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Expanding the chemical space of sp3-enriched 4,5-disubstituted oxazoles via synthesis of novel building blocks

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Chemistry of Heterocyclic Compounds Aims and scope

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.

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Authors and Affiliations

  1. Enamine Ltd., 78 Chervonotkatska St., Kyiv, 02094, Ukraine

    Evgeniy Y. Slobodyanyuk, Andrii A. Andriienko, Bohdan V. Vashchenko & Oleksandr O. Grygorenko

  2. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv, 02660, Ukraine

    Evgeniy Y. Slobodyanyuk & Dmitriy M. Volochnyuk

  3. Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine

    Andrii A. Andriienko, Bohdan V. Vashchenko, Sergey V. Ryabukhin & Oleksandr O. Grygorenko

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  1. Evgeniy Y. Slobodyanyuk
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  2. Andrii A. Andriienko
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  3. Bohdan V. Vashchenko
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  5. Sergey V. Ryabukhin
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Correspondence to Oleksandr O. Grygorenko.

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Published in Khimiya Geterotsiklicheskikh Soedinenii, 2019, 55(4/5), 421–434

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Slobodyanyuk, E.Y., Andriienko, A.A., Vashchenko, B.V. et al. Expanding the chemical space of sp3-enriched 4,5-disubstituted oxazoles via synthesis of novel building blocks. Chem Heterocycl Comp 55, 421–434 (2019). https://doi.org/10.1007/s10593-019-02475-9

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