Novel Methodology for the Efficient Synthesis of 3-Aryloxindoles: [1,2]-Phospha-Brook Rearrangement–Palladium-Catalyzed Cross-Coupling Sequence

Abstract

A novel methodology for the efficient synthesis of 3-aryloxindoles from isatin derivatives was developed. The methodology involves the formation of an oxindole having a phosphate moiety at the C-3 position via the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis followed by palladium-catalyzed cross-coupling with aryl boron reagents. The one-pot synthesis of 3-aryloxindoles from isatin derivatives is also described.

Key words

oxindole derivatives - phospha-Brook rearrangement - Brønsted base catalysis - cross-coupling - palladium catalyst

• References and Notes


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• 13 Typical Procedure for the Synthesis of Oxindole Derivatives 2 Synthesis of 2a is representative. To a solution of 1a (1.0 g, 4.3 mmol) and diphenyl phosphite (0.92 mL, 4.8 mmol) in toluene (8.7 mL) was added i-Pr₂NEt (75 μL, 0.43 mmol). The resulting mixture was stirred at room temperature for 10 min. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na₂SO₄, and evaporated. The residue was purified by column chromatography (hexane–EtOAc, 2:1) to provide 2a (1.9 g, 4.1 mmol, 94%) as a colorless oil. Compound 2a: ¹H NMR (600 MHz, CDCl₃): δ = 1.08 (t, J = 7.2 Hz, 3 H), 3.63–3.95 (m, 2 H), 7.24–7.27 (m, 5 H), 7.28–7.31 (m, 1 H), 7.36–7.40 (m, 2 H), 7.52 (dd, J = 8.4, 1.2 Hz, 1 H), 7.54 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 7.59–7.62 (m, 1 H), 7.66 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 7.94 (dd, J = 7.8, 0.60 Hz, 1 H). ¹³C NMR (150 MHz, CDCl₃): δ = 13.7, 62.0, 88.1, 93.6, 122.9, 123.2, 128.0, 128.16 (2 C), 128.23, 128.3, 130.0, 130.6, 131.2, 131.4, 132.2, 132.5, 134.7, 141.4, 141.7, 163.0, 188.5. ³¹P NMR (243 MHz, CDCl₃): δ = –10.8. IR (ATR): 3061, 2984, 1748, 1731, 1691, 1597, 1496, 1442, 1197, 1020 cm^–1. ESI-HRMS: m/z calcd for C₂₄H₁₈O₃ [M + Na]⁺: 377.1148; found: 377.1148.

The reduction of α-halocarbonyl compounds and α-halosulfoxides, which is related to the formation of byproduct 5, was discussed in the literature, see:
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• 16 Typical Procedure for the Synthesis of 3-Aryloxindoles 4 The reaction of 2a and 3e is representative (Table 1, entry 18). Pd₂(dba)₃ (6.8 mg, 7.5 μmol) and XPhos (14 mg, 30 μmol) were dissolved in toluene (0.60 mL), and the solution was stirred for 15 min. Compound 2a (0.14 g, 0.30 mmol) in toluene (2.4 mL), NaHCO₃ (50 mg, 0.60 mmol), 3e (0.11 g, 0.45 mmol), and H₂O (1.5 mL) were sequentially added, and the resulting mixture was then warmed to 60 °C. After stirred for 7 h, the reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was dried over Na₂SO₄ and evaporated. The crude mixture was purified by column chromatography (hexane–EtOAc, 4:1) to afford 4aa (72 mg, 0.24 mmol, 80%) as a white solid. Compound 4aa: ¹H NMR (400 MHz, CDCl₃): δ = 4.74 (s, 1 H), 4.90 (d, J = 15.6 Hz, 1 H), 5.00 (d, J = 15.6 Hz, 1 H), 6.79 (d, J = 7.8 Hz, 1 H), 7.02 (dd, J = 7.2, 7.2 Hz, 1 H), 7.14–7.18 (m, 1 H), 7.18–7.24 (m, 3 H), 7.24–7.37 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ =  43.9, 52.0, 109.2, 122.7, 125.1, 127.3, 127.59, 127.62, 128.3, 128.4, 128.8, 128.89, 128.92, 135.9, 136.7, 143.6, 176.1.
• 17 The exploratory investigation for reaction conditions are summarized in the Supporting Information.
• 18 With these substrates 2, the reaction without NaHCO₃ provided almost the same or slightly better yields than those obtained with NaHCO₃.
• 19 Procedure for the One-Pot Synthesis of 3-Aryloxindoles To a solution of 1a (50 mg, 0.21 mmol) and diphenyl phosphite (45 μL, 0.23 mmol) in toluene (0.42 mL) was added i-Pr₂NEt (3.6 μL, 21 μmol). The resulting mixture was then stirred at room temperature for 10 min. A stock solution of Pd₂(dba)₃ (4.8 mg, 5.3 μmol) and XPhos (10 mg, 21 μmol) in toluene (0.42 mL), toluene (3.4 mL), NaHCO₃ (35 mg, 0.42 mmol), 3e (77 mg, 0.31 mmol), and H₂O (2.1 mL) were added sequentially, and the resulting mixture was then warmed to 60 °C. After stirred for 7 h, the reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography (hexane–EtOAc, 4:1) to provide 4aa (43 mg, 0.14 mmol, 68%) as a white solid.