Copper-catalyzed Reaction Research Articles

Diastereoselective Synthesis of Bicyclo[3.3.0]octenones by Copper-Catalyzed Transannular Ring-Closing Reaction.

A novel and efficient copper-catalyzed transannular ring-closing reaction of eight-membered rings has been developed that provides a straightforward way to synthesize bicyclo[3.3.0]octane derivatives in good yields. Mechanistic studies revealed that the reaction pathway might involve chlorination followed by the Kornblum reaction. Readily accessible starting materials and good functional group tolerance make this procedure attractive.

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-Promoted One-Pot Sandmeyer-Type Reaction for the Synthesis of N-Aryltriazoles.

Herein, we report the copper-catalyzed one-pot Sandmeyer-type reaction of aromatic amines with triazoles to afford N-aryl-1,2,3-triazoles. Diazonium salts, formed from aromatic amines and tert-butyl nitrite in the presence of fluoroboric acid, reacted with triazoles in a copper-catalyzed Sandmeyer-type reaction. The reaction proceeded under mild conditions to afford N-aryltriazoles in moderate to good yields. This method is amenable to a wide range of aromatic amines and triazoles and shows diverse functional group tolerance. Inhibition of the reaction upon the addition of free radical scavengers suggested a radical pathway, in which the aryl radical, copper, and triazole formed a complex that underwent reductive elimination to give aryltriazole compounds; this is consistent with the mechanism underlying the Sandmeyer reaction. Thus, we demonstrate a new effective strategy for the construction of C-N bonds via Sandmeyer-type reactions and a valuable alternative approach for the synthesis of aryltriazole derivatives.

Photoactivatable Fluorogenic Azide-Alkyne Click Reaction: A Dual-Activation Fluorescent Probe.

Aryl azide and diaryl tetrazole are both photoactive molecules, which can form nitrene and nitrile imine intermediates respectively by photolysis. Depending on the new finding that the azide can suppress the photolysis of tetrazole in the azide-tetrazole conjugated system, we developed aryl azide-tetrazole probes for the photoactivatable fluorogenic azide alkyne click (PFAAC) reaction, in which the aryl azide-tetrazole probes were not phoroactivatable fluorogenic itself, but the triazole products after click reaction were prefluorophore that can be activated by light. Therefore, in PFAAC chemistry, the fluorescent probes can be activated by two orthogonal events: azide-alkyne click reaction and light, which leads to spatiotemporal resolution and high signal-to-noise ratio. This PFAAC process was proved in vitro by copper-catalyzed or strain-promoted azide-alkyne reactions and in live cells by spatiotemporally controlled organelle imaging. By incorporation a linker to the azide-tetrazole conjugate, this PFAAC chemistry could covalently label extra probes to the biomolecules and spatiotemporally detecting this process by photoinduced fluorescence.

4-(4-(((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)-7-chloroquinoline

The 1,2,3-triazole ring system can be easily obtained by widely used copper-catalyzed click reaction of azides with alkynes. 1,2,3-triazole exhibits myriad of biological activities, including antibacterial antimalarial, and antiviral activities. We herein reported the synthesis of quinoline-based [1,2,3]-triazole hybrid derivative via Cu(I)-catalyzed click reaction of 4-azido-7-chloroquinoline with alkyne derivative of hydroxybenzotriazole (HOBt). The compound was fully characterized by proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR), correlated spectroscopy (1H-1H-COSY), heteronuclear single quantum coherence (HSQC) and distortionless enhancement by polarization transfer (DEPT-135 and DEPT-90) NMR, ultraviolet (UV) and Fourier-transform infrared (FTIR) spectroscopies, and high-resolution mass spectrometry (HRMS). Computational studies were enrolled to predict the interaction of the synthesized compound with acetylcholinesterase, a target of primary relevance for developing new therapeutic options to counteract neurodegeneration. Moreover, the drug-likeness of the compound was also investigated by predicting its pharmacokinetic properties.

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 and Application of a Clickable Epoxomicin-Based Probe for Proteasome Activity Analysis.

The proteasome is a multisubunit protein complex responsible for the degradation of proteins, making it essential in myriad cellular processes. Several reversible and irreversible peptide substrates inspired by known proteasome inhibitors have been developed to visualize it and monitor its activity; however, they have limited commercial availability or possess fluorophores that overlap with other known chemical probes, limiting their simultaneous use. The protocols presented here describe the synthesis of a clickable epoxomicin‐based probe followed by the copper‐catalyzed installment of an azide‐containing fluorophore, and the application of the synthesized peptide in proteasome activity assays by SDS‐PAGE and flow cytometry. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Solid‐phase synthesis of clickable peptide fragment (2) Basic Protocol 2: In‐solution coupling of epoxy‐ketone moiety to fragment (2) Basic Protocol 3: Copper‐catalyzed click reaction of (3) with fluorophore of choice Basic Protocol 4: Monitoring proteasome activity by SDS‐PAGE in HEK‐293T cells Alternate Protocol: Monitoring proteasome activity by flow cytometry in HEK‐293T cells

Copper-catalyzed cascade reaction of indole and benzimidazole radicals to synthesize 3-haloindole-benzimidazole compounds

A one-pot multi-component cascade reaction strategy between benzimidazole, indole, and N-halosuccinimides was developed through the combination of the Cu(II) catalyst and (bis(trifluoroacetoxy)iodo)benzene, mediated by initiating the formation of benzimidazole nitrogen-centered radicals. This strategy realizes the formation of nitrogen radicals centered on the aromatic nitrogen atoms in the ring. On this basis, the radical-level combined synthesis of substituted 3-haloindole-benzimidazole compounds was achieved. Furthermore, this study provides a reference direction for subsequent work utilizing nitrogen radicals.

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.

Copper-catalyzed regio- and stereo-selective hydrosilylation of terminal allenes to access (E)-allylsilanes

Regioselectivity and stereoselectivity control in hydrosilylation of terminal allenes is challeging. Although the selective synthesis of vinylsilanes, branched allylsilanes or linear (Z)-allylsilanes have been achieved, transition-metal catalyzed hydrosilylation of terminal allenes to access (E)-allylsilane is difficult. Herein, we report a copper-catalyzed selective hydrosilylation reaction of terminal allenes to access (E)-allylsilanes under mild reaction conditions. The reaction shows broad substrate scope, representing an efficient method to prepare trisubstituted (E)-allylsilanes through hydrosilylation reaction of allenes and can also be applied in the synthesis of disubstituted (E)-allylsilanes. The mechanism study reveals that the E-selectivity is kinetically controlled by the catalyst but not by the thermodynamically isomerization of the (Z)-isomer.

Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction

Development and Scale-Up of a Copper-Catalyzed Sulfamidation Coupling Reaction

The Synthesis and Application of 2-Cyano and -Ester Containing Anilines: Selective Copper-Catalyzed Reductive Amination, N-Benz­ylation, and Cyclization Reactions

AbstractA convenient and practical pathway to 2-cyano and 2-ester anilines is described via efficient and selective copper(II)-catalyzed reductive amination via hydrosilylation process. Both 2-cyano and 2-ester anilines were successfully synthesized with good functional group tolerance and high selectivity. The application of the 2-cyano and -iodine containing anilines was developed in the synthesis of indoloindole derivatives via CuSO4-catalyzed N-benzylation and cyclization reaction in ‘one pot’. More interestingly, the photophysical property investigations of these 2-cyano and 2-ester containing anilines exhibit excellent fluorescent properties, which have great potential application in the development of interesting near-ultraviolet optical devices in the near future.

Stereoselective Addition of Alkynes to Ketenimines: Copper/Amine Catalyzed Sulfonyl Azide–Alkyne Cycloaddition Reactions for the Synthesis of (Z)-1,3-Enynes

Herein, we report a copper/amine catalyzed stereoselective addition of alkynes to ketenimine intermediates generated in situ from the sulfonyl azide-alkyne cycloaddition cascade for the stereoselective synthesis of (Z)-1,3-enynes. Significantly, for the first-time, enamine intermediates generated in the copper-catalyzed sulfonyl azide-alkyne cycloaddition reactions have been successfully trapped and isolated as the products. Density functional theory computations have also been performed and found to be consistent with the observed experimental stereoselectivity.

Triazole-Functionalized Mesoporous Materials Based on Poly(styrene-block-lactic acid): A Morphology Study of Thin Films.

We report the synthesis of poly(styrene-block-lactic acid) (PS-b-PLA) copolymers with triazole rings as a junction between blocks. These materials were prepared via a ‘click’ strategy which involved the reaction between azide-terminated poly(styrene) (PS-N3) and acetylene-terminated poly(D,L-lactic acid) (PLA-Ac), accomplished by copper-catalyzed azide-alkyne cycloaddition reaction. This synthetic approach has demonstrated to be effective to obtain specific copolymer structures with targeted self-assembly properties. We observed the self-assembly behavior of the PS-b-PLA thin films as induced by solvent vapor annealing (SVA), thermal annealing (TA), and hydrolysis of the as-spun substrates and monitored their morphological changes by means of different microscopic techniques. Self-assembly via SVA and TA proved to be strongly dependent on the pretreatment of the substrates. Microphase segregation of the untreated films yielded a pore size of 125 nm after a 45-min SVA. After selectively removing the PLA microdomains, the as-spun substrates exhibited the formation of pores on the surface, which can be a good alternative to form an ordered pattern of triazole functionalized porous PS at the mesoscale. Finally, as revealed by scanning electron microscopy–energy dispersive X-ray spectroscopy, the obtained triazole-functionalized PS-porous film exhibited some affinity to copper (Cu) in solution. These materials are suitable candidates to further study its metal-caption properties.

On-Surface Azide–Alkyne Cycloaddition Reaction: Does It Click with Ruthenium Catalysts?

Owing to its simplicity, selectivity, high yield, and the absence of byproducts, the “click” azide–alkyne reaction is widely used in many areas. The reaction is usually catalyzed by copper(I), which selectively produces the 1,4-disubstituted 1,2,3-triazole regioisomer. Ruthenium-based catalysts were later developed to selectively produce the opposite regioselectivity—the 1,5-disubstituted 1,2,3-triazole isomer. Ruthenium-based catalysis, however, remains only tested for click reactions in solution, and the suitability of ruthenium catalysts for surface-based click reactions remains unknown. Also unknown are the electrical properties of the 1,4- and 1,5-regioisomers, and to measure them, both isomers need to be assembled on the electrode surface. Here, we test whether ruthenium catalysts can be used to catalyze surface azide–alkyne reactions to produce 1,5-disubstituted 1,2,3-triazole, and compare their electrochemical properties, in terms of surface coverages and electron transfer kinetics, to those of the compound formed by copper catalysis, 1,4-disubstituted 1,2,3-triazole isomer. Results show that ruthenium(II) complexes catalyze the click reaction on surfaces yielding the 1,5-disubstituted isomer, but the rate of the reaction is remarkably slower than that of the copper-catalyzed reaction, and this is related to the size of the catalyst involved as an intermediate in the reaction. The electron transfer rate constant (ket) for the ruthenium-catalyzed reaction is 30% of that measured for the copper-catalyzed 1,4-isomer. The lower conductivity of the 1,5-isomer is confirmed by performing nonequilibrium Green’s function computations on relevant model systems. These findings demonstrate the feasibility of ruthenium-based catalysis of surface click reactions and point toward an electrical method for detecting the isomers of click reactions.

Synthesis of Eleven-Membered Cyclic Urea Fused Quinazolinones

AbstractStraightforward synthesis of quinazolinones having N-fused medium-sized ring urea was accomplished. Key intermediates were tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates derived from copper-catalyzed domino reaction of tert-butyl [2-(2-iodobenzamido)ethyl]carbamates and cyclic enaminones. Steric hindrance of cyclic enaminones played an important role in the formation of quinazolinone ring. The eleven-membered ring urea moiety was readily achieved by direct cyclization using 1,1′-carbonyldiimidazole (CDI) of diamino intermediate generated by readily reductive amination and deprotection of tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates.

Copper-Catalyzed Phosphorylation of N,N-Disubstituted Hydrazines: Synthesis of Multisubstituted Phosphorylhydrazides as Potential Anticancer Agents.

An efficient copper-catalyzed aerobic oxidative cross-dehydrogenative coupling reaction for the synthesis of multisubstituted phosphorylhydrazides from N,N-disubstituted hydrazines and hydrogen phosphoryl compounds is accomplished. The reaction proceeds under mild conditions without the addition of any external oxidants and bases. This work reported here represents a direct P(═O)-N-N bond formation with the advantages of being operationally simple, good functional group tolerance, and high atom and step economy. Furthermore, the selected compounds exhibit potential inhibitory activity against tumor cells, which can be used in the field of screening of anticancer agents as new chemical entities.

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.

Directed Copper-Catalyzed Tandem Radical Cyclization Reaction of Alkyl Bromides and Unactivated Olefins.

The free radical cyclization reaction is a promising strategy for ring framework formation. Herein, we report a copper-catalyzed tandem radical cyclization strategy for preparing substituted lactam derivatives. This reaction proceeds through a radical coupling approach, which not only allows a wide range of alkenes but also is quite compatible with the primary, secondary, and tertiary radicals. In addition, density functional theory calculations were performed to gain insights into the reaction mechanism.

Cell-Free Systems Enable the Production of AB5 Toxins for Diagnostic Applications.

Cell-free protein synthesis (CFPS) represents a versatile key technology for the production of toxic proteins. As a cell lysate, rather than viable cells, is used, the toxic effects on the host organism can be circumvented. The open nature of cell-free systems allows for the addition of supplements affecting protein concentration and folding. Here, we present the cell-free synthesis and functional characterization of two AB5 toxins, namely the cholera toxin (Ctx) and the heat-labile enterotoxin (LT), using two eukaryotic cell-free systems based on Chinese hamster ovary (CHO) and Spodoptera frugiperda (Sf21) cells. Through an iterative optimization procedure, the synthesis of the individual AB5 toxins was established, and the formation of multimeric structures could be shown by autoradiography. A functional analysis was performed using cell-based assays, thereby demonstrating that the LT complex induced the characteristic cell elongation of target cells after 24 h. The LT complex induced cell death at higher concentrations, starting at an initial concentration of 5 nM. The initial toxic effects of the Ctx multimer could already be detected at 4 nM. The detection and characterization of such AB5 toxins is of utmost importance, and the monitoring of intracellular trafficking facilitates the further identification of the mechanism of action of these toxins. We showed that the B-subunit of LT (LTB) could be fluorescently labeled using an LTB-Strep fusion protein, which is a proof-of-concept for future Trojan horse applications. Further, we performed a mutational analysis of the CtxA subunit as its template was modified, and an amber stop codon was inserted into CtxA’s active site. Subsequently, a non-canonical amino acid was site-specifically incorporated using bio-orthogonal systems. Finally, a fluorescently labeled CtxA protein was produced using copper-catalyzed click reactions as well as a Staudinger ligation. As expected, the modified Ctx multimer no longer induced toxic effects. In our study, we showed that CFPS could be used to study the active centers of toxins by inserting mutations. Additionally, this methodology can be applied for the design of Trojan horses and targeted toxins, as well as enabling the intracellular trafficking of toxins as a prerequisite for the analysis of the toxin’s mechanism of action.