Electronic States of Difluorocarbene Calculated by Multireference Configuration Interaction Method

We investigate the geometries and energies of seven electronic states X-1A1, A1B1, a-3B1, B-1A2,b-3A2, C1B2 and c-3B2 of CF2 carbene using internally contracted multireference configuration interaction methods including Davidson correction （icMRCIq-Q） with different basis sets aug-cc-pVXZ （X=T, Q, 5）. For the first time, the potential energy curves of electronic states of CF2 related icMRCI＋Q/aug-cc-pVTZ level. The ab initio results will and dynamics of electronic states of CF2 radical. to the lowest dissociation limit are calculated at the further increase our understanding of the structures

Difluoromethylation of O-, S-, N-, C-Nucleophiles Using Difluoromethyltri（n-butyl）ammonium Chloride as a New Difluorocarbene Source

Difluoromethyltri（n-butyl）ammonium chloride 1 was found to be an effective difluorocarbene reagent for O-, S-, N-, C-difluoromethylation under basic conditions. It is particularly remarkable that, when only 1.2 equivalent of reagent 1 was used, the difluoromethylated products were obtained in moderate to excellent yields.

Single-atom skeletal editing of 2H-indazoles enabled by difluorocarbene

A novel difluorocarbene promoted single-atom skeletal editing of 2H-indazoles is demonstrated herein.Ethyl bromodifluoroacetate was severed as the difluorocarbene source in the current protocol,facilitating the cleavage of the N-N bond via carbon atom insertion.This metal-free ring expansion reaction enables the late-stage diversification of indazole skeletons,assembling a diverse array of functionalized quinazolin-4(3H)-ones in decent yields with excellent functional group compatibility.

Difluorocarbene Chemistry： A Simple Transformation of 3,3-gem-Difluorocyclopropenes to Cyclopropenones

The cycloaddition reactions of a-acetyoxyl propynes with difluorocarbene, generated from the decomposition of FSO2CF2CO2SiMe3 in DG in the presence of 10% of NaF at 120℃ gave readily a-acetyoxyl gem-difluorocyclopropenes. When these fluorinated compounds were hydrolyzed under alkaline condition at 0℃, α-hydroxyl cyclopropenones were produced predominantly whereas treated with catalytic amounts of BF3·Et2O in Et2O, α-acetyoxyl cyclopropenones were obtained.

Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

Difluoromethylated alkynes are a versatile synthon for the diversity-oriented synthesis of difluoromethyl compounds that are of great interest in life and materials sciences.However,the catalytic cross-coupling for the synthesis of difluoromethylated alkynes remains challenging,despite impressive achievements made in the cross-coupling reactions for alkynes,including the Sonogashira reaction.Here,we report a palladium difluorocarbene involvement in catalytic coupling with terminal alkynes,representing a new mode of conjugation reaction,which circumvents the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles.The reaction uses inexpensive and abundant industrial raw material chlorodifluoromethane(ClCF_(2)H)as the difluorocarbene precursor,and features cost-effectiveness,excellent functional group tolerance,and broad substrate scope,including synthesis of drug-like complex molecules.Our mechanistic studies showed a unique catalytic pathway of this process,in which additive hydroquinone plays a pivotal role in promoting the reaction.

Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers

An unprecedented difluorocarbene-mediated C-O bond cleavage of cyclic ethers for the construction of difluoromethyl ethers is herein disclosed.This protocol is distinguished by its mild conditions,high efficiency,and wide substrate scope,which can tolerate both sensitive functional groups such as the hydroxyl group,olefin and C-C triple bonds,as well as complex molecules.It thus demonstrates excellent chemoselectivities and great potential for late-stage modification of pharmaceutical compounds and natural products.It is worth noting that this method not only introduces fluorine atoms into the final molecules,but it can also effectively form an ester or ether linkage.

Oxidation of Difluorocarbene by Pyridine N-Oxide and Ensuing Access to Carbamoyl Fluorides

A practical one-pot preparation of carbamoyl fluorides from easily obtained pyridine N-oxide,commercially available secondary amines and synthetically versatile difluorocarbene precursors(Ruppert-Prakash reagent or Chen's reagent)was developed herein,which dexterously resorted to the oxidation of difluorocarbene by external pyridine N-oxide to produce the toxic and gaseous fluorophosgene in situ.Notable features of this method include nice functionality tolerance,late-stage modification of drug molecules and the recoveryand recycle of quinoline.

Difluorocarbene-derived rapid late-stage trifluoromethylation of 5-iodotriazoles for the synthesis of^(18)F-labeled radiotracers

Difluorocarbene has emerged as a valuable intermediate to synthesize fluorides.However,difluorocarbene-derived synthesis of^(19)F/^(18)F-trifluoromethyl triazoles has not been explored.Herein,we reported the Cu(I)-promoted difluorocarbene-derived^(19)F/^(18)F-trifluoromethylation of iodotriazoles using KF/K^(18)F as the fluorine source.This approach rapidly generated a wide range of 5-trifluoromethyl-1,2,3-triazoles in good yields showing high functional group compatibility.The reaction was effective for late-stage functionalization of bioactive molecules and^(18)F-trifluoromethylation of iodotriazoles.This work provides a practical synthetic methodology for the development of triazole drugs and^(18)F-radiotracers for positron emission tomography.

Synthesis of 2-Trifluoromethyl-4-aminoquinolines via Heating-Promoted Multi-component Reaction of CF_(3)-Imidoyl Sulfoxonium Ylides and Amines with Difluorocarbene as a C1 Synthon

A thermally-induced multi-component reaction of CF_(3)-substituted imidoyl sulfoxonium ylides(TFISYs),amines and(triphenylphosphonio)difluoroacetate(PDFA)has been developed,allowing a facile access to 2-trifluoromethyl-4-aminoquinolines in high yields.The reaction proceeds smoothly with or without the addition of sulfur and utilizes difluorocarbene as a C1 synthon under simply heating conditions.Mechanistic study reveals that in-situ generated thiocarbonyl fluoride,isothiocyanate or gem-difluoroalkene might act as the key reaction intermediates.

Atom Recombination of Difluorocarbene Enables 3-Fluorinated Oxindoles from 2-Aminoarylketones

Contrary to the traditional implementation as a difluoromethyl group and recently disclosed role of C1 synthons in synthetic organic chemistry,difluorocarbene(:CF_(2))is reported herein to proceed in unprecedented atom recombination as both a C1 synthon and F1 reagent simultaneously to render valuable 3-fluorinated oxindoles from 2-aminoarylketones.The reaction does not require catalyst and features a broad range of substrates with good functional group compatibility and ease of execution.This transformation could be employed to the quick-constructions of certain bioactive molecule derivatives.The mechanistic experiments and density functional theory(DFT)calculations indicate that this atom recombination reaction of:CF_(2) for the synthesis of 3-fluorinated oxindoles may involve a rearrangement process of epoxide intermediates.

Application of carbene reactive intermediates in organic synthesis——Ⅲ.Reaction of difluorocarbene with trimethylsilyl enol ethers

The addition of difluorocarbene generated from phenyl(trifluoromethyl)mercury and anhydrous sodium iodide,with trimethylsilyl enol ethers derived from cyclohexanone,cycloheptanone, 3-pentanone and acetophenone was described.The corresponding 2,2-difluoro-1-trimethylsilyloxy- cyclopropanes were obtained in good yields.The thermal stability of these cyclopropyl derivatives was affected by the molecular strain and the nature of their substituents.Thus,1-trimethylsilyloxy- cyclopentene reacted with difluorocarbene to give only 2-fluoro-2-cyclohexen-1-one instead of the expected 1-trimethylsilyloxy-6,6-difluorobicyclo[3.1.0]hexane,and a mechanism for its formation was proposed.

Difluoromethyl phenoxathiinium salt: A new general and versatile difluoromethylating reagent with divergent ·CF_(2)H, CF_(2)H^(+), and :CF_(2) reactivities

Development of practical and versatile electrophilic difluoromethylating reagent is still a grand challenge so far due to its inherent instability or low reactivity.Herein,we report the design and synthesis of difluoromethyl phenoxathiinium tetrafluoroborate(PT-CF_(2)H^(+)BF_(4)^(-)) as a novel difluoromethylating reagent,which proves to be a bench-stable,general,powerful and versatile reagent with divergent·CF_(2)H,CF_(2)H^(+),and:CF_(2) reactivities.Making use of this reagent,we demonstrated a vast array of difluoromethyl radical transfer reactions via diverse pathways involving photocatalyst-free visible-light induction,visible-light photoredox catalysis and visible-light mediation single electron transfer of EDA complex.Moreover,the green and highly effective CF_(2)H^(+) and:CF_(2) transfer reactions were also readily accomplished.

Pentacoordinate Phosphoranes as Versatile Reagents in Fluoroalkylation Reactions

A general method for the synthesis of bench-stable bis(difluoromethyl)pentacoordinate phosphoranes has been developed.The reaction is rapid,operationally simple,and easily scalable.The pentacoordinate phosphoranes can generate both difluoromethyl radical(·CF_(2)H)and difluorocarbene(:CF_(2))intermediates.Thus,a variety of fluoroalkylation transformations havebeen achieved by·CF_(2)H,such asoxidativedifluoromethylation of electron-deficient heterocycles,nickel/photoredox dual-catalyzed difluoromethylation of aryl bromides,and photoredox difluoromethylation of alkenes,or by:CF_(2),such as gem-difluorocyclopropanation of alkenes,base-promoted difluoromethylation of heteroatom nucleophiles,Pd-catalyzed difluoromethylation of arylboronic acids,and Cu-mediated trifluoromethylation of aryl iodides(via:CF_(2) and recombined CF_(3)-).These fluoroalkylation methods have been successfully applied to late-stage fluoroalkylation of drugs and drug-like molecules.

Selective O-difluoromethylation of 1,3-diones using S-(difluoromethyl) sulfonium salt

A facile and highly efficient approach for selective O-difluoromethylation of 1,3-diones by recently developed bench-stable S-(difluoromethyl)sulfonium salt was described.And a broad range of difluoromthyl enol ethers were readily accessed in good to excellent yields under mild reaction conditions.Mechanistic studies revealed that the O-difluoromethylation reaction proceeds mainly via a difluorocarbene pathway.

DBU-Promoted Trifluoromethylation of Aryl Iodides with Difluoromethyltriphenylphosphonium Bromide

DBU-promoted trifluoromethylation of aryl iodides with difluoromethyltriphenylphosphonium bromide （DFPB） in the presence of copper source is described. In this transformation, DBU not only acts as base to deprotonate the difluoromethyl group in DFPB to generate difluoromethylene phosphonium ylide Ph3P＋CF2 , but also converts the difluorocarbene generated from ylide Ph3P＋CF2- into trifiuoromethyl anion, finally resulting in the trifluoromethy- lation of aryl iodides. The reactions proceeded smoothly to afford expected products in moderate to good yields.

Cu-Promoted Oxidative Trifluoromethylation of Terminal Alkynes with Difluoromethylene Phosphobetaine

Difluoromethylene phosphobetaine(Ph_(3)P^(+)CF_(2)CO_(2)^(-),PDFA),a known difluorocarbene reagent,was found to be able to efficiently trifluoromethylate terminal alkynes in the presence of Cu(I)and potassium fluoride.The transformation proceeded smoothly to afford the corresponding trifluoromethylated acetylenes in moderate yields.

Copper induced single electron transfer trifluorbmethylation of organic halides with 3-oxo-ω-fluorosulfonylperfluoropentyl iodide

Treatment of ICF2CF2OCF2CF2SC2F (1) with organic halides in the presence of copper powder in a co-solvent DMF/HMPA( V/V= 1:1) gave the corresponding trifluoromethylated compounds in good to excellent yields. A copper induced single electron transfer reaction mechanism is proposed.

Mechanochemical Difluoromethylations of Alcohols

Difluoromethyl ethers are formed through mechanochemical reactions of alcohols with difluorocarbene in a mixer mill.The protocol could be applied to primary,secondary,and tertiary alcohols,yielding the corresponding products in excellent yields(up to 99%)after 1 h reaction time at room temperature.The transformations proceeded under solvent-free reaction conditions,followed by product purification by filtration,which drastically reduced the amount of waste generated during the process.

Ph_3P^+CF_2CO_2^- as an F^- and:CF_2 source for trifluoromethylthiolation of alkyl halides

As trifluoromethylthiolation has received increasing attention recently, many CF_3S-reagents and trifluoromethylthiolation methods have been developed. Herein we describe trifluoromethylthiolation of alkyl halides by using Ph_3 P^+CF_2CO_2 as a fluoride and difluorocarbene source. Difluorocarbene is a versatile intermediate, but its side reactions are usually ignored and the by-products would therefore be discarded. In this work, a side reaction of difluorocarbene, the generation of a fluoride anion from difluorocarbene, was developed into a synthetic tool. Although the trifluoromethylthiolation reaction involved multi-sequential steps, the cleavage of C-F bond, the formation of CF_2=S bond, F-C(S)F_2 bond,and C-SCF_3 bond, the conversion proceeded fast and was completed within 10 min.