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
