Reaction Of Arynes Research Articles

Construction of Naphtho[2,1-d]oxazoles and 1,4-Epoxyisoquinolines via Regioselectivity-Switchable Diels-Alder Reaction of 4-Alkenyloxazoles with Arynes.

A Regioselectivity-switchable Diels-Alder reaction of arynes and 4-alkenyloxazoles was explored. By regulating the reaction temperature and the polarity of the solvent, the reaction activity of aryne was controlled to selectively react with different favorable reaction sites of 4-alkenyloxazoles, providing naphtho[2,1-d]oxazoles and 1,4-epoxyisoquinolines. Density functional theory (DFT) calculations demonstrated that the Diels-Alder reaction on acyclic dienes site needs more energy than the reaction on cyclic dienes to overcome the potential reaction barrier.

Trideuteromethylthiolation through Reaction of Arynes, S-Methyl-d3 Sulfonothioate with Sulfonamides or Amides: Access to Trideuteromethylated Sulfilimines.

A direct and practical three-component tandem reaction of arynes, S-methyl-d3 sulfonothioate with sulfonamides or amides is developed. The reaction is highly efficient and chemoselective, which allows mild synthesis of trideuteromethylated sulfilimines with broad substrate scope and good functional group compatibility, giving the products in good to excellent yields with 92%-99% deuterium incorporation. Mechanism studies disclosed sulfenamide that generated in situ is the key intermediate for the reaction. This protocol provides potential method for introduction of -SCD3 moiety for deuteration of marked drugs and drug candidates containing sulfilimine skeleton.

Recent Progress on Multi-Component Reactions Involving Nucleophile, Arynes and CO2.

Carbon dioxide (CO2) is a non-toxic, abundant and recoverable source of carbon monoxide. Despite its thermodynamically stable and kinetically inert nature, research on CO2 utilisation is ongoing. CO2-based aryne reactions, crucial for synthesising ortho-substituted benzoic acids and their cyclisation products, have garnered significant attention, and multi-component reactions (MCRs) involving CO2, aryne and nucleophilic reagents have been extensively studied. This review highlights recent advancements in CO2 capture reactions utilising phenylalkyne reactive intermediates. Mechanistic insights into these reactions are provided together with prospects for further development in this field.

Synthetic Strategies toward Ortho-3-propanoate Substituted Aryl Phosphonates by Three-Component Coupling Reactions of Arynes, Phosphites, and Acrylates.

Mild, metal-free, and operationally simple three-component coupling reactions involving arynes, phosphites, and acrylates have been achieved. The reaction proceeded well with α- or β-substituted acrylates. Additionally, various functional groups were tolerated under these reaction conditions, resulting in diverse ortho-3-propanoate-substituted aryl phosphonates. Moreover, the reaction can be used to synthesize a range of organophosphorus compounds present in natural products, materials, and biologically active compounds.

Functionalization of Siloxanes with Arynes Generated from o-Triazenylarylboronic Acids.

Herein, we report the functionalization of polyhedral oligosilsesquioxanes (POSS) and related siloxanes with arynes. Using o-triazenylarylboronic acids as aryne precursors and silica gel as the activator, the transformation of siloxane bearing various arynophilic moieties on the side chains was achieved with high yields without touching the siloxane core. This method was applied to the conjugation of POSS and pharmaceutical cores using an aryne derived from the synthetic intermediate of cabozantinib. Furthermore, orthogonal dual functionalization of POSS was realized by combining the aryne reaction with Huisgen cyclization.

Palladium(II)-catalyzed annulation of N-methoxy amides and arynes: computational mechanistic insights and substituents effects.

The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.

Switchable chemoselective aryne reactions between nucleophiles and pericyclic reaction partners using either 3-methoxybenzyne or 3-silylbenzyne.

Arynes are known to serve as highly reactive benzene-based synthons, which have gained numerous successes in preparing functionalized arenes. Due to the superb electrophilic nature of these fleeting species, however, it is challenging to modulate the designated aryne transformation chemoselectively, when substrates possess multiple competing reaction sites. Here, we showcase our effort to manipulate chemoselective control between two major types of aryne transformations using either 3-methoxybenzyne or 3-silylbenzyne, where nucleophilic addition-triggered reactions and non-polar pericyclic reactions could be differentiated. This orthogonal chemoselective protocol is found to be applicable between various nucleophiles, i.e., imidazole, N-tosylated/N-alkyl aniline, phenol, and alcohol, and an array of pericyclic reaction partners, i.e., furan, cyclopentadiene, pyrrole, cycloheptatrienone, and cyclohexene. Beyond arylation reactions, C-N bond insertion, Truce-Smiles rearrangement, and nucleophilic annulation are appropriate reaction modes as well. Moreover, this chemoselective protocol can find potential synthetic application.

Montmorillonite K-10 catalyzed synthesis of Hantzsch dihydropyridine derivatives from methyl arenes via in situ generated ammonia under microwave irradiation in neat conditions.

An expeditious, efficient, and environmentally friendly approach has been established for the synthesis of diverse Hantzsch 1,4-dihydropyridine derivatives utilizing montmorillonite K-10 as a catalyst in solvent-free conditions. The procedure entails the reaction of methyl arynes as a sustainable surrogate of aryl aldehydes, active methylene compounds, and urea hydrogen peroxide (UHP) as an oxidising agent as well as a source of ammonia under microwave irradiation, facilitated by montmorillonite K-10.

A novel three-component coupling reaction of aryne, CN derivatives, and acrylonitrile

A three-component aryne coupling reaction with CN derivatives as a nucleophile, and acrylonitrile as a third component, acting as both a proton donor and a nucleophile, has been developed.

Modular synthesis of conjugated enamidines and cascade annulation toward benzofuran-3-oxoacetate

A three-component reaction of aryne, DMF and isonitrile for the synthesis of the otherwise inaccessible chemotype, conjugated enamidines, is developed. Incubation with a Brønsted acid causes a cascade skeleton rearrangement of the enamidines to benzofuran-3-oxoacetates.

Copper-catalyzed alkynyldisulfuration of arynes: efficient access to unsymmetrical disulfides

This article investigates a copper-catalyzed alkynyl disulfuration reaction of arynes formed in situ that generates o-alkynyl aryl disulfides via the formation of one C–C bond and one C–SS bond in one pot.

Alder-ene reactions of arynes to form medium-sized and macrocyclic frameworks of sizes up to a 46-membered ring.

Macrocyclization via the intramolecular Alder-ene reaction of arynes to construct carbo- and hetero-macrocycles fused with an indoline or isoindoline moiety is described. By installing ether, ester, alkene, and cyclic tethers at an appropriate location between the aryne and the ene donor, macrocycles up to a 46-membered ring could be constructed.

Facile synthesis of dibenzothiophene S-oxides from sulfinate esters.

An efficient method to prepare dibenzothiophene S-oxides is disclosed. Suzuki-Miyaura cross-coupling of 2-bromoaryl sulfinate esters with arylboronic acids selectively at the bromo group followed by electrophilic cyclization of the resulting sulfinate ester moiety provides diverse dibenzothiophene S-oxides. Further transformations including Pummerer-type C-H propargylation and aryne reactions realize to synthesize highly functionalized dibenzothiophene derivatives.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Insights into the Regioselectivity of Metal-Catalyzed Aryne Reactions.

The synthetic potential of unsymmetrically substituted aryne intermediates is significantly hindered by regioselectivity issues. Current methods for inducing regioselectivity all rely on substrate control and are focused on non-metallated arynes. Before our initial disclosure, there was no systematic study regarding the regioselectivity of metal-catalyzed aryne reactions. By exploiting ligand control, we have induced regioselectivity in a palladium-catalyzed aryne annulation to form phenanthridinones (up to 9:91 r.r.). Through this study we have investigated: ligand effects, influence of steric perturbation, and the impact of the aryne precursor.

Ligand-Induced Regioselectivity in Metal-Catalyzed Aryne Reactions Using Borylaryl Triflates as Aryne Precursors.

The utility of reactions using unsymmetrically substituted aryne intermediates can be negatively impacted by issues with regioselectivity as these reactions are substrate controlled. This leaves no avenues for improving regioselectivity without altering the substrate which has led to numerous reports about how to enhance or reverse this regioselectivity in metal-free aryne reactions by changing the electronics. To the best of our knowledge, no such studies exist for systems with metal-bound aryne intermediates, which often suffer from worse regioselectivities. Herein we report a means of achieving regioselectivity in a metal-catalyzed aryne difunctionalization via catalyst control. Through the use of an unsymmetrical ligand environment, selectivity can be induced (up to 9:91 r.r.). These investigations demonstrate that catalyst design can influence selectivity in metal-catalyzed aryne reactions.

Facile Synthesis of Diaryl Sulfones through Arylsulfonylation of Arynes and Thiosulfonates

AbstractA mild and transition-metal-free arylsulfonylation reaction of arynes has been developed. Arynes generated in situ from 2-(trimethylsilyl)aryl triflates undergo nucleophilic addition with thiosulfonates to produce diaryl sulfones in 41–99% yield. The reaction can be scaled easily to gram-scale with the high yield maintained. Finally, mechanistic experiments showed that acetonitrile acted as a proton source.

Development of 3-triazenylaryne and its application to iterative aryne reactions via o-triazenylarylboronic acids.

Herein, a novel aryne species, 3-triazenylaryne, was developed and its regioselectivity was revealed. Based on the regioselectivity, various alkyne moieties were introduced by iodoalkynylation, and further derivatization to o-triazenylarylboronic acids as 3-alkynylaryne precursors was enabled. Therefore, 3-triazenylaryne was developed as a divergent platform for the generation of various 3-alkynylarynes.

Synthesis of Isoquinolines via the [4+2] Cycloaddition Reaction of Oxazoles and Arynes

AbstractHerein, we report our investigations on the reaction of a variety of substituted oxazoles with o‐(trimethylsilyl)aryl triflates promoted by potassium fluoride and 18‐crown‐6‐ether. Several functionalized isoquinoline compounds were obtained in moderate to good yields when the transformation was carried out at room temperature, followed by acidic workup, presumably via a [4+2] cycloaddition‐ring‐opening reaction pathway. Alternatively, bicyclic ethers were produced in reasonable yields when performing the transformation at 60 °C via a sequence of [4+2] cycloaddition, retro‐Diels‐Alder, and [4+2] cycloaddition reactions.

Access to Spiroindanolactones/lactams through an Aryne Insertion/Spirocyclization Strategy.

An efficient and metal-free strategy for the synthesis of spiro-fused indanolactones/lactams has been developed for the reaction of arynes with α-chloroacetyl lactones/lactams. This strategy provides access to spiroindanone derivatives via aryne insertion/spirocyclization.