Copper-catalyzed Cross-coupling Reaction Research Articles

Synthesis of 4,5-Disubstituted Methyl 1H-Pyrrole-2-carboxylates from 3-Chloroacrylaldehydes and Hippuric Acid

AbstractThe Vilsmeier–Haack reaction of ketones with DMF and POCl3­ produced 3-chloroacrylcarbaldehydes, which were converted into the corresponding (Z)-4-[(Z)- or (Z)-4-[(E)-3-chloroallylidene)-2-phenyloxazol-5(4H)-ones] (azlactones) or their isomeric mixtures when heated with hippuric acid in propionic anhydride. It was shown that the alcoholysis products of these compounds, resulting from the opening of the oxazolone ring, undergo copper-catalyzed intramolecular cross-coupling reactions with the formation of methyl 1H-pyrrole-2-carboxylates. Thus, a one-pot method was developed for the synthesis of methyl 1H-pyrrole-2-carboxylates starting from 4-(3-chloroallylidene)-2-phenyloxazol-5(4H)-ones.

Hydroxylamine Umpolung in Copper-Catalyzed Cross-Coupling Reactions to Synthesize N-Arylhydroxylamine Derivatives

Hydroxylamine Umpolung in Copper-Catalyzed Cross-Coupling Reactions to Synthesize <i>N</i>-Arylhydroxylamine Derivatives

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.

Copper-Catalyzed Sulfinyl Cross-Coupling Reaction of Sulfinamides.

A copper-catalyzed sulfinyl cross-coupling reaction of sulfinamides with aldehyde-derived N-tosylhydrazones is described. This approach enables facile access for the construction of structurally diverse sulfoxides via novel and efficient S-N/S-C bond interconversions, features broad substrate scope, and accommodates various functional groups as well as pharmacophores. Moreover, the given sulfinyl cross-coupling reaction could be scaled up to the gram scale and carried out in a one-pot fashion directly from aldehydes. The broad utility of produced sulfoxides is demonstrated by further transformations. A preliminary mechanistic investigation was performed, which disclosed possible reaction pathways.

Cu2O-Catalyzed Ullmann-type C[sbnd]N cross-coupling reaction of carbazole and aryl chlorides

A copper-catalyzed Ullmann-type CN cross-coupling reaction of carbazole with aryl chlorides has been developed employing N,N′-bis(thiophene-2-ylmethyl)oxalamide as ligand. The reaction proceeds at 140 °C with Cs2CO3 as the base in DMSO/MeCN to afford N-arylcarbazole in good to excellent yields. Both the heteroaromatic ring and amide structures in ligands are important for their efficiency.

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C-Si bond functionalization.

3-Silylated furfurals, readily prepared in three steps from biomass-derived furfural and 5-methylfurfural, are converted into 3-silylated 2-furyl carbinols upon condensation with organomagnesium or organolithium reagents. The hydroxy unit of the carbinol adducts can be exploited to promote C3(sp2)–Si bond functionalization through intramolecular activation. Two approaches were contemplated for this purpose. Activation by alkoxides of the C3–SiEt3 or C3–SiMe2t-Bu bonds was ineffective. Conversely, treatment of the C3-benzyldimethylsilyl-appended derivatives with tetrabutylammonium fluoride led to cyclic siloxanes, which revealed to be competent donors for copper-catalyzed cross-coupling reactions, such as arylation reactions catalyzed by Pd2(dba)3/CuI, as well as allylation and methylation reactions catalyzed by CuI⋅PPh3. C3-Benzyldimethylsilyl-appended furfurals are thus introduced as versatile platforms, providing a modular access to 3-substituted 2-furyl carbinols from renewable feedstock.

Copper-Catalyzed Cross-Coupling Between (E)-1,2-Diiodoethene and Carbazates: Entry to β-Functionalized N-Alkenylcarbazates

Aims: This work aims to widen the scope of methodologies to prepare functionalized N-alkenylcarbazates. Background: Alkenylcarbazates are generally prepared via Aza-Baylis-Hillman reactions, nucleophilic attack on ketones or a tandem carbometallation/amidation reaction of alkynes. Objective: The objective of this work is to develop a method to prepare functionalized Nalkenylcarbazates that alleviates the problem encountered in the above methods (use of electron deficient alkenes, use of stoiechiometric amounts of metal, access to symmetrical dicarbazates only). Methods: Use of copper-catalyzed cross-coupling between vinylic diiodide and carbazates to prepare functionalized N-alkenylcarbazates. Results: Various β-iodovinylcarbazates were synthesized with up to good yields. The highest yields were obtained using dicarbazates. Functionalization of β-iodovinylcarbazate demonstrated that the vinyl iodide moiety of these molecules can be substituted by a variety of functional groups via transition metal-catalyzed coupling reactions. Conclusion: Copper-catalyzed cross-coupling reaction is efficient to prepare functionalized N-alkenylcarbazates.

Cu-catalyzed cross-coupling of chlorostibine with terminal alkynes to give Sb-alkynyl stibines and products transformation

Herein, we describe an efficient copper-catalyzed cross-coupling reaction of terminal alkynes with chlorostibine 1a to synthesize a variety of Sb-alkynyl stibines. Aryl, alkyl and heteroaryl acetylenes are all tolerated. This protocol shows good functional group tolerance and broad substrate scope. These obtained Sb-alkynyl stibines were utilized as effective coupling partners to prepare 1,2,3-triazoles. The catalytic mechanism is also proposed.

The ultrasound-assisted synthesis of some novel fused-ring heterocyclic systems bearing structurally diverse benzazoles via a copper-catalyzed cross-coupling reaction

The ultrasound-assisted synthesis of some novel fused-ring heterocyclic systems bearing structurally diverse benzazoles via a copper-catalyzed cross-coupling reaction

Accessing Grignard Reluctant Aldehyde in 2-Oxoaldehyde by Organocuprates to Give [1,2] Addition and Oxidative Coupling Reactions.

Novel finding of aldehyde in 2-oxoaldehyde (2OA) is presented as it unprecedentedly disinclines to react with Grignard reagents but reacts with moderate organocuprate reagents in anaerobic condition to give [1,2] addition (α-hydroxyketones) reaction. In the presence of air, the reaction produces an efficient protocol for the synthesis of 1,2-diones through a copper-catalyzed oxidative cross-coupling reaction at room temperature. Mechanistic studies indicate that α-hydroxy ketone perhaps is generated before the hydrolysis step/acid work-up process. The α-keto group of 2OA causes to exhibit this peculiar aldehyde behavior toward these organometallic reagents.

A detailed theoretical investigation to unravel the molecular mechanism of the ligand-free copper-catalyzed Suzuki cross-coupling reaction.

The Suzuki-Miyaura coupling (SMC) represents a very efficacious method for constructing C-C bonds in organic synthesis. The ligand-free variants of SMC have been grabbing attention these days. Despite this momentousness, the mechanistic details of the ligand-free variants are scant in the literature. Herein, we have carried out a detailed mechanistic investigation into the ligand-free Cu-catalyzed SMC of unsaturated organic halides with aryl boronic acid with the aid of density functional theory (DFT) calculations employing the conductor-like polarizable continuum model (CPCM) method. The present study elucidates that in the absence of ancillary ligands on the metal, the substrates, base, and solvent molecules could act as pseudo-ancillary ligands to facilitate the cross-coupling reaction. The investigation further revealed that unsaturated halides like alkynyl halides/vinyl halides could act as good ancillary ligands for copper by forming a Cu-π intermediate and promoting a facile transmetalation process. However, regarding the oxidative addition and reductive elimination steps, a concerted pathway is observed contrary to Pd catalyzed Suzuki coupling, owing to the instability of Cu(III) species and the favourability of Csp2-Csp bond formation. In the whole set of mechanisms explored, oxidative addition/oxidative nucleophilic substitution was the rate-determining step in all the cases. A thermodynamically stable π-coordinated intermediate species where the substrate and base molecule are coordinated to the metal center is identified as the rate-determining species for the ligand-free Suzuki cross-coupling reaction. The presence of the aforesaid intermediate increases the energy span and consequently the activation barrier for the rate-determining step. This study unveiled a theoretical rationale for the high-temperature requirement in the ligand-free Cu-catalyzed SMC reaction.

Copper-Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon-Iodine Bonds.

The engagement of unactivated alkyl halides in copper-catalyzed cross-coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen abstraction ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper-catalyzed Negishi-type cross-coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon-iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi-type difluoromethylation approach has been applied to the late-stage modification of densely functionalized pharmaceutical agents and natural products.

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Unlocking the Friedel-Crafts arylation of primary aliphatic alcohols and epoxides driven by hexafluoroisopropanol

Copper-Catalyzed Coupling of Amines with Carbazates: An Approach to Carbamates.

A new approach for the preparation of carbamates via the copper-catalyzed cross-coupling reaction of amines with alkoxycarbonyl radicals generated from carbazates is described. This environmentally friendly protocol takes place under mild conditions and is compatible with a wide range of amines, including aromatic/aliphatic and primary/secondary substrates.

Copper-Catalyzed Tandem Cross-Coupling and Alkynylogous Aldol Reaction: Access to Chiral Exocyclic α-Allenols.

An enantioselective copper-catalyzed tandem cross-coupling/alkynylogous aldol reaction has been developed. The tetrasubstituted allenoates containing both central and axial chirality have been obtained in moderate to good yields and excellent enantio- and diastereoselectivity. Distinct from the previous use of Cu(I) salts, this protocol features the use of copper(II) salts as a catalytic precursor in this asymmetric cross-coupling reaction.

Well-defined organometallic Copper(III) complexes: Preparation, characterization and reactivity

• Organocopper(III) are key intermediates in a variety of copper-catalyzed cross-coupling reactions. • Four types of well-defined organocopper(III) complexes were summarized. • Development of organocopper(III) complexes will boost the new reaction discovery. Organocopper(III) species were generally considered as the key intermediates in a variety of copper-catalyzed cross-coupling reactions, aerobic oxidations, as well as enzyme-catalyzed oxidation reactions. The preparation and characterization of thermal stable organocopper(III) complexes, as well as investigation of their elementary bond-forming reductive elimination is missing in the chemistry map for a longtime, and is urgently needed, since these studies would deepen our understanding about the fundamentals of the copper catalysis and boost the new reaction discovery. In this review, the preparation and characterization of four types of well-defined copper(III) complexes including copper(III) complexes without copper-carbon bond, organocopper(III) complexes with rigid macrocyclic ligands, organocopper(III) complexes with fluoroalkylated ligands and other organocopper(III) complexes were summarized. In addition, the reactivities as well as bond-forming reductive elimination elementary reactions of a few organocopper(III) complexes were also discussed.

Copper-catalyzed cross-coupling of amino acid-derived amides with (Z)-vinyl iodides: Unexpected solvent effect and preparation of plocabulin

A copper-catalyzed cross-coupling reaction of amino acid-derived amides and (Z)-vinyl iodide was studied to improve a key step in the synthesis of plocabulin, a novel microtubule destabilizer agent of marine origin. The study revealed a profound solvent effect with 1,2-dimethoxyethane (DME), which gave consistently high yields across a large variety of the amide and (Z)-vinyl iodide substrates. The protocol was successfully utilized in the preparation of plocabulin and provided a significantly improved yield. A copper-catalyzed cross-coupling reaction of amino acid-derived amides and ( Z )-vinyl iodide was studied to improve a key step in the synthesis of plocabulin, a novel microtubule destabilizer agent of marine origin. The study revealed a profound solvent effect with 1,2-dimethoxyethane (DME), which gave consistently high yields across a large variety of the amide and ( Z )-vinyl iodide substrates. The protocol was successfully utilized in the preparation of plocabulin and provided a significantly improved yield. • Mild conditions, good yields, excellent stereoselectivity. • Unique solvent effect (DME). • Application in the preparation of plocabulin.

Copper-catalyzed aerobic oxidative cross-coupling reactions of vinylarenes with sulfinate salts: A direct approach to β-ketosulfones

A copper-catalyzed aerobic oxidative cross-coupling reactions for the synthesis of β-ketosulfones via formation of a CS bond has been demonstrated. Promoted by the crucial copper catalyst, perfect selectivity and good to excellent yields could be achieved. This method, including inexpensive copper catalyst, wide functional group tolerance, and open air conditions, make it very attractive and practical. More importantly, it also provides a versatile tool for the construction of β-ketosulfones from basic starting materials under mild conditions.

Synthesis of vinyl iodide chain-end polymers via organocatalyzed chain-end transformation.

In the presence of alkynes (CH[triple bond, length as m-dash]C-R2), iodide chain-end polymers (Polymer-I) were successfully transformed to vinyl iodide chain-end polymers (polymer-CH[double bond, length as m-dash]CR2-I) in a single step via organocatalysis. This reaction is completely metal-free and easy to carry out without using special reagents or special conditions. The polymers encompassing polyacrylates and polymethacrylate, and additional functionalities (e.g., OH and CF3) were also incorporated into the R2 moiety. The obtained Polymer-CH[double bond, length as m-dash]CR2-I further served as a useful precursor for copper-catalyzed cross-coupling reactions with various thiols (R3-SH) to yield vinyl sulfide chain-end polymers (polymer-CH[double bond, length as m-dash]CR2-SR3) with various R3 moieties. Interestingly, under selected conditions, this organocatalysis also offered block-like copolymers containing a conjugated oligo-alkyne segment and a non-conjugated polyacrylate segment. Exploiting the unique structure, the block-like copolymer was used as an efficient dispersant of carbon nanotubes.