Ynol Ethers Research Articles

ChemInform Abstract: Ynol Ethers: Synthesis and Reactivity

AbstractReview: 47 refs.

ChemInform Abstract: HOTf‐Catalyzed, Solvent‐Free Oxyarylation of Ynol Ethers and Thioethers.

A novel HOTf-catalyzed oxyarylation of ynol ethers and thioethers has been realized with aryl sulfoxides as the oxyarylating reagents, providing α-arylated esters or thioesters in good to excellent yields. Notably, all atoms of the starting materials were incorporated in the product (100% atom economy) and the reaction proceeded under very mild conditions. It was found that the reaction can be ran under air and that the best yields are obtained under solvent-free conditions.

A Concise Total Synthesis of Dictyodendrins F, H, and I Using Aryl Ynol Ethers as Key Building Blocks.

We report a concise total synthesis of dictyodendrin F and the first total syntheses of dictyodendrins H and I in six steps. In these syntheses, aryl ynol ethers were employed as the key building blocks to introduce aryl and heteroaryl rings in the dictyodendrins. This rapid synthesis utilized a novel hetero-[2 + 2]-cycloaddition reaction between two aryl ynol ethers to yield a cyclobutenone ring. The cyclobutenone was sequentially converted into a highly substituted carbazole via a retro-4π/6π-electrocyclization-N-acylation cascade reaction to provide the dictyodendrin core. Consecutive intramolecular oxidative coupling and deprotection gave dictyodendrins F, H, and I.

ChemInform Abstract: Tandem Bond‐Forming Reactions of 1‐Alkynyl Ethers

AbstractReview: 54 refs.

Tandem Bond-Forming Reactions of 1-Alkynyl Ethers.

Electron-rich alkynes, such as ynamines, ynamides, and ynol ethers, are functional groups that possess significant potential in organic chemistry for the formation of carbon-carbon bonds. While the synthetic utility of ynamides has recently been expanded considerably, 1-alkynyl ethers, which possess many of the reactivity features of ynamides, have traditionally been far less investigated because of concerns about their stability. Like ynamides, ynol ethers are relatively unhindered to approach by functional groups present in the same or different molecules because of their linear geometry, and they can potentially form up to four new bonds in a single transformation. Ynol ethers also possess unique reactivity features that make them complementary to ynamides. Research over the past decade has shown that ynol ethers formed in situ from stable precursors engage in a variety of useful carbon-carbon bond-forming processes. Upon formation at -78 °C, allyl alkynyl ethers undergo a rapid [3,3]-sigmatropic rearrangement to form allyl ketene intermediates, which may be trapped with alcohol or amine nucleophiles to form γ,δ-unsaturated carboxylic acid derivatives. The process is stereospecific, takes place in minutes at cryogenic temperatures, and affords products containing (quaternary) stereogenic carbon atoms. Trapping of the intermediate allyl ketene with carbonyl compounds, epoxides, or oxetanes instead leads to complex α-functionalized β-, γ-, or δ-lactones, respectively. [3,3]-Sigmatropic rearrangement of benzyl alkynyl ethers also takes place at temperatures ranging from -78 to 60 °C to afford substituted 2-indanones via intramolecular carbocyclization of the ketene intermediate. tert-Butyl alkynyl ethers containing pendant di- and trisubstituted alkenes and enol ethers are stable to chromatographic isolation and undergo a retro-ene/[2 + 2] cycloaddition reaction upon mild thermolysis (90 °C) to afford cis-fused cyclobutanones and donor-acceptor cyclobutanones in good to excellent yields and diastereoselectivities. This process, which takes place under neutral conditions and proceeds through an aldoketene intermediate, obviates the need to employ moisture-sensitive and/or unstable acid chlorides under basic conditions for intramolecular [2 + 2] cycloaddition reactions. Furthermore, Lewis acid-catalyzed intramolecular condensations of both ethyl and tert-butyl ynol ethers with tethered acetals efficiently provide protected five-, six-, and seven-membered cyclic Baylis-Hilman adducts. Metalated ethoxyacetylene can also participate in multiple bond-forming reactions that avoid isolation of the alkynyl ether intermediate. Lewis acid-promoted tandem additions employing epoxides/oxetanes and carbonyl compounds give rise to (Z)-α-alkylidene and α-benzylidene lactones stereoselectively in high overall yields. Three new carbon-carbon bonds and a ring are formed in this atom-economical single-flask transformation, resulting in a significant increase in molecular complexity. This Account provides a detailed overview of these useful transformations with the intention of stimulating further interest in and research on ynol ethers and their application in organic synthesis.

HOTf-Catalyzed, Solvent-Free Oxyarylation of Ynol Ethers and Thioethers.

A novel HOTf-catalyzed oxyarylation of ynol ethers and thioethers has been realized with aryl sulfoxides as the oxyarylating reagents, providing α-arylated esters or thioesters in good to excellent yields. Notably, all atoms of the starting materials were incorporated in the product (100% atom economy) and the reaction proceeded under very mild conditions. It was found that the reaction can be ran under air and that the best yields are obtained under solvent-free conditions.

ChemInform Abstract: A Rapid and Selective Synthesis of α,α‐Fluorohalo Esters via Fluorohalogenative or Difluorinative Hydration of Ynol Ethers.

AbstractThe selective trifunctionalization of CC triple bonds of ynol ethers (I) via Selectfluor‐mediated fluorohalogenative or difluorinative hydration is described.

Ynol Ethers: Synthesis and Reactivity.

Ynol ethers are highly valuable substrates offering a wide range of reactivity. These highly electron-rich heterosubstitued alkynes can be of great synthetic potential. In this mini-review, the different methods for the synthesis of ynol ethers are first presented, divided in three main approaches involving a β-elimination, a carbene rearrangement and a direct oxidation of an alkyne. Their reactivity is then summarized underlying their synthetic utility. This non-exhaustive review aims at presenting the intrinsic reactivity of these compounds, still underexploited in synthesis.

ChemInform Abstract: Construction of 1‐Naphthols via Benzannulation Based on the Reaction of Aryl tert‐Butyl Ynol Ethers with Ynamides or Ynol Ethers.

AbstractA new version of benzannulation featuring the use of aromatic tert‐butyl ynol ethers (I) as convenient precursors for arylketenes is developed.

Diverse Natural Products from Dichlorocyclobutanones: An Evolutionary Tale.

11-Nor PGE2 was prepared in our laboratory several years ago and used to obtain the corresponding ring-expanded γ-butyrolactam, γ-butyrolactone, and cyclopentanone derivatives. The conversion of a cyclobutanone into a cyclopentanone had relatively little precedent and merited further study. It was soon found that the presence of a single chlorine adjacent to the carbonyl not only greatly accelerated the reaction with ethereal diazomethane, but also substantially enhanced its regioselectivity; not surprisingly, a second chlorine further increased both. The confluence of this finding and the discovery by Krepski and Hassner that the presence of phosphorus oxychloride significantly improved the Zn-mediated dehalogenation procedure for the preparation of α,α-dichlorocyclobutanones from olefins provided the starting point for decades' worth of exciting adventures in natural product synthesis. A wide variety of naturally occurring 5-membered carbocycles (e.g., hirsutanes, cuparenones, bakkanes, guaianolides, azulenes) could thus be prepared by using dichloroketene-olefin cycloaddition, followed by regioselective one-carbon ring expansion with diazomethane. Importantly, it was also found that natural γ-butyrolactones (e.g., β-oxygenated γ-butyrolactones, lactone fatty acids) could be secured through regioselective Baeyer-Villiger oxidation of cycloadducts with m-CPBA and that naturally occurring γ-butyrolactam derivatives (e.g., amino acids, pyrrolidines, pyrrolizidines, indolizidines) could be efficiently obtained by regioselective Beckmann ring expansion of the adducts with O-(mesitylenesulfonyl)hydroxylamine (Tamura's reagent). These 5-membered carbocycles, γ-butyrolactones, and γ-butyrolactam derivatives were generally secured in enantiopure form through the use of either intrinsically chiral olefins or olefins bearing Stericol, a highly effective chiral auxiliary developed specifically for this "three-atom olefin annelation" approach. In addition, considerable useful chemistry has been developed in the context of this synthesis program. This includes new methods for olefin vicinal dicarboxylation, β-methylene-γ-butyrolactonization, γ-butyrolactone and δ-valerolactone α-methylenations, transesterification, angelic ester synthesis, chiral enol and ynol ether preparations, dichloroacetylene synthesis, and trans, trans hydroxy triad introduction. This versatile dichlorocyclobutanone-centered approach to natural product synthesis, together with the attendant new methods that have been developed, forms the basis of this Account, which is presented as an evolutionary tale. It is hoped that the Account will stimulate other research groups to seek to exploit the rich chemistry of dichlorocyclobutanones for possible solutions to problems in organic synthesis.

A single-flask synthesis of α-alkylidene and α-benzylidene lactones from ethoxyacetylene, epoxides/oxetanes, and carbonyl compounds

Low temperature treatment of (ethoxyethynyl)lithium with epoxides or oxetanes in the presence of BF3·OEt2, followed by addition of aldehydes or ketones and warming to room temperature, affords structurally diverse five- and six-membered α-alkylidene and α-benzylidene lactones (5) in good to excellent yields. This one-pot process, in which three new carbon–carbon bonds and a ring are formed, affords substituted α,β-unsaturated lactones of predominantly Z-configuration. The reaction likely occurs via alkyne–carbonyl metathesis of a hydroxy–ynol ether intermediate, acid-promoted alkene E- to Z-isomerization, and lactonization.

ChemInform Abstract: Nickel‐Promoted Highly Regioselective Carboxylation of Aryl Ynol Ether and Its Application to the Synthesis of Chiral β‐Aryloxypropionic Acid Derivatives.

AbstractA new method for the enantioselective synthesis of the optically active title propionic acid derivatives involving the synthesis of α‐substituted‐β‐aryloxyacrylic acid derivatives from aryl ynol ether and CO2 followed by the rhodium‐catalyzed asymmetric hydrogenation is developed.

Construction of 1-Naphthols via Benzannulation Based on the Reaction of Aryl tert-Butyl Ynol Ethers with Ynamides or Ynol Ethers.

A new version of benzannulation featuring the use of aromatic tert-butyl ynol ethers as the convenient precursors for arylketenes has been developed. Both ynamides and ynol ethers undergo this reaction smoothly, giving 3-amino and 3-alkoxy 1-naphthols in good to excellent yields under the heated reaction conditions. The high efficiency, excellent regioselectivity, good functional group compatibility, and broad substrate scope render this reaction particularly valuable for organic synthesis.

ChemInform Abstract: Palladium‐Catalyzed Regio‐ and Stereoselective Cross‐Addition of Terminal Alkynes to Ynol Ethers and Synthesis of 1,4‐Enyn‐3‐ones.

AbstractThe title reaction proceeds in a highly regio‐ and stereoselective manner.

Back Cover: Nickel‐Promoted Highly Regioselective Carboxylation of Aryl Ynol Ether and Its Application to the Synthesis of Chiral β‐Aryloxypropionic Acid Derivatives (Chem. Asian J. 5/2015)

Back Cover: Nickel‐Promoted Highly Regioselective Carboxylation of Aryl Ynol Ether and Its Application to the Synthesis of Chiral β‐Aryloxypropionic Acid Derivatives (Chem. Asian J. 5/2015)

ChemInform Abstract: Silver‐Catalyzed Regio‐ and Stereoselective Addition of Carboxylic Acids to Ynol Ethers.

AbstractThe reaction produces (Z)‐α‐alkoxy enol esters and can be applied to a broad spectrum of ynol ethers and carboxylic acids.

Nickel-promoted highly regioselective carboxylation of aryl ynol ether and its application to the synthesis of chiral β-aryloxypropionic acid derivatives.

Nickel(0)-promoted carboxylation of aryl ynol ether proceeded in a highly regioselective manner to produce α-substituted-β-aryloxyacrylic acid derivatives. The α-substituted-β-aryloxyacrylic acids were transformed into the corresponding β-aryloxypropionic acid derivative as an optically active form via rhodium-catalyzed asymmetric hydrogenation.

Palladium-catalyzed regio- and stereoselective cross-addition of terminal alkynes to ynol ethers and synthesis of 1,4-enyn-3-ones.

Conjugated enynes, enol ethers, and enynones are versatile building blocks that can be elaborated by a wide variety of synthetic transformations. The selective synthesis of such units is a prerequisite for their effective utilization. The synthesis of conjugated 2-phenoxyenynes through a palladium-catalyzed cross-addition of terminal alkynes to phenylethynyl ethers (hydroalkynylation) is now presented. The reaction is highly regio-, stereo-, and chemoselective, and shows excellent tolerance toward functional groups. The addition further features very mild reaction conditions (room temperature) and an inexpensive catalytic system (without a ligand and with a cheaply available Pd catalyst). The thus synthesized enynyl ethers with allylic hydroxy tethers, which survived the reaction, were shown to be ready precursors for valuable 1-en-4-yn-3-ones.

Palladium‐Catalyzed Regio‐ and Stereoselective Cross‐Addition of Terminal Alkynes to Ynol Ethers and Synthesis of 1,4‐Enyn‐3‐ones

AbstractConjugated enynes, enol ethers, and enynones are versatile building blocks that can be elaborated by a wide variety of synthetic transformations. The selective synthesis of such units is a prerequisite for their effective utilization. The synthesis of conjugated 2‐phenoxyenynes through a palladium‐catalyzed cross‐addition of terminal alkynes to phenylethynyl ethers (hydroalkynylation) is now presented. The reaction is highly regio‐, stereo‐, and chemoselective, and shows excellent tolerance toward functional groups. The addition further features very mild reaction conditions (room temperature) and an inexpensive catalytic system (without a ligand and with a cheaply available Pd catalyst). The thus synthesized enynyl ethers with allylic hydroxy tethers, which survived the reaction, were shown to be ready precursors for valuable 1‐en‐4‐yn‐3‐ones.

A rapid and selective synthesis of α,α-fluorohalo esters via fluorohalogenative or difluorinative hydration of ynol ethers.

A Selectfluor-mediated fluorohalogenative or difluorinative hydration of ynol ethers is described, giving various α,α-fluorohalo esters including α,α-bromofluoro, α,α-chlorofluoro, α,α-fluoroiodo, and α,α-difluoro derivatives in a highly selective manner under very mild reaction conditions. The resultant products can be applied to the facile synthesis of α-monofluoro-α-amino acids. This reaction represents a new advance in the trifunctionalization of alkynes.