Fused Systems Based on 2-Aminopyrimidines: Synthesis Combining Deprotolithiation-in situ Zincation with N -Arylation Reactions and Biological Properties

Madani Hedidi (1) , Julien Maillard (1) , William Erb (1) , Frédéric Lassagne (1) , Yury S Halauko (2) , Oleg A Ivashkevich (2) , Vadim E Matulis (2) , Thierry Roisnel (1) , Vincent Dorcet (1) , Monzer Hamze (3) , Ziad Fajloun (3) , Blandine Baratte (4) , Sandrine Ruchaud (4) , Stéphane Bach (4) , Ghenia Bentabed-Ababsa (5) , Florence Mongin (1)

1 ISCR - Institut des Sciences Chimiques de Rennes
2 Belarusian State University
3 Centre AZM pour la Recherche en Biotechnologie et ses Applications
4 P3H - Phophorylation de protéines et Pathologies Humaines
5 LSOA - Laboratoire de Synthèse Organique Appliquée

Various aromatic ketones were first functionalized next to the carbonyl function by deprotolithiation in the presence of a zinc salt followed by iodolysis. The outcome of the reactions was analyzed, and in particular their regioselectivity in the light of the calculated pKa values. The various halogenated ketones were next involved in copper-catalyzed twofold C-N bond formation in order to obtain fused systems based on 2-aminopyrimidines. Besides potential antibacterial effect, reached 2-aminobenzothiopyrano[4,3,2-de]quinazoline proved to inhibit PIM1 (IC50: 0.61 μM) and CDK2/cyclin A (IC50: 2.0 μM) kinases.

Domains: Chemical Sciences; Organic chemistry; Chemical Sciences; Medicinal Chemistry

Madani Hedidi, Julien Maillard, William Erb, Frédéric Lassagne, Yury S Halauko, et al.. Fused Systems Based on 2-Aminopyrimidines: Synthesis Combining Deprotolithiation-in situ Zincation with N -Arylation Reactions and Biological Properties. European Journal of Organic Chemistry, 2017, 2017 (39), pp.5903-5915. ⟨10.1002/ejoc.201701004⟩. ⟨hal-01624382⟩