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

Abstract

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 sp 3 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.

Design, Synthesis, and In Vitro Mitotic Evaluation of 3‐Amino‐Isoquinolinones as Anticancer Agents

“…The construction of a related series by employing relevant cross-coupling protocols for 6-bromosubstituted analogs is a future goal. [18]…”

“…The ability to chemoselectively react with the isoquinolinone motif has led to a diverse array of compounds that exhibit biological activity [17] . For example, modification at the C‐6 position of isoquinolones with sp 3 hybridized moieties has enabled the creation of inhibitors of Rho kinase and compounds that display significant activity against KRAS G12C‐mutant cancer cells, previously described as “undruggable” targets [18] …”

A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry

“…The data underlying this study are available in the published article and its online Supporting Information. 35 Separate from those studies, Hegui Gong and co-workers have demonstrated pyridines are suitable monodentate ligands for nickel. 58,59 Coordination sphere modification via starting material-, intermediate-, or product-nickel chelation may inhibit productive catalysis (e.g., Figure 2; entries 1, 9, and 10).…”

“…56 Despite all tested ligands successfully catalyzing the desired transformation, dtbbpy (4) was selected for further experimentation due to its generality across (hetero)aryl halide substrates (Figure 3a). 35,36,38,39 5-Fluoro-4-iodo pyridine and 5-fluoro-4-iodo-2-methylpyridine gave products 13 and 14 in 55% and 32% yield, respectively. 77 The yield for 14 was improved to 67% by inversing the stoichiometry of NHP ester (1 equiv) and 5-fluoro-4-iodo-2-methylpyridine (3 equiv).…”

“…However, most studies to date have focused on elaborating the 3-position with a dearth of examples focused on the 2-position . Existing approaches toward 2-substituted azetidines through de novo construction or late-stage functionalization include intramolecular alkylative cyclization, − formation or functionalization of a β-lactam then reduction, , C–H activation, , functionalization of azetines, − functionalization of α-lithiated intermediates, , aza Paternò-Büchi [2 + 2] cycloaddition, − ring expansion of aziridines, − and oxidative hydrogen-atom abstraction followed by cross-coupling. , Advances toward constructing 2-heteroaryl azetidines are comparatively fewer with recent examples using oxidative hydrogen-atom abstraction followed by a Minisci reaction (Figure a) , and decarboxylation of the carboxylic acid (Figure b) or redox-active ester with subsequent cross-coupling (Figure c). − These approaches offer an initial framework, but suffer from issues with regioselectivity, superstoichiometric quantities of azetidine reagents, prefunctionalization of coupling partners, and limited exploration into heteroaryl substrates with diverse functional groups, among other difficulties.…”