Fast and Highly Chemoselective Alkynylation of Thiols with Hypervalent Iodine Reagents Enabled through a Low Energy Barrier Concerted Mechanism

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking. In this article, we describe the mechanism and full scope of the alkynylation of thiols using ethynyl benziodoxolone (EBX) hypervalent iodine reagents. Computations led to the discovery of a new, three-atom concerted transition state with a very low energy barrier, which rationalizes the high reaction rate. On the basis of this result, the scope of the reaction was extended to the synthesis of aryl- and alkyl-substituted alkynes containing a broad range of functional groups. New sulfur nucleophiles such as thioglycosides, thioacids, and sodium hydrogen sulfide were also alkynylated successfully to lead to the most general and practical method yet reported for the synthesis of thioalkynes.

Photochemical Alkynylations with Hypervalent Iodine Reagents

Stephanie Grace Elizabeth Amos

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

Synthesis of Alkynylated Heterocycles by Direct C-H Alkynylation or Domino Alkynylation Reactions

Yifan Li

Heterocycles are important compounds in organic chemistry. To introduce functional groups on heterocycles or synthesize functionalized heterocycles stays a hot topic of research. Among all the functional groups, alkynes attracted a lot of attention not only because of their occurrence in organic compounds, like synthetic pharmaceuticals, natural products and organic materials, but also because of their versatile chemistry, such as metal catalyzed cyclization and [3+2] annulation reactions. Therefore, it is of great importance to introduce alkynes on heterocycles or synthesize alkynylated heterocycles in an efficient and regioselective manner. The Sonogashira reaction has dominated the introduction of alkynes on heterocycles. Even though the method is well established, there are several shortcomings such as stoichiometric waste production and poor stability or accessibility of the starting materials. To introduce alkynes on heterocycles in an efficient fashion, direct C-H alkynylation has been intensiely investigated as an alternative in the last decades. Based on the previous work in our group, direct C-H alkynylation was extended to access C2- alkynylated furans using a gold catalyst and triisopropylsilyl ethynyl benziodoxolone (TIPS-EBX). For less nucleophilic substrates like benzofurans, the use of Zn(OTf)2 was necessary to activate the EBX reagent. Although direct C-H alkynylation provides a straightforward way to access alkynylated heterocycles, it is limited to the inherently more reactive positions such as the C2 position of five-membered heterocycles or the heterocyclic ring of benzofused heterocycles. It is therefore challenging to find pathways to obtain heterocycles functionalized at other positions. Domino reactions could provide a solution to this challenge, as the metal-carbon bond could be installed on positions different from the ones obtained via a direct metallation approach. Based on this concept, unprecedented cyclization-alkynylation domino reactions were developed to access alkynylated heterocycles. Starting from easily prepared allenic ketones or ortho- ethynylated phenols or thioanisoles, C3 alkynylated furans, benzofurans and benzothiophenes can be rapidly accessed. This is a breakthrough as it allows for the introduction of alkynes on less nucleophilic positions. These products are difficult to obtain via direct C-H alkynylation as it occurred exclusively on C2 position of furans, benzofurans and benzothiophenes. Nevertheless, this approach was still limited to more reactive heterocycles. We then turned our efforts to develop domino reactions to functionalize the less reactive benzene ring. We found that with C2 or C3-substituted pyrroles as starting materials, C5 or C6 alkynylated indoles can be easily formed when combining a platinum catalyst with a bistrifluoromethyl benziodoxole reagent. In summary, a series of alkynylated heterocycles were obtained via direct alkynylation or domino reactions combining hypervalent iodine reagents and metal catalysts. This discovery is expected to find broad application to access diverse alkynylated heterocycles. It also set the bases for the development of new domino processes with different metal catalysts and electrophilic reagents in the future.

EPFL2016

Development of New Strategies of Umpolung with Cyclic Hypervalent Iodine Reagents

Paola Caramenti

Organic chemistry is essential for the development of a modern society and technical progress requires the continuous development of synthetic methodologies Novel, efficient, selective and flexible protocols are employed to access complex frameworks from simple starting materials. However, classical synthetic methods often relies on the intrinsic reactivity of functional groups, reducing the portfolio of available reactions for synthetic chemists. The reversal of classical reactivity of functional groups allows alternative disconnection pathways and can improve synthetic efficiency. The research presented in this thesis was aimed at the development of new strategies of Umpolung with hypervalent iodine reagents. Three new Umpolung methods have been investigated. First a strategy for the synthesis of enantioenriched Î±-cyano Î±-allyl ketones has been developed. Second, novel indole- and pyrrole-based hypervalent iodine reagents have been synthesized and applied in the context of metal-catalysis ad metal-free transformations. Third, a new class of umpoled enamides and enol ethers have been prepared from simple starting materials. Î±-Cyano carbonyls are important structural motifs of bioactive compounds and natural products. Nitriles are also versatile building blocks that undergo a plethora of transformations, which are usually accessed by transfer of the nucleophilic cyanide anion to electrophiles. The reactivity of cyanide can be reversed by the use of hypervalent iodine reagents. Part I focus on the application of umpoled nitriles for the functionalization of carbonyls. With these reagents, a variety of Î²-keto esters were successfully cyanated in racemic fashion. Inspired by previous results obtained in our group, a decarboxylative asymmetric allylic alkylation strategy was applied for the synthesis of enantioenriched quaternary Î±-cyano Î±-allyl ketones embedded in an indanone framework. Cyclic indanone derivatives were accessed in good yields and enantioselectivities. Indole and pyrrole heterocycles are often embedded in relevant drugs, natural products and materials. Their ubiquity inspired decades of intensive research for both their synthesis and functionalizations. Especially functionalization methods mainly focused on their intrinsic nucleophilic properties. The field exploiting their electrophilic derivatization was severely underdeveloped. An alternative strategy to access electrophilic indole and pyrrole synthons takes advantage of the unique properties of hypervalent iodine. In Part II of this thesis, indole- and pyrrole-based benziodoxoles were prepared and used for the metal-catalyzed direct indole transfer on aromatic CâH bonds. A large variety of indole-aryl frameworks, previously elusive or accessed via multi-step syntheses, were accessed in a straightforward manner, starting from simple commercially available building blocks. A direct oxidative metal-free cross-coupling for the synthesis of mixed bi-(hetero)aryl-indoles was then developed. The reaction worked well with our previously synthesized reagents, and a new class of electrophilic indoles (activated at the C2 carbon) was specifically developed for this transformation, further expanding the pool of available benziodoxoles.

EPFL2019