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The three-starting materials four-component reaction of (trifluoromethyl)alkenes, TBHP, and boronic acids is reported, delivering various useful α-trifluoromethyl-β-aryloxy tertiary alcohols in high yields and in an exclusively regioselective hydroetherification manner. TBHP serves as both the oxidant and nucleophile in this reaction, as well as the O-source of the products.

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.

Chiral sulfones, especially those compounds whose sulfone groups are directly connected to the chiral centers, are privileged building blocks in many natural products and bioactive compounds. Thus, the development of novel and efficient methods for the synthesis of these chiral sulfones becomes more important. This review focuses on the recent development of the strategies for the asymmetric synthesis of these compounds, including (1) nucleophilic substitution, (2) hydrosulfonation, (3) cross-coupling reaction, (4) dynamic kinetic resolution, (5) hydrogenation, (6) β-elimination, (7) [3 + 2] cycloaddition, (8) conjugate addition, (9) oxidation of chiral thioethers, and (10) other reactions. The typical reactions, the substrate scope, the reaction mechanism, and their applications in the synthesis of bioactive compounds will be discussed. Given the rapidly increasing interest in this topic, we believe that this review will present a timely and comprehensive understanding of the recent progress in the synthesis of chiral sulfones with sulfone moieties directly connected to the stereocenters.

The enantioselective Mannich reaction of 2H-azirines with alkynyl ketones is achieved under Zn-ProPhenol catalysis, delivering various aziridines with vicinal tetrasubstituted stereocenters in high...

The three component hydroxyletherification and hydroxylazidation reactions of (trifluoromethyl)alkenes are reported, providing various useful α-trifluoromethyl β-heteroatom substituted tertiary alcohols in high yields. The ipso-defluorooxylation of (trifluoromethyl)alkenes with oximes is completely inhibited. A pesticidal active compound could be synthesized with our method.

The first defluorinative ipso-functionalization reaction of (trifluoromethyl)alkenes is reported. This exclusively regioselective ipso-defluorooxylation of (trifluoromethyl)alkenes with oximes affords various attractive O-(1,1-difluoroallyl)oxime ethers efficiently via a chemoselective single C(sp3)-F bond activation in the CF3 group. Primary mechanism studies indicated an anionic SN2-type substitution pathway might be involved in this transformation.

A novel and efficient strategy for the transformation of trifluoromethyl ketones is reported. The selective C(α)–C(β) bond cleavage of trifluoromethyl ketones is realized with amidines under air. This transition-metal free reaction system employs green molecular oxygen as an oxidant as well as an O-source, delivering various useful 5-trifluoromethylated imidazol-4-ones in high yields. Preliminary mechanism studies indicate that this reaction proceeds through a 1,2-aryl migration pathway rather than a radical mechanism.

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 enantiosele...

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.

A general and practical strategy for 3-trifluoromethylpyrazole synthesis is reported that occurs by the three-component coupling of environmentally friendly and large-tonnage industrial feedstock 2-bromo-3,3,3-trifluoropropene (BTP), aldehydes, and sulfonyl hydrazides. This highly regioselective three-component reaction is metal-free, catalyst-free, and operationally simple and features mild conditions, a broad substrate scope, high yields, and valuable functional group tolerance. Remarkably, the reactions could be performed on a 100 mmol scale and smoothly afforded the key intermediates for the synthesis of celecoxib, mavacoxib, SC-560, and AS-136A. Preliminary mechanism studies indicated that a 1,3-hydrogen atom transfer process was involved in this transformation.

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.

An azide-free strategy for the synthesis of N-2-aryl-1,2,3-triazoles via copper-catalyzed coupling of oxime acetates and aryldiazonium tetrafluoroborates is reported. With the magic p-methoxyphenyldiazonium tetrafluoroborate as the reaction partner, this copper-catalyzed system favored the desired single electron transfer process via N–O bond cleavage of oxime acetates, while the classic single electron transfer process via C–N2 bond cleavage of aryldiazonium tetrafluoroborates was sufficiently inhibited. Significantly, various oxime acetates were suitable for this reaction, delivering the corresponding 4-substituted-N-2-aryl-1,2,3-triazoles and 4,5-disubstituted-N-2-aryl-1,2,3-triazoles in high yield. Primary mechanism studies indicated that this reaction involved a radical procedure. Furthermore, various novel and attractive tetraphenylethylene and carbazole based N-2-aryl-1,2,3-triazoles were synthesized smoothly.

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.

A domino carbopalladation reaction of haloalkynes is presented. Remarkably, the four-time carbopalladation process converts the carbon-carbon triple bonds of haloalkynes stepwise into carbon-carbon double bonds, and finally to carbon-carbon single bonds. Features of this reaction are that the carbon-carbon double bonds of stable vinyl palladium intermediates are transformed into carbon-carbon single bonds with the generation of unstable alkyl palladium intermediates. The subsequently formed π-allylpalladium species are independently trapped by N-tosylhydrazones, boronic acids, and B2 pin2 in a highly diastereoselective manner, delivering the corresponding polycyclic and twisted products with a bicyclo[3.2.1]oct-2-en-3-yl)tricyclo[3.2.1.02,4 ]octane core skeleton in moderate to good yields via C-C and C-B bond formations. Significantly, the dual roles of norbornenes, ring construction and ring expansion, and the identification of electron-rich tri(2-furyl)phosphine as the ligand are found to be critical for the success of these transformations.

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 Aβ42 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.

The first example for the generation of carbonyl ylides from palladium carbenes is reported. Systematic investigation of the substituents attached to the carbonyl group indicates that the employment of trifluoromethyl group as the substituent is very critical for the success of this transformation. The remarkable fluorine effect on thereactivity is very impressive, which allows to the construction of various trifluoromethylated oxiranes in high yields and diastereoselectivities.

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.

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.

A regio- and stereoselective method for the preparation of (Z)-vinyl thiocyanate derivatives by silver-catalyzed thiocyanation of haloalkynes is reported. This method features practical, free of ligand, broad substrate scope, excellent stereoselectivity and gram-scale synthesis. Significantly, the halogen atom of haloalkynes is retained, which allows the synthesis of 2,5-diphenylthiophene, thiazol-2-amine and trifluoromethyl sulfides derivatives via simple transformation.

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.

A new example of CN double bond formation in metal carbene insertion reactions is reported. Remarkably, the general 1,2-migration process of the corresponding ylide intermediates in X–H carbene insertion reactions that leads to C–X single bond formation is completely inhibited by replacing the H atom with a nitrogen atom. This palladium-catalyzed carbene insertion reaction with NN double bonds gave various N,N-disubstituted hydrazone products in high yields.

The first example of the epoxidation reaction of trifluoromethylketones with N-tosylhydrazones under transition-metal free conditions is reported. This epoxidation reaction provided tetrasubstituted trifluoromethylated oxiranes with excellent yields and diastereoselectivities. The salient features of this reaction include readily available starting materials, mild conditions, broad substrate scope, high efficiency, and valuable further applications. Remarkably, this reaction proceeded through an unprecedented nucleophilic addition process, and the ammonium O-anion intermediate was detected and characterized by NMR and HRMS analysis.

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.

Cyclopropanation of 2-aminoacrylates with N-tosylhydrazones could proceed smoothly under transition-metal-free conditions via a [3 + 2] cycloaddition process. This robust protocol exhibits excellent generality, delivering a wide spectrum of cyclopropane α-amino acid esters bearing contiguous quaternary carbon centers in high yields and diastereoselectivities. With these readily available products, the steric convergence of cyclopropane α-amino acids could be readily obtained.

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.

A novel and efficient method for the formation of two C–O bonds on a carbenic carbon is reported. This palladium-catalyzed coupling of N-tosylhydrazones and benzo-1,2-quinones were involved the process of carbonyl ylides generation, aromatization, and intramolecular nucleophilic addition, delivering various useful benzodioxoles in high yields.

The first example of the palladium-catalyzed primary amine-directed C(sp2)–H alkynylation of biaryl-2-amines has been developed by using (bromoethynyl)triisopropylsilane as an alkynylating reagent. This protocol exhibits a broad substrate scope, excellent regioselectivity and gram-scale synthesis. Significantly, the versatility of this straightforward method was further demonstrated by controlled mono- and di-alkynylation.

An efficient and robust protocol for the preparation of 3-substituted isocoumarins via palladium-catalyzed nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids has been developed. Remarkably, preliminary mechanistic studies indicated that the transformation might proceed via a stereo- and regioselective nucleophilic addition and C–H functionalization procedure.

A palladium-catalyzed fluoroalkylative cyclization of olefins with readily available Rf–I reagents to afford the corresponding fluoroalkylated 2,3-dihydrobenzofuran and indolin derivatives with moderate to excellent yields is reported. This novel procedure provides an efficient method for the construction of Csp3–CF2 and C–O/N bonds in one step. A wide range of functional groups are tolerated. It is proposed that a radical/SET (single electron transfer) pathway proceeding via the fluoroalkyl radical may be involved in the catalytic cycle.

Under copper-catalyzed or base-promoted conditions, a wide range of ene-yne-ketones react with H-phosphonates to afford various phosphorylated furans in good yields. A copper carbene generation or a Michael addition is proposed as the key step in the selective construction of the Csp(3)-P or Csp(2)-P bond, which is supported by carbene capture reactions and interval (31)P NMR experiments. Furthermore, this method features inexpensive metal catalysts, no usage of oxidant, and high atom economy, which make it attractive and practical.