Alkyne Moiety Research Articles

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.

Backbone-driven host-dopant miscibility modulates molecular doping in NDI conjugated polymers.

Molecular doping is the key to enabling organic electronic devices, however, the design strategies to maximize doping efficiency demands further clarity and comprehension. Previous reports focus on the effect of the side chains, but the role of the backbone is still not well understood. In this study, we synthesize a series of NDI-based copolymers with bithiophene, vinylene, and acetylenic moieties (P1G, P2G, and P3G, respectively), all containing branched triethylene glycol side chains. Using computational and experimental methods, we explore the impact of the conjugated backbone using three key parameters for doping in organic semiconductors: energy levels, microstructure, and miscibility. Our experimental results show that P1G undergoes the most efficient n-type doping owed primarily to its higher dipole moment, and better host–dopant miscibility with N-DMBI. In contrast, P2G and P3G possess more planar backbones than P1G, but the lack of long-range order, and poor host–dopant miscibility limit their doping efficiency. Our data suggest that backbone planarity alone is not enough to maximize the electrical conductivity (σ) of n-type doped organic semiconductors, and that backbone polarity also plays an important role in enhancing σ via host–dopant miscibility. Finally, the thermoelectric properties of doped P1G exhibit a power factor of 0.077 μW m−1 K−2, and ultra-low in-plane thermal conductivity of 0.13 W m−1K−1 at 5 mol% of N-DMBI, which is among the lowest thermal conductivity values reported for n-type doped conjugated polymers.

Engineered biosynthesis of alkyne-tagged polyketides.

Polyketides have demonstrated their significance as therapeutics, industrial products, pesticides, and biological probes following intense study over the past decades. Tagging polyketides with a bioorthogonal functionality enables various applications such as diversification, quantification, visualization and mode-of-action elucidation. The terminal alkyne moiety, as a small, stable and highly selective clickable functionality, is widely adopted in tagging natural products. De novo biosynthesis of alkyne-tagged polyketides offers the unique advantage of reducing the background from feeding the biorthogonal moiety itself, leading to the accomplishment of in situ generation of a clickable functionality for bioorthogonal reactions. Here, we introduce several engineering strategies to apply terminal alkyne biosynthetic machinery, represented by JamABC, which produces a short terminal alkyne-bearing fatty acyl chain on a carrier protein, to functions with different downstream polyketide synthases (PKSs). Successful results in engineering type III and type I PKSs provide engineering guidelines and strategies that are applicable to additional PKSs to produce targeted alkyne-tagged metabolites for chemical and biological applications.

Decarbonylative Sonogashira Cross-Coupling: Fruitful Marriage of Alkynes with Carboxylic Acid Electrophiles.

The Sonogashira cross-coupling is one of the most fundamental C-C bond forming reactions, wherein the strategic value of the alkyne moiety has found widespread application at the frontiers of organic chemistry, materials science and drug discovery as the cornerstone building block of chemical synthesis. Although traditional variants of Sonogashira cross-coupling involve aryl halides and pseudohalides as electrophiles, recently, tremendous advances have been made in the unconventional disconnection exploiting common carboxylic acids by decarbonylation/transmetalation pathway. This manifold (1) permits to take advantage of carboxylic acids as a ubiquitous class of substrates in organic synthesis that are derived from an orthogonal pool of precursors to aryl halides and pseudohalides, (2) combines the benefits of the palladium catalyzed C(sp2)-C(sp) coupling of terminal alkynes with the inherent presence of the carboxylic acid moiety in pharmaceuticals, natural products and organic materials. In this highlight article, we summarize recent progress generated by the decarbonylative Sonogashira cross-coupling of carboxylic acid electrophiles to produce arylalkynes and conjugated enynes as a novel avenue for chemical synthesis, whereby a large number of chemical reactions critically rely on transformations of alkynes.

Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC50 of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC50 of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface.

Synthesis of Polycyclic Aromatic Hydrocarbons Decorated by Fluorinated Carbon Acids/Carbanions.

The carboarylation reaction of biphenyl-alkynes was successfully triggered by electrophilic attack of 1,1-bis(triflyl)ethylene on the alkyne moiety to give polycyclic aromatic hydrocarbons (PAHs) decorated by superacidic carbon acid functionality. Neutralisation of thus obtained acids with NaHCO3 yielded the corresponding sodium salts, which showed improved solubility in both aqueous and organic solvents.

Triaminocyclopentadienyl Ruthenium Complexes - New Catalysts for Cascade Conversions of Propargyl Alcohols.

Various triaminocyclopentadienyl ruthenium complexes have been synthesized from Ru3(CO)12. The new complexes were tested for their ability to catalyze cascade conversions of propargyl alcohols. Their associated catalytic activities complement the activities of known diaminocyclopentadienone ruthenium complexes. In particular, the substrate scope of catalytic cycloadditions with 3‐ketolactones or phloroglucinol derivatives is extended to terpenoid‐derived propargyl alcohols containing an internal alkyne moiety. A wide range of cyclic terpenoid and phloroglucinol adducts are obtained by complementary application of both types of catalysts.

Catalytic Enantioselective Construction of Chiroptical Boron-Stereogenic Compounds.

The construction of main group heteroatom-stereogenic compounds is of great importance due to their intriguing chemical, physical, biological, and stereoelectronic properties. Despite that organoboron compounds are widely used in organic chemistry, the creation of a tetrahedral boron-stereogenic center in one enantiomeric form remains highly challenging. Given the labile nature of ligands attached to the tetracoordinate boron atom, only a handful of enantioenriched boron-stereogenic compounds have been reported via resolution or a chiral substrate-induced diastereoselective approach. To date catalytic asymmetric synthesis of boron-stereogenic compounds has remained unknown. Here, we demonstrate the first catalytic enantioselective construction of boron-stereogenic compounds via an asymmetric copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. This enantioselective CuAAC reaction not only gives access to a wide range of novel highly functionalized boron-stereogenic heterocycles in high yields with good to excellent enantioselectivities but also produces optically active terminal alkyne and triazole moieties with various potential application prospects. Further transformation of the chiral tetracoordinate boron compounds delivers several complex heterocyclic entities bearing boron-stereogenic centers without the loss of enantiopurity. Moreover, the X-ray structure, the barrier to racemization, and the HOMO/LUMO gap of selected tetracoordinate boron compounds are investigated. Notably, these novel N,N π-conjugated boron-stereogenic compounds exhibit bright fluorescence. The optical properties, including circular dichroism, quantum yield, and circular polarized luminescence spectroscopies, are examined. These features expand the chemical space of the chiroptical boron-based dye platform, which could have great potential applications in chiral optoelectronic materials.

Synthesis of Spiro[chromene-imidazo[1,2-a]pyridin]-3'-imines via 6-exo-dig Cyclization Reaction.

A transition-metal-free postmodification of the Groebke-Blackburn-Bienaymé (GBB) reaction for the synthesis of spiro[chromene-imidazo[1,2-a]pyridin]-3'-imine was discovered. The unusual transformation represents the first example of activation and the reaction of the imidazole carbon atom. In this postcondensational modification, KOt-Bu acts as a base, which, after the isomerization of an alkyne moiety to allene, causes the next unique nucleophilic reaction of the imidazole carbon atom that results in spirocyclic structures. The proposed reaction mechanism was confirmed based on the DFT calculations.

"Golden" Cascade Cyclization to Benzo[c]-Phenanthridines.

Herein, we describe a gold‐catalyzed cascade cyclization of Boc‐protected benzylamines bearing two tethered alkyne moieties in a domino reaction initiated by a 6‐endo‐dig cyclization. The reaction was screened intensively, and the scope was explored, resulting in nine new Boc‐protected dihydrobenzo[c]phenanthridines with yields of up to 98 %; even a π‐extension and two bidirectional approaches were successful. Furthermore, thermal cleavage of the Boc group and subsequent oxidation gave substituted benzo[c]phenanthridines in up to quantitative yields. Two bidirectional approaches under the optimized conditions were successful, and the resulting π‐extended molecules were tested as organic semiconductors in organic thin‐film transistors.