-free by using an organic compound Erythrosin B as the catalyst and O2 as the oxidant.

Copper-Catalyzed Enantioselective Difluoromethylation-Alkynylation of Olefins by Solving the Dilemma between Acidities and Reduction Potentials of Difluoromethylating Agents.

Molecules containing a difluoromethyl group or a propargylic stereocenter are widely used in pharmaceuticals and agrochemicals, and 1,2-functionalization of olefins is an important method for introducing the two groups into molecules simultaneously. The construction of the propargylic stereocenter with terminal alkynes usually requires bases. However, difluoromethylating agents with high reduction potentials often decompose in the presence of bases because of their acidities, and those with low reduction potentials are stable but difficult to undergo the desired single electron transfer (SET) reduction. Using the linear relationship between reduction potential differences (ΔE) and Hammett substituent constants (σ) of difluoromethyl aryl sulfones, we solved the dilemma between acidities and reduction potentials of difluoromethylating agents. Herein, we report the first enantioselective difluoromethylation-alkynylation of olefins with difluoromethyl 4-chlorophenyl sulfone with high enantioselectivity (>90 % ee). We also extended this asymmetric fluoroalkylation-alkynylation reaction with other fluoroalkyl sulfones, which enabled efficient installation of trifluoromethyl, difluoroalkyl, difluorobenzyl, (benzenesulfonyl)-difluoromethyl and monofluoromethyl groups into products.

Copper‐Catalyzed Enantioselective Difluoromethylation‐Alkynylation of Olefins by Solving the Dilemma between Acidities and Reduction Potentials of Difluoromethylating Agents

AbstractMolecules containing a difluoromethyl group or a propargylic stereocenter are widely used in pharmaceuticals and agrochemicals, and 1,2‐functionalization of olefins is an important method for introducing the two groups into molecules simultaneously. The construction of the propargylic stereocenter with terminal alkynes usually requires bases. However, difluoromethylating agents with high reduction potentials often decompose in the presence of bases because of their acidities, and those with low reduction potentials are stable but difficult to undergo the desired single electron transfer (SET) reduction. Using the linear relationship between reduction potential differences (ΔE) and Hammett substituent constants (σ) of difluoromethyl aryl sulfones, we solved the dilemma between acidities and reduction potentials of difluoromethylating agents. Herein, we report the first enantioselective difluoromethylation‐alkynylation of olefins with difluoromethyl 4‐chlorophenyl sulfone with high enantioselectivity (>90 % ee). We also extended this asymmetric fluoroalkylation‐alkynylation reaction with other fluoroalkyl sulfones, which enabled efficient installation of trifluoromethyl, difluoroalkyl, difluorobenzyl, (benzenesulfonyl)‐difluoromethyl and monofluoromethyl groups into products.

Difluoroalkylation/Lactonization of Alkenes with BrCF2CO2K via Photoredox Catalysis: Access to α,α‐Difluoro‐γ‐lactones†

Comprehensive SummaryDue to its unique electronic properties, the difluoromethylene group (CF2) has served as a valuable unity in the design of biologically active molecules. Since γ‐lactones display a broad range of biological properties, α,α‐difluoro‐γ‐lactones may exhibit unexpected biological activities, and thus their synthesis has received increasing attention. Traditional synthetic methods suffer from tedious multi‐ step processes, and very few effective methods have been reported recently. Herein, we describe the difunctionalization of alkenes with BrCF2CO2K under photoredox catalysis with the use of a boron‐Lewis acid for the access to α,α‐difluoro‐γ‐lactones. In this transformation, the alkene substrates and the used reagents, including BrCF2CO2K and the boron‐Lewis acid, PhB(OH)2 or BF3·THF, are cheap and widely available. High efficiency and atom economy may make this protocol attractive.

Chemical Conversion of 5-Fluoromethyl- and 5-Difluoromethyl-Uracil Bases in Oligonucleotides Using Postsynthetic Modification Strategy.

This article describes the postsynthetic modification of oligonucleotides (ONs) containing 2'-deoxy-5-fluoromethyluridine (dUCH2F ) and 2'-deoxy-5-difluoromethyluridine (dUCHF2 ). Reactions of fully protected and controlled pore glass (CPG)-attached ONs containing dUCH2F and dUCHF2 in basic solutions result in deprotection of all protecting groups except for the 4,4'-dimethoxytrityl group, cleavage from CPG, and conversion of the fluoromethyl or difluoromethyl groups to afford the corresponding ONs containing 5-substituted 2'-deoxyuridines. Moreover, the difluoromethyl group can be converted to formyl, oxime, or hydrazone via the postsynthetic conversion of protection- and CPG-free ON containing dUCHF2 . © 2023 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of fully protected and CPG-attached oligonucleotides containing 2'-deoxy-5-fluoromethyluridine and 2'-deoxy-5-difluoromethyluridine Basic Protocol 2: Postsynthetic modification of fully protected and CPG-attached oligonucleotides containing 2'-deoxy-5-fluoromethyluridine Basic Protocol 3: Postsynthetic modification of fully protected and CPG-attached oligonucleotide containing 2'-deoxy-5-difluoromethyluridine Basic Protocol 4: Postsynthetic modification of protection- and CPG-free oligonucleotide containing 2'-deoxy-5-difluoromethyluridine Support Protocol: Synthesis of 2'-deoxy-5-fluoromethyluridine and 2'-deoxy-5-difluoromethyluridine phosphoramidites.

Difluoromethylborates and Muonium for the Study of Isonitrile Insertion Affording Phenanthridines via Imidoyl Radicals.

The 6-(difluoromethyl)phenanthridine unit is a highly attractive fluoroalkyl-substituted planar nitrogen heterocycle in pharmaceutical and agrochemical research. In this paper, we report that difluoromethylborates can be used as a source of difluoromethyl radicals for isonitrile insertion, leading to 6-(difluoromethyl)phenanthridines. Tuning the aryl substituents in the difluoromethylborates and oxidizing reagents enabled the synthesis of 6-(difluoromethyl)phenanthridines through the generation of difluoromethyl radical and spontaneous intramolecular cyclization of the CF2H-imidoyl radical intermediates. The presence of difluoromethyl radicals was experimentally confirmed, and the reaction mechanisms including imidoyl radical and prompt cyclization reactions could be supported theoretically. Furthermore, we obtained valuable information about the imidoyl radical intermediate by performing transverse-field muon spin rotation (TF-μSR) measurements of 2-isocyano-4'-methoxy-1,1'-biphenyl and using density functional theory (DFT) calculations to interpret the spectra. Muonium, a simple free radical, preferentially adds to the carbon atom of the isonitrile unit, yielding the corresponding imidoyl radical. The temperature dependence of the muon hyperfine coupling constant and the spin relaxation of the muoniated radical signal are compatible with the intramolecular cyclization of biaryl-substituted imidoyl radicals on the μs time scale.

(SIPr)Ag(CF2 H)]: A Shelf-Stable, Versatile Difluoromethylation Reagent.

Due to its unique physical and electrophilic properties, the difluoromethyl group (-CF2 H) has been playing an irreplaceable role in the field of pharmaceutical and agrochemical industry. Methods that could efficiently incorporate the difluoromethyl group into the target molecules are increasing in the recent years. Developing a stable and efficient difluoromethylating reagent is thus highly attractive. In this review, we describe the development of a nucleophilic difluoromethylation reagent [(SIPr)Ag(CF2 H)], including its elemental reaction, difluoromethylation reaction with different types of electrophiles, and its application in the synthesis of a nucleophilic and an electrophilic difluoromethylthiolating reagent.

Enzymatic Fluoromethylation Enabled by the S-Adenosylmethionine Analog Te-Adenosyl-L-(fluoromethyl)homotellurocysteine.

Fluoromethyl, difluoromethyl, and trifluoromethyl groups are present in numerous pharmaceuticals and agrochemicals, where they play critical roles in the efficacy and metabolic stability of these molecules. Strategies for late-stage incorporation of fluorine-containing atoms in molecules have become an important area of organic and medicinal chemistry as well as synthetic biology. Herein, we describe the synthesis and use of Te-adenosyl-L-(fluoromethyl)homotellurocysteine (FMeTeSAM), a novel and biologically relevant fluoromethylating agent. FMeTeSAM is structurally and chemically related to the universal cellular methyl donor S-adenosyl-L-methionine (SAM) and supports the robust transfer of fluoromethyl groups to oxygen, nitrogen, sulfur, and some carbon nucleophiles. FMeTeSAM is also used to fluoromethylate precursors to oxaline and daunorubicin, two complex natural products that exhibit antitumor properties.

直線的分子連結を実現するテトラフルオロスルファニル化合物群：合成と開拓

Isosterism and bioisosterism are concepts in molecular design of specialty materials and drugs compounds. Fluorine and fluorine-containing functional groups are often used as isosteres and bioisosteres. Fluorine atom (F) is the most suitable isostere of hydrogen atom (H). With regard to electronegativity, fluorine is also used as a good substitute for hydroxyl (OH) group. Trifluoromethyl (CF3) group can be used as an equivalent for methyl or isopropyl groups, and difluoromethyl (-CF2H) group is an alcohol (-OH) equivalent. Pentafluoro-λ6-sulfanyl (SF5) group has recently attracted attention as a super CF3 group. This review introduces an undeveloped fluorine-containing functional group, tetrafluoro-λ6-sulfanyl (SF4) moiety. The SF4 is a unit consisting of four fluorine atoms bonded around an octahedral sulfur (VI) atom, with strong electron-withdrawing property and high lipophilicity. Characteristic of the SF4 unit are the cis- and trans-geometries connecting the two fragments. Interestingly, the trans-SF4 unit can connect two separated parts in a linear (180°) configuration via an octahedral sulfur center. Although organic compounds having an SF4 unit were known as early as the 1950s, their synthetic studies have been largely underdeveloped. We herein describe the structural and chemical characteristics of SF4-containing compounds, the background of the synthetic study, and their state-of-the-art synthetic constructions.

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups.

A synthetic route to the bench-stable fluorinated masked carbene reagent diethyl 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate, bearing a trifluoromethyl and a difluoromethyl group is reported for the first time. Its application in CuI-catalyzed cyclopropanation reactions with aromatic and aliphatic terminal alkenes under mild reaction conditions is demonstrated. In total, sixteen new cyclopropanes were synthesized in good to very good yields.

Difluorocarbene-Triggered [1+5] Annulation: Access to Functionalized 1,1-Difluoro-1,9a-dihydropyrido[2,1-c][1,4]thiazine Derivatives

Difluorocarbene-triggered [1+5] annulation is developed to access 1,1-difluoro-1,9a-dihydropyrido[2,1-c][1,4]thiazine-3,4-dicarboxylate derivatives in satisfactory to good yields via the direct reaction of potassium bromodifluoroacetate and pyridinium 1,4-zwitterionic thiolates under heating. Pyridinium 1,4-zwitterionic thiolates first nucleophilically attack difluorocarbene generated from potassium bromodifluoroacetate followed by an intramolecular nucleophilic addition to pyridiniums. This method provides an expeditious route to introduce the difluoromethyl group into the 1,9a-dihydropyrido[2,1-c][1,4]thiazine ring, even to modify drug molecules.

Electrochemical Difluoromethylation of Electron-Rich Olefins.

The electrochemical difluoromethylation of electron-rich olefins (enamides and styrene derivatives) is disclosed. The addition of the electrogenerated difluoromethyl radical from the corresponding sodium sulfinate (i.e., HCF2SO2Na) to enamides and styrenes in an undivided cell allowed the formation of a large panel of difluoromethylated building blocks in good to excellent yields (42 examples, 23-87% yields). A plausible unified mechanism was suggested according to control experiments and cyclic voltammetry measurements.