Rhodium(I)-Catalyzed Annulation of Bicyclo[1.1.0]butyl-Substituted Dihydroquinolines and Dihydropyridines

• Published in: Journal of the American Chemical Society Vol. 146; no. 22; pp. 14927 - 14934
• Main Authors: Borgini, Matteo, Huang, Qi-Nan, Chen, Pan-Pan, Geib, Steven J., Houk, K. N., Wipf, Peter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.05.2024; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Communication; Physical Sciences; Science & Technology; STRAIN-RELEASE; CONSTRUCTION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.4c04081

Bicyclo­[1.1.0]­butane-containing compounds feature a unique chemical reactivity, trigger “strain-release” reaction cascades, and provide novel scaffolds with considerable utility in the drug discovery field. We report the synthesis of new bicyclo[1.1.0]­butane-linked heterocycles by a nucleophilic addition of bicyclo[1.1.0]­butyl anions to 8-isocyanatoquinoline, or, alternatively, iminium cations derived from quinolines and pyridines. The resulting bicyclo[1.1.0]­butanes are converted with high regioselectivity to unprecedented bridged heterocycles in a rhodium­(I)-catalyzed annulative rearrangement. The addition/rearrangement process tolerates a surprisingly large range of functional groups. Subsequent chemo- and stereoselective synthetic transformations of urea, alkene, cyclopropane, and aniline moieties of the 1-methylene-5-azacyclopropa­[cd]­indene scaffolds provide several additional new heterocyclic building blocks. X-ray structure-validated quantum mechanical DFT calculations of the reaction pathway indicate the intermediacy of rhodium carbenoid and metallocyclobutane species.