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submitted on 15.07.2020 and posted on 16.07.2020by 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.