Sequential 1,3-Dipole Cycloaddition of Nitrile Imines with Alkenyl Isoxazoles and Aromatization: A One-Pot Access to 1,3,4-Triarylpyrazoles

Abstract

A novel one-pot two-step process for the preparation of 1,3,4-triarylpyrazoles is disclosed. This process involves a 1,3-dipolar cycloaddition reaction of alkenyl isoxazoles with nitrile imines generated in situ, followed by SnCl₂-promoted aromatization/elimination reaction to give a range of 1,3,4-triarylpyrazoles in a fully regioselective manner. This protocol features mild reaction conditions, easily available raw materials, and excellent regioselectivity.

Key words

cycloaddition - aromatization - one-pot reaction - regioselectivity - triarylpyrazoles

Publikationsverlauf

Eingereicht: 29. September 2022

Angenommen nach Revision: 26. Oktober 2022

Accepted Manuscript online:
26. Oktober 2022

Artikel online veröffentlicht:
23. November 2022

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• 14 3-Methyl-4-nitro-5-(1,3,4-triphenyl-4,5-dihydro-1H-pyrazol-5-yl)isoxazole (3a) Prepared from hydrazonoyl chloride 1a (50 mg, 0.22 mmol) and isoxazole 2a (75 mg, 0.26 mmol) as an orange solid; yield: 92 mg (0.22 mmol, 99%); mp 150–151 °C; R_f = 0.3 (PE–EtOAc, 20:1). ¹H NMR (600 MHz, CDCl₃): δ = 7.67 (dd, J = 7.9, 1.8 Hz, 2 H), 7.33 (d, J = 6.8 Hz, 2 H), 7.32–7.21 (m, 8 H), 7.14–7.09 (m, 2 H), 6.88 (s, 1 H), 6.07 (d, J = 3.2 Hz, 1 H), 4.76 (d, J = 3.3 Hz, 1 H), 2.54 (s, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 169.8, 153.5, 147.2, 141.1, 135.5, 128.6, 127.7, 127.2, 127.1, 126.7, 126.2, 126.1, 125.1, 124.2, 118.3, 111.1, 62.9, 56.8, 9.3. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₂₀N₄NaO₃: 447.1433; found: 447.1420. One-Pot Synthesis of Pyrazoles 4; General Procedure A dried test tube was charged with the appropriate hydrazonoyl chloride 1 (0.30 mmol) and isoxazole 2 (0.36 mmol) at rt. Et₃N (0.60 mmol) and DCM (2 mL) were added, and the mixture was stirred at rt overnight until the reaction was complete. The organic solvent was evaporated, SnCl₂ (3.00 mmol) and DMF (2 mL) were added, and the mixture was stirred at 100 ℃ for 3 h. The mixture was then diluted with EtOAc (50 mL) and washed with H₂O (3 × 20 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, PE–EtOAc). 1,3,4-Triphenyl-1H-pyrazole (4a) Prepared from hydrazonoyl chloride 1a (50 mg, 0.22 mmol) and isoxazole 2a (60 mg, 0.26 mmol) as a yellow oily liquid; yield: 39 mg (61%); R_f = 0.65 (PE–EtOAc, 30:1). ¹H NMR (600 MHz, CDCl₃): δ = 8.00 (s, 1 H), 7.81–7.76 (m, 2 H), 7.62–7.57 (m, 2 H), 7.46 (dd, J = 8.56, 7.33 Hz, 2 H), 7.37–7.25 (m, 10 H). ¹³C NMR (151 MHz, CDCl₃): δ = 150.5, 140.0, 133.2, 132.9, 129.5, 128.7, 128.6, 128.5, 128.4, 127.9, 127.0, 126.7, 126.5, 123.0, 119.0. 3-(3-Chlorophenyl)-1,4-diphenyl-1H-pyrazole (4b) Prepared from hydrazonoyl chloride 1h (50 mg, 0.19 mmol) and isoxazole 2a (52 mg, 0.23 mmol) as a yellow oily liquid; yield: 41 mg (66%); R_f = 0.65 (PE–EtOAc, 30:1). ¹H NMR (600 MHz, CDCl₃): δ = 8.01 (s, 1 H), 7.82–7.76 (m, 2 H), 7.69 (t, J = 1.84 Hz, 1 H), 7.52–7.45 (m, 2 H), 7.40 (dt, J = 7.68, 1.36 Hz, 1 H), 7.38–7.28 (m, 7 H), 7.23 (t, J = 7.84 Hz, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ = 149.0, 139.8, 135.0, 134.3, 132.4, 129.5, 129.5, 128.7, 128.7, 128.3, 128.0, 127.2, 126.9, 126.7, 126.6, 123.1, 119.0.