Light-Induced Nickel-Catalysed Negishi Cross-Coupling


    In a truly fascinating new paper, Dr Jesús Alcázar and the team from Janssen Research and Development have collaborated with the Universidad de Castilla-La Mancha to demonstrate how light can be used to enhance nickel-catalysed Negishi cross-coupling reactions, using naturally abundant metals and an E-Series with a UV-150 photochemical reactor.

    Photocatalysis and dual-catalysis has dramatically expanded the scope of C(sp3)-C(sp2) coupling, but often requires the use of rare metals, like iridium or ruthenium. Clearly, this presents a significant barrier to large-scale processing.

    Drawing on their expertise in organozinc chemistry and Vapourtec equipment, the team at Janssen proposed to replace these rare metal reagents with organozinc reagents for dual-catalytic photochemical coupling reactions.

    The group observe that photochemical reactions are often enhanced on using flow, so proceeded to use their E-Series equipped with a UV-150 continuous flow photochemical reactor to investigate this innovative catalyst pairing.

    Much to their surprise, the group found that the coupling occurred even in the absence of the photosensitiser. Pleasingly, it was also found that using commercial zincates resulted in significantly lower conversions that those produced in situ using a flow protocol. This shows that the flow protocol flow was benefitting the photochemical induction of the cross-coupling, and the preparation of a starting material that is typically unstable and challenging to handle. Using their flow protocol, the team from Janssen was able to demonstrate that the light-induced Negishi coupling was tolerant of a range of different organozinc and haloarene reagents; especially interesting is the use of chloroarenes in this reaction, as the group explain in the text that these reagents have rarely been described in the literature participating in this chemistry before. To demonstrate how easily the flow protocol can be scaled, a synthesis of one compound was performed both in flow and batch. The synthesis was carried out for 8 hours using the E-Series, producing 6.7 g of product from the flow procedure (an isolated yield of 93%). This is very impressive when compared to the 39% isolated yield achieved from the batch synthesis. The group have compared their batch and flow protocols in Table 1, reproduced from their publication.

    Table 1: Replicated from the publication, a comparison of batch and flow protocols for light-induced Negishi coupling

    “This is really interesting, and potentially very important work” says Dr Ryan Skilton, research scientist at Vapourtec “that these cross-couplings can be performed under mild conditions and using common metals will make the Negishi coupling more broadly applicable, expanding the scope of this powerful reaction”. We look forward to seeing how this research develops.

    To go to the paper click here

    To read more about the E-Series click here

    To read more about the UV-150 photochemical reactor click here

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