Regiocontrollable [2 + 2] benzannulation of γ,δ-C(sp3)–H bonds with dihaloarenes using palladium catalysis

Methylene-selective C–H functionalization at distal positions is a challenge in the field of Pd(II) catalysis. We have previously reported a ligand-enabled β,γ-C–H coupling with dihaloarenes for the synthesis of benzocyclobutenes (BCBs) as a promising class of scaffolds in drug discovery. Here we report a Pd(II)-catalysed method for the γ,δ-methylene C–H activation of free aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route for the synthesis of diversely functionalized BCBs. The development of a carboxyl-pyridone ligand is crucial for the remote C(sp³)–H activation. Notably, previous γ,δ-methylene C–H activation reactions of monoaliphatic acids are limited to carbocyclic substrates. The site-selective activation of γ,δ-C–H bonds installs the BCB pharmacophores that are one carbon atom further away from the carboxyl group than in previous studies. Given the carboxyl group can serve as hydrogen-bond donor or acceptor, such alternation of distance between two interactions can impact bioactivity.