Efficient and Flexible Synthesis of Highly Functionalised 4‐Aminooxazoles by a Gold‐Catalysed Intermolecular Formal [3+2] Dipolar Cycloaddition

Abstract

AbstractOxazoles are important motifs within bioactive and functional materials. Complex, fully substituted and functionalised 4‐aminooxazoles are accessed by an efficient intermolecular reaction between an ynamide and an N‐acylpyridinium N‐aminide in the presence of a gold catalyst. The formal [3+2] dipolar cycloaddition employs a nucleophilic nitrenoid approach to access the 1,3‐N,O‐dipole character in a controllable fashion. The selectivity for a cycloaddition pathway provides a stark contrast against the indiscriminate reactivity of electrophilic acyl nitrenes. Protocols for the formation of acyl‐functionalised aminides are reported from accessible precursors including carboxylic esters and acids. The function of these aminides in the oxazole‐forming reaction has been explored and it is shown that substantial elaboration is accommodated despite proximity to the reactive centre. As a result functional oxazole‐based motifs, such as chiral oxazoles with biologically pertinent substitution patterns, are readily accessible. The use of ynamide types that are unexplored or little used in gold catalysis has been evaluated. Unusual all‐heteroatom substitution patterns around the oxazole are shown to be accessible using thio‐ynamides. The study shows that a close stoichiometry of reactants is suitable alongside relatively low loadings of the bench‐stable precatalysts in practically straightforward multi‐mmol scale reactions. The efficiency and flexibility of this regioselective intermolecular preparation is demonstrated in the ready synthesis of oxazoles with substantial structural and functional group variation.magnified image