The Development of a Dual Pd/Cu Catalysed System for Effective Desulflinative Cross-Electrophile Biaryl Couplings

Lead Research Organisation: University of Oxford
Department Name: Oxford Chemistry


This project falls within the EPSRC Synthetic Organic Chemistry research area. Biaryl motifs are ubiquitous in medicinally relevant molecules, and predominantly rely on palladium catalysed cross-coupling reactions in their syntheses. The Suzuki-Miyaura reaction is the most widespread variant for C(sp2)-C(sp2) bond formation, which is favoured due to the use of non-toxic boron reagents and mild reaction conditions. This approach has enjoyed much success, however proves problematic for scaffolds featuring 2-substituted pyridines, due to the susceptibility of 2-pyridyl boron reagents to protodeboronation. To circumvent this limitation, a desulfinative cross-coupling mechanism has been established, using heterocyclic sulfinates in place of the boronic coupling partners in the reaction. Although the success and scope of this process has been well established, the metal sulfinates are difficult to purify and are not stable to multi-step elaboration. In collaboration with Pfizer, the group has recently developed the use of base-activated latent N-heterocyclic sulfinates, where the active sulfinate species is released via E1cb elimination. Beta-nitrile and Beta-ester sulfones have shown to be the most effective coupling agents with aryl halides, and such reactions are now routinely used in Pfizer's laboratories. As the sulfinate reagents are primarily synthesised from the corresponding halide, it follows that the pyridyl halides are attractive starting materials for the cross-coupling procedure, employed directly with a second halide in the reaction. The reaction proceeds via the installation of a masked sulfinate on one of the aryl halides, which is then de-masked to undergo desulfinative coupling with the other halide. Not only does this shorten the biaryl synthesis to a simplistic one-pot process, but additionally exploits the vast commercial availability of the halide starting materials. The group have recently proven the success of the desulfinative cross-electrophile coupling (Scheme 1), with a yield of 30% setting exciting precedent for a general reaction. This project aims to develop and optimise the cross-electrophile coupling, by exploring different ligands and transfer reagents to improve the reaction yield further. It is thought that the reaction is limited by the SNAr of the sulfinate to the halide, so future plans also aim to probe a co-catalytic system employing both palladium and copper, in order to catalyse this limiting step. This would also allow non-SNAr active halides to undergo conversion to the latent sulfinates. The group has previously shown that the SMOPS reagent undergoes high-yielding coupling with pyridyl halides in the presence of stoichiometric copper iodide, which provides potential for a copper-catalysed system. The co-catalytic system would proceed by firstly coupling the sulfinate transfer reagent with an aryl iodide using copper catalysis, followed by the base mediated demasking of the sulfinate, to finally allow the palladium-catalysed desulfinative coupling to occur and provide the desired biaryl (Scheme 2). The success of this approach will rely on the matching of substrates to the catalyst, and developing complementary catalytic systems.


10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R513295/1 01/10/2018 30/09/2023
2604923 Studentship EP/R513295/1 01/10/2021 30/09/2024 May Merino
EP/T517811/1 01/10/2020 30/09/2025
2604923 Studentship EP/T517811/1 01/10/2021 30/09/2024 May Merino