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

  • João L. Serrano
  • Pedro F. Soeiro
  • Melani A. Reis
  • Renato E. F. Boto
  • Samuel Silvestre
  • Paulo AlmeidaEmail author
Original Article


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.

Graphical abstract


2,1-Benzisoxazoles Anthranils Barbituric acid derivatives Nitroaromatic reduction Process optimization 



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).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11030_2019_9937_MOESM1_ESM.docx (1.5 mb)
Supplementary material 1 (DOCX 1490 kb)


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.CICS-UBI - Health Sciences Research CenterUniversity of Beira InteriorCovilhãPortugal
  2. 2.Department of ChemistryUniversity of Beira InteriorCovilhãPortugal
  3. 3.CNC - Center for Neuroscience and Cell BiologyUniversity of CoimbraCoimbraPortugal

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