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Synlett 2020; 31(12): 1172-1176
DOI: 10.1055/s-0039-1690885
DOI: 10.1055/s-0039-1690885
letter
Highly Regioselective Synthesis of 3,5-Substituted Pyrazoles from Bromovinyl Acetals and N-Tosylhydrazones
Q.L. and A.W. are grateful to SEQENS for grants (2014–2017 and 2017–2020). This work was supported by the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation and the Centre National de la Recherche Scientifique.Further Information
Publication History
Received: 27 February 2020
Accepted after revision: 18 March 2020
Publication Date:
09 April 2020 (online)
Abstract
A regioselective synthesis of 3,5-disubstituted pyrazoles was achieved by 1,3-dipolar cycloaddition of diazo compounds, generated in situ from N-tosylhydrazones, with unactivated bromovinyl acetals, which served as alkyne surrogates. The reaction tolerated N-tosylhydrazones bearing various substituted benzylidene groups, and a range of 3,5-disubstituted pyrazoles were obtained in yields of up to 92%.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690885.
- Supporting Information
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References and Notes
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- 12 3,5-Substituted Pyrazoles 3aa–ii; General Procedure (0.5 mmol Scale) A sealed tube filled with argon was charged with the appropriate compound 2a, 2b, or 2c (0.5 mmol, 1.0 equiv), tosylhydrazone 1 (1.25 mmol, 2.5 equiv), K2CO3 (2.25 mmol, 4.5 equiv), and THF (5 mL), and the mixture was stirred for 48 h at the reflux (oil bath, 80 °C). The reaction was quenched with aq NH4Cl, and the mixture was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo, and the residue was purified by flash column chromatography [silica gel, PE–EtOAc (7:3) for the diethoxy acetal derivatives; PE–EtOAc (1:1) for the dioxane and dioxolane derivatives]. 5-(Diethoxymethyl)-3-phenyl-1H-pyrazole (3a) Yellow oil; yield: 70 mg (57%). IR (film): 2926, 1439, 1281, 1058 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.73 (dt, J = 6.0, 1.5 Hz, 2 H), 7.43–7.23 (m, 3 H), 6.60 (s, 1 H), 5.68 (s, 1 H), 3.79–3.45 (m, 4 H), 1.23 (t, J = 7.0 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ = 149.9, 145.5, 132.3, 128.8, 128.1, 125.8, 101.1, 96.4, 61.3, 15.3. MS (ESI): m/z = 246 [M + H]+.
- 13 3,5-Substituted Pyrazoles 3e and 3f (Gram Scale); General Procedure A 500 mL round-bottomed flask filled with argon was charged with compound 2b or 2c (5.00 g, 1.0 equiv) and THF (250 mL). K2CO3 (4.5 equiv) and tosylhydrazone 1b (2.5 equiv) were then added, and the mixture was stirred at the reflux (oil bath, 80 °C) until the reaction was complete (TLC, PE–EtOAc, 90:10). The reaction was quenched with aq NH4Cl (200 mL) and the crude mixture was extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated in vacuo, and the crude product was purified by flash column chromatography [silica gel, PE–EtOAc (1:1)].
- 14 CCDC 1979196 and 1979197 contains the supplementary crystallographic data for compounds 3hh and 3ii, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.