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 difluor...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.展开更多
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-diflu...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.展开更多
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...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.展开更多
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...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.展开更多
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 p...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.展开更多
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 und...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.展开更多
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 T...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%).展开更多
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 ...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.展开更多
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 thiou...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.展开更多
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 th...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.展开更多
基金supported by the National Natural Science Foundation of China(92056201)Guangdong Basic and Applied Basic Research Foundation(2023A1515011008)Shenzhen Science and Technology Program(the Stable Support Plan Program 20220808130958001)。
文摘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.
基金The Nationa authors gratefully acknowledge the financial support from Natural Science Foundation of China (21625206, 21632009, 21372247, 21572258, 21572259, 21421002) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000) and the Syngenta Ph.D. Fellowship (Y. Gu and C. Lu).
文摘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.
基金supported by National Natural Science Foundation of China(grant no.21901196)the Natural Science Basic Research Plan in Shaanxi Province of China(grant nos.2020JQ-016 and 2021GXLH-Z-096)+1 种基金the Fundamental Research Funds for the Central Universities(grant no.xhj032021007-01)Xi’an Jiaotong University(grant no.71211920000001).
文摘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.
基金supported by the Science and Technology Foundation of Shenzhen, Shenzhen Science and Technology Innovation Committee (No. JCYJ20170818143001461)
文摘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.
基金research was made possible by the generous support of the Rhine-Westphalia Technical University of Aachen(RWTH Aachen University)We also acknowledge the Alexander von Humboldt Foundation for support of K.R.(AvH research award).
文摘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.
基金supported by the National Basic Research Program of China (2010CB126101)Shanghai Foundation of Science and Technology (09391911800)+1 种基金the National High Technology Research and Development Program of China (2006AA10A201)the Shanghai Leading Academic Discipline Project (B507)
文摘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.
基金The Shanghai Pujiang Program(No09PJ1400800)the Fundamental Research Funds for the Central Universities and the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry
文摘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%).
基金Financial support by the National Natural Science Foundation of China(grant no.21931013)and the Open Research Fund of the School of Chemistry and Chemical Engineering,Henan Normal University is gratefully acknowledged.The authors also thank the Instrumental Analysis Center of Huaqiao University for analysis support.
文摘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.
基金financial support provided by the NSFC(nos.22071057,21971065,and 21871089)STCSM(nos.20XD1421500,20JC1416800,and 18JC1415600)+1 种基金the Innovative Research Team of High-Level Local Universities in Shanghai(no.SSMU-ZLCX20180501)the Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning.
文摘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.
基金This research was made possible as a result of a generous grant from the National Natural Science Foundation of China(nos.21931013,21991122,21672238,and 21421002)the Strategic Priority Research Program of the Chinese Academy of Sciences(no.XDB20000000).
文摘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.
基金Project supported by the National Basic Research Program of China(973 Program,No.2015CB931903)the National Natural Science Foundation of China(Nos.21421002,21472222,21502214,21672242)the Chinese Academy of Sciences(Nos.XDA02020105,XDA02020106),and the Key Research Program of Frontier Sciences(CAS)(No.QYZDJSSW-SLH049)~~