Catalyst-Free Photoinduced Deaminative Functionalization of Amino Acids and Glutarimide Precursors

Functionalized N-heterocycles are found among a majority of pharmaceutical drugs, including targeted protein degraders like cereblon E3-ligase modulating drugs (CELMoDs) that often employ the glutarimide motif. Typical strategies for synthesizing these scaffolds require individualized and multistep routes from a glutamate/glutamine derivative. In contrast, alkylation with a simple α-haloglutarimide is low-yielding and limited by substrate availability. We report a generalizable pathway to forming these alkylated N-heterocycles from abundant primary amines derived from amino acids via a unique Electron Donor-Acceptor (EDA) complex. Irradiation with blue light induces the formation of a diradical species, which recombines to form traditionally unstable and often inaccessible alkyl iodides in situ, which are displaced by the introduction of an exogenous nucleophile. Overall, this transformation introduces an umpolung approach to heteroarylation by converting primary amines into electrophilic coupling partners. When employing glutamate and glutamine derivatives, this strategy can enable efficient late-stage introduction of glutarimides.