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Novel Blueprints for the Visible-Light-Mediated Assembly of C–N Bonds via Nitrogen Radicals

Periodic Reporting for period 2 - NEBULAR (Novel Blueprints for the Visible-Light-Mediated Assembly of C–N Bonds via Nitrogen Radicals)

Reporting period: 2019-07-01 to 2020-12-31

"Nitrogen-containing compounds underpin every aspect of our daily life as they form the structural basis of almost all pharmaceuticals, agrochemicals, food additives and materials. This proposal aims to deliver transformative advances for the development of new efficient and selective strategies for the synthesis of N-containing molecules by harnessing visible-light as inexpensive and sustainable source of energy.

The major scientific achievements obtained in this reporting period have been:

1) We have demonstrated, in collaboration with AstraZeneca, that the chemistry and in particular the rearrangement of nitrogen radicals can be merged with nickel catalysis to enable the preparation of remotely functionalised nitriles which are useful building blocks in organic synthesis.
2) Modern medicinal chemistry programs are now focused on assemblying libraries of 3D molecules due to higher changes of biological activity when compared to more classical flat (2D) ones. An interesting concept is the replacement of aromatic rings in anilines with the very strained bycyclo[1.1.1]pentanes. Despite the strong interest from the pharmaceutical sectors in these building blocks, their preparation is very challenging. We have demonstrated, for the first time, that nitrogen radical undergo strain-release amination with [1.1.1]propellane and that this reactivity can be used for the divergent and single-step assembly of these molecules.
3) The generation of carbon radicals from alkyl and aryl halides is a very important area of research in synthetic organic chemistry and it is usually performed using toxic and dangerous tin or silicon radicals. We have recently demonstrated that tertiary amines, upon oxidation and deprotonation, lead to the formation of alpha-aminoalkyl radicals and that these species have a reactivity profile that mirrors the one of tin radicals. In this way we have been able to activate useful building blocks using simple amine reagents in place of some of the most toxic reagents in organic chemistry.
4) In collaboration with Eli lilly, we have developed a very simple strategy that enables to ""stich"" with excellent selectivity two different amines across an olefin. In this way we have provided fast access to 1,2-diamines that are important motifs in biological chemistry and catalysis but still require multistep synthesis with previous methods.
5) Anilines are aromatic that contain a nitrogen substitutent. In general these molecules are prepared by cross-coupling reaction between an aryl halide and an amine using palladium or copper catalysis. While these reactions are very succesul the preparation of the aryl halide might sometimes be difficult. Therefore we have developed a non-canonical strategy where we use cyclohexanones as aryl electrophile surrogates and we perform a dehydrogenative coupling with amines using a dual photoredox and cobalt approach. This work has enabled the preparation of many blockbuster drugs in a shorter number of step than before and has been done in collaboration with AstraZeneca.

All of these achievements have provided improved capacity for the preparation of small organic molecules that are widespread in the core of blockbuster drugs and agrochemicals."
We have broadly worked in the field of photoredox catalysis with a particular emphasis in the development of novel methodologies for the fast assembly of C–N bonds. This has enabled sinthesis of amines, anilines, amides, peptides, and many other small-molecule buidling blocks.
1) We have demonstrated that selective late-stage amination of aromatic is possible using nitrogen-radical chemistry
2) We have demonstrated for the first time that nitrogen-radical undergo strain-release reactivity with [1.1.1]propellane
3) We have demonstrated that alpha-aminoalkyl radicals can be used for the homolytic activation of C–halogen bonds just like classical tin radicals.
4) We have provided a non canonical approach for the preparation of anilines on demands using saturated building blocks