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Synthesis of All-carbon Disubstituted Bicyclo[1.1.1]pentanes by Iron-Catalyzed Kumada CrossCoupling

preprint
submitted on 19.03.2020 and posted on 20.03.2020 by Jeremy Nugent, Bethany Shire, Dimitri F. J. Caputo, Helena D. Pickford, Frank Nightingale, Ian T. T. Houlsby, James J. Mousseau, Edward Anderson
1,3-Disubstituted bicyclo[1.1.1]pentanes (BCPs) are important motifs in drug design as surrogates for p-substituted arenes and alkynes. Access to all-carbon disubstituted BCPs via cross coupling has to date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3-C-disubstituted BCPs from 1-iodo-bicyclo[1.1.1]pentanes (iodo-BCPs) by direct iron-catalyzed crosscoupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodoBCPs as electrophiles in cross-coupling, and of Kumada coupling of tertiary iodides in general. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3-C-disubstituted BCPs including various drug analogues.

Funding

EP/S013172/1

EP/L015838/1

GA No 786683

History

Email Address of Submitting Author

edward.anderson@chem.ox.ac.uk

Institution

University of Oxford

Country

United Kingdom

ORCID For Submitting Author

0000-0002-4149-0494

Declaration of Conflict of Interest

None

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