Development of Ynamide Technologies – DYNAMITE

With the aim of developing new processes for the chemistry of ynamides, which are the molecular building blocks of key interest in the DYNAMITE project, a global and integrative approach has been selected. Thus, on one side, innovative methods have been devised for the synthesis of different classes of ynamides, relying on copper-catalyzed or copper-promoted coupling reactions by extensive screening of the reactions conditions. On the other side, the reactivity of ynamides has been explored in several transformations of interest in organic synthesis with the aim of illustrating their synthetic potential, in particular for the synthesis of nitrogen heterocycles that would be difficult to access otherwise using conventional strategies. The physico-chemical data of the ynamides prepared, the results pertaining to the experiments aimed at exploring their synthetic potential as well as the quantitative determination of their reactivity parameters should result in a better understanding of the structure-reactivity relationships for this new class of heterosubstituted alkynes.

The DYNAMITE project has contributed to the development of original and innovative methods for the preparation of ynamides relying on copper-catalyzed or promoted coupling reactions. The interest of such coupling processes is far more general and other applications have already been found in organic synthesis for the preparation of different classes of disubstituted alkynes. New processes have been developed from ynamides allowing access to nitrogen heterocycles whose interest in medicinal chemistry or agrochemistry is well known. The results acquired during the course of this project allowed obtaining other research contracts to pursue further investigation in the chemistry of ynamides or other related research fields

The DYNAMITE project has opened numerous perspectives both from the fundamental knowledge acquired and the potential applications. The discovery of new copper-catalyzed/mediated processes for the preparation of ynamides has already found other applications for the synthesis of other heterosubstituted alkynes such as those substituted by a phosphorous atom, or the synthesis of trifluoromethylated alkynes which are useful molecular building blocks. The exploration of the reactivity of ynamides has clearly demonstrated that these heterosubstituted alkynes could be successfully involved in original anionic, cationic cyclisations as well as in heterocycloadditions and in sigmatropic rearrangements. Research aimed at further exploiting these results is currently underway in the research groups involved in the project to further highlight the synthetic potential of ynamides in organic synthesis.

The DYNAMITE project has already led so far to 19 research publications in international journals of high impact factor. The results have also been disseminated during the course of 16 invited lectures in international scientific meetings and 17 invited lectures (scientific seminars) in universities or in industry in France or abroad. Some published papers in the course of this project had an important impact on the scientific community, as judged by their high citation level. This pioneering research in this innovative field has become quickly competitive worldwide. This research thus appears as a leading project with a worldwide dissemination.

Organic synthesis has evolved as a central science with implications in various domains such as biology or material science. The development of selective procedures to assemble complex molecules or pharmaceuticals from simple building blocks represents a major challenge in organic chemistry.
The chemistry of ynamides, a subgroup of heterosubstituted alkynes, has attracted the attention of several research groups in recent years. They display an exceptionally fine balance of stability and reactivity, offer unique opportunities for the inclusion of nitrogen-based functionalities into organic molecules, and are emerging as useful building blocks. Their chemistry still represents a great challenge as their efficient synthesis and the understanding of their reactivity are far away to be achieved while their synthetic potential also remains to be thoroughly exploited.
This project aims at the development of ynamides from several perspectives, ranging from their synthesis and their reactivity to the design of new procedures.
Fundamental efforts will be exerted in developing efficient and general syntheses. Despite several advances, existing procedures suffer either from low substrate scope or involve conditions that are incompatible with functionalized substrates. These limitations will be addressed by developing copper-catalyzed alkynylations of nitrogen nucleophiles with gem-dibromoalkenes or alkynyltrifluoroborates. The latter should enable an entirely new access to ynamides under mild conditions. By extending these procedures to hydroxylamine and hydrazine derivatives, the preparation of new classes of ynamides should be achievable.
The synthetic potential of ynamides will be exploited in various transformations that allow a unique and efficient access to highly functionalized complex molecular architectures. Sigmatropic rearrangements from ynamides will be investigated as a route to allenamides whose cyclization should deliver a wide range of oxygen and nitrogen heterocycles. Metathesis reactions are a class of transformations that has also hardly been investigated with ynamides. Thus, several metathesis cyclization cascades, coupled with [4+2]-cycloadditions of the resulting aminodienes, will be developed to access polycyclic nitrogen heterocycles. Ynamides appear as interesting substrates for reductive coupling reactions since the polarization of the triple bond should allow for high regioselectivities. Therefore, nickel-catalyzed reductive coupling of ynamides with imines, epoxides or enones, leading to functionalized enamides will be investigated. Additionally, the reactivity of ynamides derived from hydroxylamines or hydrazides will be explored in gold-catalyzed cycloisomerizations and metathesis.
As there is an impressive lack of physical data available for ynamides, molecular calculations will be used to determine partial charges and molecular orbitals while nucleophilicities of representative ynamides will be evaluated through kinetic measurements. Extensive NMR analysis and X-ray diffraction studies will be carried out. The effect of the electron-withdrawing group on the nitrogen atom will be systematically addressed in the explored reactions. This combination of experimental and theoretical approaches should provide useful information for the understanding of the reactivity of ynamides and allow for a better differentiation between all classes.
The ambitious nature of this proposal lies in the global approach to develop the chemistry of ynamides as a whole, from their synthesis to their reactivity and to the design of efficient transformations. The three partners involved in this project will bring their mutual or individual expertise in copper-catalysis, in the preparation and reactivity of ynamides, sigmatropic rearrangements, metathesis reactions, heterocyclic chemistry and modelization. The complementary and synergistic nature of the collaboration provides strong bases for achieving the goal of the project.