Development of Catalytic Umpolung

The development of efficient synthetic methodologies is crucial to access complex molecules in an economic, eco-friendly and safe way. The reversal of the intrinsic reactivity of functional groups, called Umpolung, allows alternative synthetic strategies and can improve synthetic efficiency. In this thesis, two new Umpolung methods have been investigated. First a novel approach for the direct alkynylation of aromatic C-H bonds has been developed to access aromatic alkynes. Secondly, novel bifunctional (thio)urea carbene catalysts have been synthesized and their use in asymmetric intermolecular heterocouplings has been investigated. Aromatic alkynes are compounds of utmost prominence as synthetic intermediates and for application in materials science. Classical synthetic methods require a prefunctionalization of the aromatic ring in addition to the alkynylation step. An alternative emerging strategy to introduce triple bonds is based on the Umpolung of acetylenes by the use of electrophilic acetylene reagents. In addition, the use of metal catalysis has recently arisen to couple aromatic C-H bonds with electrophiles in a single step. However, direct alkynylation has been only scarcely investigated. In this thesis, alkynyl hypervalent iodines, highly electrophilic acetylenes, were used for the metal-catalyzed direct alkynylation of aromatic C-H bonds. Indoles were alkynylated in C3 position using AuCl as catalyst and TIPS-EBX (1- [(triisopropylsilyl)ethynyl]-1λ3,2-benziodoxol-3(1H)-one) as source of electrophilic acetylene. The reaction proceeded under mild open-flask conditions (room temperature under air, commercial solvents). Importantly, it was the first example showcasing the superiority of alkynyl benziodoxolones over alkynyl iodoniums in alkyne transfer reactions. On contrary to other alkynylation methods, which have either a limited scope or require indole protection, this reaction tolerated a large range of functional groups and worked for unprotected indoles. Furthermore in the presence of pyridine, pyrroles were alkynylated in C2 position in high yields. This development was important in light of the instability of unprotected halogeno- pyrroles, which makes their use in cross-coupling reactions difficult. A one-pot 2- alkynylaniline cyclization/direct alkynylation was next developed. The influence of substituents on the acetylene, the iodoxole ring structure and the benzene ring substitution on the alkynyl benziodoxolones were examined. This study revealed that bulky silyl groups were ideal alkyne substituents. Preliminary mechanistic investigations indicated that the reaction proceeded either via a π activation mechanism or via an oxidative AuI/AuIII mechanism. iii Unfortunately it has not yet been possible to distinguish between both mechanisms. The alkynylation of electron-rich arenes was next explored. N,N-dialkylanilines were alkynylated with high para regioselectivity using iPrOH as solvent. This transformation represented the first one-step synthesis of para-alkynylanilines and was then extended to 1,3,5- trimethoxybenzenes.

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

New Acetylene Chemistry

Davinia Fernández González

This thesis is divided in seven main chapters including an introduction about the state of the art in the field, four main chapters describing the main part of the work, a short insight on the implications of the presented results for other research projects and a conclusion. The experimental procedures as well as spectroscopic data are grouped in a special section at the end of the thesis. Acetylenes are versatile intermediates in chemistry, biochemistry and material sciences. The functionalization of alkynes by addition reactions to carbonyl compounds, cycloaddition or coupling reactions using metal catalysis for example make them excellent building blocks for the construction of organic molecules. Furthermore, there are several examples of natural products and drugs containing an acetylene group. Usually, they are synthesized by addition of an acetylide anion to an electrophile. However, the reverse approach (Umpolung of the reactivity) via an electrophilic acetylene synthon has been more rarely used. This constitutes a serious limitation, in particular when considering that "classical" C-C bond formation is not adequate for the synthesis of quaternary centers containing an acetylene. The subject of this thesis is the development of a new class of alkynylation reactions to access propargylic quaternary centers by using hypervalent iodine reagents for the Umpolung of the normal reactivity of alkynes. We started our studies examining the alkynylation reaction with different β-keto esters using the hypervalent iodine reagent TMS-Ethynyl BenziodoXone (TMS-EBX). The excellent reactivity of this cyclic iodine reagent as alkynylation reagent led to the formation of free acetylene products even in the presence of sterically hindered ester groups. The ethynylation reaction proceeded in good yield using TBAF both as a base and fluoride source with TMS-EBX as alkynylation reagent for cyclic and non-cyclic keto esters. Different hypervalent iodine compounds have been tested for the alkynylation of cyclic keto esters. EBX reagents have shown to be generally more efficient than the established iodonium salts. Based on these first results, we next examined the alkynylation of nitro and cyano esters as well as β-keto amides, which have never been used in the past. We were pleased to see that the developed method was also applicable for these classes of compounds affording the corresponding ethynylated products in good yield. The synthetic potential of propargylic nitro compounds bearing free acetylenes was demonstrated by their transformation into propargylic triazoles, hydroxylamines and protected amines, as well as into allyl amines in good yield. We have investigated next, the asymmetric version of the alkynylation reaction under organocatalytic phase-transfer conditions. An enantiomeric excess of 40% has been obtained for cyclic keto esters using cinchona-derived catalysts. Phosphonium catalysts gave an improved enantiomeric excess (51% ee). Higher asymmetric induction has been obtained using the binaphthyl-derived catalysts developed by Maruoka, which has been tested for different substrates to give 12-79% ee. Finally, we have conducted preliminary mechanistic investigations. In situ NMR experiments, isotope labeling and structure-activity relationship studies have allowed us to propose a first crude picture of the catalytic cycle for the alkynylation reaction. In summary, we have reported the first truly general approach for the alkynylation of soft nucleophiles using hypervalent iodine reagents. The developed reaction conditions led to high yields of unprotected acetylenes with cyclic, nitro and linear keto esters as well as keto amides. Furthermore, asymmetric induction was observed using cinchona or binaphthyl derived phase-transfer catalysts (up to 79% ee). This allows a new direct access to chiral acetylene compound in high yields under operationally simple reaction conditions. Future work will be dedicated to the improvement of the enantiomeric excess as well as the scope of the reaction.

EPFL2011

Electrophilic alkynylation: the dark side of acetylene chemistry

Jonathan Brand, Jérôme Waser

In addition to the well-established nucleophilic alkynylation, the use of electrophilic alkynes can expand tremendously the scope of acetylene transfer reactions. The use of metal catalysis has recently led to a rebirth of this research area. Halogenoalkynes, hypervalent alkynyliodoniums, acetylene sulfones and in situ oxidized terminal acetylenes are the most often used reagents for electrophilic alkynylation. Heteroatoms such as N, O, S and P can be now efficiently alkynylated. For C-C bond formation, electrophilic acetylenes can be coupled with different organometallic reagents. Recently, the first breakthrough in direct C-H and C=C bond alkynylation has also been reported. Finally, sulfonyl acetylenes are efficient for alkyne transfer on carbon-centered radicals.