Anti-Friedel-Crafts alkylation via electron donor-acceptor photoinitiated autocatalysis

The ubiquity of C–H bonds in organic molecules makes C–H functionalisation one of the most valuable synthetic transformations in organic chemistry. It provides a sustainable synthetic strategy, optimising atom and step economy by eliminating the need for functional handles, instead relying on reagent control or the substrate’s innate selectivity. C–H alkylation of electron-poor aromatic species remains a particular challenge, typically relying on functional handles to direct selectivity with either traditional palladium cross-coupling or nickel photoredox methodologies. Here we introduce a highly selective, scalable, and cost effective synthetic strategy for C–H alkylation of electron-poor aromatics, exhibiting high functional group tolerance applicable to pharmaceutical compounds. This reaction leverages an autocatalytic, electron donor-acceptor triggered, radical reaction, as confirmed by both experimental and computational analyses. Notably, it demonstrates ‘anti-Friedel-Crafts’ selectivity, consistent with theoretical predictions from Fukui indices and machine learning models on previously ‘unseen’ substrates.