Ni Catalysis

In recent years, there has been a significant push to "escape the flatland" in drug discovery by preparing C(sp3)-rich molecules. The use of C(sp3)-electrophiles in metal-catalyzed cross-coupling reactions is one way to increase 3D diversity in medicinal chemistry. Redox-active C(sp3)-electrophiles allow chemists to take advantage of the 1 electron reactivity and breadth of oxidation states available under Ni catalysis. We have been taking advantage of this reactivity to develop new synthetic methods.

Thiocarbonyl Auxiliaries for Ni-Catalyzed Cross-Couplings

We reported the design of a new redox-active leaving group to engage aliphatic alcohols in cross-coupling reactions (Scheme 7a). The leaving group is inspired by those used in Barton–McCombie deoxygenation reactions, notably the ability of thiocarbonyl derivatives to accept an electron and fragment to yield an alkyl radical. Initially motivated by our desire to engage cyclopropanols in Ni-catalyzed cross-couplings and the mechanistic subtleties involved in oxidative addition with these derivatives, we have since found that thiocarbonyl-containing redox-active leavings groups are useful for a variety of novel Ni-catalyzed cross-couplings. This includes the Ni-catalyzed deoxygenative arylation of α-hydroxy ester derivatives and a new approach to thiocarboxylic acid derivatives (Scheme 7b,c). Intriguingly, we have shown through mechanistic studies that a variety of single-electron pathways are available to these redox-active leaving groups, with the exact path depending on the electronic properties of the thiocarbonyl auxiliary and the catalytic manifold being investigated (Scheme 7d).

Key References:
1) Mills, L. R.; Monteith, J. J.; Gomes, G. P.; Aspuru-Guzik, A.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2020, 142, 13246–13254.
2) Monteith, J. J.; Rousseaux, S. A. L. Org. Lett. 2021, 23, 9485–9489.
3) Monteith, J. J.; Scotchburn, K.; Mills, L. R.; Rousseaux, S. A. L. Org. Lett. 2022, 24, 619–624.
4) Monteith, J. J.; Rousseaux, S. A. L. Acc. Chem. Res. 2023, 56, 3581–3594.

Reductive Cross-Couplings with N-Hydroxyphthalimide Esters

We have investigated the use of redox-active esters in Ni-catalyzed reductive cross-couplings to access a variety of arylated products from readily available carboxylic acid building blocks (Scheme 8). The reactions we have developed, in collaboration with Merck, use readily available building blocks (cyanoacetic acid and Meldrum’s acid) and occur under base-free conditions, meaning they are exceptionally tolerant of a wide range of functional groups. Significantly, we also discovered an important chlorosilane additive effect in these Ni-catalyzed reductive couplings, demonstrating that these component plays a crucial role in the rate of radical formation. Since our initial reports, we have since applied this strategy to the synthesis of i) pharmaceutically relevant 1-aryl cyclopropylamines (in collaboration with Genentech), ii) benzylamines from glycine (in collaboration with Genentech), iii) unnatural γ-amino acid derivatives and γ-lactams under very mild reaction conditions.

Key References:
1) Gabbey, A. L.; Michel, N. W. M.; Hughes, J. M. E.; Campeau, L.-C.; Rousseaux, S. A. L. Org. Lett. 2022, 24, 3173–3178.
2) Michel, N. W. M.; Gabbey, A. L.; Edjoc, R. K.; Fagbola, E.; Hughes, J. M. E.; Campeau, L.-C.; Rousseaux, S. A. L. J. Org. Chem. 2024, 89, 16161–16169.
3) West, M. W.; Gabbey, A. L.; Huestis, M. P.; Rousseaux, S. A. L. Org. Lett. 2022, 24, 8441–8446.
4) Choi, E. S.; Rousseaux, S. A. L.; Huestis, M. P. Synlett. 2024, 35, 935–939.
5) Pearson, J. W.; Hou, T. R.; Golijanin, J.; Stewart P. I.; Choi, E. S.; Gabbey, A. L.; West, M. S.; Rousseaux, S. A. L. Org. Lett. 2024, 26, 5560–5565.