General α‐Amino 1,3,4‐Oxadiazole Synthesis via Late‐Stage Reductive Functionalization of Tertiary Amides and Lactams**
Daniel Matheau‐Raven, Darren J. Dixon
Abstract
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)(PPh 3 ) 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.