Transition-Metal-Free Controllable Single and Double Difluoromethylene Formal Insertions into C−H Bonds of Aldehydes with TMSCF2Br

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 TMSCF₂Br (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 (CF₂CF₂) 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.     

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.     

Zur Bildung und Stabilität von Difluormethylenphosphoranen,R3P⊕-C̄–F2

Inhaltsübersicht. Die Reaktion von Difluorhalogenmethanen, CF₂X₂, mit Phosphanen, R₃P, in Gegenwart von Metallen und Carbonylverbindungen, R″R′CO, führt zur Bildung geminaler Difluorolefine, R″R′C=CF₂. Die sorgfältige Untersuchung der Einzelschritte dieser komplexen Reaktion zeigt, daß intermediär Difluorhalogenmethylphosphoniumhalogenide, [R₃P–CF₂X]X, und Difluormethylenphosphorane, R₃P^⊕ – c?^?-F₂, gebildet werden. Die Phosphoniumsalze sind stabil und können als kristalline Substanzen isoliert werden. Durch Metalle oder Phosphene werden sie zu den instabilen Difluormethylenphosphoranen reduziert. Diese zersetzen sich beim Fehlen geeigneter Reaktionspartner in Phosphan und Difluorcarben, CF₂. Ihre Bildung durch Addition von CF₂ an R₃P ist nicht möglich. Mit Halogenwasserstoffen bilden sie Difluormethylphosphoniumsalze, [R₃P-CHF₂]X. Formation and Stability of Difluoromcthylene Phosphoranes, R₃P^⊕ —c?F₂ In the presence of metals and carbonyl compounds, R″R′CO, the reaction of difluoro-halomethanes, CF₂X₂, with phosphanes, R₃P, leads to the formation of geminal difluoroolefins, R″R′C=CF₂. Our investigations have proved that difluorohalomethylphosphonium halides, [R₃P–CF₂X]X, and difluoromethylene phosphoranes, R₃P^⊕–C??F₂, are formed intermediately. The phosphonium salts are stable. They can be isolated as crystalline substances. They are reduced by metals or phosphanes forming unstable difluoromethylene phosphoranes as intermediates. These decompose into phosphane and difluorocarbene, CF₂, if suitable reactants are absent. Their reaction with hydrogen halides, HX, yields difluoromethylphosphonium salts, [R₃P–CHF₂]X. The formation of difluoromethylene phosphoranes by addition of CF₂ to R₃P is not possible.     

Synthesis of Aryl-Manganese(III) Fluoride Complexes via α-Fluorine Elimination from CF3 and Difluorocarbene Generation

We report the synthesis of cyclometalated monoaryl Mn^III fluoro complexes using bis(trifluoromethyl)zinc reagent, Zn(CF₃)₂(DMPU)₂, under mild conditions via a reaction pathway that involves initial transmetalation followed by α-fluorine elimination. The formation of difluorocarbene in these reactions was detected by trapping experiments. Such facile difluorocarbene generation from Mn^III results in moderate enhancement of difluoropropanation and difluoropropenation of alkenes and alkynes using Zn(CF₃)₂(DMPU)₂ at lower temperature (20–60 °C) and short reaction time, suggesting potential application of manganese(III) perfluoroalkyl complexes as reactive species for carbene transfer reactivity.     

gem-Difluorosubstituted NH-azomethine ylides in the synthesis of 4-fluorooxazolines via the three-component reaction of imines, trifluoroacetophenones and CF2Br2

A simple one-step synthesis of a new class of fluorinated heterocycles, 4-fluoro-3-oxazolines, from diarylmethanimines, trifluoroacetophenones and CF₂Br₂ is described. The reaction proceeds via the sequential formation of difluorocarbene and a gem-difluorosubstituted NH-azomethine ylide, followed by 1,3-dipolar cycloaddition with a ketone.     

Synthetic and mechanistic aspects of the reactions between bromodifluoromethyltriphenylphosphonium bromide and dibromofluoromethyltriphenylphosphonium bromide and trialkylphosphites

Bromofluoromethyltriphenylphosphonium bromides react with trialkylphosphites in two distinct ways. Bromodifluoromethyltriphenylphosphonium bromide undergoes a rapid exchange reaction with trialkylphosphites to give the corresponding bromodifluoromethylphosphonates in good to excellent yields. A similar exchange reaction also occurred with an analogous diethoxyphenylphosphonite to give the corresponding ethoxyphenylphosphinate. Mechanistically, the exchange process involves the formation of difluorocarbene via dissociation of the intermediate difluoromethylene ylide, capture of the difluorocarbene by the trialkylphosphite to give , which captures bromine followed by dealkylation to the product, bromodifluoromethylphosphonate. The equilibria involved in the multi-step mechanism are all shifted to the phosphonate product by the final dealkylation step. In contrast, the dibromofluoromethyltriphenylphosphonium bromide does not under exchange reactions with trialkylphosphite. The phosphite serves as a halophilic reagent to abstract Br from the dibromofluoromethylphosphonium salt to generate the bromofluoromethylene ylide, which can easily be trapped in situ with aldehydes or ketones to give good yields of the E/Z-bromofluoroalkenes. No dissociation of the bromofluoromethylene ylide was observed.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

Formation and Stability of Difluoromethylene Phospho-Raiies,R3P=CF2

Abstract

Carbonyl compounds react with CBr₂F₂ in the presence of phosphanes, RP (R = Ph, NR;), and metals (M = Zn, Cd, Pb) forming geminal difluoroolefins (eq. 1)¹.

R′CHO + CBr₂F₂ + R₃P + M → R′CH=CF₂ + MBr₂ + R₃PO (1)

Without any doubt this reaction has to occur via the intermediate formation of difluoromethylene phosphoranes, which then undergo the Wittig reaction with carbonyl compounds (eq. 2). R₃P=CF₂ + R′CHO → R₃PO + R′CH=CF₂ (2).     

Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis

A palladium-catalyzed reductive difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles has been developed, representing a new mode of difluorocarbene transfer reaction. The approach uses low-cost and bulk industrial chemical chlorodifluoromethane (ClCF₂H) as the difluorocarbene precursor. It produces a variety of difluoromethylated (hetero)arenes from widely available aryl halides/triflates and proton sources, featuring high functional group tolerance and synthetic convenience without preparing organometallic reagents. Experimental mechanistic studies reveal that an unexpected Pd^0/II catalytic cycle is involved in this reductive reaction, wherein the oxidative addition of palladium(0) difluorocarbene ([Pd⁰(L_n)]=CF₂) with aryl electrophile to generate the key intermediate aryldifluoromethylpalladium [ArCF₂Pd(L_n)X], followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.     

A Systems Approach to a One-Pot Electrochemical Wittig Olefination Avoiding the Use of Chemical Reductant or Sacrificial Electrode

An unprecedented one-pot fully electrochemically driven Wittig olefination reaction system without employing a chemical reductant or sacrificial electrode material to regenerate triphenylphosphine (TPP) from triphenylphosphine oxide (TPPO) and base-free in situ formation of Wittig ylides, is reported. Starting from TPPO, the initial step of the phosphoryl P=O bond activation proceeds through alkylation with RX (R=Me, Et; X=OSO₂CF₃ (OTf)), affording the corresponding [Ph₃POR]⁺X⁻ salts which undergo efficient electroreduction to TPP in the presence of a substoichiometric amount of the Sc(OTf)₃ Lewis acid on a Ag-electrode. Subsequent alkylation of TPP affords Ph₃PR⁺ which enables a facile and efficient electrochemical in situ formation of the corresponding Wittig ylide under base-free condition and their direct use for the olefination of various carbonyl compounds. The mechanism and, in particular, the intriguing role of Sc³⁺ as mediator in the TPPO electroreduction been uncovered by density functional theory calculations.     

Formation of a trans-cycloadduct from the reaction of difluorocarbene with cis-difluorostilbene

The photochemical isomerization of trans and cis-difluorostilbenes has been studied. In the presence of a photosensitizer (biacetyl, 0.05 mol·^?1) about 75% of the trans form can be converted into the crystalline cis form. The reactions of difluorocarbene (CF₂) from the Seyferth reagent (PhHgCF₃) with cis- and trans-stilbene obey the Skell rule, i. e., stereospecific cycloaddition. However, although the reaction of CF₂ with trans-1,2-difluorostilbene yields trans-1,2-diphenyl-perfluorocyclopropane (9) as the only isolable product, the reaction of CF₂ with cis-difluorostilbene also gives the same trans-cycloadduct as the only isolable product. A possible mechanistic path involving the homolytic cleavage of the highly activated cyclopropane C—C bond facing the CF₂ group is discussed.     

The nascent translational energy of difluorocarbene produced in IR MPD of the pentafluoroethyl radical

We report upon the direct detection of difluorocarbene following infrared multiphoton photolysis of pentafluoroethyl iodide using well-defined (SLM, TEM₀₀, 80 ns pulse width) TEA CO₂-laser pulses. The rate of appearance of CF₂ at 1 mTorr pressure and RRKM modelling of the unimolecular dissociation of C₂F₃I and C₂F₅ using reasonable input parameters are presented. These support a mechanism whereby CF₂ is produced by secondary photolysis of pentafluoroethyl radicals. Measurements of the velocity of CF₂ by the transient diffusion technique lead to an estimate of 2.6 kcal/mol for its average translational energy acquired from the homolytic cleavage of the CI and CC bonds. This value is higher than that predicted from the models using reasonable spontaneous dissociation rates ( = 10⁹ s^?1). An inherent assumption of the models is that the excess energy of dissociation is distributed statistically among the vibrational modes of the reaction complex and that there are no small barriers in the exit channel.     

Chen's Reagent: A Versatile Reagent for Trifluoromethylation,Difluoromethylenation, and Difluoroalkylation in Organic Synthesis

Methyl fluorosulfonyldifluoroacetate(FSO2CF2CO2Me or MFSDA),often called"Chen's reagent",is commonly used to synthesize trifluoromethylated and difluoroalkylated compounds.This important reagent was initially developed as an efficient trifluoromethylating agent by Professor Qing-Yun Chen and co-workers at Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences in 1989.     

Nucleophilic, radical, and electrophilic (phenylsulfonyl)difluoromethylations

Selective incorporation of a fluoroalkyl moiety to modulate the properties of an organic molecule has become a frequently used strategy in life science- and materials science-related applications. In this context, selective introduction of a (phenylsulfonyl)difluoromethyl group (PhSO₂CF₂) into organic molecules has attracted much attention, since the PhSO₂CF₂ group can be regarded as a “chemical chameleon” that can be readily transformed into difluoromethyl (CF₂H), difluoromethylene (–CF₂–), and difluoromethylidene (CF₂) functionalities. This article overviews the recent development of (phenylsulfonyl)difluoromethylation reactions from 2003, including the nucleophilic (phenylsulfonyl)difluoromethylations with PhSO₂CF₂H, PhSO₂CF₂SiMe₃ and PhSO₂CF₂Br reagents, free radical (phenylsulfonyl)difluoromethylations with PhSO₂CF₂I reagent, and electrophilic (phenylsulfonyl)difluoromethylations with a hypervalent iodine(III)-CF₂SO₂Ph reagent.     

Difluorinated analogues of shikimic acid

Investigations into the quinate to shikimate transformation have been carried out, the results of which have been exploited in the synthesis of a novel difluoromethylene homologue of shikimic acid from (−)-quinic acid. Martin's sulfurane {Ph₂S[OC(CF₃)₂Ph]₂} was the reagent of choice for the key dehydration step of this synthesis. The results of investigations into the synthesis of the important natural product analogue, 6,6-difluoroshikimic acid are also reported.     

The thermal rearrangements of 1,1,2,2,4,4-hexafluorospiropentane and perfluorospiropentane

The title compounds were synthesized $\text{via}$ CF₂: addition to the respective methylenecyclopropanes. The hexafluorospiropentane thermally rearranges to 2,2,4,4-tetrafluoro-1-(difluoromethylene)cyclobutane in competition with CF₂: extrusion, whereas perfluorospiropentane decomposes exclusively by CF₂: extrusion.     

Difluorocarbene Studied with Threshold Photoelectron Spectroscopy (TPES): Measurement of the First Adiabatic Ionization Energy (AIE) of CF2

The first photoelectron band of difluorocarbene CF₂, has been studied by threshold photoelectron (TPE) spectroscopy. CF₂ was prepared by microwave discharge of a flowing mixture of hexafluoropropene, C₃F₆, and argon. A vibrationally resolved band was observed in which at least twenty‐two components were observed. In the first PE band of CF₂, the adiabatic ionization energy differs significantly from the vertical ionization energy because, for the ionization CF₂⁺ (X?²A₁)+e^? ← CF₂ (X?¹A₁), there is an increase in the FCF bond angle (by ≈20°) and a decrease in the C? F bond length (by ≈0.7 Å). The adiabatic component was not observed in the experimental TPE spectrum. However, on comparing this spectrum with an ab initio/Franck–Condon simulation of this band, using results from high‐level ab initio calculations, the structure associated with the vibrational components could be assigned. This led to alignment of the experimental TPE spectrum and the computed Franck–Condon envelope, and a determination of the first adiabatic ionization energy of CF₂ as (11.362±0.005) eV. From the assignment of the vibrational structure, values were obtained for the harmonic and fundamental frequencies of the symmetric stretching mode (ν₁′) and symmetric bending mode (ν₂′) in CF₂⁺ (X?²A₁).     

Partial oxidation of light alkanes by reductively activated oxygen in Eu-catalytic system at 40°C

Oxidation of light alkanes, CH₄, C₂H₆, and C₃H₈, could be performed at 40°C by using the EuCl₃-catalytic system (EuCl₃, O₂, Zn⁰, and CF₃CO₂H). In the case of CH₄ oxidation, MeOH was produced from CH₄ but CO₂ from CF₃CO₂H could not be avoided. However, selective oxygenations of C₂H₆ (89% selectivity) and C₃H₈ (91%) could be performed. In the oxidation of C₂H₆, EtOH was primary product and the successive oxidation of EtOH gave MeCHO and CO₂. Regio-selectivities (1°:2°) observed in the oxidation of C₃H₈ suggested that an electrophilic active oxygen species was generated in the EuCl₃-catalytic system. This active oxygen could not oxidize C-H bonds of MeOH (CF₃CO₂Me) because of a strong electron-withdrawing effect of CF₃CO-group. Eu²⁺ species produced by the reduction with Zn⁰ was studied by UV-visible spectra. The spectral data proposed that O₂ was reductively activated through the redox of Eu³⁺/Eu²⁺.     

Efficient One-Pot Synthesis of 2-Chloro-1,1, 1-trifluoro-2-alkenes Under Solvent-Free Conditions

The improved one-pot Wittig reaction had been used to prepare trifluoromethyl-containing olefins under solvent-free conditions. Treatment of aldehydes with PPh₃ and CF₃CCl₃ in the presence of K₂CO₃ at 100 °C afforded 2-chloro-1,1,1-trifluoro-2-alkenes in good to moderate yields.     

Photocatalyzed Cyanodifluoromethylation of Alkenes

Difluoromethylation is a straightforward and widely applied strategy used to incorporate HCF₂ into organic molecules. In contrast, cyanation reagents are typically volatile or highly toxic, or they require harsh reaction conditions. Incorporation of both CN and HCF₂ into organic molecules, such as alkenes, is a worthwhile but challenging task. A method for photocatalyzed cyanodifluoromethylation of alkenes has been developed, which employs a Ph₃P⁺CF₂CO₂^?/NaNH₂ (or NH₃) reagent system. Ph₃P⁺CF₂CO₂^? functions as both the HCF₂ and CN carbon source. A cyanide anion is generated in situ under mild conditions, thereby avoiding the use of toxic cyanation reagents. The photocatalytic method permits cyanodifluoromethylation of a range of alkenes under mild room temperature conditions. The CN group within the products may be further derivatized by standard methods.