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 a Ru(II)‐catalyzed/ Cu(II)‐mediated condition. 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, while 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 states for the C(3) and C(4)−product formation. This subsequently reinforces the role of energetics in dictating the observed regioselectivity. Further transformations of the products evolve the utility of the methodology thereby yielding scaffolds of synthetic relevance.

Strained cycloalkanols in C–C bond formation reactions: a boon in disguise!

“…Recently, Kapur and co-workers reported a Ru-catalyzed, Cu-mediated, site-selective C(3)/C(4)-alkylation of N -pyridylisoquinolones, by using cyclopropanols as the alkylation agents (Scheme 44e). 88 The distal functionalization occurs with an electronic bias, with the electron-donating substituent generating the C(4)-isomer preferentially and vice versa . Extensive mechanistic investigations in corroboration with the DFT calculations suggest the co-existence of both homoenolate and β-ketoalkyl radical species, in a single pot, as intermediates for C(3) and C(4)-alkylation pathways respectively.…”