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EXPANDING THE CHEMICAL SPACE OF sp3-ENRICHED 4,5-DISUBSTITUTED OXAZOLES via SYNTHESIS OF NOVEL BUILDING BLOCKS

Evgeniy Y. Slobodyanyuk, Andrii A. Andriienko, Bohdan V. Vashchenko, Dmitriy M. Volochnyuk, Sergey V. Ryabukhin, Oleksandr O. Grygorenko
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Abstract


An efficient approach to the preparation of novel sp3-enriched 4,5-disubstituted oxazoles bearing a functional group at the C-4 position is described. The method commenced with synthesis of ethyl oxazole-4-carboxylates (13 examples, 63–99% yield), with subsequent function insertion to the heterocyclic core by late-stage functional group transformation. The LiBH4-mediated reduction of ethyl oxazole-4-carboxylates was the only method which could be optimized at multigram scale (up to 40 g), and its scope was demonstrated by preparation of 13 alcohols with (cyclo)alkyl, fluoroalkyl, or N-Boc-aminoalkyl moiety at the C-5 position (47–89% yield). The utility of these key intermediates was demonstrated by the preparation of chlorides (13 examples, 90–99% yield), azides (13 examples, 83–99% yield), amines (13 examples, 80–98% yield), and sulfonyl chlorides (4 examples, 68–97% yield) – advanced building blocks for synthetic and medicinal chemistry.

 


Keywords


alcohols, amines, azides, chlorides, esters, oxazoles, sulfonyl chlorides, building blocks.

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