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In organic chemistry, alkynylation is an addition reaction in which a terminal alkyne () is added to a carbonyl group () to form an α-alkynyl alcohol (). When the acetylide is formed from acetylene (), the reaction gives an α-ethynyl alcohol. This process is often referred to as ethynylation. Such processes often involve metal acetylide intermediates. The principal reaction of interest involves the addition of the acetylene () to a ketone () or aldehyde (): RR'C=O + HC#CR'' -> RR'C(OH)C#CR'' The reaction proceeds with retention of the triple bond. For aldehydes and unsymmetrical ketones, the product is chiral, hence there is interest in asymmetric variants. These reactions invariably involve metal-acetylide intermediates. This reaction was discovered by chemist John Ulric Nef in 1899 while experimenting with reactions of elemental sodium, phenylacetylene, and acetophenone. For this reason, the reaction is sometimes referred to as Nef synthesis. Sometimes this reaction is erroneously called the Nef reaction, a name more often used to describe a different reaction (see Nef reaction). Chemist Walter Reppe coined the term ethynylation during his work with acetylene and carbonyl compounds. In the following reaction (scheme 1), the alkyne proton of ethyl propiolate is deprotonated by n-butyllithium at -78 °C to form lithium ethyl propiolate to which cyclopentanone is added forming a lithium alkoxide. Acetic acid is added to remove lithium and liberate the free alcohol. Several modifications of alkynylation reactions are known: In the Arens–van Dorp synthesis the compound ethoxyacetylene is converted to a Grignard reagent and reacted with a ketone, the reaction product is a propargyl alcohol. The Isler modification is a modification of Arens–Van Dorp Synthesis where ethoxyacetylene is replaced by β-chlorovinyl ether and lithium amide. Alkynylations, including the asymmetric variety, have been developed as metal-catalyzed reactions. Various catalytic additions of alkynes to electrophiles in water have also been developed.

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Over the past twenty years, photochemical transformations have gained in importance in organic chemistry. Indeed, the development of photocatalysts has allowed the use of visible light as an energy source for chemical transformations. More specifically, photoredox chemistry has emerged as a valuable tool for the generation of free radical intermediates, enabling the organic chemist to envisage new bond disconnections and bond formations.For the organic chemist, the triple CïºC bond, or alkyne, is a versatile functional group. Alkynes are valuable building blocks for accessing more complex scaffolds. They also have multiple applications in medicinal chemistry, materials science, and chemical biology. Hence, the development of strategies that give access to alkynes is highly relevant. Due to the innate electronics of the alkyne, its transfer was initially limited to the alkynylation of electron-poor positions (electrophiles), however the development of alkyne transfer reagents have allowed the alkynylation of electron-rich positions (nucleophiles), and, more recently, the alkynylation of radicals. Specifically, ethynylbenziodoxolones (EBXs), hypervalent iodine (III) reagents bearing an alkyne, have frequently been used for the alkynylation of radicals. In combination with photochemical conditions they have enabled the activation of multiple functional groups (for example: carboxylates, potassium alkyl trifluoroborates salts, or Î±-oxo C-H bonds) for the introduction of an alkyne.The first objective of this research was to enable the photochemical difunctionalisation of double bonds to allow the introduction of an alkyne and a second functional group using EBXs. Indeed, difunctionalisation strategies are highly valuable as they can allow a rapid increase in molecular complexity in a single step. We found that enamides and enol ethers could undergo an alkynylative difunctionalisation with EBXs in presence of a photocatalyst and a hypervalent iodine additive. This method gave access to 1-alkynyl-1,2-aminoalcohols and diols scaffolds, which can be selectively deprotected to deliver the free alcohol or free amine.The second objective of this thesis was to develop a deoxyalkynylation strategy to allow the conversion of alcohols into alkynes. Starting from cesium oxalates, in presence of a photocatalyst and the EBX reagent, we could access a broad scope of aliphatic arylalkynes. Interestingly, the key to success for this project was found in the choice of light source: to ensure high yields, two high intensity blue LED lamps (440 nm, ca. 80 W) were required. During our mechanistic studies we discovered that this light source could also generate an excited state EBX species. We then decided to explore this discovery: we were delighted to find that the EBX alone under irradiation could promote the photomediated alkynylation of carboxylates, trifluoroborates, enamides, imines and Î±-oxo C-H bonds. Although the understanding of this process is still in the preliminary stages, we believe that the discovery of the direct photoexcitation of EBXs will enable facile reaction discovery and complement photocatalysed strategies.

EPFL2022

Copper-Catalyzed Alkynylation of Hydrazides: An Easy Access to Functionalized Azadipeptides

Jérôme Waser, Eliott Hugo Joran Le Du, Julien Aymeric Borrel

We report a copper-catalyzed alkynylation of azadipeptides using ethynylbenziodoxolone (EBX) reagents. Nonsymmetrical ynehydrazides could be obtained in 25–97% yield using azaglycine derivatives as nucleophiles. The transformation is compatible with most functional groups naturally occurring on amino acid side chains and allows the transfer of silyl-, alkyl-, and aryl-substituted alkynes. The obtained α-alkynyl azaglycine products could be further functionalized by nucleophilic attack or cycloaddition on the triple bond.

2022

Direct Photoexcitation of Ethynylbenziodoxolones: An Alternative to Photocatalysis for Alkynylation Reactions**

Jérôme Waser, Diana Cavalli, Franck Le Vaillant, Stephanie Grace Elizabeth Amos

Ethynylbenziodoxolones (EBXs) are commonly used as radical traps in photocatalytic alkynylations. Herein, we report that aryl-substituted EBX reagents can be directly activated by visible light irradiation. They act as both oxidants and radical traps, alleviating the need for a photocatalyst in several reported EBX-mediated processes, including decarboxylative and deboronative alkynylations, the oxyalkynylation of enamides and the C-H alkynylation of THF. Furthermore, the method could be applied to the synthesis of alkynylated quaternary centers from tertiary alcohols via stable oxalate salts and from tertiary amines via aryl imines. A photocatalytic process using 4CzIPN as an organic dye was also developed for the deoxyalkynylation of oxalates.

WILEY-V C H VERLAG GMBH2021

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Acetylide

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Alkynylation

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