TransferNO

More than 80% of the active pharmaceutical compounds contain at least one nitrogen atom in their structures. The elaboration of C-N bonds is thus key in the chemical industry. Usually relying on the nucleophilic addition of an amine to electrophiles (halides derivatives, carbonyl compounds), their formation often comes along with overalkylation, selectivity issues and/or stoichiometric wastes. Alternative methods have been nevertheless developed but remain confidential on the industrial scale. Hydroamination, i.e. the addition of an amine across an alkene, is one of them. Despite its perfect atom economy, the intermolecular version of the reaction is nearly ergoneutral or even endothermic, i.e. the thermodynamic equilibrium is only slightly (or even not) in favor of the products’ formation, and thus this reaction is rarely employed for the synthesis of valuable compounds. Moreover, the reaction showcases a high kinetic barrier due to the electrostatic repulsion between the nucleophilic nitrogen atom and the electron-rich double bond. TransferNO aims to develop a new methodology towards the synthesis of highly valuable nitrogen-containing compounds, using O-acylated hydroxylamine derivatives as N,C-bifunctional reagents. These derivatives will be employed in metal-catalyzed transfer 1,2-carboamination reactions on alkenes, concomitantly creating a C-N and a C-C bond, the latter arising from the decarboxylation of the acyl residue. The TransferNO’s ultimate goal is thereby to go beyond the hydroamination reaction by functionalizing both carbon atoms on the alkene to increase the molecular complexity in one single step. This reaction will keep a good atom-economy, the traceless linker CO2 being the only by-product. Using a weak N-O bond allows to direct the reactivity and to introduce an orthogonal reactivity between the starting material and the amine product. High selectivity is thus expected for this reaction. Moreover, the nitrogen atom becomes here electrophilic (Umpolung strategy), hence no electrostatic repulsion between the nitrogen-containing substrate and the electron-rich double bond. Last, O-acylated hydroxylamines are easily accessible from the corresponding hydroxylamines and carboxylic acids, the latter potentially coming from renewable sources like the alkenes. The central question will be the rational design of appropriate catalytic systems to perform the transfer carboamination reaction. The nature of the acyle residue is guiding the organization of the TransferNO proposal, since the decarboxylation step has been identified as the key step. A first stage will focus on the development of a transfer hydroamination reaction using O-formylated hydroxylamines, taking advantage of the well-known decarboxylation of formate ligands. These developments will allow to study in more details the olefin insertion, to thereafter unlock the more challenging carboamination from O-acylated hydroxylamines and alkenes. The project will have a strong focus on the metal-catalyst design and on the comprehension of the mechanisms at play in the reaction. Both experimental and computational (DFT) mechanistic studies will be performed to guide the optimization of the reaction conditions. TransferNO’s goal thus encompasses the development of a new and more sustainable synthetic approach, relying on atom-, redox- and step-economy, towards the elaboration of nitrogen-containing compounds, essential for our society.