Ultrasound-mediated Tandem Synthesis of New Highly Functionalized 4-Hydroxy-quinoline Derivatives with Amidine and Imidate Skeletons from Trichloroacet-amidine(imidate), Alkynes, and Isatoic Anhydride

Introduction: In this study, using a novel design and readily available starting materials, various quinoline derivatives were synthesized by replacing imidates and amidines. Additionally, in heterocyclic chemistry, a four-component reaction involving alkynes, isatoic anhydride, trichloroacetonitrile, and various amines or alcohols yielded 4-hydroxy-quinoline-3-carboximidamide (imidate) with satisfactory efficiency. Using an inexpensive copper(I) catalyst, DMF as the solvent, and ultrasonic conditions for 40 minutes, the synthesis and characterization of new compounds can be achieved without the need for ligands or oxidants. The combination of readily available starting materials, mild reaction conditions, catalytic systems, and simple purification procedures facilitates the synthesis of a diverse range of substituted 4-hydroxy-quinoline derivatives, including those containing amidine and imidate skeletons. Methods: In this study, isatoic anhydride was employed to trap the triple bond. A copper-catalyzed reaction of alkynes, isatoic anhydride, trichloroacetonitrile, and various amines or alcohols was carried out to synthesize substituted quinoline derivatives containing amidine and imidate skeletons, as illustrated in Scheme 1. In this reaction, isatoic anhydride, at 80 °C in DMF, released carbon dioxide to generate an active intermediate. This intermediate reacted with the triple bond of the compound formed from the terminal alkyne and the amidine derivative through a [4+2] cycloaddition to produce the desired quinoline product. The advantages of this method include its simplicity and safety, the use of inexpensive materials and catalysts, ultrasonic-assisted reaction conditions that improve efficiency and speed, and good yields (72-93%). This approach is, therefore, highly attractive for the synthesis of substituted quinoline derivatives. In this study, new quinolines containing amidine and imidate skeletons were synthesized with potential for further biological evaluation. Results: To start the synthesis of compound 5a, the required starting materials, including aniline 2a, phenylacetylene 3a, trichloroacetonitrile 1, and isatoic anhydride 4, were selected. In the next step, the reaction conditions were optimized by changing the catalyst and different solvents. Among the copper catalysts investigated, CuI gave satisfactory results. Among the solvents, DMF was also the solvent of choice. Finally, the reaction was carried out in DMF using (0.019 g) 10 mol% CuI as catalyst, (0.100 g) 1.0 mmol Et3N as base, (0.142 g) 1.0 mmol of trichloroacetonitrile, (0.093 g) 1.0 mmol of aniline, and (0.163 g) 1.0 mmol of isatoic anhydride under ultrasonic irradiation at a power of 60 W. Discussion: The structure of all the synthesized compounds (5a-m) was determined by mass spectral data, IR, 1H-NMR, and 13C-NMR. For example, the mass spectrum of 5a showed a molecular ion peak at m/z = 339. The 1H-NMR spectrum of 5a showed three singlets for the OH (δ = 8.13 ppm) and two NH (δ = 5.03 and 5.96 ppm) groups with confirmed multiplets for the phenyl protons. The 13C-NMR spectrum of 5a exhibited 17 signals in agreement with the proposed structure. The NMR spectra of the rest of the compounds were found to be similar to 5a due to the different substitutions on the ring. Conclusion: In this study, a new protocol was used to synthesize a variety of 4-hydroxy-quinoline- 3-carboxyimidamides (imidates) using alkynes, isatoic anhydride, trichloroacetonitrile, and various amines or alcohols in the presence of available copper(I) iodide catalyst, under ultrasonic conditions for 40 minutes at room temperature in DMF solvent to prepare various quinolines with substituted imidate and amidine derivatives. The combination of readily available starting materials, efficient catalysis by the copper catalyst, mild reaction conditions, the use of ultrasonic conditions to improve reaction speed and efficiency, and ease of purification collectively contributes to the high yields of the synthesized compounds. Using this method, 13 new quinoline-based compounds, including those with amidine and imidate skeletons, with potential for biological evaluation, were synthesized.