Isoquinolone-4-Carboxylic Acids by Ammonia-Ugi-4CR and Copper-Catalyzed Domino Reaction

Highly substituted isoquinolone-4-carboxylic acid is an important bioactive scaffold; however, it is challenging to access it in a general and short way. A Cu-catalyzed cascade reaction was successfully designed involving the Ugi postcyclization strategy by using ammonia and 2-halobenzoic acids as crucial building blocks. Privileged polysubstituted isoquinolin-1(2H)-ones were constructed in a combinatorial format with generally moderate to good yields. The protocol, with a ligand-free catalytic system, shows a broad substrate scope and good functional group tolerance toward excellent molecular diversity. Free 4-carboxy-isoquinolone is now for the first time generally accessible by a convergent multicomponent reaction protocol.

Automated summary

A Cu-catalyzed cascade reaction was successfully designed to access highly substituted isoquinolone-4-carboxylic acid using ammonia and 2-halobenzoic acids as crucial building blocks. Privileged polysubstituted isoquinolin-1(2H)-ones were constructed in a combinatorial format with generally moderate to good yields. The protocol showed broad substrate scope and good functional group tolerance, making it possible to access free 4-carboxy-isoquinolone using a convergent multicomponent reaction protocol for the first time.