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Reverse Polarity Reductive Functionalization of Tertiary Amides via a Dual Iridium Catalyzed Hydrosilylation & SET Strategy

preprint
submitted on 15.07.2020 and posted on 16.07.2020 by Tatiana Rogova, Pablo Gabriel, Stamatia Zavitsanou, Jamie Leitch, Fernanda Duarte, Darren J. Dixon
A new strategy for the mild generation of synthetically valuable α-amino radicals from robust tertiary amide building blocks has been developed. By combining Vaska’s complex-catalyzed tertiary amide reductive activation and photochemical single electron reduction into a streamlined tandem process, metastable hemiaminal intermediates were successfully transformed into nucleophilic α-amino free radical species. This umpolung approach to such reactive intermediates was exemplified through coupling with an electrophilic dehydroalanine acceptor, resulting in the synthesis of an array of α-functionalized tertiary amine derivatives, previously inaccessible from the amide starting materials. The utility of the strategy was expanded to include secondary amide substrates, intramolecular variants and late stage functionalization of an active pharmaceutical ingredient. DFT analyses were used to establish the reaction mechanism and elements of the chemical system that were responsible for the reaction’s efficiency.

History

Email Address of Submitting Author

jamie.leitch@chem.ox.ac.uk

Institution

University of Oxford

Country

United Kingdom

ORCID For Submitting Author

0000-0001-6997-184X

Declaration of Conflict of Interest

No conflict of interest

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