Defluorinative Esterification and 1,3-Dietherification of (Trifluoromethyl)alkenes with Alcohols: Controlled Synthesis of α-Arylacrylates and 1,3-Diethers.

Purification-controlled defluorinative esterification and 1,3-dietherification of (trifluoromethyl)alkenes with alcohols are achieved, delivering various useful α-arylacrylates and 1,3-diethers in high yields. Remarkably, this reaction enables the cleavage of three C-F bonds in a CF3 group, and it is transition-metal free and catalyst-free, has simple operation, features mild conditions, is gram-scalable, and has broad substrate scope and valuable functional group tolerance. Mechanism studies indicated that the isolated monofluoroalkene-decorated 1,3-diethers are the intermediates, and the acidic property of silica gel assisted the defluorinative transformation of these 1,3-diethers to access α-arylacrylates with H2O as the oxygen source.

Access to α,α-difluoro(arylthio)methyl oxetanes from α,α-difluoro(arylthio)methyl ketones and trimethylsulfoxonium halides: scope, mechanism and applications.

A general and practical method for the synthesis of α,α-difluoro(arylthio)methyl oxetanes that occurs by the reaction of α,α-difluoro(arylthio)methyl ketones with trimethylsulfoxonium halides is reported. This reaction proceeds via the sequential Corey-Chaykovsky epoxidation and regioselective ring-expansion pathways and features mild conditions, operational simplicity, gram-scalability, a broad substrate scope and high yields. α,α-Difluoro(arylthio)methyl oxiranes have been shown to be the reaction intermediates. The obtained α,α-difluoro(arylthio)methyl oxetanes were further converted into useful sulfone, butenolide, and tetrahydrofuran derivatives.

Regioselective Synthesis of 5-Trifluoromethylpyrazoles by [3 + 2] Cycloaddition of Nitrile Imines and 2-Bromo-3,3,3-trifluoropropene.

A general and practical method for the synthesis of 5-trifluoromethylpyrazoles is reported that occurs by the coupling of hydrazonyl chlorides with environmentally friendly and large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropropene (BTP). This exclusively regioselective [3 + 2] cycloaddition of nitrile imines and with BTP is catalyst-free and operationally simple and features mild conditions, high yields, gram-scalable, a broad substrate scope, and valuable functional group tolerance. Significantly, our method has been applied for the synthesis of the key intermediate of an active agonist of sphingosine 1-phosphate receptor.

Solvent-Switched Oxidation Selectivities with O2 : Controlled Synthesis of α-Difluoro(thio)methylated Alcohols and Ketones.

The solvent-switched hydroxylation and oxygenation of α-difluoro(thio)methylated carbanions with molecular oxygen under mild conditions are reported. This strategy tames the redox reactions of the in situ generated hydroperoxy difluoromethylsulfides, in which solvent-bonding can alter their reactivity and switch the oxidation selectivities. These controllable three-component reactions of gem-difluoroalkenes, thiols and molecular oxygen afford various useful α-difluoro(thio)methylated alcohols and ketones in high yields. Significantly, this protocol has been applied in the synthesis different bioactive molecules. Mechanism studies enable the detection of the hydroperoxy difluoromethylsulfide intermediates and exclude the thiol-based radical pathway.

Fluorohalogenation of gem-Difluoroalkenes: Synthesis and Applications of α-Trifluoromethyl Halides.

A novel strategy for 1,2-dihalogenation of alkenes is reported that occurs through a sequential nucleophilic halide addition and electrophilic halogenation. By trapping the in situ generated unstable α-trifluoromethyl carbanion intermediates derived from the nucleophilic fluoride addition to electron-poor gem-difluoroalkenes, this fluorohalogenation of gem-difluoroalkenes with electrophilic haloalkynes affords various useful α-trifluoromethyl halides in high yields. A pesticidal active compound and various attractive trifluromethylated molecules could be smoothly synthesized from these obtained α-trifluoromethyl halides.

Copper-Catalyzed Unstrained C-C Single Bond Cleavage of Acyclic Oxime Acetates Using Air: An Internal Oxidant-Triggered Strategy toward Nitriles and Ketones.

A copper-catalyzed aerobic oxidative C-C single bond cleavage of acyclic unstrained oxime acetates is reported, providing various aryl nitriles and ketones in good yields. Mechanistic studies indicate a radical procedure is involved in this transformation, and the oxygen atom in the ketone products is originated from O2 in the air. Oxime acetates as an internal oxidant have been proved to be an initiator, which may promote the discovery of novel protocol for C-C bond cleavage and dioxygen activation.

Nucleophilic trifluoromethylthiolation of bromoalkynones with AgSCF3: C(sp)-SCF3 bond formation towards ynonyl trifluoromethyl sulfides.

An AgSCF3 mediated nucleophilic trifluoromethylthiolation reaction for C(sp)-SCF3 bond formation is reported. This nucleophilic trifluoromethylthiolation reaction of bromoalkynones afforded various useful ynonyl trifluoromethyl sulfides in high yields. Interestingly, the over-addition of AgSCF3 is avoided in our approach.

Intermolecular C(sp3 )-H Amination Promoted by Internal Oxidants: Synthesis of Trifluoroacetylated Hydrazones.

An intermolecular C(sp3 )-H amination reaction is reported that is promoted by internal oxidants and occurs via a C=N bond formation step. This intermolecular C(sp3 )-H amination reaction of trifluoromethyl ketones and aryldiazonium tetrafluoroborates affords various valuable trifluoroacetylated hydrazones in high yields with excellent E/Z selectivities. The salient features of this reaction type is that it is free of metal, catalyst, directing groups, and azides, and that it can be carried out under mild conditions, is operationally simple and efficient, gram-scalable, and it tolerates various functional groups. Remarkably, an ectoparasites-controlling agent was smoothly synthesized on a gram scale using our method. Aryldiazonium tetrafluoroborates served as the aminating reagents as well as an internal oxidant.

Transition-Metal-Free [3+2] Cycloaddition of Dehydroaminophosphonates and N-Tosylhydrazones: Access to Aminocyclopropanephosphonates with Adjacent Quaternary-Tetrasubstituted Carbon Centers.

A novel one-step strategy for the synthesis of aminocyclopropanephosphonates containing adjacent quaternary-tetrasubstituted carbon centers under transition-metal-free catalysis via [3+2] cycloaddition process has been developed. A series of aminocyclopropanephosphonates with adjacent quaternary-tetrasubstituted carbon centers including spirocyclopropyl adducts were obtained in moderate to excellent yields under mild reaction conditions. This protocol would find the potential applications in biochemistry and medicinal chemistry.

Copper-Catalyzed Cyanation of N-Tosylhydrazones with Thiocyanate Salt as the "CN" Source.

A novel protocol for the synthesis of α-aryl nitriles has been successfully achieved via a copper-catalyzed cyanation of N-tosylhydrazones employing thiocyanate as the source of cyanide. The features of this method include a convenient operation, readily available substrates, low-toxicity thiocyanate salts, and a broad substrate scope.

Synthesis of Polysubstituted 3-Amino Pyrroles via Palladium-Catalyzed Multicomponent Reaction.

A novel approach for the synthesis of polysubstituted 3-amino pyrroles via palladium-catalyzed three-component tandem reaction was developed. The procedure constructs various polysubstituted 3-amino pyrroles with moderate to excellent yields under mild reaction conditions with assembly efficiency, readily available starting materials, and good functional group tolerance. Furthermore, this process was successfully applied to the synthesis of different 3-phenyl-1,4-dihydropyrrolo[3,2-b]indole derivatives via an intramolecular Buchwald-Hartwig cross-coupling reaction in two steps.

Synthesis of 3-azabicyclo[3.1.0]hexane derivatives via palladium-catalyzed cyclopropanation of maleimides with N-tosylhydrazones: practical and facile access to CP-866,087.

A palladium-catalyzed cyclopropanation of internal alkenes with N-tosylhydrazones is presented. This gram-scale cyclopropanation reaction of maleimides provides a wide spectrum of 3-azabicyclo[3.1.0]hexane derivatives in high yields and diastereoselectivities. The major diastereoisomers could be easily isolated by chromatography on silica gel. This protocol provides a practical route to the mu opioid receptor antagonist CP-866,087.

Copper-Catalyzed C(sp3 )-H/C(sp3 )-H Cross-Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2-Trifluoromethyl-Substituted Dihydropyrrol-2-ols.

The first oxidative C(sp3 )-H/C(sp3 )-H cross-dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper-catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2-trifluoromethyldihydropyrrol-2-ol derivatives in a highly diastereoselective manner by cascade C(sp3 )-C(sp3 ) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aß42 lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.

Copper-Mediated [3 + 2] Oxidative Cyclization Reaction of N-Tosylhydrazones and ß-Ketoesters: Synthesis of 2,3,5-Trisubstituted Furans.

The first attempt at utilizing N-tosylhydrazones as two-carbon synthons has been successfully achieved, which underwent a copper-mediated [3 + 2] oxidative cyclization reaction to afford 2,3,5-trisubstituted furans in moderate to good yields. The features of this method include inexpensive metal catalyst, readily available substrates, high regioselectivity, and convenient operation. The studies provide important approaches for further exploration of the powerful and diverse reaction abilities of N-tosylhydrazones.

Modular Synthesis of α-Aryl Acrylamido Carboxylic Acids by Triple C-F Bond Cleavage of (Trifluoromethyl)alkenes with Unprotected Amino Acids.

A straightforward and efficient strategy for the construction of tertiary and secondary α-aryl acrylamido carboxylic acids is reported. This N-acrylation protocol of unprotected amino acids is achieved by triple C-F bond cleavage of (trifluoromethyl)alkenes. This method features mild conditions, is operationally simple, is free of transition metals and racemization, can be used on a gram scale, and is compatible with various functional moieties. Mechanistic studies indicate that oxygen atom exchange happens among H2O, NaOH, and amino acids, and the oxygen atom of the amide moiety of the product is incorporated by the ipso-defluorooxylation of (trifluoromethyl)alkene.

Chemoselective Thioacylation of Amines Enabled by Synergistic Defluorinative Coupling.

A mild and chemoselective method for the thioacylation of amines, including amino acids and peptides, using gem-difluoroalkenes and sulfide, is reported. The distinguishing of the different nucleophilic sites (S-site and diverse N-sites) by the chemoselective C-F bond functionalization of gem-difluoroalkenes enables the unique synergistic defluorinative coupling reaction. This reaction features mild conditions, is operationally simple, efficient, and gram-scalable, tolerates various functional groups, and is activator-free and without racemization. Thioamide moieties were incorporated site-specifically into bioactive compounds. The proposed mechanism is illustrated by a DFT calculation.

Triple ipso-defluoroetherification of (trifluoromethyl)alkenes with fluoroalkylated alcohols: access to fluoroalkylated orthoesters via C(sp3)-F bond cleavage.

The triple ipso-defluoroetherification of (trifluoromethyl)alkenes with fluoroalkylated alcohols by C(sp3)-F bond cleavage is reported, delivering various fluoroalkylated orthoesters in high yields. This reaction is transition-metal free and gram-scalable, features mild reaction conditions, and tolerates diverse functional groups.

Fluoroolefins-Mediated Deoxygenative Substitution of Alcohols: Chemo- and Enantiospecific Construction of C-S, C-N, C-O, and C-Se Bonds.

For over half a century, by activation of alcohols with activators, deoxygenative substitution of alcohols has been limited to employing nucleophiles with a single nucleophilic site. Herein, we demonstrate a fluoroolefin-mediated deoxygenative substitution of nonactivated and activated alcohols with diverse acidic nucleophiles, with inversion of configuration, to allow chemo- and enantiospecific construction of C-S, C-N, C-O, and C-Se bonds by the distinction of the different nucleophilic sites of the nucleophiles. The formed O-tethered monofluoroalkene was the intermediate.

α-Trifluoromethyl Carbanion-catalyzed Intermolecular Stetter Reaction of Aromatic Aldehydes with 2-Bromo-3,3,3-trifluoropropene: Synthesis of ß-Alkoxyl-ß-trifluoromethylated Ketones.

The intermolecular Stetter reaction of aromatic aldehydes with 2-bromo-3,3,3-trifluoropropene is achieved by the in situ generated α-trifluoromethyl carbanion catalyst. It not only represents the first example for α-trifluoromethyl carbanion-catalyzed umpolung reaction but also reveals a new protocol for the umpolung of aldehydes. Various useful ß-alkoxyl-ß-trifluoromethylated ketones were obtained in high yields, which could further convert to attractive bioactive compounds. Mechanism studies indicated an intramolecular 1,4-shift of the hydrogen atom was involved in this reaction.

Pd-Catalyzed Regio-, Diastereo-, and Enantioselective [3 + 2] Cycloaddition Reactions: Access to Chiral Cyclopentyl Sulfones.

The palladium-catalyzed [3 + 2] cycloaddition using in situ generated sulfone-TMM species to construct various chiral cyclopentyl sulfones in a highly regio-, diastereo- (dr >15:1), and enantioselective (up to 99% ee) manner is reported. The present strategy can tolerate different types of sulfone-TMM donors and acceptors, and enables the construction of three chiral centers in a single step, specifically with a chiral center bearing the sulfone moiety. The robust chiral diamidophosphite ligand is the key to the reactivity and selectivities of this transformation.