Aryl Alkynes Research Articles

Synthetic Strategy for Aryl(alkynyl)phosphinates by a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Alkynes.

An efficient and straightforward method for the synthesis of aryl(alkynyl)phosphinates was developed via a three-component coupling reaction involving arynes, phosphites, and alkynes. An array of aryl(alkynyl)phosphinates were produced from both aryl and aliphatic group-substituted acetylenes. This operationally simple reaction is tolerant to many functional groups, affording various aryl(alkynyl)phosphinates in moderate to good yields. The synthetic utility of alkynyl phosphinates afforded by this method was demonstrated by the elaboration of the products into various phosphorus-containing compounds.

Hantzsch Ester-Mediated Visible-Light-Induced Radical Ethoxycarbonyldifluoromethylation of Aryl Alkynes: Kinetic-Controlled Stereoselective Synthesis of Z-gem-Difluoroallyl Esters.

A kinetic-controlled photocatalyst-free visible-light-induced stereoselective synthesis of α,α-gem-difluoro-Z-allyl esters was succeeded at room temperature in moderate to excellent yields with up to Z-isomer-only stereoselectivities through a reductive radical ethoxycarbonyldifluoromethylation of terminal aryl alkynes with blue LED (465 nm)-excited Hantzsch ester. The geometry optimizations obtained by the DFT/B3LYP calculation with a standard 6-31G(d,p) basis set were also employed for the mechanism study on the formation of a key α,α-difluoroallyl ester radical intermediate, which was generated from the addition of the ethoxycarbonyldifluoromethyl radical to aryl alkyne substrates and the stabilization effect of the neighboring group. Subsequent steric hindrance-determined hydrogen generated from the Hantzsch ester radical cation led to the formation of final aryl-substituted Z-difluoroallyl esters. This methodology provided convenient access to the synthetically important Z-configured gem-difluoroallylic building blocks.

Synthesis of Benzofurans from Sulfur Ylides and ortho‐Hydroxy‐Functionalized Alkynes

AbstractThe synthesis of benzofurans from readily accessible sulfur ylides and ortho‐hydroxy aryl alkynes is reported. The transformation proceeds through an isomerization/nucleophilic addition/cyclization/aromatization cascade. The substrate scope is very general with respect to both reactants and the products are afforded in 43–94% yield under conditions which are catalyst‐free and additive‐free.magnified image

Dimerization of aryl alkynes by Grubbs-Hoveyda complex: investigation of factors affecting the efficiency of the process based on experimental and theoretical approaches

The 2nd generation Grubbs-Hoveyda complex in the presence of slight excess of triphenylphosphine was found as an efficient catalyst for the synthesis of 1,4-disubstituted enynes with preference for head-to-head coupling and Z-selectivity form in the dimerization of various terminal aryl alkynes. Selective product formation was affected by the steric and the electronic properties of the phosphine used as well as the substituents of the alkynes. In order to shed some light on the properties of the alkynes that may affect the yield of desired products a set of 14 alkyne derivatives was characterized on the basis of Density Functional Theory (DFT) using ωB97XD functional and 6-311++G(d,p) basis set. The Atoms in Molecules (AIM) theory was employed for electronic structure and topological analyses of the investigated compounds. The quantitative description of the substituent effect was carried out with assistance of the Harmonic Oscillator Model of Aromaticity (HOMA), charge of the Substituent Active Region (cSAR(X)) and Substituent Effect Stabilization Energy (SESE). It was found that substituents in the phenyl ring are able to affect the geometric and electronic structure of the alkynyl moiety. The experimental and theoretical results revealed that high activity of the investigated ruthenium complex towards dimerization of alkynes is related with σ-donor ability and bulkiness of added phosphine combined with small size aryl alkyne bearing electron-withdrawing group. However, the influence of the structure of aryl alkyne on the catalyst activity could not be easily explained only on the basis of steric and electronic factors.

Visible-Light-Induced Oxidative α-keto-Dichlorination of Arylalkynes by CuCl2 at Room Temperature.

A visible light-induced oxidative α-keto-dichlorination of terminal and internal aryl alkynes was developed to form dichloroacetophenones (DCAPs) and dichlorophenyl-acetophenones (DCPAPs), respectively, by using CuCl2 as a photoredox catalyst in the presence of air at room temperature (without using any exogenous photocatalyst). Here, photoexcited CuCl2 underwent ligand-to-metal charge transfer to generate a Cl radical, which readily added to the alkynes to form DCAPs or DCPAPs in the presence of O2 . This α-keto-dichlorination reaction is a green and mild protocol as it produced water as the only by-product. Moreover, the evaluation of green chemistry metrics indicated that the E-factor (mass of wastes/mass of products) of the current α-keto-chlorination method is around 10.1 times lower than that of a literature-reported photochemical method. The Eco Scale value (score 55, which on a scale of 0-100 indicates an acceptable synthesis) signifies that this process is simple, highly efficient, eco-friendly, and cost-effective.

Novel palladium tagged ferrite nanoparticle supported ionic liquid phase catalyst for the efficient copper-free Sonogashira coupling

An efficient protocol for the copper-free Sonogashira coupling of aryl halides with terminal alkynes using novel palladium tagged, magnetic nanoparticle supported, ionic liquid phase catalyst (Pd-SILP-Fe3O4@SiO2) in water under aerobic conditions has been developed. The newly synthesized catalyst was characterized by FTIR, XPS, SEM, TEM, XRD, EDS, VSM, ICP-AES, and BET techniques. Various substituted aryl alkynes were synthesized with excellent yields using a highly water dispersible Pd-SILP-Fe3O4@SiO2 catalyst. The synthesized nanocatalyst displayed high thermal stability, compatibility in aqueous systems, high catalytic efficiency, high turnover frequencies (TOF), easy magnetic recovery, and reusability up to 6th run. The main advantages of the protocol are its robustness, mild reaction conditions, easy set-up, easy workup, low Pd loading (0.001 mol % of Pd), higher yields, and use of water as a green solvent, which makes it both environmentally and economically appealing.

Iron(III)‐Catalyzed Difluoroalkylation of Aryl Alkynes with Difluoroenol Silyl Ether in the Presence of Trimethylsilyl Chloride

AbstractThe reaction of non‐fluorinated silyl enol ether with alkyne is useful for the synthesis of β,γ‐unsaturated carbonyl compounds. However, most of the existing methods for realizing such organic transformation usually employ stoichiometric amounts of relatively expensive Lewis acids/metallic salts. Herein, an iron(III)‐catalyzed difluoroalkylation of aryl alkynes with difluoroenol silyl ether was developed. The reactions proceeded smoothly in the presence of a catalytic amount of iron(III) chloride, stoichiometric amounts of trimethylsilyl chloride, and 4 Å molecular sieves in dichloroethane (DCE) to afford the corresponding α‐alkenyl‐α,α‐difluoroketones in modest to good yields. Remarkably, among the various metallic salts screened, cheap and less‐toxic iron(III) salt was found to be the most efficient Lewis acid catalyst for the present reaction. In addition, in the absence of iron(III) chloride or trimethylsilyl chloride, either no reaction occurred or considerably reduced reaction performance was observed. Moreover, the use of Brønsted acid to replace iron(III) chloride as reaction catalyst failed to promote the reaction. The reaction could be scaled up and the obtained difluoroalkylated carbonyl compound serves as a versatile building block which could be subjected to late‐stage diversification to be converted into useful organic molecules containing CF2H and CF2CF2 moieties. Deuterated experiments showed that the proton in the generated alkene product should originate from trace amounts of water present in the reaction system.magnified image

Genetically Encoded Aryl Alkyne for Raman Spectral Imaging of Intracellular α-Synuclein Fibrils

α-Synuclein (α-syn) is an intrinsically disordered protein involved in a group of diseases collectively termed synucleinopathies, characterized by the aggregation of α-syn to form insoluble, β-sheet-rich amyloid fibrils. Amyloid fibrils are thought to contribute to disease progression through cell-to-cell transmission, templating and propagating intracellular amyloid formation. Raman spectral imaging offers a direct characterization of protein secondary structure via the amide-I backbone vibration; however, specific detection of α-syn conformational changes against the background of other cellular components presents a challenge. Here, we demonstrate the ability to unambiguously identify cellularly internalized α-syn fibrils by coupling Raman spectral imaging with the use of a genetically encoded aryl alkyne, 4-ethynyl-l-phenylalanine (FCC), through amber codon suppression. The alkyne stretch (CC) of FCC provides a spectrally unique molecular vibration without interference from native biomolecules. Cellular uptake of FCC-α-syn fibrils formed in vitro was visualized in cultured human SH-SY5Y neuroblastoma cells by Raman spectral imaging. Fibrils appear as discrete cytosolic clusters of varying sizes, found often at the cellular periphery. Raman spectra of internalized fibrils exhibit frequency shifts and spectral narrowing relative to in vitro fibrils, highlighting the environmental sensitivity of the alkyne vibration. Interestingly, spectral analysis reveals variations in lipid and protein recruitment to these aggregates, and in some cases, secondary structural changes in the fibrils are observed. This work sets the groundwork for future Raman spectroscopic investigations using a similar approach of an evolved aminoacyl-tRNA synthetase/tRNA pair to incorporate FCC into endogenous amyloidogenic proteins to monitor their aggregation in cells.

Lewis Acid‐Assisted Transition Metal‐Free Aminocyanation of Alkynes with Arylamines and N‐Cyanosuccinimide

AbstractA transition‐metal‐free aminocyanation of aryl alkynes has been achieved using indium tribromide, InBr3 or B(C6F5)3 as a Lewis acid. This aminocyanation protocol features with non‐toxic cyanide source, a good substrate scope and potentially valuable aminocyanation products. Mechanistic studies reveal the complex formation between Lewis acid and alkyne to produce in situ alkyne nitrile as a key intermediate. Further hydroamination of alkyne nitrile with arylamines affords the E‐selective (E:Z=70:30 to 90:10) β‐aminoacrylonitrile derivatives.magnified image

Radical Multicomponent Alkyl Alkynylation of Propellane via Synergistic Photoredox and Copper Catalysis.

Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of aryl, tert-butyl groups, and internal alkynes that can impact key physicochemical properties on drug candidates. Herein, we describe a novel and efficient reaction to synthesize alkyl-alkynyl-substituted BCP derivatives by synergistic photoredox and copper catalysis at room temperature. The mild reaction conditions, simple protocol, broad functional group tolerance, and high efficiency of this procedure make it a valuable strategy for accessing alkynyl-substituted BCPs.

A Modular Approach for Diversity-Oriented Synthesis of 1,3-trans-Disubstituted Tetrahydroisoquinolines: Seven-Step Asymmetric Synthesis of Michellamines B and C.

1,3-trans-Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3-trans-disubstituted THIQ frameworks through a three-component Catellani reaction and a AuI -catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity-oriented synthesis of 1,3-trans-disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

A Modular Approach for Diversity‐Oriented Synthesis of 1,3‐trans‐Disubstituted Tetrahydroisoquinolines: Seven‐Step Asymmetric Synthesis of Michellamines B and C

Abstract1,3‐trans‐Disubstituted tetrahydroisoquinoline (THIQ) is a common heterocyclic structural unit of naphthylisoquinoline alkaloids. The assembly of this structural unit is not trivial, which constitutes a substantial challenge in the total synthesis of naphthylisoquinoline alkaloids and related pharmaceuticals. Herein, we report a modular and convergent method for the rapid assembly of 1,3‐trans‐disubstituted THIQ frameworks through a three‐component Catellani reaction and a AuI‐catalyzed cyclization/reduction cascade. With widely available simple aryl iodides, aziridines and (triisopropylsilyl)acetylene as the building blocks, this method paves a practical way for the diversity‐oriented synthesis of 1,3‐trans‐disubstituted THIQs. Based on this new method, concise syntheses of an analogue of the new drug mevidalen and four naphthylisoquinoline alkaloids have been accomplished, demonstrating the broad synthetic utility of this approach.

Free Radical Promoted Trifluoromethylthiolation of Alkynes to Access SCF3-Containing Dibenzazepines or Dioxodibenzothiazepines.

Persulfate-promoted radical cascade trifluoromethylthiolation of aryl acetylenes with AgSCF3 provides a simple reaction system for the synthesis of SCF3-substituted dibenzazepines or dioxodibenzothiazepines with good Z/E selectivity. The single-crystal X-ray diffraction data confirms the structures of the final products. A series of scaled-up experiments, further transformations, and radical inhibition experiments were operated in the reaction system.

Click chemistry‐based synthesis of new benzenesulfonamide derivatives bearing triazole ring as selective carbonic anhydrase II inhibitors

A series of 1,2,3-triazol-1-ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc-binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)-mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6-heptadiyne through copper-catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed Ki of 2.8 and 3.8 nM against hCA II and a high hCA II selectivity ratio ranging from 77.6 to 3571.4 over other isoforms. All the compounds were docked in the active site of the downloaded hCA II active site and their binding pattern confirmed their significant activity by interacting of the sulfonamide moiety with zinc ion in the active site, in addition to its hydrogen bond interaction with Thr199 and Thr200. All the above-mentioned findings pointed out towards the promising activity of the synthesized series that can be presented as a new scaffold to be further optimized as selective antiglaucoma drugs.

Site Isolation in Metal–Organic Layers Enhances Photoredox Gold Catalysis

Herein, we report the synthesis of a metal-organic layer, Hf-Ru-Au, containing Ru(bipyridine)32+-type photosensitizers and (phosphine)-AuCl catalysts for photoredox Au-catalyzed cross-coupling of allenoates, alkenes, or alkynes with aryldiazonium salts to afford furanone, tetrahydrofuran, or aryl alkyne derivatives, respectively. Site isolation of (phosphine)-AuCl complexes in Hf-Ru-Au prevents Au catalyst deactivation via ligand redistribution, Au(I) disproportionation, and aryl-phosphine reductive elimination, while the proximity between the Ru photosensitizers and Au catalysts enhances catalytic efficiency, with 14-200 times higher activity over those of the homogeneous controls in the cross-coupling reactions.

Radical Reactions of Vinyl Triflates and its Derivatives

Vinyl triflates are valuable precursors for vinyl cations, vinyl carbenes, and electrophiles for transition-metal-catalyzed cross-coupling reactions. However, in these reactions, the trifluoromethyl group is not installed in the final products. The radical reactions of vinyl triflates were limited until our beginning. We initially achieved the synthesis of α-trifluoromethylated ketones from vinyl triflates using triethyl borane as a radical initiator. Since the reaction proceeds chemoselectivity toward the conjugated vinyl triflates, we achieved the chemo- and regio-selective trifluoromethylation of 1,3-bis(vinyl triflates). We developed one-pot trifluoromethylation from aryl alkynes with perfluoroalkanesulfonic acids in the presence of AIBN as a radical initiator. In addition, a crossover experiment and DFT calculations support that the reaction proceeds through an intermolecular pathway. The radical reaction of vinyl triflates in the presence of alkenes afforded γ-trifluoromethylated ketones. We also developed a one-pot triflation-trifluoromethylation-triflation of imines leading trifluoromethyl-substituted vinyl trifluoromethanesulfonic amides.

Se-(Fluoromethyl) Benzenesulfonoselenoates: Shelf-Stable, Easily Available Reagents for Monofluoromethylselenolation.

A new class of electrophilic monofluoromethylselenolation reagents, Se-(fluoromethyl) benzenesulfonoselenoates, has been developed. They can be readily prepared from sodium benzenesulfinates, Se powder and ClCFH2 in one step under mild reaction conditions. Se-(fluoromethyl) benzenesulfonoselenoates are efficient electrophilic monofluoromethylselenolation reagents for a wide range of nucleophiles including indole, 6-azaindole, pyrrole, thiophene, electron-rich arene, aryl boronic acid and alkyne. The monofluoromethylselenolation approach features mild and environmentally friendly reaction conditions, good tolerance of various functional groups, and broad substrate scope.

Dithiocyanation of Alkynes with N‐Thiocyanato‐dibenzenesulfonimide and Ammonium Thiocyanate

AbstractOrganic thiocyanates widely exist in natural products, and act as important precursors for organic synthesis. An efficient dithiocyanation of alkynes with N‐thiocyanato‐dibenzenesulfonimide (NTSI) as the SCN+ cation and ammonium thiocyanate as the SCN‐ anion sources has been developed. Highly active electrophilic reagent NTSI could react with various types of alkynes to build C(sp2)−SCN bond to provide a variety of dithiocyanato olefin compounds under simple and mild conditions. Trace amount of water is beneficial to the dissociation of ammonium thiocyanate, which makes the SCN‐ anion easier to participate in the reaction. The protocol owns a broad substrates scope including terminal and internal, alkyl and aryl alkynes, excellent functional group tolerance and good regioselectivity.

Cycloaddition of allylic chlorides, aryl alkynes, and carbon dioxide using nanoclusters of polyoxomolybdate buckyball supported by ionic liquid on dendritic fibrous nanosilica

Due to the uncontrolled emissions of CO2 created by industrial procedures that lead to acidification of the oceans and universal warming, various methods have been utilized for direct absorption of CO2 from waste water sources. The generation of green nano catalyst with chemical adjustments to be converted to value-added products can be considered alluring. Therefore, we synthesized Polyoxomolybdate [Mo132] nanoball with different alkyl groups loaded on dendritic fibrous nanosilica by ionic liquid (DFNS/IL/Mo132) using an easy synthetic route. Owing to the DFNS/IL/Mo132 morphology, a suitable external level for CO2 uptake was generated at all Mo132 sites. Results revealed that DFNS/IL/Mo132 positively influenced the preparation efficiency of 3a,4-dihydronaphtho[2,3-c]furan-1(3H)-one through a three-element binding reaction of alkynes, allylic chlorides, and carbon dioxide. This approach is beneficial in terms of profitable efficacy and forbearance of functional groups.

Porous chitosan-derived activated N-doped carbon-supported Pd nanoparticles encaged in Al, Fe pillared montmorillonite as novel heterogeneous catalysts

Novel pillared montmorillonite encaging porous chitosan derived activated N-doped carbon-supported Pd nanoparticles catalyst (Pd@Al, Fe-Mt/N-C) was synthesized by ion-exchange of the chitosan/Pd precursors into the layered-nanospaces of Al, Fe-pillared montmorillonite and subsequent confinement carbonization. N2 adsorption-desorption study indicated that the resulting nanocomposites have rich mesoporous structures. Effective encagement and in-situ reduction of Pd species led to a decrease in surface area and N2 adsorption, respectively. TEM images of the prepared Pd@Al, Fe-Mt/N-C showed that most of the Pd species with a size of 1–3 nm were well dispersed in the interlayer spaces of the pillared montmorillonite. The catalysts showed high catalytic efficiency for the Sonogashira reactions of aryl iodides or bromides with terminal aryl alkynes, and can be recycled 20 runs with no significant loss of activities. The unique encagement of the porous carbon-supported metal catalysts in the layered nanospaces of pillared montmorillonite was further elucidated by the positron annihilation spectroscopy analysis and other structural characterization methods. This layered-nanospace confinement strategy achieves a perfect combination of the advantages of activated carbon and montmorillonite as metal nanoparticle carrier.