General α-Amino 1,3,4-Oxadiazole Synthesis via Late-Stage Reductive Functionalization of Tertiary Amides and Lactams*.

ABSTRACT: An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant α-amino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Proceeding under mild conditions using (<1 mol %) Vaska's complex (IrCl(CO)(PPh₃ )₂ ) and tetramethyldisiloxane to access the key reactive iminium ion intermediates, a broad range of α-amino 1,3,4-oxadiazole architectures were accessed from carboxylic acid feedstock coupling partners. Extension to α-amino heterodiazole synthesis was readily achieved by exchanging the carboxylic acid coupling partner for C-, S-, or N-centered Brønsted acids, and provided rapid and modular access to these desirable, yet difficult-to-access, heterocycles. The high chemoselectivity of the catalytic reductive activation step allowed late-stage functionalization of 10 drug molecules, including the synthesis of heterodiazole-fused drug-drug conjugates.

SUBMITTER: Matheau-Raven D 

PROVIDER: S-EPMC8457168 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature