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Ni-Catalyzed Reductive and Merged Photocatalytic Cross-Coupling Reactions toward sp3/sp2‑Functionalized Isoquinolones: Creating Diversity at C‑6 and C‑7 to Address Bioactive Analogues

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journal contribution
posted on 17.10.2020 by Adrien Dumas, Jean-Baptiste Garsi, Guillaume Poissonnet, Stephen Hanessian
Naturally occurring isoquinolones have gained considerable attention over the years for their bioactive properties. While the late-stage introduction of various functionalities at certain positions, namely, C-3, C-4, and C-8, has been widely documented, the straightforward introduction of challenging sp3 carbon-linked acyclic aminoalkyl or aza- and oxacyclic appendages at C-6 and C-7 remains largely underexplored. Interest in 6-substituted azacyclic analogues has recently garnered attention in connection with derivatives exhibiting anticancer activity. Reported here is the first application of the versatile and recently emerging field of Ni-catalyzed reductive cross-coupling reactions to the synthesis of 6- and 7- hetero­(cyclo)­alkyl-substituted isoquinolones. In a second and complementary approach, a new set of C-6- and C-7-substituted positional isomers of hetero­(cyclo)­alkyl appendages were obtained from the merging of photocatalytic and Ni-catalyzed coupling reactions. In both cases, 6- and 7-bromo isoquinolones served as dual-purpose reacting partners with readily available tosylates and carboxylic acids, respectively.