Regio-controllable [2+2] benzannulation with two adjacent C(sp 3 )-H bonds

Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus in modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich in C(sp )...

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Published inScience (American Association for the Advancement of Science) Vol. 380; no. 6645; pp. 639 - 644
Main Authors Yang, Ji-Min, Lin, Yu-Kun, Sheng, Tao, Hu, Liang, Cai, Xin-Pei, Yu, Jin-Quan
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 12.05.2023
Subjects
Carbon
Carboxylic acids
Catalysis
Chemical bonds
Controllability
Covalent bonds
Iodides
Oxidation
Palladium
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Summary:Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus in modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich in C(sp ) character. Here, we report a palladium-catalyzed double C-H activation of two adjacent methylene units in carboxylic acids, enabled by bidentate amide-pyridone ligands, to achieve a regio-controllable synthesis of BCBs through a formal [2+2] cycloaddition involving σ bonds only (two C-H bonds and two aryl-halogen bonds). A wide range of cyclic and acyclic aliphatic acids, as well as dihaloheteroarenes, are compatible, generating diversely functionalized BCBs and hetero-BCBs present in drug molecules and bioactive natural products.
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Author contributions: J.-Q. Y. conceived the concept. J.-M. Y. discovered and developed the [2+2] benzannulation reaction. Y.-K. L. developed the amide-pyridone ligands, completed the benzannulation of the acyclic acids and proposed the mechanism. J.-M. Y. and Y.-K. L. conducted preliminary mechanistic studies, and the transformations of BCB products. T. S., L. H., and X.-P. C. participated in substrate scope survey. J.-M. Y., Y.-K. L., and J.-Q. Y. wrote the manuscript. J.-Q. Y. directed the project.
These authors contributed equally to this work.
ISSN:0036-8075
1095-9203
DOI:10.1126/SCIENCE.ADG5282