Isoquinolones are frequently encountered in a number of medicinally important compounds. Although numerous methods have been developed for their synthesis, the ability for late stage functionalization is highly desirable to explore structure activity relationships. The literature is still devoid of methods that lead to direct and efficient access to positions 6 and 7 with motifs that have sp3 character. A recent patent describes 6-acryloylazetidine isoquinolones as good candidates to modulate the activity of KRAS G12C mutant cancer cells. Current strategies based on traditional cross-couplings such as the Suzuki, Negishi and Stille couplings have their limitations with regards to the need to use high temperatures, side-reactions and substrate accessibility. To this end, we first developed a Ni-reductive cross coupling procedure allowing the direct coupling of N-substituted 6- and 7-bromoisoquinolone with a wide range of easily accessible heterocycloalkyl tosylates with good to high yields. In a second and complementary approach, we utilized a merged photoredox cross coupling strategy. A broad range of N-substituted 6-isoquinolone-aza- and oxa-cycles were thus obtained with good to high yields by coupling bromo-isoquinolones with readily available carboxylic acid feedstock chemicals.

Exploration of Ni-catalyzed reductive and merged photocatalytic cross-coupling reactions toward functionalized isoquinolones

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.