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

Éva Frank; Zsolt Kardos; János Wölfling; Gyula Schneider

doi:10.1055/s-2007-977452

LETTER

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

Éva Frank*, Zsolt Kardos, János Wölfling, Gyula Schneider
Department of Organic Chemistry, University of Szeged, 6720 Szeged, Hungary
Fax: +36(62)544199; e-Mail: frank@chem.u-szeged.hu;

Abstract

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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

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Referenzen

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]