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Improved Synthetic Methodology, Substrate Scope and X-ray Crystal Structure for N, N’-disubstituted Guanidines

Abstract

Guanidine is a privileged scaffold in drug discovery. Herein we report our investigations into the acid promoted amination of pyrimidine-bearing cyanamide to produce N, N’-disubstituted guanidines. Hydrochloric acid was found to be a suitable catalyst, and the substrate scope using conventional heating was investigated with 23 aniline derivatives. The highest yield was obtained with anilines having pKa in the range of 2–4. Further, a microwave synthesis was developed using 3-chloroaniline as a model substrate increasing the yield from 68 to 93 %. The microwave method was especially suited for increasing yields with anilines having pKa > 3. The structure of the pyrimidine-bearing guanidines was confirmed by NMR spectroscopy, and one representative compound has been evaluated by X-ray crystallography, showing the trans-isomer as the only tautomer in solid form.
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Category

Academic article

Language

English

Author(s)

  • Vijayaragavan Elumalai
  • Václav Eigner
  • Torkild Visnes
  • Eirik Sundby
  • Bård Helge Hoff

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • Czech Academy of Sciences
  • Norwegian University of Science and Technology

Year

2024

Published in

ChemistrySelect

Volume

9

Issue

2

View this publication at Norwegian Research Information Repository