Central in fine chemistry and estimated to represent 35% of all reactions used in pharmaceutical industry, the formation of C–N bonds mainly relies on three main strategies: the N-alkylation with alkyl halides, the reductive amination of carbonyl derivatives, and the cross-coupling of aryl halides with amines. All of them require yet the use of either petroleum-based halide derivatives, or stoichiometric reducing agents and leads to the production of stoichiometric waste. The PhD project aims at developing new metal-catalyzed or radical transformations where a C–N and a C–C bonds are concomitantly created across an alkene, allowing to access molecular complexity via an atom-, step-, and redox-economical pathway.
The project will rely on the use of O-acylated hydroxylamines R2NOCOR’, obtained by simple condensation of the corresponding hydroxylamine and renewable carboxylic acids. The objective is to use these compounds as both a R2N and R’ source, taking advantage of a decarboxylative cross-coupling strategy. CO2 will thus act as a traceless linker, and its release will drive the reaction towards the formation of the amine products. Although O-acylated hydroxylamines R2NOCOR’ have been abundantly used in the literature either as R2N- or R’-sources, there exists very few reports where both part are incorporated in the final molecule. Building on preliminary results obtained in the laboratory on the hydroamination reaction (R’=H), the PhD candidate will study new catalytic systems to perform the reaction, driven by a deep understanding of the mechanistic features. Ultimately, the developed methodology will be applied to the synthesis of molecule of interest such as Venlafaxine or Salmeterol.
The PhD project will draw on ongoing research in our laboratory on the reactivity of N–O bonds and decarboxylation reactions. The PhD candidate will develop his/her skills in catalysis, organic and organometallic synthesis, working under inert atmosphere (Schlenk lines, gloveboxes), as well as in the analysis of chemical compounds (NMR, GC-MS, IR, X-Ray) and mechanistic investigations (experimental and DFT computation).