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Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions
Published on: July 30, 2017
Regiocontrollable [2 + 2] benzannulation of γ,δ-C(sp3)-H bonds with dihaloarenes using palladium catalysis
Liang Hu1, Jie-Lun Yan1, Yu-Kun Lin1
1Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
Abstract:
Methylene-selective C-H functionalization at distal positions is a challenge that remains to be addressed 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. Herein, we report a Pd(II)-catalyzed 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 benzocyclobutenes (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 mono-aliphatic acids are uniformly limited to carbocyclic substrates. The site selective activation of γ, δ-C-H bonds allows the installation of the BCB pharmacophores that are one more carbon further away from the carboxyl group which could serve as hydrogen bond donor or acceptor. Such alternation of distance between two interactions can significantly impact bioactivity.
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