Catalytic Synthesis of Chiral Phosphole Oxides via Desymmetric C–H Arylation of o-Bromoaryl Phosphine Oxides

Abstract

A palladium-catalyzed intramolecular direct arylation reaction of o-bromoaryl phosphine oxides was developed to afford a variety of P-stereogenic phosphole oxides in good yields. The enantioselectivities were closely associated with the specific structures of substrates, which ranged from 4–94%. As a result of ready availability of starting materials and simple operation to improve the enantioselectivities of the products with low ee values, the method provides a simple and straightforward procedure for the synthesis of P-stereogenic phosphole oxides.

Key words

asymmetric catalysis - C–H activation - direct arylation - phosphole oxides - palladium

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• 16a General Procedure for the Synthesis of o-Bromoarylphosphine Oxide To a stirred solution of o-bromoiodobenzene (1.3 mL, 10 mmol) in THF (10 mL) was added dropwise a solution of isopropylmagnesium chloride (2.0 M in THF, 5 mL, 10 mmol) at –40 °C. After 1 h, PCl₃ (0.9 mL, 10 mmol) was added and stirred for 40 min at the same temperature. The mixture was then allowed to stand at r.t. for 12 h and cooled at –40 °C again. A solution of proper arylmagnesium bromide (1.0 M in THF, 22 mL, 22 mmol) was added dropwise. After 1 h, the resulting mixture was then stirred at r.t. overnight. A sat. aq solution of NH₄Cl was added, and the reaction mixture was extracted three times with Et₂O. The combined organic layer was washed with water and brine and dried over MgSO₄. The solvent was then evaporated in vacuo, and the residue was purified by silica gel column chromatography with hexane as eluent to afford the corresponding phosphines. After oxidation by H₂O₂ in acetone, the crude products were purified by using flash chromatography with EtOAc as eluent, giving the pure products. Compound 1a: ¹H NMR (400 MHz, CDCl₃): δ = 7.67 (dddd, J = 12.9, 5.8, 4.8, 3.4 Hz, 2 H), 7.48–7.37 (m, 4 H), 7.31 (dd, J = 7.5, 4.3 Hz, 2 H), 7.26–7.14 (m, 4 H), 2.50 (s, 6 H). ³¹P NMR (202 MHz, CDCl₃): δ = 35.37 (s). ¹³C NMR (101 MHz, CDCl3): δ = 143.45 (d, J = 7.9 Hz), 135.82 (d, J = 9.8 Hz), 134.89 (d, J = 7.4 Hz), 133.63 (t, J = 9.5 Hz), 133.14 (d, J = 2.2 Hz), 132.70 (s), 132.19–131.79 (m), 130.00 (s), 128.95 (s), 127.24 (d, J = 10.8 Hz), 126.88 (d, J = 4.4 Hz), 125.40 (d, J = 13.2 Hz), 21.92 (d, J = 4.1 Hz).
• 17a General Procedure for the Synthesis of P-Stereogenic Phosphole Oxide To a mixture of ortho-bromoarylphosphine oxides 1a–l (1.0 mmol), Cs₂CO₃ (489 mg, 1.5 mmol), Pd(OAc)₂ (11.2 mg, 5 mol%), and L4 (30.6 mg, 10 mol%) under nitrogen atmosphere was added 4 mL of xylene in a 25 mL Schlenk tube equipped with a magnetic stir bar. The Schlenk tube was stirred at r.t. for 20 min and then at 140 °C for 4 h. The reaction mixture was cooled to r.t. and quenched with water and then extracted with CH₂Cl₂. The extraction was washed with brine and dried over Na₂SO₄. The solvent was then evaporated in vacuo, and the residue was purified by using SiO₂ column with EtOAc as eluent to afford the final products. Compound 2a: ¹H NMR (400 MHz, CDCl₃): δ = 8.20 (dd, J = 13.7, 7.6 Hz, 1 H), 7.72 (d, J = 7.7 Hz, 1 H), 7.57 (t, J = 8.6 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.43–7.32 (m, 2 H), 7.29 (t, J = 7.5 Hz, 2 H), 7.04 (dd, J = 12.1, 6.0 Hz, 2 H), 2.25 (s, 3 H), 1.79 (s, 3 H). ³¹P NMR (202 MHz, CDCl₃): δ = 31.93 (s). ¹³C NMR (101 MHz, CDCl₃): δ = 142.53 (s), 142.26 (d, J = 10.5 Hz), 142.11 – 141.87 (m), 141.02 (d, J = 11.0 Hz), 134.31 (d, J = 9.5 Hz), 133.55 (d, J = 7.9 Hz), 133.14 (d, J = 2.0 Hz), 132.54 (s), 132.23 (d, J = 2.7 Hz), 131.40 (t, J = 11.3 Hz), 130.83 (d, J = 9.8 Hz), 130.24 (s), 129.33 (t, J = 11.0 Hz), 128.72 (s), 127.74 (s), 126.01 (d, J = 11.9 Hz), 121.31 (d, J = 10.0 Hz), 118.75 (d, J = 10.1 Hz), 20.10 (d, J = 4.4 Hz), 19.42 (d, J = 4.6 Hz). Enantiomeric excess was determined by HPLC with a Chiralpak OD column (hexanes–2-PrOH = 70:30, 0.5 mL/min, 254 nm); major enantiomer t _R = 12.3 min, minor enantiomer t _R = 25.9 min. ESI-HRMS: m/z: [M + H]⁺ calcd for C₂₀H₁₇OP: 305.1090; found: 305.1094. [α]_D ²⁰ –36.2 (c 1.21, CHCl₃).
• 18 CCDC 1524935 (2a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.