Organofluorine heterocyclic motifs are widely used in medicinal chemistry. Nevertheless, some relatively simple structural cores still remain unknown. Among them, alkyl-substituted 2-trifluoroacetyloxazoles take a specific place through to much lower stability of such a core compared to aza analogs.<br/>In our ongoing research, we adapted our previously elaborated procedure for direct trifluoroacylation to the synthesis of 2-trifluoroacetyloxazoles in scales up to 70 g in a single run. Inexpensive reagents such as trifluoroacetic anhydride and triethylamine were used.<br/>The obtained compounds were studied in diverse standard synthetic transformations, including Henry reaction, reductions, condensations with malonic or cyanoacetic acid demonstrating high functional group tolerance. Most of the reactions proceeded smoothly with moderate to high or quantitative yields producing various amines, alcohols and carboxylic acids. In contrast, reductive amination of 2-trifluoroacetyloxazole appeared to be a real challenge due to the formation of stable addition semi-products. After extensive optimization, we converted 2-trifluoroacetyloxazole to the corresponding amine via aza-Wittig reaction with subsequent reduction and deprotection.<br/>In summary, we obtained a set of novel alkyl-substituted 2-trifluoroacetyloxazoles and their structurally and functionally diverse derivatives.

Straightforward trifluoroacylation of oxazoles: The scalable, cost-effective way towards diverse 2-trifluoroacetyloxazoles

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