Copper-Mediated Functionalization of Aryl Trifluoroborates

Abstract

This paper describes the Cu(OTf)₂-mediated coupling of aryl and heteroaryl trifluoroborates with tetrabutylammonium or alkali metal salts to form C–O, C–N, and C–halogen bonds. The reactions proceed under mild conditions (often room temperature over 16 hours) with carboxylate, halide, and azide salts, all nucleophiles that have been underrepresented in the copper cross-coupling literature. Preliminary results show that copper salts bearing weakly coordinating X-type ligands are essential for enabling these transformations to proceed under mild conditions.

Key words

azides - copper - coupling - carboxylation - halogenation

• References and Notes

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• 14 Under the standard conditions, the reaction is homogenous. For reactions in other solvents, see Supporting Information.
• 15 For further optimization, see Supporting Information.
• 16 For reactions with other organoboron reagents, see Supporting Information.
• 17 Cu-Mediated Nucleophile Scope of Potassium (4-Fluorophenyl) Trifluoroborate (1) or Potassium (4-Biphenyl)Trifluoroborate with Tetraalkylammonium and Alkali Salts Reported in Scheme 1 and Scheme 2Potassium (4-fluorophenyl)trifluoroborate (1, 101 mg, 0.5 mmol, 1 equiv) or potassium (4-biphenyl)trifluoroborate (130 mg, 0.5 mmol, 1 equiv), Cu(OTf)₂ (722 mg, 2 mmol, 4 equiv), and tetraalkylammonium or alkali salt (2 mmol, 4 equiv) were weighed into a 20 mL vial equipped with a magnetic stir bar. MeCN (6 mL) was added, and the vial was sealed with a Teflon-lined cap. The reaction mixture was allowed to stir at room temperature for 16 h. For products that were isolated, the reactions were diluted with Et₂O or pentane (10 mL), and this solution was washed with water (3 × 10 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The products were purified by column chromatography on silica gel. For product yields determined by ¹⁹F NMR spectroscopy, the crude reaction mixture was diluted with MeCN, 1,3,5-trifluorobenzene was added as an internal standard, and the reaction was analyzed by ¹⁹F NMR spectroscopy. For experimental and spectroscopic details, see Supporting Information.4-Fluorophenyl Pivalate (6)This reaction was performed with substrate 1 according to the general procedure. Product 6 was obtained as as a clear liquid (66 mg, 68% yield, R_f = 0.58 in 98:2 pentane–Et₂O). ¹H NMR (500 MHz, CDCl₃): δ = 7.07–6.99 (multiple peaks, 4 H), 1.35 (s, 9 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –117.51 (m, 1 F). ¹³C NMR (176 MHz, CDCl₃): δ = 177.11, 161.07 (J = 501 Hz), 146.91 (J = 5.2 Hz), 122.89 (J = 18.2 Hz), 116.05 (J = 49.4 Hz), 39.04, 27.09. IR (cm^–1): 1749, 1503, 1481, 1276, 1182, 1107, 1028, 891, 831, 796, 755. HRMS (ES): m/z [M]⁺ calcd for C₁₁H₁₃FO₂: 196.0899; found: 196.0899. The isolated yield reported in Scheme 1 (67%) represents an average of two runs (68% and 65%).
• 18 The product was intentionally hydrolyzed to the phenol. See Supporting Information for details.
• 19 General Procedure for Cu-Mediated Substrate Scope of Pivalation Reactions in Scheme 1The aryl trifluoroborate substrate (0.5 mmol, 1 equiv), Cu(OTf)₂ (723 mg, 2 mmol, 4 equiv), and sodium pivalate (248 mg, 2 mmol, 4 equiv) were weighed into a 20 mL vial equipped with a magnetic stir bar. MeCN (6 mL) was added, and the vial was sealed with a Teflon-lined cap. The reaction mixture was allowed to stir at room temperature for 16 h. For pyridine substrates, after 16 h, poly(4-vinylpyridine) (1 g) was added to the solution, and the resulting mixture was stirred for an additional 12 h at room temperature. The resulting solution was diluted with Et₂O (10 mL), and then the organic layers were washed with water (3 × 10 mL) and with a 1 M aq NH₄OH solution, saturated with EDTA (10 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under pressure. The products were purified by column chromatography on silica. For further experimental and spectroscopic details, see Supporting Information.2-Methoxypyridin-3-yl pivalate (15)This reaction was performed using potassium (2-methoxypyridin-3-yl)trifluoroborate (108 mg, 0.5 mmol, 1 equiv) according to the general procedure except with heating at 60 °C for 16 h. Product 15 was obtained as a white solid (18 mg, 17% yield, mp 54–56 °C, R_f = 0.39 in 9:1 pentane–Et₂O). ¹H NMR (500 MHz, CDCl₃): δ = 8.01 (d, J = 5.0 Hz, 1 H), 7.28 (d, J = 7.5 Hz, 1 H), 6.88 (dd, J = 7.5, 5.0 Hz, 1 H), 3.95 (s, 3 H), 1.37 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 176.32, 156.53, 143.47, 135.28, 130.46, 116.74, 53.65, 39.07, 27.09. IR (cm^–1): 1754, 1602, 1559, 1474, 1455, 1413, 1318, 1262, 1173, 1099, 1016, 885, 861, 780, 751. HRMS (ES): m/z [M + H]⁺ calcd for C₁₁H₁₅NO₃: 210.1125; found: 210.1123. The isolated yield reported in Scheme 1 (17%) represents an average of two runs (17% and 16%).
• 20 Indole substrates were not compatible with these reaction conditions.
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• 23 More common Chan-Evans-Lam nitrogen nucleophiles including potassium phthalimide, sodium saccharin, and potassium pyridone also react with aryl trifluoroborates under our standard conditions to afford modest yields of C–N coupled products. See the Supporting Information for full details.
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• 25 General Procedure for Cu-Mediated Azidation Reactions in Scheme 2The aryl trifluoroborate substrate (0.5 mmol, 1 equiv), Cu(OTf)₂ (723 mg, 2 mmol, 4 equiv), and KN₃ (162 mg, 2 mmol, 4 equiv) were weighed into a 20 mL vial equipped with a magnetic stir bar. MeCN (6 mL) was added, and the vial was sealed with a Teflon-lined cap. The reaction mixture was allowed to stir at room temperature for 12 h. For pyridine substrates, after 12 h, poly(4-vinylpyridine) (1 g) was added to the solution, and the resulting mixture was stirred for 12 h at room temperature. The resulting solution was diluted with Et₂O (10 mL), and the organic layer was extracted with H₂O (3 × 10 mL). The organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure. The products were purified by column chromatography on silica. For further experimental and spectroscopic details, see Supporting Information.4-Azidodibenzo[b,d]furan (30)This reaction was performed using potassium dibenzofuran-4-trifluoroborate (138 mg, 0.5 mmol, 1 equiv) according to the general procedure. Product 30 was obtained as a yellow oil (84 mg, 81% yield, R_f = 0.32 in hexanes). ¹H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.0 Hz, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.48 (td, J = 8.0, 1.0 Hz, 1 H), 6.36 (td, J = 8.0, 1.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.10 (dd, J = 8.0, 1.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 156.13, 147.45, 127.71, 126.14, 124.78, 123.69, 123.56, 123.15, 120.87, 117.05, 116.87, 112.00. IR: 2104, 1636, 1584, 1494, 1448, 1424, 1352, 1312, 1293, 1190, 1071, 915, 898, 845, 827, 787, 738 cm^–1. HRMS (ES): m/z [M]⁺ calcd for C₁₂H₇N₃O: 209.0589; found: 209.0582. The isolated yield reported in Scheme 2 (80%) represents an average of two runs (81% and 79%).
• 26 When the reaction was performed using Cu(OPiv)₂ with or without exogenous NaOPiv, <14% of product 6 was detected. When the reaction was performed using Cu(OPiv)₂ (4 equiv) and Cu(OTf)₂ (4 equiv), 76% of product 6 was detected. Lowering the amount of either Cu(II) species (2 equiv of each) lead to lower yields.
• 27 Yields determined by ¹⁹F NMR spectroscopic analysis of the crude reaction mixtures.
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