Synthesis of 4,4-Difluoro-1H-pyrazole Derivatives

Abstract

Fluorination of 3,5-diarylpyrazole substrates by Selectfluor^TM in acetonitrile gave 4,4-difluoro-1H-pyrazoles in addition to 4-fluoropyrazole derivatives. The structure of this new class of fluorinated heterocycle was established by X-ray crystallography.

Key words

organofluorine - fluoroheterocycle - pyrazole - selective fluorination - fluoropyrazole

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• 21 Typical Procedure (Conditions A); 4-Fluoro-3,5-diphenyl-1H-pyrazole (2d) and 4,4-Difluoro-3,5-diphenyl-4H-pyrazole (3a): 3,5-Diphenyl-1H-pyrazole (0.30 g, 1.36 mmol) and Selectfluor^TM (0.482 g, 1.36 mmol) were dissolved in MeCN (5 mL) and the mixture was heated by microwave irradiation for 15 min at 90 °C. The mixture was then extracted with CH₂Cl₂ (3 × 50 mL) and washed with NaHCO₃ (30 mL) and H₂O (30 mL). The combined extracts were dried (MgSO₄) and evaporated. Column chromatography on silica gel using hexane and EtOAc (1:1) as the eluent, gave 4-fluoro-3,5-diphenyl-1H-pyrazole (0.135 g, 45%) as pale yellow crystals; mp 185–188 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.47 (m, 2 H, 4-H), 7.48–7.51 (m, 4 H, 3-H), 7.77–7.80 (m, 4 H, 2-H), 10.3 (br s, 1 H, NH). ¹³C NMR (126 MHz, CDCl₃): δ = 128.2 (Ar), 129.0 (Ar), 129.3 (Ar), 131.1 (d, ² J _CF = 15.0 Hz, C-3), 140.0 (d, ¹ J _CF = 226.6 Hz, C-4), 148.7 (Ar). ¹⁹F NMR (376 MHz, CDCl₃): δ = –174.3 (s). MS: m/z (%, EI⁺) = 237.9 (100) [M]⁺, 107.8 (43), 76.9 (40). HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₂FN₂: 239.0983; found: 239.0972. 4,4-Difluoro-3,5-diphenyl-4H-pyrazole (3a): obtained as yellow crystals (0.122 g, 21%); mp 105–107 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.67 (m, 6 H, ArH), 8.06–8.15 (m, 4 H, ArH). ¹³C NMR (126 MHz, CDCl₃): δ = 125.4 (Ar), 125.6 (t, ¹ J _CF = 267.5 Hz, CF₂), 128.3 (Ar), 129.5 (Ar), 133.1 (Ar), 162.1 (t, ² J _CF = 23.1 Hz, C-2). ¹⁹F NMR (376 MHz, CDCl₃): δ = –116.3 (s). MS: m/z (%, EI⁺) = 256.1 (100) [M]⁺, 153.0 (45), 103.1 (99), 77.1 (36). HRMS: m/z [M + H]⁺ calcd for C₁₅H₁₁F₂N₂: 257.0890; found: 257.0894.