Anti-Friedel–Crafts alkylation via electron donor–acceptor photoinitiation

Abstract The ubiquity of C–H bonds in organic molecules makes direct C–H functionalization an atom- and step-efficient strategy in synthetic chemistry. However, direct C–H alkylation, particularly of electron-poor aromatic substrates, remains a major challenge because current methods suffer from limited selectivity, functional group tolerance and/or require harsh acidic, pyrophoric or toxic reagents. Here we introduce a selective, scalable and transition-metal-free synthetic strategy for C–H alkylation of electron-poor aromatics under mild conditions, which also exhibits high functional group tolerance applicable to the late-stage functionalization of pharmaceutical compounds. The mechanistic design exploits a redox-active phthalimide ester tag to form an electron donor–acceptor complex that fragments upon photoexcitation to yield a nucleophilic alkyl radical, which selectively alkylates the most electrophilic position of electron-deficient aromatics, thereby exhibiting ‘anti-Friedel–Crafts’ selectivity. Mechanistic studies, microkinetic modelling simulations and computational analyses indicate that the reaction then propagates via radical anion autocatalysis. The ‘anti-Friedel–Crafts’ selectivity is consistent with theoretical predictions from Fukui indices and machine-learning models that provide the framework necessary to forecast selectivity in previously ‘unseen’ substrates, thereby enabling selective alkylation of a wide range of complex molecules and late-stage pharmaceuticals.