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

25 May 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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 structurally complex α-amino 1,3,4-oxadiazole architectures were efficiently accessed from diverse 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. Furthermore, the high chemoselectivity of the catalytic reductive activation step allowed the late-stage functionalization of 10 drug molecules, including the synthesis of novel heterodiazole-fused drug-drug conjugates.

Keywords

Vaska's complex
Heterocycles
Iminum ion
Tertiary amides
Carboxylic acids
C-C coupling
Reduction
1,3,4-Oxadiazoles
Heterodiazoles

Supplementary materials

Title
Description
Actions
Title
VaskaOxadiazolesSI
Description
Actions

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