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Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles

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Abstract

Benzisoxazoles represent an important pharmacophore in medicinal chemistry. Recently, an unexpected formation of symmetric 3-substituted 2,1-benzisoxazoles through reduction of 5-(2-nitrobenzylidene)barbiturates has been described. This reductive intramolecular heterocyclization probably involves a nitroso intermediary. To improve the previous reaction conditions, the nature of the reducing agent and additives, reaction time and solvents were evaluated. By applying the optimized conditions, several symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles were prepared with an yield of 52–87%. From this set, seven compounds were novel and the unsymmetric nature of the (thio)barbituric acid moiety was explored. For that, the total synthesis, starting from the respective urea or thiourea, was successfully performed, and 11 thiobarbiturates, benzylidene barbiturate and thiobarbiturate precursors are described.

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Acknowledgements

This work is supported by FEDER funds through the POCI-COMPETE 2020-Operational Programme Competitiveness and Internationalization in Axis I-Strengthening research, technological development and innovation (Project No. 007491) and National Funds by FCT-Foundation for Science and Technology (Project UID/Multi/00709). J. L. Serrano is thankful to Santander-Totta/UBI for the fellowship (BID/ICI-UID FC/Santander Universidades-UBI/2017).

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Author notes

  1. João L. Serrano and Pedro F. Soeiro contributed equally to this work.

Authors and Affiliations

  1. CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal

    João L. Serrano, Pedro F. Soeiro, Melani A. Reis, Renato E. F. Boto, Samuel Silvestre & Paulo Almeida

  2. Department of Chemistry, University of Beira Interior, Rua Marquês d’Ávila e Bolama, 6201-001, Covilhã, Portugal

    João L. Serrano, Pedro F. Soeiro, Melani A. Reis, Renato E. F. Boto & Paulo Almeida

  3. CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-517, Coimbra, Portugal

    Samuel Silvestre

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Serrano, J.L., Soeiro, P.F., Reis, M.A. et al. Synthesis and process optimization of symmetric and unsymmetric barbiturates C5-coupled with 2,1-benzisoxazoles. Mol Divers 24, 155–166 (2020). https://doi.org/10.1007/s11030-019-09937-4

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