KOtBu-Mediated Synthesis of Dimethylisoindolin-1-ones and Dimethyl-5-phenylisoindolin-1-ones: Selective C-C Coupling of an Unreactive Tertiary sp3 C-H Bond

A new reaction for the synthesis of dimethylisoindolinones has been presented from 2-halo-N-isopropyl-N-alkylbenzamide substrates and (KOBu)-Bu-t by the selective C-C coupling of an unreactive tertiary sp(3) C-H bond. The reaction manifested an excellent selectivity toward a tertiary sp(3) C-H bond over primary or sec C-H bond. Moreover, biaryl C-C coupling along with alkyl aryl C-C coupling can be achieved in one pot using dihalobenzamides for the synthesis of biaryl 5-phenylisoindolin-1-ones. It seems that the reaction proceeds via a radical pathway in which the aryl radical translocates via 1,5-hydrogen atom transfer (HAT), forming a tertiary alkyl carbon-centered radical. The generated tertiary alkyl radical could attack the benzamide ring in a 5-exo/endo-trig manner followed by the release of an electron and a proton, leading to a five-membered isoindolinone ring. HAT seems to be responsible for the selective functionalization of the tertiary alkyl group over primary and secondary C-H bonds.