Synthesis of azido-modified enamides via C=C isomerisation of functionalised Ugi adducts

Abstract

Multicomponent reactions (MCRs) represent a cornerstone of modern organic synthesis, offering rapid access to molecular diversity through the convergent assembly of building blocks. Among these, the Ugi reaction and its variants have emerged as versatile tools for constructing functionalised scaffolds with applications in drug discovery and materials science. Herein, we report a novel library-to-library approach for the synthesis of azido-modified Ugi adducts derived from α,β-unsaturated aldehydes, followed by C=C bond isomerisation to yield azido-modified enamides. Functionalised peptidomimetics are formed under mild conditions, affording high yields and broad substrate tolerance. Subsequent base-mediated isomerisation proceeds efficiently, delivering azido-modified enamides. This tandem protocol enables the generation of diverse libraries from the initial Ugi products. The resulting enamides exhibit promising reactivity for further transformation, including intra- or intermolecular cyclisations, positioning them as valuable compounds in heterocyclic chemistry.