Copper-catalyzed Coupling Research Articles

Photochemical Synthesis of Acyl Fluorides Using Copper-Catalyzed Fluorocarbonylation of Alkyl Iodides.

Acyl fluorides are important reagents due to their unique balance between reactivity and stability. Here, we report a copper-catalyzed carbonylative coupling strategy for synthesizing acyl fluorides under photoirradiation. Alkyl iodides were transformed in high yields into acyl fluorides by using a commercially available copper precatalyst (CuBr·SMe2) and a readily available fluoride salt (KF) at ambient temperature and mild CO pressure (6 atm) under blue light irradiation.

Heterocycle compounds synthesized by amide ligand-promoted copper salt catalyzed construction of C-O(S) bonds.

We introduce a mild method for the ligand-promoted copper-catalyzed coupling of 2-halophenol to construct DBDO using cost-effective copper salts, ligands, and alkaline reagents. This method cleverly makes 2-bromophenol complete the Ullman reaction twice, achieves efficient C-O(S) bond coupling and intermolecular cyclization, and yields high amounts of oxygen(sulfur)-containing six-membered ring products. Less reactive 2-chlorophenol was also applied in this catalytic system. The application range of the copper-amide catalytic system was further expanded. Moreover, the success of a gram-scale reaction demonstrated that this operationally simple process is scalable.

Divergent Bimetallic Mechanisms in Copper(II)-Mediated C-C, N-N, and O-O Oxidative Coupling Reactions.

Copper-catalyzed aerobic oxidative coupling of diaryl imines provides a route for conversion of ammonia to hydrazine. The present study uses experimental and density functional theory computational methods to investigate the mechanism of N-N bond formation, and the data support a mechanism involving bimolecular coupling of Cu-coordinated iminyl radicals. Computational analysis is extended to CuII-mediated C-C, N-N, and O-O coupling reactions involved in the formation of cyanogen (NC-CN) from HCN, 1,3-butadiyne from ethyne (i.e., Glaser coupling), hydrazine from ammonia, and hydrogen peroxide from water. The results reveal two different mechanistic pathways. Heteroatom ligands with an uncoordinated lone pair (iminyl, NH2, OH) undergo charge transfer to CuII, generating ligand-centered radicals that undergo facile bimolecular radical-radical coupling. Ligands lacking a lone pair (CN and CCH) form bridged binuclear diamond-core structures that undergo C-C coupling. This mechanistic bifurcation is rationalized by analysis of spin densities in key intermediates and transition states, as well as multiconfigurational calculations. Radical-radical coupling is especially favorable for N-N coupling owing to energetically favorable charge transfer in the intermediate and thermodynamically favorable product formation.

Copper-catalyzed room-temperature cross-dehydrogenative coupling of secondary amides with terminal alkynes: a chemoselective synthesis of ynamides.

A copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction between secondary amides and terminal alkynes has been developed. With the aid of ligands and 3 Å molecular sieves, ynamides can be efficiently synthesized at room temperature and conveniently scaled up. A legitimate mechanism involving nitrogen-centred radicals and copper trivalent intermediates has been proposed.

Green imine synthesis from amines using transition metal and micellar catalysis.

Imines are a versatile class of chemicals with applications in pharmaceuticals and as synthetic intermediates. While imines are conventionally synthesized via aldehyde-amine condensation, their direct preparation from amines can avoid the need for the independent preparation of the aldehyde coupling partner and associated constraints with regard to aldehyde storage and purification. The direct preparation of imines from amines typically utilizes transition metal catalysis and is often well-aligned with green chemistry principles. This review provides a comprehensive overview of transition metal catalysed imine synthesis, with a particular focus on the copper-catalyzed oxidative coupling of amines. The emerging application of micellar catalysis for imine synthesis is also surveyed due to its potential to avoid the use of hazardous solvents and intensify these reactions through reduced catalyst loadings and locally increased reactant concentrations. Future directions relating to the confluence of these two areas are proposed towards the more sustainable preparation of imines.

Azaindole based fluorescent chemosensors for detecting Fe(II/III) ions and molecular logic gate implementation

A series of tridentate polypyridyl N^N^N/N^C^N-coordinating ligands (R1, L1, L2) were synthesized by copper-catalyzed Ullmann coupling (C–N bond-forming) reaction in moderate yields (∼50 %). Two charged ligands, L3 and L4 were also synthesized by methylation of L1 and L2 in moderate yields (∼45 %). These ligands were characterized by a set of analytical techniques including NMR, HRMS and single-crystal XRD. The electrochemical and photophysical properties of these ligands were examined using cyclic voltammetry, UV–vis absorption and luminescence spectroscopies. Theoretical calculations in the level of DFT and TD-DFT were also performed for the detailed studies of the optoelectronic properties of these compounds. These ligands displayed either an admixture of singlet ligand-centered (1LC) and singlet charge-transfer (1CT) transitions or pure 1LC/1CT luminescence in some cases. Ligands R1 and L1 which were highly emissive were further used as selective chemosensors for the detection of Fe(II)/(III) with a “turn-off” fluorescence behavior in a binding stoichiometry of 2:1 = ligand: M(II/III) [M = Fe(II)/Fe(III)] and a limit of detection up to 0.87–1.19 ppm level. L1 was also realized for the successful construction of the molecular logic gate.

Application of 1,4-pentanediol as a renewable solvent for copper-catalyzed Ullmann-type coupling reactions

It was demonstrated that 1,4-pentanediol as a biomass-originated polar protic solvent could be utilized as an alternative reaction medium for copper-catalyzed Ullmann-type coupling reactions of aryl iodides and various amines under mild conditions. The effect of the copper source, the base, the water, and the γ-valerolactone content of the reaction mixture on the reaction performance was investigated. Eighteen cross-coupling products were isolated with yields of 11–69 %, and high purity (>98 %). Two O-arylated products, 4-phenoxypentan-1-ol and 5-phenoxypentan-2-ol were characterized. The recycling of the solvents after product isolation was also demonstrated. These results represent an example that proves that biomass-derived safer solvents can be utilized in common, industrially important transformations.

Anaerobic photoinduced Cu(0/I)-mediated Glaser coupling in a radical pathway

The reaction mechanism of the historic copper-catalyzed Glaser coupling has been debated to be based on redox cycles of Cu ions in specific oxidation states or on a radical mechanism based on Cu(0)/Cu(I). Here, the authors demonstrate two coexisting Glaser coupling pathways which can be differentiated by anaerobic/irradiation or aerobic reaction conditions. Without O2, copper(I) acetylides undergo a photo-excited pathway to generate highly reactive alkynyl radicals, which combine together to form a homo-coupling product or individually react with diverse X-H (X = C, N, O, S and P) substrates via hydrogen atom transfer. With O2, copper(I) acetylides are oxidized to become a Cu-acetylide/Cu-O merged Cu(I/II) intermediate for further oxidative coupling. This work not only complements the radical mechanism for Glaser coupling, but also provides a mild way to access highly energetic alkynyl radicals for efficient organic transformations.

Synthesis of Sulfoximines by Copper-Catalyzed Oxidative Coupling of Sulfinamides and Aryl Boronic Acids.

A novel copper-catalyzed cross-coupling reaction of sulfinamides and aryl boronic acids is developed. The reaction is highly chemoselective and stereospecific, which allows mild synthesis of optically pure sulfoximines with broad scope and functional group tolerance. The utility of this method is demonstrated by the asymmetric synthesis of pharmaceutical intermediates.

Oxidative addition of an alkyl halide to form a stable Cu(III) product.

The step that cleaves the carbon-halogen bond in copper-catalyzed cross-coupling reactions remains ill defined because of the multiple redox manifolds available to copper and the instability of the high-valent copper product formed. We report the oxidative addition of α-haloacetonitrile to ionic and neutral copper(I) complexes to form previously elusive but here fully characterized copper(III) complexes. The stability of these complexes stems from the strong Cu-CF3 bond and the high barrier for C(CF3)-C(CH2CN) bond-forming reductive elimination. The mechanistic studies we performed suggest that oxidative addition to ionic and neutral copper(I) complexes proceeds by means of two different pathways: an SN2-type substitution to the ionic complex and a halogen-atom transfer to the neutral complex. We observed a pronounced ligand acceleration of the oxidative addition, which correlates with that observed in the copper-catalyzed couplings of azoles, amines, or alkynes with alkyl electrophiles.

Desymmetrization of meso-dibromocycloalkenes by copper-catalyzed asymmetric borylative coupling with alkynes

Desymmetrization of meso-dibromocycloalkenes by copper-catalyzed asymmetric borylative coupling with alkynes

Copper and Silver Catalysis in the (3 + 2) Cycloaddition of Neutral Three-Atom Components with Terminal Alkynes.

The introduction of the copper-catalyzed azide-alkyne coupling (CuAAC) to 1,3-dipolar cycloadditions was pivotal to their popularization in synthetic chemistry and to their application to multiple other domains of science. The reaction rate enhancement observed when coinage metal acetylide intermediates are involved in the cyclization process greatly expanded the structural and conditional range in which (3 + 2) cycloadditions may take place with terminal alkynes. Herein, we report that comparable rate enhancements, in nature and level, are induced by copper and silver catalysts in the intramolecular (3 + 2) cycloaddition of terminal alkynes with "neutral" three-atom components (TACs), specifically alkynyl sulfides. Through careful observations amidst reaction optimization, experimental, and DFT mechanistic studies, a pathway involving a proton-coupled cyclometallation key step is proposed. The sets of catalytic conditions that have been developed allow us to overcome several scope limitations previously presented by the thermally promoted (3 + 2) cycloaddition of "neutral" TACs, thus expanding their synthetic and applicative potential.

A sustainable avenue for the synthesis of propargylamines and benzofurans using a Cu-functionalized MIL-101(Cr) as a reusable heterogeneous catalyst

A heterogeneous copper-catalyzed A3 coupling reaction of aldehydes, amines, and alkynes for the synthesis of propargylamines and benzofurans has been developed. Here, the modified metal–organic framework MIL-101(Cr)-SB-Cu complex was chosen as the heterogeneous copper catalyst and prepared via post-synthetic modification of amino-functionalized MIL-101(Cr). The structure, morphology, thermal stability, and copper content of the catalyst were determined by FT-IR, PXRD, SEM, TEM, EDX, TGA, XPS, and ICP-OES. The catalyst shows high catalytic activity for the aforementioned reactions under solvent-free reaction conditions. High yields, low catalyst loading, easy catalyst recovery and reusability with not much shrink in catalytic activity, and a good yield of 82% in gram-scale synthesis are some of the benefits of this protocol that drove it towards sustainability.

Non-Covalent Interactions Enforce Conformation in Switchable and Water-Soluble Diketopiperazine-Pyridine Foldamers.

To reach their potential as mimics of the dynamic molecules present in biological systems, foldamers must be designed to display stimulus-responsive behavior. Here we report such a foldamer architecture based on alternating pyridine-diketopiperazine linkers. Epimerization is conveniently prevented through a copper-catalyzed coupling protocol. The compounds' native unswitched conformation is first discovered in the solid and solution state. The foldamers can be solubilized in DMSO and pH 9.5 buffer, retaining conformational control to a large degree. Lastly, dynamic switching is demonstrated through treatment with acid, leading to behaviour we describe as stimulus-responsive sidechain reconfiguration.

Asymmetric Synthesis of β-Aminoboronates via Copper-Catalyzed Reductive Coupling of Vinyl Boronates with Imines.

We report a copper-catalyzed asymmetric reductive coupling of vinyl boronates with imines, which directly access enantiomerically enriched β-aminoalkylboronates. Stereoselective addition of the in situ generated chiral α-borylalkyl copper to N-phosphinoyl imines provided target products in good yields with high diastereo- and enantioselectivity. Vinyl boronate with methylated acenaphthoquinone as a boron ligand was essential to efficiently spawn asymmetric products, and organic transformations of the boron moiety, along with the easily removable N-protecting group, proved their synthetic utility.

Copper-Catalyzed Coupling of N-Phenoxyacetamides and 2H-Azirines for Synthesis of α-Amino Oxime Ethers

AbstractCopper-catalyzed coupling reaction involving N-phenoxyacetamides and 2H-azirines is described, in which N–O and C–N bonds are broken and restructured. This protocol provides an efficient strategy for the highly regioselective synthesis of racemic α-amino oxime ethers. In addition, this strategy can be used to modify natural products and is gram-scale compatible.

Copper-Catalyzed Carbonylative Cross-Coupling of Alkyl Iodides with Alcohols and Sodium Hydroxide: Synthesis of Esters and Carboxylic Acids

AbstractA general and inexpensive catalytic system is reported for the copper-catalyzed carbonylative coupling between alkyl iodides and alcohols or sodium hydroxide. Upon reaction with catalytic amounts of copper(I) chloride and N,N,N′,N′′,N′′-pentamethyldiethylenetriamine under a mild pressure of carbon monoxide (5 bar), a range of secondary and tertiary alkyl iodides are readily converted into the corresponding esters and carboxylic acids without competing direct nucleophilic substitution. Main advantages of this procedure include its broad applicability, the use of an especially inexpensive and available catalytic system, and its user-friendliness.

Copper-catalyzed cross-dehydrogenative coupling of P(O)−H compounds with O-/S-nucleophiles

The copper-catalyzed cross-dehydrogenative coupling of P(O)−H compounds with O-/S-nucleophiles to construct P−O bonds and P−S bonds for the synthesis of phosphinates and phosphinothioates was developed. A broad range of O- and S-nucleophiles are well tolerated in this transformation, affording the target products with good to excellent yields. This protocol is effective and convenient, which not only employed inexpensive copper iodide as the catalyst, but also avoided the use of hazadous and toxic reagents. Through the step-by-step control experiments and competitive experiments, we proposed a plausible reaction mechanism, and further confirmed that the reaction may follow a radical process.

Cu-Catalyzed Polychloromethylamination of Styrenes through C(sp3 )-H Bond Cleavage.

A copper-catalyzed three-component coupling reaction has been developed allowing the rapid building of valuable complex highly functionalized β-polychloromethyl amines from simple styrenes, arylamines, and dichloromethane/chloroform. Using aryldiazonium salts as a radical initiator, a series of corresponding products are obtained with moderate to good yields under a carbon dioxide or nitrogen atmosphere (50 psi). In addition, good functional group tolerance can be observed.

Cu/Oxalic Diamide-Catalyzed Coupling of Terminal Alkynes with Aryl Halides.

N1-(2,6-Dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxalamide (DMPPO) was revealed to be a more effective ligand for copper-catalyzed coupling reaction of (hetero)aryl halides with 1-alkynes than previously reported ones. Only 3 mol % CuCl and DMPPO are required to make the coupling complete at 100 °C (for bromides) and 80 °C (for iodides). Both (hetero)aryl and alkyl substituted 1-alkynes worked well under these conditions, leading to the formation of internal alkynes in great diversity.