Highly Regioselective Synthesis of 3,5-Substituted Pyrazoles from Bromovinyl Acetals and N-Tosylhydrazones

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%.

Key words

pyrazoles - 1,3-dipolar cycloaddition - bromovinyl acetals - tosylhydrazones

• 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.