Copper-mediated Cyclization Research Articles

Synthesis of furoquinolinones/pyranones/coumarins via a copper-catalyzed heteroannulation of oxime acetates and 1,3-cyclic dicarbonyls

A divergent copper-mediated cyclization between oxime acetates and distinct 1,3-cyclic dicarbonyl compounds such as 4-hydroxyquinolinones/pyranones/coumarins was developed. Using the same reaction conditions, an array of furan-fused heterocycles such as furoquinolinones/pyranones/coumarins were prepared in good to high yields. The products possess a less common substitution pattern than those in previous syntheses. The mildness of the protocol enables a broad scope without affecting sensitive functionalities such as azido, alcohol, terminal alkyne, alkyl ester, and alkyl halide groups. Mechanistic investigations infer a purely organometallic pathway, excluding the participation of radical intermediates. Ultimately, the heteroannulation was exploited as the key step in a short and high-yielding synthesis of the phytoestrogen coumestrol.

Copper-Mediated Cyclization of Terminal Alkynes with CF3-Imidoyl Sulfoxonium Ylides To Construct 5-Trifluoromethylpyrroles.

A copper-mediated [3 + 2] cyclization of CF3-imidoyl sulfoxonium ylides and terminal alkynes has been demonstrated. This work provides a practical approach for assembling 5-trifluoromethylpyrroles with the merits of a broad substrate scope, good functional tolerance, and mild reaction conditions. Control experiments and DFT studies indicate that this reaction may involve the addition of π-bonds of terminal alkynes by copper-carbene radicals and hydrogen migration.

Copper-mediated cyclization of thiosemicarbazones leading to 1,3,4-thiadiazoles: Structural elucidation, DFT calculations, in vitro biological evaluation and in silico evaluation studies

Cancer's global impact necessitates innovative and less toxic treatments. Thiosemicarbazones (TSCs), adaptable metal chelators, offer such potential. In this study, we have synthesized N (4)-substituted heterocyclic TSCs from syringaldehyde (TSL1, TSL2), and also report the unexpected copper-mediated cyclization of the TSCs to form thiadiazoles (TSL3, TSL4), expanding research avenues. This work includes extensive characterization and studies such as DNA/protein binding, molecular docking, and theoretical analyses to demonstrate the potential of the as-prepared TSCs and thiadiazoles against different cancer cells. The DFT results depict that the thiadiazoles exhibit greater structural stability and reduced reactivity compared to the corresponding TSCs. The docking results suggest superior EGFR inhibition for TSL3 with a binding constant value of − 6.99 Kcal/mol. According to molecular dynamics studies, the TSL3-EGFR complex exhibits a lower average RMSD (1.39 nm) as compared to the TSL1-EGFR complex (3.29 nm) suggesting that both the thiadiazole and thiosemicarbazone examined here can be good inhibitors of EGFR protein, also that TSL3 can inhibit EGFR better than TSL1. ADME analysis indicates drug-likeness and oral availability of the thiadiazole-based drugs. The DNA binding experiment through absorption and emission spectroscopy discovered that TSL3 is more active towards DNA which is quantitatively calculated with a Kb value of 4.74 × 106 M−1, Kq value of 4.04 × 104 M−1and Kapp value of 5 × 106 M−1. Furthermore, the BSA binding studies carried out with fluorescence spectroscopy showed that TSL3 shows better binding capacity (1.64 × 105 M−1) with BSA protein. All the compounds show significant cytotoxicity against A459-lung, MCF-7-breast, and HepG2-liver cancer cell lines; TSL3 exhibits the best cytotoxicity, albeit less effective than cisplatin. Thiadiazoles demonstrate greater cytotoxicity than the TSCs. Overall, the promise of TSCs and thiadiazoles in cancer research is highlighted by this study. Furthermore, it unveils unexpected copper-mediated cyclization of the TSCs to thiadiazoles.

Two-Step, One-Pot Pyrrole Synthesis by Iron-Catalyzed ­Carboamination/Copper-Mediated Cyclization

AbstractHerein we report a method for pyrrole synthesis via iron-catalyzed carboamination/copper-mediated cyclization that is completely regioselective for the formation of 1,2,4-trisubstituted products. This two-step, one-pot process offers significant improvements to previously reported conditions including the use of a readily available copper(I) source and a markedly less arduous experimental procedure. Exploration of the substrate scope reveals a variety of arylacetylenes undergo pyrrole formation to afford single isomer products. Isotopic labelling data points to a mechanism involving activation of the alkyne moiety by the copper(I) reagent during the cyclization step.

Copper-Mediated Cyclization of o-Hydroxyaryl Enaminones with 3-Indoleacetic Acids toward the Synthesis of 3-Indolmethyl-Chromones.

Here, we describe a copper-mediated tandem decarboxylative coupling/annulation protocol of o-hydroxyaryl enaminones with 3-indoleacetic acids. A series of 3-indolmethyl-chromones were afforded in up to 97% yield. A one-pot method for 3-indolmethyl-chromones from o-hydroxy acetophenones, N, N-dimethylformamide dimethyl acetal, and 3-indoleacetic acids was also developed. Derivatization of the products was conducted to provide various indolmethyl-substituted pyrimidines. Moreover, a biological evaluation revealed that some compounds had anti-influenza viral activities.

Cu-Catalyzed Dimerization of Indole Derived Oxime Acetate for Synthesis of Biimidazo[1,2-a]indoles.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.

Synthesis of 3-Halo-7-azaindoles through a 5-endo-dig Electrophilic Cyclization Reaction

Biologically useful 7-azaindoles were synthesized by electrophilic cyclization of 3-alkynyl-N,N-dimethylpyridine-2-amines with molecular iodine. By this simple atom-economical approach under ambient reaction conditions, a library of interesting 3-iodo-7-azaindoles were synthesized in high yields. To synthesize the corresponding 3-bromo- and 3-chloro-7-azaindoles, an environmentally benign copper-mediated cyclization was employed, with inexpensive, nontoxic, and noncorrosive sodium chloride and sodium bromide as the sources of chlorine and bromine, respectively.

Synthesis of substituted pyrazines from N-allyl malonamides

Synthesis of highly substituted pyrazines from geminal diazides via thermal or copper-mediated cyclization and modification of the obtained pyrazines.

Copper-Mediated Cyclization Approach to 3H- and 1H-Indoles

Key words copper - 1H-indoles - 3H-indoles - N-aryl enamines - oxidative coupling

Copper-mediated dimerization to access 3a,3a'-bispyrrolidinoindoline: diastereoselective synthesis of (+)-WIN 64821 and (-)-ditryptophenaline.

A copper-mediated cyclization and dimerization of tryptamine or tryptophan was developed to generate a C2-symmetry C3(sp(3))-C3(sp(3)) bridge with two contiguous stereogenic quaternary carbons in one step. Impressively, the ratio between exo and endo cyclization products varies when different protecting groups of Nb are utilized. This dimerization reaction could be conducted in gram scale. With this dimerization method, both endocyclotryptophan (+)-WIN 64821 and exocyclotryptophan (-)-ditryptophenaline were synthesized in 5 steps.

Unexpected cyclization of tritylamines promoted by copper salt through C-H and C-N bond cleavages to produce acridine derivatives.

Herein, we demonstrate that tritylamines undergo an unprecedented copper-mediated cyclization involving the cleavages of two C-H bonds and one C-N bond to give 9-arylacridine derivatives. This kind of acridines is of interest due to their biological properties and their unique optical and electro- and photochemical properties. Some of obtained acridine derivatives exhibit intense fluorescence in the solid state.

A copper-mediated cyclization reaction of hydrazine with enediynones providing pyrazolo[1,5-a]pyridines

2,7-Disubstituted pyrazolo[1,5-a]pyridines were synthesized in good chemical yields by the reaction of enediynones with hydrazine, followed by addition of copper chloride. This reaction can tolerate many functional groups.

Copper-Mediated Cyclization−Halogenation and Cyclization−Cyanation Reactions of β-Hydroxyalkynes and o-Alkynylphenols and Anilines

The CuX (X = I, Br, Cl, CN)-mediated cyclization-halogenation and cyclization-cyanation reactions of beta-hydroxyalkynes and o-alkynylphenol and -aniline derivatives give rise to 3-halo- and 3-cyanofuro[3,2-b]pyrroles, 3-iodo-, 3-bromo-, and 3-cyanobenzofurans, and 3-cyanoindoles, respectively.

Novel Synthesis of Azepine Derivatives via Copper-Mediated Cyclization of 2-Aza-hepta-2,4-dien-6-ynyl Anions. Intramolecular Addition of Organocopper Centers to the C−C Triple Bond

Deprotonation of alkynyl imines 1 with LDA at low temperature and subsequent transmetalation with copper thiophenolate gives the annulated azepines 11a-i in 41-73% yield after aqueous workup. The key step of the reaction is a copper-mediated intramolecular nucleophilic attack at the triple bond. [reaction: see text]

Facile and Effective Copper‐Mediated Cyclization Reaction of Cyclopropylideneacetic Acids (or Esters) and Cyclopropylideneacetonitriles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Facile and effective copper-mediated cyclization reaction of cyclopropylideneacetic acids (or esters) and cyclopropylideneacetonitriles.

The full details of the copper-mediated cyclization reaction of cyclopropylideneacetic acids (or esters) and cyclopropylidenenitriles, the synthetic application of this reaction, and the study of the reaction mechanism are reported.

Copper-mediated cyclization and oxygenation of heterocyclic aldimines

Copper-mediated cyclization and oxygenation of heterocyclic aldimines

Synthesis of biphenylenes and tetraphenylenes using copper-catalyzed coupling of arylzinc intermediates

Biphenylene and some of its 2,3,6,7- and 1,8-substituted derivatives were synthesized using the CuCl2-mediated intramolecular coupling of an organozinc species prepared from 2,2′-dilithiobiaryls with one or two molar equiv. of ZnCl2 or ZnBr2 in THF. Although most of the reactions of 2,2′-dilithiobiaryls with CuCl2 in THF in the absence of ZnCl2 or ZnBr2 led to biphenylenes as a major product, similar reactions of the organozinc species with CuCl2 in THF produced biphenylenes in much better yields, due to smooth transmetallation and reductive elimination reactions. In particular, the copper-mediated cyclization of benzannelated organozinc intermediates, prepared from equimolar proportions of 2,2′-dilithiobiaryls with ZnCl2, proceeded smoothly and selectively to afford the desired biphenylenes in 46–81% yield except for the reaction of the zinc intermediate derived from 4,4′,5,5′-tetramethoxy-2,2′-dilithiobiphenyl with ZnCl2 (1.0 molar equiv.). The reaction of the tetramethoxy-substituted organozinc species with CuCl2 produced 2,3,6,7,10,11,14,15-octamethoxytetraphenylene as a major product in 67% yield.