Palladium-Catalysed Sonogashira Reactions of 16-(Hydroxymethylidene)-3-methoxy-α-estrone

Abstract

Sonogashira reactions of steroids have been studied. The reaction of α-estron-16-methylidenyloxy triflate with various alkynes afforded novel alkynylvinylidene steroids. The reactions proceeded in good to quantitative yields, with excellent E-selectivity and with a broad synthetic scope.

Key words

estrone - steroids - Sonogashira coupling - palladium - alkynes

• References and Notes

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• 9 (E)-16-(3-Phenylprop-2-ynylidene)-3-methoxy-α-estrone (3a) Compound 2 (0.225 mmol, 100 mg), CuI (0.006 mmol, 2.5 mol%, 1.1 mg), Pd(OAc)₂ (0.006 mmol, 2.5 mol%, 1.3 mg), XPhos (0.012 mmol, 5.0 mol%, 5.7 mg), and phenylacetylene (0.338 mmol, 35 mg) were dissolved in THF (5 mL) and NEt₃ (1 mL). The reaction mixture was stirred at r.t. for 6 h. The solution was diluted with H₂O and extracted with EtOAc (3×). The crude product was purified by column chromatography on silica (elution system heptane/EtOAc, 20:1). Yield: 86 mg (97%); mp 54–55 °C. ¹H NMR (250 MHz, CDCl₃): δ = 0.79–0.88 (m, 3 H), 1.10 (s, 3 H, Me), 1.43–1.51 (m, 2 H), 1.76–1.83 (m, 1 H), 2.09–2.17 (m, 1 H), 2.24–2.32 (m, 2 H), 2.40–2.48 (m, 1 H), 2.79–2.92 (m, 3 H), 3.76 (s, 3 H, OMe), 6.59 (d, ⁴ J = 2.71 Hz, 1 H), 6.67–6.72 (m, 2 H), 7.18 (d, ³ J = 8.58 Hz, 1 H), 7.36–7.39 (m, 3 H), 7.50–7.54 (m, 2 H).¹³C NMR (63 MHz, CDCl₃): δ = 25.5 (CH₃), 28.1, 28.3, 29.9, 30.3, 32.2 (CH₂), 41.3, 43.0, 47.6 (CH), 50.8 (C), 55.2 (OCH₃), 87.2, 101.0 (C≡C), 111.7, 113.5, 114.5 (CH), 122.7 (C), 126.9, 128.5, 129.2 (CH), 131.8 (C), 131.9 (CH), 138.0, 146.1, 157.5 (C), 207.4 (C=O). IR (ATR,): 2918 (w), 2187 (w), 1711 (w), 1609 (w), 1498 (w), 1448 (w), 1257 (m), 1076 (m), 1016 (s), 870 (w), 793 (s), 755 (m), 688 (m), 531 (w) cm^–1. MS (EI, 70 eV): m/z (%) = 397 (16), 396 (M⁺, 78), 227 (15), 210 (14), 186 (10), 178 (11), 174 (15), 173 (12), 165 (24), 160 (14), 158 (13), 153 (13), 152 (12), 147 (11), 145 (15), 144 (11), 141 (23), 140 (100), 139 (96), 129 (16), 128 (17), 126 (17), 115 (25), 114 (18), 102 (18), 91 (21), 65 (11). ESI-HRMS: m/z calcd for C₂₈H₂₉O [M + H⁺]: 397.21621; found: 397.21644.