Reaction of γ-Bromoacetoacetanilide with 2-Thioxo-1,2-dihydropyridine-3-carbonitriles: Synthesis and Properties of New β-Ketoamides Bearing Nicotinonitrile and Thieno[2,3-b]pyridine Fragments

Abstract

The reaction of γ-bromoacetoacetanilide with 2-thioxo-1,2-dihydropyridine-3-carbonitriles afforded novel β-ketoamides bearing a heterocyclic fragment, namely 4-{(3-cyanopyridin-2-yl)thio}-3-oxo-N-phenylbutanamides and 3-(3-aminothieno[2,3-b]pyridin-2-yl)-3-oxo-N-phenylpropanamides. The structure of the reaction products was found to be critically dependent on the reaction conditions: under mild conditions, the S-alkylation products are formed, whereas upon heating in the presence of bases, these intermediates undergo Thorpe–Ziegler isomerization to give the corresponding thienopyridine β-ketoamides. Prolonged heating of the latter leads to further cascade cyclization, affording 4-hydroxythieno[2,3-b:4,5-b']dipyridin-2(1H)-ones. All synthesized compounds were subjected to in silico bioavailability assessment and molecular docking to identify potential protein targets.