Nucleophilic Difluoromethylation of Epoxides with PhSO(NTBS)CF2H by a Preorganization Strategy

Unlike the facile synthesis of β‐monofluoromethyl alcohols by nucleophilic monofluoromethylation of epoxides, the synthesis of β‐difluoromethyl alcohols by nucleophilic difluoromethylation of epoxides still remains a challenge. Herein, studies on tackling this problem with PhSO(NTBS)CF₂H ( 2 ; TBS=tert‐butyldimethylsilyl) are reported. The preorganization of 2 and epoxides with BF₃ ? Et₂O was found to be crucial for the reaction. The reaction shows excellent regioselectivity and has a broad substrate scope. The facile transformation of the ring‐opened products to β‐difluoromethyl, γ‐difluoromethyl, and β‐difluoromethylenyl alcohols demonstrates the synthetic utility of the reaction.     

[(SIPr)Ag(CF2H)]: A Shelf-Stable,Versatile Difluoromethylation Reagent

Due to its unique physical and electrophilic properties, the difluoromethyl group (−CF₂H) 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(CF₂H)], 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.     

Perfluoro and polyfluorosulfonic acids: XVI. Difluoromethanesulfonic acids as a precursor of CF2: In the synthesis of difluoromethyl poly- and perfluoroalkanesulfonates

Difluoromethanesulfonic acid (1) readily reacts with P₂O₅ at room temperature to give difluoromethyl difluoromethanesulfonate (2) and SO₂ in stead of the expected acid anhydride. If perfluorosulfonic acid (3) perfluorocarboxylic acid (5) or KI was added to this reaction mixture, difluoromethyl perfluorosulfonate (4), difluoromethyl perfluorocarboxylate (6) and HCF₂I (7) was formed respectively in addition to 2. A similar result was obtained using POCl₃ or SOCl₂ instead of P₂O₅ as dehydrating agent. The mechanisms of the formation of difluorocarbene were discussed.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

Difluoromethylation of Amines with Zn(CF3)Br · 2 CH3CN,Cd(CF3)2 · 2 CH3CN and the System Bi(CF3)3/AlCl3

The reactions of Zn(CF₃)Br · 2 CH₃CN, Cd(CF₃)₂ · 2 CH₃CN or Bi(CF₃)₃/AlCl₃ with tertiary amines lead to the formation of quaternary ammonium salts of the general formula [R₃NCF₂H]X. The reaction of 4‐N,N‐dimethylaminopyridine with Zn(CF₃)Br · 2 CH₃CN yields (N‐difluoromethyl)‐4‐N,N‐dimethylaminopyridinium bromide. Bi(CF₃)₃/AlCl₃ reacts with 1,4‐diazabicyclo[2.2.2]octane to form a mixture of mono‐ and bis(difluoromethylammonium) salts.     

Chlorination and decarboxylation of (heptafluoronaphthalen-2-yl)acetic acid. Synthesis of 2-(dichloromethyl)- and 2-(difluoromethyl)heptafluoronaphthalenes

Decarboxylation of (heptafluoronaphthalen-2-yl)acetic acid in DMF in the presence of NaHCO₃ gave 2-methylheptafluoronaphthalene, and treatment with PCl₅ on heating afforded dichloro(heptafluoronaphthalen-2-yl)acetic acid. Decarboxylation of the latter in DMF led to the formation of 2-(dichloromethyl)-heptafluoronaphthalene which was converted to 2-(difluoromethyl)heptafluoronaphthalene by heating with cesium fluoride.     

Fluoride-induced nucleophilic (phenylthio)difluoromethylation of carbonyl compounds with [difluoro(phenylthio)methyl]trimethylsilane (TMS-CF2SPh)

A fluoride-induced nucleophilic (phenylthio)difluoromethylation method using TMS-CF₂SPh has been achieved. This new methodology efficiently transfers “PhSCF₂” group into both enolizable and non-enolizable aldehydes and ketones to give corresponding (phenylthio)difluoromethylated alcohols in good to excellent yields. Diphenyldisulfide can also be (phenylthio)difluoromethylated into PhSCF₂SPh in high yield. The reaction with methyl benzoate, however, gives only low yield of (phenylthio)difluoromethyl phenyl ketone. The above-obtained PhSCF₂-containing alcohols can be further transformed into difluoromethyl alcohols using an oxidation-desulfonylation procedure. This new type of nucleophilic (phenylthio)difluoromethylation methodology may have other potential applications in the medicinal and agrochemical fields.     

Photoredox Catalysis for the Synthesis of N-CF2H Compounds Using 1-((N-(difluoromethyl)-4-methylphenyl)-sulfonamido)pyridin-1-ium Trifluoromethanesulfonate

N-(difluoromethyl)amino (−NCF₂H) compounds are of great interest given their unique and underexplored physiochemical properties. The lack of structural diversity in NCF₂H compounds is likely due in part to the shortage of protocols for efficient installation. Presented herein is a new shelf-stable pyridinium reagent that enables the direct installation of the N-(difluoromethyl)sulfonamide moiety [N(Ts)CF₂H)] onto (hetero)arenes and alkenes for the diversification of aryl and alkyl NCF₂H compounds. The described protocol utilizes blue light photoredox catalysis and displays broad functional group tolerance with excellent chemoselectivity. Additional transformations and applicability towards a photoredox continuous flow protocol are also demonstrated.     

(CF3)2PAsH2 und (CF3)2AsAsH2

(CF₃)₂PAsH₂ and (CF₃)₂AsAsH₂ (CF₃)₂PAsH₂ is obtained in yields between 30 and 60% according to eq. (1) (CF₃)₂AsAsH₂ is formed by the analogous reaction with (CF₃)₂AsI, but is not sufficiently stable to be isolated. Both compounds are decomposed according to eq. (2) (CF₃)₂PAsH₂ can be studied in solution below ?40°C; it is characterized by molar mass determination and by its n.m.r. spectra (¹H, ¹⁹F, ³¹P). Reactions with polar [HBr, (CH₃)₂AsH, (CH₃)₂PN(CH₃)₂] and nonpolar [Br₂, As₂(CH₃)₄] reagents proceed by cleavage of the P? As bond.     

Perfluoralkyltellur-Verbindungen: Oxidation von (CF3)2Te Darstellungen und Eigenschaften von (CF3)2TeCl2, (CF3)2TeBr2, (CF3)2Te(ONO2)2 und (CF3)2TeO [1]

Perfluorosalkyl Tellurium Compounds: Oxidation of (CF₃)₂Te; Preparations and Properties of (CF₃)₂TeCl₂, (CF₃)₂TeBr₂, (CF₃)₂Te(ONO₂)₂, and (CF₃)₂TeO From the oxidation of (CF₃)₂Te with Cl₂, Br₂, O₂, and ClONO₂ the new trifluoromethyl tellurium compounds (CF₃)₂TeCl₂, (CF₃)₂TeBr₂, (CF₃)₂TeO, and (CF₃)₂Te(ONO₂)₂ are prepared. The ¹⁹F, ¹³C and ¹²⁵Te n.m.r. spectra, the vibrational and mass spectra as well as the chemical properties of these compounds are described. By variation of the reaction conditions CF₃TeCl₃ and CF₃TeBr₃ are also formed. It has not been possible to isolate (CF₃)₂TeI₂, but there is some evidence that it is formed as an intermediate. (CF₃)₂Te reacts with ozone to a very unstable compound, which decomposes at low temperature.     

The Reactions of Zn(CF3)Br · 2 CH3CN with Phenol,Pentafluorophenol, their Potassium and Ammonium Salts

Triphenoxymethane, tris(pentafluorophenoxy)methane, phenyl(difluoromethyl)ethers, and tetrakis(pentafluorophenoxy)ethene were prepared via carbenoid reactions of Zn(CF₃)Br · 2 CH₃CN and the corresponding phenol or the potassium or ammonium salts in the presence of the auxiliary acid BF₃ · O(CH₃)₂. The products were identified by their melting and boiling points and in part by their NMR and mass spectra as well as elemental analysis.     

Design and synthesis of the novel branched fluorinated surfactant intermediates with CF3CF2CF2C(CF3)2 group

Here we reported a novel and efficient method for the synthesis of the critical intermediates of branched fluorinated surfactants with CF₃CF₂CF₂C (CF₃)₂- group using HFPD as starting material. The reaction conditions were mild and easy to handle, which was promisingly applied to the industrial production.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.     

Darstellung und charakterisierung von (CF3)2PPH2 und (CF3)2AsPH2

(CF₃)₂EPH₂ (E = P,As) may be prepared in high yield by the cleavage of M-P bonds in compounds of the type R₃MPH₂ (M = Si, Ge, Sn) with (CF₃)₂EX (X = Cl, Br, I). The direction of bond fission depends on X and on the reaction temperature. These new compounds may also be obtained, but in lower yield, by the reaction of LiAl(PH₂)₄ with (CF₃)₂EX. Application of the principle of this reaction to other R′₂EX compounds [(CH₃)₂PCl, (CH₃)₂AsI, F₂PX (X = Br, I)] has been investigated. The IR and NMR spectra of the new compounds are reported.     

Preparation and Structure of [Me3N(CF3)2BCCB(CF3)2NMe3]

Bis‐trimethylamine‐ethynyl‐di‐bis(trifluoromethyl)borane [Me₃N(CF₃)₂BCCB(CF₃)₂NMe₃] ( 1 ) has been prepared from trimethylamine‐ethynyl‐bis(trifluoromethyl)borane, [HCCB(CF₃)₂NMe₃], and dimethylamino‐bis(trifluoromethyl)borane, (CF₃)₂BNMe₂. The structure of 1 has been determined by x‐ray crystallography. In the solid state the molecule possesses crystallographic C_i symmetry. The acetylenic attachment to the boron atom is characterized by a short B–C bond length of 1.565(4) Å and an essentially linear B–C–C′ bond angle of 178.1(4)°.     

Difluorocarbene-Induced Ring-Opening Difluoromethylation-Halogenation of Cyclic (Thio)Ethers with TMSCF2X (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. TMSCF₂X (X=Br, Cl) are unique reagents to achieve this synthetic purpose, which serve as both the difluorocarbene source and the halide ion source.     

A convenient,transition metal-free synthesis of difluoromethyl selenoethers from organic selenocyanates and TMSCF2H

An efficient and transition metal-free method for the synthesis of aryl or alkyl difluoromethyl selenides (RSeCF₂H) from the corresponding selenocyanates (RSeCN) and TMSCF₂H/t-BuOK is described. The reaction performed in THF at 0?°C for 24?h or at room temperature for 6?h supplied a series of RSeCF₂H in good to high yields. The successful preparation of difluoromethylselenolated sulfadimethoxine derivative and the scaled-up synthesis of 1-benzyl-5-((difluoromethyl)selanyl)indoline, as examples, suggested good practicability of this method. Advantages of the reaction include mild reaction conditions, good functional group tolerance, a wide range of substrates, and high efficiency. This protocol offered a number of novel difluoromethyl selenoethers, which would accelerate use of such compounds in the areas of life science.     

Kinetics and products of chlorine atom initiated oxidation of HCF2OCF2OCF2CF2OCF2H and HCF2O(CF2O)n‐(CF2CF2O)mCF2H

Smog chamber/FTIR techniques were used to measure k(Cl + HCF₂OCF₂OCF₂‐CF₂OCF₂H) = k(Cl + HCF₂O(CF₂O)_n(CF₂CF₂O)_mCF₂H) = (5.0 ± 1.4) × 10^?17 cm³ molecule^?1 s^?1 in 700 Torr of N₂/O₂ diluent at 296 ± 1 K. The Cl‐initiated atmospheric oxidation of HCF₂OCF₂OCF₂CF₂OCF₂H and the sample of HCF₂O(CF₂O)_n(CF₂CF₂O)_mCF₂H used in this work gave COF₂ in molar yields of (476 ± 36)% and (859 ± 63)%, respectively, with no other observable carbon containing products (i.e., essentially complete conversion of both hydrofluoropolyethers into COF₂). The results are discussed with respect to the atmospheric chemistry and environmental impact of hydrofluoropolyethers of the general formula HCF₂O(CF₂O)_n(CF₂CF₂O)_mCF₂H. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 40: 819–825, 2008