2026 | 2025 | 2024 | 2023 | 2022 | 2021 | 2020 | 2019 | 2018 | 2017 | 2016 | 2015 | 2014 | 2013 | 2012 | 2011 | 2010 | 2009 | 2008
Synthesis and structure of novel pyrimidine-thioethers: structural effects on reactivity along with an unpredicted dimethylamination reaction
Authors: Inês C. C. Costa; Luís M. T. Frija; André F. Augusto; José A. Paixão; Maria L. S. Cristiano
Ref.: ChemPhysChem 26(18), e202500308 (2025)
Abstract: Buchwald-Hartwig reactions have been in the spotlight over the past years due to their usefulness in creating a wide range of chemical skeletons applied in drug discovery. Aminopyrimidines are heterocyclic structures with significant biological relevance and compounds bearing the amino- and diaminopyrimidine motifs have been associated with antiviral, antibacterial, antiparasitic, antifungal, anticancer, and anti-inflammatory properties. Given the notable status of aminopyrimidines in the design of target-specific drug candidates, the synthesis and structure of four aminopyrimidine-arylsulfide conjugates (3, 4, 5, and 6) are reported that are designed to inhibit trypanothione reductase, a key enzyme in the redox pathway of trypanosomatids. When applying the Buchwald-Hartwig synthetic approach, the formation of different products is witnessed by altering the reaction conditions, observing that regioselectivity is conditioned by reaction time and by Boc-protection of the starting 2,6-dichloropyrimidin-4-amine. The electron-withdrawing character of the protecting group appears to increase the susceptibility of the pyrimidine at C2 for further reaction with the solvent, DMF, yielding the corresponding diaminopyrimidine-based conjugates. The crystal structures of the novel aminopyrimidine-arylsulfide conjugate and their Boc-protected 2,6-dichloropyrimidin-4-amine precursors are disclosed and discussed.
