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Abstract
AbstractAn 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.
Highlights
An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant aamino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described
Traditional syntheses of a-amino 1,3,4-oxadiazoles are largely based on indirect condensation approaches where the oxadiazole unit is constructed through dehydration of a 1,2diacylhydrazine.[2k,4] The need for multistep synthesis, and harsh dehydration conditions typically dictates that the oxadiazole be introduced at an early stage in the synthetic sequence, and a direct and late-stage introduction of this motif would be both desirable and enabling.[5]
The dormant amide can be reductively activated with exquisite chemoselectivity by Vaskas complex (IrCl(CO)(PPh3)2), at low catalyst loadings, and 1,1,3,3tetramethyldisiloxane (TMDS), affording an O-silylated hemiaminal which is smoothly transformed into a reactive iminium ion upon treatment with Brønsted or Lewis acids
Summary
An iridium-catalyzed reductive three-component coupling reaction for the synthesis of medicinally relevant aamino 1,3,4-oxadiazoles from abundant tertiary amides or lactams, carboxylic acids, and (N-isocyanimino) triphenylphosphorane, is described. Advancing our groups program on reductive amide functionalization, the late-stage synthesis of a-amino 1,3,4oxadiazoles presented an attractive and unsolved challenge. This strategy would allow the late-stage functionalization (LSF) of amide or lactams, and carboxylic acid containing active pharmaceutical ingredients (APIs), providing a-amino 1,3,4-oxadiazoles with complex structural and chemical features.
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