General radical difluoromethylation using difluoroacetic anhydride via photoredox catalysis

CF_(2)H-containing molecules play pivotal roles in diverse fields from medicinal chemistry to materials science. However, the application of existing CF_(2)H reagents as a source of CF_(2)H radical is limited by their reactivity and preparation. Herein, we develop a simple and general visible-light-catalyzed radical difluoromethylation reaction of alkenes, dienes, and heteroaromatics using commercially available, easy-to-handle, and low-cost difluoroacetic anhydride as the CF_(2)H reagent. This scalable protocol enables the convenient synthesis of a range of CF_(2)H-containing compounds under mild conditions, exhibiting a broad substrate scope and functional group tolerance. Potential applications are further demonstrated by gram-scale synthesis, sunlight experiments, derivatization experiments as well as the synthesis of bioactive molecules.

Switching from 2-pyridination to difluoromethylation:ligand-enabled nickel-catalyzed reductive difluoromethylation of aryl iodides with difluoromethyl 2-pyridyl sulfone

The divergent reductive cross-coupling with an ambident electrophile is rare.Previously,we demonstrated a nickel-catalyzed reductive 2-pyridination of aryl iodides with difluoromethyl 2-pyridyl sulfone(2-Py SO_(2)CF_(2)H)via selective C(sp^(2))-S bond cleavage of the sulfone by using a phosphine ligand.In this communication,we report a novel nickel-catalyzed reductive coupling of aryl iodides and 2-Py SO_(2)CF_(2)H reagent,which constitutes a new method for aromatic difluoromethylation.The use of a tridentate terpyridine ligand is pivotal for the selective C(sp^(3))-S bond cleavage of the sulfone.This method employs readily available nickel catalyst and 2-Py SO_(2)CF_(2)H as the difluoromethylation reagent,providing a facile access to difluoromethylarenes under mild reaction conditions without pre-generation of arylmetal reagents.

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.

Nickel-Catalyzed Difluoromethylation of Arylboronic Acids with Bromodifluoromethane

Although bromodifluoromethane （BrCF2H） is a simple and readily available fluorine source, direct formation of difluoromethylated arenes with BrCF2H has not been reported. Herein, we describe an efficient method to access difluoromethylated arenes through a nickel-catalyzed difluoromethylation of arylboronic acids with BrCF2H. The reaction exhibits high efficiency, good functional group tolerance and broad substrate scope, thus providing an efficient route for applications in drug discovery and development. Preliminary mechanistic studies reveal that a difluoromethyl radical is involved in the reaction.

Difluoromethylation of 2-Hydroxychalcones Using Sodium 2-Chloro-2,2-difluoroacetate as Difluoromethylating Agent

Difluoromethylation of 2-hydroxychalcones using sodium 2-chloro-2,2-difluoroacetate as the difluoro- methylating agent was developed. Under facile conditions, a wide range of aryl difluoromethyl ethers were obtained in yields of 36%--80%. It is noteworthy that the new addition products, 2,2-difluoro-2H-benzofuran derivatives, were also synthesized in the reactions. The yield of 2,2-difluoro-2H-benzofuran derivative could be up to 35% when 3-methyl-2-hydroxychalcone was used as the reactant. A plausible reaction mechanism was proposed.

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.

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.

A bench-stable reagent for C-4 selective deuteriodifluoromethylation of azines

Deuteriodifluoromethyl(CF_(2)D)is a challenging and important functional group due to difficult deuterium incorporation and lack of effective precursor reagents.Herein,we report a bench-stable reagent,deuteriodifluoromethyl phosphine(DDFP)from cheap deuterium source for selectivity deuteriodifluoromethylation of azines with a high deuterium incorporation yield.The late-stage modification of complex molecules further confirmed the potential of this reagent for practical applications.We expect that our reagent to find applications in synthesis of isotope-labelled molecules of interests for drug-discovery and related ilucidation of mechanism of action.

Ligand-Controlled Copper-Catalyzed Highly Regioselective Difluoromethylation of Allylic Chlorides/Bromides and Propargyl Bromides

Highly regiodivergent copper-catalyzed allylic/propargylic difluoromethylation reactions by employing different ligands are described. When 5,6-dimethyl-1,10-phenanthroline was used as the ligand, exclusively α-difluoromethylated products were obtained, while γ-selective difluoromethylated products were generated when N-heterocyclic carbene-SIPr was used as the ligand. Likewise, high α- vs. γ-selectivities were achieved in the presence of similar copper catalysts for the reactions of propargyl bromides. Moreover, a copper-catalyzed asymmetric allylic difluoromethylation reaction with moderate to good enantioselectivity by the use of chiral ligands was developed.

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.

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.

Activation of Trifluoromethylthio Moiety by Appending Iodonium Ylide under Copper Catalysis for Electrophilic Trifluoromethylation Reaction

A novel iodonium-ylide compound 2 that appends a trifluoromethylthio （SCF3） group is disclosed as a new, shelf-stable electrophilic trifluoromethylation reagent. Unlike known shelf-stable electrophilic trifluoromethylation reagents, 2 has a stable SCF3 group which is activated by appending iodonium ylide under copper catalysis via sul- fonium ylide to generate a cationic trifluoromethyl （CF3） species. Reagent 2 was found to be an efficient electro- philic trifluoromethylation reagent for a wide range of silyl enol ethers 3 under copper catalysis. Cyclic and acyclic a-trifiuoromethyl ketones 4 were obtained by reagent 2 in moderate to good yields. On the other hand, a difluoro- methylthio analogue 5 did not affect intermolecular transfer difluoromethylation to substrates. Instead, intramolecu- lar 1,4-migration proceeded similar to the Stevens rearrangement to provide 6 in 21% yield, independent of the presence of nucleophiles 3.

Facile synthesis of α-difluoromethyl α-propargylamines from CF_2H-substituted N-tert-butanesulfinyl ketimines

Stereoselective approach for preparation ofα-difluoromethylα-propargylamines has been developed.1,2-Addition of lithium acetylides to diverse chiral difluoromethylated（S）-N-tert-butanesulfinyl ketimines by using Ti（O^iPr）_4 as catalyst and THF as solvent afforded N-tert-butanesulfinamides in good to excellent yields（51-93%） and good diastereoselectivities（dr.85：15 to 93：7）.The N-tert -butanesulfinyl group can be readily cleaved under mild acidic condition（4 mol/L HCl in dioxane） to provide the correspondingα-difiuoromethylα-propargylamine in excellent yields（90-95%）.

An efficient three-component domino synthesis of difluoromethyl-containing 1,4-dihydropyridines under solvent and catalyst free conditions

The difluoromethyl-containing Hantzsch 1,4-dihydropyridines were synthesized in good yields by a one-pot cyclocondensation of ethyl difluoroacetoacetate (EDFAA),a variety of aromatic aldehydes and ammonium acetate under solvent and catalyst free conditions.The comparison of reaction conditions and products was made among the different 1,3-carbonyl substrates (ethyl acetoacetate,ethyl difluoroacetoacetate and ethyl trifluoroacetoacetate) for the Hantzsch reaction.

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.

Full-Spectrum Fluoromethyl Sulfonation via Modularized Multicomponent Coupling

Modular free-assembly construction of mono-,di-,and tri-fluoromethyl sulfones was comprehensively achieved by a combination of halides,a sulfur dioxide surrogate,and halofluorocarbons.The industrial raw material thiourea dioxide served as the sulfur dioxide source,combined with readily available fluorocarbon sources such as 2-bromo-2-fluoroacetate and chlorodifluoromethane(ClCF_(2)H,Freon)employed as fluoromethyl reagents.Notably,four methyl sulfone-containing pharmaceuticals were modified into three types of fluoromethyl sulfones,displaying their great potential for drug discovery via the current strategy.Mechanistic studies further demonstrated that C-F…H-N interactions between thiourea dioxide and halofluorocarbons play a key role in stabilizing monofluoromethyl electrophiles and difluorocarbene species.

Chlorodifluoromethane triggered formation of difluoromethylated arenes catalyzed by palladium

Subject Code:B02With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zhang Xingang（张新刚）from the Institute of Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences demonstrates the first direct catalytic difluoromethylations from ClCF2H,

Photoexcitation of Dihydroquinazolinone Anionic Compounds:Difluoroalkylarylation and Difluoroalkylamination of Alkenes

The direct excitation of dihydroquinazolinone(DHQ)anions by visible light has been demonstrated by photophysical experiments.The excited-state DHQ anion serves as both a potent reductant and a radical precursor in a redox neutral radical cascade,circumventing the use of an external photoredox catalyst.Various gem-difluoroalkyl radicals(CF_(2)H and CF_(2)R)are produced from the excited-state DHQ anions,leading to the first example of intermolecular 1,2-difluoroalkylarylation(CF_(2)H-and CF_(2)R-arylation)of alkenes in overall redox-neutral manner.Similarly,1,2-difluoroalkylamination of styrenes has also been realized,offering a practical pathway for the preparation of diverseβ-CF_(2)H amines.This general and efficient strategy for the generation of CF_(2)H and CF_(2)R radicals exhibits great potential for applications in drug discovery.