Ion-Tagged Phosphines as Ligands for Suzuki Coupling of Aryl Halides in a Phosphonium Ionic Liquid

Abstract

Gramine-based N-substituted phosphines were synthesized and utilized as ligands in Suzuki–Miyaura coupling of aryl bromides and chlorides in the room temperature ionic liquid trihexyltetradecylphosphonium bis(trifluoromethanesulfonyl)imide. Increased yields were achieved with ion-tagged ligands compared to ligands bearing pendant amines, likely due to higher solubility of the former. Cyclohexyl groups on the phosphine moiety generally resulted in higher yields than tert-butyl groups. In addition, a biphasic ionic liquid/water system outperformed catalysis in neat ionic liquid and provided higher yields at lower temperatures.

Key words

palladium - catalysis - ionic liquids - cross-coupling - green chemistry

• References and Notes

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• 30 Synthesis of 1-(Di-tert-butylphosphino)-3-di-methylaminomethylindole (1): A solution of n-butyl-lithium (1.6 M, 7.2 mL, 11.5 mmol) in hexanes was added via syringe to a cooled (–78 °C) solution of gramine (2.01 g, 11.5 mmol) in THF (50 mL). The resulting yellow solution was stirred for 1 h at r.t. before again cooling to –78 °C. A solution of t-Bu₂PCl (2.083 g, 11.53 mmol) in THF (5 mL) was added via cannula. The reaction solution was stirred for 20 h at ambient temperature, after which the volatiles were removed in vacuo. The waxy yellow solid was dissolved in CH₂Cl₂ and the precipitated solids were removed by filtration over a pad of Celite on a sintered glass funnel. CH₂Cl₂ was removed in vacuo. Colorless crystals of 1-(di-tert-butylphosphino)-3-dimethylaminomethylindole (2.93 g, 83%) were grown from the slow evaporation of MeCN at r.t.; mp 80 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.84 (d, ³ J _HH = 7.8 Hz, 1 H, H7), 7.65 (d, ³ J _HH = 7.8 Hz, 1 H, H4), 7.35 (s, 1 H, H2), 7.21 (t, ³ J _HH = 7.8 Hz, 1 H, H6), 7.14 (t, ³ J _HH = 7.8 Hz, 1 H, H5), 3.64 (s, 2 H, CH₂), 2.28 (s, 6 H, NMe₂), 1.22 (d, ³ J _HP = 13.2 Hz, 18 H, CMe₃). ¹³C NMR (150.8 MHz, CDCl₃): δ = 144.5 (s, C4a), 129.9 (d, ² J _CP = 8.9 Hz, C2), 129.0 (d, C7a), 122.1 (d, C6), 120.1 (s, C5), 119.0 (s, C4), 116.1 (s, C3), 113.2 (d, ³ J _CP = 20.2 Hz, C7), 55.0 (s, CH₂), 45.6 (s, NMe₂), 35.3 (d, ¹ J _CP = 25.0 Hz, PC), 29.4 (d, ² J _CP = 16.4 Hz, PCMe ₃). ³¹P NMR (161.9 MHz, CDCl₃): δ = 71.3 (s). MS (ESI): m/z (%) = 341.1 (5) [MNa]⁺, 318.6 (18) [MH]⁺, 274.2 (100) [M – NMe₂]⁺. Anal. Calcd for C₁₉H₃₁N₂P: C, 71.66; H, 9.81; N, 8.80. Found: C, 71.70; H, 10.39; N, 8.83. Synthesis of 1-(Di-tert-butylphosphino)-3-trimethyl-ammoniummethylindole Iodide (1a): Iodomethane (0.391 g, 2.75 mmol) was added to a solution of compound 1 (0.844 g, 2.75 mmol) in toluene (60 mL) via syringe. The reaction mixture was stirred for 16 h at ambient temperature after which the white powder was isolated via filtration. 1-(Di-tert-butylphosphino)-3-trimethylammoniummethylindole iodide (1.15 g, 91%) was obtained by washing the solids with hexanes (10 mL) and drying in vacuo; mp 224 °C (dec.). ¹H NMR (600 MHz, DMSO-d ₆): δ = 8.03 (s, 1 H, H2), 7.83 (m, 2 H, H4, H7), 7.27 (t, ³ J _HH = 7.8 Hz, 1 H, H5), 7.22 (t, ³ J _HH = 7.8 Hz, 1 H, H6), 4.78 (s, 2 H, CH₂), 3.08 (s, 9 H, NMe₃), 1.18 (d, ³ J _HP = 12.8 Hz, 18 H, CMe₃). ¹³C NMR (150.8 MHz, DMSO-d ₆): δ = 143.5 (d, ² J _CP = 20.51 Hz, C7a), 136.3 (s, C2), 128.2 (d, C4a), 122.7 (s, C5), 121.1 (s, C6), 118.9 (s, C7), 113.1 (s, C4), 106.3 (s, C3), 60.1 (s, CH₂), 51.7 (s, NMe₃), 34.7 (d, ¹ J _CP = 25.49 Hz, PC), 28.7 (d, ² J _CP = 15.99 Hz, PCMe ₃). ³¹P NMR (161.9 MHz, DMSO-d ₆): δ = 75.0 (s). MS (ESI): m/z (%) = 274.1 (100) [M – NMe₃]⁺. Anal. Calcd for C₂₀H₃₄N₂PI: C, 52.18; H, 7.44; N, 6.08. Found: C, 52.26; H, 7.77; N, 6.06. Synthesis of 1-(Dicyclohexylphosphino)-3-dimethylaminomethylindole (2): A solution of n-butyllithium (1.6 M, 3.7 mL, 5.9 mmol) in hexanes was added via syringe to a cooled (–78 °C) solution of gramine (1.01 g, 5.8 mmol) in THF (25 mL). The resulting yellow solution was stirred for 1 h at r.t. before cooling again to –78 °C. A solution of Cy₂PCl (1.35 g, 5.8 mmol) in THF (5 mL) was added via cannula. The reaction solution was stirred for 20 h at ambient temperature, after which the volatiles were removed in vacuo. The waxy yellow solid was dissolved in CH₂Cl₂, the insoluble solids were removed by filtration over a pad of Celite on a sintered glass funnel, and CH₂Cl₂ was removed in vacuo. Colorless crystals of 1-(dicyclohexyl-phosphino)-3-dimethylaminomethyl indole (1.05 g, 49%) were grown from the slow evaporation of MeCN at r.t.; mp 71 °C. ¹H NMR (600 MHz, CDCl₃): δ = 7.73 (d, ³ J _HH = 7.8 Hz, 1 H, H7), 7.62 (d, ³ J _HH = 7.8 Hz, 1 H, H4), 7.20 (t, ³ J _HH = 6.6 Hz, 1 H, H6), 7.14 (s, 1 H, H2), 7.12 (t, ³ J _HH = 8.4 Hz, 1 H, H5), 3.63 (s, 2 H, CH₂), 2.28 (s, 6 H, NMe₂), 2.09 (br s, 2 H, Cy), 1.85 (d, J = 10.8 Hz, 2 H, Cy), 1.76 (d, J = 13.2 Hz, 2 H, Cy), 1.65 (m, 4 H, Cy), 1.47 (br s, 2 H, Cy), 1.31 (m, 2 H, Cy), 1.14 (m, 8 H, Cy). ¹³C NMR (150.8 MHz, CDCl₃): δ = 143.4 (br s, C4a), 129.7 (br s, C2), 127.9 (br s, C7a), 122.1 (s, C6), 120.1 (br s, C5), 119.2 (s, C4), 116.3 (s, C3) 112.7 (d, ³ J _CP =16.0 Hz, C7), 54.9 (s, CH₂), 45.6 (s, NMe₂), 36.5 (d, ² J _CP = 14.5 Hz, PCHCH₂), 29.5 (d, ¹ J _CP = 20.5 Hz, PCH), 28.2 (d, ³ J _CP = 6.7 Hz, PCHCH₂ CH₂), 26.9 (d, ² J _CP = 13.8 Hz, PCHCH₂), 26.8 (d, ³ J _CP = 7.6 Hz, PCHCH₂ CH₂), 26.4 (s, PCHCH₂CH₂ CH₂). ³¹P NMR (161.9 MHz, CDCl₃): δ = 48.7 (s). MS (ESI): m/z (%) = 393.6 (34) [MNa]⁺, 371.5 (5) [MH]⁺, 326.6 (100) [M – NMe₂]⁺. Anal. Calcd for C₂₃H₃₅N₂P: C, 74.56; H, 9.52; N, 7.56. Found: C, 74.90; H, 9.82; N, 7.38. Synthesis of 1-(Dicyclohexylphosphino)-3-trimethyl-ammonium-methylindole Iodide (2a): Iodomethane (0.193 g, 1.36 mmol) was added to a solution of compound 2 (0.503 g, 1.36 mmol) in toluene (30 mL) via syringe. The reaction mixture was stirred for 16 h at ambient temperature, after which the white powder was isolated by filtration. 1-(Dicyclohexylphosphino)-3-trimethylammonium-methyl-indole iodide (0.67 g, 96%) was obtained by washing the solid with Et₂O (10 mL) and drying in vacuo; mp 202 °C (dec.). ¹H NMR (600 MHz, DMSO-d ₆): δ = 7.88 (s, 1 H, H2), 7.82 (d, ³ J _HH = 7.8 Hz, 1 H, H7), 7.72 (d, ³ J _HH = 7.8 Hz, 1 H, H4), 7.24 (t, ³ J _HH = 7.2 Hz, 1 H, H5), 7.20 (t, ³ J _HH = 7.2 Hz, 1 H, H6), 5.14 (s, 2 H, CH₂), 3.42 (s, 9 H, NMe₃), 2.29 (s, 2 H, Cy), 1.85 (br d, J = 8.3 Hz, 2 H, Cy), 1.72 (d, J = 11.4 Hz, 2 H, Cy), 1.61 (d, J = 8.3 Hz, 4 H, Cy), 1.36 (m, 4 H, Cy), 1.20 (m, 2 H, Cy), 1.05 (m, 6 H, Cy). ¹³C NMR (150.8 MHz, DMSO-d ₆): δ = 142.3 (s, C7a), 134.8 (s, C2), 128.9 (s, C4a), 122.7 (s, C5), 121.1 (s, C6), 118.9 (s, C7), 112.6 (s, C4), 106.2 (s, C3), 60.1 (s, CH₂), 51.6 (s, NMe₃), 35.1 (d, ² J _CP = 15.0 Hz, PCHCH₂), 28.7 (d, ¹ J _CP = 18.7 Hz, PCH), 27.6 (d, ³ J _CP = 6.1 Hz, PCHCH₂ CH₂), 26.0 (d, ² J _CP = 13.7 Hz, PCHCH₂), 25.8 (d, ³ J _CP = 7.5 Hz, PCHCH₂ CH₂), 25.7 (s, PCHCH₂CH₂ CH₂). ³¹P NMR (161.9 MHz, CDCl₃): δ = 55.2 (s). MS (ESI): m/z (%) = 326.2 (100) [M – NMe₃]⁺. Anal. Calcd for C₂₄H₃₈N₂PI: C, 56.25; H, 7.47; N, 5.47. Found: C, 56.28; H, 7.57; N, 5.40. General Procedure for Suzuki–Miyaura Coupling Reactions (Thermal): Phenylboronic acid (50.6 mg, 0.415 mmol), Pd₂(dba)₃ (5.2 mg, 0.00566 mmol), ligand (0.0136 mmol), cesium carbonate (184.3 mg, 0.566 mmol), and aryl halide (0.377 mmol) were sequentially added to a 10-mL conical microwave vial in an inert atmosphere dry box. The mixture was suspended in [P₆₆₆₁₄][NTf₂] (1.0 mL) and degassed H₂O (0.6 mL) as appropriate (Tables 2 and 3) and stirred for 48 h at 180 °C in the sealed vial immersed in an oil bath. The reaction mixture was diluted with Et₂O (1.0 mL) containing 1% decane and filtered through a pad of Celite. A 0.1-mL aliquot was diluted with Et₂O (0.9 mL) and analyzed by GC–FID. Yields reported are the average of triplicate trials. General Procedure for Suzuki–Miyaura Coupling Reactions (Microwave): Phenylboronic acid (50.6 mg, 0.415 mmol), Pd₂(dba)₃ (5.2 mg, 0.00566 mmol), ligand (0.0136 mmol), cesium carbonate (184.3 mg, 0.566 mmol), and aryl halide (0.377 mmol) were sequentially added to a 10-mL conical microwave vial in an inert atmosphere dry box. The mixture was suspended in [P₆₆₆₁₄][NTf₂] (1.0 mL) and degassed H₂O (0.6 mL) as appropriate (Tables 2 and 3) and stirred for 3 h at 180 °C in the sealed vial in a Biotage Initiator microwave synthesizer. The reaction mixture was diluted with Et₂O (1.0 mL) containing 1% decane and filtered through a pad of Celite. A 0.1-mL aliquot was diluted with Et₂O (0.9 mL) and analyzed by GC–FID. Yields reported are the average of triplicate trials. Crystallographic data (excluding structure factors) for 1a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication CCDC 943804. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, [fax: [phone] or e-mail: [e-mail]].