Tandem Bond-Forming Reactions of 1-Alkynyl Ethers

Abstract

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...

Hypercoordinate iodine(III) promoted reactions and catalysis: an update on current mechanistic understanding

“…Alkynes are useful functional groups in synthesis owing to their application in a multitude of synthetic transformations. Enhanced reactivity as well as the biological significance makes heteroatom substituted alkynes such as ynamides and thioalkynes more important among alkynes . Hypercoordinate iodine reagents such as ethynylbenziodoxolone (EBX) act as excellent electrophilic alkyne transfer agents whereas in traditional methods alkynes are typically added as nucleophiles .…”

Unusual Behavior of Ketoximes: Reagentless Photochemical Pathway to Alkynyl Sulfides

“…Alkynes have emerged as building blocks in modern synthesis and transition-metal-mediated chemistry. − Exiguous heteroatom-substituted alkynes polarize the triple bond; thus, among N-, O-, S-, and P-heteroatoms, the N-substituted alkynes (ynamides) have been explored to a great extent. − The prominence of sulfur in biomolecules and materials − motivated chemistry practitioners to develop various synthetic methodologies for the synthesis of alkynyl sulfides. Conventional umpolung tendencies of sulfur and alkyne are well explored along with a vast variety of alkynylating reagents − and cross-dehydrogenative couplings (CDC) (Figure a–c) .…”

The chemistry of ynol and thioynol ethers

“…1 Ynol ethers in particular have been shown to possess a broad range of reactivity that can be exploited in the synthesis of complex molecules in order to gain access to otherwise difficult compounds whose preparation would be difficult or cumbersome via classical methods. 2 Both ynol ethers and alkynyl thioethers possess similarities in reactivity, given the polarised nature of the electron rich double bond. For example, this reactivity was recently exploited by Tan and Zhu 3 et al in a regioselective oxyarylation reaction to form a range of useful α-arylated products from both the ynol ether and alkynyl thioether (Scheme 1).…”