Total Synthesis of Horsfiline: A Palladium-Catalyzed Domino Heck-Cyanation Strategy

Abstract

A total synthesis of horsfiline has been accomplished featuring a key intramolecular palladium-catalyzed domino Heck-cyanation sequence for the formation of the 3,3′-disubstituted oxindole.

domino reaction - palladium - Heck - cyanation - oxindole - horsfiline

References and Notes

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Experimental Procedure: To a degassed solution of iodoanilide 14 (1.90 g, 3.29 mmol, 1.0 equiv) in DMF (16 mL) were added K₄Fe(CN)₆˙3H₂O (306.0 mg, 0.72 mmol, 0.22 equiv), Na₂CO₃ (350.0 mg, 3.30 mmol, 1.0 equiv) and Pd(OAc)₂ (22.0 mg, 0.1 mmol, 0.03 equiv). After being stirred at 120 ˚C under an argon atmosphere for 3 h, the reaction mixture was quenched with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by flash chromatography (SiO₂, heptane-EtOAc, 95:5 → 90:10) to give the corresponding oxindole 15 (0.94 g, 60%) as a light orange solid. Compound 15: ^¹H NMR (500 MHz, CDCl₃): δ = 7.06 (d, J = 2.6 Hz, 1 H), 7.02 (d, J = 8.6 Hz, 1 H), 6.88 (dd, J = 8.6, 2.6 Hz, 1 H), 5.17 (d, J = 11.0 Hz, 1 H), 5.11 (d, J = 11.0 Hz, 1 H), 3.92 (d, J = 9.7 Hz, 1 H), 3.80 (s, 3 H), 3.73 (d, J = 9.7 Hz, 1 H), 3.62-3.51 (m, 2 H), 3.02 (d, J = 16.7 Hz, 1 H), 2.79 (d, J = 16.7 Hz, 1 H), 0.92 (t, J = 8.2 Hz, 2 H), 0.84 (s, 9 H), 0.00 (s, 3 H), -0.01 (s, 3 H), -0.03 (s, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 175.4, 156.4, 135.4, 129.1, 116.2, 114.3, 111.2, 110.6, 69.9, 66.5, 66.1, 55.8, 51.9, 25.7, 21.7, 18.1, 17.7, -1.4, -5.6, -5.7. HRMS (ES+): m/z [M + Na]⁺ calcd for C₂₄H₄₀N₂O₄Si₂Na: 499.2424; found: 499.2415.

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