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The difluoromethyl group (CF2H) is of great interest in the area of medicinal chemistry. However, the investigation of molecular scaffolds containing this group has been hampered by the limitation of synthetic methods for the introduction of CF2H into heteroarenes. Herein we disclose a new strategy for the direct introduction of a difluoromethyl group into heteroarenes via the copper-mediated C–H oxidative difluoromethylation of heteroarenes with TMSCF2H. This mild and regioselective method enables the convenient synthesis of a range of difluoromethylated heteroarenes in high yields. The usage of 9,10-phenanthrenequinone (PQ) as an oxidant is critical to the success of this new difluoromethylation reaction.

The direct synthesis of C(CF

The development of catalytic carboacylation of simple olefins, which would enable the rapid construction of ketones with high levels of complexity and diversity, is very challenging. To date, the vast majority of alkene carboacylation reactions are typically restricted to single- and two-component methodologies. Here we describe a three-component carboacylation of alkenes via the merger of radical chemistry with nickel catalysis. This reaction manifold utilizes a radical relay strategy involving radical addition to an alkene followed by alkyl radical capture by an acyl-nickel complex to forge two vicinal C−C bonds under mild conditions. Excellent chemoselectivity and regioselectivity have been achieved by utilizing a pendant weakly chelating group. This versatile protocol allows for facile access to a wide range of important β-fluoroalkyl ketones from simple starting materials., To date the carboacylation of alkenes has been reported only in single- and two-component methodologies. Here, the authors report a three-component nickel-catalyzed carboacylation of olefins which enables the rapid construction of ketones with high levels of complexity and diversity.

A mild and efficient method for the regioselective deoxygenative C H trifluoromethylthiolation of heteroaryl N-oxides with AgSCF3 is presented, employing p-toluenesulfonic anhydride and tetra-n-butylammonium iodide as the activators. This reaction delivers a series of C2-trifluoromethylthiolated heteroaromatic compounds in moderate to excellent yields. It provides a complementary method for C H trifluoromethylthiolation reactions.

Aryl trifluoromethyl ethers (ArOCF3 ) are prevalent in pharmaceuticals, agrochemicals, and materials. However, methods for the general and efficient synthesis of these compounds are extremely underdeveloped and limited. Herein, we describe a highly efficient and general procedure for the direct O-trifluoromethylation of unprotected phenols through a silver-mediated cross-coupling reaction using CF3 SiMe3 as the CF3 source and exogenous oxidants. This novel oxidative trifluoromethylation provides access to a wide range of aryl trifluoromethyl ethers from simple phenols. The mild process was also applied to the late-stage trifluoromethylation of a medicinally relevant compound.

A tunable chemoselective trifluoromethanesulfonylation and trifluoromethylation of arenediazonium tetrafluoroborates with Langlois' reagent (NaSO2CF3) was developed. The Cu2O-catalyzed reaction in DMSO gave aryl trifluoromethanesulfones as the major products. On the other hand, the trifluoromethylated arenes were produced in the presence of oxidant tert-butyl hydroperoxide, CuBF4(MeCN)4, and 2,2';6',2″-terpyridine (tpy). Both of these transformations proceed under mild conditions and tolerate functional groups.

A visible light-induced selective hydrobromodifluoromethylation of alkenes using CF2Br2 was developed. This transformation proceeded smoothly in the presence of catalytic eosin Y at room temperature to give various hydrobromodifluoromethylated compounds with broad functional group tolerance.

A copper-mediated oxidative difluoromethylation of terminal alkynes using nucleophilic TMSCF2H in the presence of an oxidant 9,10-phenanthraquinone was developed. This reaction provided a direct and efficient method for preparation of difluoromethylated alkynes.

An efficient asymmetric vinylogous Mannich (AVM) addition reaction of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines has been developed. This reaction provided various optical active α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles in excellent yields, complete γ-site ­regioselectivity, and excellent diastereoselectivities.

A copper-promoted Ritter-type trifluoroethoxylation of (hetero)arenediazonium tetrafluoroborates with TMSOCH2CF3 was developed. The resulting trifluoroethyl imidates are potentially valuable in organic synthesis and medicinal chemistry.

The bromodifluoromethylation of heteroaromatics (benzofuran, benzo[b]thiophene, and 2H-chromen-2-one) with sodium bromodifluoromethanesulfinate (BrCF2SO2Na) was developed. This reaction proceeded smoothly at room temperature to afford the bromodifluoromethylated products in moderate to high yields.

A novel copper-mediated oxidative trifluoromethylthiolation of quinones was developed. This protocol provided an efficient and practical approach to a series of trifluoromethylthiolated quinones.

A copper-catalyzed chemo- and stereoselective oxidative bis-trifluoromethylthiolation of propiolic acid derivatives was achieved by using carboxylic acid as the activating group and formic acid as a cosolvent. The reaction of propiolic acid derivatives and AgSCF

A new method for the efficient synthesis of alkynyl trifluoromethyl sulfides was developed. By combining AgSCF3 and NCS in N,N-dimethylacetamide, an electrophilic active intermediate was produced, which was then treated with a variety of terminal alkynes to afford the corresponding trifluoromethanesulfenylated products in moderate to excellent yields.

The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF3 group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon-CF3 bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF3 anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF3 cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants. In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF3SiMe3 in the presence of oxidants. We have focused most of our efforts on constructing carbon-CF3 bonds via direct trifluoromethylation of various C-H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C-H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C-H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or -catalyzed cross-coupling reactions with CF3SiMe3. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P-CF3 bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C-H bonds, and P-H bonds as novel nucleophiles in transition-metal-mediated or -catalyzed cross-coupling reactions with CF3SiMe3, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon-SCF3 bonds by using CF3SiMe3 and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF3- and CF3S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF3 and SCF3 moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields.

Aptamer–drug conjugates (ApDCs) are promising targeted drug delivery systems for reducing toxicity while increasing the efficacy of chemotherapy. However, current ApDC technologies suffer from problems caused by the complicated preparation and low controllability of drug–aptamer conjugation. To solve such problems, we have designed and synthesized a therapeutic module for solid phase synthesis, which is a phosphoramdite containing an anticancer drug moiety and a photocleavable linker. Using this module, we have realized automated and modular synthesis of ApDCs, and multiple drugs were efficiently incorporated into ApDCs at predesigned positions. The ApDCs not only recognize target cancer cells specifically, but also release drugs in a photocontrollable manner. We demonstrated the potential of automated and modular ApDC technology for applications in targeted cancer therapy.

The unexpected direct C—H triflylation of styrenes (I) with sodium triflinate (II) affording title compounds (III) is reported.

Visible light-induced monofluoromethylenation of benzofurans and benzothiophenes with ethyl bromofluoroacetate was developed. This method provided a convenient access to novel α-fluoro-α-heteroarylesters under mild reaction conditions.

A visble-light-induced hydroaryldifluoromethylation of alkenes with α,α-difluoroarylacetic acids for preparation of difluoroalkylated arenes has been developed. This reaction proceeds through the hypervalent iodine reagent promoted decarboxylation and subsequent radical hydroaryldifluoromethylation.

It is highly desirable, although very challenging, to develop self-healable materials exhibiting both high efficiency in self-healing and excellent mechanical properties at ambient conditions. Herein, a novel Cu(II)-dimethylglyoxime-urethane-complex-based polyurethane elastomer (Cu-DOU-CPU) with synergetic triple dynamic bonds is developed. Cu-DOU-CPU demonstrates the highest reported mechanical performance for self-healing elastomers at room temperature, with a tensile strength and toughness up to 14.8 MPa and 87.0 MJ m-3 , respectively. Meanwhile, the Cu-DOU-CPU spontaneously self-heals at room temperature with an instant recovered tensile strength of 1.84 MPa and a continuously increased strength up to 13.8 MPa, surpassing the original strength of all other counterparts. Density functional theory calculations reveal that the coordination of Cu(II) plays a critical role in accelerating the reversible dissociation of dimethylglyoxime-urethane, which is important to the excellent performance of the self-healing elastomer. Application of this technology is demonstrated by a self-healable and stretchable circuit constructed from Cu-DOU-CPU.

An efficient method for the construction of chiral gamma-trifluoromethylated alpha,beta-unsaturated delta-lactone, a widely existing pharmacophore, has been developed and successfully applied for synthesis of gamma-trifluoromethylated goniothalamins. The

A palladium-catalyzed anti-Markovnikov hydroalkylation of β,β-difluorinated homoallylic alcohols with alkylzinc reagents has been developed. This method affords a wide range of synthetically useful gem-difluorinated compounds with good functional group compatibility.

Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes with three (EH3I), two (EH2I), one (EHI), or no protons (EI), are possible. In the present work an analysis method is presented that from pH-inhibition data allows one to distinguish between the different complexes and determine which protonation state is preferred. It is also possible to determine the pH-independent binding constants of the inhibitor. Analysis of pH data for imino- and azasugar inhibition of β-glucosidases revealed that basic glycosidase inhibitors bind as the monoprotonated (EHI) complex. Three neutral inhibitors were also studied and two of these were also bound exclusively as the EHI complex while a third bound both as a EHI and a EH2I complex.

A mild and versatile approach for the direct introduction of ethoxycarbonyldifluoromethyl-group to heteroarenes via visible-light photocatalysis has been developed. The new photoredox protocol has enabled the difluoromethylenation of heteroarenes containi

A convenient and practical method for the asymmetric synthesis of trifluoromethylated aziridines was developed. The reactions of sulfur ylide with (S)-N-tert-butanesulfinyl ketimines gave trifluoromethylated aziridines 3 in moderate to excellent yields (4

A series of novel ,-difluorinated Goniothalamin analogues 4a-4i and 6a-6i were synthesized. The key steps included the construction of C-5 stereocenter adjacent to gem-difluoromethylene group by way of lipase AK catalyzed kinetic resolution, the introduct

For the first time the title reaction is presented providing a wide range of trifluoromethylated alkanes.

A Pd-catalyzed Overman rearrangement of α-fluoroalkylated allylic trichloroacetimidates has been developed. This reaction allows for an efficient synthesis of γ-fluoroalkylated allylic amine derivatives with excellent regio- and stereo-selectivities under mild conditions.

The palladium-catalyzed direct α-arylations of α,α-difluoroketones with diverse aryl bromides have been developed by using rac -BINAP as ligand and Cs 2 CO 3 as a mild base in xylene. This method provides an efficient and straightforward access to a variety of α-aryl-α,α-difluoroketones with broad substrate scope.

A new application of trifluoromethylating reagent, methyl fluorosulfonyldifluoroacetate (FO

The reaction of diaryliodonium salts with difluoromethyltriflate in the presence of TBAT and CuTC gave the corresponding trifluoromethylated arenes in moderate yields. Compared to other difluorocarbene-derived trifluoromethylation reactions, the current one proceeded at mild reaction conditions (room temperature) within short reaction time (5 min).

The bromodifluoromethylation of heteroaromatics (benzofuran, benzo[b]thiophene, and 2H-chromen-2-one) with sodium bromodifluoromethanesulfinate (BrCF2SO2Na) was developed. This reaction proceeded smoothly at room temperature to afford the bromodifluoromethylated products in moderate to high yields.

An iron-mediated three-component chlorotrifluoromethylation of both styrenes and aliphatic alkenes has been presented here. This reaction employs ferric chloride (FeCl3) as the Cl source and the Langlois reagent (CF3SO2Na) as the CF3 source. It provides a convenient pathway towards a wide range of chlorotrifluoromethylated compounds.

Under visible-light photoredox conditions, difluoromethyltriphenylphosphonium bromide was used as the precursor of the CF2H radical for bromodifluoromethylation of alkenes. The presence of catalytic CuBr2 resulted in the selective formation of the bromodifluoromethylated products.

A tunable decarboxylative trifluoromethylthiolation of cinnamic acids with AgSCF3 was developed to afford trifluoromethylthiolated alkenes or ketones by using transition metal-mediated conditions.

An unexpected regioselective synthesis of vinyl triflones was developed. This iodine-mediated C–H triflylation of styrenes with CF3SO2Na occurred at room temperature affording various vinyl triflones, which could be used for the preparation of other CF3SO2-containing compounds.

A new synthetic method of trifluoromethylated phosphonates was developed via electrophilic trifluoromethylation with Togni reagent. A variety of β-keto phosphonates were converted into the corresponding α-trifluoromethyl-β-keto phosphonates in moderate to good yields. This protocol could also be extended to other fluoroalkylation reactions, such as pentafluoroethylation.

Bromodifluoromethylphosphonium bromide was solely used as the precursor of difluorocarbene. Herein, an unprecedented visible-light-induced hydrodifluoromethylation of alkenes with bromodifluoromethylphosphonium bromide using H2O and THF as hydrogen sources for the synthesis of difluoromethylated alkanes is described. This difluoromethylation is characterized by mild reaction conditions, ready availability of reagents, and excellent functional-group tolerance.

The title reaction provides an efficient access to novel trifluoromethylthiolated quinones.

The development of an efficient and practical method for the preparation of alkyl trifluoromethyl ethers is urgently demanding. The silver-mediated oxidative O-trifluoromethylation of primary, secondary, and tertiary alcohols with TMSCF3 under mild reaction conditions is established to provide a novel approach to a broad range of alkyl trifluoromethyl ethers. Further, this method is applied to the late-stage O-trifluoromethylation of complex natural products and prescribed pharmaceutical agents.

Ag(I)-mediated conversion of structurally diverse phenols to their CF3-ethers is achieved using CF3-SiMe3 as commercially available CF3-nucleophile.

A one-pot nickel-catalyzed allylation of aromatic aldehydes with α-halo-β,β-difluoropropene-containing compounds promoted by ZnEt(2) under mild conditions was described. The reaction displays moderate to good regio- and diastereoselectivity, tolerates a wide range of functional groups, and provides an efficient method for the synthesis of γ-fluorinated homoallylic alcohols.

A method for the preparation of chiral β-aryl-β-trifluoromethyl-β-aminoarones has been developed involving the Mannich-type reactions of ketone-derivative enolates with chiral aryl CF3-substituted N-tert-butanesulfinyl ketimines. This method tolerates a wide of aromatic ketones, giving the products in moderate to excellent yields (up to 91%) with good diastereoselectiveties (up to 93:7 dr). Acidic cleavage of the tert-butanesulfinyl group gave optically pure β-aryl-β-trifluoromethyl-β-aminoarones in excellent yields (up to 98%), which can be further transformed into CF3-substituted aziridine derivatives.

A copper-mediated oxidative cross-coupling reaction of terminal alkynes with readily available α-silyldifluoromethylphosphonates under mild conditions has been developed. This method allows for an efficient synthesis of a series of synthetically useful α,α-difluoropropargylphosphonates with excellent functional group compatibility.