Alkyne Moiety Research Articles

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.

Sulfilimines as Transformable and Retainable Directing Groups in Rhodium-Catalyzed ortho-C-H Bond Functionalization.

Shown herein is the first time that the sulfilimine is utilized as a directing group for Rh(III)-catalyzed C-H activation/annulation with intermolecular and intramolecular alkyne compounds. Sulfilimine serves as a transformable directing group, an internal oxidant, in the annulation with an alkyne moiety via N-S bond cleavage. Notably, the retention of sulfilimine as a directing group is also achieved in the Rh(III)-catalyzed ortho-alkynylation with alkyne bromides.

Highly Fluorinated Peptide Probes with Enhanced In Vivo Stability for 19 F-MRI.

A labeling strategy for in vivo 19 F-MRI (magnetic resonance imaging) based on highly fluorinated, short hydrophilic peptide probes, is developed. As dual-purpose probes, they are functionalized further by a fluorophore and an alkyne moiety for bioconjugation. High fluorination is achieved by three perfluoro-tert-butyl groups, introduced into asparagine analogues by chemically stable amide bond linkages. d-amino acids and β-alanine in the sequences endow the peptide probes with low cytotoxicity and high serum stability. This design also yielded unstructured peptides, rendering all 27 19 F substitutions chemically equivalent, giving rise to a single 19 F-NMR resonance with <10Hz linewidth. The resulting performance in 19 F-MRI is demonstrated for six different peptide probes. Using fluorescence microscopy, these probes are found to exhibit high stability and long circulation times in living zebrafish embryos. Furthermore, the probes can be conjugated to bovine serum albumin with only amoderate increase in 19 F-NMR linewidth to ≈30Hz. Overall, these peptide probes are hence suitable for in vivo 19 F-MRI applications.

Synthesis of 2-Pyrazolines with a CF3- and Alkyne-Substituted Quaternary Carbon Center via [3 + 2] Cycloaddition of β-CF3-1,3-enynes and Diazoacetates.

Given the importance of both the CF3 group and the alkyne moiety in synthetic/medicinal chemistry, we report here the first example of efficient synthesis of 2-pyrazolines with a CF3- and alkyne-substituted quaternary carbon center. This methodology has the advantages of high functional group compatibility, the avoidance of base and open-flask conditions, easily available and easy to handle reagent, and broad substrate scope. Notably, this protocol allows for the late-stage functionalization of biologically active molecules and the gram-scale synthesis.

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes.

Alkynyl selenides have attracted considerable research interest recently, owing to their applications in the biological and pharmaceutical fields. The Cu-catalyzed tandem reaction for the synthesis of novel alkynyl imidazopyridinyl selenides is presented. A one-pot synthesis route afforded alkynyl imidazopyridinyl selenides in moderate to good yields. This was achieved by a two-step reaction between terminal alkynes and diimidazopyridinyl diselenides, generated from imidazo[1,2-a]pyridines and Se powder, using 10 mol % of CuI and 1,10-phenanthroline as the catalytic system under aerobic conditions. The C(sp2)–Se and C(sp)–Se bond-formation reaction can be performed in one-pot by using inexpensive and easy to handle Se powder as the Se source. The reaction proceeded with terminal alkynes having various substitutions, such as aryl, vinyl, and alkyl groups. The obtained alkynyl imidazopyridinyl selenide was found to undergo nucleophilic substitution reaction on Se atom using organolithium reagents and 1,3-dipolar azide–alkyne cycloaddition based on the alkyne moiety.

New Synthetic Routes to Introduce Sp 3-Defects in Carbon Nanotubes with a Variety of Functional Groups

The controlled functionalization of single-walled carbon nanotubes (SWNTs) with luminescent sp 3-defects has emerged as a powerful tool to enhance their usually low photoluminescence quantum yields and has created the potential to employ them for bioimaging and optical sensors. For that, it is necessary to match and adapt the substituents of the sp 3-defects to the desired application. To attach a large variety of complex substituents to sp 3-defects an universal approach is required. Here, we introduce sp 3-defects to polymer-wrapped (6,5) SWNTs via diazonium salt chemistry [ACS Nano 2021, 15, 5147–5157] bearing an alkyne moiety and subsequently add the desired substituent by click-chemistry. This opens up the possibility to introduce many different functional groups such as stable organic radicals, photosensitizers or fluorophores, which are already available for click-reactions. This approach is not limited to E11* defects introduced by diazonium chemistry, but can be further extended to more red-shifted E11*− defects [Nat. Commun. 2021, 12, 2119].

Design, Synthesis, and Applications of ortho -Sulfur Substituted Arylphosphanes

Design, Synthesis, and Applications of <i>ortho</i> -Sulfur Substituted Arylphosphanes

Combined Brønsted Base-Promoted CO2 Fixation into Benzylic C-H Bonds of Alkylarenes.

Interest in developing methods for direct CO2 fixation into readily available unfunctionalized C-H bonds in organic substances has recently surged. In contrast to the well-studied carboxylations of alkynyl C(sp)-H and aromatic C(sp2)-H bonds, carboxylation of benzylic C(sp3)-H bonds to produce 2-arylacetic acids is limited to photoirradiation reactions and continues to be a challenging issue because of the low chemical reactivity. We herein describe that a combined Brønsted base (i.e., LiO-t-Bu/CsF and LiOCEt3/CsF) achieves benzylic carboxylation of electron-deficient, -neutral, and -rich alkylarenes and enables various functionalities, including fragile ones such as bromide, alkene, alkyne, and carbonyl moieties. Dicarboxylation at the benzylic position is also established. Cs-alkoxide generated in situ acts as a reactive base, as demonstrated in experiments with independently prepared CsO-t-Bu and by 133Cs nuclear magnetic resonance studies.

The Use of Bridging Ligand Substituents to Bias the Population of Localized and Delocalized Mixed-Valence Conformers in Solution.

The electronic structure and associated spectroscopic properties of ligand‐bridged, bimetallic ‘mixed‐valence’ complexes of the general form {M}(μ‐B){M+} are dictated by the electronic couplings, and hence orbital overlaps, between the metal centers mediated by the bridge. In the case of complexes such as [{Cp*(dppe)Ru}(μ‐C≡CC6H4C≡C){Ru(dppe)Cp*}]+, the low barrier to rotation of the half‐sandwich metal fragments and the arylene bridge around the acetylene moieties results in population of many energy minima across the conformational energy landscape. Since orbital overlap is also sensitive to the particular mutual orientations of the metal fragment(s) and arylene bridge through a Karplus‐like relationship, the different members of the population range exemplify electronic structures ranging from strongly localized (weakly coupled Robin‐Day Class II) to completely delocalized (Robin‐Day Class III). Here, we use electronic structure calculations with the hybrid density functional BLYP35‐D3 and a continuum solvent model in combination with UV‐vis‐NIR and IR spectroelectrochemical studies to show that the conformational population in complexes [{Cp*(dppe)Ru}(μ‐C≡CArC≡C){Ru(dppe)Cp*]+, and hence the dominant electronic structure, can be biased through the steric and electronic properties of the diethynylarylene (Ar) moiety (Ar=1,4‐C6H4, 1,4‐C6F4, 1,4‐C6H2‐2,5‐Me2, 1,4‐C6H2‐2,5‐(CF3)2, 1,4‐C6H2‐2,5‐iPr2).

Study on halogen promoted cyclization of 2‐alkynylthiobenzimidazoles

AbstractElectrophile promoted nucleophilic cyclization of 2‐alkynylthiobenzimidazoles was investigated. N‐halosuccinimides were chosen as electrophile source in formation of substituted benzimidazo[2,1‐b]thiazoles and benzimidazo[2,1‐b][1,3]thiazines. Reaction pathway via 6‐endo‐dig or 5‐exo‐dig cyclization of substrates depended on substituents to the alkyne moiety, though with bromine electrophile in some cases benzimidazole moiety predominated alkyne and aromatic substitution reaction was observed. Compounds with prolonged linkage in 2‐(propynylthio)methylbenzimidazoles formed only 7‐endo‐dig products.

Development of Universal and Clickable Film by Mimicking Melanogenesis: On-Demand Oxidation of Tyrosine-Based Azido Derivative by Tyrosinase.

A tyrosine-based azido derivative (TBAD) that permits both substrate-independent surface coating and clickable film functionalization by mimicking natural melanogenesis is synthesized here. In contrast to catechol derivatives, which are generally susceptible to oxidation by air under ambient conditions, the monophenol-based TBAD remains stable under alkaline and neutral conditions and is activated to oxidized quinone in situ by tyrosinase to initiate melanin-like polymerization. The resulting poly(TBAD) film can be formed on various substrates including noble metals, metal oxides, and synthetic polymers, which can undergo click reaction with terminal alkyne moieties on the entire surface or a specific region through Cu(I)-catalyzed azide-alkyne cycloaddition. The enzyme-mediated coating can rapidly form thin films (≈10nm) and produce a uniform film morphology, which are important aspects in surface chemistry. This on-demand, clickable coating may become a significant tool for bioconjugation, soft lithography, and labeling techniques.

A facile approach for the fabrication of antibacterial nanocomposites: A case study for AgNWs/Poly(1,4-Cyclohexanedimethylene Acetylene Dicarboxylate) composite networks by aza-Michael addition

Nanotechnological improvements allow the production of new generation materials among which nanocomposite-based polymers are increasingly applied for wide variety of applications due to the demand increment of improving life quality of mankind. This article describes a simple, facile and fast route which could be adopted for the synthesis of metal nanocomposite materials with a variety of polymers. In this purpose, the cysteamine compound containing an amine (–NH2) and a thiol (–SH) functional groups was incorporated onto silver nanowires (NH2-AgNWs). Next, poly(1,4-Cyclohexanedimethylene Acetylene Dicarboxylate) (PCA) possessing electron deficient internal alkyne moiety is synthesized starting from acetylene dicarboxylic acid (ADCA). Finally, one-pot aza-Michael addition is then realized between prepared NH2-AgNWs and synthesized PCA to achieve a series of cross-linked antibacterial nanocomposite networks (PCA:NH2-AgNWs = 1; 5; 10 wt%). The nanocomposites and intermediates are fully characterized by Fourier transform infrared and proton nuclear magnetic resonance (FT-IR, 1H NMR) spectroscopies, gel permeation chromatography (GPC) scanning electron microscopy (SEM), Energy–dispersive X-ray spectroscopy (EDS), thermogravimetric and differential scanning calorimetry analyses (TGA and DSC) and antibacterial test. The results reveal that the higher content of AgNWs in the network has occasioned the enhancement in thermostability and glass transition temperature. The antibacterial efficacy tests against Escherichia coli (E. coli, G − ) andStaphylococcus aureus (S.aureus, G + ) further indicate that higher rate of inhibition is attained for nanocomposite network including 10 wt% AgNWs compared to others and pristine PCA. Consequently, a polyester based AgNWs/PCA nanocomposite with antibacterial activity has been considered as a versatile candidate for various promising nanocomposite applications.

Nickel‐Catalyzed Hydroborylative Polycyclization of Allenynes: an Atom‐Economical and Diastereoselective Synthesis of Bicyclic 5‐5 Fused Rings

AbstractA diastereoselective synthesis of borylated bicyclic 5‐5 fused ring systems by a domino Ni‐catalyzed hydroborylative polycyclization of allenynes has been developed. The reaction provides two new C−C and one C−B bonds and constitutes an atom‐economical method. It occurs rapidly, in absence of inert atmosphere, with an inexpensive Ni‐based catalyst and HBpin as boron source. The procedure showed excellent tolerance to functional groups and a wide scope. Derivatization of the borylated bicycles has been performed to explore the synthetic utility of the products. Experimental and DFT‐calculation results suggest that the process starts by an oxidative cyclometallation involving Ni(0) and both the allene and the alkyne moieties, followed by a stereoselective σ‐metathesis with HBpin. Formation of the second ring takes place through a non‐fully coplanar 1,2‐insertion into the Ni−H bond to give a nickelacyclohexene which finally evolves by reductive elimination.magnified image

Synthesis of a novel A-b-(B-co-C)-type terpolymer with a regioregular poly(3-hexylthiophene) segment and its application to intrinsically stretchable transistor memory

To date, a variety of organic semiconductors with high stretchability have been developed for applications in wearable electronic devices. However, there is still a problem of irreversible damage by repeated stretching/releasing cycles, resulting in a low lifetime for the devices. In this study, a novel A-b-(B-co-C)-type terpolymer, where A and B-co-C were regioregular poly(3-hexylthiophene) (P3HT) and poly(nbutyl acrylate-co-acrylic acid) segments, respectively, was successfully synthesized by the copper-catalyzed azide-alkyne cycloaddition reaction of α-chain-end-functionalized P3HT with an azide moiety and α-chain-end-functionalized poly(nbutyl acrylate-co-tbutyl acrylate) with an alkyne moiety, followed by deprotection of tbutyl groups with trifluoroacetic acid. The AFM and OM images of the terpolymer films showed that no cracks formed even when stretched up to 100%. This may be due to the synergistic effect of the low Tg-inducible nbutyl acrylate and hydrogen-bonding-inducible acrylic acid repeating units in the copolymer segment. In addition, the results of organic transistor memory using terpolymer thin films showed that the transferred/stretched electrets could preserve their device performance and produce stable bipolar charge trapping by applying electrical writing/erasing processes.

Azide-Alkyne Click Chemistry over a Heterogeneous Copper-Based Single-Atom Catalyst

One-pot three-component regioselective azide-alkyne cycloadditions are central reactions for synthesizing pharmaceuticals and fine chemicals and are also applied for in vivo metabolic labeling biotechnology. Homogeneous catalysts based on copper species coordinated with ancillary ligands are regularly used to perform this reaction, offering superior catalytic activity and selectivity compared to conventional heterogeneous counterparts based on supported copper nanoparticles. However, the challenge of catalyst recovery limits the use of these homogeneous compounds in many large-scale applications. In this work, we report the high catalytic performance of a family of Cu-based single-atom catalysts for triazole synthesis, with an emphasis on the fundamental understanding of the structure and function of the catalyst. The catalysts were prepared via tricyanomethanide polymerization to create a joint electronic structure where the mesoporous graphitic carbon nitride carrier acts as a ligand for the atomically dispersed copper species. The material properties and the precise metal location/coordination (i.e., deposited in the heptazine pore of carbon nitride, substituted in the framework of carbon nitride, hosted in a vacancy, or entrapped in sandwich-like arrangement) were characterized through a battery of spectroscopic and theoretical methods. The catalysts were employed in the synthesis of 1,2,3-triazoles employing azide-alkyne click reaction under base-free conditions. The single-atom Cu catalysts demonstrated improved activity and selectivity compared to the homogeneous reference catalyst. Density functional theory calculations corroborated the results and showed that the reaction proceeds through a barrier given by the activation of the acetylenic moiety on Cu1. The activity of this step was primarily affected by the coordination of the metal with the support. Therefore, understanding the metal coordination in single-atom catalysts is critical to further optimizing single-atom catalysts and greening synthetic chemistry.

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition

Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 μM.

Enantioselective synthesis of indole-based unnatural β-Alkynyl α-amino acid derivatives via chiral phosphoric acid catalysis.

The synthesis of unnatural α-amino acid derivatives has attracted considerable interest in recent years, as they are ubiquitous in protein synthesis and peptide-based drug discovery. Herein, we reported the chiral phosphoric acid catalyzed asymmetric reaction of indoles with β,γ-alkynyl-α-imino esters for the enantioselective synthesis of unnatural indole-based α-amino acid derivatives. This asymmetric organocatalysis protocol enables efficient synthesis of unnatural α-amino acid derivatives with a tetrasubstituted stereogenic center and an alkyne moiety with up to 99% yield and 98% ee, resulting in operationally simple conditions, short reaction time, and broad substrate scope.

Catalytic Asymmetric Michael Reaction of Methyl Alkynyl Ketone Catalyzed by Diphenylprolinol Silyl Ether.

The asymmetric Michael reaction of methyl alkynyl ketone and α,β-unsaturated aldehyde catalyzed by diphenylprolinol silyl ether was developed. Although methyl alkynyl ketone is a good Michael acceptor, it also acts as a Michael donor to afford the synthetically important δ-oxo aldehydes with excellent enantioselectivity. The products possessing several functional groups, such as alkyne, ketone, and aldehyde moieties, are useful chiral building blocks for further synthesis. Using this reaction as a key step, a side chain of atorvastatin (Lipitor), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was synthesized in a two-pot sequence with excellent diastereo- and enantioselectivities.

Substrate Profiling of Anion Methyltransferases for Promiscuous Synthesis of S-Adenosylmethionine Analogs from Haloalkanes.

Biocatalytic alkylation reactions can be performed with high chemo‐, regio‐ and stereoselectivity using S‐adenosyl‐l‐methionine (SAM)‐dependent methyltransferases (MTs) and SAM analogs. Currently, however, this methodology is limited in application due to the rather laborious protocols to access SAM analogs. It has recently been shown that halide methyltransferases (HMTs) enable synthesis and recycling of SAM analogs with readily available haloalkanes as starting material. Here we expand this work by using substrate profiling of the anion MT enzyme family to explore promiscuous SAM analog synthesis. Our study shows that anion MTs are in general very promiscuous with respect to the alkyl chain as well as the halide leaving group. Substrate profiling further suggests that promiscuous anion MTs cluster in sequence space. Next to iodoalkanes, cheaper, less toxic, and more available bromoalkanes have been converted and several haloalkanes bearing short alkyl groups, alkyl rings, and functional groups such as alkene, alkyne and aromatic moieties are accepted as substrates. Further, we applied the SAM analogs as electrophiles in enzyme‐catalyzed regioselective pyrazole allylation with 3‐bromopropene as starting material.

The fungal elicitor eutypine from Eutypa lata activates basal immunity through its phenolic side chains.

Grapevine trunk diseases (GTDs) affect grape production and reduce vineyard longevity worldwide. Since the causative fungi also occur in asymptomatic trunks, we address disease outbreak in terms of altered chemical communication between host and endophyte. Here, we identified four chemically similar secondary metabolites secreted by the GTD-associated fungus Eutypa lata to analyse their modes of action in a grapevine cell culture of Vitis rupestris, where microtubules were tagged by GFP. Treatment with the metabolite eutypine activated defence responses, evident from extracellular alkalinisation and induction of defence genes. Eutypinol, instead, eliminated microtubules, in contrast to the other three compounds. Furthermore, we evaluated the effect of four corresponding chemical analogues of these compounds, sharing the phenolic but lacking the alkyne moiety. These analogues were able to induce similar defence responses in V. rupestris cells, albeit at reduced amplitude. Since closely related moieties differing only in details of the side groups at the phenolic ring differ significantly with respect to the response of the host cell, we propose that these fungal compounds act through a specific binding site at the membrane of grapevine cells. We corroborate this specificity by combination experiments, where the eutypine and the eutypinol analogues behave competitively with respect to the elicited responses. In summary, Eutypa lata secretes compounds that elicit host defence in a specific manner by interfering with early events of immunity signalling. This supports the notion that a real understanding of GTDs has to address inter-organismic chemical communication.