Ynol Ethers Research Articles

Catalytic Cycloaddition Reactions of Ynol and Thioynol Ethers

Comprehensive SummaryElectron‐rich alkynes, such as ynol and thioynol ethers, have proven to be versatile and appealing partners in catalytic cycloaddition reactions, and thus have raised considerable attentions owing to the practical application in the modular assembly of valuable carbo‐ and heterocycles. The past decades have witnessed inspiring advances in this emerging field, and an increasing number of related discoveries have been exploited. Divided into two main sections on the basis of substrate type, in each section this comprehensive review will initially summarize their synthetic preparations and subsequently examine their reactivity in every sort of catalytic cycloaddition with emphasis on the methodology development, aimed at providing an access to this burgeoning area and encouraging further innovations in the near future. Key ScientistsFor the cycloaddition of ynol ethers, in 2004, Kozmin et al. firstly developed a silver‐catalyzed [2 + 2] cycloaddition of siloxy alkynes with electron‐poor olefins. In 2012, Hiyama et al. realized a palladium‐catalyzed formal [4 + 2] annulation of alkynyl aryl ethers with internal alkynes. In the same year, Sun et al. discovered an efficient [6 + 2] cyclization between siloxy alkynes and 2‐(oxetan‐3‐yl)benzaldehydes by applying HNTf2 as catalyst. In 2017, Wender et al. first utilized vinylcyclopropanes (VCPs) as coupling partners in the [5 + 2] annulation of ynol ethers. In 2018 and 2020, Ye et al. reported zinc‐catalyzed formal [3 + 2] and [4 + 3] cycloaddition, respectively. For the cycloaddition of thioynol ethers, in 2004, Hilt et al. realized a [4 + 2] cycloaddition by employing the alkynyl sulfides and acyclic 1,3‐dienes. In 2006, a ruthenium‐catalyzed [2 + 2] cycloaddition of thioynol ethers with bicyclic alkenes was accomplished by Tam. In 2014, Sun et al. reported an elegant iridium‐catalyzed click reaction of thioalkynes with azides.

Phototriggered Generation of Ynol Ethers and Their Rearrangement to Ketenes.

This study developed reactions for the phototriggered generation of reactive ynol ethers using alkoxycyclopropenones. The resulting ynol ethers underwent rearrangement to ketenes, which subsequently participated in cycloaddition with alkynes and the acylation of amines. The alkoxy groups in the ynol ethers significantly influenced on the reactivity toward their rearrangement to ketenes. Reasonable transition state structures for the rearrangement reaction were found through density functional theory calculations, and the reactivity of the ynol ethers could be predicted by these calculations.

Gold-Catalyzed Regio- and Stereoselective α-Acyloxy-β-Alkynylation of Ynol Ethers

Enol esters and conjugated enynes are valuable structural motifs for synthetic chemistry and material sciences. Herein, the synthesis of tetra-substituted enol ester 2-iodobenzoate derivatives was achieved in good yields at room temperature through a gold-catalyzed acyloxyalkynylation of sensitive ynol ethers with ethynylbenziodoxolones (EBXs), the latter acting as bifunctional reactants. The conversion is highly regioselective with a broad substrate scope. Mechanistically, an Au(III) species is the key intermediate of an Au(I)/Au(III) redox cycle. The reaction is synthetically useful and can easily be scaled up to gram scale.

Access to Substituted Indenol Ethers via a Regioselective Intermolecular Carbopalladation Cascade.

Alkyne carbopalladation reactions can rapidly generate multiple new C-C bonds; however, regioselectivity is challenging for intermolecular variants. Using ynol ethers, we observe complete regiocontrol of migratory insertion followed by a second migratory insertion with a pendant alkene to turn-over the catalytic cycle. The resulting products are oligosubstituted 1-indenol ethers with defined stereochemistry based on the initial alkene geometry. Blocking β-hydride elimination allowed for C-H and C-C reductive elimination steps for catalyst turnover.

Highly dispersed nano‐copper catalyst on porous polyvinyl chloride for highly regioselective borylation of alkynes

We developed a highly regioselective synthesis of multi‐substituted alkenylboronates via a heterogeneous ligand‐free nano‐copper catalyst that was highly dispersed and supported on the porous polyvinyl chloride. In this catalytic system, substituents on the terminal alkynes could affect the configuration of products. Terminal alkynes and general internal alkynes gave β‐selective borylation products, whereas heteroatom‐substituted alkynes like alkynamides, thioacetylenes, and ynol ethers gave α‐selective borylation products in good chemical yields with exclusive regioselectivity.

Gold but not Old: Gold(I)-Catalyzed [2+2] and Formal (4+2) Cycloaddition of Ynol Ethers with Alkenes

Gold but not Old: Gold(I)-Catalyzed [2+2] and Formal (4+2) Cycloaddition of Ynol Ethers with Alkenes

Synthesis of push-pull-activated ynol ethers and their evaluation in the bioorthogonal hydroamination reaction.

A new class of push-pull-activated alkynes featuring di- and trifluorinated ynol ethers was synthesized. The difluorinated ynol ether exhibited an optimal balance of stability and reactivity, displaying a substantially improved half-life in the presence of aqueous thiols over the previously reported 1-haloalkyne analogs while reacting just as fast in the hydroamination reaction with N,N-diethylhydroxylamine. The trifluorinated ynol ether reacted significantly faster, exhibiting a second order rate constant of 0.56 M-1 s-1 in methanol, but it proved too unstable toward thiols. These fluorinated ynol ethers further demonstrate the importance of the hyperconjugation-rehybridization effect in activating alkynes and demonstrate how substituent effects can both activate and stabilize alkynes for bioorthogonal reactivity.

Synthesis of Cyclobutanones by Gold(I)-Catalyzed [2 + 2] Cycloaddition of Ynol Ethers with Alkenes.

A broad scope synthesis of cyclobutanones by gold(I)-catalyzed [2 + 2] cycloaddition of ynol ethers with alkenes has been developed. We also found that internal aryl ynol ethers can undergo (4 + 2) cycloaddition reaction with alkenes leading to the corresponding chromanes.

Synthesis of γ,δ-Unsaturated Esters and Amides via Au(I)-Catalyzed Reactions of Aryl Ynol Ethers or Ynamides with Allylic Alcohols

AbstractPolarized alkynes such as ynol ethers and ynamides have attracted much attention due to their inherent unique reactivity. Herein, we report Au(I)-catalyzed hydroalkoxylation/Claisen rearrangement cascade reactions of aryl ynol ethers and ynamides with allylic alcohols. At the first stage (hydroalkoxylation) of this cascade reaction, attack of allylic alcohols to aryl ynol ethers or ynamides occurs at the α-position of the polarized alkynes in a completely regioselective manner. Claisen rearrangement of the resulting adducts subsequently takes place to give γ,δ-unsaturated esters or amides, respectively. The [Au(IPr)NTf2] catalyst is most effective for this reaction, and the reaction proceeds under mild conditions (in the case of aryl ynol ether: in THF, 60 °C; in the case of ynamides: in toluene, 80 °C) in an atom-economical way.

Gold(I)-Catalyzed Intermolecular Formal [4+2] Cycloaddition of O-Aryl Ynol Ethers and Enol Ethers: Synthesis of Chromene Derivatives.

Gold(I)‐catalyzed formal [4+2] cycloaddition of O‐aryl ynol ethers 1 and enol ethers 2 is described. This intermolecular reaction between two electron‐rich unsaturated systems takes place, under mild conditions, in the presence of 5 mol% [IPrAu(CH3CN)]SbF6 as catalyst giving chromene derivatives with good yields. The cycloaddition is completely regio‐ and stereoselective, as well as versatile for both reactives. Silyl enol ethers can also react in the same way and under the same reaction conditions with quantitative yields. A plausible mechanism through a selective addition of the enol ether to the alkyne gold activated complex followed by an intramolecular aromatic electrophilic substitution is proposed. Several experimental results support the presence of a cationic oxonium intermediate prior to the aromatic substitution. The reaction represents a new entry to the chromene core.

Zinc-Catalyzed Asymmetric Formal [4+3] Annulation of Isoxazoles with Enynol Ethers by 6π Electrocyclization: Stereoselective Access to 2H-Azepines.

6π electrocyclization has attracted interest in organic synthesis because of its high stereospecificity and atom economy in the construction of versatile 5-7-membered cycles. However, examples of asymmetric 6π electrocyclization are quite scarce, and have to rely on the use of chiral organocatalysts, and been limited to pentadienyl-anion- and triene-type 6π electrocyclizations. Described herein is a zinc-catalyzed formal [4+3] annulation of isoxazoles with 3-en-1-ynol ethers via 6π electrocyclization, leading to the site-selective synthesis of functionalized 2H-azepines and 4H-azepines in good to excellent yields with broad substrate scope. Moreover, this strategy has also been used to produce chiral 2H-azepines with high enantioselectivities (up to 97:3 e.r.). This protocol not only is the first asymmetric heptatrienyl-cation-type 6π electrocyclization, but also is the first asymmetric reaction of isoxazoles with alkynes and the first asymmetric catalysis based on ynol ethers.

One-Pot Reaction of Carboxylic Acids, Ynol Ethers, and m-CPBA for Synthesis of α-Carbonyloxy Esters.

A novel one-pot reaction of carboxylic acids, ynol ethers, and m-CPBA for the synthesis of α-carbonyloxy esters in the presence of Ag2O is described. This process provides a direct approach to α-carbonyloxy esters with the achievement of formation of three C-O bonds. The protocol is featured with readily available starting materials and broad substrate scope. Control reactions and isotope-labeling reactions were conducted to elucidate a plausible mechanism.

One-Pot Reaction of Carboxylic Acids and Ynol Ethers for The Synthesis of β-Keto Esters.

An one-pot reaction of carboxylic acids and ynol ethers for the synthesis of β-keto esters has been developed. Under promotion of Ag2O, various carboxylic acids and ynol ethers could transform to α-acyloxy enol esters, which undergo a following DMAP-catalyzed rearrangement to deliver β-keto esters rapidly. This method provides a direct approach to β-keto esters from carboxylic acids without any preactivation. The protocol features mild reaction conditions, broad substrate scope, and the products could be transformed to an array of compounds.

Accessing 4-oxy-substituted isoquinolinones via C-H activation and regioselective migratory insertion with electronically biased ynol ethers.

The rhodium-catalyzed C-H activation and annulation with ynol ethers to directly provide 4-oxy substituted isoquinolinones is reported. The polarized nature of ynol ethers provides an electronic bias for controlling the regioselectivity of the migratory insertion process. While the highly reactive nature of ynol ethers presents a challenge, mild conditions were found to provide product in moderate to good yield. Utility was demonstrated by application in the synthesis of a prolyl-4-hydroxylase inhibitor framework.

Benign catalysis with zinc: atom-economical and divergent synthesis of nitrogen heterocycles by formal [3 + 2] annulation of isoxazoles with ynol ethers

A zinc-catalyzed formal [3 + 2] annulation of isoxazoles with ynol ethers has been developed, leading to the atom-economical and divergent synthesis of 2-alkoxyl 1H-pyrroles and 3H-pyrroles, respectively.

Ynol Ethers as Ketene Equivalents in Rhodium-Catalyzed Intermolecular [5 + 2] Cycloaddition Reactions.

The previously unexplored metal-catalyzed [5 + 2] cycloadditions of vinylcyclopropanes (VCPs) and electron-rich alkynes (ynol ethers) have been found to provide a highly efficient, direct route to dioxygenated seven-membered rings, a common feature of numerous natural and non-natural targets and building blocks for synthesis. The reactions proceed in high yield at room temperature and tolerate a broad range of functionalities. Substituted VCPs were found to react with high regioselectivity.

Aryl Ynol Ethers: Stable, Readily Available and Useful Precursors of Highly Reactive Ketenium Ions

Background: Ketenium ions are rarely used in chemical synthesis, despite a strong potential and their high reactivity, which can be mostly attributed to their difficult generation. There is therefore an important need for efficient methods enabling their in situ generation from stable and readily available starting materials in order to fully exploit the unique reactivity of ketenium ions. Keywords: Ynol ethers, ketenium ions, electrophilicity, bistriflimide, heterosubstituted alkynes, reactive intermediates.

Synthesis of (E)‐α,β‐Unsaturated Carbonyls via Silver‐Catalyzed Tandem Epoxide Rearrangement/Intermolecular Carbonyl‐ Heteroalkyne Metathesis

AbstractA regio‐ and stereoselective method for the synthesis of (E)‐α,β‐unsaturated carbonyls has been developed via a silver‐catalyzed tandem epoxide rearrangement/intermolecular carbonyl‐heteroalkyne metathesis. Various heteroalkynes including ynol ethers, ynamides, and thioalkynes work well for this transformation, leading to the production of (E)‐α,β‐unsaturated esters, amides, and thioesters in moderate to excellent yields with good functional group compatibility. It represents one of the rare examples of regio‐ and stereoselective intermolecular alkyne‐carbonyl metathesis (ACM).magnified image

ChemInform Abstract: The Chemistry of Ynol and Thioynol Ethers

AbstractReview: 64 refs.

1‐Ethynyl Ethers as Efficient Thermal Crosslinking System for Hole Transport Materials in OLEDs

A new crosslinking concept based on a thermally activated one‐component building block with thermally initiated crosslinkable ynol ether is introduced. For polystyrene matrices with glass transition temperatures below the reaction temperature, full conversion is reached within 30 min at 160 °C without employing any catalysts or co‐reactants. The ynol ethers are chemically inert toward a variety of reaction conditions (e.g., radicals and strong bases) and consequently applicable to a wide range of materials for organic electronics. The crosslinkable solid compounds are bench‐stable over more than a year. The broad applicability is demonstrated with a liquid model compound and a specifically designed crosslinking monomer introduced successfully as building block into polystyrenes with pending hole transporting groups. A detailed study of crosslinking kinetics by infrared measurements as well as an alternative method of crosslinker content determination utilizing differential scanning calorimetry is presented. The crosslinkable polymer and the corresponding noncrosslinkable molecule tris(4‐(3,6‐dibutoxy‐9H‐carbazol‐9‐yl)phenyl)amine (BuO6TCTA) are synthesized and investigated as hole transport layers (HTLs) in phosphorescent organic light emitting diodes (OLEDs). OLEDs with crosslinked and noncrosslinked HTLs show efficiencies around 80 cd A−1, indicating negligible influence of the crosslinking process on the device performance while yielding better HTL durability against solvent rinsing.