β-Ketoamides in Thieno[2,3-b]pyridine Series: Synthesis, Quantum Chemical Studies and 2,4-D Herbicide Safening Effects

Abstract

The aim of this work was to synthesize previously unknown thieno[2,3-b]pyridines bearing a β-ketoamide moiety, to study their structure, and to evaluate their agrochemical potential as 2,4-D herbicide safeners. A series of 3-(3-aminothieno[2,3-b]pyridine-2-yl)-3-oxo-N-phenylpropanamides were prepared via S-alkylation of readily available 2-thioxonicotinonitriles or 3-cyanopyridine-2-thiolates with γ-bromoacetoacetanilide, followed by base-promoted Thorpe–Ziegler cyclization. The structure of 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide was unambiguously established by single-crystal X-ray diffraction. Quantum chemical calculations (B3LYP-D3BJ/6-311+G(2d,p)) revealed that the ketone form is significantly more stable than the enol tautomer with a calculated equilibrium constant in DMSO of 1.52 × 10−5, which is consistent with the absence of enol form signals in the NMR spectra. The calculated IR frequencies, after scaling, showed excellent agreement with experimental data. Additionally, we found that 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide undergoes intramolecular cyclization upon heating in AcOH or DMF, to give 4-hydroxy-7,9-dimethylthieno [2,3-b:4,5-b′]dipyridin-2(1H)-one via aniline elimination, thus providing an alternative route to tricyclic thieno [2,3-b;4,5-b]dipyridine ensembles. Agrochemical screening demonstrated that some compounds exhibit pronounced antidote activity against the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in sunflower seedlings, with root and hypocotyl protection reaching 119–156% in laboratory tests. Field trials for the three most active compounds confirmed their efficacy, providing crop yield increases of 46–57% relative to the herbicide-only control. These results indicate that the newly synthesized thienopyridine β-ketoamides represent a promising class of 2,4-D herbicide safeners.