Catalytic Selective Amination of Unactivated C(sp3)-H Bonds – ALCA-N

Alkanes represent a major carbon-based feedstock that, paradoxically, remain very rarely used in organic synthesis. Their lack of reactivity makes their transformation energetically demanding thus poorly selective. Accordingly, the conversion of alkanes to higher-value products requires to design new transformations enabling the site-selective introduction of a functional group into their carbon framework.

Catalytic C-H activation processes have recently emerged as new efficient methods in organic synthesis. Their application to alkanes, however, remains highly challenging because of the lack of any directing group able to control the selectivity of the reactions. This is a major hurdle that imposes to conceive new strategies that do not rely on the inherent reactivity of the different types of C-H bonds.

In this context, the ALCA-N proposal targets the development of a reagent- and catalyst-controlled approach for the selective intermolecular C(sp3)-H amination of alkanes. These reactions will involve the C(sp3)-H insertion of metal-bound nitrenes that will be generated by an oxidative process in the presence of iodine(III) reagents. Based on several preliminary results obtained by both partners, experimental (partner 1) and theoretical (partner 2) studies will be combined to design novel catalysts (dirhodium(II) complexes) and nitrene sources (sulfamates). These will be tailored such as they will induce the in situ formation of sufficiently discriminating rhodium-bound nitrene species and lead to on-demand functionalization of primary, secondary, or tertiary C-H bonds, respectively. Such a toolbox for selective catalytic C-H amination will be developed thanks to a better understanding of the interaction between the rhodium-bound nitrene species and the substrate.

The ALCA-N project, ultimately, should demonstrate that alkanes are valuable synthons in total synthesis. On the other hand, catalytic C-H amination reactions will be applied to the late-stage functionalization of natural products to tune their biological properties.