Environmentally Benign Atroposelective Synthesis of Fluorinated Oxindole–Coumarin Hybrid Structures

Abstract

The significance of multifunctional compounds exhibiting prevalent pharmacophores in the health sciences and increasingly tight manufacturing regulations demand synthetic methods that give efficient access to such scaffolds without resorting to hazardous solvents or additives, expensive reagents or catalysts, and at minimum energy consumption, preferably by avoiding time-consuming and wasteful work-up procedures. Herein, a base-promoted method that produces atropisomeric structures with high diastereoselectivities from fluorooxindoles and 4-chloro-3-nitrocoumarins via dechlorinative Csp²–Csp³ bond formation is described. The reaction occurs under environmentally benign conditions with readily available triethylamine in isopropyl alcohol at room temperature within 1 h. The oxindole–coumarin adducts are obtained in high yields and dr’s up to 37:1 without the need for chromatographic purification.

Keywords

Atroposelective synthesis - Green chemistry - Organofluorines - Oxindoles - Coumarins

Publikationsverlauf

Eingereicht: 20. August 2025

Angenommen nach Revision: 30. September 2025

Accepted Manuscript online:
30. September 2025

Artikel online veröffentlicht:
29. Oktober 2025

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• 44a Representative example of the atroposelective synthesis procedure
• 44b N-Phenyl-3-fluoro-2-oxindole (20.5 mg, 0.09 mmol), 4-chloro-7-methoxy-3-nitrocoumarin (23.0 mg, 0.09 mmol), and triethylamine (0.2 mL, 1.5 mmol) were combined and isopropyl alcohol (0.8 mL) was added. The resulting mixture was stirred at 25 °C for 1 h. Upon completion, the solvent was removed under vacuum and the residue was extracted with ethyl acetate and water. The combined organic layers were dried over sodium sulfate and concentrated to isolate 4i (35.7 mg, 0.08 mmol) as a yellow crystalline solid in 91% yield. The dr was determined as 7:1 using ¹⁹F NMR spectroscopy. ¹H NMR (400 MHz, CD₃CN) δ 7.72–7.63 (m, 3H), 7.62–7.54 (m, 4H), 7.30 (m, 1H), 7.11 (d, J = 9.2 Hz, 1H), 7.07–7.01 (m, 2H), 6.93 (dd, J = 9.1, 2.6 Hz, 1H), 3.87 (s, 3H). ¹³C{¹H} NMR (100 MHz, CD₃CN) δ 167.92, 167.71, 164.47, 157.34–153.08 (m), 144.54, 134.09 (d, J = 4.5 Hz), 132.75, 130.14, 130.06, 129.41, 126.98 (d, J = 2.7 Hz), 126.79, 126.53, 125.96, 125.09 (d, J = 3.8 Hz), 123.18, 114.48, 111.92 (d, J = 2.8 Hz), 106.38 (d, J = 4.8 Hz), 102.08, 92.33 (d, J = 187.1 Hz), 56.16. ¹⁹F NMR (376 MHz, CD₃CN) δ −146.55. HR-MS (ESI-TOF) m/z: [M+Na]⁺ calcd for C₂₄H₁₅FN₂O₆ 469.0806, found 469.0807. Melting point range: 191–196 °C
• 44c Atroposelective Synthesis at 1.0 mmol scale
• 44d N-Phenyl-3-fluoro-2-oxindole (227.0 mg, 1.0 mmol), 4-chloro-3-nitrocoumarin (225.0 mg, 1.0 mmol), and triethylamine (0.2mL, 1.5 mmol) were combined in a vial and isopropyl alcohol (0.8 mL) was added. The resulting mixture was stirred at 25 °C for 1 h. Upon completion, the solvent was removed under vacuum and the remaining residue was extracted with ethyl acetate and water. The combined organic layers were dried over sodium sulfate and concentrated to isolate 3b (378.5 mg, 0.9 mmol) as a white crystalline solid in 91% yield. The dr was determined as 20:1 using ¹⁹F NMR spectroscopy. The ¹H and ¹⁹F NMR spectra were in agreement with the literature.⁴³