Regiocontrol via Electronics: Insights into a Ru-Catalyzed, Cu-Mediated Site-Selective Alkylation of Isoquinolones via a C-C Bond Activation of Cyclopropanols

Abstract

A site-selective C(3)/C(4)-alkylation of N-pyridylisoquinolones is achieved by employing C-C bond activation of cyclopropanols under Ru(II)-catalyzed/Cu(II)-mediated conditions. The regioisomeric ratios of the products follow directly from the electronic nature of the cyclopropanols and isoquinolones used, with electron-withdrawing groups yielding predominantly the C(3)-alkylated products, whereas the electron-donating groups primarily generate the C(4)-alkylated isomers. Density functional theory calculations and detailed mechanistic investigations suggest the simultaneous existence of the singlet and triplet pathways for the C(3)- and C(4)-product formation. Further transformations of the products evolve the utility of the methodology thereby yielding scaffolds of synthetic relevance.

Keywords: C−C activation; Ru-catalysis; regioisomeric ratio; singlet and triplet states; site-selective C−H alkylation.