Direct C–H Alkylation of Naphthoquinones with Amino Acids Through a Revisited Kochi–Anderson Radical Decarboxylation: Trends in Reactivity and Applications

Abstract

In our ongoing research program into the discovery of new anticancer drugs , we were interested in the preparation of naphthoquinone scaffolds bearing aminoalkyl side-chains. Following this aim, we revisited the Kochi–Anderson radical decarboxylation of amino acids in order to set up a versatile route to the direct functionalization of naphthoquinones. The best reaction conditions were applied to a selected series of compounds in a systematic methodological study which allowed us to establish important trends in reactivity. We found that α-substituted β-amino acids were the most suitable substrates for the radical addition. In contrast, α-amino acids gave modest results. The influence of the amine protecting groups on the reaction outcome has also been studied. This practical procedure allows the introduction of various unsymmetrical moieties, including orthogonally protected linear aminoalkyl chains or chiral dipeptidic chains, and opens the door to a wide scope of easily accessible chemical diversity.