1-Alkynyltriazenes as Functional Analogues of Ynamides

The chemical reactivity of 1-alkynyltriazenes has been investigated and is found to parallel the reactivity of ynamides. The similarity in reactivity of these two classes of compounds is demonstrated by addition reactions with acids, by cycloaddition reactions with ketenes, tetracyanoethene, and cyclopropanes, as well as by intramolecular cyclization reactions. The presence of reactive triazene groups in the products enables subsequent transformations. Overall, our results suggest that 1-alkynyltriazenes should become valuable reagents in synthetic organic chemistry.

Investigations of the Chemistry of 1-Alkynyltriazenes

Florian Gérald Perrin

The chemistry of aromatic triazenes is well known, and has been explored for more than a century. These compounds have emerged as very useful intermediates, because of their unique reactivity. This functionality can notably be used to access many other functional groups, and it is present in certain bioactive compounds. Recently, our laboratory has reported a novel synthesis of triazenes using nitrous oxide, which allows the synthesis of 1-alkynyltriazenes. These compounds are poorly known, as their synthesis is not trivial by other routes. This thesis aims to explore the reactivity of these compounds. We have shown that the chemical reactivity of 1-alkynyltriazenes parallels what has been observed for ynamides. The similarity in reactivity of these two classes of compounds is demonstrated by addition reactions with acids and by cycloaddition reactions with ketenes and tetracyanoethene. The presence of the reactive triazene groups in the products allowed for subsequent transformations. We also studied the reactivity of these substrates in Ru-catalyzed [2+2] cycloadditions. The triazenes serve as unique vinyl cation surrogates. Under acidic conditions, the triazene functionality can be replaced by a variety of groups including halides, alkoxides, sulfoxides, amides, arenes and heteroarenes, providing efficient access to a pool of chiral and achiral polycyclic compounds The formation of very reactive cations using cyclic alkenenyl triazenes is described in a short study. It seems that the strained vinyl cation can be formed, but that its high reactivity prevents it to react selectively with weak nucelophiles. In the final part of this work, first results of a rhodium-catalyzed reaction with bifunctional boronic acids are presented. We show that 1-alkynyltriazenes react in the presence of rhodium to form indene derivatives. The unique reactivity of the triazenes lead to the formation of unexpected compounds. Overall, our results suggest that 1-alkynyltriazenes will become valuable reagents in synthetic organic chemistry.

EPFL2018

Engaging 1-Alkynyl Triazenes in Transition Metal-Catalyzed and Fluorinative Transformations

Jin Fay Tan

Triazenes have garnered great attention for their anti-cancer properties and versatility in organic chemistry. Recently, a novel synthesis of 1-alkynyl triazenes was reported. This thesis describes the compatibility, reactivity and applications of 1-alkynyl triazenes in various transition metal-catalyzed and fluorinative transformations.Chapter 1 provides an introduction to the discovery, biological activities and chemical reactivity of aryl triazenes. The recent procedure on 1-alkynyl triazene synthesis is described, followed by the context for experimental work presented in this thesis.In Chapter 2, we demonstrate Ru-catalyzed [2 + 2 + 2] cyclotrimerizations of 1-alkynyl triazenes to form densely substituted arenes and pyridines. The regioselectively installed triazenyl moiety can be elaborated into a range of useful substituents. The largely unknown coordination chemistry of 1-alkynyl triazenes with Cp*RuCl is investigated, leading to the isolation of several complexes that may provide insights into catalyst design.In Chapter 3, we explore the use of 1-alkynyl triazenes as fluoro alkyne surrogates in Rh-catalyzed olefinic C-H annulations with a rare Lossen rearrangement, leading to 4-fluoro-2-pyridones after a subsequent Wallach fluorination. The triazenyl pyridone intermediates are further transformed into other value-added fluorine-containing functional groups.In Chapter 4, we study the reactivity of 1-alkynyl triazenes in Ag-catalyzed cyclizations with propiolic acids, forming most notably the unreported 6-fluoro pyrones. A mechanistically intriguing 1,5-carbonyl transposition has been unraveled. The triazenyl unit is shown to serve as a traceless activating group for Diels-Alder cycloadditions.Chapter 5 describes perfluorinations and regiodivergent oxyfluorinations of 1-alkynyl triazenes, which provide tunable selective access to 1,1,2,2-tetrafluoro alkyl triazenes, Î±-difluoro triazenyl ketones and Î±-difluoro acyl triazenes. Mechanistic investigations of these fluorinative transformations have been subsequently explored.Finally in Chapter 6, we offer an outlook on the potential opportunities with the chemistry of 1-alkynyl triazenes.

EPFL2021

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