Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation

Clemenceau, Antonin and Thesmar, Pierre and Gicquel, Maxime and Le Flohic, Alexandre and Baudoin, Olivier. (2020) Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation. Journal of the American Chemical Society, 142 (36). pp. 15355-15361.

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Official URL: https://edoc.unibas.ch/78323/

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Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Synthetische Chemie (Baudoin)
UniBasel Contributors:Baudoin, Olivier
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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edoc DOI:
Last Modified:09 Sep 2021 01:30
Deposited On:13 Oct 2020 07:48

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