Copper-catalyzed Three-component Reaction Research Articles

Synthesis of Aryl Alkyl Thioethers via a Copper-Catalyzed Three-Component Reaction with DABSO, Aryldiazonium Salts, and Alkyl Bromides.

We developed a method for synthesizing aryl alkyl thioether compounds via a three-component reaction involving aryldiazonium salts, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide), and alkyl bromides. Optimal yields were achieved when a copper catalyst was used in conjunction with zinc and tetrabutylammonium bromide in an acetonitrile solvent at 130 °C for 10 h. This methodology demonstrates good functional group tolerance and enables the successful synthesis of various aryl alkyl thioethers with moderate to high yields.

Copper-catalyzed three-component reaction to construct thietane ring using elemental sulfur

Thietanes are vital aliphatic four-membered rings associated with various pharmaceuticals, building blocks and synthons of intermediates used in the total synthesis of natural products and biomolecules. Also, 4-thiazolidinone is a core pharmacophore of many drug molecules. Based on their various applications in medicinal chemistry and organic synthesis, an effort has been made to achieve a thietane ring on 4-thiazolidinone nucleus via quasi-benzylic acid-type intramolecular rearrangement using elemental sulfur, benzyl bromide and Cu(I). The designed methodology is environmentally benign, cheap, and easily accessible, with a broad range of substrate scopes and carried out by the employment of earth-abundant metal catalysts like copper.

Copper-Catalyzed Three-Component Synthesis of β-Hydroxysulfides from Styrene Oxide, Aryl Iodide, and Carbon Disulfide.

A copper-catalyzed three-component coupling reaction of styrene oxide, aryl iodide, and carbon disulfide for the construction of β-hydroxysulfides has been developed. In this process, readily available CS2 was used as the sulfur source to construct C-S bonds for the synthesis of phenyl-β-hydroxysulfides and (benzo[d]thiazol)-β-hydroxysulfides. This process features mild reaction conditions, simple operation, and wide substrate scope (>50 examples).

Copper-Catalyzed Three-Component Synthesis of Highly Substituted Morpholines.

Unprotected, highly substituted morpholines were obtained through a copper-catalyzed three-component reaction utilizing amino alcohols, aldehydes, and diazomalonates. The transformation was effective for diversely substituted aldehydes and for a broad range of readily available vicinal amino alcohols, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids. Epimerization of morpholines using light-mediated stereochemical editing was demonstrated, and the unprotected morpholine products were readily elaborated through efficient transformations.

Cu-catalyzed three-component C[sbnd]S[sbnd]P coupling for the synthesis of trisubstituted allenyl phosphorothioates

A copper-catalyzed three-component reaction involving cyclic carbonates, elemental sulfur, and H-phosphonates is presented. It proceeds with excellent yields and provides an attractive approach for the construction of valuable trisubstituted allenyl phosphorothioates using a one-step strategy. Moreover, this method can be easily adapted to large-scale preparation.

Copper-Catalyzed Three-Component Tandem Reaction of Alkynes, α-Diazo Esters, and TMSN3 to Access N-Substituted 1,2,3-Triazoles.

An efficient copper-catalyzed three-component tandem reaction of alkynes, α-diazo esters, and TMSN3 to construct triazoles has been developed. Through this strategy, a number of diverse N-substituted 1,2,3-triazoles were conveniently obtained in moderate to good yields from simple and readily available starting materials using K2CO3 as the base. The mechanism of the tandem Cu-catalyzed azide-alkyne cycloaddition (CuAAC) and Cu-carbenoid-participated C-N coupling reaction has been investigated.

One-Pot Knoevenagel/Imination/6π-Azaelectrocyclization Sequence for the Synthesis of Disubstituted Nicotinonitriles.

We report on a copper-catalyzed three-component reaction for the synthesis of disubstituted nicotinonitriles using 3-bromopropenals, benzoylacetonitriles, and ammonium acetate (NH4OAc). The Knoevenagel-type condensation of 3-bromopropenals with benzoylacetonitriles gives δ-bromo-2,4-dienones that contain strategically placed functional groups that react with the ammonia generated in situ to give the corresponding azatrienes. These azatrienes can then be transformed into trisubstituted pyridines under the reaction conditions via a reaction sequence involving 6π-azaelectrocyclization and aromatization.

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.

Copper-catalyzed 2,3-dihydro-1,2,4-triazoles synthesis through [3+2]-cycloaddition of nitrile ylides with azodicarboxylates

A copper-catalyzed three-component reaction of diazo compounds, nitriles, and azodicarboxylates to construct 2,3-dihydro-1,2,4-triazoles is reported. Key to the success is the utilization of azodicarboxylates to trap the in-situ formed nitrile ylides from diazo compounds by [3 ​+ ​2]-cycloaddition. Both the acceptor-only and donor-acceptor diazo compounds are all tolerated to the strategy. The synthetic value of this protocol is illustrated by gram-scale synthesis and valuable transformation of the obtained 2,3-dihydro-1,2,4-triazoles.

Base-controlled copper-catalyzed multi-component cascade reactions of cyanamides, diaryliodonium triflates and propargylamine for rapid assembly of polysubstituted 2-aminoimidazoles and 2-iminoimidazoles

Base-controlled copper-catalyzed three-component and four-component cascade reactions of cyanamides, dirayliodonium triflates, and propargylamine were established for the rapid synthesis of 2-aminoimidazoles and 2-iminoimidazoles.

Copper-catalyzed ring-opening sulfonylation of cyclopropanols via the insertion of sulfur dioxide toward the synthesis of γ-keto aryl sulfones

A copper-catalyzed three-component sulfonylation reaction is presented. This protocol provides easy and straightforward access to structurally diverse γ-keto aryl sulfones with good yields, mild reaction conditions, low catalyst loading, and good functional group tolerance.

Copper-catalyzed radical-mediated intermolecular cyanomonofluoroalkylation of alkenes and alkynes.

A novel copper-catalyzed three-component reaction of monofluoroalkylation agents, alkenes and TMSCN is described. In addition, alkynes could also be compatible with the reaction system to obtain three-component products for the first time with moderate yield and excellent E/Z stereoselectivity. This reaction provides a facile method for the synthesis of cyanomonofluoroalkyl compounds, which may serve as potentially useful organic intermediates for further transformations. Preliminary mechanistic investigation indicated that monofluoroalkyl free radicals were involved in the cyanomonofluoroalkylation process.

Copper-Catalyzed Germyl-Azidation of Alkenes with Germanium Hydrides and Trimethylsilyl Azide.

The incorporation of a germyl group and another functional fragment across the C═C bond is a challenging task due to the prevailing hydrogermylation reaction. Herein, an efficient copper-catalyzed three-component reaction of alkenes, germanium hydrides, and trimethylsilyl azide has been disclosed. This transformation allows the concomitant introduction of germyl and azide groups across the double bonds in a highly regioselective manner with tert-butyl hydroperoxides as the bystanding oxidant. The resulting β-germyl azides could be easily converted into β-germyl amine and 1,2,3-triazoles of significant value.

Cu-Catalyzed Diarylthiolation of Ynones with Aryl Iodides and Elemental Sulfur: An Access to Tetrasubstituted (Z)-1,2-Bis(arylthio)alkenes and Benzo[b][1,4]dithiines.

A copper-catalyzed three-component reaction of ynones, aryl iodides, and elemental sulfur via a syn-addition process is established. The reaction features operational practicality, broad substrate scope, and readily accessible scale-up synthesis by affording a series of (Z)-1,2-bis(arylthio)alkenes in good to excellent yield. Moreover, benzo[b][1,4]dithiines can be also constructed efficiently by using 1,2-diiodobenzene as the coupling partner.

Copper-catalyzed Z-selective synthesis of acrylamides and polyacrylamides via alkylidene ketenimines

It remains very important to discover and study new fundamental intermediates consisting of carbon and nitrogen as the abundant elements of organic molecules. The unique alkylidene ketenimine could be formed in situ under mild conditions by an unexpected copper-catalyzed three-component reaction of alkyne, azide and water involving a successive cycloaddition, N2 extrusion and carbene-assisted rearrangement. Only Z-α,β-unsaturated amides instead of E-α,β-unsaturated amides or triazoles were acquired from alkylidene ketenimines with excellent selectivities and stereospecificities. In addition, a series of “approximate” alternating copolymers (poly (triazole-alt-Z-acrylamides)) with high Mns and yields were efficiently afforded by multicomponent polymerization through a very simple operation basing on this multicomponent reaction.

Copper-Catalyzed Three-Component Cascade Annulation for Divergent Syntheses of Imidazoles and Dihydroimidazoles.

The first example of divergent N-heterocycle syntheses through a copper-catalyzed three-component reaction of α,β-unsaturated ketoximes, paraformaldehyde, and amines has been documented. In particular, this divergent synthetic strategy was achieved by controlling the reaction conditions to afford the corresponding imidazoles and dihydroimidazoles in moderate to good yields with a broad substrate scope and good functional group compatibility.

Copper-catalyzed three-component reaction to synthesize polysubstituted imidazo[1,2-a]pyridines.

An efficient three-component one-pot and operationally simple cascade of 2-aminopyridines with sulfonyl azides and terminal ynones is reported, providing a variety of polysubstituted imidazo[1,2-a]pyridine derivatives in moderate to excellent yields. In particular, the reaction goes a through CuAAC/ring-cleavage process and forms a highly active intermediate α-acyl-N-sulfonyl ketenimine with base free.

A copper-catalyzed three-component reaction of dithioacetals with diazo ketones and ketimines.

A copper-catalyzed three-component reaction of dithioacetals with diazo-ketones and ketimines has been reported. This reaction proceeds via trapping of the highly active sulfur ylide species, which are generated from thioacetal and carbene intermediates, with isatin-derived ketimine, providing an efficient protocol for the synthesis of acyclic thioacetal derivatives and medium-sized sulfur-containing heterocycles in good to high yields under mild reaction conditions with a broad substrate scope.

A copper-catalyzed three-component reaction of alkenes, cycloketone oximes and DABCO·(SO2)2: Direct C(sp2)-H cyanoalkylsulfonylation

A copper-catalyzed three-component reaction of alkenes, cycloketone oximes and DABCO·(SO2)2 is developed, which provides a convenient route for the synthesis of diverse (E)-cyanoalkylsulfonyl alkenes in moderate to good yields with excellent regio- and stereoselectivity. A broad substrate scope with excellent functional group tolerance is observed. A plausible radical pathway is proposed, which involves copper-catalyzed ring-opening CC bond cleavage of O-acyl oxime and insertion of sulfur dioxide. During the reaction process, cyanoalkyl radical and cyanoalkylsulfonyl radical are the key intermediates.

Copper-Catalyzed Three-Component Reactions of α-Ketoaldehyde, 1,3-Dicarbonyl Compound, and Organic Boronic Acid in Water: A Route to 1,4-Diketones.

A novel three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl compounds, and organic boronic acids catalyzed by CuO in water has been developed to give a wide range of products containing 1,3/1,4-diketones. The method has some advantages such as the use of readily available starting materials, wide substrate scopes, excellent yields, gram-scale synthesis, and mild reaction conditions.