Metal-Free Catalyzed Defluorinative O-Arylation of Pyrazolones with Polyfluoroarenes

Abstract

An efficient and general method for defluorinative O-arylation of pyrazolones has been successfully developed under metal-free conditions. This methodology allows for the synthesis of desired products by using a wide range of pyrazolones and polyfluoroarenes as starting materials. The compatibility of various substrates was demonstrated, ensuring the applicability of this method. Furthermore, the synthesis of the target compounds at a gram scale and the ability to perform late-stage modifications highlight the potential of this approach in preparative pharmaceutical synthesis and organofluorine chemistry.

Key words

defluorinative - O-arylation - pyrazolones - polyfluoroarenes - metal-free

• References and Notes

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• 11 1-Methyl-2-phenyl-1H-indole (3a) – Typical ProcedureAdded 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (1a, 34.8 mg, 0.2 mmol, 1.0 equiv), N,N-diethyl-2,3,4,5,6-pentafluorobenzamide (2a, 64.08 mg, 0.24 mmol, 1.2 equiv), and Cs₂CO₃ (130.0 mg, 0.4 mmol, 2.0 equiv) in 2.0 mL of CH₃CN. The solution was warmed up to 80 ℃ and was stirred for 12 h until the reaction was complete as indicated by TLC. The reaction mixture was then quenched with H₂O, extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel to obtain the product. N,N-Diethyl-2,3,5,6-tetrafluoro-4-[(3-methyl-1-phenyl-1H-pyrazol-5-yl)oxy]benzamide (3a)The crude was purified by flash chromatography using petroleum ether/ethyl acetate (15:1) to afford 3a as colorless oil (69.0 mg, 81% yield). TLC: R_f = 0.16 (petroleum ether/ethyl acetate = 15:1; UV). ¹H NMR (400 MHz, CDCl₃): δ = 7.70 (d, J = 7.2 Hz, 2 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 1 H), 5.48 (s, 1 H), 3.60 (q, J = 7.2 Hz, 2 H), 3.24 (q, J = 7.2 Hz, 2 H), 2.27 (s, 3 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.9, 151.1, 149.0, 142.9 (dm, J = 248.0 Hz), 141.0 (dm, J = 299.0 Hz), 137.9, 134.2 (t, J = 13.0 Hz), 129.2, 127.2, 122.9, 114.1 (t, J = 13.0 Hz), 89.5, 43.4, 40.0, 14.6, 14.2, 12.9. ¹⁹F NMR (376 MHz, CDCl₃): δ = –142.00 to –142.14 (m, 2 F), –152.27 to –152.40 (m, 2 F). HRMS (ESI-TOF): m/z calcd for C₂₁H₂₀F₄N₃O₂ [M + H]⁺: 422.1486; found: 422.1480.