Copper-catalyzed Multicomponent Reaction Research Articles

Copper-Catalyzed Multicomponent Coupling Reaction of Primary Aromatic Amines, Rongalite, and Alkynes: Access to N-Aryl Propargylamines.

In this work, a practical copper-catalyzed multicomponent coupling reaction of primary aromatic amines, rongalite, and alkynes for the direct synthesis of N-aryl propargylamines has been developed. This method could overcome the substrate limitation in A3 coupling reactions of primary aromatic amines, formaldehyde, and alkynes. Mechanistic studies revealed that rongalite acts as not only the active C1 unit but also the accelerator to activate the in situ-generated N-arylmethanimines for the coupling reaction with alkynes. This coupling reaction is highly efficient and features a broad substrate scope, as well as utility with scale-up synthesis and converting the corresponding product N-aryl propargylamines into useful heterocyclic skeletons.

An aerobic copper-catalyzed multi-component reaction strategy for N′,N′-diaryl acylhydrazine synthesis: reactions and mechanism

A sequential multi-component reaction of aldehydes and aryl hydrazines for the synthesis of N',N'-diaryl acylhydrazines with high regioselectivity has been achieved via an aerobic copper-catalyzed process.

Copper-Catalyzed Multicomponent Reactions of Intramolecular and Intermolecular Thiotrifluoromethylation of Alkenes: Access to CF3-Containing 2-Iminothiazolidines and Isothioureas.

A copper-catalyzed multicomponent reaction of secondary amines bearing allyl substitution, isothiocyanates, and Togni reagent II has been developed under Cs2CO3 in DCE at 75 °C. An intermolecular multicomponent reaction of thioureas, activated and unactivated alkenes, and Togni reagent II has also been developed under DMAP in acetonitrile at room temperature. These two alkene difunctionalization reactions provide CF3-containing 2-iminothiazolindines and isothioureas in moderate to excellent yields with broad substrate scope and good functional group tolerance, respectively.

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles.

In the presence of copper sulfate, three- or four-component reactions of 2-methylindole, aromatic aldehydes and various cyclic dienophiles in refluxing toluene afforded diverse spirotetrahydrocarbazoles. This reaction is an important development of the Levy reaction by using 2-methylindole to replace ethyl indole-2-acetate and successfully provides facile access to important polysubstituted spiro[carbazole-3,3'-indolines], spiro[carbazole-2,3'-indolines], spiro[carbazole-3,5'-pyrimidines] and spiro[carbazole-3,1'-cycloalkanes] in satisfactory yields and with high diastereoselectivity.

Synthesis of β-Polychlorinated Alkynes Enabled by Copper-Catalyzed Multicomponent Reaction.

Functional molecules bearing polychlorinated moieties usually play versatile roles in organic synthesis and biochemistry. A copper-catalyzed multicomponent polychloro-carboalkynylation of alkenes presents an efficient and operationally simple approach for the synthesis of β-polychlorinated alkynes. Mechanistic experiments were conducted demonstrating that an in situ generated copper acetylide complex was the real catalyst and reactive intermediate during the copper-catalytic cycle. And enantioselective exploration demonstrated potential application for the synthesis of chiral β-polychlorinated alkynes.

Selective Synthesis of 2-(1,2,3-Triazoyl) Quinazolinones through Copper-Catalyzed Multicomponent Reaction

We describe here our results from the copper-catalyzed three component reaction of 2-azidobenzaldehyde, anthranilamide and terminal alkynes, using Et3N as base, and DMSO as solvent. Depending on the temperature and amount of Et3N used in the reactions, 1,2,3-triazolyl-quinazolinones or 1,2,3-triazolyl-dihydroquinazolinone could be obtained. When the reactions were performed at 100 °C using 2 equivalents of Et3N, 1,2,3-triazolyl-dihydroquinazolinone was formed in 82% yield, whereas reactions carried out at 120 °C using 1 equivalent of Et3N provided 1,2,3-triazolyl-quinazolinones in moderate-to-good yields.

Copper-Catalyzed Multicomponent Trifluoromethylphosphorothiolation of Alkenes: Access to CF3-Containing Alkyl Phosphorothioates.

An unprecedented copper-catalyzed multicomponent radical-based reaction involving alkenes, P(O)H compounds, sulfur powder, and Togni reagent II at room temperature has been developed. A variety of highly functionalized CF3-containing S-alkyl phosphorothioates can be directly prepared from a wide range of activated and unactivated alkenes. Moreover, this protocol highlights its potential in the late-stage functionalization of complex molecules and opens up a new avenue for the construction of C(sp3)-S-P bonds.

Recent developments and perspectives in the copper-catalyzed multicomponent synthesis of heterocycles.

Heterocyclic compounds have become an inevitable part of organic chemistry due to their ubiquitous presence in bioactive compounds. Copper-catalyzed multicomponent synthesis of heterocycles has developed as the most convenient and facile synthetic route towards complex heterocyclic motifs. In this review, we discuss the advancements in the field of copper-catalyzed multicomponent reactions for the preparation of heterocycles since 2018.

Copper catalyzed five-component domino strategy for the synthesis of nicotinimidamides.

A library of medicinally and synthetically important nicotinimidamides was synthesized by a copper-catalyzed multicomponent domino reaction of oxime esters, terminal ynones, sulfonyl azides, aryl aldehydes and acetic ammonium. Its synthetic pathway involves the formation of a highly reactive N-sulfonyl acetylketenimine, characterized by high selectivity, combinations of potential nucleophiles and electrophiles, mild reaction conditions and a wide substrate scope, and is a rare five-component example of a CuAAC/ring-opening reaction.

Copper-catalyzed regio- and chemoselective selenosulfonylation of 1,6-enynes from sulfur dioxide

An efficient copper-catalyzed multicomponent reaction of 1,6-enynes, diselenides, DABCO·(SO2)2, and cycloketone oxime esters was achieved, providing cyanoalkylsulfonated pyrrolidines in moderate to good yields.

One-Pot Copper-Catalyzed Three-Component Reaction of Sulfonyl Azides, Alkynes, and Allylamines To Access 2,3-Dihydro-1H-imi­dazo[1,2-a]indoles

A copper-catalyzed multicomponent reaction of sulfonyl azides, alkynes, and allylamines affording 2,3-dihydro-1H-imidazo-[1,2-a]indoles in moderate yields is reported. Four C–N bonds are constructed­ by way of azide-alkyne cycloaddition (CuAAC) and double Ullmann-type coupling reactions in a one-pot process.

Copper-catalyzed cascade three-component azide–alkyne cycloaddition/condensation/transesterification: easy access to 3-triazolylcoumarins

A novel and efficient strategy has been developed for the synthesis of 3-triazolylcoumarins in a one-pot, copper-catalyzed multicomponent reaction involving a cascade reaction of salicylaldehydes, ethyl 2-azidoacetate, and arylacetylenes.

Copper-Catalyzed Synthesis of Thiadiazine-1-oxides in Reusable Aqueous Medium under External [Ag]/Ligand/Base-Free Conditions.

We report herein a copper-catalyzed multicomponent reaction of simple NH-sulfoximine with readily available aldehyde and TMSN3 in hot water and aerobic conditions. The reaction tolerated a broad range of functional groups under external [Ag]/ligand/base-free conditions and can form three C-N bonds in a one-pot transformation, thus representing an extremely cost-effective protocol to biologically active sulfoximine derivatives. This aqueous catalytic system could be circularly utilized in consecutive runs of gram-scale preparations of thiadiazine-1-oxides without extra addition of the copper catalyst and PTA. Mechanistically, an ″ortho-binding″ effect in ortho-bromo NH-sulfoximine was proposed to control the chemoselectivity; thus, the other free halides such as bromo- or iodo-atoms in aldehydes2 were compatible in the reaction.

A copper-catalyzed multicomponent reaction for the synthesis of thioamide skeletons

In this report, in situ generated sulfide has been reacted with sulfonylketimine derived from the reaction of alkynes and sulfonyl azides by the action of copper salts to form a wide range of thioamide derivatives. Various terminal alkynes including aromatic, heteroaromatic, and aliphatic alkynes have been well tolerated and the reaction also shows good generality along with azides.

Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1H-[1,2,3]Triazolo[4,5-c]quinoline Derivatives

A practical copper-catalyzed multicomponent reaction has been developed for the synthesis of 1 H-[1,2,3]triazolo[4,5- c]quinoline derivatives from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This protocol integrated consecutive base-promoted condensation, [3 + 2] cycloaddition, copper-catalyzed SNAr, and denitrogenation cyclization sequences. Preliminary mechanistic studies revealed that CuBr2 acted as a multifunctional catalyst to streamline this domino process. The mild catalytic system enabled effective construction of one C-C and four C-N bonds in one operation.

Copper-Catalyzed Multicomponent Reaction of DABCO·(SO2)2, Alcohols, and Aryl Diazoniums for the Synthesis of Sulfonic Esters.

A Cu-catalyzed multicomponent cascade reaction of DABCO·(SO2)2 (DABSO), alcohol, and aryl diazonium tetrafluoroborate was developed which afforded sulfonic esters in moderate to good chemical yields. In this reaction, the SO2 surrogate DABSO was used for the first time in the synthesis of sulfonic aliphatic esters. This multicomponent reaction was carried out under mild conditions and tolerated a wide range of substrates, which provides a new and efficient strategy for the synthesis of sulfonic esters.

Synthesis of (arylselanyl)- and (arylsulfenyl)-alkyl-1,2,3-triazolo-1,3,6-triazonines via a copper-catalyzed multicomponent reaction

An efficient copper-catalyzed multicomponent reaction was developed for the synthesis of (arylselanyl)- or (arylsulfenyl)-alkyl-1,2,3-triazolo-1,3,6-triazonines. The products were obtained in moderate to excellent yields via the reaction of o-phenylenediamine, 2-azidobenzaldehyde and different arylchalcogenyl alkynes using catalytic copper iodide in 1,4-dioxane at 100 °C. The reactions tolerated a range of substituents on the arylchalcogenyl alkynes and proved to be an efficient methodology for the combinatorial synthesis of new selenium or sulfur-containing triazonine derivatives.

ChemInform Abstract: Synthesis of S‐Aryl Phosphorothioates by Copper‐Catalyzed Phosphorothiolation of Diaryliodonium and Arenediazonium Salts.

Green methods for the synthesis of S-aryl phosphorothioates have been developed based on copper-catalyzed multicomponent reactions involving diaryliodonium/arenediazonium salts, elemental sulfur, and R2P(O)H compounds. Most target products are obtained with these two methods in good to high yields at room temperature. These transformations allow the direct formation P–S and C–S bonds in one reaction.

Synthesis of S-Aryl Phosphorothioates by Copper-Catalyzed Phosphorothiolation of Diaryliodonium and Arenediazonium Salts.

Green methods for the synthesis of S-aryl phosphorothioates have been developed based on copper-catalyzed multicomponent reactions involving diaryliodonium/arenediazonium salts, elemental sulfur, and R2P(O)H compounds. Most target products are obtained with these two methods in good to high yields at room temperature. These transformations allow the direct formation P-S and C-S bonds in one reaction.

Tuning of Copper-Catalyzed Multicomponent Reactions toward 3-Functionalized Oxindoles.

A tunable copper-catalyzed azide-alkyne cycloaddition (CuAAC)-initiated multicomponent reaction strategy for the construction of 3-functionalized indolin-2-ones is reported. Upon controlling the ring opening of four-membered O-heterocyclic intermediates, this unique method enables the divergent derivatization of N-protected isatins to give three-component (3-CR) and four-component (4-CR) adducts, respectively.