Stereoselective Synthesis of Novel Δ⁵-Androstenoarylpyrazoline Derivatives by BF₃·OEt₂-Induced Intramolecular 1,3-Dipolar Cycloaddition

Abstract

The phenylhydrazones of an unsaturated d-seco-pregnene aldehyde underwent BF₃·OEt₂-induced intramolecular 1,3-dipolar cycloaddition to afford new pyrazoline-fused Δ⁵-androstene derivatives under extremely mild conditions. The ring closures ­occurred stereoselectively in good to excellent yields via the corresponding azomethine imine intermediates and showed marked dependence on the electronic feature of the p-phenyl substituent.

Key words

steroids - hydrazones - 1,3-dipolar cycloaddition - ste­reoselectivity - Lewis acid

References and Notes

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• 12 Procedure for the Synthesis of 6c A mixture of 2 (359 mg, 1.00 mmol), 4-methoxyphenyl-hydrazine hydrochloride (3c, 175 mg, 1.00 mmol) and NaOAc (200 mg, 2.44 mmol) in MeOH (5 mL) was stirred for 1 h at r.t. The white precipitate was filtered off and dried to give pure 4c (407 mg, 85%). Compound 4c was dissolved in CH₂Cl₂ (10 mL) and BF₃·OEt₂ (0.09 mL, 0.3 mmol) was added dropwise at 0 °C under a nitrogen atmosphere. After 20 min, the reaction was quenched by the addition of 1 M aq NaHCO₃ (20 mL). The organic phase was separated, the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic phases were dried over Na₂SO₄. Evaporation in vacuo and recrystallization from CH₂Cl₂-hexane afforded 453 mg (95%) of 6c as white crystals; R _f = 0.32 (EtOAc-CH₂Cl₂, 10:90). ¹H NMR (400 MHz, CDCl₃): δ = 0.76 (s, 3 H, 18-H₃), 1.05 (s, 3 H, 19-H₃), 1.16 (m, 2 H), 1.39 (m, 1 H), 1.44 (d, 3 H, J = 6.0 Hz, 21-H₃), 1.51 (m, 1 H), 1.58-1.69 (m, 6 H), 1.80-1.91 (m, 4 H), 2.03 (s, 3 H, 3-Ac-H₃), 2.45 (m, 2 H), 2.49 (m, 1 H), 2.77 (d, 1 H, J = 11.2 Hz, 17-H), 3.65 (m, 1 H, 20-H), 3.78 (s, 3 H, 4′-OMe), 4.62 (m, 1 H, 3-H), 5.39 (d, 1 H, J = 4.8 Hz, 6-H), 6.85 (d, 2 H, J = 8.8 Hz, 2′-H, 6′-H), 7.05 (d, 2 H, J = 8.8 Hz, 3′-H, 5′-H). ¹³C NMR (100 MHz, CDCl₃): δ = 14. 4 (C-18), 19.3 (C-19), 20.4 (C-21), 20.7 (CH₂), 21.4 (3-Ac-CH₃), 25.4 (CH₂), 27.7 (CH₂), 31.5 (C-8), 31.8 (CH₂), 36.8 (C-10), 36.9 (CH₂), 37.3 (CH₂), 38.1 (CH₂), 40.0 (C-13), 50.0 (C-9), 55.6 (4′-OMe), 57.6 (C-14), 61.3 (C-20), 72.2 (C-17), 73.7 (C-3), 114.3 (2 C, C-2′, C-6′), 118.3 (2 C, C-3′, C-5′), 121.9 (C-6), 139.9 (C-5), 142.3 (C-1′), 154.7 (C-4′), 164.3 (C-16), 170.5 (Ac-CO). MS (EI): m/z (relative intensity) = 476 (100) [M⁺], 461 (18), 187 (30) [C₃₀H₄₀N₂O₃]