Synlett 2022; 33(20): 2043-2047
DOI: 10.1055/a-1968-2769
letter

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

Mei-Mei Li
a   State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. of China
,
Hui Huang
a   State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. of China
,
Jun Lu
a   State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. of China
b   Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, 999077, P. R. of China
› Author Affiliations
This study was supported by the National Natural Science Foundation of China (Grants Nos. 81803374 and 82273812), the China Postdoctoral Science Foundation (2020M673565XB), the Xinglin Scholar Research Promotion Project of Chengdu University of Traditional Chinese Medicine (Nos. BJRC2020002 and BSH2019027), and Scientific Research Foundation of the Science and Technology Department of Sichuan Province (Grant No. 2018JY0599).


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.

Supporting Information



Publication History

Received: 29 September 2022

Accepted after revision: 26 October 2022

Accepted Manuscript online:
26 October 2022

Article published online:
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; Rf = 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%); Rf = 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%); Rf = 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.